WO2024246019A1

WO2024246019A1 - Pyrido[3,4-d]pyrimidin-4-one and pyrimido[5,4-d]pyrimidin-4-one derivatives as trem2 agonists for the treatment of parkinson's disease

Info

Publication number: WO2024246019A1
Application number: PCT/EP2024/064558
Authority: WO
Inventors: Julie CHARPENTIER; Maria Emilia Di Francesco; Guido Galley; Wolfgang Guba; Fionn Susannah O'HARA; Flore Marie Aude REGGIANI; Stefan Berchtold; Roland Johann HUMM; Angélique PATINY-ADAM; Nicolas ZEIDAN
Original assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Current assignee: F Hoffmann La Roche AG; Hoffmann La Roche Inc
Priority date: 2023-05-30
Filing date: 2024-05-28
Publication date: 2024-12-05
Anticipated expiration: 2025-11-30

Abstract

The invention provides compounds having the general formula (I) wherein A, B, R¹, R², R³, R⁵, and R⁶ are as described herein, compositions including the compounds, processes of manufacturing the compounds and the compounds for use in methods of treatment or prevention of diseases that are associated with TREM2, such as e.g. Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

Description

F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland Case: P38548 TREM2 AGONISTS Field of the Invention The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Triggering Receptor Expressed on Myeloid cells 2 (TREM2) agonists for the treatment or prevention of Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke. Background of the Invention Microglia are immune cells resident in the central nervous system (CNS) which play a crucial role in the CNS development and maintenance of brain homeostasis through synaptic pruning and removal of apoptotic neurons (Paolicelli R.C. et al., Science 2011, 9;333(6048):1456-8 doi: 10.1126/science.1202529). Microglia are also key players in response to neurodegenerative conditions and neuropathological lesions, whereby they shift into an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to the lesion sites and phagocytosis of dead cells and debris. (Lue L.F. et al., Mol. Neurobiol.2010, 41(2-3):115-28, doi: 10.1007/s12035-010-8106-8). Microglia express a multitude of receptors on their surface, which play a key role in sensing the environmental changes and enabling the complex crosstalk regulating their physiological functions. TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is one of these cell surface receptors, which in brain is selectively expressed on microglia and plays a key role in their survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445–453 (2003). https://doi.org/10.1038/nri1106). TREM2 is a single-pass transmembrane receptor that belongs to the Immunoglobulin superfamily (Ig-SF). It is composed of a ligand binding extracellular immunoglobulin variable-like domain (IgV) followed by a long stalk domain, a single transmembrane helix and a short cytosolic tail that does not have signal transduction motifs. CNE/15.05.2024 Downstream signal transduction is mediated through its interaction with the effector protein DAP12, a transmembrane disulphide-linked adapter dimer which expression and cellular localization at the plasma membrane are dependent on TREM2, and which is associated to TREM2 transmembrane helix via lysine-aspartic acid interaction (K156-D50) forming a signaling complex (Zhong L. et al., J Biol Chem.2015;290(25):15866–77). Given its short extracellular domain, DAP12 lacks ligand-binding capabilities. Endogenous ligands of TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cellular debris, myelin and Aβ oligomers. Stimulation of the TREM2/DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of DAP12, which results in recruitment of Syk kinase to activate downstream signaling molecules. Activation of TREM2 plays a key role in microglia signaling and function, including survival, migration, amyloid plaque insulation, beta-amyloid phagocytosis, myelin debris clearance and the transition from the homeostatic to the disease-associated microglia (DAM) state in the context of a neurodegenerative environment (Condello, C. et al., Nat Commun 6, 6176, 2015, doi: org/10.1038/ncomms7176; Poliani et al., J Clin Invest, 2015 May;125(5):2161-70, doi: 10.1172/JCI77983; Zhao et al., Neuron, 2018 Mar 7;97(5):1023-1031.e7, doi: 10.1016/j.neuron.2018.01.031; Keren-Shaul H. et al., Cell, 2017 Jun 15;169(7):1276-1290.e17. doi: 10.1016/j.cell.2017.05.018). Genetic variants of TREM2 have been implicated in a multitude of neurodegenerative diseases (Hou J. et al. Molecular Neurodegeneration (2022) 17:84; doi: org/10.1186/s13024-022-00588- y). TREM2 variants resulting in lack of TREM2 expression were identified as the cause of the Nasu-Hakola Disease (NHD), or Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy (PLOSL), a fatal condition manifesting with progressive pre-senile dementia and characterized by loss of myelin and bone abnormalities, consistent with TREM2 expression in myeloid cells microglia and osteoclasts (Paloneva, J. et al., Am J Hum Genet. 2002,71(3):656-62, doi: 10.1086/342259). Similarly, missense mutations of TREM2 have been associated with increased risk of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several of these TREM2 variants have been implicated with impaired microglia function and their reduced response to neurodegenerative diseases. (Kleinberger, G. et al., Sci. Transl. Med.2014, 6, 243ra86). Moreover, genomic-wide association studies (GWAS) showed a strong link between a number of rare loss of function (LoF) variants of TREM2 and an increased risk of late onset Alzheimer’s disease (LOAD) (Guerreiro R. et al., N Engl J Med.2013, 368(2):117–27; Jonsson T. et al., N Engl J Med.2013, 368(2):107–16). Amongst those, the R47H variant, a LoF mutation associated with structural alterations within the extracellular domain of TREM2 resulting in impaired ability to bind endogenous ligands, was linked to a ca.3 fold increased risk of LOAD (Sudom, A. et al., J Biol Chem.201810;293(32):12634-12646; doi: 10.1074/jbc.RA118.002352). Studies are ongoing to elucidate the mechanism by which TREM2 LoF mutations contribute to AD. It is likely that patients carrying these mutations have impaired microglia function including reduced clearance of extracellular aggregates (e.g. amyloid and myelin debris) and apoptotic neurons, ultimately reducing their capacity to fight the disease and increasing their susceptibility to neurodegeneration. Indeed decreased microglia activation and failure to cluster around the amyloid plaque were observed in mouse models deficient for TREM2 or DAP12, confirming the central role of TREM2 signalling in microglia function and response to Alzheimer’s pathological hallmarks. In light of all this evidence, pharmacological activation of TREM2 appears to be a viable therapeutic intervention. The small molecules disclosed herein are potent and selective agonists of TREM2. Summary of the Invention In a first aspect, the present invention provides compounds of formula (I)

wherein A, B, R¹, R², R³, R⁵, and R⁶ are as defined herein. In further aspects, the invention provides compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I). Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non- limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl. The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C_1-6-alkoxy”). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non- limiting example of alkoxy is methoxy. The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl). The term “cycloalkyl” as used herein refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C_3-10-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1- bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. A particularly preferred, yet non-limiting example of cycloalkyl is cyclopropyl. The term “cycloalkenyl” as used herein refers to a partially unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C3-10-cycloalkyl”). In some preferred embodiments, the cycloalkenyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkenyl” refers to cycloalkenyl 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 cycloalkenyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C₆-C₁₀-aryl”), wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g.9H-fluoren-9-yl). A particularly preferred, yet non-limiting example of aryl is phenyl. The terms “heterocyclyl” and “heterocycloalkyl” are used herein interchangeably and refer to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, more preferably 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. “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4- piperidyl, piperazinyl, pyrrolidinyl, oxazolidinyl, dihydropyrazinyl (e.g., 1,2-dihydropyrazin-6- yl), morpholinyl, 2-azaspiro[3.3]heptan-2-yl, 7-azaspiro[3.5]nonan-7-yl, 8- azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan, and 3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl. The term "heteroaryl" refers to a mono- or multivalent, monocyclic or bicyclic ring system having a total of 5 to 10 ring members, preferably 5 to 8 ring members, more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O, S and N. Some preferred, yet non-limiting examples of heteroaryl include thiazolyl (e.g. thiazol-2-yl); oxazolyl (e.g. oxazol-2-yl); oxadiazolyl; 5,6- dihydro-4H-cyclopenta[d]thiazol-2-yl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g.2-pyridyl); pyrazolyl (e.g. pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; imidazolyl (e.g. imidazole-1-yl); benzoxazolyl (e.g. benzoxazol-2-yl), 2,3-dihydrobenzofuranyl; and oxazolo[5,4-c]pyridin-2-yl. The term “cyano” refers to a –CN (nitrile) group. The term “oxo” refers to a group =O. The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, and 2,2,2-trifluoroethyl. The term “haloalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, (1,1,1-trifluoropropan-2-yl)oxy, and 2,2,2-trifluoroethoxy. The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2. The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment. The term “prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition. Compounds of the Invention In a first aspect, the present invention provides a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: X¹, X² and X³ are each independently selected from N and CH; A is selected from C3-C10-cycloalkyl, C3-C10-cycloalkenyl, C6-C10-aryl, 5- to 10- membered heteroaryl, and 3- to 10-membered heterocyclyl; B is selected from 4a 4_b R R N O R^4c R¹, R², and R³ are each independently selected from hydrogen, halogen, cyano, C1-C6- alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, and halo-C₁-C₆-alkoxy; R^4a is selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆- alkyl, halo-C₁-C₆-alkoxy, and a group

R^4b and R^4c are each independently selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and oxo; R⁵ is selected from C₁-C₆-alkyl, halo-C₁-C₆-alkyl, 3- to 10-membered heterocyclyl and C3-C10-cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one substituent selected from halogen and C1-C6-alkyl; R⁶ is selected from hydrogen and fluoro; R⁷ and R⁸ are each independently selected from hydrogen, halogen, C₁-C₆-alkyl, halo-C₁- C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10- cycloalkyl, and 3- to 10-membered heterocyclyl; and C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H- triazole, 2H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4- oxadiazolyl, and 1,3,4-oxadiazolyl. In one embodiment, the present invention provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X¹, X² and X³ are each independently selected from N and CH; A is selected from C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkenyl, C₆-C₁₀-aryl, 5- to 10- membered heteroaryl, and 3- to 10-membered heterocyclyl; B is selected from 4a 4_b R R N O R^4c R¹, R², and R³ are each independently selected from hydrogen, halogen, cyano, C1-C6- alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, and halo-C₁-C₆-alkoxy; R^4a is selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6- C alkyl, halo-C₁-C₆-alkoxy, and a group ; R^4b and R^4c are each independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and oxo; R⁵ is selected from C1-C6-alkyl, halo-C1-C6-alkyl, 3- to 10-membered heterocyclyl and C₃-C₁₀-cycloalkyl; wherein said C₃-C₁₀-cycloalkyl is optionally substituted with one substituent selected from halogen and C1-C6-alkyl; R⁶ is selected from hydrogen and fluoro; R⁷ and R⁸ are each independently selected from hydrogen, halogen, C₁-C₆-alkyl, halo-C₁- C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10- cycloalkyl, and 3- to 10-membered heterocyclyl; and C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H- triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; or (iii) X¹ and X² are N and X³ is CH; or. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C6-C10-aryl and C3-C10-cycloalkyl; R¹ is selected from halo-C₁-C₆-alkyl and halogen; R² is selected from hydrogen and halogen; and R³ is selected from hydrogen and halogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C6-C10-aryl and C3-C10-cycloalkyl; R¹ is selected from halo-C1-C6-alkyl and halogen; R² is selected from hydrogen and halogen; and R³ is hydrogen. In a further preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is C₆-C₁₀-aryl; R¹ is halogen; R² is halogen; and R³ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF₃, CHF₂, fluoro and chloro; R² is selected from hydrogen and fluoro; and R³ is selected from hydrogen and fluoro. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF₃, CHF₂, fluoro and chloro; R² is selected from hydrogen and fluoro; and R³ is hydrogen. In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is phenyl; R¹ is chloro; R² is fluoro; and R³ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described

