EP4720061A1 - Trem2 agonists - Google Patents

Abstract

The invention provides compounds having the general formula (I) wherein A, B, R1, R2, R3, R7, and R8 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds in the treatment or prevention of diseases that are associated with TREM2.

Description

F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland Case: P38396 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, CNE/14.05.2024 a single transmembrane helix and a short cytosolic tail that does not have signal transduction motifs. Downstream signal transduction is mediated through its interaction with the effector protein DAP12, a transmembrane disulphide-linked adapter dimer which expression and cellular 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.2018 10;293(32):12634-12646; doi: 10.1074/jbc.RA118.002352). Studies are ongoing to elucidate the mechanism by which TREM2 LoF mutations contribute to AD. It is likely that patients carrying these mutations have impaired microglia function including reduced clearance of extracellular aggregates (e.g. amyloid and myelin debris) and apoptotic neurons, ultimately reducing their capacity to fight the disease and increasing their susceptibility to neurodegeneration. Indeed decreased microglia activation and failure to cluster around the amyloid plaque were observed in mouse models deficient for TREM2 or DAP12, confirming the central role of TREM2 signalling in microglia function and response to Alzheimer’s pathological hallmarks. 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, R⁷, and R⁸ 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 H R N R N N N R^{5a 5b} O _R ^R5c R^4c R^6a N 6^c O R R^6b 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 and R^5a are selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C₁-C₆-alkyl, halo-C₁-C₆-alkoxy, and a group ; R^6a 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, independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6- alkoxy, and oxo; 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; D is selected from cyclopropyl, phenyl, 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; R⁷ 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; R⁸ is selected from hydrogen, 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; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10- membered heterocycle; R⁹ and R¹⁰ 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 R¹¹ and R¹² are each independently selected from hydrogen, halogen, C₁-C₆-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and 3- to 10-membered heterocyclyl. In a further 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 N N ^{N N} N N O _N O ^N _N N

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; R⁷ 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; and R⁸ is selected from hydrogen, 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; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10- membered heterocycle. 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) X² and X³ are N and X¹ is CH; or (iii) X¹, X² and X³ are all N; or (iv) X² and X³ are CH and X¹ is N; or (v) X¹ and X² are N and X³ is CH. 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; or (iii) X² and X³ are CH and X¹ is 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 C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkenyl, C₆-C₁₀-aryl, and 5- to 10-membered heteroaryl; R¹ is selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and C₁-C₆-alkoxy; R² is selected from hydrogen, halogen, and C1-C6-alkyl; and R³ is selected from hydrogen and halogen. 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 cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl; R¹ is selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy; R² is selected from hydrogen, fluoro, and methyl; and R³ 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: A is selected from C₃-C₁₀-cycloalkyl and C₆-C₁₀-aryl; R¹ is selected from halogen and halo-C1-C6-alkyl; R² is selected from hydrogen and halogen; and R³ is selected from hydrogen and halogen. 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 cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; R¹ is selected from fluoro, chloro, CHF2 and CF3; R² is selected from hydrogen and fluoro; and R³ 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: B is selected from 4a 4_b H R N R N N N R^{5a 5b} O _R ^R5c R^4c R^6a N 6^c O R R^6b R^4a and R^5a are selected from hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and a group ; R^6a is selected from hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and a group ; 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; D is selected from cyclopropyl, phenyl, 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; R^4b and R^6b are selected from hydrogen, halogen, cyano, C₁-C₆-alkyl, and oxo; R^4c and R^6c are selected from hydrogen, halogen, and C₁-C₆-alkyl; R^5b and R^5c are both hydrogen; R⁹ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C3- C₁₀-cycloalkyl, halo-C₃-C₁₀-cycloalkyl, and 3- to 10-membered heterocyclyl; R¹¹ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and 3- to 10-membered heterocyclyl; and R¹⁰ and R¹² are selected from hydrogen and C₁-C₆-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from: N _N N In a 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 R^4b, R^5b, and R^6b are selected from hydrogen, halogen and C₁-C₆-alkyl; R^4c, R^5c, and R^6c are selected from hydrogen and halogen; R⁹ is selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; R¹¹ is selected from hydrogen, C₁-C₆-alkyl, and C₁-C₆-alkoxy; R¹⁰ and R¹² are both hydrogen; C is selected from cyclopropyl, pyridyl and pyrazolyl; and D is selected from cyclopropyl and pyrazolyl. 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 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 B In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R⁷ is selected from C₁-C₆-alkyl, halo-C₁-C₆-alkyl and C₃-C₁₀-cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one C1-C6-alkyl substituent; R⁸ is selected from hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and C₃-C₁₀- cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one C1-C6-alkyl substituent; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10- membered heterocycle. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R⁷ is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1- methylcyclopropyl, and cyclobutyl; R⁸ is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1- difluoroethyl, cyclopropyl, 1-methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a pyrrolidine ring. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R⁷ is C₁-C₆-alkyl; and R⁸ is selected from C₁-C₆-alkyl and halo-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 R⁷ and R⁸ are both methyl. 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) X² and X³ are N and X¹ is CH; or (iii) X¹, X² and X³ are all N; or (iv) X² and X³ are CH and X¹ is N; or (v) X¹ and X² are N and X³ is CH; A is selected from C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkenyl, C₆-C₁₀-aryl, and 5- to 10-membered heteroaryl; B is selected from 4a 4_b H R N R N N N R^5a O _R ^{5b R5c} R^4c R^6a N R^6c O R^6b R¹ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy; R² is selected from hydrogen, halogen, and C₁-C₆-alkyl; R³ is selected from hydrogen and halogen; R^4a and R^5a are selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and a group ; R^6a is selected from hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and a group ; R^4b and R^6b are selected from hydrogen, halogen, cyano, C1-C6-alkyl, and oxo; R^4c and R^6c are selected from hydrogen, halogen, and C₁-C₆-alkyl; R^5b and R^5c are both hydrogen; 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; D is selected from cyclopropyl, phenyl, 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; R⁷ is selected from C1-C6-alkyl, halo-C1-C6-alkyl and C3-C10-cycloalkyl; wherein said C₃-C₁₀-cycloalkyl is optionally substituted with one C₁-C₆-alkyl substituent; R⁸ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C10- cycloalkyl; wherein said C₃-C₁₀-cycloalkyl is optionally substituted with one C1-C6-alkyl substituent; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10- membered heterocycle; R⁹ is selected from hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃- C10-cycloalkyl, halo-C3-C10-cycloalkyl, and 3- to 10-membered heterocyclyl; R¹¹ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and 3- to 10-membered heterocyclyl; and R¹⁰ and R¹² are selected from hydrogen and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X² and X³ are N and X¹ is CH; or (iii) X¹, X² and X³ are all N; or (iv) X² and X³ are CH and X¹ is N; or (v) X¹ and X² are N and X³ is CH; A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl; B is selected from

R¹ is selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy; R² is selected from hydrogen, fluoro, and methyl; R³ is selected from hydrogen and fluoro; R⁷ is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1- methylcyclopropyl, and cyclobutyl; R⁸ is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1- difluoroethyl, cyclopropyl, 1-methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a pyrrolidine ring. 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; or (iii) X² and X³ are CH and X¹ is N; A is selected from C3-C10-cycloalkyl and C6-C10-aryl; B is selected from R^6a N 6^c O R R^6b R¹ is selected from halogen and halo-C1-C6-alkyl; R² is selected from hydrogen and halogen; R³ is selected from hydrogen and halogen; R^4a and R^5a are a group R^6a is a group ; R^4b, R^5b, and R^6b are selected from hydrogen, halogen and C1-C6-alkyl; R^4c, R^5c, and R^6c are selected from hydrogen and halogen; R⁷ is C1-C6-alkyl; R⁸ is selected from C1-C6-alkyl and halo-C1-C6-alkyl; R⁹ is selected from hydrogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, and C₃-C₁₀-cycloalkyl; R¹¹ is selected from hydrogen, C₁-C₆-alkyl, and C₁-C₆-alkoxy; R¹⁰ and R¹² are both hydrogen; C is selected from cyclopropyl, pyridyl and pyrazolyl; and D is selected from cyclopropyl and pyrazolyl. 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; or (iii) X² and X³ are CH and X¹ is N; A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; B is selected from R¹ is selected from fluoro, chloro, CHF₂ and CF₃; R² is selected from hydrogen and fluoro; R³ is selected from hydrogen and fluoro; and R⁷ and R⁸ are both methyl. 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) X² and X³ are N and X¹ is CH; or (iii) X¹, X² and X³ are all N; or (iv) X² and X³ are CH and X¹ is N; or (v) X¹ and X² are N and X³ is CH; A is selected from C3-C10-cycloalkyl, C3-C10-cycloalkenyl, C6-C10-aryl, and 5- to 10-membered heteroaryl; B is selected from N N ^{N N} N N O _N O ^N _N N R¹ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy; R² is selected from hydrogen, halogen, and C1-C6-alkyl; R³ is selected from hydrogen and halogen; R⁷ is selected from C1-C6-alkyl, halo-C1-C6-alkyl and C3-C10-cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one C1-C6-alkyl substituent; and R⁸ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C10- cycloalkyl; wherein said C₃-C₁₀-cycloalkyl is optionally substituted with one C₁-C₆-alkyl substituent; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10- membered heterocycle. 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) X² and X³ are N and X¹ is CH; or (iii) X¹, X² and X³ are all N; or (iv) X² and X³ are CH and X¹ is N; or (v) X¹ and X² are N and X³ is CH; A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl; B is selected from N N ^{N N} N N O _N O ^N _N N R¹ is selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy; R² is selected from hydrogen, fluoro, and methyl; R³ is selected from hydrogen and fluoro; R⁷ is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1- methylcyclopropyl, and cyclobutyl; and R⁸ is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1- difluoroethyl, cyclopropyl, 1-methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a pyrrolidine ring. 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; or (iii) X² and X³ are CH and X¹ is N; A is selected from C3-C10-cycloalkyl and C6-C10-aryl; B is selected from N N ^{N N} N N O _N O N _N N R¹ is selected from halogen and halo-C₁-C₆-alkyl; R² is selected from hydrogen and halogen; R³ is selected from hydrogen and halogen; R^4a and R^5a are a group ; R^6a is a group ; R^4b, R^5b, and R^6b are selected from hydrogen, halogen and C1-C6-alkyl; R^4c, R^5c, and R^6c are selected from hydrogen and halogen; R⁷ is C₁-C₆-alkyl; R⁸ is selected from C1-C6-alkyl and halo-C1-C6-alkyl; R⁹ is selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; R¹¹ is selected from hydrogen, C1-C6-alkyl, and C1-C6-alkoxy; R¹⁰ and R¹² are both hydrogen; C is selected from cyclopropyl, pyridyl and pyrazolyl; and D is selected from cyclopropyl and pyrazolyl. 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; or (iii) X² and X³ are CH and X¹ is N; A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; B is selected from N N ^{N N} N N O _N O N _N N R¹ is selected from fluoro, chloro, CHF₂ and CF₃; R² is selected from hydrogen and fluoro; R³ is selected from hydrogen and fluoro; and R⁷ and R⁸ are both methyl. 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: (i) X¹ and X³ are N and X² is CH; or (ii) X¹, X² and X³ are all N; or (iii) X² and X³ are CH and X¹ is N; A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; B is ; R¹ is selected from fluoro, chloro, CHF2 and CF3; R² is selected from hydrogen and fluoro; R³ is selected from hydrogen and fluoro; and R⁷ and R⁸ are both methyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X¹ and X³ are N and X² is CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X² and X³ are N and X¹ is CH. In a preferred 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 all N. