TREM2 agonists

Abstract

The invention provides compounds having the general formula (I) wherein X, Y, A1, A2, R1, R2, R3a, R3b, R4a, and R4b are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds in the treatment or prevention of diseases that are associated with TREM2.

Description

[0001] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P60011

[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 conditions associated with a loss of function of human TREM2.

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

[0008] 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.

[0009] TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is one of these cell surface receptors, which in brain is selectively expressed on microglia and plays a key role in their survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445-453 (2003). https: / / doi.org / 10.1038 / nri1106). TREM2 is a single-pass transmembrane receptor that belongs to the Immunoglobulin superfamily (Ig-SF). It is composed of a ligand binding extracellular immunoglobulin variable-like domain (IgV) followed by a long stalk domain, a single transmembrane helix and a short cytosolic tail that does not have signal transduction motifs. Downstream signal transduction is mediated through its interaction with the effector protein DAP12, a transmembrane disulphide-linked adapter dimer which expression and cellular

[0010] CNE / 20.02.2026localization at the plasma membrane are dependent on TREM2, and which is associated to TREM2 transmembrane helix via lysine-aspartic acid interaction (K156-D50) forming a signaling complex (Zhong L. et al., J Biol Chem. 2015;290(25): 15866-77). Given its short extracellular domain, DAP12 lacks ligand-binding capabilities. Endogenous ligands of TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cellular debris, myelin and Aβ oligomers. Stimulation of the TREM2 / DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of DAP 12, which results in recruitment of Syk kinase to activate downstream signaling molecules.

[0011] Activation of TREM2 plays a key role in microglia signaling and function, including survival, migration, amyloid plaque insulation, beta-amyloid phagocytosis, myelin debris clearance and the transition from the homeostatic to the disease-associated microglia (DAM) state in the context of a neurodegenerative environment (Condello, C. et al., Nat Commun 6, 6176, 2015, doi: org / 10.1038 / ncomms7176; Poliani et al., J Clin Invest, 2015 May;125(5):2161-70, doi: 10.1172 / JCI77983; Zhao et al., Neuron, 2018 Mar 7;97(5): 1023-1031.e7, doi: 10.1016 / j. neuron.2018.01.031; Keren-Shaul H. et al., Cell, 2017 Jun 15;169(7):1276-1290.el7. doi: 10.1016 / j. cell.2017.05.018).

[0012] Genetic variants of TREM2 have been implicated in a multitude of neurodegenerative diseases (Hou J. etal. 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).

[0013] 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., NEngl 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.RA118.002352). Studies are ongoing to elucidate the mechanism by which TREM2 LoF mutations contribute to AD. It is likely that patients carrying these mutations have impaired microglia function including reduced clearance of extracellular aggregates (e.g. amyloid and myelin debris) and apoptotic neurons, ultimately reducing their capacity to fight the disease and increasing their susceptibility to neurodegeneration. Indeed decreased microglia activation and failure to cluster around the amyloid plaque were observed in mouse models deficient for TREM2 or DAP12, confirming the central role of TREM2 signalling in microglia function and response to Alzheimer’s pathological hallmarks.

[0014] 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.

[0015] of the Invention

[0016] In a first aspect, the present invention provides compounds of formula (I)

[0017]

[0018] wherein X, Y, A1, A2, R1, R2, R3a, R3b, R4a, and R4bare as defined herein.

[0019] 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

[0020]

[0021] of the Invention

[0022] Definitions

[0023] 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.

[0024] 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 non-limiting 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.

[0025] 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).

[0026] The term “cyano” refers to a group –C≡N, i.e. a nitrile group.

[0027] 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 6ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, l-bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, and l-bicyclo[2.2.2]octanyl. Particularly preferred, yet nonlimiting examples of cycloalkyl are cyclopropyl, bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl and cyclohexyl.

[0028] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C6-C10-aryl”), wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g. 9H-fluoren-9-yl). A particularly preferred, yet non-limiting example of aryl is phenyl.

[0029] The term "heteroaryl" refers to a monocyclic aromatic ring having a total of 5 to 6 ring members, containing one or more heteroatoms. Preferably, the heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. More preferably, the heteroaryl comprises 1 to 3 heteroatoms independently selected from O, S and N. Most preferably, the heteroaryl comprises 1 to 2 nitrogen atoms. 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- 1-yl). Some preferred, yet non-limiting examples of heteroaryl include pyridyl and pyrazolyl.

[0030] The term "fused bicyclic heteroaryl" refers to a bicyclic ring system having a total of 9 to 10 ring members, wherein at least one of the two rings is aromatic and wherein at least one of the two rings contains one or more heteroatoms. Preferably, the fused bicyclic heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. More preferably, the fused bicyclic heteroaryl comprises 1 to 3 heteroatoms independently selected from O, S andN. Most preferably, the fused bicyclic heteroaryl comprises 1 to 3 nitrogen atoms. Some preferred, yet non-limiting examples of fused bicyclic heteroaryl include pyrazolo[l,5-a]pyrimidine, [l,2,4]triazolo[l,5-a]pyridine.

[0031] 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, thietanyl, and tetrahydrofuranyl. Preferred, yet non-limiting examples of heterocyclyl groups include 1,2-dihydropyridiynl and oxetanyl.

[0032] 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. Preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1 -difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. A particularly preferred, yet non-limiting example of haloalkyl is tri fluoromethyl.

[0033] 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.

[0034] 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.

[0035] The abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2.

[0036] 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 ofmaintenance 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.

[0037] 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.

[0038] Compounds of the Invention

[0039] In a first aspect, the present invention provides a compound of formula (I)

[0040]

[0041] or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0042] A1is selected from the group consisting of N and CR7;

[0043] A2is selected from the group consisting of O and CR5R6;

[0044] B is selected from the group consisting of 5- to 10-membered aryl, Cs-Cio-cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;

[0045] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[0046] X and Y are each independently selected from CH and N;

[0047] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group

[0048]

[0049] ; wherein said Ci-Ce-alkyl is optionally substituted with 1 substituent selected from Ci-Ce-alkoxycarbonyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce- alkoxy, and (C1-C6-alkyl)3Si-C1-C6-alkoxy;R2is selected from the group consisting of C6-C10-aryl, 5- to 6-membered heteroaryl, C3- Cio-cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said C6-C10-aryl, 5- to 6- membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6-membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Ci-Ce-alkyl, Ci-Ce-alkoxy, and halo-Ci-Ce-alkyl;

[0050] R3ais selected from the group consisting of 5- to 6-membered heteroaryl, 9- to 10- membered fused bicyclic heteroaryl, and 3- to 6-membered heterocyclyl, wherein: (i) said 5- to 6-membered heteroaryl and 9- to 10-membered fused bicyclic heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo- Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, C3- Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, halo- Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, C3-C10- cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy; and

[0051] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and optionally 1-3 further substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, C3- Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy;

[0052] R3bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0053] R4ais selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0054] R4bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0055] R5and R6are each independently selected from the group consisting of hydrogen and halogen;

[0056] R7is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce-alkyl; R8is selected from the group consisting of hydrogen, halogen, hydroxy, oxo, cyano, Ci- Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and Ci-Ce-alkyl- S(O)2-; and

[0057] R9is selected from the group consisting of hydrogen, halogen, oxo, and Ci-Ce-alkyl.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0058] A1is selected from the group consisting of N and CR7;

[0059] A2is selected from the group consisting of O and CR5R6;

[0060] B is selected from the group consisting of 5- to 10-membered aryl, Cs-Cio-cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;

[0061] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[0062] X and Y are each independently selected from CH and N;

[0063] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group

[0064] B

[0065] R

[0066]

[0067] 8; wherein said Ci-Ce-alkyl is optionally substituted with 1 substituent selected from Ci-Ce-alkoxycarbonyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce- alkoxy, and (C1-C6-alkyl)3Si-C1-C6-alkoxy;

[0068] R2is selected from the group consisting of C6-C10-aryl, 5- to 6-membered heteroaryl, C3- Cio-cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said C6-C10-aryl, 5- to 6- membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6-membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Ci-Ce-alkyl, Ci-Ce-alkoxy, and halo-Ci-Ce-alkyl;

[0069] R3ais selected from the group consisting of 5- to 6-membered heteroaryl, 9- to 10- membered fused bicyclic heteroaryl, and 3- to 6-membered heterocyclyl, wherein: (i) said 5- to 6-membered heteroaryl and 9- to 10-membered fused bicyclic heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo- Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, C3- Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, halo- Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, C3-C10- cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy; and

[0070] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and optionally 1-3 further substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, C3- Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy;

[0071] R3bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0072] R4ais selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0073] R4bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0074] R5and R6are each independently selected from the group consisting of hydrogen and halogen;

[0075] R7is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce-alkyl; R8is selected from the group consisting of hydrogen, halogen, oxo, cyano, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and Ci-Ce-alkyl-S(O)2-; and

[0076] R9is selected from the group consisting of hydrogen, halogen, oxo, and Ci-Ce-alkyl.

[0077] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0078] A1is selected from the group consisting of N and CR7;

[0079] A2is selected from the group consisting of O and CR5R6;

[0080] X and Y are each independently selected from CH and N;

[0081] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, C3-C10- cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said Cs-Cio-cycloalkyl and 3- to 6-membered heterocyclyl are optionally substituted with 1 Ci-Ce-alkyl substituent; R2is selected from the group consisting of C6-C10-aryl, 5- to 6-membered heteroaryl, C3- Cio-cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said C6-C10-aryl, 5- to 6- membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6-membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0082] R3ais selected from the group consisting of 5- to 6-membered heteroaryl, 9- to 10- membered fused bicyclic heteroaryl, and 3- to 6-membered heterocyclyl, wherein: (i) said 5- to 6-membered heteroaryl and 9- to 10-membered fused bicyclic heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, C3- Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, C3-C10- cycloalkyl-Ci-Ce-alkoxy, Cs-Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce- alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy; and

[0083] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and optionally 1-3 further substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, C3- Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy;

[0084] R3bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0085] R4ais selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0086] R4bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0087] R5and R6are each independently selected from the group consisting of hydrogen and halogen; and

[0088] R7is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce-alkyl.

[0089] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0090] A1is CR7;

[0091] A2is O; and

[0092] R7is selected from the group consisting of hydrogen and halogen.

[0093] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0094] A1is CR7;

[0095] A2is O; and

[0096] R7is selected from the group consisting of hydrogen and fluoro.

[0097] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A1is CR7;

[0098] A2is O; and

[0099] R7is hydrogen.

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

[0101]

[0102] wherein X, Y, A2, R1, R2, R3a, R3b, R4a, and R4bare as defined herein.

[0103] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound of formula (I) is a compound of formula (I.ii):

[0104]

[0105] wherein X, Y, A2, R1, R2, R3a, R3b, R4a, and R4bare as defined herein.

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

[0107]

[0108] wherein X, Y, A2, R1, R2, R3a, R3b, R4a, and R4bare as defined herein.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the compound of formula (I) is a compound of formula (I.iv):

[0109]

[0110] wherein X, Y, A2, R1, R2, R3a, R3b, R4a, and R4bare as defined herein.

[0111] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0112] R1is selected from the group consisting of methyl, isopropyl, n-propyl, 1 -methylbutyl, 3- methoxy-l-methyl-propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, ethylacetate, 2-(2-methoxyethoxy)ethyl, 2-trimethylsilylethoxymethyl, and a group

[0113]

[0114] B selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, 1,3,4-oxadiazolyl, pyridyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptanyl, 7- oxaspiro[3.5]nonanyl, 2-thiaspiro[3.3]heptanyl, and oxetanyl;

[0115] L is selected from the group consisting of a covalent bond, –CH₂–, and –(CH₂)₂–;

[0116] R8is selected from the group consisting of hydrogen, fluoro, hydroxy, oxo, cyano, methyl, ethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, and methyl-S(O)2-; and R9is selected from the group consisting of hydrogen, fluoro, oxo, and methyl.

[0117] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0118] R1is selected from the group consisting of methyl, isopropyl, n-propyl, 1 -methylbutyl, 3- methoxy-l-methyl-propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,ethylacetate, 2-(2-methoxyethoxy)ethyl, 2-trimethylsilylethoxymethyl, and a group

[0119]

[0120] B selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptanyl, 7- oxaspiro[3.5]nonanyl, 2-thiaspiro[3.3]heptanyl, and oxetanyl;

[0121] L is selected from the group consisting of a covalent bond, –CH₂–, and –(CH₂)₂–;

[0122] R8is selected from the group consisting of hydrogen, fluoro, oxo, cyano, methyl, ethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, and methyl-S(O)2-; and

[0123] R9is selected from the group consisting of hydrogen, fluoro, oxo, and methyl.

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

[0125] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group

[0126]

[0127] B selected from the group consisting of Cs-Cio-cycloalkyl and 3- to 10-membered heterocyclyl;

[0128] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[0129] R8is selected from the group consisting of hydrogen, halogen, cyano, halo-Ci-Ce-alkyl, and Ci-Ce-alkoxy; and

[0130] R9is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl.

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

[0132] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group

[0133]

[0134] B selected from the group consisting of Cs-Cio-cycloalkyl and 3- to 10-membered heterocyclyl;

[0135] L is a covalent bond;

[0136] R8is selected from the group consisting of hydrogen, halogen, cyano, halo-Ci-Ce-alkyl, and Ci-Ce-alkoxy; and

[0137] R9is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl.

[0138] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0139] R1is selected from the group consisting of methyl, isopropyl, 2,2,2-trifluoroethyl, and a Rx

[0140] B

[0141] group R

[0142]

[0143] 8

[0144] B selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentanyl, tetrahydropyranyl, tetrahydrofuranyl, and 2- oxaspiro[3.3]heptanyl;

[0145] L is selected from the group consisting of a covalent bond and –(CH₂)₂–;

[0146] R8is selected from the group consisting of hydrogen, fluoro, cyano, CF3, and methoxy;

[0147] and

[0148] R9is selected from the group consisting of hydrogen, fluoro, and methyl.

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

[0150] R1is selected from the group consisting of methyl, isopropyl, 2,2,2-trifluoroethyl, and a Rx

[0151] B

[0152] group R

[0153]

[0154] 8

[0155] B selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, bicyclof 1.1.1 ]pentanyl, and tetrahydropyranyl;

[0156] L is a covalent bond;

[0157] R8is selected from the group consisting of hydrogen, fluoro, cyano, CF3, and methoxy;

[0158] and

[0159] R9is selected from the group consisting of hydrogen, fluoro, and methyl.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0160] R⁹

[0161] B

[0162] R1is a group R

[0163]

[0164] 8'

[0165] B selected from the group consisting of cyclopropyl, tetrahydropyranyl, tetrahydrofuranyl, and 2-oxaspiro[3.3]heptanyl;

[0166] L is selected from the group consisting of a covalent bond and –(CH₂)₂–; and

[0167] R8and R9are both hydrogen.

[0168] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of Ci-Ce-alkyl and Cs-Cio-cycloalkyl.

[0169] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is selected from the group consisting of methyl and cyclopropyl.

[0170] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is Ci-Ce-alkyl.

[0171] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is methyl.

[0172] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of C6-C10-aryl and Cs-Cio-cycloalkyl, wherein said C6-C10-aryl and C3-C10-cycloalkyl are substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, and halo-Ci-Ce-alkyl.

[0173] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl, wherein said phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro, chloro, methyl, methoxy, CHF2, and CF3.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of phenyl, spiro[3.3]heptanyl, and cyclohexyl, wherein said phenyl, spiro[3.3]heptanyl, and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro, chloro, methyl, methoxy, CHF2, and CF3.

[0174] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[0175]

[0176] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[0177]

[0178] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[0179]

[0180]

[0181] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is C6-C10-aryl substituted with 1-3 substituents independently selected from the group consisting of halogen and halo-Ci-Ce-alkyl.

[0182] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is phenyl substituted with 1-3 substituents independently selected from the group consisting of chloro, fluoro, CHF2, and CF3.

[0183] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[0184]

[0185] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[0186]

[0187] In one embodiment, the present invention provides a compound of formula (I) as described herein,

[0188]

[0189] or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is

[0190] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is C6-C10-aryl substituted with 1-3 halogen substituents.

[0191] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is phenyl substituted with 1-3 halogen substituents independently selected from fluoro and chloro.

[0192] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[0193]

[0194] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is C6-C10-aryl substituted with 1-3 halogen substituents.

[0195] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is phenyl substituted with 1-3 halogen substituents independently selected from chloro and fluoro.

[0196] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is F F

[0197]

[0198] or

[0199] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is C6-C10-aryl substituted with 2 halogen substituents.

[0200] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is phenyl substituted with 2 halogen substituents independently selected from chloro and fluoro.

[0201] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is ci

[0202]

[0203] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein:

[0204] (i) said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl-C1-C6-alkyl, and 3- to 6-membered heterocyclyl-C1-C6-alkyl; and

[0205] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of C1-C6-alkyl, C3-C10-cycloalkyl, and C1-C6-alkoxy.

[0206] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of pyridyl, pyridazinyl, pyrazolyl, 2-triazolyl, 1-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,6-dihydropyridazinyl, and 1,2-dihydropyridyl, wherein:

[0207] (i) said pyridyl, pyridazinyl, pyrazolyl, 2-triazolyl, 1-triazolyl, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl is optionally substituted with 1-2 substituents independently selected from the group consisting of methyl, CHF2, CF3, 2,2,2-trifluoroethyl, methoxy, cyclopropyl, 3 -fluorocyclobutyl, 3 -fluoro- l-bicyclo[l.l.l]pentanyl, 3,3- difluorocyclobutyl-CH2-, and tetrahydrofuranyl-CH2-; and

[0208] (ii) said 1,6-dihydropyridazinyl and 1,2-dihydropyridyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl.

[0209] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the

[0210]

[0211]

[0212] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein:

[0213] (i) said 5- to 6-membered heteroaryl is optionally substituted with 1 substituent selected from the group consisting of C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl-C1-C6-alkyl, and 3- to 6-membered heterocyclyl-C1-C6-alkyl; and

[0214] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from the group consisting of C1-C6-alkyl, C3-C10-cycloalkyl.

[0215] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of pyridyl, pyridazinyl, pyrazolyl, 1,6-dihydropyridazinyl, and 1,2-dihydropyridyl, wherein:

[0216] (i) said pyridyl, pyridazinyl, and pyrazolyl is optionally substituted with 1 substituent selected from the group consisting of methyl, CHF2, CF3, 2,2,2-trifluoroethyl, methoxy, cyclopropyl, 3 -fluorocyclobutyl, 3 -fluoro- l-bicyclo[l.l.l]pentanyl, 3,3- difluorocyclobutyl-CH2-, and tetrahydrofuranyl-CH2-; and

[0217] (ii) said 1,6-dihydropyridazinyl and 1,2-dihydropyridyl is substituted with oxo and 1 further substituent selected from the group consisting of methyl and cyclopropyl.

[0218] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of:

[0219]

[0220]

[0221] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais 5- to 6-membered heteroaryl substituted with 1 substituent selected from the group consisting of C1-C6-alkoxy and C3-C10-cycloalkyl.

[0222] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of pyridazinyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl.

[0223] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the

[0224]

[0225] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0226] R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein:(i) said 5- to 6-membered heteroaryl is optionally substituted with 1 substituent selected from the group consisting of C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl-C1-C6-alkyl, and 3- to 6-membered heterocyclyl-C1-C6-alkyl; and

[0227] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from the group consisting of C1-C6-alkyl, C3-C10-cycloalkyl;

[0228] R3bis hydrogen;

[0229] R4ais selected from the group consisting of hydrogen and C1-C6-alkyl; and

[0230] R4bis selected from the group consisting of hydrogen and C1-C6-alkyl.

[0231] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0232] R3ais selected from the group consisting of pyridyl, pyridazinyl, pyrazolyl, 1,6- dihydropyridazinyl, and 1,2-dihydropyridyl, wherein:

[0233] (i) said pyridyl, pyridazinyl, and pyrazolyl is optionally substituted with 1 substituent selected from the group consisting of methyl, CHF2, CF3, 2,2,2-trifluoroethyl, methoxy, cyclopropyl, 3 -fluorocyclobutyl, 3 -fluoro- l-bicyclo[l.l.l]pentanyl, 3,3- difluorocyclobutyl-CH2-, and tetrahydrofuranyl-CH2-; and

[0234] (ii) said 1,6-dihydropyridazinyl and 1,2-dihydropyridyl is substituted with oxo and 1 further substituent selected from the group consisting of methyl and cyclopropyl; R3bis hydrogen;

[0235] R4ais selected from the group consisting of hydrogen and methyl; and

[0236] R4bis selected from the group consisting of hydrogen and methyl.

[0237] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0238] R3a

[0239]

[0240]

[0241] R3bis hydrogen;

[0242] R4ais selected from the group consisting of hydrogen and methyl; and

[0243] R4bis selected from the group consisting of hydrogen and methyl.

[0244] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0245] R3ais 5- to 6-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkoxy and Cs-Cio-cycloalkyl;

[0246] R3bis hydrogen;

[0247] R4ais hydrogen; and

[0248] R4bis hydrogen.

[0249] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0250] R3ais selected from the group consisting of pyridazinyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl;

[0251] R3bis hydrogen;

[0252] R4ais hydrogen; and

[0253] R4bis hydrogen.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0254] R3ais selected from the group consisting of:

[0255]

[0256] R3bis hydrogen;

[0257] R4ais hydrogen; and

[0258] R4bis hydrogen.

[0259] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein:

[0260] (i) said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of C1-C6-alkoxy and C3-C10-cycloalkyl; and

[0261] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1 C1-C6-alkyl substituent.

[0262] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of pyridyl, pyrazolyl, and 1,2-dihydropyridyl, wherein:

[0263] (i) said pyridyl and pyrazolyl is substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl; and

[0264] (ii) said 1,2-dihydropyridyl is substituted with oxo and 1 methyl substituent.

[0265] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of:

[0266]

[0267] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais 5- to 6-membered heteroaryl substituted with 1 substituent selected from the group consisting of C1-C6-alkoxy and C3-C10-cycloalkyl.

[0268] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of pyridyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl.

[0269] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of:

[0270]

[0271] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3a

[0272]

[0273] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3a

[0274]

[0275] , and R3b, R4a, and R4bare all hydrogen.

[0276] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0277] R3bis hydrogen;

[0278] R4ais selected from the group consisting of hydrogen and C1-C6-alkyl; and

[0279] R4bis selected from the group consisting of hydrogen and C1-C6-alkyl.

[0280] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0281] R3bis hydrogen;

[0282] R4ais selected from the group consisting of hydrogen and methyl; and

[0283] R4bis selected from the group consisting of hydrogen and methyl.

[0284] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3b, R4a, and R4bare all hydrogen.

[0285] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (la):

[0286]

[0287] (la)

[0288] wherein X, Y, R1, R2, and R3aare as defined herein.

[0289] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (la’):

[0290]

[0291] (la’)

[0292] wherein X, Y, R1, R2, and R3aare as defined herein.

[0293] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (la”):

[0294]

[0295] (la”)

[0296] wherein X, Y, R1, R2, and R3aare as defined herein.

[0297] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (le):

[0298]

[0299] (le)wherein R1, R2, and R3aare as defined herein.

[0300] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (If):

[0301]

[0302] (If)

[0303] wherein R1, R2, and R3aare as defined herein.

[0304] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0305] (i) X and Y are both CH; or

[0306] (ii) X is N and Y is CH; or

[0307] (iii) X is CH and Y is N.

[0308] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0309] (i) X and Y are both CH; or

[0310] (ii) X is N and Y is CH.

[0311] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X and Y are both CH.

[0312] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X is N and Y is CH.

[0313] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X is CH and Y is N.

[0314] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0315] (i) X and Y are both CH; or

[0316] (ii) X is N and Y is CH; or

[0317] (iii) X is CH and Y is N;A1is selected from the group consisting of N and CR7;

[0318] A2is O;

[0319] B is selected from the group consisting of 5- to 10-membered aryl, Cs-Cio-cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;

[0320] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[0321] R1is selected from the group consisting of Ci-Ce-alkyl halo-Ci-Ce-alkyl, and a group R⁹

[0322] B

[0323] R

[0324]

[0325] 8'; wherein said Ci-Ce-alkyl is optionally substituted with 1 substituent selected from Ci-Ce-alkoxycarbonyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce- alkoxy, and (C1-C6-alkyl)3Si-C1-C6-alkoxy;

[0326] R2is selected from the group consisting of C6-C10-aryl and Cs-Cio-cycloalkyl, wherein said C6-C10-aryl and Cs-Cio-cycloalkyl are substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- alkoxy, and halo-Ci-Ce-alkyl;

[0327] R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein:

[0328] (i) said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce- alkyl, Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, halo-Cs-Cio- cycloalkyl-Ci-Ce-alkyl, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl; and (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of Ci-Ce-alkyl, Cs-Cio-cycloalkyl, and Ci-Ce-alkoxy;

[0329] R3bis hydrogen;

[0330] R4ais selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0331] R4bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0332] R7is selected from the group consisting of hydrogen and halogen;

[0333] R8is selected from the group consisting of hydrogen, halogen, hydroxy, oxo, cyano, Ci- Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and Ci-Ce-alkyl- S(O)2-; and

[0334] R9is selected from the group consisting of hydrogen, halogen, oxo, and Ci-Ce-alkyl.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0335] (i) X and Y are both CH; or

[0336] (ii) X is N and Y is CH; or

[0337] (iii) X is CH and Y is N;

[0338] A1is selected from the group consisting of N and CR7;

[0339] A2is O;

[0340] B selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, 1,3,4-oxadiazolyl, pyridyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptanyl, 7- oxaspiro[3.5]nonanyl, 2-thiaspiro[3.3]heptanyl, and oxetanyl;

[0341] L is selected from the group consisting of a covalent bond, -CH2-, and -(CH2)2-;

[0342] R1is selected from the group consisting of methyl, isopropyl, n-propyl, 1 -methylbutyl, 3- methoxy-l-methyl-propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, ethylacetate, 2-(2-methoxyethoxy)ethyl, 2-trimethylsilylethoxymethyl, and a group

[0343]

[0344] R2is selected from the group consisting of phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl, wherein said phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro, chloro, methyl, methoxy, CHF2, and CF3;

[0345] R3ais selected from the group consisting of pyridyl, pyridazinyl, pyrazolyl, 2H-triazolyl, 1H-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,6-dihydropyridazinyl, and 1,2- dihydropyridyl, wherein:

[0346] (i) said pyridyl, pyridazinyl, pyrazolyl, 2H-triazolyl, 1H-triazolyl, 1,2,4- oxadiazolyl, and 1,3,4-oxadiazolyl is optionally substituted with 1-2 substituents independently selected from the group consisting of methyl, CHF2, CF3, 2,2,2- trifluoroethyl, methoxy, cyclopropyl, 3 -fluorocyclobutyl, 3 -fluoro- 1- bicyclo[l.l.l]pentanyl, 3,3-difluorocyclobutyl-CH2-, and tetrahydrofuranyl- CH2-; and(ii) said 1,6-dihydropyridazinyl and 1,2-dihydropyridyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl; and

[0347] R3bis hydrogen;

[0348] R4ais selected from the group consisting of hydrogen and methyl;

[0349] R4bis selected from the group consisting of hydrogen and methyl;

[0350] R7is selected from the group consisting of hydrogen and fluoro;

[0351] R8is selected from the group consisting of hydrogen, fluoro, hydroxy, oxo, cyano, methyl, ethyl,

[0352] 2,2-difluoroethyl, methoxy, methoxymethyl, and methyl-S(O)2-; and

[0353] R9is selected from the group consisting of hydrogen, fluoro, oxo, and methyl.