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

selected from: Cl F F F F In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group

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

R^4b is selected from hydrogen and C1-C6-alkyl; R^4c is hydrogen; C is selected from pyridyl, pyrazolyl and 2H-triazole; R⁷ is selected from C1-C6-alkyl, C1-C6-alkoxy and C3-C10-cycloalkyl; and R⁸ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R^4b is selected from hydrogen and C1-C6-alkyl; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁷ is selected from C1-C6-alkyl and C3-C10-cycloalkyl; and R⁸ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from N N O N N N N N N O O N _N N O In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from N N O N N O In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁷ is selected from C₁-C₆-alkyl and C₁-C₆-alkoxy; and R⁸ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁷ is C1-C6-alkyl; and R⁸ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁷ is selected from methyl and methoxy; and R⁸ is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁵ is C1-C6-alkyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁵ is methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁶ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁶ is halogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; or (iii) X¹ and X² are N and X³ is CH; A is selected from C6-C10-aryl and C3-C10-cycloalkyl; R¹ is selected from halo-C1-C6-alkyl and halogen; R² is selected from hydrogen and halogen; R³ is selected from hydrogen and halogen;

R^4b is selected from hydrogen and C₁-C₆-alkyl; R^4c is hydrogen; R⁵ is C1-C6-alkyl; C is selected from pyridyl, pyrazolyl, and 2H-triazole; R⁶ is selected from hydrogen and fluoro; R⁷ is selected from C1-C6-alkyl, C1-C6-alkoxy and C3-C10-cycloalkyl; and R⁸ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; or (iii) X¹ and X² are N and X³ is CH; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF₃, CHF₂, fluoro and chloro; R² is selected from hydrogen and fluoro; R³ is selected from hydrogen and fluoro; B is selected from: N N O N N N N N N O O N _N N O R⁵ is methyl; and R⁶ is selected from hydrogen and fluoro. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is selected from C₆-C₁₀-aryl and C₃-C₁₀-cycloalkyl; R¹ is selected from halo-C1-C6-alkyl and halogen; R² is selected from hydrogen and halogen; R³ is hydrogen; R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁵ is C₁-C₆-alkyl; R⁶ is selected from hydrogen and halogen; R⁷ is selected from C1-C6-alkyl and C1-C6-alkoxy; and R⁸ is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF3, CHF2, fluoro and chloro; R² is selected from hydrogen and fluoro; R³ is hydrogen;

R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁵ is methyl; R⁶ is selected from hydrogen and fluoro; R⁷ is selected from methyl and methoxy; and R⁸ is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF3, CHF2, fluoro and chloro; R² is selected from hydrogen and fluoro; R³ is hydrogen;

R⁵ is methyl; and R⁶ is selected from hydrogen and fluoro. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is selected from C₆-C₁₀-aryl and C₃-C₁₀-cycloalkyl; R¹ is selected from halo-C1-C6-alkyl and halogen; R² is selected from hydrogen and halogen; R³ is selected from hydrogen and halogen;

R^4b is selected from hydrogen and C1-C6-alkyl; R^4c is hydrogen; R⁵ is C₁-C₆-alkyl; C is selected from pyridyl and pyrazolyl; R⁷ is selected from C₁-C₆-alkyl and C₃-C₁₀-cycloalkyl; and R⁸ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is phenyl; R¹ is selected from CF₃, fluoro and chloro; R² is fluoro; R³ is hydrogen; B is selected from: N N O

N N O R⁵ is C1-C6-alkyl; R⁷ is selected from C₁-C₆-alkyl and C₃-C₁₀-cycloalkyl; and R⁸ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is C6-C10-aryl; R¹ is halogen; R² is halogen; R³ is hydrogen;

R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁷ is C1-C6-alkyl; and R⁸ is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is phenyl; R¹ is chloro; R² is fluoro; R³ is hydrogen; B is selected from R⁷ is C₁-C₆-alkyl; and R⁸ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3- methyl-pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran- 4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran- 4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)oxan-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)oxan-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahydropyran-4- yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4- yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran- 4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]- 2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]- 2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran- 4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; and 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; and 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one. In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein as free bases. In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Certain isotopically-labeled compounds 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. 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. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, 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 The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary. If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature. If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically/enantiomerically enriched starting materials and intermediates. Using such diastereomerically/enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically/enantiomerically enriched compounds of formula (I). A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) - insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl.1996, 35, 2056). A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY.1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section. The following abbreviations are used in the present text: °C degrees celsius ¹H proton Å ångström Alk alkyl c concentration CAS Chemical Abstracts Service registry number CH₃CN acetonitrile CO₂ carbon dioxide DIPEA N,N-Diisopropylethylamine DMEM Dulbecco's modified eagle medium DMF N,N-Dimethylformamide DMSO dimethylsulfoxide DMSO-d6 hexadeuterodimethylsulfoxide EC₅₀ half maximal effective concentration EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq equivalent ESI electron spray ionization Ex. example FBS fetal bovine serum g gram g/L gram per liter h hour HATU hexafluorophosphate azabenzotriazole tetramethyl uronium HBTU hexafluorophosphate benzotriazole tetramethyl uronium HCOOH formic acid HEK human embryonic kidney HPLC high performance liquid chromatography J coupling constant kg kilogram M molar m/z mass-to-charge ratio MeOH methanol mg milligram MgSO₄ magnesium sulfate MHz megahertz min minute ml milliliter mm millimeter mmol millimole MS mass spectrometry Na₂SO₃ sodium sulfite Na2SO4 sodium sulfate NaHCO3 sodium bicarbonate NBS N-bromosuccinimide NCS N-chlorosuccinimide neg. negative NH₄Cl ammonium chloride nm nanometer NMR nuclear magnetic resonance spectroscopy pH potential of hydrogen pos. positive POY3 phosphorus oxitrihalide psi pounds per square inch R Rectus according to the Cahn–Ingold–Prelog priority rules RP reverse phase RPM revolutions per minute s second S Sinister according to the Cahn–Ingold–Prelog priority rules SFC supercritical fluid chromatography TFA trifluoroacetic acid TLC thin layer chromatography µl microliter µm micrometer µmol micromoles Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) αD specific rotation at 589 nm δ chemical shift in parts per million In the following schemes, R^A refers to a group

, wherein A, B, R¹, R² and R³ are as defined herein. Scheme 1

Y¹, Y² = Cl, Br R^A, R^B, R⁵, R⁶ and X¹, X², X³ according to claim definition Compounds of general formula Ia can be prepared as described in Scheme 1 by reacting intermediate II first with a boronic acid (or a boronic acid derivative) III under palladium catalysed conditions (a palladium source such as (1,1'-bis(diphenylphosphino)- ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0) and a base such as cesium carbonate or sodium carbonate) to form compound IV. This intermediate can be reacted with amine R^B-H (V) in presence of a base like N,N-diisopropylethylamine, triethylamine or the like in a dipolar aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone to form Ia (nucleophilic substitution). In addition, compound IV can be reacted with amine R^B-H (V) using palladium-catalysed coupling conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(0), a suitable ligand such as Xantphos and a base such as cesium carbonate or sodium tert.-butoxide to form compound Ia (metal-catalysed coupling). Scheme 2

Intermediates IIa can be prepared from compound VI by coupling with amine VII using amide coupling reagents such as HATU, HBTU, EDC or the like followed by reaction of the formed intermediate VIII with an orthoester IX at elevated temperatures. Alternatively, compound VIII can be reacted with an acid chloride X (or an acid anhydride) and a base like N,N- diisopropylethylamine, triethylamine or pyridine to form intermediate XI which is then cyclised by heating in presence of a base, in presence of trimethylsilyl chloride or in a suitable solvent without additive such as acetic acid (Scheme 2). Scheme 3

Y¹, Y² = Cl, Br R⁵, R⁶ according to claim definition Intermediates IIb can be prepared from compound XII by coupling with amine VII using amide coupling reagents such as HATU, HBTU, EDC or the like, followed by halogenation using N- bromosuccinimide or N-chlorosuccinimide in a suitable solvent to give compound XV. This compound can be reacted with an acid anhydride or an orthoester IX at elevated temperatures to form intermediate IIb (Scheme 3). Scheme 4

Y= Cl, Br R , R according to claim definition Intermediates IIc can be prepared from compound XVI by coupling with amine VII using amide coupling reagents such as HATU, HBTU, EDC or the like, followed by reaction with orthoester IX to form compound XVIII. Reaction of this compound with an inorganic halogenation reagent such as phosphorous oxychloride or phosphorous oxybromide XIX with or without an additional base gives intermediate IIc (Scheme 4). Scheme 5

Y, Y = Cl, Br R , R , R , R and X , X , X according to claim definition Compounds of general formula Ib can be prepared as described in Scheme 5 by reacting intermediate IV with boronic acid derivative XIX using a palladium catalyst and a base to form intermediate XX, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound Ib. Preferred catalysts are palladium on charcoal or platinum oxide in ethyl acetate, ethanol or methanol with or without the addition of further reagents like magnesium oxide or triethylamine. Scheme 6

XXV Intermediates IVa (R^A is preferably a cycloaliphatic group) can be prepared from compound XXII (available from XXI by amide coupling) by reacting it with a carboxylic acid XXIII under oxydative coupling conditions (using for example ammonium persulfate in dimethylsulfoxide at temperatures of 0 °C to 50 °C, Minisci reaction, additional blue LED irradiation can be applied) to form compound XXIV. This intermediate is reacted with anhydride or orthoester IX under elevated temperatures to give intermediate IVa. Furthermore, compound XXII can be first cyclised using anhydride or orthoester IX to form intermediate XXV which can then be reacted with carboxylic acid XXIII under oxydative coupling conditions (using for example ammonium persulfate in dimethylsulfoxide at temperatures of 0 °C to 50 °C, Minisci reaction, additional blue LED irradiation can be applied) to form intermediate IVa (Scheme 6). Scheme 7