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X² and X³ are CH and X¹ is N. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X¹ and X² are N and X³ is CH. 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 C3-C10- cycloalkyl, C₃-C₁₀-cycloalkenyl, C₆-C₁₀-aryl, and 5- to 10-membered heteroaryl. 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 H N N N 5a R R_{5b R} ^5c wherein R^4a, R^4b, R^4c, R^5a, R^5b, and R^5c are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R² is selected from hydrogen, halogen, and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from hydrogen and halogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^4a is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and a group , wherein R⁹, R¹⁰ and C are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^5a is selected from hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, and a group , wherein R⁹, R¹⁰ and C are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^6a is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and a group , wherein R¹¹, R¹² and D are as defined herein. 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, halogen, cyano, C₁-C₆-alkyl, and oxo. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^6b is selected from hydrogen, halogen, cyano, C1-C6-alkyl, and oxo. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^4c is selected from hydrogen, halogen, and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^6c is selected from hydrogen, halogen, and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^5b 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^5c is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from C1-C6- alkyl, halo-C1-C6-alkyl and C3-C10-cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one C₁-C₆-alkyl substituent. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C10-cycloalkyl; wherein said C3-C10- cycloalkyl is optionally substituted with one C₁-C₆-alkyl substituent. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10-membered heterocycle. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁹ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10- cycloalkyl, and 3- to 10-membered heterocyclyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from hydrogen and C₁-C₆-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹¹ is selected from hydrogen, C₁-C₆-alkyl, halo-C₁-C₆-alkyl, C₁-C₆-alkoxy, and 3- to 10-membered heterocyclyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹² is selected from hydrogen and C₁-C₆-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl. 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

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

In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from hydrogen, fluoro, chloro, cyano, CHF₂, CF₃, methyl, and methoxy. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R² is selected from hydrogen, fluoro, and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R³ 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 R⁷ is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1-methylcyclopropyl, and cyclobutyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1-difluoroethyl, cyclopropyl, 1- methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁷ and R⁸, taken together with the atoms to which they are attached, form a pyrrolidine ring. 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; or (iii) X² and X³ are CH and X¹ is N. 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 C3-C10-cycloalkyl and C6-C10-aryl. In a 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 R^6a N R^6c O R^6b wherein R^4a, R^4b, R^4c, R^5a, R^5b, R^5c, R^6a, R^6b, R^6c are as described herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is ,wherein R^4a, R^4b, and R^4c are as described herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is ,wherein R^5a, R^5b, and R^5c are as described herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is ,wherein R^6a, R^6b, and R^6c are as described herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is ,wherein R^6a, R^6b, and R^6c are as described herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from halogen and halo-C1-C6-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R² 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 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 R^4a is a group , wherein R⁹, R¹⁰, and C are as defined herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^5a is a group , wherein R⁹, R¹⁰, and C are as defined herein. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^6a is a group , wherein R¹¹, R¹², and D are as defined herein. 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 selected from hydrogen, halogen and C₁-C₆-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^5b is selected from hydrogen, halogen and C₁-C₆-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^6b is selected from hydrogen, halogen and C1-C6-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^4c 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 R^5c 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 R^6c 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 R⁷ is C1-C6-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁸ is selected from C1-C6-alkyl and halo-C1-C6-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁹ is selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ 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 R¹¹ is selected from hydrogen, C₁-C₆-alkyl, and C₁-C₆-alkoxy. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹² 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 A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl. 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 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 . 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 . 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 . 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 . In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from fluoro, chloro, CHF2 and CF3. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R² 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 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 C is selected from cyclopropyl, pyridyl and pyrazolyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein C is selected from cyclopropyl and pyridyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^4b, R^5b, and R^6b are selected from hydrogen, fluoro and methyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R^4c, R^5c, and R^6c are 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 R⁷ is methyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁸ is methyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R⁹ is selected from hydrogen, methyl, methoxy, and cyclopropyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R¹¹ is selected from hydrogen, methyl and methoxy. 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-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4- d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]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]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(3R)-3-(1-methylpyrazol-4-yl)-1- piperidyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-3- methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-3- methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4- c]pyridin-6-yl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(trifluoromethyl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-3-methyl- pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidyl]- 3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidyl]- 3-methyl-pyrido[3,4-d]pyrimidin-4-one; 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; 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; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4- c]pyridin-6-yl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-2,3-dimethyl- pyrido[3,4-d]pyrimidin-4-one; 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; 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; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(3S)-3-(1-methylpyrazol-4-yl)-1- piperidyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(3R)-3-(1-methylpyrazol-4-yl)-1- piperidyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidyl]- 2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidyl]- 2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 3-fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,4- d]pyrimidin-8-yl]benzonitrile; 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(2-fluoro-4-methyl-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4- d]pyrimidin-4-one; 2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4- d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)phenyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-methyl-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]octan-6-yl- pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-dimethylcyclohexyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-3-(2,2,2- trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-cyclobutyl-2-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]- 3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-cyclobutyl-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2-(1-bicyclo[1.1.1]pentanyl)-8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-cyclopentyl-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2-tert-butyl-8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(1-methylcyclopropyl)-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-methyl-3-(1-methylcyclopropyl)-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-2-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one; 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; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazol-5-yl)morpholin- 4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(3-methyl-1,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin- 4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(1,2,4-triazol-1- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(2-methylpyrazol-3- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3,3-dimethyl-4-(1-methylpyrazol-4-yl)pyrrolidino]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(5-methyl-1,2,4-oxadiazol-3- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-(3-methoxyphenyl)-3-methyl-pyrrolidino]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 6-[(3aR,6aR)-3a-phenyl-3,4,6,6a-tetrahydro-1H-furo[3,4-c]pyrrol-5-yl]-8-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-(3,5-dimethylpyrazol-1-yl)piperidino]-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[6-(3-pyridyl)-3-azabicyclo[4.1.0]heptan-3- yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(2-cyclopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6- yl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(triazol-1-yl)piperidino]pyrimido[5,4- d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(3-methyl-1,2,4-oxadiazol-5- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 6-(2-tert-butyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-8-(4-chloro-2-fluoro-phenyl)- 2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(1-methylpyrazol-4- yl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(3-methyl-1,2,4-oxadiazol-5- yl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-keto-4-(p-tolyl)piperazino]-2,3-dimethyl-pyrimido[5,4- d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(1,2,4-triazol-1- yl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-(4-cyclopropyltriazol-1-yl)pyrrolidino]-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-(7-methyl-2,6-dioxa-9-azaspiro[4.5]decan-9- yl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-methyl-3-(p- tolyl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 4-[8-(4-chloro-2-fluoro-phenyl)-4-keto-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-6-yl]-1- cyclopropyl-piperazine-2-carbonitrile; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a]pyridin-3-yl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholin- 4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-methyl-6-phenyl-tetrahydropyran-4- yl]pyrimido[5,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-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; 2,3-dimethyl-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; 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)cyclobutyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-8-(3-methyl-1-bicyclo[1.1.1]pentanyl)-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol- 4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 3-[2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-4-oxo-pyrido[3,4- d]pyrimidin-8-yl]bicyclo[1.1.1]pentane-1-carbonitrile; 8-(3-methoxy-1-bicyclo[1.1.1]pentanyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 5-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one; 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one; 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one; 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one; 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-isopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(1,1-difluoroethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol- 