[0354] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0355] (i) X and Y are both CH; or

[0356] (ii) X is N and Y is CH; or

[0357] (iii) X is CH and Y is N;

[0358] A1is CR7;

[0359] A2is O;

[0360] B selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptanyl, 7- oxaspiro[3.5]nonanyl, 2-thiaspiro[3.3]heptanyl, and oxetanyl;

[0361] L is selected from the group consisting of a covalent bond, -CH2-, and -(CH2)2-;

[0362] R1is selected from the group consisting of methyl, isopropyl, n-propyl, 1 -methylbutyl, 3- methoxy-l-methyl-propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, ethylacetate, 2-(2-methoxyethoxy)ethyl, 2-trimethylsilylethoxymethyl, and a group

[0363]

[0364] R2is selected from the group consisting of phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl, wherein said phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro, chloro, methyl, methoxy, CHF2, and CF3;R3ais selected from the group consisting of pyridyl, pyridazinyl, pyrazolyl, 1,6- dihydropyridazinyl, and 1,2-dihydropyridyl, wherein:

[0365] (i) said pyridyl, pyridazinyl, and pyrazolyl is optionally substituted with 1 substituent selected from the group consisting of methyl, CHF2, CF3, 2,2,2- trifluoroethyl, methoxy, cyclopropyl, 3 -fluorocyclobutyl, 3 -fluoro- 1- bicyclo[l.l.l]pentanyl, 3,3-difluorocyclobutyl-CH2-, and tetrahydrofuranyl- CH2-; and

[0366] (ii) said 1,6-dihydropyridazinyl and 1,2-dihydropyridyl is substituted with oxo and 1 further substituent selected from the group consisting of methyl and cyclopropyl; and

[0367] R3bis hydrogen;

[0368] R4ais selected from the group consisting of hydrogen and methyl;

[0369] R4bis selected from the group consisting of hydrogen and methyl;

[0370] R7is hydrogen;

[0371] R8is selected from the group consisting of hydrogen, fluoro, oxo, cyano, methyl, ethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, and methyl-S(O)2-; and

[0372] R9is selected from the group consisting of hydrogen, fluoro, oxo, and methyl.

[0373] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0374] (i) X and Y are both CH; or

[0375] (ii) X is N and Y is CH;

[0376] A1is CR7;

[0377] A2is O;

[0378] B selected from the group consisting of Cs-Cio-cycloalkyl and 3- to 10-membered heterocyclyl;

[0379] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[0380] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group R9

[0381] y"-L

[0382] R

[0383]

[0384] 8'

[0385] R2is C6-C10-aryl substituted with 1-3 substituents independently selected from the group consisting of halogen and halo-Ci-Ce-alkyl;R3ais 5- to 6-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkoxy and Cs-Cio-cycloalkyl;

[0386] R3b, R4a, R4b, and R7are all hydrogen;

[0387] R8is selected from the group consisting of hydrogen, halogen, cyano, halo-Ci-Ce-alkyl, and Ci-Ce-alkoxy; and

[0388] R9is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl.

[0389] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0390] (i) X and Y are both CH; or

[0391] (ii) X is N and Y is CH;

[0392] A1is CR7;

[0393] A2is O;

[0394] B selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentanyl, tetrahydropyranyl, tetrahydrofuranyl, and 2- oxaspiro[3.3]heptanyl;

[0395] L is selected from the group consisting of a covalent bond and -(CH2)2-;

[0396] R1is selected from the group consisting of methyl, isopropyl, 2,2,2-trifluoroethyl, and a R9,

[0397] y"-L

[0398] group R

[0399]

[0400] 8

[0401] R2is phenyl substituted with 1-3 halogen substituents independently selected from chloro and fluoro;

[0402] R3ais selected from the group consisting of pyridyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl; R3b, R4a, R4b, and R7are all hydrogen; R8is selected from the group consisting of hydrogen, fluoro, cyano, CF3, and methoxy;

[0403] and

[0404] R9is selected from the group consisting of hydrogen, fluoro, and methyl.

[0405] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0406] (i) X and Y are both CH; or

[0407] (ii) X is N and Y is CH; or(iii) X is CH and Y is N;

[0408] A1is CR7;

[0409] A2is O;

[0410] B is selected from the group consisting of 5- to 10-membered aryl, Cs-Cio-cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;

[0411] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[0412] R1is selected from the group consisting of Ci-Ce-alkyl halo-Ci-Ce-alkyl, and a group R9

[0413] y"-L

[0414] R

[0415]

[0416] 8'; wherein said Ci-Ce-alkyl is optionally substituted with 1 substituent selected from Ci-Ce-alkoxycarbonyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce- alkoxy, and (C1-C6-alkyl)3Si-C1-C6-alkoxy;

[0417] R2is selected from the group consisting of C6-C10-aryl and Cs-Cio-cycloalkyl, wherein said C6-C10-aryl and Cs-Cio-cycloalkyl are substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- alkoxy, and halo-Ci-Ce-alkyl;

[0418] R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein:

[0419] (i) said 5- to 6-membered heteroaryl is optionally substituted with 1 substituent selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce- alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl-Ci- Ce-alkyl, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl; and

[0420] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from the group consisting of C1-C6-alkyl, C3-C10-cycloalkyl; R3bis hydrogen;

[0421] R4ais selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0422] R4bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0423] R7is hydrogen;

[0424] R8is selected from the group consisting of hydrogen, halogen, oxo, cyano, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and Ci-Ce-alkyl-S(O)2-; and

[0425] R9is selected from the group consisting of hydrogen, halogen, oxo, and Ci-Ce-alkyl.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0426] (i) X and Y are both CH; or

[0427] (ii) X is N and Y is CH; or

[0428] (iii) X is CH and Y is N;

[0429] A1is CR7;

[0430] A2is O;

[0431] B selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptanyl, 7- oxaspiro[3.5]nonanyl, 2-thiaspiro[3.3]heptanyl, and oxetanyl;

[0432] L is selected from the group consisting of a covalent bond, -CH2-, and -(CH2)2-;

[0433] R1is selected from the group consisting of methyl, isopropyl, n-propyl, 1 -methylbutyl, 3- methoxy-l-methyl-propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, ethylacetate, 2-(2-methoxyethoxy)ethyl, 2-trimethylsilylethoxymethyl, and a group R9

[0434] y"-L

[0435] R

[0436]

[0437] 8'

[0438] R2is selected from the group consisting of phenyl, spiro[3.3]heptanyl, and cyclohexyl, wherein said phenyl, spiro[3.3]heptanyl, and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro, chloro, methyl, methoxy, CHF2, and CF3;

[0439] R3ais selected from the group consisting of pyridyl, pyridazinyl, pyrazolyl, 1,6- dihydropyridazinyl, and 1,2-dihydropyridyl, wherein:

[0440] (i) said pyridyl, pyridazinyl, and pyrazolyl is optionally substituted with 1 substituent selected from the group consisting of methyl, CHF2, CF3, 2,2,2- trifluoroethyl, methoxy, cyclopropyl, 3 -fluorocyclobutyl, 3 -fluoro- 1- bicyclo[l.l.l]pentanyl, 3,3-difluorocyclobutyl-CH2-, and tetrahydrofuranyl- CH2-; and

[0441] (ii) said 1,6-dihydropyridazinyl and 1,2-dihydropyridyl is substituted with oxo and 1 further substituent selected from the group consisting of methyl and cyclopropyl; and

[0442] R3bis hydrogen;R4ais selected from the group consisting of hydrogen and methyl;

[0443] R4bis selected from the group consisting of hydrogen and methyl;

[0444] R7is hydrogen;

[0445] R8is selected from the group consisting of hydrogen, fluoro, oxo, cyano, methyl, ethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, and methyl-S(O)2-; and

[0446] R9is selected from the group consisting of hydrogen, fluoro, oxo, and methyl.

[0447] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0448] (i) X and Y are both CH; or

[0449] (ii) X is N and Y is CH;

[0450] A1is CR7;

[0451] A2is O;

[0452] B selected from the group consisting of Cs-Cio-cycloalkyl and 3- to 10-membered heterocyclyl;

[0453] L is a covalent bond;

[0454] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group R9

[0455] y"-L

[0456] R

[0457]

[0458] 8

[0459] R2is C6-C10-aryl substituted with 1-3 substituents independently selected from the group consisting of halogen and halo-Ci-Ce-alkyl;

[0460] R3ais 5- to 6-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkoxy and Cs-Cio-cycloalkyl;

[0461] R3b, R4a, R4b, and R7are all hydrogen

[0462] R8is selected from the group consisting of hydrogen, halogen, cyano, halo-Ci-Ce-alkyl, and Ci-Ce-alkoxy; and

[0463] R9is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl.

[0464] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0465] (i) X and Y are both CH; or

[0466] (ii) X is N and Y is CH;

[0467] A1is CR7;A2is O;

[0468] B selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, bicyclof 1.1.1 ]pentanyl, and tetrahydropyranyl;

[0469] L is a covalent bond;

[0470] R1is selected from the group consisting of methyl, isopropyl, 2,2,2-trifluoroethyl, and a R9,

[0471] y"-L

[0472] group R

[0473]

[0474] 8

[0475] R2is phenyl substituted with 2 halogen substituents independently selected from chloro and fluoro;

[0476] R3ais selected from the group consisting of pyridyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl; R3b, R4a, R4b, and R7are all hydrogen;

[0477] R8is selected from the group consisting of hydrogen, fluoro, cyano, CF3, and methoxy;

[0478] and

[0479] R9is selected from the group consisting of hydrogen, fluoro, and methyl.

[0480] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0481] (i) X and Y are both CH; or

[0482] (ii) X is N and Y is CH;

[0483] A1is CR7;

[0484] A2is O;

[0485] R1is selected from the group consisting of Ci-Ce-alkyl and Cs-Cio-cycloalkyl;

[0486] R2is C6-C10-aryl substituted with 1-3 halogen substituents;

[0487] R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein:

[0488] (i) said 5- to 6-membered heteroaryl is substituted with 1 substituent selected from the group consisting of Cl-C6-alkoxy and C3-C10-cycloalkyl; and

[0489] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1 Cl-C6-alkyl substituent; and

[0490] R3b, R4a, R4b, and R7are all hydrogen.In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0491] (i) X and Y are both CH; or

[0492] (ii) X is N and Y is CH;

[0493] A1is CR7;

[0494] A2is O;

[0495] R1is selected from the group consisting of methyl and cyclopropyl;

[0496] R2is phenyl substituted with 1-3 halogen substituents independently selected from fluoro and chloro;

[0497] R3ais selected from the group consisting of pyridyl, pyrazolyl, and 1,2-dihydropyridyl, wherein:

[0498] (i) said pyridyl and pyrazolyl is substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl; and

[0499] (ii) said 1,2-dihydropyridyl is substituted with oxo and 1 methyl substituent; and R3b, R4a, R4b, and R7are all hydrogen.

[0500] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0501] (i) X and Y are both CH; or

[0502] (ii) X is N and Y is CH;

[0503] A1is CR7;

[0504] A2is O;

[0505] R1is Ci-Ce-alkyl;

[0506] R2is C6-C10-aryl substituted with 2 halogen substituents;

[0507] R3ais 5- to 6-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkoxy and Cs-Cio-cycloalkyl; and

[0508] R3b, R4a, R4b, and R7are all hydrogen.

[0509] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[0510] (i) X and Y are both CH; or

[0511] (ii) X is N and Y is CH;

[0512] A1is CR7;

[0513] A2is O;

[0514] R1is methyl;R2is phenyl substituted with 2 halogen substituents independently selected from chloro and fluoro;

[0515] R3ais selected from the group consisting of pyridyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl; and R3b, R4a, R4b, and R7are all hydrogen

[0516] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is selected from:

[0517] 8-(4-chloro-2-fluoro-phenyl)-6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-methyl-[ 1,2,4]triazolo[4,3 -a]pyri din-3 -one;

[0518] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0519] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0520] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2- methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0521] 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2- methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0522] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0523] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0524] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0525] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluorophenyl)-2-methyl- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0526] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluorophenyl)-2-methyl- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0527] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S,4R)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0528] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2-fluoro-phenyl)-2-cy cl opropyl-6-[(2S,4R)-2-(2 -methoxy -4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0529] 8-(4-chloro-2-fluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(2 -methoxy -4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0530] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0531] 8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[0532] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0533] 8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(6-methoxypyridazin-3-yl)tetrahydropyran-4-yl]- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0534] 8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(6-methoxypyridazin-4-yl)tetrahydropyran-4-yl]- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0535] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(6-methoxypyridazin-3-yl)tetrahydropyran- 4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0536] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(6-methoxypyridazin-4-yl)tetrahydropyran- 4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0537] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[0538] 8-(4,4-difluorocyclohexyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran- 4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[0539] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[0540] 8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(2,2,2- trifluoroethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0541] 8-(4-chlorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- [1.2.4]triazolo[4,3-a]pyrazin-3-one;

[0542] 3-fluoro-4-[2-methyl-3-oxo-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- [1.2.4]triazolo[4,3-a]pyrazin-8-yl]benzonitrile;

[0543] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0544] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-cy cl opropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0545] 8-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0546] 8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4-yl)tetrahydropyran- 4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0547] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0548] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0549] 2-cyclopropyl-8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0550] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0551] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0552] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0553] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0554] 6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- 2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0555] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(lH-pyrazol-4-yl)tetrahydropyran-4-yl]- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0556] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2- methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0557] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[2-fluoro-4- (trifluoromethyl)phenyl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0558] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4- (difluoromethyl)-2-fluoro-phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0559] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4-(difluoromethyl)-2-fluoro- phenyl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0560] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0561] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4-(difluoromethyl)phenyl]-2- methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0562] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0563] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluoro-4-methoxy-phenyl)- 2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0564] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluoro-4- methoxy-phenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0565] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-(2,2,2-trifluoroethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0566] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(2,2,2-trifluoroethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0567] 2-cyclopropyl-6-[(2R,4S)-2-[l-[(3,3-difluorocyclobutyl)methyl]pyrazol-4-yl]tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0568] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[trans-l-(3-fluorocyclobutyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0569] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-[[(3S)-tetrahydrofuran-3- yl]methyl]pyrazol-4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0570] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-[[(3S)-tetrahydrofuran-3- yl]methyl]pyrazol-4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0571] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[cis-l-(3-fluorocyclobutyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0572] 2-cyclopropyl-6-[(2S,4R)-2-[l-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0573] 2-cyclopropyl-6-[(2R,4S)-2-[l-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0574] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(trifluoromethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0575] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-(trifluoromethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyrazol-4-yl]tetrahydropyran-4-yl]-[1,2,4]triazolo[4,3-a]pyrazin-3-one;

[0576] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0577] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0578] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(2- trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0579] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(2,2-difluoroethyl)-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0580] 2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0581] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (oxetan-3-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0582] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0583] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluoro-4-methyl-phenyl)-2- methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0584] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclobutyl)-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0585] 2-cyclopentyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0586] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3R)- tetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0587] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3 S)- tetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0588] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- tetrahydropyran-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0589] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lR)-2,2- difluorocyclopropyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0590] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lS)-2,2- difluorocyclopropyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3- methyloxetan-3-yl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0591] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(2- fluoroethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0592] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- isopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0593] 2-benzyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0594] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(l- fluorocyclopropyl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0595] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(5- ethyl-l,3,4-oxadiazol-2-yl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0596] ethyl 2-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- 3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]acetate;

[0597] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[2-(2- methoxy ethoxy)ethyl]-[l, 2, 4]triazolo[4,3-a]pyrazin-3-one;

[0598] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lR,3S)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0599] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lS,3R)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0600] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lR,3R)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0601] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lS,3S)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0602] cis- and trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]cyclobutanecarbonitrile;

[0603] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(l- methyltri azol-4-yl)methyl]-[l, 2, 4]triazolo[4,3-a]pyrazin-3-one;

[0604] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(7- oxaspiro[3.5]nonan-2-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0605] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-((2RS)- oxetan-2-ylmethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0606] cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-methoxycyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0607] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[2- (oxetan-3-yl)ethyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0608] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3- methoxy-2-pyridyl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0609] cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[3-(methoxymethyl)cyclobutyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0610] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(2,2- dioxo-2λ6-thiaspiro[3.3]heptan-6-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0611] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [[(lS,5R)-3-oxabicyclo[3.1.0]hexan-6-yl]methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; cis- and trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]-l-methyl-cyclobutanecarbonitrile; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-propyl- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0612] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3R)- 4,4-difluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0613] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3 S)- 4,4-difluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0614] trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- 3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]cyclobutanecarbonitrile;

[0615] cis-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-3- oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]cyclobutanecarbonitrile;

[0616] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lRS)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0617] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lR)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0618] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lS)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0619] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(lRS)- l-methylbutyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0620] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS)-l-(2,2- difluoroethyl)pyrrolidin-3-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [[(3RS)-tetrahydrofuran-3-yl]methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0621] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [[(3RS)-tetrahydropyran-3-yl]methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0622] 1-[[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-3- oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]methyl]cyclobutanecarbonitrile;

[0623] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lRS,3RS)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0624] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(lRS)- 3-methoxy-l-methyl-propyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0625] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3RS)- l-methylsulfonylpyrrolidin-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0626] methyl 3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l, 2, 4]triazolo[4, 3 -a]pyrazin-2-yl]bicyclo[l.l.l]pentane-l -carboxylate; 6-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-[1,2,4]triazolo[4,3-a]pyrazin-3-one;

[0627] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[0628] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[0629] 2-cyclopropyl-6-[(2R,4S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0630] 2-cyclopropyl-6-[(2R,4S,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0631] 2-cyclopropyl-6-[(2S,4S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0632] 2-cyclopropyl-6-[(2R,4R,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0633] 2-cyclopropyl-6-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0634] 6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0635] 6-[(4S,6S)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(4S,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0636] 2-cyclopropyl-6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0637] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[rac-(4S,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2- dimethyl-tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0638] trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0639] cis-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(3- fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0640] cis-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(3- methoxy cyclobutyl)-[l, 2, 4]triazolo[4,3-a]pyrazin-3-one;

[0641] trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (3-methoxycyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0642] trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- 3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]-l-methyl-cyclobutanecarbonitrile;

[0643] cis-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-3- oxo-[ 1,2,4]triazolo[4,3 -a]pyrazin-2-yl]- 1 -methyl-cyclobutanecarbonitrile;

[0644] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-(p-tolyl)- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0645] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3 S)- tetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0646] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(2- tetrahydrofuran-3-ylethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0647] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(2- oxaspiro[3.3]heptan-6-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0648] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0649] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3R)- tetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0650] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(3-fluorocyclobutyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0651] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl- tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0652] 8-(4-chloro-2-fluoro-phenyl)-6-[(4S,6S)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl- tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0653] 2-cyclopropyl-6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(2,4-difluorophenyl)- [l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0654] 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0655] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[3-(trifluoromethyl)- 1 -bicyclof 1.1.1 ]pentanyl]-[ 1,2,4]triazolo[4,3 -a]pyrazin-3 -one;

[0656] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0657] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (difluorom ethyl)- 1 -bicyclof 1.1.1 ]pentanyl]-[ 1,2,4]triazolo[4,3 -a]pyrazin-3 -one;

[0658] 2-cyclopropyl-6-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0659] 2-cyclopropyl-6-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0660] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-3-methyl-pyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0661] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-3-methyl-pyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0662] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-5-methyl-pyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0663] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-5-methyl-pyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0664] 2-cyclopropyl-6-[(2R,4S)-2-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0665] 2-cyclopropyl-6-[(2R,4S)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0666] 2-cyclopropyl-6-[(2S,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0667] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0668] 2-cyclopropyl-6-[(2S,4R)-2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0669] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4- fluorocyclohexyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0670] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[rac-(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)-2-methyl- tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0671] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(2- methyl-3-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0672] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)-4-fluoro-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0673] 2-cyclopropyl-6-[(2R,4R)-2-(l-cyclopropylpyrazol-4-yl)-4-fluoro-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0674] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0675] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR,4RS)-4-hydroxytetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0676] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS,4SR)-4-fluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0677] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR,4RS)-4-fluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0678] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(l- hydroxycyclopropyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0679] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(l- fluorocyclopropyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0680] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(3- methyl-4-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0681] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(3- methyl-4-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0682] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0683] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(6-methoxypyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclopropyl-6-[(2S,4R)-2-(6-methoxypyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0684] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS,4SR)-4- fluorotetrahydrofuran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3 SR,4RS)-4- fluorotetrahydrofuran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-isopropyl-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0685] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-tetrahydropyran-4-yl-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0686] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(4RS)-3,3- difluorotetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(4SR)-3,3- difluorotetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3RS)- 4,4-difluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0687] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-[(3 SR)- 4,4-difluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0688] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR,4RS)-3-fluorotetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0689] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS,4SR)-3-fluorotetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0690] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS,4RS)-4-fluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0691] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR,4SR)-4-fluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0692] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS,4RS)-4- fluorotetrahydropyran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3 SR,4SR)-4- fluorotetrahydropyran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2R,4S)-2-(6-methoxypyridazin-4-yl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0693] 8-(4-chloro-2,6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-tetrahydropyran-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0694] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(trans-4- fluorocyclohexyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0695] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0696] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(3,3-difluorotetrahydropyran-4-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0697] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(4,4-difluorotetrahydropyran-3-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0698] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(3-fluorotetrahydropyran-4-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0699] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(4-fluorotetrahydropyran-3-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0700] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-isopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0701] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3-fluorocyclobutyl)-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0702] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0703] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclobutyl)-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0704] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(3,3-difluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0705] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclopentyl)-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0706] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(3,3-difluorocyclopentyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0707] 2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0708] 8-(4-chloro-2,6-difluoro-phenyl)-2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0709] 2-cyclopropyl-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(2 -methoxy -4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0710] 2-cyclopropyl-6-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0711] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0712] 2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0713] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0714] 2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0715] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0716] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0717] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0718] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0719] 8-(4-chloro-2,6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0720] 2-cyclobutyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0721] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclobutyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0722] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- pyridazin-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0723] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(5- methylpyridazin-4-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0724] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(5-methylpyridazin-4-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[0725] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l,5-dimethyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; and2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(5-methoxy-l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one.

[0726] 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.

[0727] 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.

[0728] 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. In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein 1-6, preferably 1-3, of the hydrogen atoms are replaced by deuterium atoms.

[0729] 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 non-labeled reagent previously employed.Processes of Manufacturing

[0730] 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.

[0731] 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.

[0732] 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).

[0733] 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).

[0734] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0735] 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.

[0736] The following abbreviations are used in the present text:

[0737] °C Degrees Celsius

[0738] 1H Proton

[0739] Å Ångström

[0740] ACN Acetonitrile

[0741] Aik Alkyl

[0742] BPin Pinacol Borane

[0743] c Concentration

[0744] C18 Octadecylsilyl Silica Gel

[0745] CAS Chemical Abstracts Service Registry Number

[0746] CH3CN Acetonitrile

[0747] CHCI3 Chloroform

[0748] CO2 Carbon DioxideCs2CO3Caesium Carbonate

[0749] CuBr2Copper(II) Bromide

[0750] Cu(OAc)2Copper(II) Acetate

[0751] DCM Dichloromethane

[0752] DCE Dichloroethane

[0753] DIPEA N,N-Diisopropylethylamine

[0754] DMEM Dulbecco's modified Eagle Medium

[0755] DMF N,N-Dimethylformamide

[0756] DMSO Dimethylsulfoxide

[0757] DMSO-d6 Hexadeuterodimethylsulfoxide

[0758] EC50Half maximal effective concentration

[0759] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimideEquiv. Equivalent

[0760] ESI Electron spray ionization

[0761] EtOAc Ethyl Acetate

[0762] EtOH Ethanol

[0763] Ex. Example

[0764] FBS Fetal bovine serum

[0765] FCC Flash column chromatography

[0766] g Gram

[0767] g / L Gram per liter

[0768] h Hour

[0769] H2O Water

[0770] HATU Hexafluorophosphate azabenzotriazole tetramethyl uronium HBTU Hexafluorophosphate benzotriazole tetramethyl uronium HCl Hydrogen Chloride

[0771] HCO2H Formic Acid

[0772] HEK Human embryonic kidney

[0773] HPLC High performance liquid chromatography [Ir(OMe)(1,5-cod)]2Bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) ISCO Teledyne ISCO flash chromatography system

[0774] J Coupling constant

[0775] K2CO3Potassium Carbonate

[0776] kg KilogramKOAc Potassium Acetate

[0777] K3PO4 Tripotassium Phosphate

[0778] M Molar

[0779] m / z Mass-to-charge ratio

[0780] MeOH Methanol

[0781] μg Microgram

[0782] mg Milligram

[0783] MgO Magnesium Oxide

[0784] MgSO4Magnesium Sulfate

[0785] MHz Megahertz

[0786] min Minute

[0787] ml Milliliter

[0788] mm Millimeter

[0789] μmol Micromole

[0790] mmol Millimole

[0791] MS Mass spectrometry

[0792] N2Nitrogen

[0793] Na2SO3 Sodium Sulfite

[0794] Na2SO4Sodium Sulfate

[0795] NaHCO3 Sodium Bicarbonate

[0796] NBS N-bromosuccinimide

[0797] neg. Negative

[0798] NH4Cl Ammonium Chloride

[0799] NH3H2O Ammonium Hydroxyde, aqueous Ammonia

[0800] nm Nanometer

[0801] NMR Nuclear magnetic resonance spectroscopy

[0802] NPLC Normal Phase Liquid Chromatography

[0803] Pd / C Palladium on Carbon

[0804] PdCl2(dtbpf) [1,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2.DCM complex 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane

[0805] PdCl2(PPh3)2 Dichlorobis(triphenylphosphine)palladium(II)

[0806] PE Petroleum ether

[0807] pH Potential of hydrogenpos. Positive

[0808] psi Pounds per square inch

[0809] PtO2Platinum(IV) Oxide

[0810] R Rectus according to the Cahn-Ingold-Prelog priority rules RP Reverse phase

[0811] RPM Revolutions per minute

[0812] s Second

[0813] S Sinister according to the Cahn-Ingold-Prelog priority rules SFC Supercritical fluid chromatography

[0814] / Bu tert-butyl

[0815] TEA Triethylamine

[0816] TFA Trifluoroacetic acid

[0817] TMSI Trimethylsilyl iodide

[0818] THF Tetrahydrofuran

[0819] TLC Thin layer chromatography

[0820] tR Retention time

[0821] μl Microliter

[0822] μm Micrometer

[0823] μmol Micromoles

[0824] αD Specific rotation at 589 nm

[0825] δ Chemical shift in parts per million

[0826] 4-DPAIPN 2,4,5,6-Tetrakis(diphenylamino)isophthalonitrile

[0827] Scheme 1

[0828]

[0829] Compounds of general formula la and lb can be prepared as described in Scheme 1. For the synthesis of C-linked derivatives la, intermediate II can either be directly reacted first with boronic acid or boronic acid derivative III under palladium catalysed conditions (a palladium source such as (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride di chloromethane complex or [l,r-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and a base such as cesium carbonate, potassium carbonate or sodium carbonate) to form compound IV. Intermediate IV can then be reduced by treatment with a suitable reagent like hydrogen and a catalyst (such as PtO2 or Pd / C and an additive such as MgO) to form compound la. Applying these reductive conditions, compounds with a suitable substituent R2 can be transformed into compounds of structure Ic as well, for example if a simultaneous dehalogenation of substituent R2 takes place. R1 can also be converted to R1 ’ via mono or di -fluorination with a suitable fluorinating reagent such as, but not limited to, DAST or Morp-DAST. Both inversion or retention of configuration of newly generated chiral centers are possible, depending from the availability of the starting materials. The FGI sequence is not limited to one-step reaction, but it includes multi-step routes. In some instances, Mitsunobu reaction and conditions may be employed to access all relevant epimers. For the synthesis of N-linked derivatives lb, intermediate II can be reacted with intermediate 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 lb (nucleophilic substitution). In addition, compound II can be reacted with intermediate 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).Scheme 2

[0830] Za'b= Br, Cl, I R1, R2, R3a'3b, R4a'4band X, Y according to claim definition

[0831]

[0832] The present compounds of formula Ila can be prepared by sequential functionalizations to install the various substituents around core VI as described in Scheme 2 by first reacting heterocyclic compound VI with boronic acid (or a boronic acid derivative) VII under palladium catalyzed coupling conditions (a palladium source such as (l,l'-bis(diphenylphosphino)-ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and abase such as cesium carbonate or sodium carbonate) to form compound VIII. Compound IX may be accessed from VIII by iridium catalyzed borylation (using an iridium source such as Bis(l,5-cyclooctadiene)di-p-methoxydiiridium(I), a suitable phenanthroline ligand and boron ester source). Furthermore, intermediate IX can be reacted with a halide source (such as CuBr2) to form compound IIa.