Compounds Ic can be prepared according to Scheme 7. Compound XXVI is reacted with boronic acid III under palladium catalysed conditions to give compound XXVII. This intermediate is further reacted with amine V in presence of a base like N,N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone to form XXVIII. Reaction of this compound with N- bromosuccinimide in a suitable solvent leads to formation of XXIX, which is transformed to compound XXXI by palladium-catalysed reaction with tin derivative XXX. Aminolysis of ester XXXI with amine IX in a solvent like ethanol or methanol gives rise to compound XXXII which is treated with a base like sodium methoxide to achieve cyclisation to compounds XXXIII. Oxydation with a suitable reagent such as selenium dioxide leads to aldehyde XXXVI which can then finally be transformed to compound Ic by using a fluorinating reagent like DAST or Deoxo- fluor. In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the process is as described in any one of schemes 1 to 7. In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein. TREM2 Agonistic Activity Compounds of the present invention are TREM2 agonists. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for restoring the function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of restoring the function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for restoring the function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides a method for restoring the function of human TREM2 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) as described herein to the subject. TREM2 agonist potency of the compounds of formula (I) according to the invention was measured using a HEK cell line expressing human TREM2 and DAP12. Upon binding of small molecule ligands to the TREM2 receptor, Syk kinase is recruited and activated by DAP12. The resulting increased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit. To perform the assay, frozen HEK293-TREM2/DAP12 cells were thawed, adjusted and plated by using Certus at 20,000 cells per well in a 384 well plate, in 10 μL of DMEM media without Phenolred and supplemented with 5% FBS. Compounds in dose response (1:3) were diluted in DMSO (highest concentration 10mM) and added to the cells from a Low Dead Volume plate using the ECHO (0-20 uM), diluting 500x (20 nL in 10 µl cell suspension; highest concentration 20uM, DMSO concentration 0.2% in all wells). Neutral (DMSO) and stimulator (1µM tool compound) controls were also added. Cells were incubated for 30 minutes at 37°C, 5% CO2 and 95% humidity. After compound addition and incubation, 2.5μL of lysis buffer was added by using the Certus. After a quick spin, plates were shaken for 30 minutes at 450 RPM, at room temperature and in the dark. After complete lysis, AlphaLisa reagents were added by Certus to the lysate, and fluorescence intensity was measured using a Pherastar plate reader (Excitation: 680nm/Emission: 615nm). EC50 values were calculated by using Genedata Screener, normalized to DMSO and 100% activity to the tool compound. TREM2 agonistic potencies of the compounds of formula (I) according to the invention as measured in the assay described above are presented in table 1. TREM2 agonistic potencies of reference compounds as measured in the assay described above are presented in table 2. Table 1 hTREM2 hTREM2 Ex. Ex. EC₅₀ (µM) EC₅₀ (µM) 1 0.007 17 0.015 2 0.003 18 0.002 3 0.125 19 0.103 4 0.023 20 0.015 5 0.007 21 0.245 6 0.119 22 0.665 7 0.002 23 0.020 8 0.014 24 0.237 9 0.001 25 0.024 10 0.005 26 2.143 11 0.026 27 0.019 12 0.010 28 0.144 13 0.025 29 0.647 14 0.046 30 0.962 15 0.004 31 0.052 16 0.165 32 0.109 hTREM2 hTREM2 Ex. Ex. EC50 (µM) EC50 (µM) 33 1.334 52 1.444 34 1.884 53 0.725 35 0.014 54 0.040 36 2.130 55 1.849 37 0.050 56 0.032 38 0.012 57 0.164 39 0.748 58 0.579 40 0.809 59 0.046 41 0.093 Table 2 42 1.920 Reference hTREM2 Example EC50 (µM) 43 0.020 1 0.840 44 0.409 2 0.031 45 0.707 3 0.012 46 0.038 4 0.400 47 1.608 5 0.022 48 0.135 6 0.003 49 0.013 7 0.051 50 0.929 51 0.020 Using the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein for use as a therapeutically active substance. In a further aspect, the present invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof. In one embodiment, said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Parkinson’s disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is rheumatoid arthritis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Alzheimer’s disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke. Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier. In one embodiment, there is provided a pharmaceutical composition according to Example 60 or 61. The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions). The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules. Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi- solid substances and liquid polyols, etc. Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc. Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi- solid or liquid polyols, etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated. Examples The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples. In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization. The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers. According to the Cahn-Ingold- Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration. For the compounds described in the patent the absolute stereochemistry was arbitrarily assigned. All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise. The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. The following intermediates were prepared according to the procedures provided herein, are commercially available or can be prepared according to literature procedures. Intermediate A1: 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one

Step 1: 5-amino-2-chloro-N-methyl-isonicotinamide

To a solution of 5-amino-2-chloro-isonicotinic acid (800 mg, 4.64 mmol) in dichloromethane (10 ml) at room temperature were added methylamine hydrochloride (438 mg, 6.49 mmol), N,N- diisopropylethylamine (1.8 g, 2.43 ml, 13.9 mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.07 g, 5.56 mmol) and 1-hydroxybenzotriazole hydrate (710 mg, 4.64 mmol) and the mixture was stirred for 42 h. The solvent was evaporated. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried with Na2SO4, filtrated and evaporated. The crude mixture was purified by flash chromatography (silica gel, gradient dichloromethane / methanol 100:0 to 92:8) to give 5-amino-2-chloro-N-methyl-isonicotinamide (724 mg, 84% yield) as light yellow solid, MS m/z: 186.0 [M+H]⁺, ESI pos. Step 2: 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide

To a solution of 5-amino-2-chloro-N-methyl-isonicotinamide (700 mg, 3.77 mmol) in N,N- dimethylformamide (7.5 ml) was added N-bromosuccinimide (806 mg, 4.53 mmol) and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtrated and evaporated. The crude mixture was purified by flash chromatography (silica gel, gradient heptane / ethyl aceate 100/0 to 50/50) to give 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (961 mg, 96% yield) as light yellow solid, MS m/z: 264.0 [M+H]⁺, ESI pos. Step 3: 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one

To a solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (961 mg, 3.63 mmol) in 1,1,1-trimethoxyethane (3.2 g, 3.35 ml, 26.6 mmol) was added acetic acid (218 mg, 208 µl, 3.63 mmol) and the reaction mixture was stirred 20 h at 135 °C. As the reaction was not yet completed more 1,1,1-trimethoxyethane (1.31 g, 1.37 ml, 10.9 mmol) and acetic acid (109 mg, 104 µl, 1.82 mmol) were added and stirring was continued overnight at 135 °C. After evaporating excess in vaccuo the crude mixture was purified by flash chromatography (silica gel, gradient heptane/ethyl acetate 100/0 to 60/40) to give 8-bromo-6-chloro-2,3-dimethyl- pyrido[3,4-d]pyrimidin-4-one (789 mg, 75%) as light yellow solid, MS m/z: 290.0 [M+H]⁺, ESI pos. Intermediate A2: 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one 3-[(2,2-difluoroacetyl)amino]-N-methyl-isonicotinamide To a solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see Intermediate A1, 0.600 g, 2.27 mmol) in dry tetrahydrofuran (15 ml) was added at 0 °C 2,2-difluoroacetic acid anhydride (395 mg, 282 µl, 2.27 mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated and triturated in diethyl ether to afford 2-bromo-6- chloro-3-[(2,2-difluoroacetyl)amino]-N-methyl-isonicotinamide (678 mg, 88% yield) as white solid, MS m/z: 344.0 [M+H]⁺, ESI pos. Step 2: 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one

A solution of 2-bromo-6-chloro-3-[(2,2-difluoroacetyl)amino]-N-methyl-isonicotinamide (678 mg, 1.98 mmol) in acetic acid (8 ml) was heated at 110 °C for 3 h. The reaction mixture was concentrated in vacuo and triturated in diethyl ether to afford 8-bromo-6-chloro-2- (difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (510 mg, 79% yield) as white solid, MS m/z: 326.0 [M+H]⁺, ESI pos. Intermediate A3: 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A1 from trifluoroacetic acid anhydride instead of 2,2-difluoroacetic acid anhydride in step 1. Yellow solid, MS m/z: 344.0 [M+H]⁺, ESI pos. Intermediate A4: 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one N-methyl-1H-pyrimidine-6-carboxamide

To a solution of 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylic acid (CAS 7164-43-4, 5 g, 29.2 mmol) in N,N-dimethylformamide (120 ml) N,N-diisopropylethylamine (15.1 g, 20.4 ml, 117 mmol) and methylamine hydrochloride (3.95 g, 58.4 mmol) were added at room temperature. HATU (14.4 g, 38 mmol) was added portionwise and the mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo to remove most of the solvent and the residue was suspended in a mixture of 150 ml of methanol/methyl tert-butyl ether=1:1. The suspension was stirred for 10 min before it was filtered off and washed with methanol/methyl tert-butyl ether. The obtained solids were dried in vacuo to yield 5-amino-2,4-diketo-N-methyl- 1H-pyrimidine-6-carboxamide (4.0 g, 67% yield) as yellow solid. MS m/z: 185.0 [M+H]⁺, ESI pos. Step 2: 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione A suspension of 5-amino-2,4-diketo-N-methyl-1H-pyrimidine-6-carboxamide (3 g, 16.3 mmol) in triethyl orthoacetate (13.2 g, 15 ml, 81.5 mmol) and acetic acid (980 mg, 933 µl, 16.3 mmol) was stirred for 5 h at 130 °C. The reaction mixture was diluted with methyl tert-butyl ether and stirred for another 5 min before solids were filtered off and washed with methyl tert-butyl ether. Solids were dried in vacuo to obtain the title compound 2,3-dimethyl-5H-pyrimido[5,4- d]pyrimidine-4,6,8-trione (3.26 g, 86.5% yield) as yellow solid, MS m/z: 209.0 [M+H]⁺, ESI pos. Step 3: 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one

To a solution of 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (3.2 g, 15.4 mmol) in phosphorus oxychloride (49.35 g, 30 ml, 322 mmol) a mix of N,N-diisopropyl ethylamine (2.0 g, 2.68 ml, 15.4 mmol) and N,N-dimethylformamide (181 mg, 192 µl, 2.48 mmol) was added dropwise at room temperature. The mixture was stirred overnight at 130 °C, then concentrated to dryness. The residue was taken up with dichloromethane. Water was added and the mixture was extracted two times with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to obtain the title compound 6,8-dichloro-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one (1.44 g, 38% yield) as brown solid, MS m/z: 245.0 [M+H]⁺, ESI pos. Intermediate A5: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl- pyrido[3,4-d]pyrimidin-4-one To a solution of 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A2, 500 mg, 1.54 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (269 mg, 1.54 mmol) in 1,4-dioxane (9 ml) and water (3 ml) was added cesium carbonate (1.51 g, 4.62 mmol). The reaction mixture was purged and backfilled with argon three times, then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (63 mg, 0.077 mmol, 0.050 eq) was added. After purging and filling with argon again, the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-30%) and then triturated in diethyl ether to afford 6-chloro-8-(4- chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (235 mg, 41%yield) as off-white solid, MS m/z: 374.1 [M+H]⁺, ESI pos. Intermediate A6: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)- pyrido[3,4-d]pyrimidin-4-one

To a solution of 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one (Intermediate A3, 250 mg, 0.73 mmol) in 1,4-dioxane (3 ml), water (1 ml) was added 4-chloro- 2-fluorophenylboronic acid (127 mg, 0.73 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol, 0.05 eq) and cesium carbonate (713 mg, 2.19 mmol). Then the mixture was degassed with nitrogen three times and stirred at 30 °C for 16 h under nitrogen atmosphere. The reaction mixture was added into water (20 ml) and extracted with dichloromethane (20 ml x 3). The combined organic layers were washed with brine (50 ml) and dried over Na₂SO₄, then concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 1:1) to give 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin- 4-one (60 mg, 21% yield) light yellow solid, MS m/z: 392.0 [M+H]⁺, ESI pos. Intermediate A7: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl- pyrimido[5,4-d]pyrimidin-4-one