4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-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]-2,3-dimethyl-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]-2,3-dimethyl-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]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidyl]- 2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidyl]- 2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)phenyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)-3- pyridyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 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; 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; 13-(4-chloro-2-fluoro-phenyl)-11-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2,7,10,12- tetrazatricyclo[7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin- 4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin- 4-yl]pyrimido[5,4-d]pyrimidin-4-one; 6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(5-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one; 8-[2-fluoro-5-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-(difluoromethyl)pyrrolidino]-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(6,6-difluoro-3-bicyclo[3.1.0]hexanyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-[4-(difluoromethyl)cyclohexyl]-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholino]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(2-methylpyrazol-3-yl)-6- azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(1-methylpyrazol-3-yl)-6- azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one; 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-8-one; 8-(4-chloro-2-fluoro-phenyl)-6-[2-[1-(2,2-difluoroethyl)pyrazol-4-yl]morpholino]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4- yl]morpholino]pyrimido[5,4-d]pyrimidin-4-one; and 8-(4-chloro-2-fluoro-phenyl)-6-[2-[1-(2,2-difluorocyclopropyl)pyrazol-4-yl]morpholino]- 2,3-dimethyl-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 i-PrMgCl·LiCl isopropylmagnesium chloride lithium chloride complex J coupling constant kg kilogram LED light-emitting diode 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 Pd/C palladium on charcoal 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) XantPhos Pd G3 [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate XPhos-Pd-G3 (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino- 1,1′-biphenyl)]palladium(II) methanesulfonate αD specific rotation at 589 nm δ chemical shift in parts per million In the following schemes, R^A refers to a group and R^B refers to a group , wherein A, B, R¹, R² and R³ are as defined herein. Scheme 1 Compounds of general formula Ia and Ib can be prepared 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. For compounds containing N- linked residues R^B this intermediate can be reacted with amine R^B-H (V) in presence of a base like N,N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone to form 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). For C-linked derivatives Ib the corresponding halogen derivatives R^B-X³ (VI) can be first transformed into organozinc compounds R^B-Zn-X³ (VII) by reacting with zinc under anhydrous conditions. This organometallic reagent can then be reacted with intermediate IV using palladium-catalysed conditions to produce compounds of formula 1b using a metal-catalysed coupling (Scheme 1). Scheme 2 Intermediates IIa can be prepared from compound VIII by coupling with amine IX using amide coupling reagents such as HATU, HBTU, EDC or the like followed by reaction of the formed intermediate X with an orthoester XI at elevated temperatures. Alternatively, compound X can be reacted with an acid chloride XII (or an acid anhydride) and a base like N,N-diisopropyl ethylamine, triethylamine or pyridine to form intermediate XIII which is then cyclised by heating in presence of a base or a suitable solvent such as acetic acid (Scheme 2). Scheme 3 Y¹, Y² = Cl, Br R⁷, R⁸ according to claim definition Intermediates IIb can be prepared from compound XIV by coupling with amine IX 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 XVI. This compound can be reacted with orthoester XI at elevated temparatures to form intermediate IIb intermediate IIc (Scheme 3). Scheme 4 Y= Cl, Br R⁷, R⁸ according to claim definition Intermediates IIc can be prepared from compound XVII by coupling with amine IX using amide coupling reagents such as HATU, HBTU, EDC or the like, followed by reaction with orthoester XI to form compound XIX. Reaction of this compound with an inorganic halogenation reagent such as phosphorous oxychloride or phosphorous oxybromide XX with or without an additional base gives intermediate IIc (Scheme 4). Scheme 5 Compounds Ic can be prepared from compound XV by reacting it with an orthoester to form intermediate XXI which can then be transformed to compound XXII by nucleophilic substitution or metal-catalyzed coupling with reactants V or VII (details see also description of Scheme 1). Either intermediate XXI, or intermediate XXII can then be reacted with carboxylic acid XXIII at oxydative coupling conditions (Minisci-reaction) to form compound XXIV or Ic, respectively. From compound XXIV the aforementioned nucleophilic substitution or metal-catalyzed coupling reactions with reagent V or VII can be used to produce compounds Ic (Scheme 5). Scheme 6 R^A, R^B, R⁷, R⁸ according to claim definition Compounds Id can be prepared according to Scheme 6. Compound XXV is reacted with amine V in presence of a base like N,N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethylsulfoxide or N- methylpyrrolidone to form XXVI which is further reacted with boronic acid III to give compound XXVII. Reaction of this compound with N-bromosuccinimide in a suitable solvent leads to formation of XXVIII, which is transformed to compound XXX by palladium-catalysed reaction with tin derivative XXIX. Aminolysis of ester XXX with amine IX in a solvent like ethanol or methanol gives rise to compound XXXI which is treated with a base like sodium methoxide to achieve cyclisation to compounds Id. Scheme 7 Furthermore compounds of formula If or Ig can be obtained by late stage functionalization or a related transformation of an already existing compound Ie. Such processes include hydrogenation of a compound with a partially unsaturated carbocycle to give a saturated carbocycle in position R^A or an alkylation of a suitable substituent R^B with an alkylating agent and a base (Scheme 7) 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 the following table. hTREM2 hTREM2 hTREM2 Ex. EC50 Ex. EC50 Ex. EC50 (µM) (µM) (µM) 1 0.545 20 0.329 39 2.561 2 0.249 21 0.965 40 4.095 3 0.457 22 0.019 41 4.651 4 0.368 23 0.112 42 0.079 5 0.031 24 0.735 43 0.112 6 3.089 25 0.004 44 3.303 7 0.074 26 0.148 45 0.060 8 1.879 27 1.041 46 0.855 9 4.999 28 0.049 47 0.920 10 1.629 29 0.054 48 0.427 11 1.360 30 0.125 49 0.951 12 0.297 31 0.556 50 0.932 13 0.663 32 0.026 51 3.074 14 0.032 33 2.311 52 0.324 15 0.021 34 0.133 53 3.469 16 0.395 35 0.330 54 0.124 17 0.216 36 0.511 55 0.599 18 0.071 37 2.006 56 0.542 19 0.016 38 0.190 57 4.428 hTREM2 hTREM2 hTREM2 Ex. EC50 Ex. EC50 Ex. EC50 (µM) (µM) (µM) 58 4.905 78 0.075 98 1.326 59 3.848 79 0.143 99 0.076 60 0.218 80 1.141 100 1.843 61 0.078 81 2.659 101 0.237 62 0.109 82 0.432 102 0.941 63 0.403 83 3.738 103 3.731 64 1.637 84 0.026 104 0.270 65 0.255 85 0.072 105 1.867 66 3.249 86 0.179 106 0.340 67 0.027 87 0.274 107 0.211 68 0.251 88 0.376 108 0.034 69 0.157 89 0.377 109 0.578 70 0.192 90 0.592 110 0.491 71 0.398 91 0.740 111 1.589 72 0.118 92 1.299 112 0.031 73 0.088 93 1.404 113 1.388 74 0.156 94 1.849 114 0.216 75 0.124 95 3.911 115 0.564 76 0.050 96 4.298 116 0.020 77 0.258 97 4.944 117 0.586 hTREM2 hTREM2 hTREM2 Ex. EC50 Ex. EC50 Ex. EC50 (µM) (µM) (µM) 118 1.330 138 0.004 158 0.106 119 0.034 139 0.187 159 1.160 120 0.217 140 0.017 160 0.198 121 0.321 141 0.085 161 0.055 122 0.020 142 0.549 162 1.095 123 0.055 143 0.142 163 0.356 124 1.694 144 0.002 164 0.038 125 0.881 145 0.005 165 0.041 126 0.421 146 0.208 166 0.047 127 0.516 147 0.294 167 0.065 128 0.047 148 0.571 129 0.002 149 0.144 130 0.018 150 0.012 131 0.023 151 0.066 132 0.042 152 0.306 133 0.227 153 0.548 134 0.078 154 0.735 136 0.089 155 0.101 136 0.288 156 0.055 137 0.168 157 0.203 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 168 or 169. 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: 6,8-dichloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one Step 1: 3-amino-2,6-dichloro-isonicotinic acid To a suspension of 3-amino-2,6-dichloro-isonicotinic acid methyl ester (1000 mg, 4.52 mmol) in tetrahydrofuran (12 ml) and water (4 ml) was added at 0 °C lithiumhydroxide (325 mg, 13.57 mmol) and the mixture was stirred for one hour at 0 °C and after that at room temperature overnight. Water was added and the mixture was extracted once with ethyl acetate. The aqueous phase was made acidic (pH 4) by addition of 3 M hydrochloric acid. The formed precipitate was dried in vacuo to yield the title compound (592 mg, 60% yield) as a yellow solid, MS m/z: 205.1 [M-H]-, ESI pos. Step 2: 3-amino-2,6-dichloro-N-methyl-pyridine-4-carboxamide To a solution of 3-amino-2,6-dichloro-pyridine-4-carboxylic acid (1000 mg, 4.83 mmol), methylamine hydrochloride (489 mg, 7.25 mmol) in anhydrous dimethylformamide (10 ml) was added N,N-diisopropyl ethylamine (1873 mg, 14.5 mmol), and the mixture was stirred at 25 °C for 10 min. Then HATU (2.76 g, 7.25 mmol) was added and the reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was extracted with ethyl acetate (3 times 50 ml) and the combined organic layers were washed with saturated brine twice, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:1) to obtain 3-amino-2,6-dichloro-N-methyl-pyridine-4- carboxamide (864 mg, 3.93 mmol, 81% yield) as a white solid, MS m/z: 220.1 [M+H]⁺, ESI pos. Step 3: 6,8-dichloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one Trimethyl orthoformate (2.08 g, 19.6 mmol) was added to 3-amino-2,6-dichloro-N-methyl- pyridine-4-carboxamide (864.0 mg, 3.93 mmol) in 1,4-dioxane (5 ml). Toluene-4-sulfonic acid (676 mg, 3.93 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated, followed by addition of saturated NaHCO3 solution. The formed solid was collected by vacuum filtration, washed with water and dried to give the title compound 6,8-dichloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one (800 mg, 88% yield) as a white solid, MS m/z: 230.1 [M+H]⁺, ESI pos. Intermediate A2: 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- diisopropyl ethylamine (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 vacuo 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 A3: 8-bromo-6-chloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one To 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see intermediate A2, 870 mg, 3.29 mmol) was added at room temperature trimethyl orthoformate (6.63 g, 6.9 ml, 62.49 mmol) followed by hydrochloric acid 25% in water (dropwise, 480 mg, 400 µ, 3.29 mmol). The resulting mixture was stirred at room temperature for 4 h. The reaction was concentrated in vacuo to afford 8-bromo-6-chloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one (892 mg, 91% yield) as white solid, MS m/z: 276.0 [M+H]⁺, ESI pos. Intermediate A4: 6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one To a solution of 5-amino-2-chloro-N-methyl-isonicotinamide (see Intermediate A2, 350 mg, 1.89 mmol) in 1,1,1-trimethoxyethane (1.66 g, 1.74 ml, 13.83 mmol) acetic acid (113 mg, 108 µl, 1.89 mmol) was added and the reaction was stirred overnight at 135 °C. The excess reagents were evaporated in vacuo to give 6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (392 mg, 99% yield) as light yellow solid, MS m/z: 210.1 [M+H]⁺, ESI pos. Intermediate A5: 6,8-dichloro-3-ethyl-pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A1 from ethylamine hydrochloride instead of methylamine hydrochloride in step 2. White solid, MS m/z: 244.1 [M+H]⁺, ESI pos. Intermediate A6: 6,8-dichloro-3-cyclopropyl-pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A1 from cyclopropylamine instead of methylamine hydrochloride in step 2. White solid, MS m/z: 256.1 [M+H]⁺, ESI pos. Intermediate A7: 6,8-dichloro-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A1 from 2,2,2-trifluoroethylamine instead of methylamine hydrochloride in step 2. Light yellow gum, MS m/z: 297.9 [M+H]⁺, ESI pos. Intermediate A8: 8-bromo-6-chloro-2-ethyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one To a solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see Intermediate A2, 0.600 g, 2.27 mmol) in dry 1,4-dioxane (12 ml) was added at room temperature 1,1,1- trimethoxypropane (1.52 g, 1.61 ml, 11.3 mmol) followed by p-toluenesulfonic acid monohydrate (432 mg, 2.27 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness and then triturated in methanol (2 ml). The light yellow solid was filtered, washed with methanol (2 ml) and dried in vacuo to afford 8-bromo-6-chloro-2-ethyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one (475 mg, 67% yield) as white solid, MS m/z: 304.0 [M+H]⁺, ESI pos. Intermediate A9: 2-(1-bicyclo[1.1.1]pentanyl)-8-bromo-6-chloro-3-methyl-pyrido[3,4- d]pyrimidin-4-one Step 1: 3-(bicyclo[1.1.1]pentane-1-carbonylamino)-2-bromo-6-chloro-N-methyl-pyridine-4- carboxamide To a solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see Intermediate A2, 500 mg, 1.89 mmol) in dichloromethane (8 ml) were added bicyclo[1.1.1]pentane-1-carboxylic acid (212 mg, 1.