[0833] Scheme 3

[0834]

[0835] The present compounds of formula lib can be prepared from described compound X by nucleophilic substitution (with a suitable hydrazine source such as, but not limited to, N-Boc-hydrazine). Furthermore, intermediate XI can be reacted with with boronic acid (or a boronic acid derivative) VI under palladium catalyzed coupling 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 compound XII. The hydrazine protecting group can be typically removed by treatment with acids like hydrochloric acid, affording compound XIII. This intermediate can then be cyclized to compound XIV by treatment with a suitable coupling reagent (a coupling reagent such as, but not limited to, 4-nitrophenyl chloroformate or CDI or triphosgene) and a base such as TEA or DIPEA. Furthermore, compound XV can be accessed via halogenation promoted by a halide source such as NBS or NCS or NIS. Typically the R1group may be installed via alkylation (e.g. using a base such as NaH, and a suitable alkyl-halide R1-Za-c). Alkylation typically proceeds preferentially at the N position, such that a mono-alkylated product may be isolated, and an independent alkylation reaction may be carried out to install an R1group. Wherease R1is a cycloalkyl group, it may be installed via a metal -catalyzed cross-coupling, such as a Chan-Lam reaction (e.g. where R1= cyclopropyl) from a suitably functionalized-boronic acid R1-B(OH)2 using a copper(II) catalyst (such as CuOAc).

[0836] Scheme 4FGI

[0837] Za'b= Br, Cl, I

[0838] R1, R2, R3a'3b, R4a'4band

[0839] X, Y according

[0840]

[0841] to claim definition

[0842] Furthermore, compounds of general formula Ic can be prepared as described in Scheme 4 by late stage modification of R3a. Such functional group interconversion (FGI) of residue R3ato residue R3ainclude removal of a protecting group, halogenation and / or alkylation reactions (for instance on NH-pyridones, NH pyrazoles and NH pyridazinones) and can be performed according to known conditions for related compounds published in the literature. The FGI sequence is not limited to one-step reaction, but it includes multi-step routes.

[0843] Scheme 5OH

[0844] NBS or NCS or NIS

[0845] Za'c= Br, Cl, I LG = Za cor OTf, OMs, OTs R1, R2, R3a'3b, R4a'4band X, Y according to claim definition

[0846]

[0847] The present compounds of formula la can be prepared from described compound XVI by Boc protection (with a suitable Boc source such as Boc anhydride). Furthermore, intermediate XI can be reacted with with boronic acid (or a boronic acid derivative) VII under palladium catalyzed coupling conditions (a palladium source such as (l,l'-bis(diphenylphosphino)-ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and abase such as cesium carbonate or sodium carbonate) to form compound XII. XII can be further decorated with a halogen promoted by a halide source such as NBS or NCS or NIS, delivering XVII. The hydrazine protecting group can be typically removed by treatment with acids like hydrochloric acid, affording compound XVIII. This intermediate can then be cyclized to compound XV by treatment with a suitable reagent (a reagent such as, but not limited to, 4-nitrophenyl chloroformate or CDI or triphosgene) and a base such as TEA or DIPEA. Typically the SEM group may be installed via alkylation (e.g. using a base such as NaH, and a suitable alkyl-halide SEM-Za c). For the synthesis of C-linked derivatives XIX, intermediate lib ’ can either be directly reacted first withboronic acid or boronic acid derivative III under palladium catalysed conditions (a palladium source such as (1 J'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride di chloromethane complex or [l,l'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and a base such as cesium carbonate, potassium carbonate or sodium carbonate) to form compound XIX. Intermediate XIX can then be reduced by treatment with a suitable reagent like hydrogen and a catalyst (such as Pd / C and an additive such as MgO) to form compound XX. The SEM group can typically be removed by treatment with acids like triflic acid, affording compound lie. Finally la can be accessed via alkylation. The R1group may be installed via alkylation (e.g. using a base such as NaH, and a suitable alkyl-halide R1-210or an alkyl bearing an alternative convenient leaving group such as triflate, mesylate, tosylate). In some cases, R1may also be installed via photoredox catalysis or similar radical promoted mechanism. In some other cases, R1is installed via Chan-Lam coupling or Buchwald coupling under palladium catalysed conditions. In both cases, the source of R1may be a boronic acid or ester. Alkylation typically proceeds preferentially at the N position, such that a mono-alkylated product may be isolated, and an independent alkylation reaction may be carried out to install an R1group.

[0848] Scheme 6

[0849] OH NBS or NCS or NIS R— B' or Br2, base OH VII Z

[0850]

[0851] OAn alternative way to access compounds lib is described in Scheme 6. Starting from described compound XVI, cyclization by treatment with a suitable reagent (a reagent such as, but not limited to, 4-nitrophenyl chloroformate or CDI or triphosgene) and a base such as TEA or DIPEA would deliver intermediate XXI. R1group may be installed via alkylation (e.g. using a base such as NaH, and a suitable alkyl-halide R

[0852]

[0853] -Za-c). Whereas R1is a cycloalkyl group, it may also be installed via a metal-catalyzed cross-coupling, such as a Chan-Lam reaction (e.g. where R1= cyclopropyl) from a suitably functionalized-boronic acid R1-B(OH)2using a copper(II) catalyst (such as CuOAc), delivering XXII. Halogenation is performed via treatment with NBS, NCS or NIS. The halogen Zb may also be interconverted to Za by treatment with TMSBr. Both XXIII and XXIV can be reacted with boronic acid (or a boronic acid derivative) VII under palladium catalyzed 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 lib. In addition, intermediate XXI may also be employed in the alternative synthesis of compound lib’. The SEM group may be installed via alkylation (e.g. using a base such as NaH, and a suitable alkyl-halide SEM-Za c). For the synthesis of derivatives XLI, intermediate XL can either be directly reacted first with boronic acid or boronic acid derivative VII under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride di chloromethane complex or [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) and a base such as cesium carbonate, potassium carbonate or sodium carbonate) to form compound XLI. XLI then may undergo electrophilic halogenation using either NBS, NCS or NIS or a bromine source such as Br2 in combination with a suitable base such as, but not limited to, DBU, delivering intermediate lib’.

[0854] Scheme 7llb O H

[0855] R— B' 'OH R— Z O H O H LiTMP, l2o XXVI XXVII

[0856] = Br, Cl, I R1, R2, R3a-3b1R4a-4band X, Yaccording to claim definition

[0857] tBuONO CH2Zc2

[0858] H2N—NH2H2O

[0859]

[0860] XXIX

[0861] Compounds of general formula lib can be prepared as described in the scheme starting from intermediate XXV. The reaction of XXV with N-Boc hydrazine or semicarbazide results in the formation of cyclized intermediate XXVI. This intermediate is then coupled with either an alkyl halide R’-Zc(e.g. using a base such as NaH, K2CO3or Na2CO3) or a boronic acid R’-B(0H)2 via a metal catalyzed cross coupling such as Chan-Lam reaction to introduce the R1group, yielding compound XXVII. Subsequent treatment of XXVII with a strong base such as lithium 2, 2,6,6-tetramethylpiperidide (LiTMP) and (Zc)2 as halogen source may introduce a halogen atom such as but not limited to iodine to form intermediate XXVIII. A final Suzuki cross-coupling reaction under palladium catalyzed coupling conditions (a palladium source such as but not limited to (1, 1 '-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and a base such as cesium carbonate) between intermediate XXVIII and boronic acid VII provides the compound of formula lib. In an alternative pathway, compounds of general formula XXXII can be synthesized from intermediate XXIX. Treatment of XXIX with hydrazine hydrate gives intermediate XXX, which then undergoes cyclization by treatment with a suitable agent such as 4-nitrophenyl chloroformate or CDI ortriphosgene to yield compound XXXI. The final step involves reacting XXXI in a Sandmeyer reaction, using tert-butyl nitrite and a dihalomethane (CILZ0?) to swap the aromatic amino group for a suitable halogen, to afford the compound of formula XXXII.

[0862] Scheme 8

[0863] Z”c= Br, Cl, I R1, R2, R3a-3b, R^-*andX, Yaccording to claim definition

[0864]

[0865] Furthermore, an alternative way to access compound la is described in Scheme 8. Compounds of general formula la can be prepared as outlined in the general reaction scheme. The synthesis begins with a Minisci reaction of intermediate XXXIII with a suitable carboxylic acid under oxidative conditions to yield compound XXXIV. This is followed by a palladium catalyzed Suzuki cross-coupling reaction (a palladium source such as but not limited to (l,l'-bis(diphenylphosphino)-ferrocene)palladium(II) dichloride and a base such as cesium carbonate) with a boronic ester derivative of formula III to furnish intermediate XXXV. Compound XXXV is then reacted with tert-butyl carbazate to deliver intermediate XXXVI. Catalytic hydrogenation of XXXVI using a catalyst such as, but not limited to, Pd / C under a hydrogen atmosphere provides the saturated intermediate XXXVII. Such reaction may also be run in presence of further reagents such as MgO. The tert-butyloxycarbonyl (Boc) protecting group on XXXVII is subsequently cleaved underacidic conditions to give the hydrazine-containing intermediate XXXVIII. This amine then undergoes an intramolecular cyclization with a suitable agent such as, but not limited to, 4-nitrophenyl chloroformate or CDI or triphosgene to form the annulated intermediate XXXIX. In the final step, R1 may be inserted via alkylation using a suitable base such as a carbonate or NaH and an alkyl halide such as R’-Zc. Alternatively, a cycloalkyl R1 such as the cyclopropyl may be einstalled via metal catalyzed cross-coupling such as the Chan-Lan-reaction, using copper as metal source and boronic acid R1-B(OH)2as alkyl source, providing the final compound of formula la.

[0866] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the process is as described in any one of schemes 1 to 8.

[0867] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, when manufactured according to any one of the processes described herein.

[0868] TREM2 Agonistic Activity

[0869] 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.

[0870] 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.

[0871] 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.

[0872] 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.

[0873] 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 resultingincreased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit.

[0874] 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.

[0875] 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.

[0876] 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.

[0877] 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.

[0878] Table 1

[0879] hTREM2 hTREM2

[0880] Ex. Ex.

[0881] ECso (pM) ECso (pM)

[0882] 1 0.105 6 0.052

[0883] 2 1.490 7 1.392

[0884] 3 0.007 8 0.016

[0885] 4 0.020 9 0.094

[0886] 5 1.037 10 0.153

[0887]

[0888]

[0889] hTREM2 hTREM2 Ex. Ex.

[0890] ECso (uM) ECso (uM)

[0891] 11 2.739 31 0.967

[0892] 12 0.041 35 0.026

[0893] 13 0.257 36 0.193

[0894] 14 0.019 37 0.011

[0895] 15 0.034 38 0.190

[0896] 16 0.212 39 0.596

[0897] 17 0.084 40 3.422

[0898] 18 20.000 41 0.056

[0899] 19 0.056 42 0.012

[0900] 20 13.449 43 0.002

[0901] 21 0.063 44 0.005

[0902] 22 6.667 45 0.007

[0903] 23 0.123 46 0.006

[0904] 24 0.058 47 2.222

[0905] 25 0.018 48 0.058

[0906] 26 0.016 49 0.022

[0907] 28 0.030 50 0.105

[0908] 29 0.004 51 0.077

[0909] 30 0.018 52 1.714

[0910]

[0911]

[0912] hTREM2 hTREM2 Ex. Ex.

[0913] ECso (uM) ECso (uM)

[0914] 53 0.012 72 0.009

[0915] 54 0.064 73 0.005

[0916] 55 0.015 74 0.051

[0917] 56 0.040 75 0.034

[0918] 57 0.031 76 0.017

[0919] 58 0.008 77 0.014

[0920] 59 1.166 78 0.018

[0921] 60 0.018 79 0.835

[0922] 61 2.013 80 0.034

[0923] 62 0.012 81 0.009

[0924] 63 0.015 82 1.213

[0925] 64 0.019 83 0.013

[0926] 65 0.060 84 0.022

[0927] 66 0.107 85 3.761

[0928] 67 0.020 86 0.587

[0929] 68 0.014 87 0.046

[0930] 69 0.160 88 0.013

[0931] 70 0.019 89 0.012

[0932] 71 0.015 90 0.008

[0933]

[0934]

[0935] hTREM2 hTREM2 Ex. Ex.

[0936] ECso (uM) ECso (uM)

[0937] 91 0.007 110 0.005

[0938] 92 0.016 111 0.004

[0939] 93 0.199 112 0.008

[0940] 94 0.021 113 0.011

[0941] 95 0.438 114 0.058

[0942] 96 0.034 115 0.047

[0943] 97 0.005 116 1.790

[0944] 98 0.122 117 0.189

[0945] 99 0.391 118 0.149

[0946] 100 0.030 119 0.850

[0947] 101 0.144 120 0.092

[0948] 102 0.451 121 0.145

[0949] 103 0.014 122 0.019

[0950] 104 0.165 123 2.436

[0951] 105 0.036 124 0.077

[0952] 106 0.045 125 1.300

[0953] 107 0.014 126 0.031

[0954] 108 0.020 127 0.021

[0955] 109 0.009 128 2.067

[0956]

[0957]

[0958] hTREM2 hTREM2 Ex. Ex.

[0959] ECso (uM) ECso (uM)

[0960] 129 1.410 148 0.262

[0961] 130 0.009 149 0.020

[0962] 131 0.012 150 0.016

[0963] 132 0.033 151 0.002

[0964] 133 0.046 152 0.004

[0965] 134 0.008 153 0.004

[0966] 135 0.147 154 1.624

[0967] 136 0.004 155 0.107

[0968] 137 0.013 156 2.510

[0969] 138 0.011 157 0.028

[0970] 139 0.008 158 1.707

[0971] 140 0.008 159 0.031

[0972] 141 0.012 160 0.138

[0973] 142 0.024 161 0.042

[0974] 143 0.007 162 0.864

[0975] 144 0.002 163 0.748

[0976] 145 2.772 164 0.223

[0977] 146 4.350 165 1.925

[0978] 147 0.005 166 0.071

[0979]

[0980]

[0981] hTREM2 hTREM2 Ex. Ex.

[0982] ECso (uM) ECso (uM)

[0983] 167 0.083 175 1.387

[0984] 168 0.070 176 0.218

[0985] 169 0.059 177 0.043

[0986] 170 0.127 178 0.634

[0987] 171 0.509 179 3.470

[0988]

[0989] 172 0.729

[0990] 173 0.050

[0991] 174 0.042

[0992]

[0993] Using the Compounds of the Invention

[0994] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, as described herein for use as a therapeutically active substance.

[0995] In a further aspect, the present invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition described herein.

[0996] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.

[0997] 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 compositiondescribed 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.

[0998] 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.

[0999] In one embodiment, said condition associated with a loss of function of human TREM2 is selected from the group consisting of Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, stroke, dry age-related macular degeneration (“AMD”, intermediate and end stage with geographic atrophy), retinovascular disease (wet AMD, diabetic retinopathy / diabetic macular oedema, retinal vein occlusion, sickle cell retinopathy, macular telangiectasis, radiation retinopathy), polypoidal choroidal vasculopathy, uveitides (inflammatory, infectious and post-surgical, including chorioretinitis and retinitis and secondary retinovascular complications), myopic macular choroidal neovascularization (CNV) / atrophy, CNV secondary to macular dystrophies, idiopathic CNV, inflammatory and infectious macular atrophy, inherited and acquired retinal / macular dystrophies / degeneration including rod cone dystrophies, central serous chorioretinopathy, blunt ocular trauma (commotio retinae / atrophy), drug-induced retinopathies / uveitis and acute and chronic glaucomas.

[1000] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Parkinson’s disease.

[1001] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is rheumatoid arthritis.

[1002] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Alzheimer’s disease.

[1003] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis.

[1004] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease.In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia.

[1005] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis.

[1006] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease.

[1007] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke.

[1008] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is dry AMD.

[1009] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is intermediate AMD.

[1010] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is geographic atrophy.

[1011] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is wet AMD.

[1012] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is diabetic retinopathy / diabetic macular oedema.

[1013] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is retinal vein occlusion.

[1014] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is sickle cell retinopathy.

[1015] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is macular telangiectasis.

[1016] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is radiation retinopathy.In a preferred embodiment, said condition associated with a loss of function of human TREM2 is polypoidal choroidal vasculopathy.

[1017] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is uveitides (inflammatory, infectious or post-surgical, including chorioretinitis and retinitis and secondary retinovascular complications).

[1018] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is myopic macular choroidal neovascularization (CNV) / atrophy.

[1019] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is CNV secondary to macular dystrophies.

[1020] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is idiopathic CNV.

[1021] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is inflammatory or infectious macular atrophy.

[1022] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is inherited or acquired retinal / macular dystrophy / degeneration, including rod cone dystrophies, central serous chorioretinopathy, blunt ocular trauma (commotio retinae / atrophy), drug-induced retinopathies / uveitis and acute and chronic glaucomas.

[1023] Pharmaceutical Compositions and Administration

[1024] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[1025] In one embodiment, there is provided a pharmaceutical composition according to Example 233 or 234.

[1026] 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).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.

[1027] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

[1028] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[1029] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[1030] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[1031] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[1032] 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.

[1033] Numbered Clauses

[1034] The invention is further described by the following numbered clauses:

[1035] 1. A compound of formula (I)

[1036]

[1037] or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1038] A1is selected from the group consisting of N and CR7;

[1039] A2is selected from the group consisting of O and CR5R6;

[1040] B is selected from the group consisting of 5- to 10-membered aryl, Cs-Cio-cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;

[1041] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[1042] X and Y are each independently selected from CH and N;

[1043] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group

[1044]

[1045] ; wherein said Ci-Ce-alkyl is optionally substituted with 1 substituent selected from Ci-Ce-alkoxycarbonyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce- alkoxy, and (C1-C6-alkyl)3Si-C1-C6-alkoxy;

[1046] R2is selected from the group consisting of C6-C10-aryl, 5- to 6-membered heteroaryl, C3- Cio-cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said C6-C10-aryl, 5- to 6- membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6-membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Ci-Ce-alkyl, Ci-Ce-alkoxy, and halo-Ci-Ce-alkyl;

[1047] R3ais selected from the group consisting of 5- to 6-membered heteroaryl, 9- to 10- membered fused bicyclic heteroaryl, and 3- to 6-membered heterocyclyl, wherein: (i) said 5- to 6-membered heteroaryl and 9- to 10-membered fused bicyclic heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo- Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, C3- Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, halo- Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, C3-C10- cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-memberedheterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy; and

[1048] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and optionally 1-3 further substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, C3- Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy;

[1049] R3bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[1050] R4ais selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[1051] R4bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[1052] R5and R6are each independently selected from the group consisting of hydrogen and halogen;

[1053] R7is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce-alkyl; R8is selected from the group consisting of hydrogen, halogen, hydroxy, oxo, cyano, Ci- Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and Ci-Ce-alkyl- S(O)2-; and

[1054] R9is selected from the group consisting of hydrogen, halogen, oxo, and Ci-Ce-alkyl.

[1055] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1056] A1is CR7;

[1057] A2is O; and

[1058] R7is selected from the group consisting of hydrogen and halogen.

[1059] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1060] A1is CR7;

[1061] A2is O; and

[1062] R7is selected from the group consisting of hydrogen and fluoro.

[1063] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A1is CR7;

[1064] A2is O; and

[1065] R7is hydrogen.

[1066] The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1067] R1is selected from the group consisting of methyl, isopropyl, n-propyl, 1 -methylbutyl, 3- methoxy-l-methyl-propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, ethylacetate, 2-(2-methoxyethoxy)ethyl, 2-trimethylsilylethoxymethyl, and a group R9

[1068] B^J

[1069] y"-L

[1070] R

[1071]

[1072] 8

[1073] B selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, 1,3,4-oxadiazolyl, pyridyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptanyl, 7- oxaspiro[3.5]nonanyl, 2-thiaspiro[3.3]heptanyl, and oxetanyl;

[1074] L is selected from the group consisting of a covalent bond, -CH2-, and -(CFh)?-;

[1075] R8is selected from the group consisting of hydrogen, fluoro, hydroxy, oxo, cyano, methyl, ethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, and methyl-S(O)2-; and

[1076] R9is selected from the group consisting of hydrogen, fluoro, oxo, and methyl.

[1077] The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1078] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group R9

[1079] B^J

[1080] y"-L

[1081] R

[1082]

[1083] 8

[1084] B selected from the group consisting of Cs-Cio-cycloalkyl and 3- to 10-membered heterocyclyl;

[1085] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[1086] R8is selected from the group consisting of hydrogen, halogen, cyano, halo-Ci-Ce-alkyl, and Ci-Ce-alkoxy; and

[1087] R9is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl.The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1088] R1is selected from the group consisting of methyl, isopropyl, 2,2,2-trifluoroethyl, and a

[1089] B

[1090] groupR

[1091]

[1092] ;

[1093] B selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentanyl, tetrahydropyranyl, tetrahydrofuranyl, and 2- oxaspiro[3.3]heptanyl;

[1094] L is selected from the group consisting of a covalent bond and -(CFh)?-;

[1095] R8is selected from the group consisting of hydrogen, fluoro, cyano, CF3, and methoxy;

[1096] and

[1097] R9is selected from the group consisting of hydrogen, fluoro, and methyl.

[1098] The compound of formula (I) according to any one of clauses 1 to 4, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is Ci-Ce-alkyl.

[1099] The compound of formula (I) according to clause 8, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1is methyl.

[1100] The compound of formula (I) according to any one of clauses 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of C6-C10-aryl and Cs-Cio-cycloalkyl, wherein said C6-C10-aryl and Cs-Cio-cycloalkyl are substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, and halo-Ci-Ce-alkyl.

[1101] The compound of formula (I) according to any one of clauses 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl, wherein said phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro, chloro, methyl, methoxy, CHF2, and CF3.

[1102] The compound of formula (I) according to any one of clauses 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[1103]

[1104] 13. The compound of formula (I) according to any one of clauses 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is C6-C10-aryl substituted with 1-3 substituents independently selected from the group consisting of halogen and halo-Ci-Ce- alkyl.

[1105] 14. The compound of formula (I) according to any one of clauses 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is phenyl substituted with 1-3 substituents independently selected from the group consisting of chloro, fluoro, CHF2, and CF3.

[1106] 15. The compound of formula (I) according to any one of clauses 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[1107]

[1108] The compound of formula (I) according to any one of clauses 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of:

[1109]

[1110] The compound of formula (I) according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein:

[1111] (i) said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl-C1-C6-alkyl, and 3- to 6-membered heterocyclyl-C1-C6-alkyl; and

[1112] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of C1-C6-alkyl, C3-C10-cycloalkyl, and C1-C6-alkoxy.

[1113] The compound of formula (I) according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of pyridyl, pyridazinyl, pyrazolyl, 2-triazolyl, 1-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,6-dihydropyridazinyl, and 1,2-dihydropyridyl, wherein:(i) said pyridyl, pyridazinyl, pyrazolyl, 2-triazolyl, 1-triazolyl, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl is optionally substituted with 1-2 substituents independently selected from the group consisting of methyl, CHF2, CF3, 2,2,2-trifluoroethyl, methoxy, cyclopropyl, 3 -fluorocyclobutyl, 3 -fluoro- l-bicyclo[l.l.l]pentanyl, 3,3- difluorocyclobutyl-CH2-, and tetrahydrofuranyl-CH2-; and

[1114] (ii) said 1,6-dihydropyridazinyl and 1,2-dihydropyridyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of methyl, cyclopropyl, and methoxy.

[1115] The compound of formula (I) according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of:

[1116]

[1117]

[1118] 20. The compound of formula (I) according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais 5- to 6-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkoxy and C3- Cio-cycloalkyl.

[1119] 21. The compound of formula (I) according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of pyridazinyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl.

[1120] 22. The compound of formula (I) according to any one of clauses 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of:

[1121]

[1122] The compound of formula (I) according to any one of clauses 1 to 22, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1123] R3bis hydrogen;

[1124] R4ais selected from the group consisting of hydrogen and C1-C6-alkyl; and

[1125] R4bis selected from the group consisting of hydrogen and C1-C6-alkyl.

[1126] The compound of formula (I) according to any one of clauses 1 to 22, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1127] R3bis hydrogen;

[1128] R4ais selected from the group consisting of hydrogen and methyl; and

[1129] R4bis selected from the group consisting of hydrogen and methyl.

[1130] The compound of formula (I) according to any one of clauses 1 to 22, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3b, R4a, and R4bare all hydrogen.

[1131] The compound of formula (I) according to any one of clauses 1 to 25, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is a compound of formula (la):

[1132]

[1133] wherein X, Y, R1, R2, and R3aare as defined in any one of clauses 1 to 25.

[1134] The compound of formula (I) according to any one of clauses 1 to 26, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1135] (i) X and Y are both CH; or

[1136] (ii) X is N and Y is CH; or(iii) X is CH and Y is N.

[1137] The compound of formula (I) according to any one of clauses 1 to 26, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X and Y are both CH.

[1138] The compound of formula (I) according to any one of clauses 1 to 26, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X is N and Y is CH.

[1139] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1140] (i) X and Y are both CH; or

[1141] (ii) X is N and Y is CH; or

[1142] (iii) X is CH and Y is N;

[1143] A1is selected from the group consisting of N and CR7;

[1144] A2is O;

[1145] B is selected from the group consisting of 5- to 10-membered aryl, Cs-Cio-cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;

[1146] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[1147] R1is selected from the group consisting of Ci-Ce-alkyl halo-Ci-Ce-alkyl, and a group

[1148] B

[1149] R

[1150]

[1151] 8; wherein said Ci-Ce-alkyl is optionally substituted with 1 substituent selected from Ci-Ce-alkoxycarbonyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce- alkoxy, and (C1-C6-alkyl)3Si-C1-C6-alkoxy;

[1152] R2is selected from the group consisting of C6-C10-aryl and Cs-Cio-cycloalkyl, wherein said C6-C10-aryl and Cs-Cio-cycloalkyl are substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce- alkoxy, and halo-Ci-Ce-alkyl;

[1153] R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6- membered heterocyclyl, wherein:

[1154] (i) said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce- alkyl, Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, halo-Cs-Cio- cycloalkyl-Ci-Ce-alkyl, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl; and(ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of Ci-Ce-alkyl, Cs-Cio-cycloalkyl, and Ci-Ce-alkoxy;

[1155] R3bis hydrogen;

[1156] R4ais selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[1157] R4bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[1158] R7is selected from the group consisting of hydrogen and halogen;

[1159] R8is selected from the group consisting of hydrogen, halogen, hydroxy, oxo, cyano, Ci- Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and Ci-Ce-alkyl- S(O)2-; and

[1160] R9is selected from the group consisting of hydrogen, halogen, oxo, and Ci-Ce-alkyl.

[1161] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1162] (i) X and Y are both CH; or

[1163] (ii) X is N and Y is CH; or

[1164] (iii) X is CH and Y is N;

[1165] A1is selected from the group consisting of N and CR7;

[1166] A2is O;

[1167] B selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, 1,3,4-oxadiazolyl, pyridyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxaspiro[3.3]heptanyl, 7- oxaspiro[3.5]nonanyl, 2-thiaspiro[3.3]heptanyl, and oxetanyl;

[1168] L is selected from the group consisting of a covalent bond, -CH2- and -(CH2)2-;

[1169] R1is selected from the group consisting of methyl, isopropyl, n-propyl, 1 -methylbutyl, 3- methoxy-l-methyl-propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, ethylacetate, 2-(2-methoxyethoxy)ethyl, 2-trimethylsilylethoxymethyl, and a group R9

[1170] y"-L

[1171] R

[1172]

[1173] 8

[1174] R2is selected from the group consisting of phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl, wherein said phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro, chloro, methyl, methoxy, CHF2, and CF3;R3ais selected from the group consisting of pyridyl, pyridazinyl, pyrazolyl, 2-triazolyl, 1H-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,6-dihydropyridazinyl, and 1,2- dihydropyridyl, wherein:

[1175] (i) said pyridyl, pyridazinyl, pyrazolyl, 2-triazolyl, 1-triazolyl, 1,2,4- oxadiazolyl, and 1,3,4-oxadiazolyl is optionally substituted with 1-2 substituents independently selected from the group consisting of methyl, CHF2, CF3, 2,2,2- trifluoroethyl, methoxy, cyclopropyl, 3 -fluorocyclobutyl, 3 -fluoro- 1- bicyclo[l.l.l]pentanyl, 3,3-difluorocyclobutyl-CH2-, and tetrahydrofuranyl- CH2-; and

[1176] (ii) said 1,6-dihydropyridazinyl and 1,2-dihydropyridyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of methyl, methoxy, and cyclopropyl; and

[1177] R3bis hydrogen;

[1178] R4ais selected from the group consisting of hydrogen and methyl;

[1179] R4bis selected from the group consisting of hydrogen and methyl;

[1180] R7is selected from the group consisting of hydrogen and fluoro;

[1181] R8is selected from the group consisting of hydrogen, fluoro, hydroxy, oxo, cyano, methyl, ethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, and methyl-S(O)2-; and R9is selected from the group consisting of hydrogen, fluoro, oxo, and methyl.