Step 1: ethyl 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylate

A solution of (4-chloro-2-fluoro-phenyl)-boronic acid (1.33 g, 7.63 mmol) and 5-amino-2,6- dichloro-pyrimidine-4-carboxylic acid ethyl ester (1.5 g, 6.35 mmol) in 1,4-dioxane (28.85 mL) was purged with argon. Then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (525 mg, 0.635 mmol, 0.10 eq) and 3 M aqueous cesium carbonate solution (6.35 ml, 19.1 mmol) were added, and the reaction was heated overnight to 60 °C while stirring under argon. The reaction mixture was filtered over Celite, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na₂SO₄ and evaporated. The product was purified by flash chromatography (silica gel, 10 - 50% ethyl acetate in heptane) to yield ethyl 5-amino-2-chloro-6-(4-chloro-2-fluoro- phenyl)pyrimidine-4-carboxylate (1.64 g, 74% yield) as yellow powder, MS m/z: 330.0 [M+H]⁺, ESI pos. Step 2: 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid

To a solution of ethyl 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylate (1.64 g, 4.97 mmol) in tetrahydrofuran (20 ml) and water (20 ml) was added aqueous lithium hydroxide solution (0.5 M, 14.9 ml, 7.45 mmol) and the mixture was stirred for 1 h at room temperature. Then hydrochloric acid (2 M, 8 ml) was added, the volatiles were evaporated and the formed precipitate was filtered, washed with water and dried under high vacuum to yield 5- amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid (1.49 g, 95% yield) as yellow solid, MS m/z: 302.0 [M+H]⁺, ESI pos. Step 3: 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4-carboxamide

5-Amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid (1.0 g, 3.18 mmol) was dissolved in N,N-dimethylformamide (15 ml). N,N-diisopropylethylamine (1.64 g, 2.2 ml, 12.7 mmol) and methylamine hydrochloride (429 mg, 6.36 mmol) were added, then HATU (1.57 g, 4.13 mmol) was added portionwise and the mixture was stirred overnight. The reaction was diluted with water and extracted with ethyl acetate twice. The combined organic layers were washed with NH4Cl solution and brine, dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate in heptane) to yield 5- amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4-carboxamide (429 mg, 42% yield) as yellow solid, MS m/z: 315.0 [M+H]⁺, ESI pos.

4-carboxamide

To a solution of 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4- carboxamide (272 mg, 0.846 mmol) in tetrahydrofuran (5 ml) was added 2,2-difluoroacetic acid anhydride (147 mg, 105 µl, 0.846 mmol) at 0 °C. The reaction was stirred at room temperature overnight. The volatiles were evaporated to yield 2-chloro-6-(4-chloro-2-fluoro-phenyl)-5-[(2,2- difluoroacetyl)amino]-N-methyl-pyrimidine-4-carboxamide (332 mg, 97% yield) as yellow solid, MS m/z: 393.1 [M+H]⁺, ESI pos.

A solution of 2-chloro-6-(4-chloro-2-fluoro-phenyl)-5-[(2,2-difluoroacetyl)amino]-N-methyl- pyrimidine-4-carboxamide (332 mg, 0.819 mmol) in acetic acid (4.1 ml) was stirred for 1 h at 110 °C. The volatiles were evaporated and the product was purified by flash column chromatography (silica gel, 5-50% ethyl acetate in heptane) to yield 6-chloro-8-(4-chloro-2- fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrimido[5,4-d]pyrimidin-4-one (98 mg, 32% yield) as off-white solid, MS m/z: 375.1 [M+H]⁺, ESI pos. Intermediate A8: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

Step 1: 2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2,2,2- trifluoroacetyl)amino]pyrimidine-4-carboxamide

To a solution of 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4- carboxamide (see Intermediate A7, 2.2 g, 6.98 mmol) in tetrahydrofuran (30 ml) was added 4- dimethylaminopyridine (85 mg, 0.7 mmol) and trifluoroacetic acid anhydride (1.48 ml, 10.5 mmol) at 0 °C. The reaction was stirred at 30 °C for 16 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, then concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 5:1) to give 2-chloro- 6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4- carboxamide (2.2 g, 75% yield) as light yellow gum. Step 2: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one To a solution of 2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2,2,2- trifluoroacetyl)amino]pyrimidine-4-carboxamide (1.4 g, 3.41 mmol) in dichloromethane (20 ml) was added triethylamine (14.2 ml, 102.15 mmol) and trimethylsilyl chloride (4.33 ml, 34.1 mmol) at 0 ℃ and the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo to give 6-chloro-8-(4- chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (1.34 g, 100% yield) as light yellow solid. MS m/z: 393.0 [M+H]⁺, ESI pos. Intermediate A9: 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one N-methyl-pyrimidine-4-carboxamide

To a solution of 5-amino-2-chloro-pyrimidine-4-carboxylic acid (3 g, 17.3 mmol) in N,N- dimethylformamide (50 ml) was added methylamine hydrochloride (1.75 g, 25.9 mmol) and N,N-diisopropyl ethylamine (6.7 g, 9.06 ml, 51.9 mmol) at room temperature. Then, HATU (7.89 g, 20.74 mmol) was added and the mixture was stirred at room temperature for 3 days. The solvent was evaporated and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na₂SO₄ and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to afford 5-amino-2-chloro-N- methyl-pyrimidine-4-carboxamide (2.6 g, 81% yield) as pink solid, MS m/z: 187.0 [M+H]⁺, ESI pos. Step 2: 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-pyrimidine-4-carboxamide

2,2-Difluoroacetic acid anhydride (1.03 g, 0.73 µl, 5.89 mmol) was added to a solution of 5- amino-2-chloro-N-methyl-pyrimidine-4-carboxamide (1.1 g, 5.89 mmol) in tetrahydrofuran (33 ml) at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C, then the cooling bath was removed and the reaction mixture was warmed to room temperature over 1 h. The volatiles were evaporated in vacuo and the crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to afford 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl- pyrimidine-4-carboxamide (1.12 g, 72% yield) as colorless oil, MS m/z: 265.1 [M+H]⁺, ESI pos. Step 3: 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide

To a solution of 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-pyrimidine-4-carboxamide (322 mg, 1.22 mmol) in dimethyl sulfoxide / water (600:1) was added 3-(trifluoromethyl)- bicyclo[1.1.1]pentane-1-carboxylic acid (2.19 g, 12.17 mmol). The reaction mixture was sparged with argon. A freshly prepared solution of ammonium persulfate (1.67 g, 7.3 mmol) in sparged dimethyl sulfoxide / water (600:1) was added under argon and the reaction mixture was stirred at 40 °C for 18 h. The reaction mixture was quenched with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to afford 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide (240 mg, 44% yield) as light yellow solid, MS m/z: 397.1 [M-H]-, ESI neg. Step 4: 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one

To a solution of 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide (230 mg, 0.49 mmol) in toluene (5 ml) was added p-toluenesulfonic acid monohydrate (9 mg, 49 µmol) and the mixture was heated to 110 °C for 1 h. The reaction mixture was diluted with saturated NaHCO3-solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to afford the title compound (120 mg, 61% yield) as white foam, MS m/z: 381.1 [M+H]⁺, ESI pos. Intermediate A10: 6-chloro-8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl- pyrimido[5,4-d]pyrimidin-4-one

The title compound was prepared in analogy to Intermediate A9 from 4,4- difluorocyclohexanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1- carboxylic acid in step 3. White foam, MS m/z: 365.1 [M+H]⁺, ESI pos. Intermediate A11: 6-chloro-2-(difluoromethyl)-8-[3-(difluoromethyl)-1- bicyclo[1.1.1]pentanyl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one

The title compound was prepared in analogy to Intermediate A9 from 3-(difluoromethyl)- bicyclo[1.1.1]pentane-1-carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1- carboxylic acid in step 3. White solid, MS m/z: 363.2 [M+H]⁺, ESI pos. Intermediate A12: 6-chloro-2-(difluoromethyl)-8-(2,4-difluorophenyl)-3-methyl-pyrimido[5,4- d]pyrimidin-4-one

The title compound was prepared in analogy to Intermediate A7 from (2,4- difluorophenyl)boronic acid instead of (4-chloro-2-fluoro-phenyl)-boronic acid in step 1. Yellow foam, MS m/z: 359.1 [M+H]⁺, ESI pos. Intermediate A13: 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one -3-methyl-pyrido[3,4-d]pyrimidin-4-one

In a flask was added 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4- one (Intermediate A2, 1 g, 3.08 mmol) and palladium on charcoal (10%, 100 mg), and the flask was purged with argon. Ethyl acetate (15 ml) and triethylamine (468 mg, 644 µl, 4.62 mmol) were added and the argon balloon was replaced with hydrogen. The reaction was allowed to stir for 3 h. The product was purified by flash column chromatography (silica gel, 2-10% ethyl acetate in heptane) to afford 6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (283 mg, 37% yield) as white solid. MS m/z: 246.0 [M+H]⁺, ESI pos. Step 2: 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one

To a degassed solution of 6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (450 mg, 1.83 mmol) in 12 ml of dimethylsulfoxide / water (600:1), a solution of ammonium persulfate (2.51 g, 11 mmol) in the same dimethylsulfoxide / water mixture (24 ml) was added and the reaction was stirred at 40 °C for 18 h. The reaction was diluted in ethyl acetate and washed with water, then brine. The product was purified by flash column chromatography (silica gel, heptane/ethyl acetate) to give the title compound (130 mg, 16% yield) as white solid. MS m/z: 380.2 [M+H]⁺, ESI pos. Intermediate A14: 6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

Step 1: 2-chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide To a solution of 5-amino-2-chloro-N-methyl-pyrimidine-4-carboxamide (see Intermediate A9 step 1, 6.0 g, 32.2 mmol) and 4-dimethylaminopyridine (393 mg, 3.22 mmol) in tetrahydrofuran (60 ml) was added trifluoroacetic acid anhydride (5.35 ml, 38.6 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed by brine (100 ml) and dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethylacetate = 1:0 to 2:1) to give 2-chloro-N- methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (8.0 g, 88% yield) as off- white solid. MS m/z: 283.1 [M+H]⁺, ESI pos. Step 2: 6-chloro-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

To a solution of 2-chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (7.0 g, 24.77 mmol, 1.0 eq) in dichloromethane (100 ml) were added triethylamine (34.4 ml, 248 mmol), then dropwise trimethylsilyl chloride (15.8 ml, 124 mmol) at 0 °C under nitrogen. The mixture was then stirred at 25 °C for 2 h under nitrogen. To the mixture was added dropwise 1 M aqueous hydrochloric acid until pH = 3-4, then it was extracted with dichloromethane (100 ml x 2). The combined organic layers were washed with brine (100 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethylacetate = 1:0 to 1:1) to give 6-chloro-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (3.8 g, 58% yield) as light yellow solid. MS m/z: 265.2 [M+H]⁺, ESI pos. Step 3: 6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one