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (544 mg, 2.84 mmol) and 4-dimethylaminopyridine (462 mg, 3.78 mmol), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na₂SO₄, and evaporated. The residue was purified by column chromatography (silica gel, petroleum ether, ethyl acetate = 1:1) to give 3-(bicyclo[1.1.1]pentane-1-carbonylamino)-2-bromo-6-chloro-N-methyl-pyridine-4- carboxamide (230 mg, 0.64 mmol, 34% yield) as light yellow solid. MS m/z: 330.0 [M+H]⁺ ESI pos. Step 2: 2-(1-bicyclo[1.1.1]pentanyl)-8-bromo-6-chloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one A solution of 3-(bicyclo[1.1.1]pentane-1-carbonylamino)-2-bromo-6-chloro-N-methyl-pyridine- 4-carboxamide (230 mg, 0.64 mmol) in acetic acid (3.0 ml) was stirred at 110 °C for 16 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic extracts were washed with brine, dried over Na₂SO₄ and evaporated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to give 2-(1-bicyclo[1.1.1]pentanyl)-8-bromo-6-chloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one (200 mg, 92% yield) as light yellow solid, MS m/z: 342.0 [M+H]⁺ ESI pos. Intermediate A10: 8-bromo-6-chloro-3-cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one Step 1: 3-amino-2-bromo-6-chloro-N-cyclopropyl-isonicotinamide To a solution of 3-amino-2-bromo-6-chloro-isonicotinic acid (2 g, 7.56 mmol) in dry N,N- dimethylformamide (60 ml) cyclopropylamine (1.29 g, 1.6 ml, 22.6 mmol) and N-ethyl diisopropylamine (5.86 g, 7.84 ml, 45.4 mmol) were added. The reaction mixture was cooled at 0 °C and HATU (4.9 g, 12.9 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with saturated NaHCO3 solution and water, and was extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0 to 100%) to afford 3- amino-2-bromo-6-chloro-N-cyclopropyl-isonicotinamide (464 mg, 21% yield) as white solid, MS m/z: 292.0 [M+H]⁺, ESI pos. Step 2: 8-bromo-6-chloro-3-cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one To a solution of 3-amino-2-bromo-6-chloro-N-cyclopropyl-isonicotinamide (460 mg, 1.58 mmol) in dry 1,4-dioxane (9 ml) was added at room temperature 1,1,1-trimethoxyethane (951 mg, 1.01 ml, 7.92 mmol) followed by p-toluenesulfonic acid monohydrate (301 mg, 1.58 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and then triturated in methanol (3 ml). The solid was filtered, washed with methanol (3 ml) and dried in vacuo to afford 8-bromo-6-chloro-3-cyclopropyl-2-methyl- pyrido[3,4-d]pyrimidin-4-one (440 mg, 88% yield) as white solid, MS m/z: 316.0 [M+H]⁺, ESI pos. Intermediate A11: 8-bromo-6-chloro-2-methyl-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin- 4-one To a solution of 5-amino-2-chloropyridine-4-carboxylic acid (300 mg, 1.74 mmol) in dichloromethane (9 ml) 2,2,2-trifluoroethylamine (258 mg, 2.61 mmol) and N-ethyl diisopropylamine (0.91 mL, 5.22 mmol) were added at room temperature. Then, 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (400 mg, 2.09 mmol) and 1- hydroxybenzotriazole hydrate (235 mg, 1.74 mmol) were added at room temperature. The mixture was stirred at 30 °C for 12 h. The solvent was evaporated. Then water (100 ml) and ethyl acetate (50 ml) were added and the layers were separated. The aqueous layer was extracted three times with ethyl acetate (50 ml). The combined organic layers were dried with Na2SO4, filtrated and evaporated. The residue was purified by preparative TLC (silica, petroleum ether/ethyl acetate = 3:2) to give 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)pyridine-4- carboxamide (350 mg, 1.38 mmol, 79% yield) as a light yellow solid. MS m/z: 254.1 [M+H]⁺, ESI pos. Step 2: 3-amino-2-bromo-6-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide To a solution of 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (130 mg, 0.51 mmol) in dimethylformamide (3 ml) was added N-bromosuccinimide (110 mg, 0.62 mmol) and the reaction mixture was stirred at 30 °C for 12 h. The mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed by brine (50 ml x 3), dried over Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Spherical C18, 20-45 um, 100A; mobile phase: water / 0.1%TFA / acetonitrile, flow rate: 40ml/min) to give 3-amino-2-bromo-6-chloro-N- (2,2,2-trifluoroethyl)pyridine-4-carboxamide (150 mg, 88% yield) as light brown solid. MS m/z: 333.9 [M+H]⁺, ESI pos. Step 3: 8-bromo-6-chloro-2-methyl-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one To a solution of 3-amino-2-bromo-6-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (150 mg, 0.45 mmol) in 1,4-dioxane (5 ml) were added trimethyl orthoacetate (271 mg, 2.26 mmol) and p-toluene sulfonic acid (155 mg, 0.9 mmol), and the reaction was stirred at 110 °C for 12 h. The reaction was concentrated in vacuo and the residue which was purified by preparative HPLC (column: Spherical C18, 20-45um, 100A; mobile phase: water / 0.1% TFA / acetonitrile, flow rate: 50 ml/min) to give 8-bromo-6-chloro-2-methyl-3-(2,2,2-trifluoroethyl)pyrido[3,4- d]pyrimidin-4-one (100 mg, 0.28 mmol, 62% yield) as off-white solid. MS m/z: 358.0 [M+H]⁺, ESI pos. Intermediate A12: 8-bromo-6-chloro-3-cyclobutyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A11 from cyclobutylamine instead of 2,2,2-trifluoroethylamine in step 1. Light yellow solid, MS m/z: 328.0 [M+H]⁺, ESI pos. Intermediate A13: 8-bromo-6-chloro-2-cyclobutyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one 4-carboxamide To a solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see Intermediate A2, 300 mg, 1.13 mmol) in pyridine (3 ml) were added 4-dimethylaminpyridine (28 mg, 0.23 mmol) and cyclobutanecarbonyl chloride (208 mg, 1.7 mmol) at 0 °C and the reaction was stirred at 0 ° to 20 °C for 12 h. Then the reaction was concentrated in vacuo and the residue was purified by preparative HPLC (column: Spherical C18, 20-45um, 100A, mobile phase: (water with 0.1%TFA, acetonitrile, flow rate: 80ml/min) to give 2-bromo-6-chloro-3- (cyclobutanecarbonylamino)-N-methyl-pyridine-4-carboxamide (120 mg, 31% yield) as white solid. MS m/z: 346.0 [M+H]⁺, ESI pos. Step 2: 8-bromo-6-chloro-2-cyclobutyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one To a solution of 2-bromo-6-chloro-3-(cyclobutanecarbonylamino)-N-methyl-pyridine-4- carboxamide (120 mg, 0.35 mmol) in acetic acid (4 ml) and the reaction mixture was stirred at 110 °C for 12 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column: Spherical C18, 20-45um, 100A; mobile phase: water with 0.1%TFA, acetonitrile, flow rate 60 ml/min) to give 8-bromo-6-chloro-2-cyclobutyl-3-methyl- pyrido[3,4-d]pyrimidin-4-one (45 mg, 0.14 mmol, 40% yield) as off-white solid. MS m/z: 330.0 [M+H]⁺, ESI pos. Intermediate A14: 8-bromo-6-chloro-2-methyl-3-(1-methylcyclopropyl)pyrido[3,4- d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A11 from 1- methylcyclopropanamine instead of 2,2,2-trifluoroethylamine in step 1. Light yellow solid, MS m/z: 329.9 [M+H]⁺, ESI pos. Intermediate A15: 8-bromo-6-chloro-2-cyclopentyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one To a solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see Intermediate A2, 300 mg, 1.13 mmol) in pyridine (5 ml) was added 4-dimethylaminpyridine (28 mg, 0.23 mmol). Then cyclopentanecarbonyl chloride (301 mg, 2.27 mmol) was added dropwise to the mixture while keeping the temperature between 0-5 °C. After addition, the mixture was stirred at 0 °C for 2 h, then warmed to 50 °C and stirred for 12 h. The mixture was poured into water (50 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic layer were washed by brine (50 ml), dried over Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 1:2) to give the 8-bromo-6-chloro-2-cyclopentyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one (210 mg, 54% yield) as white solid. Intermediate A16: 8-bromo-6-chloro-2-cyclopropyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A13 from cyclopropanecarbonyl chloride instead of cyclobutanecarbonyl chloride in step 1. Light brown solid, MS m/z: 315.9 [M+H]⁺, ESI pos. Intermediate A17: 8-bromo-2-tert-butyl-6-chloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A13 from pivaloyl chloride instead of cyclobutanecarbonyl chloride in step 1. White solid, MS m/z: 330.0, 332.0 [M+H]⁺, ESI pos. Intermediate A18: 8-bromo-6-chloro-2-(1,1-difluoroethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4- one The title compound was prepared in analogy to Intermediate A13 from 2,2-difluoropropionyl chloride instead of cyclobutanecarbonyl chloride in step 1. Light brown solid, MS m/z: 339.9 [M+H]⁺, ESI pos. Intermediate A19: 8-bromo-6-chloro-3-ethyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A11 from ethylamine instead of 2,2,2-trifluoroethylamine in step 1. Light yellow solid, MS m/z: 304.0 [M+H]⁺, ESI pos. Intermediate A20: 8-bromo-6-chloro-2-isopropyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A13 from 2-methylpropionyl chloride instead of cyclobutanecarbonyl chloride in step 1. Light yellow solid, MS m/z: 318.0 [M+H]⁺, ESI pos. Intermediate A21: 8-bromo-6-chloro-3-methyl-2-(1-methylcyclopropyl)pyrido[3,4- d]pyrimidin-4-one The title compound was prepared in analogy to Intermediate A13 from 1-methyl- cyclopropanecarbonyl chloride instead of cyclobutanecarbonyl chloride in step 1. Off-white solid, MS m/z: 328.1 [M+H]⁺, ESI pos. Intermediate B1: 8-bromo-6-chloro-3-methyl-pyrido[3,2-d]pyrimidin-4-one Step 1: 8-bromo-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one Bromine (2.0 g, 650 µl, 12.6 mmol) was added dropwise to 3-amino-6-chloro-picolinamide (CAS 175358-01-7, 540 mg, 3.15 mmol) in acetic acid (13.5 ml) at 0 °C. After 30 min, the reaction mixture was allowed to warm to room temperature. The reaction was quenched by adding aqueous Na2SO3 solution and the mixture extracted with ethyl acetate. The organic layer was washed with brine and dried with Na₂SO₄ and evaporated. The crude product was dissolved in acetic acid diethoxymethyl ester (CAS 14036-06-7, 10.2 g, 10.3 ml, 63 mmol) and stirred at 150 °C overnight. After cooling down to room temperature the crystalline material formed was washed with water and dichloromethane to afford the title compound (589 mg, 65% yield, 90% purity) as a light yellow solid which was used directly for the next step, MS m/z: 260.0, 262.0 [M+H]⁺, ESI pos. Step 2: 8-bromo-6-chloro-3-methyl-pyrido[3,2-d]pyrimidin-4-one To a solution of 8-bromo-6-chloro-3H-pyrido[3,2-d]pyrimidin-4-one (589 mg, 2.0 mmol) in N,N-dimethylformamide (8 ml) was added sodium hydride (98 mg, 2.44 mmol) at 0 °C and the mixture was stirred for 30 min. Iodomethane (433 mg, 191 µl, 3.05 mmol) was added at room temperature and the reaction was stirred for 60 min. The reaction mixture was poured in water and extracted two times with ethyl acetate. The organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated to dryness to yield the title compound (341 mg, 61% yield) as a light yellow solid. MS m/z: 274.0, 276.0 [M+H]⁺, ESI pos. Intermediate B2: 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,2-d]pyrimidin-4-one Step 1: 3-amino-4-bromo-6-chloro-picolinic acid To a solution of 3-amino-4-bromo-6-chloro-picolinic acid methyl ester (CAS 1073182-89-4, 1.3 g, 4.65 mmol) in tetrahydrofuran (17 ml) and methanol (8.5 ml) was added 1 M aqueous lithium hydroxide solution (7.0 ml, 7.0 mmol). After stirring for 4 h, 3 M aqueous hydrochloric acid (2.33 ml, 7.0 mmol) was added and the solvents were removed in vacuo. The resulting solid was filtered and rinsed with cold water. After drying under high vaccum 3-amino-4-bromo-6-chloro- picolinic acid (1.1 g, 89% yield) was isolated as light brown powder, MS m/z: 251.0, 253.0 [M+H]⁺, ESI pos. Step 2: 3-amino-4-bromo-6-chloro-N-methyl-picolinamide 3-Amino-4-bromo-6-chloro-picolinic acid (500 mg, 1.79 mmol) and methylamine hydrochloride (181 mg, 2.68 mmol) were dissolved in N,N-dimethylformamide (14 ml) and N,N-diisopropyl ethylamine (694 mg, 920 µl, 5.37 mmol) was added. After cooling the mixture to 0 °C HATU (817 mg, 2.15 mmol) was added. The reaction mixture was stirred at room temperature overnight, then diluted with water and ethyl acetate and extracted. The combined organic layers were washed with saturated NaHCO₃ and brine, dried over dry Na₂SO₄ and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0 to 20%) to give 3-amino-4-bromo-6-chloro-N-methyl-picolinamide (371 mg, 75% yield) as light yellow powder, MS m/z: 264.0, 266.0 [M+H]⁺, ESI pos. Step 3: 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,2-d]pyrimidin-4-one To a solution of 3-amino-4-bromo-6-chloro-N-methyl-picolinamide (371 mg, 1.4 mmol) in 1,1,1-trimethoxyethane (1.24 g, 1.31 ml, 10.3 mmol) was added acetic acid (84 mg, 80 µl, 1.4 mmol) and the reaction was stirred over two nights at 135 °C. The reaction mixture was concentrated to dryness and the crude material was purified by flash chromatography (silica gel, 100% dichloromethane) to yield the product which still contained some starting material. Further trituration in diethyl ether gave 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,2-d]pyrimidin-4-one (250 mg, 59% yield) as light yellow powder. MS m/z: 288.0, 290.0 [M+H]⁺, ESI pos. Intermediate C1: 6,8-dichloro-3-methyl-pyrimido[5,4-d]pyrimidin-4-one Step 1: 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylic acid methyl ester Sodium bicarbonate (5 g, 59.5 mmol) and 12,4-diketo-5-nitro-1H-pyrimidine-6-carboxylic acid methyl ester (CAS 6311-73-5, 1 g, 4.65 mmol) were suspended in water (50 ml). Sodium dithionate (5 g, 24.3 mmol) was added portionwise at room temperature and the mixture was stirred for 1 h. Solids were filtered off, washed with water and dried in vacuo to obtain 5-amino- 2,4-diketo-1H-pyrimidine-6-carboxylic acid methyl ester (443 mg, 50% yield) as yellow solid which was used directly in the next step. Step 2: 