[1182] 32. The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1183] (i) X and Y are both CH; or

[1184] (ii) X is N and Y is CH;

[1185] A1is CR7;

[1186] A2is O;

[1187] B selected from the group consisting of Cs-Cio-cycloalkyl and 3- to 10-membered heterocyclyl;

[1188] L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;

[1189] R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a group R9

[1190] y"-L

[1191] R

[1192]

[1193] 8R2is C6-C10-aryl substituted with 1-3 substituents independently selected from the group consisting of halogen and halo-Ci-Ce-alkyl;

[1194] R3ais 5- to 6-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkoxy and Cs-Cio-cycloalkyl;

[1195] R3b, R4a, R4b, and R7are all hydrogen;

[1196] R8is selected from the group consisting of hydrogen, halogen, cyano, halo-Ci-Ce-alkyl, and Ci-Ce-alkoxy; and

[1197] R9is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl.

[1198] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

[1199] (i) X and Y are both CH; or

[1200] (ii) X is N and Y is CH;

[1201] A1is CR7;

[1202] A2is O;

[1203] B selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[l.l.l]pentanyl, tetrahydropyranyl, tetrahydrofuranyl, and 2- oxaspiro[3.3]heptanyl;

[1204] L is selected from the group consisting of a covalent bond and -(CH2)2-;

[1205] R1is selected from the group consisting of methyl, isopropyl, 2,2,2-trifluoroethyl, and a

[1206] B, l

[1207] Z'-'L

[1208] group

[1209]

[1210] R2is phenyl substituted with 1-3 halogen substituents independently selected from chloro and fluoro;

[1211] R3ais selected from the group consisting of pyridyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl;

[1212] R3b, R4a, R4b, and R7are all hydrogen; R8is selected from the group consisting of hydrogen, fluoro, cyano, CF3, and methoxy;

[1213] and

[1214] R9is selected from the group consisting of hydrogen, fluoro, and methyl.

[1215] The compound of formula (I) according to clause 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is selected from:8-(4-chloro-2-fluoro-phenyl)-6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3-one;

[1216] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1217] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1218] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1219] 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1220] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1221] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1222] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1223] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluorophenyl)-2- methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1224] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluorophenyl)-2- methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1225] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S,4R)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1226] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1227] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1228] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1229] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1230] 8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[1231] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(6-methoxypyridazin-3-yl)tetrahydropyran- 4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1232] 8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(6-methoxypyridazin-4-yl)tetrahydropyran- 4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1233] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(6-methoxypyridazin-3- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1234] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(6-methoxypyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1235] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[1236] 8-(4,4-difluorocyclohexyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[1237] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[1238] 8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (2,2,2-trifluoroethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1239] 8-(4-chlorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1240] 3-fluoro-4-[2-methyl-3-oxo-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-8-yl]benzonitrile;

[1241] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one

[1242] 8-(4-chloro-2,6-difluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1243] 8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1244] 8-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1245] 8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1246] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1247] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1248] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1249] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1250] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1251] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1252] 6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1253] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(lH-pyrazol-4-yl)tetrahydropyran-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1254] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1255] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[2-fluoro-4- (trifluoromethyl)phenyl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1256] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4- (difluoromethyl)-2-fluoro-phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1257] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4-(difluoromethyl)-2- fluoro-phenyl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1258] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1259] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1260] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4- (difluoromethyl)phenyl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1261] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1262] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluoro-4-methoxy- phenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1263] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluoro- 4-methoxy-phenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-(2,2,2-trifluoroethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1264] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(2,2,2-trifluoroethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1265] 2-cyclopropyl-6-[(2R,4S)-2-[l-[(3,3-difluorocyclobutyl)methyl]pyrazol-4- yl]tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[trans-l-(3-fluorocyclobutyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1266] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-[[(3S)-tetrahydrofuran-3- yl]methyl]pyrazol-4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1267] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-[[(3S)-tetrahydrofuran-3- yl]methyl]pyrazol-4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1268] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[cis-l-(3-fluorocyclobutyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1269] 2-cyclopropyl-6-[(2S,4R)-2-[l-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1270] 2-cyclopropyl-6-[(2R,4S)-2-[l-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1271] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(trifluoromethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1272] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-(trifluoromethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1273] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[ 1 -(3 -fluoro- 1 - bicyclo[1.1.1]pentanyl)pyrazol-4-yl]tetrahydropyran-4-yl]-[1,2,4]triazolo[4,3-a]pyrazin-3-one;

[1274] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1275] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1276] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1277] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(2,2-difluoroethyl)-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1278] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (oxetan-3-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1279] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1280] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluoro-4-methyl- phenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1281] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclobutyl)- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1282] 2-cyclopentyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1283] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3R)-tetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1284] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3S)-tetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1285] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- tetrahydropyran-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1286] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lR)-2,2- difluorocyclopropyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1287] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lS)-2,2- difluorocyclopropyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1288] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3-methyloxetan-3-yl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1289] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (2-fluoroethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1290] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- isopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1291] 2-benzyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1292] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(l-fluorocyclopropyl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1293] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(5-ethyl-l,3,4-oxadiazol-2-yl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;ethyl 2-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]acetate;

[1294] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [2-(2-methoxyethoxy)ethyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1295] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lR,3S)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1296] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lS,3R)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1297] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lR,3R)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1298] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lS,3S)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1299] cis- and trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]cyclobutanecarbonitrile;

[1300] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(1 -methyltri azol -4-yl)methyl]-[l, 2, 4]triazolo[4,3-a]pyrazin-3-one;

[1301] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (7-oxaspiro[3.5]nonan-2-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1302] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- ((2RS)-oxetan-2-ylmethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1303] cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-methoxycyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1304] cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1305] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [2-(oxetan-3-yl)ethyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1306] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3-methoxy-2-pyridyl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1307] cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[3-(methoxymethyl)cyclobutyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (2,2-dioxo-2λ6-thiaspiro[3.3]heptan-6-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1308] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [[(lS,5R)-3-oxabicyclo[3.1.0]hexan-6-yl]methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;cis- and trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]-l-methyl- cyclobutanecarbonitrile;

[1309] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- propyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1310] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3R)-4,4-difluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1311] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3S)-4,4-difluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1312] trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]cyclobutanecarbonitrile; cis-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]cyclobutanecarbonitrile;

[1313] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lRS)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1314] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lR)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1315] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lS)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1316] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lRS)-l-methylbutyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1317] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS)-l-(2,2- difluoroethyl)pyrrolidin-3-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;

[1318] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [[(3RS)-tetrahydrofuran-3-yl]methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1319] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [[(3RS)-tetrahydropyran-3-yl]methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1320] l-[[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- 3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]methyl]cyclobutanecarbonitrile;

[1321] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lRS,3RS)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1322] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(lRS)-3-methoxy-l-methyl-propyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS)-l-methylsulfonylpyrrolidin-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; methyl 3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[1,2,4]triazolo[4,3-a]pyrazin-2-yl]bicyclo[1.1.1]pentane-1-carboxylate;

[1323] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[1324] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-b]pyridazin-3-one;

[1325] 2-cyclopropyl-6-[(2R,4S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1326] 2-cyclopropyl-6-[(2R,4S,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1327] 2-cyclopropyl-6-[(2S,4S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1328] 2-cyclopropyl-6-[(2R,4R,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1329] 2-cyclopropyl-6-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1330] 6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1331] 6-[(4S,6S)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1332] 6-[(4S,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1333] 2-cyclopropyl-6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1334] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[rac-(4S,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2- dimethyl-tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1335] trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;cis-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- 2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1336] cis-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- 2-(3-methoxycyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1337] trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-methoxycyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]-l-methyl- cyclobutanecarbonitrile;

[1338] cis-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]-l-methyl- cyclobutanecarbonitrile;

[1339] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-(p-tolyl)- [ 1,2,4]triazolo[4,3 -a]pyrazin-3 -one;

[1340] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3S)-tetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1341] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (2-tetrahydrofuran-3-ylethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1342] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (2-oxaspiro[3.3]heptan-6-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1343] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4- yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1344] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3R)-tetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1345] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(3-fluorocyclobutyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1346] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1347] 8-(4-chloro-2-fluoro-phenyl)-6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl- tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1348] 8-(4-chloro-2-fluoro-phenyl)-6-[(4S,6S)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl- tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1349] 2-cyclopropyl-6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1350] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-[1,2,4]triazolo[4,3-a]pyrazin-3-one;

[1351] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1352] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1353] 2-cyclopropyl-6-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1354] 2-cyclopropyl-6-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1355] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-3-methyl-pyrazol-4-yl)tetrahydropyran-4-yl]- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1356] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-3-methyl-pyrazol-4-yl)tetrahydropyran-4-yl]- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1357] 2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-5-methyl-pyrazol-4-yl)tetrahydropyran-4-yl]- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1358] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-5-methyl-pyrazol-4-yl)tetrahydropyran-4-yl]- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1359] 2-cyclopropyl-6-[(2R,4S)-2-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1360] 2-cyclopropyl-6-[(2R,4S)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1361] 2-cyclopropyl-6-[(2S,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1362] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1363] 2-cyclopropyl-6-[(2R,4S)-2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1364] 2-cyclopropyl-6-[(2S,4R)-2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1365] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4- fluorocyclohexyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[rac-(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)-2- methyl-tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1366] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (2-methyl-3-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1367] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)-4-fluoro-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1368] 2-cyclopropyl-6-[(2R,4R)-2-(l-cyclopropylpyrazol-4-yl)-4-fluoro-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1369] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1370] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR,4RS)-4-hydroxytetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1371] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS,4SR)-4-fluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1372] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR,4RS)-4-fluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1373] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (l-hydroxycyclopropyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1374] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (l-fluorocyclopropyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1375] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (3-methyl-4-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1376] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (3-methyl-4-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1377] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S)-2-(l-cyclopropylpyrazol-4- yl)morpholin-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1378] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(6-methoxypyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1379] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2S,4R)-2-(6-methoxypyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1380] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS,4SR)-4- fluorotetrahydrofuran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3 SR,4RS)-4- fluorotetrahydrofuran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;

[1381] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-isopropyl-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1382] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-tetrahydropyran-4-yl-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1383] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(4RS)-3,3- difluorotetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;

[1384] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(4SR)-3,3- difluorotetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;

[1385] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS)-4,4-difluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1386] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR)-4,4-difluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1387] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR,4RS)-3-fluorotetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1388] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS,4SR)-3-fluorotetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1389] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3RS,4RS)-4-fluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1390] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- [(3 SR,4SR)-4-fluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1391] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS,4RS)-4- fluorotetrahydropyran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;

[1392] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3 SR,4SR)-4- fluorotetrahydropyran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;

[1393] 2-cyclopropyl-6-[(2R,4S)-2-(6-methoxypyridazin-4-yl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1394] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-tetrahydropyran-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(trans-4- fluorocyclohexyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1395] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R)-2-(l-cyclopropylpyrazol-4- yl)morpholin-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1396] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3,3-difluorotetrahydropyran-4-yl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;

[1397] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(4,4-difluorotetrahydropyran-3-yl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;

[1398] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3-fluorotetrahydropyran-4-yl)-[l,2,4]triazolo[4,3-a]pyrazin- 3 -one;

[1399] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(4-fluorotetrahydropyran-3-yl)-[l,2,4]triazolo[4,3-a]pyrazin- 3 -one;

[1400] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-isopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1401] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3-fluorocyclobutyl)-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1402] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclobutyl)- 8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1403] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3- difluorocyclopentyl)-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclopentyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;

[1404] 2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1405] 8-(4-chloro-2,6-difluoro-phenyl)-2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1406] 2-cyclopropyl-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1407] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1408] 2-cyclopropyl-6-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1409] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1410] 2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1411] 8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1412] 2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1413] 8-(4-chloro-2,6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1414] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1415] 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1416] 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1417] 8-(4-chloro-2,6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1418] 2-cyclobutyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-2-cyclobutyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1419] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- pyridazin-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1420] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (5-methylpyridazin-4-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;

[1421] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(5-methylpyridazin-4-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;

[1422] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l,5-dimethyl-6-oxo-pyridazin-3- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; and

[1423] 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(5-methoxy-l-methyl-6-oxo-pyridazin- 3-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one.

[1424] The compound of formula (I) according to any one of clauses 1 to 34 or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a therapeutically active substance.

[1425] A pharmaceutical composition comprising a compound of formula (I) according to any one of clauses 1 to 34, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a therapeutically inert carrier.

[1426] 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 clauses 1 to 34, or a pharmaceutically acceptable salt or a stereoisomer thereof, or the pharmaceutical composition according to clause 36.

[1427] The method according to clause 37, wherein said condition associated with a loss of function of human TREM2 is selected from the group consisting of Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, stroke, dry age-related macular degeneration (“AMD”, intermediate and end stage with geographic atrophy), retinovascular disease (wet AMD, diabetic retinopathy / diabetic macular oedema, retinal vein occlusion, sickle cell retinopathy, macular telangiectasis, radiation retinopathy), polypoidal choroidal vasculopathy, uveitides (inflammatory, infectious and post-surgical, including- Ill - chorioretinitis and retinitis and secondary retinovascular complications), myopic macular choroidal neovascularization (CNV) / atrophy, CNV secondary to macular dystrophies, idiopathic CNV, inflammatory and infectious macular atrophy, inherited and acquired retinal / macular dystrophies / degeneration including rod cone dystrophies, central serous chorioretinopathy, blunt ocular trauma (commotio retinae / atrophy), drug-induced retinopathies / uveitis and acute and chronic glaucomas.

[1428] 39. A compound according to any one of clauses 1 to 34, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition according to clause 36, for use in a method according to clause 37 or 38.

[1429] 40. Use of a compound according to any one of clauses 1 to 34, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to clause 36, in a method according to clause 37 or 38.

[1430] 41. Use of a compound according to any one of clauses 1 to 34, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to clause 37 or 38.

[1431] 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.

[1432] 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.

[1433] 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.

[1434] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 24.1. If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls.

[1435] Intermediates A

[1436] Intermediate A 1: l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-py ran-6-y 1 ] py razol e

[1437] Step 1: 16-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl1 trifluoromethanesulfonate

[1438]

[1439] To a solution of l-cyclopropylpyrazole-4-carbaldehyde (CAS RN: 1082066-00-9; 4.5 g, 33.1 mmol, 1.0 equiv.) and 3-butyn-l-ol (CAS RN: 927-74-2; 3.47 g, 49.6 mmol, 1.5 equiv.) in DCM (80 mL) was added dropwise trifluoromethane sulfonic acid (7.93 mL, 99.16 mmol, 3.0 equiv.) at -10 °C. After addition, the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (400 mL) and extracted with DCM (200 mL x 3) The reunited organic layers were washed with brine, dried over Na2SO4and filtered. The solvent was removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (7.00 g, 63% yield) as a light yellow oil. MS m / z: 339.1 [M+H]+, ESI pos

[1440] Step 2: l-cyclopropyl-4-r4-(4A5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran- 6-yllpyrazole

[1441] N 0-5

[1442] N*.

[1443]

[1444] To a solution of [6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (23.0 g, 67.9 mmol, 1.0 equiv.) in 1,4-Dioxane (400 mL) was added bis(pinacolato)diboron (20.7 g, 81.6 mmol, 1.2 equiv.), KOAc (20.0 g, 204 mmol, 3.0 equiv.) and Pd(dppf)C12. DCM complex (2.77 g, 3.40 mmol, 5.0 mol%). Then the mixture was degassed via N2 bubbling for three times and the reaction was stirred at 90 °C for 2 h under N2. The reactionmix\ / = / ture was poured into water (40 mL) and extracted with EtOAc (20 mL x 3). The reunited organic layers were washed with brine (20 mL x 3), dried over Na2SO4and the solvent removed0\

[1445] under reduced pressure. Purification by RP HPLC (C18, water / ACN gradient + 0.1% HCO2H) delivered the title OTO- compound (20.0 g, 93% yield) as a brown oil. MS m / z: 317.2 [M+H]+, ESI pos

[1446] 5 The Intermediates provided in the following table were generated in analogy to Intermediate Al, using the respective commercially available building blocks and following the same order of steps as described for Intermediate Al. A skilled person will be aware that variants and / or alternative procedures for both the cyclization and cross coupling steps may be applied. For example, in some cases, 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane may 0 be used as coupling reagent for the Miyaura borylation step, the duration of the reaction [h] was modified or the reaction was conducted at a different temperature [°C], Also, in some cases, reverse phase (RP) or normal phase FCC or HPLC were used as purification methods instead of or in addition to FCC.

[1447] I nt. Structure Systematic Name Building Blocks MS 0Q O- (ESI):

[1448] m / z / °

[1449] A2 j Z 2-methoxy-5-[4- 6-methoxy-3- 318.3 (4,4, 5, 5 -tetramethyl- pyridinecarboxaldehyde CAS [M+H]+, 0

[1450] \

[1451] l,3,2-dioxaborolan-2- RN: 65873-72-5 and 3-butyn- ESI pos yl)-3,6-dihydro-2 / 7- l-ol CAS RN: 927-74-2

[1452] pyran-6-yl]pyridine

[1453] A3 2-methoxy-4-[4- 2-methoxyisonicotinaldehyde 318.3 (4,4, 5, 5 -tetramethyl- CAS RN: 72716-87-1 and 3- [M+H]+, l,3,2-dioxaborolan-2- butyn-l-ol CAS RN: 927-74-2 ESI pos yl)-3,6-dihydro-2 / 7- pyran-6-yl]pyridine

[1454]

[1455] \

[1456] o

[1457] A4 3-methoxy-6-[4- 6-methoxypyridazine-3- 319.2 9

[1458] zz- (4,4, 5, 5 -tetramethyl- carbaldehyde CAS RN: 90237- [M+H]+,?°=

[1459] l,3,2-dioxaborolan-2- 25-5 and 3-butyn-l-ol CAS ESI pos ° \

[1460] o* yl)-3,6-dihydro-2Z7- RN: 927-74-2

[1461] I roO CD-O- d pyran-6-yl]pyridazine

[1462] A5 O., N 1^KN1„ < 2-methyl-6-[4-(4, 4,5,5- l-methyl-6-oxo-pyridazine-3- 319.2 0-\ _

[1463] tetram ethyl- 1,3,2- carbaldehyde CAS: 1467710- [M+H]+, 0^

[1464] dioxaborolan-2-yl)-3,6- 08-2 and 3-butyn-l-ol CAS ESI pos. dihydro-2H-pyran-6- RN: 927-74-2

[1465] yl]pyridazin-3-one

[1466] A60■'-A 1 2-methyl-5-[4-(4,4,5,5- l-methyl-6-oxo-l,6- 375.3 '"'N'N tetraethyl- 1,3,2- dihydropyridazine-4- [M+H]+, A A C dioxaborolan-2-yl)-3,6- carbaldehyde CAS RN: ESI pos.

[1467] O^J

[1468] dihydro-2H-pyran-6- 1001620-75-2 and 3-butyn-l-ol yl]pyridazin-3-one CAS RN: 927-74-2

[1469] A7 2-cyclopropyl-5-[4- 1 -cyclopropyl-6-oxo- 401.1 A N'MS A 0-\J

[1470] (4,4,5,5-tetraethyl- pyridazine-4-carbaldehyde (see [M+H]+, A M l,3,2-dioxaborolan-2- preparation from commercially ESI pos °A

[1471] yl)-3,6-dihydro-2H- available 5-chloro-2- pyran-6-yl]pyridazin-3- cyclopropyl-pyridazin-3-one

[1472] one CAS RN: 14628-34-3 below.

[1473] With 3-butyn-l-ol CAS RN:

[1474] 927-74-2

[1475] A8 2-benzyl-5-[4-(4,4,5,5- 1 -benzyl-6-oxo- 1,6- 451.3 tetraethyl- 1,3,2- dihydropyridazine-4- [M+H]+, dioxaborolan-2-yl)-3,6- carbaldehyde CAS RN: ESI pos dihydro-2Z / -pyran-6- 1001620-76-3 and and 3- yl]pyridazin-3-one butyn-l-ol CAS RN: 927-74-2

[1476]

[1477] A9 Y \ /

[1478] — Si trimethyl-[2-[[4-[4- l-((2- 407.2 o (4,4, 5, 5 -tetramethyl- (trimethylsilyl)ethoxy)methyl)- [M+H]+,,N-~ °, \ oA<- R A l,3,2-dioxaborolan-2- lH-pyrazole-4-carb aldehyde ESI pos roO- yl)-3,6-dihydro-2JY- CAS RN: 869558-91-8 and 3- pyran-6-yl]pyrazol-l- butyn-l-ol CAS RN: 927-74-2 yl]methoxy]ethyl]silane

[1479] A10 1 -cyclopropyl-4-[2- 1 -cyclopropylpyrazole-4- 331.2 methyl-4-(4, 4,5,5- carbaldehyde CAS RN: [M+H]+, tetramethyl- 1,3,2- 1082066-00-9 and 4-pentyn-2- ESI pos dioxaborolan-2-yl)-3,6- ol CAS RN: 2117-11-5

[1480] dihydro-27 / -pyran-6- yl]pyrazole

[1481] All l-methyl-4-[4-(4, 4,5,5- 1 -methylpyrazole-4- 291.2

[1482] VA - m Otn O-- o-Vz tetramethyl- 1,3,2- carbaldehyde CAS RN: 25016- [M+H]+, —N J R X

[1483] dioxaborolan-2-yl)-3,6- 11-9 and 3-butyn-l-ol CAS ESI pos \J \ ° dihydro-27 / -pyran-6- RN: 927-74-2

[1484] x is

[1485] 1 v* yl]pyrazole

[1486] A19 l-cyclopropyl-3- 1 -cy cl opropyl-3 -methyl- \H- 330.8 and methyl-4-[4-(4, 4,5,5- pyrazole-4-carboxaldehyde [M+H]+, A20 tetramethyl- 1,3,2- CAS RN: 2158550-87-7 and 1- ESI pos dioxaborolan-2-yl)-3,6- cy cl opropyl - 5 -methyl -1H- dihydro-27 / -pyran-6- pyrazole-4-carboxaldehyde yl]pyrazole and 1- CAS RN: 1823223-73-9 and 3- cyclopropyl-5-methyl- butyn-l-ol CAS RN: 927-74-2

[1487] 4-[4-(4, 4,5,5- *in this case, the mixture of tetramethyl- 1,3,2- intermediates Al 9 and A20 dioxaborolan-2-yl)-3,6- was obtained as a result of the

[1488]

[1489] dihydro-2 / / -pyran-6- cyclization on a mixture of

[1490] Y " Z / / - \ i

[1491] \z= yl]pyrazole starting materials.

[1492] P ° \

[1493] ° \

[1494] All roo- 2-cyclopropyl-4-[4- 2-Cy cl opropyl-2 / 7- 1,2,3- 318.1 tno- (4,4, 5, 5 -tetramethyl- triazole-4-carboxaldehyde [M+H]+, l,3,2-dioxaborolan-2- CAS RN: 2705257-83-4 ESI pos yl)-3,6-dihydro-2Z7- pyran-6-yl]tri azole

[1495] All 1 -cyclopropyl-4-[4- 1 -Cyclopropyl- 1H- 1,2,3- 318.2 (4,4, 5, 5 -tetramethyl- triazole-4-carboxaldehyde [M+H]+, l,3,2-dioxaborolan-2- CAS RN: 1260667-77-3 ESI pos yl)-3,6-dihydro-2Z7- pyran-6-yl]tri azole

[1496] A13 1 -cyclopropyl-4-[6- l-(l-cyclopropyl-lH-pyrazol- 331.5 CQ O- methyl-4-(4, 4,5,5- 4-yl)ethanone CAS [M+H]+, 40 —- tetramethyl- 1,3,2- RN: 1784673-98-8 ESI pos dioxaborolan-2-yl)-2,3- _ J

[1497] dihydropyran-6- yl]pyrazole

[1498]

[1499] Synthesis of the aldehyde building block for Intermediate A7:

[1500] l-cyclopropyl-6-oxo-pyridazine-4-carbaldehyde

[1501]

[1502] 5 Step 1: 2-cyclopropyl-5-vinyl-pyridazin-3-one

[1503]

[1504] To a colorless solution of 5-chloro-2-cyclopropyl-pyridazin-3-one (CAS: 14628-34-3, 56.0 g, 262.6 mmol, 1.0 eq.) in 1,4-dioxane (1000 mL) and water (100 mL) were added potassium trimethyl(vinyl)boranuide (52.41 g, 393.9 mmol, 1.5 eq.) and Cs2CO3(171.12 g, 525.2 mmol, 2.0 eq.). The reaction mixture was purged three times with N2. Pd(dppf)C12-DCM (6.43 g, 7.88 mmol, 0.03 eq.) was added to the reaction mixture under N2 and the reaction mixture was stirred at 90 °C for 4 h. H2O (500 mL) was added to the reaction and extracted with EtOAc (2 x 500 ml). The combined extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 75% EtOAc in PE) to give 2-cyclopropyl-5-vinyl-pyridazin-3-one (33.0 g, 203.47 mmol, 65.9% yield) as a yellow solid. LC-MS: m / z = 163.2 [M+H]+, ESI pos.

[1505] Step 2: l-cyclopropyl-6-oxo-pyridazine-4-carbaldehyde (key starting material for the cyclization)

[1506]

[1507] Ozone was bubbled through a solution of 2-cyclopropyl-5-vinyl-pyridazin-3-one (33.0 g, 203.47 mmol, 1.0 eq.) in DCM (200 mL) and MeOH (200 mL) at -70 °C for 30 min. Then, N2 was bubbled into the mixture at -70 °C to strip the ozone. The reaction turned into blue suspension which was allowed to warm to 0 °C and to this solution was added dropwise a solution of PPI13 (106.65 g, 406.93 mmol, 2.0 eq.) in DCM (200 mL). The mixture was stirred Ih at 25 °C under N2 which yielded a yellow solution. The reaction mixture was concentrated and 150 mL MeOH were added upon which a white solid precipitated. The solid was filtered off and the filtrate was concentrated in vacuo. Purification by preparative HPLC (Phenomenex Luna C 18, 150 x 25 mm, 10 pm 30 - 40% CH3CN in H2O) yielded l-cyclopropyl-6-oxo-pyridazine-4-carbaldehyde (22.8 g, 138.89 mmol, 68.26% yield) as pink solid, confirmed). LC-MS: m / z = 183.2 [M+HjO], ESI pos.

[1508] Intermediate A12: l-cyclopropyl-4-16,6-dimethyl-4-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)-2,5-dihydropyran-2-yl]pyrazole

[1509]

[1510] -4-yl)-l-hydroxy-5-methyl-hex-4-en-3-one

[1511]

[1512] Under inert N2 atmosphere, to a solution of mesityl oxide (2.16 g, 22.0 mmol, 1.5 equiv.) in THF (30 mL) at - 65 °C was slowly added LDA (15 mL, 29.4 mmol, 2.0 equiv.) dropwise over 30 min. The mixture was stirred for 30 min at - 65 °C. Then l-cyclopropylpyrazole-4-carbaldehyde (2.00 g, 14.7 mmol, 1.0 equiv.) was slowly added to the mixture. The mixture was stirred at -70 °C for 1 h inert N2 atmosphere. The reaction mixture was poured into NH4CI solution (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (30 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiCh, 120 g, PE / EtOAc gradient) delivered the title compound (2.30 g, 67% yield) as a light yellow solid. MS: m / z 235.1 [M+H]+, ESI pos.