To a solution of 6-chloro-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (1.0 g, 3.78 mmol) in dimethylsulfoxide (75 ml) was added 4,4-difluorocyclohexane carboxylic acid (1.86 mg, 11.3 mmol), ammonium persulfate (3.45 g, 15.12 mmol) and [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl- N]phenyl-C]Iridium(III) hexafluorophosphate (CAS 870987-63-6, 42 mg, 0.04 mmol, 0.01 eq). The mixture was degassed and purged with nitrogen, then the mixture was stirred at 25 °C for 16 h and irradiated with a 455 nm blue LED. The reaction mixture was purified by preparative MPLC (column: Spherical C18, 20-45 µm, 100 A, water + 0.1% formic acid / acetonitrile, flow rate 100ml/min) and the eluent was lyophilized to give a product 6-chloro-8-(4,4- difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (1.0 g, 69% yield) as light brown solid. MS m/z: 383.1 [M+H]⁺, ESI pos. Intermediate A15: 6-chloro-8-(4-chlorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4- d]pyrimidin-4-one

The title compound was prepared in analogy to Intermediate A6 from 4-chlorophenylboronic acid instead of 4-chloro-2-fluorophenylboronic acid in step 1. Yellow solid, MS m/z: 374.0 [M+H]⁺, ESI pos. Intermediate A16: 6-chloro-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

The title compound was prepared in analogy to Intermediate A14 from 3- (difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 4,4-difluorocyclohexane carboxylic acid in step 3. Yellow solid, MS m/z: 374.0 [M+H]⁺, ESI pos. Intermediate A17: 6-chloro-8-(4-chlorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one

The title compound was prepared in analogy to Intermediate A7 from 4-chlorophenylboronic acid instead of (4-chloro-2-fluoro-phenyl)-boronic acid acid in step 1 and trifluoroacetic acid anhydride instead of 2,2-difluoroacetic acid anhydride step 4, light yellow gum, MS m/z: 375.0 [M+H]⁺, ESI pos. Intermediate Name Structure Source B1 2-(1-methylpyrazol-4- commercial, yl)morpholine CAS 1375963- 52-2 B₂ 2-(2-methyl-4- commercial, pyridyl)morpholine CAS 1211523- 01-1 B3 2-(2-methoxy-4- commercial, pyridyl)morpholine CAS 2091599- 93-6 B4 2-(1-cyclopropylpyrazol-4- N known, yl)-6-methyl-morpholine ^N NH CAS O 2738496- 25-6 B5 1-methyl-4-[4-(4,4,5,5- known, tetramethyl-1,3,2- dioxaborolan-2-yl)-3,6- CAS 2738350- dihydro-2H-pyran-6-yl]-4H- 63-3 pyrazole Chiral Separation of Intermediate B1: 2-(1-Methylpyrazol-4-yl)morpholine (Intermediate B1) was separated by chiral SFC (column AD-H, 5 µm, 100 x 4.6 mm, 20-40% MeOH + 0,2% diethylamine) to yield (+)- 2-(1- methylpyrazol-4-yl)morpholine (+)-B1 as the first eluting enantiomer and (-)- 2-(1- methylpyrazol-4-yl)morpholine (-)-B1 as the second eluting enantiomer. (+)- 2-(1- methylpyrazol-4-yl)morpholine: yellow oil, αD(589nm) 20 °C = +13.36° (c = 0.1 g/L, MeOH). Intermediate B6: 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyridine

To a solution of 2-methoxyisonicotinaldehyde (1.0 g, 7.29 mmol) in dichloromethane (10 ml) was added at 3-butyn-1-ol (767 mg, 0.833 ml, 10.94 mmol) under argon. Then the mixture was cooled to -10 ℃ and trifluoromethanesulfonic acid (3.28 g, 1.92 ml, 21.9 mmol) was added. After stirring for 30 min at -10 °C the mixture was warmed to room temperature and stirring was continued overnight. The reaction mixture was diluted with saturated NaHCO₃-solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to afford [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl] trifluoromethanesulfonate (870 mg, 32% yield) as colorless oil, MS m/z: 340.1 [M+H]⁺, ESI pos. Step 2: 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridine To a solution of [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (870 mg, 2.31 mmol) in 1,4-dioxane (15 ml) were added bis(pinacolato)diboron (1.17 g, 4.62 mmol), potassium acetate (906 mg, 9.23 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (189 mg, 0.231 mmol, 0.10 eq). The mixture was purged and backfilled with argon three times, then stirred at 90 °C for 2 h. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-80%) to afford 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridine (656 mg, 81% yield) as colorless oil, MS m/z: 318.3 [M+H]⁺, ESI pos. Intermediate B7: 2-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]triazole

The title compound was prepared in analogy to Intermediate B6 from 2-methyl-2H-1,2,3- triazole-4-carboxaldehyde (CAS 1104078-88-7) instead of 2-methoxyisonicotinaldehyde. Light yellow oil, MS m/z: 292.1 [M+H]⁺, ESI pos. Example 1: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one A solution of 2-(2-methyl-4-pyridyl)morpholine (Intermediate B2, 48 mg, 0.267 mmol), 6- chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A5, 50 mg, 0.134 mmol) and N,N-diisopropylethylamine (52 mg, 70 µl, 401 µmol ) in dimethyl sulfoxide (1 ml) was stirred at 120 °C for 2 h. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated to dryness. The residue was purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 µm, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford the title compound (47 mg, 66% yield) as yellow powder, MS m/z: 516.2 [M+H]⁺, ESI pos. Example 2 and 3: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2- methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2- (difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4- one

The enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one (Example 1) were separated by chiral SFC (column Daicel IH, 5 µm, 250 x 20 mm, 20% methanol + 0,2% diethylamine). The solvent was evaporated to give 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2- methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one (15 mg, 36% yield), second eluting isomer (t = 1.64 min), as yellow solid, MS m/z: 516.1 [M+H]⁺, ESI pos. and 8-(4-chloro-2- fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one (15 mg, 36%) first eluting isomer (t = 1.22 min), as yellow solid, MS m/z: 516.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 4: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one

To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4- d]pyrimidin-4-one (Intermediate A6, 50 mg, 0.13 mmol) in 1,4-dioxane (2 ml) was added tris(dibenzylideneacetone)dipalladium (6 mg, 0.01 mmol, 0.05 eq), Xantphos (7.5 mg, 0.01 mmol, 0.1 eq) and (2R)-2-(1-methylpyrazol-4-yl)morpholine (32 mg, 0.19 mmol). The mixture was degassed with nitrogen three times and stirred at 100 °C for 16 h under nitrogen. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column Phenomenex Luna C18, 150 x 25 mm x 10 µm, water + 0.1% formic acid / acetonitrile, flow rate 25 ml/min) to give the title compound (4.5 mg, 7% yield) as light yellow solid. MS m/z: 523.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 5 and 6 were prepared in analogy to Examples 1 by starting from the indicated intermediates instead of intermediate B2. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediate (ESI): m/z 8-(4-chloro-2-fluoro- phenyl)-2-(difluoromethyl)- 3-methyl-6-[(2S)-2-(1- 505.3 5 (+)-B1 methylpyrazol-4- [M+H]⁺ yl)morpholino]pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2-(difluoromethyl)- 3-methyl-6-[(2R)-2-(1- 505.2 6 (-)-B1 methylpyrazol-4- [M+H]⁺ yl)morpholino]pyrido[3,4- d]pyrimidin-4-one Example 7: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one

To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl- pyrimido[5,4-d]pyrimidin-4-one (Intermediate A7, 62 mg, 0.15 mmol) and 2-(2-methyl-4- pyridyl)morpholine (Intermediate B2, 54 mg, 0.30 mmol) in N,N-dimethylformamide (1 ml) was added N,N-diisopropylethylamine (97 mg, 131 µl, 0.75 mmol) and the mixture was heated to 120 °C for 90 min. The solution was directly submitted to preparative HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm, acetonitrile / water + 0.1% triethylamine) to give the title compound (27 mg, 35% yield) as yellow solid, MS m/z: 517.2 [M+H]⁺, ESI pos. Example 8 and 9: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2- methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)- 2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4- d]pyrimidin-4-one

The enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (Example 7, 23 mg) were separated by chiral SFC (column: chiral IC, 5 µm, 250 x 20 mm, 40% methanol + 0,2% diethylamine). The solvent was evaporated to give 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6- [(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (9 mg, 39% yield), first eluting isomer (t = 4.19 min), as yellow solid, MS m/z: 517.2 [M+H]⁺, ESI pos. and 8-(4- chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (9 mg, 39%) second eluting isomer (t = 5.25 min), as yellow solid, MS m/z: 517.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 10: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one

The title compound was prepared in analogy to Example 7 from Intermediate (+)-B1 instead of Intermediate B2, yellow solid, MS m/z: 506.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 11: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)- pyrimido[5,4-d]pyrimidin-4-one (Intermediate A8, 60 mg, 0.15 mmol) in dimethylsulfoxide (2 ml) was added N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) and (2S)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-B1, 38 mg, 0.23 mmol) and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was acidified by formic acid until pH = 5-7. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml/min) to give the title compound (14 mg, 17% yield) as light yellow solid. MS m/z: 524.1 [M+H]⁺, ESI pos. The following Examples 12 to 14 were prepared in analogy to Examples 7 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediates (ESI): m/z 2-(difluoromethyl)-3- methyl-6-[(2S)-2-(1- methylpyrazol-4- yl)morpholino]-8-[3- A9 and (+)- 512.1 12 (trifluoromethyl)-1- B1 [M+H]⁺ bicyclo[1.1.1]pentanyl]pyri mido[5,4-d]pyrimidin-4- one 8-(4,4-difluorocyclohexyl)- 2-(difluoromethyl)-3- methyl-6-[(2S)-2-(1- A10 and (+)- 496.4 13 methylpyrazol-4- B1 [M+H]⁺ yl)morpholino]pyrimido[5, 4-d]pyrimidin-4-one 2-(difluoromethyl)-8-[3- (difluoromethyl)-1- bicyclo[1.1.1]pentanyl]-3- A11 and (+)- 494.4 14 methyl-6-[(2S)-2-(1- B1 [M+H]⁺ methylpyrazol-4- yl)morpholino]pyrimido[5, 4-d]pyrimidin-4-one Example 15 and Example 16: 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4- pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4- chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one The title compounds were prepared in analogy to Example 11 from Intermediate B3 instead of Intermediate (+)-B1 followed by separation of enantiomers by chiral SFC (column Daicel Chiralpak AD 250 mm × 30 mm, 10 µm, isopropanol / 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]- 3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one as the first eluting enantiomer, light yellow solid, MS m/z: 551.1 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2- (2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4- one as the second eluting enantiomer, light yellow solid, MS m/z: 551.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 17 and Example 18 and Example 19 and Example 20: 8-(4-chloro-2-fluoro-phenyl)- 6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)- 2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2- (1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)- 2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one The title compounds were prepared in analogy to Example 11 from Intermediate B4 instead of Intermediate (+)-B1 followed by separation of diastereomers by preparative HPLC (column: Phenomenex Synergi C18, 150 x 25 mm x 10 µm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml/min) and secondly by separation of enantiomers by chiral SFC (column Daicel Chiralpak AD 250 mm × 30 mm, 10 µm, ethanol / 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6- methyl-morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4- chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3- methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6- [(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)- 2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one, light yellow gums, MS m/z: 564.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 21 and Example 22 and Example 23: 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6- [2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one and 2- (difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6- [(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4- one