5-(ethoxymethyleneamino)-2,4-diketo-1H-pyrimidine-6-carboxylic acid methyl ester A suspension of 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylic acid methyl ester (440 mg, 2.38 mmol) in diethoxymethyl acetate (4.0 g, 4 ml, 24.5 mmol) was stirred for 2 h at 80 °C. The mixture was cooled down to room temperature and methyl tert-butyl ether was added. The suspension was stirred for 5 min before the solids were filtered off and washed with methyl tert- butyl ether. Solids were dried in vacuo to obtain the crude title compound (512 mg, 85% yield) as white solid which was used directly in the next step. Step 3: 3-methyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione A suspension of 5-(ethoxymethyleneamino)-2,4-diketo-1H-pyrimidine-6-carboxylic acid methyl ester (400 mg, 1.66 mmol) in a 33% solution of methylamine in ethanol (4 ml, 32.1 mmol) was stirred over night at 80 °C. Solids were filtered off, washed with ethanol, then dried in vacuo to obtain the crude title compound 3-methyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (350 mg, 100%) as light yellow solid. MS m/z: 195.1 [M+H]⁺, ESI pos. Step 4: 6,8-dichloro-3-methyl-pyrimido[5,4-d]pyrimidin-4-one To a suspension of 3-methyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (375 mg, 1.93 mmol) in phosphorus oxychloride (8.23 g, 5 ml, 53.6 mmol) a mix of N,N-diisopropyl ethylamine (250 mg, 337 µl, 1.93 mmol) and dimethylformamide (23 mg, 24 µl, 311 µmol) was added dropwise at room temperature. The mixture was stirred at 130 °C overnight. The reaction mixture was concentrated to dryness. The residue was taken up with dichloromethane, quenched with water and extracted two times with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, methanol in dichloromethane 0-5%) to obtain the title compound (128 mg, 24% yield, 85% purity) as brown solid, MS m/z: 231.0, 233.0 [M+H]⁺, ESI pos. Intermediate C2: 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one Step 1: 5-amino-2,4-diketo-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-diisopropyl ethylamine (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 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 C3: 11,13-dichloro-2,7,10,12-tetrazatricyclo[7.4.0.0^3,7]trideca-1(9),2,10,12- tetraen-8-one To a suspension of methyl 5-amino-2,6-dichloro-pyrimidine-4-carboxylate (CAS 502184-51-2, 1.5 g, 6.76 mmol) in dry toluene (45 ml) were added 5-methoxy-3,4-dihydro-2H-pyrrole (CAS 5264-35-7, 4.18 ml, 40.5 mmol) and phosphorus oxychloride (3.78 ml, 40.5 mmol). After stirring at 100 °C for 18 h, the mixture was concentrated in vacuo, quenched with cold saturated NaHCO3 aqueous solution (300 ml), and extracted with ethyl acetate (2 x 250 ml). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 0- 95% acetonitrile in chloroform) to give the title compound (436 mg, 25% yield) as a yellow solid, MS m/z: 257.2 [M+H]⁺, ESI pos. Intermediate C4: 6-chloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one Step 1: 5-amino-2-chloro-N-methyl-pyrimidine-4-carboxamide To a solution of 5-amino-2-chloro-pyrimidine-4-carboxylic acid ethyl ester (500 mg, 2.48 mmol) in ethanol (1.65 ml) was added methylamine in water (40%, 2.7 ml, 31 mmol) and the reaction mixture was stirred at 70 °C for 2 h. The solvent was evaporated to give 5-amino-2-chloro-N- methyl-pyrimidine-4-carboxamide (455 mg, 98% yield) as an orange solid, MS m/z: 187.0 [M+H]⁺, ESI pos. Step 2: 6-chloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one To a solution of 5-amino-2-chloro-N-methyl-pyrimidine-4-carboxamide (455 mg, 2.44 mmol) in 1,1,1-trimethoxyethane (2.15 g, 2.25 ml, 17.88 mmol) was added acetic acid (146 mg, 140 µl, 2.44 mmol) and the reaction mixture was stirred at 135°C for 16 h. The volatiles were evaporated to give 6-chloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (531 mg, 94% yield) as orange solid, MS m/z: 211.0 [M+H]⁺, ESI pos. Intermediate D1: 4-(4-bromotetrahydropyran-2-yl)-1-methyl-pyrazole To a solution of 1-methylpyrazole-4-carbaldehyde (2 g, 18.2 mmol) in dichloromethane (25 ml) was added 3-buten-1-ol (1.38 g, 1.64 ml, 19.1 mmol) under argon. Hydrobromic acid (33% solution in acetic acid (13.4 g, 9.9 mL, 54.5 mmol) was added at room temperature in one portion and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was carefully quenched with saturated NaHCO3 solution and washed with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography (silica gel, 0-50% ethyl acetate / ethanol = 3:1 in heptane) to afford 4-(4-bromotetrahydropyran-2-yl)-1-methyl-pyrazole (2.87 g, 62% yield) as light yellow oil, 245.1 [M+H]⁺, ESI pos. Intermediate D2: (2S)-4-bromo-2-methyl-6-phenyl-tetrahydropyran The title compound was prepared in analogy to Intermediate D1 from (2S)-pent-4-en-2-ol instead of 3-buten-1-ol, light yellow oil. Intermediate Name Structure Source E1 2-(1-methylpyrazol-4- commercial, yl)morpholine CAS 1375963- 52-2 E₂ 3-(1-methylpyrazol-4- commercial, yl)piperidine CAS 1340528- 88-2 E3 2-(2-methyl-4- N commercial, pyridyl)morpholine NH CAS O 1211523- 01-1 E4 2-(2-methoxy-4- commercial, pyridyl)morpholine CAS 2091599- E5 2-(1-cyclopropylpyrazol-4- known, yl)morpholine CAS 1780917- 09-0 _E6 1-methyl-4,5,6,7-tetrahydro- commercial, 1H-pyrazolo[3,4-c]pyridine 2 CAS dihydrochloride 1228878- 69-0 E7 2- commercial, (trifluoromethyl)morpholine CAS hydrochloride 1196152- 51-8 E8 1,2,3,4-tetrahydro-2,7- commercial, naphthyridine hydrochloride CAS 1354940- 72-9 _E9 4,4-difluoro-3-(1- known, methylpyrazol-4- CAS yl)piperidine 2738350- 76-8 E10 2-(1-cyclopropylpyrazol-4- known, yl)-6-methyl-morpholine CAS 2738496- 25-6 E11 2-(1H-pyrazol-4- commercial, yl)morpholine CAS 2287299- 71-0 _E12 2-(3-methyl-1,2,4-oxadiazol- commercial, 5-yl)morpholine CAS 1304007- 87-1 E13 3-(1,2,4-triazol-1- commercial, yl)piperidine CAS 774511-83- 0 E14 3-(2-methylpyrazol-3- commercial, yl)piperidine CAS 1251925- 05-9 _E15 4-(4,4-dimethylpyrrolidin-3- commercial, yl)-1-methyl-pyrazole CAS dihydrochloride 2 HCl 1820704- 38-8 E16 5-methyl-3-(3-piperidyl)- commercial, 1,2,4-oxadiazole CAS HCl 895572-60- 8 E17 3-(3-methoxyphenyl)-3- commercial, methyl-pyrrolidine CAS 28707-86-0 E18 rac-(3aR,6aR)-3a-phenyl- commercial, 1,3,4,5,6,6a- CAS hexahydrofuro[3,4-c]pyrrole 2137900- 33-3 E19 3-(3,5-dimethylpyrazol-1- commercial, yl)piperidine CAS 1250773- 31-9 E20 6-(3-pyridyl)-3- azabicyclo[4.1.0]heptane ^{2 HCl} _commercial, dihydrochloride CAS 2416237- 55-1 E21 2-cyclopropyl-5,6,7,8- commercial, tetrahydropyrido[4,3- CAS d]pyrimidine 880361-75- 1 E22 3-(triazol-1-yl)piperidine commercial, dihydrochloride 2 HCl CAS 2460755- 72-8 E23 3-methyl-5-(3-piperidyl)- commercial, 1,2,4-oxadiazole CAS hydrochloride _HCl 1181540- 59-9 _E24 2-tert-butyl-4,5,6,7- commercial, tetrahydropyrazolo[1,5- HCl CAS a]pyrazine hydrochloride 2126163- 03-7 E25 1-methyl-4-pyrrolidin-3-yl- commercial, pyrazole dihydrochloride CAS 2 HCl 1949815- 97-7 E26 5,6,7,8-tetrahydro-1,6- commercial, naphthyridine 2 HCl CAS dihydrochloride 348623-30- 3 _E27 3-methyl-5-pyrrolidin-3-yl- commercial, 1,2,4-oxadiazole CAS hydrochloride _HCl 1121057- 52-0 E28 1-(p-tolyl)piperazin-2-one commercial, CAS 893748-24- 8 E29 1-pyrrolidin-3-yl-1,2,4- commercial, triazole dihydrochloride 2 HCl CAS 1909316- 43-3 E30 4-cyclopropyl-1-pyrrolidin- commercial, 3-yl-triazole dihydrochloride CAS 2 HCl 2031269- 60-8 E31 7-methyl-2,6-dioxa-9- commercial, O azaspiro[4.5]decane _NH CAS O 1493588- 45-6 _E32 3-methyl-3-(p- commercial, tolyl)pyrrolidine CAS 1248449- 06-0 E33 1-cyclopropylpiperazine-2- commercial, carbonitrile CAS 1311569- 64-8 E34 3-pyrrolidin-3-yl-5,6,7,8- commercial, tetrahydro- CAS [1,2,4]triazolo[4,3-a]pyridine 2418658- d^{ihydrochloride} _{2 HCl} 65-6 _E35 2-(3-methyl-1,2,4-oxadiazol- known, 5-yl)morpholine CAS 1304007- 87-1 E36 2-(5-methyl-1,2,4-oxadiazol- commercial, 3-yl)morpholine CAS hydrochloride HCl 1443979- 69-8 E₃₇ 3-(difluoromethyl)- commercial, pyrrolidine hydrochloride CAS HCl 1376176- 56-5 E38 8-(1H-pyrazol-3-yl)-6- commercial, azaspiro[3.4]octane CAS dihydrochloride ^{2 HCl} 2503203- 01-6 Intermediate E39: 2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine To a solution of 4-iodo-1-(oxetan-3-yl)pyrazole (CAS 1314393-99-1, 600 mg, 2.4 mmol) in tetrahydrofuran (6 ml) was added i-PrMgCl·LiCl (in tetrahydrofuran (1.3 M, 2.8 ml, 3.6 mmol, 1.5 eq) at -70 °C in nitrogen atmosphere. After stirring the mixture -70 °C for 0.5 h a solution of 2-chloro-N-methoxy-N-methylacetamide (396 mg, 2.88 mmol, 1.2 eq) in tetrahydrofuran (4 ml) was added dropwise to the mixture at -70 °C. Then stirring was continued at 0 °C for 1 h. The reaction mixture was poured into saturated ammonium chloride solution (50 ml), the aqueous phase was extracted with dichloromethane (50 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried with anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 1:1) and concentrated under reduced pressure to give 2-chloro-1-[1-(oxetan-3-yl)pyrazol-4- yl]ethanone (300 mg, 1.5 mmol, 62% yield) as light yellow solid, MS m/z: 201.3 [M+H]⁺ ESI pos. Step 2: 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanone To a solution of 2-chloro-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanone (3.60 g, 17.9 mmol) in dimethyl sulfoxide (60 ml) were added N-benzylethanolamine (2.71 g, 17.9 mmol), potassium carbonate (4.96 g, 35.9 mmol) and potassium iodide (2.98 g, 17.9 mmol). Then the mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (500 ml) and extracted with dichloromethane (200 ml x 3). The combined organic phase was washed with brine (500 ml), dried over Na₂SO₄ and concentrated in vacuo to give 2-[benzyl(2-hydroxyethyl)amino]-1-[1- (oxetan-3-yl)pyrazol-4-yl]ethanone (5.0 mg, 88% yield) as light yellow oil, MS m/z: 316.4 [M+H]⁺ ESI pos. Step 3: 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanol To a solution of 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanone (5.0 g, 13.6 mmol) in methanol (80 ml) was added sodium borohydride (2.06 g, 54.5 mmol) at 0 °C and the mixture was stirrred at 0 °C for 1 h. The reaction mixture was poured into aqueuous saturated NH4Cl solution (300 ml) and the aqueous layer was extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine (200 ml x 3), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: UniSil 10-120, C1870 x 250 mm, water + 0.1% formic acid / acetonitrile, flow rate 140ml/min). The pH of the eluent was adjusted to 8-9 with ammonium hydroxide and the mixture was extrated with ethyl acetate (200 ml x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentracted under reduce pressure to give 2-[benzyl(2- hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanol (3.6 g, 83% yield) as colorless oil, MS m/z: 318.2 [M+H]⁺ ESI pos. Step 4: 4-benzyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine To a solution of 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanol (2.5 g, 7.88 mmol) in toluene (40 ml), stirred and purged with nitrogen and cooled to 0 °C, were added diisopropyl azodicarboxylate (1.66 ml, 9.45 mmol) and triphenylphosphine (2.48 g, 9.45 mmol) in portions. Then the mixture was stirred at 25℃ for 12 h under nitrogen atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by reversed phase HPLC (column: Spherical C18, 20-45 um, 100A, water + 0.1% formic acid / acetonitrile, flow rate: 50ml/min). The eluent was extrated with ethyl acetate (200 ml x 2) and the combined organic layers were dried and concentrated in vacuo to give 4-benzyl-2-[1-(oxetan-3-yl)pyrazol- 4-yl]morpholine (1.2 g, 51% yield) as colorless oil, MS m/z: 300.2 [M+H]⁺ ESI pos. Step 5: 2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine To a solution of 4-benzyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine (1.2 g, 4.01 mmol) in methanol (15 ml). After degassing with nitrogen three times, Pd/C (10%, 213 mg) was added and an atmosphere of hydrogen was applied. The reaction was stirred at 50 °C for 12 h under hydrogen (15 psi). The reaction was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the crude product was diluted with ethyl acetate (100 ml) and washed with water (100 ml) and brine (100 ml). Then the organic phase was dried over Na2SO4, filltered and concentrated in vacuo to give the title compound (800 mg, 95% yield) as light yellow oil, MS m/z: 210.1 [M+H]⁺ ESI pos. Intermediate (+)-E1: (+)- 2-(1-methylpyrazol-4-yl)morpholine 2-(1-Methylpyrazol-4-yl)morpholine (Intermediate E1) 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 as the first eluting enantiomer and (-)- 2-(1-methylpyrazol-4- yl)morpholine 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). Examples Example 1: 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one To a solution of 6,8-dichloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A1, 150 mg, 0.65 mmol) in a mixture of toluene (10 ml) and ethanol (5 ml) were added 4- chlorophenylboronic acid (102 mg, 0.65 mmol), sodium carbonate (276 mg, 2.61 mmol) and tetrakis(triphenylphosphine)-palladium(0) (60 mg, 0.05 mmol, 0.08 eq). After degassing with nitrogen 3 times, the resulting mixture was stirred at 75 °C for 16 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 ml). Then the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC-A (column: Welch Ultimate XB-SiOH 250*50*10um; mobile phase: hexane- ethanol, flow rate 100 ml/min) to give 6-chloro-8-(4-chlorophenyl)-3-methyl-pyrido[3,4- d]pyrimidin-4-one (120 mg, 45% yield) as white solid, MS m/z: 306.1 [M+H]⁺ ESI pos. Step 2: 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one To a solution of 6-chloro-8-(4-chlorophenyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (90 mg, 0.29 mmol), 2-(1-methylpyrazol-4-yl)morpholine (Intermediate E1, 74 mg, 0.44 mmol) in N- methyl pyrrolidone (3 ml) was added N,N-diisopropyl ethylamine (152 mg, 1.18 mmol) and the mixture was heated under microwave irradiation at 150 °C for 12 h. The mixture was poured into water (40 ml), extracted with ethyl acetate twice, washed by brine (3 x 30 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (Column Phenomenex luna L18, 150*25 mm*10 um, water + formic acid / acetonitrile, flow rate: 25 ml/min) to give 8-(4-chlorophenyl)-3-methyl-6-[2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one (28 mg). This racemate was separated by SFC (column Daicel Chiralcel OD 250 mm*30 mm, 10 um, solvent: acetonitrile / isopropylalcohol / 0.1% ammonium hydroxide, flow rate 75 ml/min) to give 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one as first eluting enantiomer with retention time 1.18 min (other enantiomer retention time 1.51 min), light yellow solid, MS m/z: 437.