[1513] Step 2: 6-(l-cyclopropylpyrazol -4-yl )-2.2-di methyl -tetrahydropyran-4-one

[1514]

[1515] To a solution of l-(l-cyclopropylpyrazol-4-yl)-l-hydroxy-5-methyl-hex-4-en-3-one (9.00 g, 38.4 mmol, 1.0 equiv.) in DCM (200 mL) was added Amberlyst 15 (36.0 g, 113 mmol, 2.95 equiv.) then the mixture was stirred for 8 h at 25 °C. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (1.10 g, 12% yield) as a light yellow oil. MS: m / z 235.2 [M+H]+, ESI pos.

[1516] Step 3: r2-(l-cyclopropylpyrazol-4-yl)-6,6-dimethyl-2,5-dihydropyran-4-yl] LL2,2,3,3,4,4,4-nonafluorobutane- 1 -sulfonate

[1517]

[1518] To a stirred solution of 6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-one (3.66 g, 13.6 mmol, 1.0 equiv.) in THF (72 mL) was added 1,1,2,2,3,3,4,4,4-nonafhiorobutane-l-sulfonyl fluoride (6.16 g, 20.4 mmol, 1.5 equiv.) and DBU (4.05 mL, 27.2 mmol, 2.0 equiv.). The reaction was stirred at 25 °C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (80 mL x 3). The organic layers were washed with brine (150 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by RP (Cl 8, H2O / ACN gradient+ 0.1% HCO2H) delivered the title compound (6.70 g, 95% yield) as a yellow oil. MS: m / z 517.2 [M+H]+, ESI pos.

[1519] Step 4: l-cyclopropyl-4-[6,6-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihy dropy ran-2-y 1 ] py razol e

[1520]

[1521] A mixture of [2-(l-cyclopropylpyrazol-4-yl)-6,6-dimethyl-2,5-dihydropyran-4-yl] 1,1,2,2,3,3,4,4,4-nonafluorobutane-l-sulfonate (6.70 g, 13.0 mmol, 1.0 equiv.), bis(pinacolato)diboron (3.95 g, 15.6 mmol, 1.2 equiv.), KOAc (3.82 g, 38.9 mmol, 3.0 equiv.) and Pd(dppf)C12. DCM (847 mg, 1.04 mmol, 8.0 mol%.) in 1,4-dioxane (135 mL) was degassed with N23 times and stirred for 1 h at 90 °C under N2. The reaction mixture was cooled to RT and was filtered through celite, then concentrated in vacuo. Purification by FCC (Si Ch, PEZEtOAc gradient) delivered the title compound (4.40 g, 99% yield) as a yellow oil. MS: m / z 345.3 [M+H]+, ESI pos.

[1522] The Intermediates provided in the following table were generated in analogy to Intermediate Al, using the respective commercially available building blocks and following the same order of steps as described for Intermediate AL A skilled person will be aware that variants and / or alternative procedures for both the synthesis of the enol triflate and cross coupling steps may be applied. For example, in some cases, the equivalents or source of triflate, the base, the duration of the reaction [h] were modified or the reaction was conducted at a different temperature [°C], Also, in some cases, reverse phase (RP) or normal phase FCC or HPLC were used as purification methods instead of or in addition to FCC.Int. Structure Systematic Name Building Blocks MS (ESI): m / z

[1523] A18 ethyl 4-(4, 4,5,5 - ethyl 4-oxotetrahydropyran-2- 283.1 tetramethyl- 1,3,2- carboxylate CAS RN: 287193- [M+H]+, dioxaborolan-2-yl)-3,6- 07-1. ESI pos dihydro-27 / -pyran-2- carb oxy late

[1524] The building block may also

[1525] * Tri fluoromethyl sulfonic

[1526] be isolated as a mixture of

[1527] anhydride (CAS RN: 358-23-6) two regioisomers in relation

[1528] used as triflate source, 2,6- to the position of the double

[1529] ditert-butyl-4-methylpyridine

[1530] bond.

[1531] (CAS RN: 38222-83-2 ) used as base.

[1532]

[1533] Synthesis of chiral intermediates A

[1534] Synthesis of [(65)-6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2J / -pyran-4-yl1 5 trifluoromethanesulfonate Ala and [(67?)-6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2J / -pyran-4- yl] trifluoromethanesulfonate Alb

[1535] chiral SFC

[1536]

[1537] Starting from intermediate Al - step 1 [6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4- 10 yl] trifluoromethanesulfonate (8.75 g, 25.9 mmol, 1.0 equiv.), chiral SFC separation (Chiral Column CHIRALCEL OD-H, 250 mm x 5 mm, 5 pm, EtOH) delivered the title compounds [(65)- 6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2Z7-pyran-4-yl] trifluoromethanesulfonate Ala (3.13g, 36% yield, tR. 1.138 min, OD) as an orange oil and [(67?)-6-(l-cyclopropylpyrazol-4-yl)- 3,6-dihydro-2J / -pyran-4-yl] trifluoromethanesulfonate Alb (2.76g, 32% yield, tR. 1.879 min,) as 15 an orange oil.Synthesis of l-cyclopropyl-4-[(67?)-4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2J / -pyran-6-yl]pyrazole A17b

[1538]

[1539] T

[1540] z —

[1541] To a solution of [(67?)-6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2J / -pyran-4-yl]

[1542] / 0

[1543] trifluoromethanesulfonate Alb (1.00 g, 2.96 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) was added / ^ z

[1544] 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.31 g, 3.55 mmol, 1.2 equiv.), KOAc (0.871 g, 8.88 mmol, 3.00 equiv.) and Pd(dppf)Cl2.DCM (241 mg, 0.296 mmol, 10 mol%). The mixture was stirred for 1 h at 90 °C under N2. The reaction mixture was concentrated in vacuo. Purification by FCC (SiO2, Petroleum Ether / EtOAc gradient), followed by Y

[1545] chiral SFC separation chiral (Chiral Column CHIRALCEL OD-H, 250 mm x 5 mm, 5 pm, IPA +

[1546] V / /

[1547] 0.05% Diethylamine) delivered the title compound (799 mg, 71% yield, tR. 0.979 min) as a colorless oil. MS: m / z 373.2 [M+H]+, ESI pos.0\

[1548] z —

[1549] ZE

[1550] Table of morpholine intermediates A

[1551] Intermediate Name Structure CAS RN

[1552] A13 2-( 1 -methylpyrazol-4- 1375963- yl)morpholine 52-2

[1553] A14 2-(l-cyclopropylpyrazol-4- 1780917- yl)morpholine 09-0

[1554]

[1555] A14-TFA 2-(l-cyclopropylpyrazol-4- 3026327- Salt yl)morpholine;2,2,2- 21-6

[1556] trifluoroacetic acid

[1557]

[1558] Intermediate A15: 2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholine

[1559]

[1560] Step la: 4-iodo-l-tetrahydropyran-2-yl-pyrazole

[1561]

[1562] To a light yellow solution of 4-iodopyrazole (25.0 g, 129 mmol, 1.0 equiv.) in DCM (300 mL) were added TsOH (2.22 g, 12.9 mmol, 0.1 equiv.) and 3,4-dihydro-2H-pyran (21.7 g, 258 mmol, 2.0 equiv.). The reaction mixture was stirred for 12 h at 25 °C. The mixture was washed with water (300 mL) and then brine (300 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (30.0 g, 84% yield) as a colorless oil. MS: m / z 195.1 [M-C5H8O+H], ESI pos.

[1563] Step lb: 2-chloro-l-(l-tetrahydropyran-2-ylpyrazol-4-yl)ethanone

[1564]

[1565] O

[1566] Under inert N2 atmosphere, to a solution of 4-iodo-l-tetrahydropyran-2-yl-pyrazole (30.0 g, 108 mmol, 1.0 equiv.) in THF (300 mL) was added i-PrMgCl. LiCl in THF 1.3 M (124 mL, 162 mmol, 1.5 equiv.) at -70 °C. The mixture was stirred at -70 °C for 30 min. Then, a solution of 2-chloro-N-methoxy-N-methylacetamide (17.8 g, 129 mmol, 1.2 equiv.) in THF (50 mL) was added at -70°C and the mixture was stirred at 0 °C for 1.5 h. The reaction mixture was poured into sat. aq. NH4CI (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 3). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, petroleum ether / ethyl acetate gradient) delivered the title compound (26.0 g, 96% yield) as a light yellow oil. MS: m / z 145.0 [M+H-C5H8O], ESI pos.

[1567] Step 2: l-(benzylamino)propan-2-ol

[1568]

[1569] To a solution of benzylamine (25.5 mL, 233 mmol, 1.0 equiv.) in ACN (400 mL) were added propylene oxide (16.3 mL, 233 mmol, 1.0 equiv.) and Ca(OTf)2 (39.5 g, 117 mmol, 0.5 equiv.). The reaction was stirred at 20 °C for 12 h. The reaction was concentrated in vacuo. The residue was diluted with water (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over Na2SO4then concentrated in vacuo. Purification by prep-HPLC (Kromasil Eternity XT 250 x 80mm x 10um, H2O / ACN gradient + 0.05% NH4OH v / v) delivered the title compound (26.0 g, 67% yield) as a light yellow oil. MS: m / z 166.1 [M+H]+, ESI pos.

[1570] Step 3: 2-[benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethanone

[1571]

[1572] To a solution of 2-chloro-l-(l-tetrahydropyran-2-ylpyrazol-4-yl)ethanone (Intermediate 1 step 2 26.0 g, 114 mmol, 1.0 equiv.) in DMSO (250 mL) was added K2CO3(31.4 g, 227 mmol, 2.0 equiv.), KI (18.9 g, 114 mmol, 1.0 equiv.) and l-(benzylamino)propan-2-ol Intermediate 2 step 7; 18.8 g, 114 mmol, 1.0 equiv.). The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO4, and concentrated in vacuo. Purification by prep-MPLC (Spherical Cl 8, H2O / ACN gradient + 0.1% HCO2H), followed byadjustment of the compound-containing eluent fractions pH to 8 with NH3. H2O, and extraction with EtOAc (500 mL x 3) followed by washing the combined organic layers with brine (500 mL), drying over Na2SO4, filtering, and concentrating in vacuo delivered the title compound (28.0 g, 69% yield) as a light yellow oil. MS: m / z 358.2 [M+H]+, ESI pos.

[1573] Step 4: 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]amino]propan-2-ol

[1574]

[1575] To a solution of 2-[benzyl(2-hydroxypropyl)amino]-l-(l-tetrahydropyran-2-ylpyrazol-4-yl)ethanone (28.0 g, 78.3 mmol, 1.0 equiv.) in methanol (280 mL) at 0 °C was added NaBH4 (8.89 g, 235 mmol, 3.0 equiv.) in portions. The mixture was stirred at 0 °C for 1 h. The mixture was poured into saturated aqueous NH4CI (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the title compound (28g, 99% yield) as a light yellow oil. The compound was directly used in the next step without further characterization. MS: m / z 360.2 [M+H]+, ESI pos.

[1576] Step 5: 4-benzyl-2-methyl-6-(1H-pyrazol-4-yl)morpholine

[1577]

[1578] To a solution of l-[benzyl-[2-hydroxy-2-(l-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]amino]propan-2-ol (28.0 g, 77.9 mmol, 1.0 equiv.) in 1,4-dioxane (112 mL) was added H2O (56 mL) and HC1 (56.0 mL, 672 mmol, 8.63 equiv.). The reaction mixture was stirred at 110 °C for 2 h. The mixture was cooled to RT and the pH was adjusted to 8 with saturated aqueous NaHCCL. The aqueous layer was extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (500 mL x 3), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by prep-MPLC (Spherical C18, H2O / ACN gradient + 0.1% HCO2H) followed byextraction with EtOAc (500 mL x 3) delivered the title compound (16.0 g, 80% yield) as a light yellow oil. MS: m / z 258.1 [M+H]+, ESI pos.

[1579] Step 6: 4-benzyl-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholine

[1580]

[1581] To a mixture of 4-benzyl-2-methyl-6-(1H-pyrazol-4-yl)morpholine (16.0 g, 62.2 mmol, 1.0 equiv.) in 1,4-dioxane (250 mL) was added cyclopropylboronic acid (10.7 g, 124 mmol, 2.0 equiv.), Pyridine (12.6 mL, 155 mmol, 2.5 equiv.), DMAP (30.4 g, 249 mmol, 4.0 equiv.) and Cu(OAc)2 (11.3 g, 62.2 mmol, 1.0 equiv.). The resulting mixture was bubbled with O2 for 1 min and then stirred at 100 °C for 16 h under an O2 atmosphere at 103421 Pa (15 psi). The mixture was diluted with EtOAc (250 mL) and filtered through a pad of celite. The filtrate was poured into water (1000 mL) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, and concentrated in vacuo. Purification by prep-MPLC (Spherical C18, H2O / ACN gradient + 0.1% HCO2H) followed by extraction with EtOAc (300 mL x 3) delivered the title compound (15.0 g, 81% yield) as a light yellow oil. MS: m / z 298.1 [M+H]+, ESI pos.

[1582] Step 7: 2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine

[1583]

[1584] To a suspension of 4-benzyl-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (15.0 g, 50.4 mmol, 1.0 equiv.) in MeOH (200 mL) was added Pd / C (5.37 g, 5.04 mmol, 0.100 equiv.) and the reaction mixture was degassed with H2 three times. The reaction mixture was stirred at 50 °C for 12 h under H2 (15 Psi). The reaction mixture was cooled to RT, filtered through a pad of celite, and the filtrate was concentrated in vacuo to obtain the title compound (10.0 g, 96% yield) as a light yellow oil. MS: m / z 208.2 [M+H]+, ESI pos.Synthesis of rac-(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine A15a and rac-(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine A15b

[1585] AND Enantiomer AND Enantiomer

[1586] chiral SFC

[1587] 2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine A15 was separated by prep-NPLC (column Welch Ultimate XB-CN, 5 um, 250 x 70 mm, Hexane-EtOH+ 0.1% NH4OH). rac-(2R,6S)-2-(1-

[1588]

[1589]

[1590] -4-yl)-6-methyl-morpholine A15a was collected as a light yellow oil (tR = 0.324) MS: m / z 208.1 [M+H]+, ESI pos. 'H NMR (400 MHz, CHL0R0F0RM-7) 5 ppm 0.95 - 1.02 (m, 2 H) 1.06 - 1.14 (m, 2 H) 1.18 (d, J=6.36 Hz, 3 H) 2.53 (dd,.7=12.10, 10.39 Hz, 1 H) 2.72 -2.83 (m, 1 H) 2.90 (brd, 7=11.98 Hz, 1 H) 3.01 (dd, 7=12.41, 1.90 Hz, 1 H) 3.54 (tt, 7=7.34, 3.79 Hz, 1 H) 3.65 - 3.79 (m, 1 H) 4.49 (dd, 7=10.58, 2.38 Hz, 1 H) 7.45 (d, 7=4.16 Hz, 2 H).

[1591] Intermediate A16: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-4-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole

[1592] F

[1593] Step 1: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyrazole

[1594]

[1595] To a solution of (3-fluoro-l-bicyclo[l.l.l]pentanyl)hydrazine;dihydrochloride (2.00 g, 10.6 mmol, 1.0 equiv.) in EtOH (20 mL) were added 1,1,3,3-tetramethoxypropane (1.74 g, 10.6 mmol, 1.0 equiv.) and HC1 (2.64 mL, 31.7 mmol, 3.0 equiv.). The mixture was stirred at 80 °C for 2 h. The reaction mixture was poured into water (50 mL) and extracted with DCM (40 mL x 3). The combined organic layers were dried over Na2SO4then concentrated in vacuo to obtain the title compound (1.52 g, 93% yield) as a brown oil. MS: m / z 153.2 [M+H], ESI pos.

[1596]

[1597] To a yellow solution of 1 -(3 -fluoro- l-bicyclo[l.l.l]pentanyl)pyrazole (1.52 g, 10.0 mmol, 1.0 equiv.) in AcOH (15 mL) was added NIS (1.35 g, 6.00 mmol, 0.6 equiv.). The mixture was stirred at 80 °C for 5 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, petroleum ether / ethyl acetate gradient) delivered the title compound (2.27 g, 78% yield) as a brown oil. MS: m / z 279.1 [M+H]+, ESI pos.

[1598] Step 3: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-4-vinyl-pyrazole

[1599]

[1600] To a solution of 1 -(3 -fluoro- l-bicyclo[l.l.l]pentanyl)-4-iodo-pyrazole (2.27 g, 8.16 mmol, 1.0 equiv.) in 1,4-di oxane (25 mL) and water (2.5 mL) were added potassium vinyltrifluoroborate (1.64 g, 12.2 mmol, 1.5 equiv.), Cs2CO3(5.31 g, 16.3 mmol, 2.0 equiv.) and Pd(dppf)C12. DCM (666 mg, 0.820 mmol, 0.1 equiv.). The mixture was stirred at 90 °C for 2 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (953 mg, 56% yield) as a light yellow oil. MS: m / z 179.1 [M+H]+, ESI pos.

[1601] Step 4: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyrazole-4-carbaldehyde

[1602]

[1603] OA solution of 1 -(3 -fluoro- l-bicyclo[l.l.l]pentanyl)-4-vinyl-pyrazole (753 mg, 4.23 mmol, 1.0 equiv.) in DCM (20 mL) was stirred at -75 °C for 0.5 h under ozone. Polymeric-PPh3 (4.31 g, 12.7 mmol, 3.0 equiv.) was added at -75 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo. Purification by FCC (SiO2, petroleum ether / ethyl acetate gradient) delivered the title compound (417 mg, 55% yield) as a white solid. 'HNMR (400 MHz, CHLOROFORM-d) 5 = 9.89 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 2.72 (d, J = 2.0 Hz, 6H)

[1604] Step 5: [6-[1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate

[1605]

[1606] To a solution of 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyrazole-4-carbaldehyde (410 mg, 2.28 mmol, 1.0 equiv.) and 3-butyn-l-ol (239 mg, 3.41 mmol, 1.5 equiv.) in DCM (41 mL) was added trifluoromethane sulfonic acid (0.600 mL, 6.83 mmol, 3.0 equiv.) at -10 °C. The mixture was stirred at -10 °C for 2 h. The reaction mixture was poured into NaHCCL solution (50 mL) and extracted with DCM (50 mL x 3). The organic layers were washed with brine (20 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by RP-HPLC (NH3. H2O) followed by lyophilization delivered the title compound (443 mg, 51% yield) as a yellow oil. MS: m / z 383.1 [M+H]+, ESI pos.

[1607]

[1608] Step 6: 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-4-[4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole

[1609]

[1610] To a solution of [6-[l-(3-fluoro-l-bicyclo[l.l.l]pentanyl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (390 mg, 1.02 mmol, 1.0 equiv.) in 1,4-dioxane (8 mL) was added 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (448 mg, 1.22 mmol, 1.2 equiv.), KOAc (300 mg, 3.06 mmol, 3.0 equiv.) and Pd(dppf)C12. DCM (83.2 mg, 0.100 mmol, 10 mol%). The mixture was stirred at 90 °C for 1 h. The mixture was poured into water (30 mL) and extracted with EtOAc (50 mL x 3). The organic layers were washed with brine (50 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by prep-HPLC (Phenomenex luna Cl 8 150 x 40 mm 15 pm; mobile phase, water / ACN gradient + 0.225% HCO2H) followed by lyophilization delivered the title compound (210 mg, 49% yield) as a yellow oil. MS: m / z 417.2 [M+H]+, ESI pos.

[1611] Intermediates B

[1612] Intermediate B1: 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-one

[1613] ci

[1614] ifj

[1615] BrXX / -

[1616]

[1617] o

[1618] Step 1: 8-bromo-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-one

[1619]

[1620] 8-Bromo-2H-[l,2,4]triazolo[4,3-a]pyridin-3-one (CAS RN: 1207970-25-9; 390 mg, 1.82 mmol, 1.0 equiv.) was dissolved in Acetone (8.77 mL). lodomethane (1.14 mL, 18.2 mmol, 10 equiv.) and K2CO3(504 mg, 3.64 mmol, 2.0 equiv.) were added at RT. The reaction mixture was stirred for 3h at 40 °C. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, DCM / MeOH gradient) delivered the title compound (341 mg, 82% yield) as a light brown solid. MS m / z: 230.0 [M+H]+, ESI pos

[1621] Step 2: 8-(4-chloro-2-fluoro-phenyl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-one

[1622]

[1623] 8-bromo-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3-one (340 mg, 1.49 mmol, 1.0 equiv.) was dissolved in 1,4-Dioxane (9.52 mL). (4-chloro-2-fluoro-phenyl)boronic acid (312 mg, 1.79 mmol, 1.2 equiv.) and K3PO4 (949 mg, 4.47 mmol, 3.0 equiv.) in water (1.36 mL) were added atRT. The mixture was degassed via Argon bubbling and PdC12(dtbpf) (97.2 mg, 149 pmol, 10 mol%) was added at RT. The mixture was stirred for 16 h at 60 °C. The reaction mixture was diluted with water and extracted with EtOAc. The reunited organic layers were washed with water and brine, dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, Heptane / EtOAc gradient) delivered the title compound (383 mg, 93% yield) as a light yellow solid. MS m / z: 278.1 [M+H]+, ESI pos

[1624] Step 3: 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-one

[1625] ci

[1626]

[1627] 8-(4-chloro-2-fluoro-phenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3-one (310 mg, 1.12 mmol, 1.0 equiv.) and bis(pinacolato)diboron (340 mg, 1.34 mmol, 1.2 equiv.) were suspended in Heptane (8 mL) at RT. The mixture was degassed via Argon bubbling before 3,4,7,8-tetramethyl-1,10-phenanthroline (26.4 mg, 112 pmol, 0.100 equiv.) and [Ir(OMe)(l,5-cod)]2 (37.0 mg, 56 pmol, 5.0 mol%) were added. The reaction mixture was stirred for 16 h at 100 °C. The reaction mixture was diluted with water and extracted with EtOAc. The organic layers were dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, Heptane / EtOAc, then DCM / MeOH gradient) delivered the title compound (165 mg, 24% yield) as a light yellow solid. MS m / z: 322.1 [M-BPin+H]+, ESI pos

[1628] Step 4: 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-one

[1629]

[1630] 8-(4-chloro-2-fluoro-phenyl)-2-methyl -6-(4,4, 5, 5 -tetramethyl- 1, 3,2-dioxab orolan-2-yl)-[l,2,4]triazolo[4,3-a]pyridin-3-one (140 mg, 347 pmol, 1.0 equiv.) was dissolved in MeOH (1.2 mL) and water (1.2 mL). CuBr2 (232 mg, 1.04 mmol, 3.0 equiv.) were added at RT. The mixture was stirred for 18 h at 85 °C. The reaction mixture was diluted with water and extracted with EtOAc. The reunited organic layers were dried over MgSO4and the solvent removed under reduced pressure. Purification by FCC (SiCh, Heptane / EtOAc) delivered the title compound (69.0 mg, 47% yield) as a yellow solid. MS m / z: 358.0[M+H]+, ESI pos

[1631] Intermediate B2: 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one

[1632]

[1633] Step 1: fert-butyl A-r(3-chloropyrazin-2-yl)amino1carbamate

[1634]

[1635] To a solution of (3-chloropyrazin-2-yl)hydrazine (CAS RN: 63286-28-2; 30.0 g, 208 mmol, 1.0 equiv.) in THF (300 mL) was added TEA (34.8 mL, 249 mmol, 1.2 equiv.). di- / c / 7-butyl di carb onate (54.4 g, 249 mmol, 1.2 equiv.) at 0 °C. The reaction was stirred at 25 °C for 12 h under N2. The crude was concentrated under reduced pressure, water (200 mL) was added and the acqueous phase extracted with EtOAc (300 mL x 3). The reunited organic layers were dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (44.0 g, 87% yield) as a yellow solid. MS m / z: 189.1 [M+H]+, ESI pos

[1636]

[1637] -(4-chloro-2-fluoro- in-2-

[1638]

[1639] To a solution of 4-chloro-2-fluorophenylboronic acid (CAS RN: 160591-91-3; 23.5 g, 135 mmol, 1.5 equiv.) in 1,4-Dioxane (250 mL) and water (25 mL) was added tert-butyl N-[(3-chloropyrazin-2-yl)amino]carbamate (22.0 g, 89.9 mmol, 1.0 equiv.), Na2CC>3 (28.6 g, 270 mmol, 3.0 equiv.) and PdCl2(PPh3)2(3.16 g, 4.50 mmol, 5.0 mol%). The reaction was then degassed with three cycles of vacuum for and the mixture was stirred at 90 °C for 12 h under N2atmosphere. The crude was concentrated under reduced pressure, water (200 mL) was added and the aqueous phase extracted with EtOAc (300 mL x 3). The reunited organic layers were dried over Na2SO4 and the solvent removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (22.0 g, 72% yield) as a yellow solid. MS m / z: 339.1 [M+H]+, ESI pos

[1640] Step 3: tert-butyl N-[[5-bromo-3-(4-chloro-2-fluoro-phenyl)pyrazin-2-yl]amino]carbamate

[1641] ci

[1642]

[1643] To a solution of tert-butyl N-[[3-(4-chloro-2-fluoro-phenyl)pyrazin-2-yl]amino]carbamate (12.0 g, 35.4 mmol, 1.0 equiv.) in CHCh (120 mL) was added NBS (7.57 g, 42.5 mmol, 1.2 equiv.) at 0 °C. The reaction was then stirred at 20 °C for 12 h. To the reaction mixture was added H2O (100 mL) and extracted with DCM (100 mL x 2). The reunited organic layers were washed with brine, dried over anhydrous Na2SO4 and the solvent removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (6.00 g, 41% yield) as a yellow oil. MS m / z: 419.1 [M+H]+, ESI pos

[1644] Step 4: r5-bromo-3-(4-chloro-2-fluoro-phenyl)pyrazin-2-yl1hydrazine

[1645] ci

[1646]

[1647] To a solution of tert-butyl N-[[5-bromo-3-(4-chloro-2-fluoro-phenyl)pyrazin-2-yl]amino]carbamate (7.00 g, 16.8 mmol, 1.0 equiv.) in DCM (10 mL) was added 2 M HC1 in 1,4-Dioxane (100.0 mL, 200.0 mmol, 11.9 equiv.). The reaction was stirred at 20 °C for 2 h. The mixture was concentrated in vacuo, then the residue was poured into NaHCO3sat. sol. (100 mL) and extracted with EtOAc (100 mL x 3). The reunited organic layers were washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give the title compound (4.50 g, 85% yield) as a red solid. The compound was used into the next step without further purification. MS m / z: 319.0 [M+H]+, ESI pos

[1648] Step 5: 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one

[1649] ci

[1650]

[1651] To a solution of [5-bromo-3-(4-chloro-2-fluoro-phenyl)pyrazin-2-yl]hydrazine (4.5 g, 14.2 mmol, 1.0 equiv.) and TEA (2.37 mL, 17.0 mmol, 1.2 equiv.) in THF (50 mL), was added dropwise 4-nitrophenyl chloroformate (3.14 g, 15.6 mmol, 1.1 equiv.) in THF (10 mL) at 0 °C. The reaction was stirred at 25 °C for 2 h under N2. The mixture was then filtered and the cake further dried to deliver the title compound (5.00 g, 14.6 mmol, over quant, yield) as a yellow solid. The compound was used into the next step without further purification. MS m / z: 345.0 [M+H]+, ESI pos

[1652] Step 6: 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one

[1653]

[1654] A mixture of 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one (2.00 g, 5.82 mmol, 1.0 equiv), Cu(OAc)2 (1.16 g, 6.40 mmol, 1.1 equiv.), cyclopropylboronic acid (1.00 mg, 11.6 mmol, 2.0 equiv.), Na2CO3(1.23 mg, 11.6 mmol, 2.0 equiv.) and 2,2’ -bipyridine (1.00 mg, 6.40 mmol, 1.1 equiv.) was suspended in DCE (30 mL). The resulting mixture was stirred at 70 °C for 12 h under O2 (15 Psi). The reaction mixture was poured into water (200 mL) and extracted with EtOAc (150 mL x 3). The organic phase was washed with brine (250 mL) anddried over Na2SO4, then the solvent was removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (1.2 g, 54% yield) as a light yellow solid. MS m / z: 382.9 [M+H]+, ESI pos.