Step 1: 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one

A mixture of 6-chloro-2-(difluoromethyl)-8-(2,4-difluorophenyl)-3-methyl-pyrimido[5,4- d]pyrimidin-4-one (Intermediate A12, 110 mg, 0.245 mmol), 2-methoxy-4-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (Intermediate B6, 117 mg, 0.368 mmol), potassium carbonate (102 mg, 0.74 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 24 µmol, 0.10 eq) in 1,4-dioxane (2.5 ml) and water (0.5 ml) was flushed with argon and stirred at 60 °C for 2 h. The reaction mixture was diluted with saturated NaHCO₃-solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to afford 2-(difluoromethyl)-8-(2,4- difluorophenyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methyl- pyrimido[5,4-d]pyrimidin-4-one (111 mg, 86% yield) as light yellow foam, MS m/z: 514.3 [M+H]⁺, ESI pos. Step 2: 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6- [(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4- one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one

To a solution of 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[6-(2-methoxy-4-pyridyl)-3,6- dihydro-2H-pyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one (105 mg, 0.204 mmol) in ethyl acetate (2 ml) was added palladium on charcoal (10%, 44 mg) under argon. The flask was evacuated and backfilled with argon three times and then filled with hydrogen. The reaction mixture was stirred at room temperature under hydrogen for 3 h, then it was filtered on dicalite and washed with ethyl acetate. The combined organic layers were concentrated. The residue was purified by preparative HPLC (column: YMC Triart, C18, 100 mm × 30 mm, 5 µm, mobile phase: water / 0.1% formic acid - acetonitrile, 0-100%) to afford 2-(difluoromethyl)-8-(2,4- difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4- d]pyrimidin-4-one (48 mg, 45% yield) as white powder, MS m/z: 516.3 [M+H]⁺, ESI pos. An amount of 44 mg of this compound was separated by chiral SFC (column chiral Lux C4, 5 µm, 250 x 20 mm, 40% methanol + 0,2% diethylamine, flow rate 90 ml/min) to give 2- (difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one (17 mg, 39% yield), first eluting enantiomer, white powder, MS m/z: 516.3 [M+H]⁺, ESI pos. and 2-(difluoromethyl)-8-(2,4-difluorophenyl)- 6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin- 4-one (18 mg, 41% yield), second eluting enantiomer, white powder, MS m/z: 516.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 24 to 31 were prepared in analogy to Examples 21 to 23 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediates (ESI): m/z 2-(difluoromethyl)-6- [(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4- yl]-3-methyl-8-[3- 538.5 24 A9 and B6 (trifluoromethyl)-1- [M+H]⁺ bicyclo[1.1.1]pentanyl]pyri mido[5,4-d]pyrimidin-4- one 2-(difluoromethyl)-6- F [(2R,4S)-2-(2-methoxy-4- F F pyridyl)tetrahydropyran-4- O F yl]-3-methyl-8-[3- 538.5 25 N A9 and B6 N N F (trifluoromethyl)-1- [M+H]⁺ N N bicyclo[1.1.1]pentanyl]pyri O O mido[5,4-d]pyrimidin-4- one 8-(4,4-difluorocyclohexyl)- 2-(difluoromethyl)-6- [(2S,4R)-2-(2-methoxy-4- 522.5 26 A10 and B6 pyridyl)tetrahydropyran-4- [M+H]⁺ yl]-3-methyl-pyrimido[5,4- d]pyrimidin-4-one 8-(4,4-difluorocyclohexyl)- 2-(difluoromethyl)-6- [(2R,4S)-2-(2-methoxy-4- 522.5 A10 and B6 pyridyl)tetrahydropyran-4- [M+H]⁺ yl]-3-methyl-pyrimido[5,4- d]pyrimidin-4-one 8-(4,4-difluorocyclohexyl)- F F 2-(difluoromethyl)-3- methyl-6-[(2R,4S)-2-(1- F 495.4 N N N F methylpyrazol-4- A10 and B5 [M+ ⁺ N H] N N yl)tetrahydropyran-4- O O yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4,4-difluorocyclohexyl)- F F 2-(difluoromethyl)-3- methyl-6-[(2S,4R)-2-(1- F 495.4 N N N F methylpyrazol-4- A10 and B5 [M ⁺ N +H] N N yl)tetrahydropyran-4- O O yl]pyrimido[5,4- d]pyrimidin-4-on 2-(difluoromethyl)-8-[3- (difluoromethyl)-1- bicyclo[1.1.1]pentanyl]-6- 520.5 [(2S,4R)-2-(2-methoxy-4- A11 and B6 [M+H]⁺ pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrimido[5,4- d]pyrimidin-4-one 2-(difluoromethyl)-8-[3- (difluoromethyl)-1- bicyclo[1.1.1]pentanyl]-6- 520.5 31 [(2R,4S)-2-(2-methoxy-4- A11 and B6 [M+H]⁺ pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrimido[5,4- d]pyrimidin-4-one Example 32 and Example 33: 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan- 4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one and 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one

Step 1: 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methyl-8- [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one

To a flask containing 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 17 µmol, 0.10 eq), 2-methoxy-4-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (Intermediate B6, 71 mg, 222 µmol), 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (Intermediate A13, 65 mg, 171 µmol) and potassium carbonate (71 mg, 514 µmol) under argon was added toluene (1.43 ml) and water (0.28 ml). The reaction vessel was sealed the heated to 60 °C for 1 h. The reaction was cooled and diluted with saturated sodium bicarbonate solution. The product was extracted with ethyl acetate, washed with water and brine, and concentrated in vacuo. The residue was purified by column chromatography to give 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4- one (82.5 mg, 78% yield) as light brown solid. MS m/z: 535.3 [M+H]⁺, ESI pos. Step 2: 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one and 2- (difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one

To a vial containing 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]- 3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (82 mg, 0.154 mmol) and palladium on charcoal (10%, 8 mg) under argon, was added ethanol (2 ml). The argon balloon was replaced with a hydrogen balloon, the reaction mixture was sparged and purged, and the mixture was stirred overnight. The reaction was filtered through a pad of silica and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20- 40% ethyl acetate in heptane) to give 2-(difluoromethyl)-6-[(rac)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (70 mg, 84% yield) as a colorless oil. The cis-enantiomers were separated by chiral SFC to obtain 2-(difluoromethyl)-6-[(2R,4S)-2-(2- methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (13 mg, 16% yield) as second eluting enantiomer light yellow oil, MS m/z: 537.2 [M+H]⁺, ESI pos. and 2-(difluoromethyl)-6- [(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (13 mg, 16% yield) as first eluting enantiomer light, yellow oil, MS m/z: 537.2 [M+H]⁺, ESI pos. absolute stereochemistry arbitrarily assigned. The following Examples 34 to 39 were prepared in analogy to Examples 21 to 23 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediates (ESI): m/z 2-(difluoromethyl)-3- methyl-6-[(2S,4R)-2-(1- methylpyrazol-4- 510.2 34 yl)tetrahydropyran-4-yl]-8- A13 and B5 [M+H]⁺ [3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyri do[3,4-d]pyrimidin-4-one 2-(difluoromethyl)-3- methyl-6-[(2R,4S)-2-(1- methylpyrazol-4- 510.2 35 yl)tetrahydropyran-4-yl]-8- A13 and B5 [M+H]⁺ [3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyri do[3,4-d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2- 531.4 36 (difluoromethyl)-6- A5 and B6 [M+H]⁺ [(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2- (difluoromethyl)-6- 531.4 37 [(2R,4S)-2-(2-methoxy-4- A5 and B6 [M+H]⁺ pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2- Cl fluorophenyl)-2- (difluoromethyl)-3-methyl- F F 504.1 38 N N N F 6-[(2R,4S)-2-(1- A5 and B5 ⁺ N [M+H] N methylpyrazol-4-yl)oxan- O O 4-yl]pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2- Cl fluorophenyl)-2- (difluoromethyl)-3-methyl- F F 504.1 39 N N 6-[(2S,4R)-2-(1- A5 and B5 N F [M ⁺ N +H] N methylpyrazol-4-yl)oxan- O O 4-yl]pyrido[3,4- d]pyrimidin-4-one Example 40 and Example 41 and Example 42: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6- [(2R,4S)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2- fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one Step 1: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[6-(2-methyltriazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

To a suspension of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)- pyrimido[5,4-d]pyrimidin-4-one (Intermediate A8, 250 mg, 0.64 mmol) and 2-methyl-4-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]triazole (Intermediate B7, 444 mg, 0.76 mmol) in 1,4-dioxane (10 ml) and water (1 ml) was added cesium carbonate (518 mg, 1.59 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (26 mg, 0.03 mmol, 0.05 eq). After degassing with nitrogen three times, the resulting mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction mixture was added into 0.1 M hydrochloric acid (150 ml) and extracted with ethyl acetate (100 ml × 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 : 1 to 1 : 2) to afford 8-(4-chloro-2-fluoro-phenyl)-3- methyl-6-[6-(2-methyltriazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one (240 mg, 72% yield) as light yellow oil. MS m/z: 522.1 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2- fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6- [rac-(2R,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one