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 2: 8-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one The title compound was prepared in analogy to Example 1 from 2-fluoro-4- (trifluoromethyl)phenylboronic acid instead of 4-chlorophenylboronic acid in step 1 and (+)-2- (1-methylpyrazol-4-yl)morpholine instead of 2-(1-methylpyrazol-4-yl)morpholine in step 2 omitting the chiral SFC separation. Yellow solid, MS m/z: 489.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 3: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one To a solution of 8-bromo-6-chloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A3, 834 mg, 3.04 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (530 mg, 3.04 mmol) in 1,4- dioxane (15 ml) and water (5 ml), was added cesium carbonate (2.97 g, 9.11 mmol). The reaction mixture was purged and backfilled with argon 3 times. Next, 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (124 mg, 152 µmol, 0.05 eq) was added and the mixture was purged and backfilled with argon 3 times. The reaction mixture was stirred at room temperature for 16 h, then diluted with water and extracted two times with dichloromethane. The combined organic layers were washed with water and brine, dried over Na₂SO₄ and concentrated in vacuo. The crude material was triturated in diethyl ether to afford 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-pyrido[3,4-d]pyrimidin- 4-one (870 mg, 87% yield) as light yellow solid, MS m/z: 324.1 [M+H]⁺, ESI pos.1H NMR (300 MHz, DMSO-d6) δ = 8.45 (s, 1H), 8.12 (s, 1H), 7.68 - 7.54 (m, 2H), 7.46 (dd, J = 1.9, 8.4 Hz, 1H), 3.51 (s, 3H). Step 2: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one To a solution of 2-(1-methylpyrazol-4-yl)morpholine (Intermediate E1, 134 mg, 0.8 mmol) and 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (130 mg, 0.4 mmol) in N-methyl pyrrolidone (3 ml) was added N,N-diisopropyl ethylamine (0.21 ml, 1.2 mmol) and the mixture was stirred at 150 °C for 16 h. The reaction mixture was added into water (50 ml) and extracted with ethyl acetate (2 x 30 ml). The combined organic layers were washed with brine (2 x 50 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ethyl acetate) to give 8-(4-chloro-2-fluoro-phenyl)-3- methyl-6-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (110 mg). This racemate was separated by SFC (column Daicel Chiralcel OD-3, 50 mm*4.6 mm, 3 um, mobile phase 50% acetonitrile / isopropylalcohol / 0.05% diethylamine, flow rate 3 ml/min) to give 8- (4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,4- d]pyrimidin-4-one as first eluting enantiomer with retention time 1.25 min (other enantiomer retention time 0.85 min), yellow solid, MS m/z: 455.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 4-12 were prepared in analogy to Example 3 by coupling the indicated intermediate instead of intermediate E1. For chiral examples the absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediate (ESI): m/z 8-(4-chloro-2-fluoro- phenyl)-3-methyl-6-[(3R)- 453.2 4 3-(1-methylpyrazol-4-yl)-1- E2 [M+H]⁺ piperidyl]pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-3-methyl-6-[(2R)- 2-(2-methyl-4- 466.1 5 E3 pyridyl)morpholin-4- [M+H]⁺ yl]pyrido[3,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-6-[(2R)-2-(1- cyclopropylpyrazol-4- 481.1 6 E5 yl)morpholin-4-yl]-3- [M+H]⁺ methyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[(2S)-2-(1- cyclopropylpyrazol-4- 481.1 E5 yl)morpholin-4-yl]-3- [M+H]⁺ methyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-3-methyl-6-(1- methyl-5,7-dihydro-4H- 439.2 E6 pyrazolo[3,4-c]pyridin-6- [M+H]⁺ yl)pyrido[3,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-3-methyl-6-[(2R)- 2- 443.1 E7 (trifluoromethyl)morpholin- [M+H]⁺ 4-yl]pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-(3,4-dihydro-1H- 422.2 2,7-naphthyridin-2-yl)-3- E8 [M+H]⁺ methyl-pyrido[3,4- d]pyrimidin-4-one Cl 8-(4-chloro-2-fluoro- F phenyl)-6-[(3R)-4,4- 489.1 N N N difluoro-3-(1- E9 [M+ ⁺ N H] N N methylpyrazol-4-yl)-1- F O F piperidyl]-3-methyl- pyrido[3,4-d]pyrimidin-4- one 8-(4-chloro-2-fluoro- phenyl)-6-[(3S)-4,4- difluoro-3-(1- 489.1 12 methylpyrazol-4-yl)-1- E9 [M+H]⁺ piperidyl]-3-methyl- pyrido[3,4-d]pyrimidin-4- one Example 13: 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 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A2, 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 E1, 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 um, water (0.225% 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 um, 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). Example 14: 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 Example 13, 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. Example 15: 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4- yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 13 from Intermediate E5 instead of Intermediate E1 in step 2, first eluting enantiomer with retention time 1.58 min, light yellow solid, MS m/z: 495.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 16: 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4- yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 13 from Intermediate E5 instead of Intermediate E1 in step 2, second eluting enantiomer with retention time 2.58 min, light yellow solid, MS m/z: 495.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 17: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H- pyrazolo[3,4-c]pyridin-6-yl)pyrido[3,4-d]pyrimidin-4-one 6-Chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (see Example 13, 25 mg, 74 µmol), 1-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine dihydrochloride (Intermediate E6, 16 mg, 74 µmol), tris(dibenzylideneacetone)dipalladium (3 mg, 3.7 µmol, 0.05 eq), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2 mg, 3.7 µmol, 0.05 eq), cesium carbonate (96 mg, 296 µmol) in 1,4-dioxane (0.5 ml) was stirred at 100 °C for 15 min under argon. 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 crude material was purified by preparative HPLC (column Gemini NX, 12 nm, 5um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford 8-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6- yl)pyrido[3,4-d]pyrimidin-4-one (2 mg, 5% yield) as yellow powder, MS m/z: 439.2 [M+H]⁺, ESI pos.1H NMR (300 MHz, DMSO-d6) δ = 7.65 - 7.51 (m, 2H), 7.47 - 7.36 (m, 2H), 7.23 (s, 1H), 4.71 (s, 2H), 3.92 (t, J = 5.7 Hz, 2H), 3.77 (s, 3H), 3.53 (s, 3H), 2.64 - 2.59 (m, 2H), 2.44 (s, 3H). Example 18: 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 17 from Intermediate E8 instead of Intermediate E6, yellow powder, MS m/z: 436.2 [M+H]⁺, ESI pos. Example 19: 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 Example 13, 30 mg, 0.09 mmol) in 1,4-dioxane (1.5 ml) were added 2-(2-methyl-4- pyridyl)morpholine (Intermediate E3, 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 um, 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. Example 20: 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 Example 19, second eluting enantiomer with retention time 2.08 min, yellow solid, MS m/z: 480.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 21-30 were prepared in analogy to Example 19 and 20 by coupling the indicated intermediate instead of intermediate E3. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediate (ESI): m/z 8-(4-chloro-2-fluoro- phenyl)-6-[(2S)-2-(2- methoxy-4- 496.1 21 E4 pyridyl)morpholin-4-yl]- [M+H]⁺ 2,3-dimethyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[(2R)-2-(2- methoxy-4- 496.1 E4 pyridyl)morpholin-4-yl]- [M+H]⁺ 2,3-dimethyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6- 467.1 [(3S)-3-(1-methylpyrazol-4- E2 [M+H]⁺ yl)-1-piperidyl]pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6- 467.1 [(3R)-3-(1-methylpyrazol-4- E2 [M+H]⁺ yl)-1-piperidyl]pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[(2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6- 509.2 E10 methyl-morpholin-4-yl]-2,3- [M+H]⁺ dimethyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[(2R,6S)-2-(1- cyclopropylpyrazol-4-yl)-6- 509.1 E10 methyl-morpholin-4-yl]-2,3- [M+H]⁺ dimethyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[(2S,6S)-2-(1- cyclopropylpyrazol-4-yl)-6- 509.1 27 E10 methyl-morpholin-4-yl]-2,3- [M+H]⁺ dimethyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[(2R,6R)-2-(1- cyclopropylpyrazol-4-yl)-6- 509.1 28 E10 methyl-morpholin-4-yl]-2,3- [M+H]⁺ dimethyl-pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[(3R)-4,4- difluoro-3-(1- 503.1 29 methylpyrazol-4-yl)-1- E9 [M+H]⁺ piperidyl]-2,3-dimethyl- pyrido[3,4-d]pyrimidin-4- one 8-(4-chloro-2-fluoro- phenyl)-6-[(3S)-4,4- difluoro-3-(1- 503.1 30 methylpyrazol-4-yl)-1- E9 [M+H]⁺ piperidyl]-2,3-dimethyl- pyrido[3,4-d]pyrimidin-4- one Example 31: 3-fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-8-yl]benzonitrile To a solution of 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A2, 300 mg, 1.04 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (181 mg, 1.04 mmol) in 1,4- dioxane (5 ml) and water (1.5 ml), was added cesium carbonate (1.02 g, 3.12 mmol). The reaction mixture was purged and backfilled with argon three times and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (42 mg, 0.052 mmol, 0.050 eq) was added. The reaction mixture was purged and backfilled with argon three times. The reaction mixture was stirred at room temperature for 16 hours. 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 0-60%) and then triturated in diethyl ether to afford 4-(6-chloro-4-keto-2,3-dimethyl-pyrido[3,4-d]pyrimidin-8- yl)-3-fluoro-benzonitrile (200 mg, 42% yield) as light yellow solid, MS m/z: 329.1 [M+H]⁺, ESI pos. Step 2: 3-fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-8-yl]benzonitrile A flask was charged with (2S)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 73 mg, 58 µl, 438 µmol), 4-(6-chloro-4-keto-2,3-dimethyl-pyrido[3,4-d]pyrimidin-8-yl)-3-fluoro- benzonitrile (100 mg, 219 µmol), N,N-diisopropyl ethylamine (85 mg, 115 µl, 657 µmol) and dimethyl sulfoxide (1.5 ml). The reaction mixture was stirred at 120 °C for 16 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 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford the title compound (24 mg, 24% yield) as yellow solid, MS m/z: 460.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 32: 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 31 from 2-(4-chloro-2,6-difluoro- phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane at a reaction temperature of 80 °C instead of (4- chloro-2-fluoro-phenyl)boronic acid at room temperature in step 1, yellow solid, MS m/z: 487.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 33: 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]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 A2, 300 mg, 1.04 mmol) in 1,4-dioxane (10 ml) were added 2,4-difluorobenzeneboronic acid (164 mg, 1.04 mmol), sodium carbonate (331 mg, 3.12 mmol) and tetrakis(triphenylphosphine)- palladium(0) (60 mg, 0.05 mmol, 0.05 eq). After degassing with nitrogen 3 times, the resulting mixture was stirred at 100 °C for 16 h. Then mixture was poured into water (200 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic layers were dried over Na2SO4 and the solution was concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether: 30%) to give 6-chloro-8-(2,4-difluorophenyl)-2,3-dimethyl- pyrido[3,4-d]pyrimidin-4-one (110 mg, 33% yield) as light yellow solid, MS m/z: 322.0 [M+H]⁺, ESI pos. Step 2: 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one To a solution of 6-chloro-8-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (47 mg, 0.15 mmol) in N-methylpyrrolidone (2 ml) was added (2S)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-E1, 37 mg, 0.22 mmol), N,N-diisopropyl ethylamine (0.12 ml, 0.73 mmol) and the mixture heated under microwave irradiation at 150 ℃ for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by preparative HPLC (Column Phenomenex Luna L18, 150*25 mm*10 um, water + formic acid / acetonitrile, flow rate: 25 ml/min) to give the title compound (6 mg, 9% yield) as yellow solid, MS m/z: 453.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 34: 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 33 from (2R)-2-(1-methylpyrazol-4- yl)morpholine instead of (2S)-2-(1-methylpyrazol-4-yl)morpholine in step 2, yellow solid, MS m/z: 453.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 35: 8-(2-fluoro-4-methyl-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 33 from 2-fluoro-4- methylphenylboronic acid instead of 2,4-difluorobenzeneboronic acid in step 1 and (2R)-2-(1- methylpyrazol-4-yl)morpholine instead of (2S)-2-(1-methylpyrazol-4-yl)morpholine in step 2, yellow solid, MS m/z: 449.