[1655] Intermediate B3: 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2-methyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one

[1656] from Intermediate B2 5 6-bromo-8-(4-chloro-2-\ -2H-

[1657]

[1658] ,2, ',3-< in-3-one.

[1659] To a solution of 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one (500 mg, 1.46 mmol, 1.0 equiv.) and K2CO3(402 mg, 2.91 mmol, 2.0 equiv.) in DMF (10 mL) was added iodomethane (181 pL, 2.91 mmol, 2.0 equiv.) at 0 °C. The reaction was stirred at 25 °C for 2 h under N2. The reaction mixture was poured into water (50 ml) and extracted with EtO Ac (25 mL x 3). The reunited organic layers were washed with brine (25 mL) dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (400 mg, 1.12 mmol, 77% yield) as a light yellow solid. MS m / z: 356.8 [M+H]+, ESI pos

[1660] Intermediate B4: 6-bromo-2-cyclopropyl-8-(2,4-difluorophenyl)-[1,2,4]triazolo[4,3-a]pyrazin-3-one

[1661] N<^N. I I N

[1662] N^ /

[1663]

[1664] Intermediate B2 - 1 tert-. in-2-yl

[1665] Step 1: tert-butyl N-113-(2,4-difluorophenyl)pyrazin-2-yl1amino1carbamate

[1666]

[1667] To a solution of 2,4-difluorophenylboronic acid (CAS RN: 144025-03-6; 968 mg, 6.13 mmol, 1.5 equiv.) in 1,4-Dioxane (20 mL) and water (2 mL) was added tert-butyl N-[(3-chloropyrazin-2-yl)amino]carbamate (1.00 g, 4.09 mmol, 1.0 equiv.), Na2CO3(1.30 g, 12.2 mmol, 3.0 equiv.) and PdCl2(PPh3)2(143 mg, 0.200 mmol, 5.0 mol%). The reaction was then degassed with three cycles of vacuum / N2for and the mixture was stirred at 90 °C for 12 h under N2 atmosphere. The crude was concentrated under reduced pressure, water (200 mL) was added and the aqueous phase extracted with EtOAc (300 mL x 3). The reunited organic layers were dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (1.00 g, 76% yield) as a yellow solid. MS m / z: 267.2 [M-tBu+H]+, ESI pos

[1668] N

[1669]

[1670] To a solution of tert-butyl N-[[3-(2,4-difluorophenyl)pyrazin-2-yl]amino]carbamate (1.00 g, 3.10 mmol, 1.0 equiv.) in CHCI3 (15 mL) was added NBS (663 mg, 3.72 mmol, 1.2 equiv.) at 0 °C. The reaction was then stirred at 10 °C for 12 h. To the reaction mixture was added H2O (100 mL) and extracted with DCM (100 mL x 2). The reunited organic layers were washed with brine, dried over anhydrous Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (400 mg, 32% yield) as a yellow solid. MS m / z: 345.1 [M-tBu+H]+, ESI pos

[1671] 3: I5-bromo-3-(2,4-di

[1672] H

[1673] N

[1674]

[1675] To a solution of tert-butyl N-[[5-bromo-3-(2,4-difluorophenyl)pyrazin-2-yl]amino]carbamate (400 mg, 1.00 mmol, 1.0 equiv.) in DCM (1 mL) was added 2 M HC1 in 1,4-Dioxane (5.00 mL, 10.0 mmol, 10 equiv.). The reaction was stirred at 20 °C for 4 h. The mixture was concentrated in vacuo, then the residue was poured into NaHCO3 sat. sol. (100 mL) and extracted with EtOAc (100 mL x 3). The reunited organic layers were washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to give the title compound (270 mg, 90% yield) as a grey solid. The compound was used into the next step without further purification. MS m / z: 303.0 [M+H]+, ESI pos

[1676] Step 4: 6-bromo-8-(2,4-difluorophenyl)-2H-ri,2,41triazolor4,3-a1pyrazin-3-one

[1677]

[1678] To a solution of [5-bromo-3-(2,4-difluorophenyl)pyrazin-2-yl]hydrazine (270 mg, 0.900 mmol, 1.0 equiv.) TEA (0.150 mL, 1.08 mmol, 1.2 equiv.) in THF (4 mL) was added dropwise 4-nitrophenyl chloroformate (199 mg, 0.990 mmol, 1.1 equiv.) in THF (2 mL) at 0 °C. The reaction was stirred at 20 °C for 2 h under N2. The mixture was then poured in water (50 mL) and extracted with DCM (30 mL x 3). The reunited organic layers were dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (5.00 g, 14.6 mmol, over quant, yield) as a yellow solid. MS m / z: 327.0 [M+H]+, ESI pos

[1679] Step 5: 6-bromo-2-cyclopropyl-8-(2,4-difluorophenyl)-rL2,41triazolol4,3-a1pyrazin-3-one

[1680] F

[1681]

[1682] O

[1683] A mixture of 6-bromo-8-(2,4-difluorophenyl)-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one (200 mg, 0.610 mmol, 1.0 equiv.), Cu(OAc)2 (122 mg, 0.670 mmol, 1.1 equiv), cyclopropylboronic acid (105 mg, 1.22 mmol, 2.0 equiv), Na2CO3 (130 mg, 1.22 mmol, 2.0 equiv.) and 2,2’ -bipyridine (105 mg, 0.670 mmol, 1.1 equiv.) was suspended in DCE (5 mL). The resulting mixture was stirred at 70 °C for 12 h under O2 (15 Psi). The reaction mixture was poured into water (200 mL) andextracted with EtOAc (150 mL x 3). The organic layer was washed with brine (250 mL) and dried over Na2SO4, then the solvent was removed under reduced pressure. Purification by FCC (SiCh, PE / EtOAc gradient) delivered the title compound (140.0 mg, 62% yield) as a light yellow solid. MS m / z: 368.9 [M+H]+, ESI pos.

[1684] Intermediate B5: 6-bromo-8-(2.4-difluorophenvl)-2-methyl-rL2.41triazolor4.3-a1pyrazin-3-one

[1685]

[1686] Starting from Intermediate B4 - Step 4 6-bromo-8-(2,4-difluorophenyl)-2H-[l,2,41triazolo[4,3-a]pyrazin-3-one

[1687] To a solution of 6-bromo-8-(2,4-difluorophenyl)-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one (1.00 g, 3.06 mmol, 1.0 equiv.) in DMF (10 mL) were added K2CO3(845 mg, 6.11 mmol, 2.0 equiv.) and iodomethane (0.590 mL, 9.17 mmol, 3.0 equiv.). The reaction mixture was stirred for 2 h at 20 °C. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (20 mL). The organic layer was dried over Na2SO4and concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (1.00 g, 2.93 mmol, 96% yield) as a yellow solid. MS: m / z 341.1; 343.1 [M+H]+, ESI pos.

[1688] Alternative synthesis of intermediates B4

[1689] As described in general scheme 6, intermediates B4 and B5 can be accessed in an alternative synthesis sequence described below in the forward sense.

[1690] Intermediate B4: 6-bromo-2-cvclopropyl-8-(2.4-difluorophenyl)-rL2.41triazolor4.3-a1pyrazin-3 -one

[1691]

[1692] Step 1 (3-chloropyrazin-2-yl)hydrazine

[1693]

[1694] To a solution of 2,3-dichloropyrazine (20.0 g, 134 mmol, 1.0 equiv.) and TEA (27.2 g, 269 mmol, 2.0 equiv.) in ethanol (100 mL) was added hydrazine hydrate (10.6 g, 201 mmol, 1.5 equiv.) at 25 °C. The mixture was stirred at 80 °C for 10 h. The reaction mixture was cooled at 0 °C. The resulting mixture was filtered and the resulting solid was washed with ice EtOH (50 mL). The crude product was triturated with MTBE (10 V) at 25 °C for 30 min to obtain the title compound (16.0 g, 78% yield) as a yellow solid.

[1695] Step 2: 8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one

[1696] Cl

[1697]

[1698] O

[1699] To a solution of (3-chloropyrazin-2-yl)hydrazine (10.0 g, 69.18 mmol, 1.0 equiv.) in THF (400 mL) was added TEA (11.54 mL, 83.01 mmol, 1.2 equiv.). 4-Nitrophenyl chloroformate (14.64 g, 72.63 mmol, 1.05 equiv.) in THF (100 mL) was added at 20 °C and the mixture was stirred for 5 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo. DCM (50 mL) was added. The mixture was filtered a second time. The solid was triturated with DCMZEtOAc (100 mL / 50 mL) for 2 h. The mixture was filtered. The cake was dried in vacuo to obtain the title compound (16.0 g, 93.8 mmol, 85.4% yield) as a yellow solid. MS: m / z 171.2 [M+H]+, ESI pos.

[1700] Step 3: 8-chloro-2-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrazin-3-oneCl

[1701]

[1702] O

[1703] To a solution of 8-chloro-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one (275 g, 1610 mmol, 1.0 equiv.) in DCE (13.75 L) were added cyclopropylboronic acid (277 g, 3220 mmol, 2.0 equiv.), Cu(OAc)2 (322 g, 1770 mmol, 1.1 equiv.), 2,2’ -Bipyridine (277 g, 1774 mmol, 1.1 equiv.) andNa2CO3(342 g, 3225 mmol, 2.0 equiv.). The resulting mixture was bubbled with O2 for 1 min and then stirred at 70 °C for 5 h under O2 atmosphere (15 Psi). The reaction mixture was filtered. The filtrate was concentrated in vacuo. Purification by FCC (Si O2, petroleum ether / EtOAc gradient) delivered the title compound (187 g, 44% yield) as a yellow solid. MS: m / z 211.0 [M+H]+, ESI pos.

[1704] Step 4: 6-bromo-8-chloro-2-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one

[1705] Cl

[1706]

[1707] O

[1708] To a solution of 8-chloro-2-cyclopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one (31.0 g, 147 mmol, 1.0 equiv.) in DCE (350 mL) was added silver trifluoromethanesulfonate (5.67 g, 22.1 mmol, 0.15 equiv.) and NBS (52.4 g, 294 mmol, 2.0 equiv.) at 20 °C. The reaction was heated to 80 °C and stirred for 5 h. The reaction mixture was poured into NaHCO3solution (1 L) and extracted with DCM (1 L x 2). The combined organic layers were washed with brine (1 L). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / DCM / EtOAc gradient) and concentration in vacuo delivered a brown solid. The solid was triturated in PE (60 mL) and EtOAc (60 mL) for 1 h. The solids were collected by filtration, washed with PE and EtOAc, and concentrated in vacuo to obtain the title compound as a crude. The mixture was not purified or quantified and was directly used in the next step. MS: m / z 289.0; 291.0 [M+H]+, ESI pos.

[1709]

[1710] 5: 6-bromo-2-cvclopropvl-8-(2,4-di |-F1,2, ■ 3-; in-3-one Intermediate B4

[1711]

[1712] To a solution of 6-bromo-8-chloro-2-cyclopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one (1.00 g, 2.94 mmol, 1.0 equiv.) in 1,4-Dioxane (10 mL) and Water (1 mL) were added 2,4- difluorobenzeneboronic acid (460 mg, 2.94 mmol, 1.0 equiv.), Cs2CO3(2.39 g, 7.34 mmol, 2.5 equiv.) and Pd(dppf)C12. DCM (140 mg, 0.180 mmol, 6.0 mol%.) at 20 °C. The reaction mixture was purged with N2 for 3 times and heated to 70 °C stirred for 1.5 h. Further equivalents of 2,4- difluorobenzeneboronic acid (121 mg, 0.760 mmol, 0.26 equiv.) were added and the mixture was stirred at 70 °C for 30 min. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) was followed by trituration with ACN (5 mL) for 5 min. The resulting mixture was filtered. The cake was collected and further dried in vacuo to obtain the title compound (675 mg, 63% yield) as a yellow solid. MS: m / z 367.0; 369.0 [M+H]+, ESI pos.

[1713] The Intermediates in the following table were generated in analogy to Intermediate B4 - alternative synthesis, following the same order of steps as described and starting from Intermediate B4 - alternative synthesis - Step 4. A skilled person will be aware that variants and / or alternative procedures for hydrazine addition, annulation, bromination, cross coupling and Chan-Lam steps may be applied. For example, in some cases, the reagents’ equivalents and the duration of the reaction [h] were modified or the reaction was conducted at a different temperature [°C], More specifically, boronic acids may be replaced by boronic ester reagents where relevant due to commercial availability of the reagent. Also, in some cases, reverse phase (RP) or normal phase FCC or HPLC were used as purification methods instead of or in addition to FCC. Any relevant deviation from the standard conditions will be marked with * in the relevant entries.

[1714] MS

[1715] Int. Boronic Acid / Ester Structure Systematic Name (ESI): No. Source

[1716] m / z

[1717]

[1718] B6 5 -n 6-bromo-2-cyclopropyl-8- 2-(4,4- 370.9 (4,4-difluorocyclohexen- 1 - difluorocyclohex- 1 - [M+H]+, X tr yl)-[l,2,4]triazolo[4,3- en-l-yl)-4, 4,5,5- ESI pos a]pyrazin-3-one tetram ethyl- 1,3,2- dioxaborolane CAS A RN: 1227068-84-9

[1719] (*0.95 equiv.), *4.0 equiv. Cs2CO3, 14 mol%,

[1720] Pd(dppf)Cl2. DCM, 50

[1721] °C 2.5 h

[1722] B7 6-bromo-2-cyclopropyl-8- 2-[4-(difluoromethyl)- 399.3

[1723] [4-(difluoromethyl)-2- 2-fluoro-phenyl]- [M+H]+, fluoro-phenyl]- 4,4, 5, 5 -tetramethyl- ESI pos [l,2,4]triazolo[4,3- 1,3,2-dioxaborolane CAS RN: 2410032-62- a]pyrazin-3-one X 9

[1724] (*1.3 equiv.), *3.0 m m equiv. Cs2CO3, 20 mol%,

[1725] Pd(dppf)Cl2. DCM, 85

[1726] °C 45 min

[1727] B8 6-bromo-2-cyclopropyl-8- (2-fluoro-4- 379.3 (2-fluoro-4-methoxy- methoxyphenyl)boroni [M+H]+, phenyl)-[ 1,2,4]triazolo[4,3 - c acid CAS RN: ESI pos 162101-31-7 a]pyrazin-3-one

[1728] (*1.3 equiv.), *3.0 equiv. Cs2CO3, 20 mol%,

[1729]

[1730] Pd(dppf)Cl2. DCM, 85

[1731] °C 45 min

[1732]

[1733] Furthermore, 6-bromo-8-chloro-2-cyclopropyl-rL2,4]triazolor4,3-a]pyrazin-3-one Intermediate B4 - alternative synthesis - Step 4 may be further converted to a di-bromo intermediate, which may be then employed in the following Suzuki cross couplings towards Intermediate B4.

[1734] Step 1: 6,8-dibromo-2-cyclopropyl-ri,2,41triazolc>r4,3-a1pyrazin-3-one

[1735] Br

[1736]

[1737] O

[1738] Starting from Intermediate B4 - alternative synthesis - Step 4.

[1739] A mixture of 6-bromo-8-chloro-2-cyclopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one (22.0 g, 76.0 mmol, 1.0 equiv.) and TMSBr (40.11 mL, 304 mmol, 4.0 equiv.) in ACN (300 mL) was stirred for 16 h at 80 °C. The reaction mixture was quenched with half-saturated aq. NaHCCL (500 mL) and extracted with EtOAc (300 mL) and DCM (300 mL x 3). The combined organic layers were washed with brine (400 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by FCC (SiO2, PE / DCM / EtOAc gradient) delivered the title compound (24.2 g, 95% yield) as a yellow solid. MS: m / z 333.0; 335.0 [M+H]+, ESI+

[1740] Step 2: 6-bromo-2-cyclopropyl-8-(2,4-difluorophenyl)-rL2,41triazolor4,3-a]pyrazin-3-one Intermediate B4

[1741]

[1742] OA mixture of 6,8-dibromo-2-cyclopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one (1.00 g, 2.99 mmol, 1.0 equiv.), 2,4-difluorobenzeneboronic acid (567 mg, 3.59 mmol, 1.2 equiv.), Cs2CO3(2.93 g, 8.98 mmol, 3.0 equiv.), and Pd(dppf)C12. DCM (245 mg, 0.300 mmol, 10 mol%) in 1,4-Dioxane (10 mL) and Water (1 mL) was stirred for 16 h at 25 °C. The reaction mixture was poured into 5 water (20 mL) and extracted with DCM (20 mL x 3). The organic layers were washed with brine A

[1743] (30 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (791 mg, 72% yield) as a yellow solid. MS: m / z 367.0; 369.0 [M+H]+, ESI pos.

[1744] The Intermediates in the following table were generated in analogy to Intermediate B4 - 10 alternative synthesis, following the same order of steps as described and starting from Intermediate B4 - alternative synthesis - Step 4 followed by the bromination step. A skilled person will be aware that variants and / or alternative procedures for hydrazine addition, annulation, bromination, cross coupling and Chan-Lam steps may be applied. For example, in some cases, the reagents’ equivalents and the duration of the reaction [h] were modified, or the reaction was 15 conducted at a different temperature [°C], More specifically, boronic acids may be replaced by boronic ester reagents where relevant due to commercial availability of the reagent. Also, in some cases, reverse phase (RP) or normal phase FCC or HPLC were used as purification methods instead of or in addition to FCC. Any relevant deviation from the standard conditions will be marked with * in the relevant entries.

[1745] Int. Boronic Acid / Ester

[1746] Structure Systematic Name MS (ESI): m / z No. Source

[1747] B9 6-bromo-8-(4-chloro-2,6- 2-(4-chloro-2,6- 401.2; 403.2 difluoro-phenyl)-2- difluorophenyl)-4,4, 5,5- [M+H]+, ESI cyclopropyl- tetramethyl- 1,3,2- pos [l,2,4]triazolo[4,3- dioxaborolane CAS RN:

[1748] a]pyrazin-3-one 1165935-84-1

[1749] *1.0 equiv., *ovemight at

[1750] RT.

[1751]

[1752] B26 F 6-bromo-2-cyclopropyl- 4,4,5,5-tetramethyl-2- 387.1 [M+H]+,

[1753] 8-(2,4,6-trifluorophenyl)- (2,4,6-trifluorophenyl)- ESI pos [l,2,4]triazolo[4,3- 1,3,2-dioxaborolane CAS

[1754] F^ JT^JLV

[1755] a]pyrazin-3-one RN: 325143-04-2

[1756] *1.1 equiv., 3.0 equiv.

[1757] Br

[1758] 0 K2CO3*70 °C for 3h.

[1759] B27 F 6-bromo-2-cyclopropyl- 2-(4-Fluoro- 1 -cyclohexen- 353.3 [M+H]+,

[1760] 8-(4-fluorocyclohexen- 1 - l-yl)-4,4,5,5-tetramethyl- ESI pos yl)-[l,2,4]triazolo[4,3- 1,3,2-dioxaborolane CAS

[1761] a]pyrazin-3-one RN: 1356111-12-0

[1762] *1.1 equiv., 2.0 equiv.

[1763] Br

[1764] 0 Cs2CO3, 20 mol%

[1765] Pd(dppf)Cl2. DCM *70 °C

[1766] for 30 min.

[1767]

[1768] Alternative synthesis of intermediates B5

[1769] As described in general scheme 6, intermediates B4 and B5 can be accessed in an alternative synthesis sequence described below in the forward sense.

[1770] 5 Intermediate B5: 6-bromo-8-(2.4-difluorophenvl)-2-methvl-ri.2.41triazolor4.3-a1pvrazin-3-one

[1771] F

[1772]

[1773] O

[1774] Starting from Intermediate B4 -Step 2: 8-chloro-2J -rE2,4]triazolol4,3-a]pyrazin-3-one

[1775] Step 1: 8-chloro-2-rnethyl-rE2,4]triazolol4,3-a]pyrazin-3-oneCl

[1776]

[1777] o

[1778] A mixture of 8-chloro-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one (5.00 g, 29.3 mmol, 1.00 equiv.), K2CO3(8.10 g, 58.6 mmol, 2.00 equiv.), and Mel (2.19 mL, 35.2 mmol, 1.20 equiv.) in DMF (80 mL) was stirred for 4 h at 20 °C. The reaction mixture was added into water (100 mL) under N2 and extracted with EtOAc (80 mL x 6). The organic layer was dried over Na2SO4then concentrated in vacuo to obtain the title compound (4.30 g, 79% yield) as a yellow solid. MS: m / z 185.1 [M+H]+, ESI pos. The product was used in the next step without further purification.

[1779] Step 2: 6-bromo-8-chloro-2-methyl-rL2,41triazolor4,3-a]pyrazin-3-one

[1780] Cl

[1781]

[1782] o

[1783] To a mixture of 8-chloro-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one (4.03 g, 21.8 mmol, 1.00 equiv.) in DCE (50 mL) were added NBS (7.77 g, 43.7 mmol, 2.00 equiv.) and AgOTf (841 mg, 3.28 mmol, 15 mol%). The resulting mixture was stirred for 4 h at 80 °C under N2. The reaction mixture was added into sat. NaHCO3 (80 mL) and extracted with EtOAc (70 mL x 3). The organic layers were washed with brine (120 mL x 3). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (3.82 g, 61% yield) as a yellow solid. MS: m / z 263.0; 265.0 [M+H]+, ESI pos.

[1784] Step 3: 6-bromo-8-(2,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one

[1785]

[1786] To a solution of 6-bromo-8-chloro-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one (53.0 mg, 0.201 mmol, 1.0 equiv.) in 1,4-dioxane (5.3 mL) was added (2,4-difluorophenyl)boronic acid (41.3 mg, 0.262 mmol, 1.3 equiv.) followed by a solution of Cs2CO3(197 mg, 0.603 mmol, 3.0 equiv.) in water (1.06 mL). The mixture was degassed with N2 for 5 min. Pd(dppf)C12. DCM (33.3 mg, 0.040 mmol, 20 mol%) was added. The tube was sealed and the resulting solution was stirred at 80 °C for 30 min. The mixture was cooled to RT and poured into aq. sat. NaHCCL. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuo. Purification by FCC (SiO2, heptane / EtOAc gradient) followed by high pressure RP-FCC (C18, water / ACN gradient) delivered the title compound (12.0 mg, 17% yield) as ayellow solid. MS: m / z 341.1; 343.1 [M+H]+, ESI pos.

[1787] The Intermediates in the following table were generated in analogy to Intermediate B5 - alternative synthesis, following the same order of steps as described and starting from Intermediate B5 - alternative synthesis - Step 2. A skilled person will be aware that variants and / or alternative procedures for hydrazine addition, annulation, bromination, cross coupling and methylation steps may be applied. For example, in some cases, the reagents’ equivalents and the duration of the reaction [h] were modified, or the reaction was conducted at a different temperature [°C], More specifically, boronic acids may be replaced by boronic ester reagents where relevant due to commercial availability of the reagent or alternative suitable bases such as K2CO3were used. Also, in some cases, reverse phase (RP) or normal phase FCC or HPLC were used as purification methods instead of or in addition to FCC. Any relevant deviation from the standard conditions will be marked with * in the relevant entries.

[1788] Boronic Acid / Ester MS (ESI): hit. No. Structure Systematic Name

[1789] Source m / z

[1790] B10 6-bromo-8-(4- 4- 339.2;

[1791] chlorophenyl)-2-methyl- chl oropheny lb oroni 341.2 [l,2,4]triazolo[4,3- c acid pinacol ester [M+H]+, a]pyrazin-3-one CAS RN: 195062- ESI pos 61-4

[1792] (*1.2 equiv.), *3.0

[1793] equiv. K2CO3, 15

[1794] mol%,

[1795]

[1796] *3.0 equiv. K2CO3, 15 Pd(dppf)Cl2. DCM, mol%, 3 h

[1797] Pd(dppf)Cl2. DCM, 3 h

[1798] Bll Cl 6-bromo-8-(4-chloro- 2-(4-chloro-2,6- 375.1;

[1799] 2,6-difluoro-phenyl)-2- difluorophenyl)- 377.0 methyl- 4,4, 5, 5 -tetramethyl- [M+H]+, [l,2,4]triazolo[4,3- 1, 3, 2 -di oxab orol ane ESI pos A a]pyrazin-3-one CAS RN: 1165935- Br

[1800] 0 84-1, *3 h

[1801] B12 F F 6-bromo-8-(4,4- 2-(4,4- 345.0;

[1802] difluorocyclohexen-1- difluorocyclohex- 1 - 346.9 yl)-2-methyl- en-l-yl)-4, 4,5,5- [M+H]+, [l,2,4]triazolo[4,3- tetramethyl- 1,3,2- ESI pos N. _ / a]pyrazin-3-one dioxaborolane CAS

[1803] O RN: 1227068-84-9, m

[1804] *3.0 equiv. K2CO3,

[1805] 15 mol%, Pd(dppf)Cl2. DCM,

[1806] 3 h

[1807] B13 6-bromo-8-[2-fluoro-4- 2-fluoro-4- 391.2;

[1808] (trifluoromethyl)phenyl] (trifluoromethyl)ph 393.2 -2-methyl- enylboronic acid [M+H]+, [l,2,4]triazolo[4,3- CAS RN: 503309- ESI pos a]pyrazin-3-one 11-3

[1809]

[1810] B14 F F 6-bromo-8-[4- 2-[4- 373.2;

[1811] (difluoromethyl)-2- (difluoromethyl)-2- 375.2 JM fluoro-phenyl]-2- fluoro-phenyl]- [M+H]+, methyl- 4,4, 5, 5 -tetramethyl- ESI pos [l,2,4]triazolo[4,3- 1, 3, 2 -di oxab orol ane

[1812] Br ^[\

[1813] 0 a]pyrazin-3-one CAS RN: 2410032- 62-9, *45 min

[1814] B15 6-bromo-8-[4- 2-(4- 355.2;

[1815] (difluoromethyl)phenyl] (difluoromethyl)ph 357.2 -2-methyl- enyl)-4, 4,5,5- [M+H]+, [l,2,4]triazolo[4,3- tetramethyl- 1,3,2- ESI pos a]pyrazin-3-one dioxaborolane CAS

[1816] 1 1 RN: 1234319-14-2

[1817] y z°2

[1818] (*1.1 equiv.), *3.0 equiv. K2CO3, 15 H5< ‘

[1819] co m mol%,

[1820] Pd(dppf)Cl2. DCM,

[1821] 70 °C 1 h

[1822] B16 6-bromo-2-methyl-8- 4,4, 5, 5 -tetramethyl- 359.1;

[1823] (2,4,6-trifluorophenyl)- 2-(2,4,6- 361.1 [l,2,4]triazolo[4,3- trifluorophenyl)- [M+H]+, a]pyrazin-3-one 1, 3, 2 -di oxab orol ane ESI pos CAS RN: 325143- 04-2

[1824] (*1.1 equiv.), *3.0 equiv. K2CO3, 15 mol%, Pd(dppf)Cl2. DCM,

[1825] 70 °C overnight

[1826]

[1827] B17 6-bromo-8-(2-fluoro-4- (2-fluoro-4- 353.3;

[1828] methoxy-phenyl)-2- methoxyphenyl)bor 355.3 methyl- onic acid CAS RN: [M+H]+, [l,2,4]triazolo[4,3- 162101-31-7, *85 ESI pos a]pyrazin-3-one °C

[1829] B18 6-bromo-2-methyl-8-(p- 4- 319.3;

[1830] tolyl)- methylphenylboron 321.3 [l,2,4]triazolo[4,3- ic acid CAS RN: [M+H]+, 0

[1831] a]pyrazin-3-one 5720-05-8, *60 °C ESI pos for 40 min

[1832] Br JOC 0N-

[1833] CO L*- B19 6-bromo-8-(2-fluoro-4- 2-fluoro-4- 337.3;

[1834] methyl-phenyl)-2- methylphenylboron 339.3 jfj methyl- ic acid CAS RN: [M+H]+,

[1835] [l,2,4]triazolo[4,3- 170981-26-7, *60 ESI pos a]pyrazin-3-one °C for 10 min

[1836] Br

[1837] 0

[1838]

[1839] Furthermore, 6-bromo-8-chloro-2-cyclopropyl-ri,2,4]triazolol4,3-a]pyrazin-3-one Intermediate

[1840]

[1841] B5 - alternative synthesis - Step 2 may be further converted to a di-bromo intermediate, which may be then employed in the following Suzuki cross couplings towards Intermediate B5.