To a solution of 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[6-(2-methyltriazol-4-yl)-3,6-dihydro- 2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (150 mg, 0.29 mmol) in ethyl acetate (8 ml) was added magnesium oxide (116 mg, 2.87 mmol), triethylamine (35 mg, 0.34 mmol) and palladium on charcoal (10%, 61 mg). The mixture was degassed with hydrogen three times, then stirred at 25 °C for 2 h under hydrogen atmosphere (15 Psi). The reaction mixture was filtered through a pad of Celite. The filtrate was diluted with ethyl acetate (100 ml) and washed with 1M hydrochloric acid (50 ml x 2) and brine (50 ml), then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[2-(2-methyltriazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one. This diasteromeric racemate was separated by chiral SFC (column Daicel Chiralpak AD 250 mm × 30 mm, 10 µm, isopropanol / 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro- phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (12 mg, 4% yield), first eluting enantiomer, white solid, MS m/z: 546.3 [M+Na]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6- [(2S,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one (17 mg, 6% yield), second eluting enantiomer white solid, MS m/z: 524.3 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazol- 4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (6 mg, 2% yield), off-white solid, MS m/z: 524.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 43 to 52 were prepared in analogy to Examples 21 to 23 by starting from the indicated intermediates. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediates (ESI): m/z 8-(4,4-difluorocyclohexyl)- 3-methyl-6-[(2R,4S)-2-(1- methylpyrazol-4- 513.3 43 A14 and B5 yl)tetrahydropyran-4-yl]-2- [M+H]⁺ (trifluoromethyl)pyrimido[ 5,4-d]pyrimidin-4-one 8-(4,4-difluorocyclohexyl)- 3-methyl-6-[(2S,4R)-2-(1- methylpyrazol-4- 513.3 44 A14 and B5 yl)tetrahydropyran-4-yl]-2- [M+H]⁺ (trifluoromethyl)pyrimido[ 5,4-d]pyrimidin-4-one 8-(4-chlorophenyl)-3- methyl-6-[(2S,4R)-2-(1- methylpyrazol-4- 504.1 45 A15 and B5 yl)tetrahydropyran-4-yl]-2- [M+H]⁺ (trifluoromethyl)pyrido[3,4 -d]pyrimidin-4-one Cl 8-(4-chlorophenyl)-3- methyl-6-[(2R,4S)-2-(1- F methylpyrazol-4- 504.1 46 F N N A15 and B5 N F yl)tetrahydropyr ⁺ N an-4-yl]-2- [M+H] N O O (trifluoromethyl)pyrido[3,4 -d]pyrimidin-4-one Cl 8-(4-chlorophenyl)-3- methyl-6-[rac-(2R,4R)-2- F F (1-methylpyrazol-4- 504.1 N N N F A15 and B5 yl)tetrahyd ⁺ N ropyran-4-yl]-2- [M+H] N O O (trifluoromethyl)pyrido[3,4 -d]pyrimidin-4-one 8-(4-chloro-2- fluorophenyl)-6-[(2S,4R)- 2-(2-methoxypyridin-4- 550.1 A8 and B6 yl)oxan-4-yl]-3-methyl-2- [M+H]⁺ (trifluoromethyl)pyrimido[ 5,4-d]pyrimidin-4-one 8-(4-chloro-2- fluorophenyl)-6-[(2R,4S)- 2-(2-methoxypyridin-4- 550.1 A8 and B6 yl)oxan-4-yl]-3-methyl-2- [M+H]⁺ (trifluoromethyl)pyrimido[ 5,4-d]pyrimidin-4-one 8-(4-chloro-2-fluoro- Cl phenyl)-3-methyl-6-[rac- (2R,4R)-2-(1- F F F 523.2 N N N F methylpyrazol-4- A8 and B5 [M+H]⁺ N N N yl)tetrahydropyran-4-yl]-2- O O (trifluoromethyl)pyrimido[ 5,4-d]pyrimidin-4-one Cl 8-(4-chloro-2-fluoro- F F phenyl)-3-methyl-6- F 523.2 N N N F [(2R,4S)-2-(1- A8 and B5 [M+H ⁺ N ] N N methylpyrazol-4- O O yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[ 5,4-d]pyrimidin-4-one 8-(4-chloro-2-fluoro- Cl phenyl)-3-methyl-6- [(2S,4R)-2-(1- F F 523.2 52 F N N N F methylpyrazol-4- A8 and B5 [M+H]⁺ N N N yl)tetrahydropyran-4-yl]-2- O O (trifluoromethyl)pyrimido[ 5,4-d]pyrimidin-4-one Example 53: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1-methylpyrazol- 4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one

The title compound was prepared in analogy to Example 21 from Intermediate A7 and instead of Intermediate A12 and Intermediate B5 instead of Intermediate B6, light brown solid, MS m/z: 505.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 54 and Example 55: 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6- [(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2- (1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1-

4-yl)-

2H-pyran-4-yl]-2-

d]pyrimidin-4-one and 6-[3-

2H-

4-carboxamide

To a suspension of 6-chloro-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (Intermediate A16, 200 mg, 0.53 mmol) and 1- methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (Intermediate B5, 366 mg, 0.63 mmol) in 1,4-dioxane (5 ml) and water (0.5 ml) was added cesium carbonate (513 mg, 1.58 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (21 mg, 0.03 mmol, 0.05 eq). After being degassed with nitrogen three times, the resulting mixture was stirred at 80 °C for 2 h under nitrogen atmosphere. The mixture was poured into water (100 ml), the aqueous layer was separated and extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 : 1 to 1 : 3) to afford a mixture of 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1-methylpyrazol-4-yl)-3,6- dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3- (difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1-methylpyrazol-4-yl)-3,6-dihydro- 2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (210 mg, 51 : 44) and was used for the next step. Step 2: 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide

To a solution of 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1- methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin- 4-one and 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1-methylpyrazol-4- yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (190 mg, 0.37 mmol) in ethyl acetate (15 ml) was added magnesium oxide (150 mg, 3.74 mmol), triethylamine (45 mg, 0.45 mmol) and palladium on charcoal (10%, 60 mg). The reaction mixture was degassed with hydrogen three times, then stirred at 25 °C for 2 h under hydrogen (15 Psi). The mixture was filtered through a pad of Celite. The filtrate was diluted with ethyl acetate (100 ml) and washed with hydrochloric acid (1M, 30 ml) and brine (30 ml), then dried over Na₂SO₄ and concentrated to give crude 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N- methyl-2-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5-[(2,2,2- trifluoroacetyl)amino]pyrimidine-4-carboxamide (190 mg, 96% yield) as light yellow oil. MS m/z: 529.2 [M+H]⁺, ESI pos. Step 3: 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one To a solution of 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4- carboxamide (190 mg, 0.36 mmol) in dichloromethane (8 ml) was added triethylamine (0.5 ml, 3.6 mmol) at 25 °C. Then trimethylsilyl chloride (0.23 ml, 1.8 mmol) was added dropwise at 0 °C under nitrogen and the reaction was stirred at 25 °C for 2 h. Hydrochloric acid (1 M) was added to the reaction mixture to adjust the pH to 3-5 and the aqueous mixture was extracted with dichloromethane (50 ml x 3). The combined organic layers were washed with brine (50 ml x 3) and dried over Na₂SO₄, then concentrated in vacuo. The residue was combined purified by preparative HPLC (column Phenomenex Luna C18150 x 25 mm x 10 µm, water with 0.225% formic acid / acetonitrile, flow rate 25 ml/min) to give 8-[3-(difluoromethyl)-1- bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (105 mg, 57% yield) as light yellow solid. MS m/z: 511.3 [M+H]⁺, ESI pos. Step 4: 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

Racemic 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (105 mg) was separated by chiral SFX (column Daicel Chiralcel OX 250 mm x 30 mm, 10 µm, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 70 ml/min) to afford 8- [3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (41 mg, 39% yield) as first eluting enantiomer, white solid, MS m/z: 511.2 [M+H]⁺, ESI pos. and 8-[3- (difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (35 mg, 33% yield) as second eluting enantiomer, white solid, MS m/z: 511.2 [M+H]⁺, ESI pos. Example 56, Example 57 and Example 58: 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chlorophenyl)-3-methyl-6-[rac- (2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one

The title compounds were prepared in analogy to Example 54 and 55 from Intermediate A17 instead of Intermediate A16, light yellow solids, MS m/z: 505.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 59: 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one

Step 1: methyl 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylate

To a solution of 2,6-dichloropyrimidine-4-carboxylic acid methyl ester (1.0 g, 4.83 mmol) in 1,4-dioxane (32 ml) were added (4-chloro-2-fluoro-phenyl)boronic acid (842 mg, 4.83 mmol) and cesium carbonate (4.72 g, 14.5 mmol) at room temperature. The mixture was degassed before 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (395 mg, 0.483 µmol, 0.10 eq) was added and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-50%) to obtain methyl 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylate (983 mg, 60%) as light yellow solid, MS m/z: 301.0 [M+H]⁺, ESI pos. Step 2: methyl 6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimidine-4-carboxylate

To a solution of 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid methyl ester (235 mg, 0.780 mmol) in N,N-dimethylformamide (4 ml) were added (2S)-2-(1-methylpyrazol- 4-yl)morpholine (Intermediate (+)-B1, 144 mg, 0.858 mmol) and N,N-diisopropyl ethylamine (202 mg, 272 µl, 1.56 mmol) at room temperature and the mixture was stirred for 2 h at 110°C. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) obtain methyl 6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate (304 mg, 90% yield) as yellow solid. MS m/z: 432.1 [M+H]⁺, ESI pos. Step 3: methyl 5-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate

To a solution of methyl 6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate (275 mg, 0.637 mmol) in dichloromethane (6 ml) was added N-bromosuccinimide (125 mg, 0.70 mmol) at room temperature and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted two times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to obtain methyl 5-bromo-6-(4-chloro-2-fluoro- phenyl)-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (225 mg, 65% yield) as yellow solid, MS m/z: 512.1 [M+H]⁺, ESI pos. Step 4: methyl 6-(4-chloro-2-fluoro-phenyl)-5-prop-1-ynyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate

To a solution of methyl 5-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate (190 mg, 0.372 mmol) in N,N-dimethylformamide (3 ml) was added tributyl(prop-1-ynyl)stannane (184 mg, 170 µl, 0.558 mmol) at room temperature. The mixture was degassed with argon before tetrakis(triphenylphosphine) palladium(0) (43 mg, 37 µmol, 0.10 eq) was added. The mixture was stirred for 1 h at 110 °C in a microwave. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to obtain methyl 6-(4-chloro-2-fluoro-phenyl)-5-prop-1-ynyl-2- [(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (182 mg, 97% yield) as light yellow solid, MS m/z: 470.2 [M+H]⁺, ESI pos. Step 5: 6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-prop-1-ynyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxamide

Methyl 6-(4-chloro-2-fluoro-phenyl)-5-prop-1-ynyl-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrimidine-4-carboxylate (180 mg, 0.383 mmol) was dissolved in a solution of methylamine (40% in methanol, 4.77 ml, 38.3 mmol) at room temperature and the mixture was stirred for 2 h at 50 °C. The reaction mixture was concentrated to dryness. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to obtain 6- (4-chloro-2-fluoro-phenyl)-N-methyl-5-prop-1-ynyl-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrimidine-4-carboxamide (160 mg, 80% yield) as yellow solid, MS m/z: 469.2 [M+H]⁺, ESI pos. Step 6: 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-8-one To a solution of 6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-prop-1-ynyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxamide (160 mg, 0.341 mmol) in ethanol (2.5 ml) was added sodium ethoxide (232 mg, 3.41 mmol) at room temperature and the mixture was stirred overnight at 80°C. The reaction mixture was diluted with water and extracted four times with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0-5%) to obtain 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one (71 mg, 42% yield) as yellow solid, MS m/z: 469.1 [M+H]⁺, ESI pos. Step 7: 4-(4-chloro-2-fluoro-phenyl)-7-methyl-8-oxo-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde

To a solution of 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one (20 mg, 43 µmol) in 1,4-dioxane (1 ml) was added selenium dioxide (9.5 mg, 85.3 µmol) at room temperature and the mixture was stirred for 2 h at 100 °C. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0-8%) to obtain 4-(4-chloro-2- fluoro-phenyl)-7-methyl-8-oxo-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4- d]pyrimidine-6-carbaldehyde (18 mg, 83% yield) as yellow solid, MS m/z: 483.1 [M+H]⁺, ESI pos. Step 8: 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one

To a solution of 4-(4-chloro-2-fluoro-phenyl)-7-methyl-8-oxo-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde (7 mg, 14.5 µmol) in dichloromethane (1 ml) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (2.7 M in toluene, 54 µl, 145 µmol) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated NaHCO3-solution and extracted two times with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by preparative HPLC (Gemini NX C-18, 5 µm, 100 x 30 mm, acetonitrile / water) to obtain the title compound (2 mg, 26% yield) as yellow solid, MS m/z: 505.1 [M+H]⁺, ESI pos. Reference Examples Reference Example 1: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol- 4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one