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 36: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p- tolyl)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 A2, 200 mg, 0.69 mmol) in 1,4-dioxane (6 ml) and were added 4-methylphenylboronic acid (94 mg, 0.69 mmol), cesium carbonate (678 mg, 2.08 mmol), bis(diphenylphosphino) ferrocene- palladium(II)dichloride dichloromethane complex (28 mg, 0.03 mmol, 0.05 eq) and water (2 ml). Then the reaction mixture was degassed with nitrogen three times and stirred at 25 °C for 12 h under nitrogen. The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na₂SO₄ and concentrated in vacuum. The solid was triturated in petroleum ether / ethyl acetate = 5:1 (20 ml) and collected by filtration to give 6-chloro-2,3-dimethyl-8-(p- tolyl)pyrido[3,4-d]pyrimidin-4-one (180 mg, 86% yield) as grey solid, MS m/z: 300.2 [M+H]⁺, ESI pos. Step 2: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4- d]pyrimidin-4-one To a solution of 6-chloro-2,3-dimethyl-8-(p-tolyl)pyrido[3,4-d]pyrimidin-4-one (60 mg, 0.2 mmol) in N-methyl pyrrolidone (2 ml) were added (2R)-2-(1-methylpyrazol-4-yl)morpholine (50 mg, 0.3 mmol) and N,N-diisopropyl ethylamine (0.1 ml, 0.6 mmol), and the reaction was heated under microwave irradiation at 150 °C for 16 h. The reaction mixture was filtered and the filtrate was purified by preparative HPLC (column: Waters Xbridge C18, 150 x 25mm x 10 um, acetonitrile / water + 0.225% formic acid), flow rate 25 ml/min) to give 2,3-dimethyl-6-[(2R)-2- (1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidin-4-one (15 mg, 18% yield) as yellow solid. , MS m/z: 431.3 [M+H]⁺, ESI pos. absolute stereochemistry arbitrarily assigned. Example 37: 2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p- tolyl)pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 36 from (2S)-2-(1-methylpyrazol-4- yl)morpholine instead of (2R)-2-(1-methylpyrazol-4-yl)morpholine in step 2, yellow solid, MS m/z: 431.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 38: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one Step 1: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-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 (see Example 13, 300 mg, 0.89 mmol) in N-methylpyrrolidone (4 ml) were added 2-(1H- pyrazol-4-yl)morpholine (Intermediate E11, 204 mg, 1.33 mmol) and N,N-diisopropyl ethylamine (0.44 ml, 2.66 mmol) and the mixture was heated under microwave irradiation at 150 °C for 16 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, then the residue was purified by column chromatography (silica gel, ethyl acetate / MeOH = 1:5 to 10:1) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one (70 mg, 14% yield) a light yellow solid, MS m/z: 455.2 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one To a solution of 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one (35 mg, 0.08 mmol) and 3-iodooxetane (28 mg, 0.15 mmol) in dimethylformamide (1 ml) was added cesium carbonate (75 mg, 0.23 mmol) and the mixture was stirred at 50 °C for 16 h. The reaction mixture was added into water (50 ml) and extracted with dichloromethane (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3) and dried over Na₂SO₄, then concentrated in vacuum. The residue was purified by preparative TLC (ethyl acetate / methanol = 10:1) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-[1- (oxetan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (30 mg, 72% yield) as a green solid. The enantiomers were separated by SFC (column Daicel Chiralpak AD, 250 mm x 30 mm, 10 um, solvent ethanol + 0.1% ammonium hydroxide, flow rate 70 ml/min) to give as first eluting compound (retention time 1.08 min) 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6- [(2R)-2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (2.8 mg, 10%) as light yellow gum, MS m/z: 511.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 39: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 38, step 2 second eluting compound (retention time 1.62 min) light yellow gum, MS m/z: 511.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 40: 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]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 A2, 500 mg, 1.73 mmol) in ethanol (3 ml) were added toluene (6 ml), water (0.9 ml), 2-(4,4- dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 859217-67-7, 409 mg, 1.73 mmol), sodium carbonate (551 mg, 5.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol, 0.05 eq). After degassing with nitrogen three times, the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate/ petroleum ether = 1:1) to give 6-chloro-8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl- pyrido[3,4-d]pyrimidin-4-one (370 mg, 67% yield) as a white solid, MS m/z: 318.1 [M+H]⁺, ESI pos. Step 2: 8-(4,4-dimethylcyclohexen-1-yl)-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-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin- 4-one (130 mg, 0.41 mmol) in 1,4-dioxane (3 ml) were added 2-(2-methyl-4-pyridyl)morpholine (Intermediate E3, 109 mg, 0.615 mmol), cesium carbonate (400 mg, 1.23 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol, 0.08 eq), Xantphos (47 mg, 0.08 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 (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and evaporated. The residue was purified by column chromatography (silica gel, dichloromethane / ethyl acetate = 10:1) to give 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (130 mg). The enantiomers were separated by SFC (column Daicel Chiralpak AD, 250 mm x 30 mm, 10 um, solvent ethanol + 0.1% ammonium hydroxide, flow rate 75 ml/min) to give as first eluting compound (retention time 2.1 min), MS m/z: 460.4 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 41: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidin-4-one Step 1: 6-chloro-2,3-dimethyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]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 A2, 500 mg, 1.73 mmol) in 1,4-dioxane (12 ml) were added 4,4,5,5-tetramethyl-2-[4- (trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane (CAS 683242-93-5, 478 mg, 1.73 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (71 mg, 0.09 mmol, 0.05 eq), cesium carbonate (1.69 g, 5.2 mmol), and water (4 ml). After degassing with nitrogen three times the reaction mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. The reaction mixture was added into water (50 ml) and extracted with dichloromethane (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3) and dried over Na₂SO₄, then concentrated in vacuum. The formed precipitate was triturated in petroleum ether / ethyl acetate = 5:1 and collected by filtration. Solid, MS m/z: 358.1 [M+H]⁺, ESI pos. Step 2: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidin-4-one To a solution of 6-chloro-2,3-dimethyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4- d]pyrimidin-4-one (170 mg, 0.48 mmol) in 1,4-dioxane (1 ml) were added (2R)-2-(1- methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 119 mg, 0.71 mmol), cesium carbonate (387 mg, 1.19 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.02 mmol, 0.05 eq), Xantphos (27.5 mg, 0.05 mmol, 0.1 eq). Then the mixture was degassed by nitrogen 3 times and heated to 100 °C for 12 h. The reaction mixture was added into water (50 ml) and extracted with ethyl acetate (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na₂SO₄ and concentrated. The residue was purified by preparative HPLC (column Waters Xbridge C18150 x 50 mm x 10 um, water with 10 mM ammonium carbonate / acetonitrile, flow rate 60 ml/m) to give the title compound (80 mg, 34% yield) as a light yellow solid, MS m/z: 489.2 [M+H]⁺, ESI pos. The following Examples 42-45 were prepared in analogy to Example 41 by coupling the indicated boronic acid derivative instead of 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)- cyclohexen-1-yl]-1,3,2-dioxaborolane. The absolute stereochemistry was assigned arbitrarily. Boronic MS Ex. Structure Name acid (ESI): derivative m/z 2,3-dimethyl-6-[(2R)-2-(1- methylpyrazol-4- CAS 485.1 42 yl)morpholin-4-yl]-8-[4- 214360-65- [M+H]⁺ (trifluoromethyl)phenyl]pyri 3 do[3,4-d]pyrimidin-4-one 8-(4-chlorophenyl)-2,3- dimethyl-6-[(2R)-2-(1- CAS methylpyrazol-4- 451.2 43 195062-61- yl)morpholin-4- [M+H]⁺ 4 yl]pyrido[3,4-d]pyrimidin- 4-one 8-(4-chloro-2-methyl- phenyl)-2,3-dimethyl-6- CAS [(2R)-2-(1-methylpyrazol-4- 465.2 44 1030832- yl)morpholin-4- [M+H]⁺ 75-7 yl]pyrido[3,4-d]pyrimidin- 4-one 8-[2-fluoro-4- (trifluoromethyl)phenyl]- 2,3-dimethyl-6-[(2R)-2-(1- CAS 503.2 45 methylpyrazol-4- 1689509- [M+H]⁺ yl)morpholin-4- 92-9 yl]pyrido[3,4-d]pyrimidin- 4-one Example 46: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]octan- 6-yl-pyrido[3,4-d]pyrimidin-4-one Step 1: 6-chloro-2,3-dimethyl-8-spiro[2.5]oct-6-en-6-yl-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 A2, 280 mg, 0.97 mmol) in 1,4-dioxane (6 ml) were added 4,4,5,5-tetramethyl-2-spiro[2.5]oct-6-en- 6-yl-1,3,2-dioxaborolane (CAS 859219-46-8, 227 mg, 0.97 mmol), cesium carbonate (948 mg, 2.91 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (40 mg, 0.05 mmol, 0.05 eq), and water (2 ml). The mixture was degassed by nitrogen three times and stirred at 30 °C for 16 h. After cooling down to room temperature the precipitate was washed with petroleum ether to remove the solids by filtration. The solution was evaporated to give crude product which was used directly for the next step, MS m/z: 316.2 [M+H]⁺, ESI pos. Step 2: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]oct-6-en-6- yl-pyrido[3,4-d]pyrimidin-4-one To a solution of 6-chloro-2,3-dimethyl-8-spiro[2.5]oct-6-en-6-yl-pyrido[3,4-d]pyrimidin-4-one (135 mg, 0.43 mmol) in 1,4-dioxane (3 ml) were added (2R)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-E1, 107 mg, 0.64 mmol), tris(dibenzylideneacetone)dipalladium (31 mg, 0.03 mmol, 0.08 eq), cesium carbonate (418 mg, 1.28 mmol), Xantphos (49.5 mg, 0.09 mmol, 0.2 eq) and the mixture was stirred at 100 °C for 16 h under nitrogen. The reaction mixture was poured into water (40 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and evaporated. The residue was purified by column chromatography (column Phenomenex Luna C18, 150 x 25mm x 10 um, water + 0.1% formic acid / acetonitrile, flow rate 25 ml/min) to give 2,3-dimethyl-6- [(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]oct-6-en-6-yl-pyrido[3,4- d]pyrimidin-4-one (58 mg, 29% yield) as yellow solid, MS m/z: 447.2 [M+H]⁺, ESI pos. Step 3: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]octan-6-yl- pyrido[3,4-d]pyrimidin-4-one To a solution of 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]oct- 6-en-6-yl-pyrido[3,4-d]pyrimidin-4-one (58 mg, 0.13 mmol) in methanol (2 ml) was added palladium on charcoal (10%, 10 mg) and the mixture was hydrogenated under an atmosphere of 30 psi hydrogen at 50 °C for 2 h. The crude mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (column: Phenomenex luna C18, 150 x 25 mm x 10 um, water + 0.1% formic acid / acetonitrile, flow rate 25 ml/min) to give the title compound (27 mg, 44% yield) as light yellow solid, MS m/z: 449.2 [M+H]⁺, ESI pos. Example 47: 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 46 from 2-(4,4-difluorocyclohex-1-en-1- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 1227068-84-9) instead of 4,4,5,5-tetramethyl- 2-spiro[2.5] oct-6-en-6-yl-1,3,2-dioxaborolane in step 1 and hydrogenation for 16 h at 50 °C and atmospheric pressure in step 3, light yellow solid, MS m/z: 459.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 48: 8-(4,4-dimethylcyclohexyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 46 from 8-(4,4-dimethylcyclohexen-1- yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (Example 40) instead of 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8- spiro[2.5]oct-6-en-6-yl-pyrido[3,4-d]pyrimidin-4-one using atmospheric pressure for 16 h at room temperature in step 3, light yellow solid, MS m/z: 462.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 49: 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-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)-3-ethyl-pyrido[3,4-d]pyrimidin-4-one To a solution of 6,8-dichloro-3-ethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A5, 240 mg, 0.98 mmol) in 1,4-dioxane (10 ml) were added 4-chloro-2-fluorophenylboronic acid (189 mg, 1.08 mmol), sodium carbonate (314 mg, 2.95 mmol) and tetrakis(triphenylphosphine) palladium(0) (91 mg, 0.08 mmol, 0.08 eq). The reaction mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. After cooling down to room temperature the reaction was added into water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (100 ml) and dried over Na2SO4, then concentrated under reduce pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to give 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-ethyl-pyrido[3,4-d]pyrimidin-4-one (115 mg, 35% yield) as white solid, MS m/z: 338.2 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-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)-3-ethyl-pyrido[3,4-d]pyrimidin-4-one (110 mg, 0.33 mmol) in N-methylpyrrolidone (2 ml) were added 2-(1-methylpyrazol-4- yl)morpholine (Intermediate E1, 82 mg, 0.49 mmol) and N,N-diisopropyl ethylamine (126 mg, 0.98 mmol). Then the reaction was heated under microwave irradiation at 150 °C for 16 h. After cooling down to room temperature the reaction mixture was added into water (50 ml) and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (50 ml x 2) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by preparative HPLC (column Waters Xbridge C18, 150 x 25 mm x 10 um, water + 10mM ammoniumcarbonate / acetonitrile, flow rate 25 ml/min) NH4HCO3) to give 8-(4-chloro-2- fluoro-phenyl)-3-ethyl-6-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (65 mg). This racemate was separated by SFC (column Daicel Chiralpak OD 250 mm*30 mm, 10 um, solvent: acetonitrile/methanol/0.1% ammonium hydroxide, flow rate 70 ml/min) to give the title compound (8 mg, 12% yield) as second eluting enantiomer with retention time 0.99 min (other enantiomer retention time 0.71 min), yellow solid, MS m/z: 469.