[1842] Step 1: 6,8-dibromo-2-methyl-ll,2,4]triazolol4,3-a]pyrazin-3-oneBr

[1843]

[1844] O

[1845] from Intermediate B4 alternative synthesis - Step 4.

[1846] A mixture of 6-bromo-8-chloro-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one (3.82 g, 14.5 mmol, 1.0 equiv.) and TMSBr (8.88 g, 58.0 mmol, 4.0 equiv.) in ACN (60 mL) was stirred for 12 h at 80 °C. The reaction mixture was added into sat. NaHCO3 (60 mL) and extracted with DCM (50 mL x 3). The organic layers were reunited and then washed with brine (50 mL x 3). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (3.55g, 76% yield) as a green solid. MS: m / z 307.0; 309.0 [M+H]+, ESI pos.

[1847] Step 2: 6-bromo-8-(2,4-difluorophenyl)-2-methyl-[1,2,4]triazolo[4,3-a]pyrazin-3-one

[1848] F

[1849]

[1850] O

[1851] A mixture of 6,8-dibromo-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one (2.70 g, 8.77 mmol, 1.0 equiv.), 2,4-difluorobenzeneboronic acid (1.94 g, 12.3 mmol, 1.4 equiv.), Cs2CO3(8.56 g, 26.3 mmol, 3.0 equiv.), and Pd(dppf)C12. DCM (0.210 g, 0.260 mmol, 3 mol%) in 1,4-dioxane (30 mL) and water (3 mL) was degassed with N2 three times and stirred for 2 h at 40 °C under a N2 atmosphere. The reaction mixture was poured into H2O (50 mL) and extracted with DCM (50 mL x 2). The organic layers were washed with brine (60 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (2.40 g, 80% yield) as a yellow solid. MS: m / z 341.0; 343.0 [M+H]+, ESI pos.

[1852] The Intermediates in the following table were generated in analogy to Intermediate B5 -alternative synthesis, following the same order of steps as described and starting from Intermediate B5 - alternative synthesis - Step 2, followed by bromination. A skilled person will be aware that variants and / or alternative procedures for hydrazine addition, annulation,bromination, cross coupling and methylation steps may be applied. For example, in some cases, the reagents’ equivalents and the duration of the reaction [h] were modified, or the reaction was conducted at a different temperature [°C], More specifically, boronic acids may be replaced by boronic ester reagents where relevant due to commercial availability of the reagent or alternative 5 suitable bases such as K2CO3were used. Also, in some cases, reverse phase (RP) or normal phase FCC or HPLC were used as purification methods instead of or in addition to FCC. Any relevant deviation from the standard conditions will be marked with * in the relevant entries.

[1853] Boronic

[1854] MS (ESI): I nt. No. Structure Systematic Name Acid / Ester

[1855] m / z Source

[1856] B20

[1857] F6-bromo-2-methyl-8-[4- 4- 373.0;

[1858] AF(trifluoromethyl)phenyl]- trifluoromethylp 375.0[M+H] 0 [l,2,4]triazolo[4,3- henylboronic+, ESI pos a]pyrazin-3-one acid CAS RN: n5- 128796-39-4,

[1859] 0 *30 mol%,

[1860] Pd(dppf)Cl2. DC

[1861] M, 40 °C 2h

[1862]

[1863] Intermediate B21: 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- 0 difluorophenyl)-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one

[1864] Step 1: fert-butyl A-l(3-chloropyrazin-2-yl)amino1carbamate

[1865]

[1866] (3-chloropyrazin-2-yl)hydrazine (CAS RN: 63286-28-2; 10.0 g, 69.2 mmol, 1.00 equiv.) was dissolved in THF (120 mL). TEA (11.6 mL, 83.0 mmol, 1.2 equiv.) and (Boc)2O (19.3 mL, 83.0 mmol, 1.2 equiv.) dissolved in THF (50 mL) were added at 0 °C. The mixture was stirred overnight at RT. The reaction mixture was diluted with water and extracted with EtOAc. The reunited organic layers were dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiCE, Heptane / EtOAc gradient) delivered the title compound (15.7 g, 93%) as a light brown solid. MS m / z: 243.1 [M-H]', ESI neg

[1867] Step 2: terLbutyl 7V-[[3-(2,4-difluorophenyl)pyrazin-2-yl]amino]carbamate

[1868] F

[1869]

[1870] To a solution of tert-butyl A-[(3-chloropyrazin-2-yl)amino]carbamate (25.0 g, 102 mmol, 1.0 equiv.) in 1,4-dioxane (500 mL) / water (50 mL) were added (2,4-difluorophenyl)boronic acid (CAS RN: 144025-03-6; 24.2 g, 153 mmol, 1.5 equiv.), Na2CO3(32.5 g, 306 mmol, 3.0 equiv.) and PdCl2(PPh3)2(3.59 g, 5.11 mmol, 5.0 mol%). The reaction was then degassed with vacuum / and the mixture was stirred at 90 °C for 18 h under N2 atmosphere. The reaction was poured into water (300mL) and extracted with EtOAc (3x150 mL). The organic phase was washed with brine (200mL) and dried over Na2SO4, then concentrated in vacuum to give the crude mixture. Purification by FCC (SiO2, Heptane / EtOAc gradient) delivered the title compound (30.3 g, 92%) as a light brown foam. MS m / z: 232.2 [M-H]', ESI neg

[1871] Step 3: tert-butyl A-[[5-bromo-3-(2,4-difluorophenyl)pyrazin-2-yl]amino]carbamate

[1872] F

[1873]

[1874] N-bromosuccinimide (9.94 g, 55.85 mmol, 1.2 equiv.) was added to a solution of tert-butyl 7V-[[3-(2,4-difluorophenyl)pyrazin-2-yl]amino]carbamate 1.0 equiv.) in CHC13(230 mL). The reaction mixture was stirred overnight at RT. To the reaction mixture was added H2O and extracted with DCM. The reunited organic layers were dried over Na2SO4and the solvent was removed underreduced pressure. Purification by FCC (SiO2, Heptane / EtOAc gradient) delivered the title compound (4.80 g, 25%) as a brown solid. MS m / z: 399.1 [M-H]', ESI neg

[1875] Step 4: r5-bromo-3-(2,4-difluorophenyl)pyrazin-2-yl1hydrazine hydrochloride

[1876]

[1877] To a solution of tert-butyl N-[[5-bromo-3-(2,4-difluorophenyl)pyrazin-2-yl]amino]carbamate (4.80 g, 11.7 mmol, 1.0 equiv.) in DCM (30 mL) was added 4 M HC1 in 1,4-Dioxane (11.7 mL, 46.9 mmol, 4.0 equiv.). The reaction was stirred overnigh at 20 °C. The mixture was diluted with MTBE and stirred for 15 min. The precipitated solids were filtered off and washed with TBME, then dried in vacuo to obtain the title compound (4.28 g, over quant.) as a light brown solid. The compound was used in the next step without further purification. MS m / z: 302.9 [M+H]+, ESI pos

[1878] Step 5: 6-bromo-8-(2,4-difluorophenyl)-2H-rE2,41triazolor4,3-a1pyrazin-3-one

[1879]

[1880] To a solution of [5-bromo-3-(2,4-difluorophenyl)pyrazin-2-yl]hydrazine hydrochloride (4.28 g, 12.7 mmol, 1.0 equiv.) and TEA (5.30 mL, 38.0 mmol, 3.0 equiv.) in THF (90 mL), was added dropwise 4-nitrophenyl chloroformate (2.81 g, 13.9 mmol, 1.1 equiv.) in THF (20 mL) atRT. The reaction was stirred at 25 °C for 2 h under N2. The mixture was then filtered and mother liquor further concentrated under reduced pressure. Purification by FCC (SiO2, DCM: MeOH gradient) and RP ISCO (C18, water / ACN gradient) delivered the title compound (3.30 g, 78%) as a light yellow solid. The compound was used in the next step without further purification. MS m / z: 326.9 [M+H]+, ESI pos

[1881] Step 6: 6-bromo-8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-rL2,41triazolor4,3-a]pyrazin-3-one

[1882]

[1883] K2CO3(971.9 mg, 7.03 mmol, 2.0 equiv.) and 2-(trimethylsilyl)ethoxymethyl chloride (879 mg, 935 pL, 5.27 mmol, 1.5 equiv.) were added atRT to a solution of 6-bromo-8-(2,4-difluorophenyl)-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one (1.15 g, 3.52 mmol, 1.0 equiv.) in DMF (25 mL). The reaction mixture was stirred for 2 h at RT, then diluted with water and extracted EtOAc (2x). The reunited organic layers were dried over Na2SO4and the solvent removed under reduced pressure. Purification by FCC (SiO2, Heptane / EtOAc gradient) delivered the title compound (1.30 g, 77%) as a yellow solid. MS m / z: 459.0 [M+H]+, ESI pos

[1884] Step 7: 6-r(6A)-6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2J / -pyran-4-yl]-8-(2,4- i-2-(2-trimethvlsilvlethoxvmethvl)-ri,2, ■ 3-; in-3-one

[1885]

[1886] To a solution of [6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethane sulfonate Alb (888 mg, 2.62 mmol, 1.2 equiv.) in 1,4-Dioxane (11 mL) were added bis(pinacolato)diboron (944 mg, 3.72 mmol, 1.7 equiv.) and KOAc (858 mg, 8.75 mmol, 4.0 equiv.) at RT. The reaction mixture was degassed with Argon before Pd(dppf)C12. DCM complex (181 mg, 0.218 mmol, 10 mol%) was added. Then the reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (2x). The reunited organic layers were dried over Na2SO4and the solvent removed under reduced pressure to deliver the crude boronic ester intermediate. The crude intermediate was taken up with 1,4-di oxane (20 mL) and 6-bromo-8-(2,4-difluorophenyl)-2-(2 -trimethyl silyl ethoxymethyl)-[ 1,2, 4]triazolo[4, 3-a]pyrazin-3-one (1.00 g, 2.19 mmol, 1.0 equiv.) was added, followed by Cs2CO3(1.42 g, 4.37 mmol, 2.0 equiv.) dissolved in water (2.5 mL). The reaction mixture was degassed with Argon before Pd(dppf)C12. DCM complex (181 mg, 219 pmol, 10mol%) was added. The reaction mixture was stirred for 2 h at 60 °C. The reaction mixture was diluted with water and extracted with EtOAc(2x). The reunited organic layers were dried over Na2SO4and the solvent rmeoved under reduced pressure. Purification by FCC (SiO2, Heptane / EtOAc gradient) delivered the title compound (910 mg, 71%) as a dark red solid. MS m / z: 567.1 [M+H]+, ESI pos

[1887] Step 8: 6-r(2AAM-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2- (2-trimethylsilylethoxymethyl)-ri,2,41triazolor4,3-a1pyrazin-3-one (Example 66)

[1888]

[1889] A solution of 6-[(6A)-6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2J / -pyran-4-yl]-8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one (700 mg, 1.24 mmol, 1.0 equiv.) in EtOAc (12 mL) was treated with TEA (207 pL, 1.48 mmol, 1.2 equiv.). Magnesium oxide (498 mg, 12.4 mmol, 10.0 equiv.) was then added and the reaction mixture was degassed with Argon / vacuum. Then Pd / C 10% (263 mg, 247 pmol, 20 mol%) and the reaction mixture was degassed with Argon / vacuum a second time. The reaction was then degassed and backfilled with H2 (1 atm) The mixture was vigorously stirred at RT for 3h. The reaction mixture was filtered over decalite and washed with EtOAc. The filtrate was concentrated in vacuo.

[1890] Purification by FCC (SiO2, Heptane / EtOAc gradient) delivered the title compound (516 mg, 70%) as a yellow solid. MS m / z: 569.6 [M+H]+, ESI pos

[1891] Step 9: 6-r(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)- 2H-rE2,41triazolor4,3-a]pyrazin-3-one

[1892]

[1893] To a solution of 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one (1.80 g, 3.17 mmol, 1.0 equiv.) in DCM (20 mL) was added TFA (2.44 mL, 31.7 mmol, 10 equiv.) at 0 °C.The mixture was stirred for 5 h at RT. The reaction mixture was quenched with sat. Na2CO3solution at 0 °C and extracted with DCM (x 2). The organic layers were dried over Na2SO4then concentrated in vacuo. The crude material was dissolved in methanol (15 mL) and NH4OH (4.44 g, 4.93 mL, 31.7 mmol, 10 equiv.) was added. The mixture was stirred for 1 h at RT. The reaction mixture was diluted with water and extracted with EtOAc (x 3). The organic layers were dried over Na2SO4then concentrated in vacuo. The aqueous layer was concentrated in vacuo. Purification by FCC (SiCh, MeOH / DCM gradient) delivered the title compound (1.15 g, 80% yield) as a yellow solid. 439.4 [M+H]+, ESI pos

[1894] Intermediate B28: 6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2J / -[l,2,4]triazolo[4,3-a]pyrazin-3-one

[1895]

[1896] To a solution of (3-chloropyrazin-2-yl)hydrazine (CAS RN: 63286-28-2; 30.0 g, 208 mmol, 1.0 equiv.) and TEA (43.3 mL, 311 mmol, 1.5 equiv.) in THF (1.25 L) was added a solution of 4-nitrophenyl chloroformate (CAS RN: 7693-46-1; 43.9 g, 218 mmol, 1.05 equiv.) in THF (250 mL) over 1 h at 25-30 °C. The mixture was stirred for 3 h at 30 °C. The reaction mixture was filtered and the filter cake was washed with DCM (500 mL). The filtrate was concentrated in vacuo. The residue was triturated with DCM (300 mL) and EtOAc (300 mL) for 1 h and filtered. The filter cake was washed with EtOAc (100 mL) and dried to obtain the title compound (86.0 g, 243% yield) as a light yellow solid. MS: m / z 171.0 [M+H]+, ESI pos.

[1897] Step 2: 8-chloro-2-(2-trimethylsilylethoxymethyl)-rL2,41triazolol4,3-a1pyrazin-3-oneci

[1898]

[1899] \

[1900] To a suspension of 8-chloro-2H-[l,2,4]triazolo[4,3-a]pyrazin-3-one (69.0 g, 405 mmol, 1.0 equiv.) in DCM (700 mL) was added DIEA (212 mL, 1220 mmol, 3.01 equiv.) at 0 °C. After 5 min, 2-(trimethylsilyl)ethoxymethyl chloride (CAS RN: 76513-69-4; 108 mL, 610 mmol, 1.51 equiv.) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and at 25 °C for 2 h. The mixture was poured into water (1 L) and extracted with DCM (700 mL x 3). The combined organic layers were washed with brine (2 L x 3), dried over Na2SO4, and concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (97.4 g, 80% yield) as an orange oil. MS: m / z 301.1 [M+H]+, ESI pos.

[1901] Step 3: 8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-rL2,41triazolol4,3-a1pyrazin-3-one

[1902]

[1903] A mixture of 8-chloro-2-(2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one (5.00 g, 16.6 mmol, 1.0 equiv.), 2,4-difluorobenzeneboronic acid (CAS RN: 144025-03-6; 2.89 g, 18.3 mmol, 1.1 equiv.), Cs2CO3(16.3 g, 49.9 mmol, 3.0 equiv.), and Pd(dppf)C12. DCM (1.09 g, 1.33 mmol, 8.0 mol%) in 1,4-dioxane (50 mL) and water (5 mL) was degassed with N2 three times and stirred for 2 h at 90 °C under a N2 atmosphere. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by FCC (SiCh, PE / EtOAc gradient) delivered the title compound (4.60 g, 73% yield) as a yellow oil. MS: m / z 379.1 [M+H]+, ESI pos.

[1904] Step 4: 6-bromo-8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-rL2,41triazolol4,3-alpyrazin-3-one

[1905]

[1906] To a suspension of 8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one (43.0 g, 114 mmol, 1.0 equiv.) and NaHCO3 (28.6 g, 340 mmol, 3.0 equiv.) in 1,2-di chloroethane (1.4 L) was added dropwise a solution of Br2 (34.3 mL, 398 mmol, 3.5 equiv.) in 1,2-di chloroethane (328 mL). The mixture was stirred at 25 °C for 2 h. DBU (17.1 mL, 114 mmol, 2.0 equiv.) was added and the mixture was stirred at 40 °C for 2 h. The reaction was quenched with saturated aqueous Na2SOs (1 L) at 20 °C and extracted with DCM (1 L x 3). The combined organic layers were washed with brine (1 L x 3), dried over Na2SO4, and concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (44.0 g, 86% yield) as a yellow solid. MS: m / z 457.2 [M+H]+, ESI pos.

[1907] Step 5: 6-r6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2J / -pyran-4-yl]-8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-rL2,41triazolor4,3-a]pyrazin-3-one

[1908] , N

[1909] ' N

[1910] /

[1911] Si-

[1912]

[1913] \

[1914] A mixture of 6-bromo-8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one (1.00 g, 2.19 mmol, 1.0 equiv.), l-cyclopropyl-4-[4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (1.04 g, 3.29 mmol, 1.5 equiv.), Na2CO3(695 mg, 6.56 mmol, 3.0 equiv.), and Pd(dppf)C12. DCM (90.0 mg, 0.110 mmol, 5.0 mol%) in 1,4-dioxane (10 mL) and water (1 mL) was degassed with N2 three times and stirred for 2 h at 90 °C under N2. The mixture was diluted with EtOAc (30 mL) and filtered through a pad of celite. The filtrate was concentrated in vacuo. Purification by FCC (SiCh, PE / EtOAc gradient) delivered the title compound (700 mg, 56% yield) as a brown oil. MS: m / z 567.2 [M+H]+, ESI pos.

[1915]

[1916] -4-vl)tetrahvdropvran-4-vl]-8-(2,4-difluorophenvl)-2-(2-trimethvlsilvlethoxvmethvl)-r 1,2,

[1917]

[1918] 3-; in-3-one

[1919] /

[1920] Si-

[1921]

[1922] \

[1923] Pd / C (564 mg, 0.530 mmol, 0.2 equiv.) was added to EtOAc (2 mL) under Ar. A solution of 6-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one (1.50 g, 2.65 mmol, 1.0 equiv.) in EtOAc (15 mL) was added to the suspension, followed by MgO (1.07 g, 26.5 mmol, 10 equiv.). The mixture was degassed with H2three times and stirred for 4 h at 25 °C under H2(15 Psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo. Purification by prep-HPLC (Waters XBridge Cl 8 150 mm x 40 mm x 10 pm, MeCN / H2O gradient + 0.225% HCO2H) delivered the title compound (320 mg, 21% yield) as a yellow oil. MS: m / z 569.2 [M+H]+, ESI pos.

[1924] -4-vl)tetrahvdropvran-4-vl]-8-(2,4-difluorophenvl)-2J / - in-3-one

[1925]

[1926] To a solution of 6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one (320 mg, 0.560 mmol, 1.0 equiv.) in DCM (1 mL) was added TFA (0.940 mL, 10.0 mmol, 17.8 equiv.). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH (1 mL) and 7 M NH3 in MeOH (1 mL) was added. The mixture was stirred at 25 °C for 1 h. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (120 mg, 49% yield) as a yellow solid. MS: m / z 439.2 [M+H]+, ESI pos.Intermediate B22: 6-chloro-2-cyclopropyl-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1927]

[1928] Step 1: 6-chloro-3-hydrazino-pyridazin-4-amine

[1929] NH2

[1930] NH

[1931]

[1932] A mixture of 3,6-dichloropyridazin-4-amine (25.0 g, 152 mmol, 1.0 equiv.) in hydrazine hydrate (104 mL, 2.130 mol, 14 equiv.) was stirred for 2 h at 105 °C. The reaction mixture was cooled to room temperature, triturated in H2O (100 mL), and stirred for 30 min. The precipitate was collected by filtration, washed with H2O (50 mL) and ACN (30 mL) then dried in vacuo to obtain the title compound (18.7 g, 77% yield) as a white solid. MS: m / z 160.0 [M+H]+, ESI pos.

[1933] Step 2: 8-amino-6-chloro-2J / -[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1934]

[1935] To a mixture of 6-chloro-3-hydrazino-pyridazin-4-amine (18.7 g, 117 mmol, 1.0 equiv.) and TEA (16.3 mL, 117 mmol, 1.00 equiv.) in THF (150 mL) at 0 °C was added dropwise a solution of triphosgene (38.3 g, 129 mmol, 1.1 equiv.) in THF (150 mL) over 40 min under N2. The reaction was stirred at 0 °C for 2 h under N2. The reaction mixture was poured into sat NaHCO3(800 mL). The solid was collected by filtration, washed with water (20 mL) and MeCN (20 mL). The solid was collected by filtration, washed with water (20 mL) and ACN (20 mL), then further dried to deliver the title compound (12.5 g, 57% yield) as a brown solid. MS: m / z 186.2 [M+H]+, ESI pos.

[1936] Step 3: 6-chloro-8-iodo-2J / -[l,2,4]triazolo[4,3-b]pyridazin-3-oneI

[1937]

[1938] O

[1939] To a solution of 8-amino-6-chloro-2H-[l,2,4]triazolo[4,3-b]pyridazin-3-one (11.5 g, 62.0 mmol, 1.0 equiv.) in ACN (80 mL) was added CH2I2 (40.0 mL, 478 mmol, 7.7 equiv.) followed by dropwise addition of tert-butylnitrite (29.5 mL, 248 mmol, 4.0 equiv.). The reaction was stirred at 90 °C for 1 h under N2. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (100 mL x 2). The organic layers were washed with brine (80 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PEZEtOAc gradient followed by DCM / MeOH gradient) followed by trituration with EtOAc (50 mL) and purification of the filtrate by prep-HPLC (Phenomenex luna C 18 150 x 25mm; water / ACN gradient + HCO2H) delivered the title compound (2.90 g, 13% total yield) as a yellow solid. MS: m / z 296.8 [M+H]+, ESI pos.

[1940] Step 4: 6-chloro-2-cyclopropyl-8-iodo-[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1941] I

[1942]

[1943] O

[1944] A mixture of 6-chloro-8-iodo-2H-[l,2,4]triazolo[4,3-b]pyridazin-3-one (300 mg, 1.01 mmol, 1.0 equiv.), Cu(OAc)2 (202 mg, 1.11 mmol, 1.1 equiv.), cyclopropylboronic acid (104 mg, 1.21 mmol, 1.2 equiv.), Na2CO3(215 mg, 2.02 mmol, 2.00 equiv.), and 2,2’ -bipyridine (174 mg, 1.11 mmol, 1.1 equiv.) in DCE (18 mL) was stirred for 12 h at 80 °C under O2 (15 Psi). The reaction mixture was cooled to room temperature. EtOAc (50 mL) and water (50 mL) were added. The aqueous phase was extracted with EtOAc (30 mL x 2). The organic layers were washed with brine (60 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (80.0 mg, 23% yield) as a yellow solid. MS: m / z 336.9 [M+H]+, ESI pos.

[1945] Step 5: 6-chloro-2-cyclopropyl-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-b]pyridazin-3-oneF

[1946]

[1947] To a solution of 6-chloro-2-cyclopropyl-8-iodo-[l,2,4]triazolo[4,3-b]pyridazin-3-one (260 mg, 0.770 mmol, 1.0 equiv.) in 1,4-dioxane (5 mL) and water (0.500 mL) were added 2,4-difluorobenzeneboronic acid (122 mg, 0.770 mmol, 1.0 equiv.), PdCh(PPh3)2 (54.2 mg, 80.0 pmol, 10 mol%), and Na2CO3 (246 mg, 2.32 mmol, 3.0 equiv.). The reaction was degassed with N2 three times and stirred for 5 h at 90 °C under a N2 atmosphere. The reaction mixture was cooled to RT. EtOAc (40 mL) and water (40 mL) were added. The aqueous phase was extracted with EtOAc (30 mL x 2). The organic layers were washed with brine (60 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by prep-HPLC (Phenomenex luna Cl 8 150 x 25mm; water / ACN gradient) delivered to obtain the title compound (170 mg, 68% yield) as a yellow solid. MS: m / z 323.0 [M+H]+, ESI pos.

[1948] Intermediate B23: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1949]

[1950] Step 1: 6-chloro-8-iodo-2-methyl-rL2,4]triazolol4,3-b]pyridazin-3-one

[1951]

[1952] Starting from Intermediate B22 Step 3: 6-chloro-8-iodo-2J / -[l,2,4]triazolo[4,3-b]pyridazin-3-oneA mixture of 6-chloro-8-iodo-2H-[l,2,4]triazolo[4,3-b]pyridazin-3-one (5.40 g, 18.2 mmol, 1.0 equiv.), K2CO3(7.55 g, 54.7 mmol, 3.00 equiv.), and iodomethane (2.27 mL, 36.4 mmol, 2.00 equiv.) in DMF (60 mL) was stirred for 4 h at 20 °C. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 2). The organic layers were washed with brine (200 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (4.20 g, 74% yield) as a green solid. MS: m / z 311.0 [M+H]+, ESI pos.

[1953] Step 2: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-methyl-ri,2,41triazolor4,3-b1pyridazin-3-one Cl

[1954] X X / N- CI^N"

[1955]

[1956] O

[1957] To a solution of 6-chloro-8-iodo-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one (2.20 g, 7.09 mmol, 1.0 equiv.) in 1,4-Dioxane (25 mL) and Water (5 mL) was added 4-chloro-2-fluorophenylboronic acid (1.36 g, 7.79 mmol, 1.1 equiv.), PdCl2(PPh3)2 (497 mg, 0.710 mmol, 10 mol%), and Na2CO3(2.25 g, 21.3 mmol, 3.0 equiv.). The reaction was degassed with N2 three times and stirred for 8 h at 90 °C under a N2 atmosphere. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 2). The organic layers were washed with brine (50 mL). The organic layer was dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, PE / EtOAc gradient) delivered the title compound (1.07 g, 48% yield) as a yellow solid. MS: m / z 313.1 [M+H]+, ESI pos.

[1958] Intermediate B24: 6-chloro-8-(2,4-difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1959]

[1960] OStep 1: 6-chloro-2 / / -[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1961]

[1962] To a suspension of 3,6-dichloropyridazine (250 mg, 1.68 mmol, 1.0 equiv.) in ethanol (4 mL) and water (1 mL) was added hydrazinecarboxamide hydrochloride (374 mg, 3.36 mmol, 2.0 equiv.) and HC1 35% (0.612 mg, 0.0168 mmol, 0.010 eq) at rt. The mixture was stirred over night at 90 °C. The reaction mixture was concentrated to dryness. The crude material was triturated with Ethanol (3 mL x 2) to obtain the title compound (360 mg, 101% yield) as a light yellow solid. MS: m / z 171.2 [M+H]+, ESI pos.

[1963] Step 2: 6-chloro-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1964]

[1965] A mixture of 6-chloro-2H-[l,2,4]triazolo[4,3-b]pyridazin-3-one (2.39 g, 14.0 mmol, 1.0 equiv.), Cs2CO3(6.85 g, 21.0 mmol, 1.5 equiv.), and iodomethane (3.98 g, 28.0 mmol, 2.0 equiv.) in ACN (60 mL) was stirred for 4 h at 50 °C. The reaction mixture was filtered, and the solids were washed with ACN. The filtrate solution was concentrated to dryness. Purification by FCC (SiO2, MeOH / DCM gradient) delivered the title compound (1.05 g, 40% yield) as a yellow solid. MS: m / z 185.0 [M+H]+, ESI pos.