Step 1: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one To a solution of 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A1, 750 mg, 2.6 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (453 mg, 2.6 mmol) in 1,4- dioxane (12 ml) and water (4 ml), was added cesium carbonate (2.54 g, 7.8 mmol). The reaction mixture was purged and backfilled with argon 3 times and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (106 mg, 130 µmol, 0.05 eq) was added. The reaction mixture was purged and backfilled with argon 3 times and stirred at room temperature for 16 h. The mixture was diluted with water and extracted 3 times with ethyl acetate. The organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0- 60%) and then triturated in diethyl ether to afford 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one (556 mg, 62% yield) as light yellow solid, MS m/z: 338.1 [M+H]⁺, ESI pos., 1H NMR (300 MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.65 - 7.56 (m, 2H), 7.48 - 7.43 (m, 1H), 3.55 (s, 3H), 2.52 (br s, 3H). Step 2: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one

To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4- one (120 mg, 0.35 mmol) and 2-(1-methylpyrazol-4-yl)morpholine (Intermediate B1, 89 mg, 0.53 mmol) in in N-methyl pyrrolidone (1 ml) was added N,N-diisopropyl ethylamine (138 mg, 1.06 mmol). The mixture was heated under microwave irradiation at 150 °C for 12 h and then purified by preparative HPLC (column Phenomenex Luna C18150 x 25mm x 10 µm, water + 0.1% formic acid / acetonitrile, flow rate 25 ml/min) to give the product 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (50 mg). This racemate was separated by SFC (column Daicel Chiralcel OD 250 mm*30 mm, 10 µm, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one as first eluting enantiomer with retention time 2.06 min (other enantiomer retention time 2.46 min), light yellow solid, MS m/z: 469.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned.1H NMR (400 MHz, DMSO-d6) δ = 7.74 (s, 1H), 7.61 - 7.50 (m, 2H), 7.46 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 4.55 (br d, J = 8.7 Hz, 1H), 4.29 (br d, J = 12.6 Hz, 1H), 4.12 (br d, J = 12.6 Hz, 1H), 4.02 (br d, J = 10.4 Hz, 1H), 3.81 (s, 3H), 3.74 - 3.67 (m, 1H), 3.52 (s, 3H), 3.43 (br d, J = 3.8 Hz, 1H), 3.05 - 2.89 (m, 2H), 2.44 (s, 3H). Reference Example 2: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol- 4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one

The tile compound was prepared in analogy to Reference Example 1, second eluting enantiomer with retention time 2.46 min, light yellow solid, MS m/z: 469.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Reference Example 3: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4- one (see Reference Example 1, 30 mg, 0.09 mmol) in 1,4-dioxane (1.5 ml) were added 2-(2- methyl-4-pyridyl)morpholine (Intermediate B2, 24 mg, 0.13 mmol), cesium carbonate (87 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (6.5 mg, 0.01 mmol, 0.08 eq) and Xantphos (10 mg, 0.02 mmol, 0.2 eq) and the mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by chromatography (silica gel plate, dichloromethane / ethyl acetate = 10:1)to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(2-methyl-4-pyridyl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one (30 mg). This racemate was separated by SFC (column Daicel Chiralcel OD 250 mm*30 mm, 10 µm, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 80 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl- 6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one as first eluting enantiomer with retention time 1.02 min (other enantiomer retention time 2.08 min), yellow solid, MS m/z: 480.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Reference Example 4: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one

The tile compound was prepared in analogy to Reference Example 3, second eluting enantiomer with retention time 2.08 min, yellow solid, MS m/z: 480.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Reference Example 5: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one

6,8-Dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (Intermediate A4, 850 mg, 3.47 mmol) was dissolved in 1,4-dioxane (20 ml) and (4-chloro-2-fluoro-phenyl)boronic acid (605 mg, 3.47 mmol) and 2 M cesium carbonate in water (5.2 ml, 10.41 mmol) were added at room temperature. The mixture was degassed before 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (283 mg, 347 µmol, 0.10 eq) was added. The mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0-100%) to obtain 6-chloro-8-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (928 mg, 76% yield) as light brown solid, MS m/z: 339.0 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one

6-Chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (25 mg, 0.074 mmol) was dissolved in dimethyl sulfoxide (1 ml) and (2S)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-B1, 25 mg, 0.174 mmol) and N,N-diisopropyl ethylamine (48 mg, 64 µl, 0.369 mmol) were added at room temperature. The mixture was stirred for 2 h at 120 °C. The reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0-4%) to obtain the title compound (30 mg, 85%) as yellow solid, MS m/z: 470.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Reference Examples 6 and 7: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl- 4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one

To a solution of 2-(2-methyl-4-pyridyl)morpholine (Intermediate B2, 43 mg, 0.24 mmol) in dimethyl sulfoxide (1 ml) were added 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one (see Reference Example 5, 55 mg, 0.16 mmol) and N,N- diisopropyl ethylamine (23 mg, 0.18 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (40 ml x 2). Organic phase was washed with brine (100 ml x 3), dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ether = 1:0) to give 8-(4- chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4- d]pyrimidin-4-one (44 mg). The enantiomers were separated by chiral SFC (column Daicel Chiralpak AD, 250 mm × 30 mm, 10µm, ethanol + 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (19 mg, 42% yield) as first eluting enantiomer with a retention time of 1.05 min, light yellow solid, MS m/z: 481.2 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one (21 mg, 47% yield) as second eluting enantiomer with a retention time of 1.44 min, light yellow solid, MS m/z: 481.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 60 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg Example 61 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

Claims

Claims 1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein: X¹, X² and X³ are each independently selected from N and CH; A is selected from C3-C10-cycloalkyl, C3-C10-cycloalkenyl, C6-C10-aryl, 5- to 10- membered heteroaryl, and 3- to 10-membered heterocyclyl; B is selected from 4a 4_b R R N O R^4c R^4a ^4c O R R^4b R¹, R², and R³ are each independently selected from hydrogen, halogen, cyano, C₁- C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and halo-C1-C6-alkoxy; R^4a is selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo- C1-C6-alkyl, halo-C1-C6-alkoxy, and a group

; R^4b and R^4c are each independently selected from hydrogen, halogen, cyano, C1-C6- alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, and oxo; R⁵ is selected from C1-C6-alkyl, halo-C1-C6-alkyl, 3- to 10-membered heterocyclyl and C3-C10-cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one substituent selected from halogen and C₁-C₆- alkyl; R⁶ is selected from hydrogen and fluoro; R⁷ and R⁸ are each independently selected from hydrogen, halogen, C1-C6-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, halo-C₁-C₆-alkoxy, C₃-C₁₀-cycloalkyl, halo- C3-C10-cycloalkyl, and 3- to 10-membered heterocyclyl; and C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H- triazole, 2H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4- oxadiazolyl, and 1,3,4-oxadiazolyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; or (iii) X¹ and X² are N and X³ is CH; or.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C₆-C₁₀-aryl and C₃-C₁₀-cycloalkyl; R¹ is selected from halo-C1-C6-alkyl and halogen; R² is selected from hydrogen and halogen; and R³ is selected from hydrogen and halogen.

5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C₆-C₁₀-aryl and C₃-C₁₀-cycloalkyl; R¹ is selected from halo-C1-C6-alkyl and halogen; R² is selected from hydrogen and halogen; and R³ is hydrogen.

6. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF3, CHF2, fluoro and chloro; R² is selected from hydrogen and fluoro; and R³ is selected from hydrogen and fluoro.

7. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF₃, CHF₂, fluoro and chloro; R² is selected from hydrogen and fluoro; and R³ is hydrogen.

8. The compound of formula (I) according to any one of claims 1 to 3, or a

pharmaceutically acceptable salt thereof, wherein the group _is selected from: 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein:

R^4b is selected from hydrogen and C₁-C₆-alkyl; R^4c is hydrogen; C is selected from pyridyl, pyrazolyl and 2H-triazole; R⁷ is selected from C₁-C₆-alkyl, C₁-C₆-alkoxy and C₃-C₁₀-cycloalkyl; and R⁸ is hydrogen. 10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein B is selected from N N O N N N N N N O O

^N _N N O 11. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein:

R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁷ is selected from C1-C6-alkyl and C1-C6-alkoxy; and R⁸ is hydrogen. 12. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein:

R^4a is a group R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁷ is selected from methyl and methoxy; and R⁸ is hydrogen. 13. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable

14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R⁵ is C1-C6-alkyl. 15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R⁵ is methyl. 16. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; or (iii) X¹ and X² are N and X³ is CH; A is selected from C₆-C₁₀-aryl and C₃-C₁₀-cycloalkyl; R¹ is selected from halo-C₁-C₆-alkyl and halogen; R² is selected from hydrogen and halogen; R³ is selected from hydrogen and halogen;

R^4b is selected from hydrogen and C₁-C₆-alkyl; R^4c is hydrogen; R⁵ is C1-C6-alkyl; C is selected from pyridyl, pyrazolyl, and 2H-triazole; R⁶ is selected from hydrogen and fluoro; R⁷ is selected from C1-C6-alkyl, C1-C6-alkoxy and C3-C10-cycloalkyl; and R⁸ is hydrogen. 17. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; or (iii) X¹ and X² are N and X³ is CH; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF₃, CHF₂, fluoro and chloro; R² is selected from hydrogen and fluoro; R³ is selected from hydrogen and fluoro; B is selected from: N N O N N N N N N O O N _N N O R⁵ is methyl; and R⁶ is selected from hydrogen and fluoro. 18. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is selected from C₆-C₁₀-aryl and C₃-C₁₀-cycloalkyl; R¹ is selected from halo-C1-C6-alkyl and halogen; R² is selected from hydrogen and halogen; R³ is hydrogen; R^4b is hydrogen; R^4c is hydrogen; C is selected from pyridyl and pyrazolyl; R⁵ is C₁-C₆-alkyl; R⁶ is is selected from hydrogen and halogen; R⁷ is selected from C1-C6-alkyl and C1-C6-alkoxy; and R⁸ is hydrogen. 19. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R¹ is selected from CF3, CHF2, fluoro and chloro; R² is selected from hydrogen and fluoro; R³ is hydrogen;

R⁵ is methyl; and R⁶ is selected from hydrogen and fluoro. 20. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol- 4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6- [(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3- methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3- methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3- methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4- d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3- methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4- d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-6-[(2S,4R)-2-(2- methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4- one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-6-[(2R,4S)-2-(2- methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4- one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4- one; 2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4- one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1- methylpyrazol-4-yl)oxan-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1- methylpyrazol-4-yl)oxan-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3- methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3- methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; and 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one. 21. A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance. 22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier. 23. A method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22. 24. The method according to claim 23, wherein said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke. 25. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for use in a method according to claim 23 or 24. 26. Use of a compound according to any one of claims 1 to 20, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to claim 22, in a method according to claim 23 or 24. 27. Use of a compound according to any one of claims 1 to 20, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to claim 23 or 24. 28. The invention as described hereinbefore.