[1966] Step 3: 6-chloro-8-iodo-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1967]

[1968] A solution of 6-chloro-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one (50.0 mg, 0.265 mmol, 1.0 equiv.) in THF (1 mL) was cooled to - 45 °C. LiTMP. LiCl 1 M (0.292 mL, 0.292 mmol, 1.1 equiv.) was added dropwise. The mixture was stirred for 30 min at - 45 °C. I2 (101 mg, 0.398 mmol, 1.5 equiv.) in THF (0.500 mL) was added. The reaction mixture was stirred for 2 h at - 45 °C. Thereaction mixture was quenched with sat. NH4CI at the same temperature and slowly warmed up to RT. The water phase was then extracted with EtOAc (x 2). The organic layers were dried over Na2SO4then concentrated in vacuo. Purification by FCC (SiO2, EtOAc / Heptane gradient) delivered the title compound (49.3 mg, 60% yield) as a yellow solid. MS: m / z 310.9 [M+H]+, ESI pos.

[1969] Step 4: 6-chloro-8-(2,4-difluorophenyl)-2-methyl-ri,2,41triazolor4,3-b1pyridazin-3-one

[1970] F

[1971]

[1972] O

[1973] A mixture of 6-chloro-8-iodo-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one (400 mg, 1.29 mmol, 1.0 equiv.), 2,4-difluorobenzeneboronic acid (224 mg, 1.42 mmol, 1.1 equiv.), and 3 M Cs2CO3 3M in water (0.859 mL, 2.58 mmol, 2.0 equiv.) in 1,4-dioxane (8 mL) was degassed with Ar. PdC12(dppf). DCM (105 mg, 0.129 mmol, 10 mol%) was added. The mixture was stirred overnight at 30 °C. The reaction mixture was diluted with water and extracted with EtOAc (x 2). The organic layers were washed with water and brine, dried over Na2SO4then concentrated in vacuo. Purification by FCC (C18, water / ACN gradient) delivered the title compound (147 mg, 38% yield) as a yellow solid. MS: m / z 297.0 [M+H]+, ESI pos.

[1974] Intermediate B25: 6-chloro-8-(4,4-difluorocyclohexyl)-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one

[1975]

[1976] Starting from Intermediate B24 Step 2: 6-chloro-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one A mixture of 6-chloro-2-methyl-[l,2,4]triazolo[4,3-b]pyridazin-3-one (78.0 mg, 0.423 mmol, 1.0 equiv.), 4,4-difluorocyclohexanecarboxylic acid (694 mg, 4.23 mmol, 10.0 equiv.), AgNOs (35.9 mg, 0.211 mmol, 50 mol%), and (NH4)2S2O8 (289 mg, 1.27 mmol, 3.0 equiv.) in DMSO (2.1 mL)and H2O (70 pL) was stirred under Ar for 18 h at 40 °C. The reaction mixture was quenched with sat. NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Double purification by RP-FCC (H2O / ACN gradient) delivered the title compound (41.9 mg, 26% yield) as an orange solid. MS: m / z 303.1 [M+H]+, ESI pos. Example 1: 8-(4-chloro-2-fluoro-phenyl)-6- 1 rac-(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-rE2,41triazolor4,3-a]pyridin-3-one

[1977]

[1978] Starting from Intermediates Al and Bl

[1979] Step 1: 8-(4-chloro-2-fluoro-phenyl)-6-r6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl1-2-methyl-ri,2,41triazolc>r4,3-a1pyridin-3-one

[1980]

[1981] Intermediate 6-bromo-8-(4-chloro-2-fluoro-phenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3-one Bl (50.0 mg, 140 pmol, 1.0 equiv.) was suspended in 1,4-Dioxane (1.0 mL). Intermediate 1-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole Al (88.7 mg, 280 pmol, 2.0 equiv.) and 3 M Cs2CO3sol. in water (140 pL, 421 pmol, 3.0 equiv.) were added at RT. The mixture was degassed via Argon bubbling before Pd(dppf)C12. DCM complex (11.6 mg, 14.0 pmol, 10 mol%). The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The reunited organic layers were dried over MgSO4 and the solvent removed under reduced pressure. Purification by RP ISCO (Cl 8, water / ACN gradient) delivered the title compound (51.5 mg, 66% yield) as a light brown solid. MS m / z: 466.2 [M+H]+, ESI pos.

[1982] Step 2: 8-(4-chloro-2-fluoro-phenyl)-6-rrac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-rE2,41triazolor4,3-a]pyridin-3-one

[1983]

[1984] To a solution of 8-(4-chloro-2-fluoro-phenyl)-6-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3-one (50.0 mg, 107 pmol, 1.0 equiv.) in EtOAc (1 mL) and TEA (18.0 pL, 129 pmol, 1.2 equiv.) were added MgO (43.3 mg, 1.07 mmol, 10 equiv.) and PtO2 (4.87 mg, 21.5 pmol, 20 mol%). The mixture was stirred under H2 for 2 h. The reaction mixture was filtered through a syringe filter and washed with a solvent mixture of DCM / MeOH 9 / 1. The filtrate was concentrated under reduced pressure. Purification by FCC (SiO2, DCM / MeOH gradient) delivered the title compound as a single cis-diastereomer (7.6 mg, 14%) and as a light yellow solid. MS m / z: 468.2 [M+H]+, ESI pos.

[1985] The Examples in the following table were generated in analogy to Example 1, using the respective building blocks A and B and following the same order of steps as described for Example 1. A skilled person will be aware that variants and / or alternative procedures for both the cross coupling and reduction steps may be applied.

[1986] For example, in some cases, Pd / C may be used as catalyst in the hydrogenation step

[1987] For example, in some cases, the duration of the reaction [h] was modified or the reaction was conducted at a different temperature [°C], Also, in some cases, reverse phase (RP) or normal phase FCC or HPLC were used as purification methods instead of or in addition to FCC. Enantiomers were assigned arbitrarily.

[1988] In some cases (marked with *) chiral SFC was used as purification method to separate the two enantiomers. The retention times are reported.

[1989] Ex. Structure Systematic Name Intermedia MS tR tes (ESI):

[1990] m / z

[1991]

[1992] Cl 8-(4-chloro-2-fluoro- A 1 and B2 495.3 1.957 phenyl)-2-cyclopropyl-6- [M+H]+, min <1 [(2S,4R)-2-(l- ESI pos N-, N<=\^N- cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]- O^J0

[1993] [l,2,4]triazolo[4,3- a]pyrazin-3-one

[1994] *SFC: Chiral Column

[1995] DAICEL CHIRALPAK AD,

[1996] 250 mm x 30 mm, 10 pm,

[1997] iPrOH + 0.1% NH3H2O

[1998] Cl 8-(4-chloro-2-fluoro- Al and B2 495.3 2.200 phenyl)-2-cyclopropyl-6- [M+H]+, min <1 [(2R,4S)-2-(l- ESI pos cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]- °^J0

[1999] [l,2,4]triazolo[4,3- a]pyrazin-3-one

[2000] *SFC: Chiral Column

[2001] DAICEL CHIRALPAK AD,

[2002] 250 mm x 30 mm, 10 pm,

[2003] iPrOH + 0.1% NH3H2O

[2004] Cl 8-(4-chloro-2-fluoro- Al and B3 469.2 1.757 phenyl)-6-[(2R,4S)-2-(l- [M+H]+, min cyclopropylpyrazol-4- ESI posF^ _ yl)tetrahydropyran-4-yl]- 2-methyl- o^J0[l,2,4]triazolo[4,3- a]pyrazin-3-one

[2005] *SFC: Chiral Column

[2006] DAICEL CHIRALPAK AS,

[2007] 250 mm x 30 mm, 10 pm, 35%

[2008] EtOH + 0.1% NH3H2O

[2009]

[2010] Cl 8-(4-chloro-2-fluoro- A 1 and B3 469.2 1.973 phenyl)-6-[(2S,4R)-2-(l- [M+H]+, min cyclopropylpyrazol-4- ESI pos N--, NU^N- yl)tetrahydropyran-4-yl]-N3..^AX / _2-methyl- o ° [l,2,4]triazolo[4,3- *SFC: Chiral Column a]pyrazin-3-one

[2011] DAICEL CHIRALPAK AS,

[2012] 250 mm x 30 mm, 10 pm, 35%

[2013] EtOH + 0.1% NH3H2O

[2014] Cl

[2015] 8-(4-chloro-2-fluoro- A2 and B2 496.2 2.460 JU) phenyl)-2-cyclopropyl-6- [M+H]+, min [(2R,4S)-2-(6-methoxy-3- ESI pos z°Y%

[2016] pyridyl)tetrahydropyran-4-0y 1 ] - [ 1,2,4]triazolo[4,3 - a]pyrazin-3-one

[2017] *SFC: Chiral Column

[2018] DAICEL CHIRALPAK IK,

[2019] 250 mm, 10 pm, 65%

[2020] EtOH: DCM 4:1 + 0.1%

[2021] NH3H2O

[2022] F 2-cyclopropyl-6-[(2S,4R)- Al and B4 479.1 2.21

[2023] 2-(l-cyclopropylpyrazol- [M+H]+, min 4-yl)tetrahydropyran-4- ESI pos N^.

[2024] yl]-8-(2,4-difluorophenyl)- [l,2,4]triazolo[4,3- oj 0

[2025] a]pyrazin-3-one

[2026] *SFC: Chiral Column

[2027] DAICEL CHIRALPAK IK,

[2028] 250 mm, 10 pm, 66% EtOH +

[2029] 0.1%NH3H2O

[2030]

[2031] F 2-cyclopropyl-6-[(2R,4S)- Al and B4 479.1 2.577

[2032] 2-(l-cyclopropylpyrazol- [M+H]+, min 4-yl)tetrahydropyran-4- ESI pos

[2033] N-, yl]-8-(2,4-difluorophenyl)- 0 [l,2,4]triazolo[4,3- a]pyrazin-3-one

[2034] *SFC: Chiral Column

[2035] DAICEL CHIRALPAK IK,

[2036] 250 mm, 10 pm, 66% EtOH +

[2037] 0.1%NH3H2O

[2038] Cl 8-(4-chloro-2-fluoro- A3 and B2 496.3 1.951 phenyl)-2-cyclopropyl-6- [M+H]+, min ■"•0 [(2S,4R)-2-(2-methoxy-4- ESI pos NA NAN, pyridyl)tetrahydropyran-4- y 1 ] - [ 1,2,4]triazolo[4,3 -0a]pyrazin-3-one

[2039] *SFC: Chiral Column

[2040] DAICEL CHIRALPAK OX,

[2041] 250 mm, 10 pm, 55%

[2042] MeOH: ACN=4:l + 0.1%

[2043] NH3H2O

[2044] Cl 8-(4-chloro-2-fluoro- A3 and B2 496.2 2.439 phenyl)-2-cyclopropyl-6- [M+H]+, min JO)

[2045] x,0 F^A [(2R,4S)-2-(2-methoxy-4- ESI posN<n N< A^N- pyridyl)tetrahydropyran-4- y 1 ] - [ 1,2,4]triazolo[4,3 - 0 a]pyrazin-3-one

[2046] *SFC: Chiral Column

[2047] DAICEL CHIRALPAK OX,

[2048] 250 mm, 10 pm, 55%

[2049] MeOH: ACN=4:l + 0.1%

[2050] NH3H2O

[2051]

[2052] F 8-(2,4-difluorophenyl)-2- A 1 and 453.2 4.076 methyl-6-[(2R,4S)-2-(l- B24 [M+H]+, min <1 cyclopropylpyrazol-4- ESI posN-,

[2053] yl)tetrahydropyran-4-yl]- *1.2 equiv.

[2054] XyN- o^l o [l,2,4]triazolo[4,3- Al. Pd / C

[2055] b]pyridazin-3-one 10% used

[2056] in the

[2057] *SFC: Chiral Column SZ 250

[2058] hydrogenat

[2059] x 20 mm, 5 pm, 39% MeOH

[2060] ion step.

[2061] F

[2062] 8-(2,4-difluorophenyl)-2- A 4 and B5 455.0 1.528 JO methyl-6-[(2R,4S)-2-(6- [M+H]+, min F^y^

[2063] methoxypyridazin-3- *1.2 equiv. ESI pos yl)tetrahydropyran-4-yl]- A4. 3.0

[2064] XJ0[l,2,4]triazolo[4,3- equiv.

[2065] a]pyrazin-3-one Na2CO3,

[2066] *SFC: Chiral Column 90 °C 2h;

[2067] DAICEL CHIRALPAK AD,

[2068] Pd / C 10%

[2069] 250 x 30 mm, 10 pm, 60%

[2070] used in the

[2071] EtOH + 0.1% NH3H2O

[2072] hydrogenat

[2073] ion step.

[2074] F

[2075] 2-cyclopropyl-8-(2,4- A 4 and B4 481.3 1.803 JO difluorophenyl)-6- [M+H]+, min [(2A,4S)-2-(6- *1.3 equiv. ESI pos Vr"-^

[2076] methoxypyridazin-3- A4. 3.0

[2077] 0

[2078] yl)tetrahydropyran-4-yl]- equiv.

[2079] [l,2,4]triazolo[4,3- Na2CO3,

[2080] *S...

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A1is selected from the group consisting of N and CR7;A2is selected from the group consisting of O and CR5R6;B is selected from the group consisting of 5- to 10-membered aryl, C3-C10- cycloalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl; L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;X and Y are each independently selected from CH and N;R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and agroup; wherein said Ci-Ce-alkyl is optionally substituted with 1 substituent selected from Ci-Ce-alkoxycarbonyl, Ci-Ce-alkoxy, Ci-Ce- alkoxy-Ci-Ce-alkoxy, and (C1-C6-alkyl)3Si-C1-C6-alkoxy;R2is selected from the group consisting of C6-C10-aryl, 5- to 6-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said C6-C10-aryl, 5- to 6-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6- membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Ci-Ce- alkyl, Ci-Ce-alkoxy, and halo-Ci-Ce-alkyl;R3ais selected from the group consisting of 5- to 6-membered heteroaryl, 9- to 10- membered fused bicyclic heteroaryl, and 3- to 6-membered heterocyclyl, wherein:(i) said 5- to 6-membered heteroaryl and 9- to 10-membered fused bicyclic heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, C3-C10- cycloalkyl-Ci-Ce-alkyl, halo-Cs-Cio-cycloalkyl-Ci-Ce-alkyl, C3-C10- cycloalkyl-Ci-Ce-alkoxy, Cs-Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy; and(ii) said 3- to 6-membered heterocyclyl is substituted with oxo and optionally 1-3 further substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce- alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, C3-C10- cycloalkyl-Ci-Ce-alkoxy, Cs-Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy;R3bis selected from the group consisting of hydrogen and Ci-Ce-alkyl;R4ais selected from the group consisting of hydrogen and Ci-Ce-alkyl;R4bis selected from the group consisting of hydrogen 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, halogen, hydroxy, and Ci-Ce- alkyl;R8is selected from the group consisting of hydrogen, halogen, hydroxy, oxo, cyano, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, Ci-Ce-alkoxy-Ci-Ce-alkyl, and Ci-C6-alkyl-S(O)2-; andR9is selected from the group consisting of hydrogen, halogen, oxo, and Ci-Ce- alkyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:A1is CR7;A2is O; andR7is selected from the group consisting of hydrogen and halogen.

3. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R1is selected from the group consisting of methyl, isopropyl, n-propyl, 1- methylbutyl, 3 -methoxy- 1-methyl-propyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, ethylacetate, 2-(2-methoxyethoxy)ethyl, 2-Btrimethylsilylethoxymethyl, and a group R8B selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, triazolyl, 1,3,4-oxadiazolyl, pyridyl, pyridazinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, 3-oxabicyclo[3.1.0]hexanyl, 7- oxaspiro[3,5]nonanyl,2-thiaspiro[3.3]heptanyl, and oxetanyl;L is selected from the group consisting of a covalent bond, –CH2–, and –(CH2)2–; R8is selected from the group consisting of hydrogen, fluoro, hydroxy, oxo, cyano, methyl, ethyl, 2,2-difluoroethyl, methoxy, methoxymethyl, and methyl-S(O)2-; andR9is selected from the group consisting of hydrogen, fluoro, oxo, and methyl4. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:R1is selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and a R9B^Jy"-Lgroup R8B selected from the group consisting of Cs-Cio-cycloalkyl and 3- to 10-membered heterocyclyl;L is selected from the group consisting of a covalent bond and Ci-Ce-alkyl;R8is selected from the group consisting of hydrogen, halogen, cyano, halo-Ci-Ce- alkyl, and Ci-Ce-alkoxy; andR9is selected from the group consisting of hydrogen, halogen, and Ci-Ce-alkyl.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected fromthe group consisting of C6-C10-aryl and Cs-Cio-cycloalkyl, wherein said C6-C10-aryl and Cs-Cio-cycloalkyl are substituted with 1-3 substituents independently selected from the group consisting of halogen, Ci-Ce-alkyl, Ci-Ce-alkoxy, and halo-Ci-Ce- alkyl.

6. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2is selected from the group consisting of phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl, wherein said phenyl, spiro[3.3]heptanyl, bicyclo[l.l.l]pentanyl, and cyclohexyl are substituted with 1-3 substituents independently selected from fluoro, chloro, methyl, methoxy, CHF2, and CF3.

7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl, wherein:(i) said 5- to 6-membered heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of Ci-Ce-alkyl, halo-Ci-Ce- alkyl, Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, halo-Cs-Cio- cycloalkyl-Ci-Ce-alkyl, and 3- to 6-membered heterocyclyl-Ci-Ce-alkyl; and (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1-2 further substituents independently selected from the group consisting of Ci-Ce-alkyl, Cs-Cio-cycloalkyl, and Ci-Ce-alkoxy.

8. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais 5- to 6- membered heteroaryl substituted with 1 substituent selected from the group consisting of C1-C6-alkoxy and C3-C10-cycloalkyl.

9. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3ais selected from the group consisting of pyridazinyl and pyrazolyl, substituted with 1 substituent selected from the group consisting of methoxy and cyclopropyl.

10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3b, R4a, and R4bare all hydrogen.

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:(i) X and Y are both CH; or(ii) X is N and Y is CH.

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein said compound of formula (I) is selected from: 8-(4-chloro-2-fluoro-phenyl)-6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyridin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluorophenyl)- 2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluorophenyl)- 2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S,4R)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2-fluoro-phenyl)-2-cy cl opropyl-6-[(2S,4R)-2-(2 -methoxy -4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(2 -methoxy -4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2S)-2-(l-cyclopropylpyrazol-4- yl)morpholin-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(6-methoxypyridazin-3- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(6-methoxypyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(6-methoxypyridazin-3- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(6-methoxypyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;8-(4,4-difluorocyclohexyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-b]pyridazin-3-one;8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(2,2,2-trifluoroethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chlorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;3-fluoro-4-[2-methyl-3-oxo-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-8-yl]benzonitrile;8-(4-chloro-2-fluoro-phenyl)-2-methyl -6- [(2R,4 S)-2-( 1 -methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-cy cl opropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(2,2-difluorospiro[3.3]heptan-6-yl)-2-methyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(2,4-difluorophenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-methyl-6-oxo-pyridazin-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-pyridazin-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(lH-pyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[2-fluoro-4- (trifluoromethyl)phenyl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4- (difluoromethyl)-2-fluoro-phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4- (difluoromethyl)-2-fluoro-phenyl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[4- (trifluoromethyl)phenyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[4- (difluoromethyl)phenyl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluoro-4- methoxy-phenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2- fluoro-4-methoxy-phenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-(2,2,2-trifluoroethyl)pyrazol- 4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(2,2,2-trifluoroethyl)pyrazol- 4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-[l-[(3,3-difluorocyclobutyl)methyl]pyrazol-4- yl]tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[trans-l-(3- fluorocyclobutyl)pyrazol-4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-[[(3S)-tetrahydrofuran-3- yl]methyl]pyrazol-4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-[[(3S)-tetrahydrofuran-3- yl]methyl]pyrazol-4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[cis-l-(3- fluorocyclobutyl)pyrazol-4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;2-cyclopropyl-6-[(2S,4R)-2-[l-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-[l-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(trifluoromethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[l-(trifluoromethyl)pyrazol-4- yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-[ 1-(3-fluoro-1-bicyclo[1.1.1]pentanyl)pyrazol-4-yl]tetrahydropyran-4-yl]-[1,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(2-trimethylsilylethoxymethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(2,2- difluoroethyl)-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(oxetan-3-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2-fluoro-4- methyl-phenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3- difluorocyclobutyl)-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopentyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3R)-tetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3S)-tetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-tetrahydropyran-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lR)-2,2- difluorocyclopropyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lS)-2,2- difluorocyclopropyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3-methyloxetan-3-yl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(2-fluoroethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-isopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-benzyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(l-fluorocyclopropyl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(5-ethyl-l,3,4-oxadiazol-2-yl)methyl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;ethyl 2-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]acetate;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[2-(2-methoxyethoxy)ethyl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(lR,3S)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin- 3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(lS,3R)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin- 3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(lR,3R)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin- 3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(lS,3S)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3-a]pyrazin- 3 -one;cis- and trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2- yl]cyclobutanecarbonitrile;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(l-methyltriazol-4-yl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(7-oxaspiro[3.5]nonan-2-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-((2RS)-oxetan-2-ylmethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-methoxycyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[2-(oxetan-3-yl)ethyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3-methoxy-2-pyridyl)methyl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;cis- and trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[3-(methoxymethyl)cyclobutyl]-[l,2,4]triazolo[4,3-a]pyrazin- 3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(2,2-dioxo-2λ6-thiaspiro[3.3]heptan-6-yl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[[(l S,5R)-3-oxabicyclo[3.1,0]hexan-6-yl]methyl]- [ 1,2,4]triazolo[4,3 -a]pyrazin-3 -one;cis- and trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]-l-methyl- cyclobutanecarbonitrile;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-propyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]cyclobutanecarbonitrile; cis-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]cyclobutanecarbonitrile; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lRS)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lR)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(lS)-3,3- difluorocyclopentyl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(lRS)-l-methylbutyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS)-l-(2,2- difluoroethyl)pyrrolidin-3-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[[(3RS)-tetrahydrofuran-3-yl]methyl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[[(3RS)-tetrahydropyran-3-yl]methyl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;1-[[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2- yl]methyl]cyclobutanecarbonitrile;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(lRS,3RS)-3-methoxycyclopentyl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(lRS)-3-methoxy-l-methyl-propyl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3RS)-l-methylsulfonylpyrrolidin-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;methyl 3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[1,2,4]triazolo[4,3-a]pyrazin-2-yl]bicyclo[1.1.1]pentane-1-carboxylate;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[3-(trifluoromethyl)-l-bicyclo[l.

1. l]pentanyl]- [ 1,2,4]triazolo[4,3 -a]pyrazin-3 -one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-b]pyridazin-3-one;2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-[l,2,4]triazolo[4,3-b]pyridazin-3-one;2-cyclopropyl-6-[(2R,4S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl- tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2R,4S,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl- tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2S,4S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl- tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2R,4R,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl- tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(4S,6S)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(4S,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl-tetrahydropyran-4-yl]-8- (2,4-difluorophenyl)-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2-dimethyl- tetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-8-(2,4-difluorophenyl)-6-[rac-(4S,6R)-6-(l-cyclopropylpyrazol-4-yl)- 2,2-dimethyl-tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; cis-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; cis-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-methoxycyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; trans-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-methoxycyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; trans-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]-l-methyl- cyclobutanecarbonitrile;cis-3-[6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-3-oxo-[l,2,4]triazolo[4,3-a]pyrazin-2-yl]-l-methyl- cyclobutanecarbonitrile;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-(p-tolyl)- [ 1,2,4]triazolo[4,3 -a]pyrazin-3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3S)-tetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(2-tetrahydrofuran-3-ylethyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(2-oxaspiro[3.3]heptan-6-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R)-2-(l-cyclopropylpyrazol-4- yl)morpholin-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3R)-tetrahydropyran-3-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3- one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-[l-(3-fluorocyclobutyl)pyrazol- 4-yl]tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-6-[(4R,6R)-6-(l-cyclopropylpyrazol-4-yl)-2,2- dimethyl-tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(4S,6S)-6-(l-cyclopropylpyrazol-4-yl)-2,2- dimethyl-tetrahydropyran-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2-methyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-[1,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (difluoromethyl)-l-bicyclo[l.l.l]pentanyl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 2-cyclopropyl-6-[(2S,4R)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-3-methyl-pyrazol-4-yl)tetrahydropyran- 4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-3-methyl-pyrazol-4-yl)tetrahydropyran- 4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2S,4R)-2-(l-cyclopropyl-5-methyl-pyrazol-4-yl)tetrahydropyran- 4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-5-methyl-pyrazol-4-yl)tetrahydropyran- 4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2S,4R)-2-(2-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyltriazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2S,4R)-2-(5-cyclopropyl-l,3,4-oxadiazol-2-yl)tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4- fluorocyclohexyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-8-(2,4-difluorophenyl)-6-[rac-(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)- 2-methyl-tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(2-methyl-3-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)-4-fluoro-tetrahydropyran-4- yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4R)-2-(l-cyclopropylpyrazol-4-yl)-4-fluoro-tetrahydropyran- 4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]- [ 1,2,4]triazolo[4,3 -a]pyrazin-3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3 SR,4RS)-4-hydroxytetrahydrofuran-3-yl]- [ 1,2,4]triazolo[4,3 -a]pyrazin-3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3RS,4SR)-4-fluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3 SR,4RS)-4-fluorotetrahydrofuran-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(l-hydroxycyclopropyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(l-fluorocyclopropyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-methyl-4-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(3-methyl-4-pyridyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2S)-2-(l-cyclopropylpyrazol-4- yl)morpholin-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2R,4S)-2-(6-methoxypyridazin- 4-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl opropyl-6-[(2S,4R)-2-(6-methoxypyridazin- 4-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS,4SR)-4- fluorotetrahydrofuran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3 SR,4RS)-4- fluorotetrahydrofuran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6- [(2R,4 S)-2-( 1 -cy clopropylpyrazol-4-yl)tetrahy dropyran-4-yl] -2-i sopropyl -8-(2,4, 6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-tetrahydropyran-4- yl-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(4RS)-3,3- difluorotetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(4SR)-3,3- difluorotetrahydropyran-4-yl]-8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3RS)-4,4-difluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3 SR)-4,4-difluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3 SR,4RS)-3-fluorotetrahydropyran-4-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3RS,4SR)-3-fluorotetrahydropyran-4-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3RS,4RS)-4-fluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-[(3 SR,4SR)-4-fluorotetrahydropyran-3-yl]-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3RS,4RS)-4- fluorotetrahydropyran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[(3 SR,4SR)-4- fluorotetrahydropyran-3-yl]-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;-cyclopropyl-6-[(2R,4S)-2-(6-methoxypyridazin-4-yl)tetrahydropyran-4-yl]-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;-(4-chloro-2,6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-tetrahydropyran-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3- one;-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (trans-4-fluorocyclohexyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R)-2-(l-cyclopropylpyrazol-4- yl)morpholin-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3,3-difluorotetrahydropyran-4-yl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(4,4-difluorotetrahydropyran-3-yl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3-fluorotetrahydropyran-4-yl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(4-fluorotetrahydropyran-3-yl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-isopropyl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3- fluorocyclobutyl)-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3-fluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3- difluorocyclobutyl)-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one; 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclobutyl)-[l,2,4]triazolo[4,3-a]pyrazin- 3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(3,3- difluorocyclopentyl)-8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3- one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(3,3-difluorocyclopentyl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one;2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-2-cyclobutyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-8-(2,4,6- trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]- 8-(2,4-difluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]- 8-(2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-2-cyclopropyl-6-[(2R,4S)-2-(l-cyclopropyl-6-oxo- 3-pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;2-cyclobutyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8- (2,4,6-trifluorophenyl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chl oro-2, 6-difluoro-phenyl)-2-cy cl obutyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-pyridazin-4-yl-[l,2,4]triazolo[4,3-a]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,4- difluorophenyl)-2-(5-methylpyridazin-4-yl)-[l,2,4]triazolo[4,3-a]pyrazin-3-one;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(5-methylpyridazin-4-yl)-[l,2,4]triazolo[4,3- a]pyrazin-3-one; and2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(l,5-dimethyl-6-oxo-pyridazin- 3-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one; and2-cyclopropyl-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(5-methoxy-l-methyl-6-oxo- pyridazin-3-yl)tetrahydropyran-4-yl]-[l,2,4]triazolo[4,3-a]pyrazin-3-one.

13. The compound of formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a therapeutically active substance.

14. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a therapeutically inert carrier.

15. A compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition according to claim 14 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, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition according to claim 14.

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