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 50: 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-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 Example 49 from 6,8-dichloro-3-cyclopropyl- pyrido[3,4-d]pyrimidin-4-one (Intermediate A6) instead of 6,8-dichloro-3-ethyl-pyrido[3,4- d]pyrimidin-4-one (Intermediate A5) in step 1, light yellow solid, MS m/z: 481.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 51: 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-3- (2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 49 from 6,8-dichloro-3-(2,2,2- trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one (Intermediate A7) instead of 6,8-dichloro-3-ethyl- pyrido[3,4-d]pyrimidin-4-one (Intermediate A5) in step 1, yellow solid, MS m/z: 523.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 52: 8-(4-chloro-2-fluoro-phenyl)-3-cyclobutyl-2-methyl-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)-3-cyclobutyl-2-methyl-pyrido[3,4-d]pyrimidin-4- one To a solution of 8-bromo-6-chloro-3-cyclobutyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A12, 200 mg, 0.61 mmol) in 1,4-dioxane (6 ml) were added 4-chloro-2- fluorophenylboronic acid (106 mg, 0.61 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (25 mg, 0.03 mmol, 0.05 eq), cesium carbonate (595 mg, 1.83 mmol) and water (2 ml). 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-cyclobutyl-2-methyl-pyrido[3,4- d]pyrimidin-4-one (160 mg, 69% yield) as light yellow solid, MS m/z: 378.1 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-3-cyclobutyl-2-methyl-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)-3-cyclobutyl-2-methyl-pyrido[3,4- d]pyrimidin-4-one (60 mg, 0.16 mmol) and (2R)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 32 mg, 0.19 mmol) in 1,4-dioxane (3 ml) were added cesium carbonate (65 mg, 0.48 mmol), XantPhos (9 mg, 0.02 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (7 mg, 0.01 mmol, 0.05 eq). The mixture was degassed with nitrogen three times and stirred at 100 °C for 12 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 10um), water + 0.1% formic acid / acetonitrile, flow rate 60 ml/min) to give the title compound (13 mg, 16% yield) as light yellow solid. MS m/z: 509.1 [M+H]⁺, ESI pos. The following Examples 53-59 were prepared in analogy to Example 52 by coupling the indicated intermediate instead of Intermediate A12 in step 1. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediate (ESI): m/z 8-(4-chloro-2-fluoro- phenyl)-2-methyl-6-[(2R)- 2-(1-methylpyrazol-4- 537.2 53 A11 yl)morpholin-4-yl]-3-(2,2,2- [M+H]⁺ trifluoroethyl)pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2-cyclobutyl-3- methyl-6-[(2R)-2-(1- 509.1 methylpyrazol-4- A13 [M+H]⁺ yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin- 4-one 2-(1- bicyclo[1.1.1]pentanyl)-8- (4-chloro-2-fluoro-phenyl)- 3-methyl-6-[(2R)-2-(1- 521.3 A9 methylpyrazol-4- [M+H]⁺ yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-2-cyclopentyl-3- methyl-6-[(2R)-2-(1- 523.4 methylpyrazol-4- A15 [M+H]⁺ yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin- 4-one 2-tert-butyl-8-(4-chloro-2- fluoro-phenyl)-3-methyl-6- [(2R)-2-(1-methylpyrazol-4- 511.2 A17 yl)morpholin-4- [M+H]⁺ yl]pyrido[3,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-3-methyl-2-(1- methylcyclopropyl)-6- 509.3 58 [(2R)-2-(1-methylpyrazol-4- A21 [M+H]⁺ yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-2-methyl-3-(1- methylcyclopropyl)-6- 509.2 59 [(2R)-2-(1-methylpyrazol-4- A14 [M+H]⁺ yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin- 4-one Example 60: 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazol- 4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one Step 1: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-3-methyl-pyrido[3,4-d]pyrimidin- 4-one To a solution of 8-bromo-6-chloro-2-cyclopropyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A16, 445 mg, 1.41 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (247 mg, 1.41 mmol) in 1,4-dioxane (7.5 ml) and water (2.5 ml) was added cesium carbonate (1.38 g, 4.24 mmol). The reaction mixture was purged and backfilled with argon three times. Then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (58 mg, 0.071 mmol, 0.05 eq) was added. The mixture was purged and backfilled with argon three times and stirred at 30 °C for 1 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 0-50%) to afford 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2- cyclopropyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one (95 mg, 13% yield) as white solid, MS m/z: 364.0 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-3-methyl-pyrido[3,4- d]pyrimidin-4-one (30 mg, 0.082 mmol) in 1,4-dioxane (3 ml) was added at room temperature (2S)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 18 mg, 0.107 mmol) followed by cesium carbonate (81 mg, 0.247 mmol) in water (1 ml). The mixture was degassed for 10 min by bubbling argon through the mixture. Then was added PdCl(crotyl)QPhos (CAS 1252598-33- 6, 7.5 mg, 0.0082 mmol, 0.10 eq) and degassing was continued for 5 min. The tube was sealed and heated to 60 °C for 18 h. The mixture was treated with aqueous saturated NaHCO3 solution (10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column Gemini NX, 12 nm, 5 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford the title compound (2.5 mg, 6% yield) as yellow powder, MS m/z: 495.2 [M+H]⁺, ESI pos. Example 61: 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-2-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 60 from 8-bromo-6-chloro-3-ethyl-2- methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A19) instead of 6,8-dichloro-3-cyclopropyl- pyrido[3,4-d]pyrimidin-4-one (Intermediate A16) in step 1, yellow solid, MS m/z: 483.0 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 62: 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazol- 4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one Step 1: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin- 4-one To a solution of 8-bromo-6-chloro-3-cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A10, 440 mg, 1.4 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (244 mg, 1.4 mmol) in 1,4-dioxane (6 ml) and water (2 ml) was added cesium carbonate (1.37 g, 4.2 mmol). The reaction mixture was purged and backfilled with argon three times. Then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (57 mg, 0.07 mmol, 0.050 eq) was added. After purging and backfilling with argon 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 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 0-60%) and then triturated in diethyl ether to afford 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin-4- one (178 mg, 33% yield) as light yellow solid, MS m/z: 364.1 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one A flask was charged with (2S)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 46 mg, 36 µl, 0.275 mmol), 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-pyrido[3,4- d]pyrimidin-4-one (50 mg, 0.137 mmol), N,N-diisopropyl ethylamine (53 mg, 72 µl, 0.412 mmol) and dimethyl sulfoxide (1 ml), and the mixture was stirred at 120 °C for 16 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 Gemini NX, 12 nm, 5 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford the title compound (14 mg, 21% yield) as yellow powder, MS m/z: 495.3 [M+H]⁺, ESI pos. Example 63: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 66 from 8-bromo-6-chloro-2,3- dimethyl-pyrido[3,2-d]pyrimidin-4-one (Intermediate B2) instead of 8-bromo-6-chloro-3- cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A10) in step 1 and 2-(1- methylpyrazol-4-yl)morpholine (Intermediate E1) instead of (2S)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-E1) in step 2, light brown solid, MS m/z: 469.3 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 64 and 65: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6- [(2R)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,2-d]pyrimidin-4-one The enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one (Example 63, 42 mg) were separated by chiral SFC (column chiral OD-H, 5 um, 250 x 20 mm, 45% methanol + 0,2% diethylamine). The solvent was evaporated to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one (15 mg, 36% yield), first eluting isomer (t = 1.78 min), as light yellow solid, MS m/z: 469.1 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)- 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,2-d]pyrimidin-4-one (15 mg, 36%) second eluting isomer (t = 2.44 min), as light yellow solid, MS m/z: 469.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 66: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one To a mixture of (4-chloro-2-fluoro-phenyl)boronic acid (19 mg, 0.11 mmol), 8-bromo-6-chloro- 3-methyl-pyrido[3,2-d]pyrimidin-4-one (Intermediate B1, 30 mg, 0.11 mmol) and cesium carbonate (105 mg, 0.321 mmol), 1,4-dioxane (480 µl) and water (144 µl) were added. The tube was set under argon atmosphere and tetrakis(triphenylphosphine)palladium (6 mg, 0.0054 mmol, 0.050 eq) was added. The mixture was heated to 55°C overnight. The reaction mixture was extracted two times with ethyl acetate. The combined organic layers were washed with water anµd brine, dried over Na₂SO₄ and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane / 0-50% ethyl acetate) to give the title compound (14 mg, 40% yield) as a white solid, MS m/z: 324.1 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-pyrido[3,2-d]pyrimidin-4-one (50 mg, 0.148 mmol) in toluene (2 ml) were added under argon 2-(1-methylpyrazol-4- yl)morpholine (Intermediate E1, 30 mg, 0.178 mmol), sodium tert-butylate (19 mg, 0.193 mmol) and XPhos-Pd-G3 (9 mg, 0.010 µmol, 0.070 eq) and the mixture was stirred at 100 °C for 8 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 reverse phase chromatography (column: YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to give 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one (19 mg). This racemate was separated by chiral SFC (column chiral OD-H, 5 um, 250 x 20 mm, 45% methanol + 0,2% diethylamine) to give 8- (4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,2- d]pyrimidin-4-one (7 mg, 10% yield) as second eluting isomer (t = 2.45min), light yellow solid, MS m/z: 455.3 [M+H]⁺, ESI pos. Example 67: 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 Step 1: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one 6,8-Dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (Intermediate C2, 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 (+)-E1, 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. Example 68: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 67 from 6,8-dichloro-3-methyl- pyrimido[5,4-d]pyrimidin-4-one (Intermediate C1) instead of 6,8-dichloro-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one (Intermediate C2) in step 1, yellow solid, MS m/z: 456.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 69: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 67 from (2R)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (-)-E1) instead of (2S)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1) in step 2, yellow solid, MS m/z: 470.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 70: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazol-5- 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 (see Example 67, 25 mg, 0.074 mmol) was dissolved in N,N-dimethylformamide (0.5 ml). Then 2-(3- methyl-1,2,4-oxadiazol-5-yl)morpholine (Intermediate E12, 19 mg, 0.111 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. A few drops of water were added. The reaction mixture was purified by preparative HPLC (column Gemini NX-C18, 300 x 100 mm x 5 um, water / acetonitrile) to obtain the title compound (24 mg, 70% yield) as yellow solid, MS m/z: 472.1 [M+H]⁺, ESI pos. Example 71 and 72: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(3-methyl-1,2,4- oxadiazol-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2- fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazol-5-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one The enantiomers of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (Example 70, 16 mg) were separated by chiral SFC (column YMC chiral SZ, 5 um, 250 x 20 mm, 5 um, 35% methanol + 0,2% diethylamine). The solvent was evaporated to give 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6- [(2R)-2-(3-methyl-1,2,4-oxadiazol-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (6 mg, 37% yield), first eluting isomer (t = 3.00 min), as light yellow solid, MS m/z: 472.1 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (6 mg, 37%) second eluting isomer (t = 3.68 min), as light yellow solid, MS m/z: 472.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 73-98 were prepared in analogy to Example 70 by coupling the indicated intermediate instead of Intermediate E12 and, if desired, followed by separation of enantiomers as described in Examples 71 and 72. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediate (ESI): m/z 8-(4-chloro-2- fluorophenyl)-2,3-dimethyl- 6-[2-(5-methyl-1,3,4- 472.1 73 E35 oxadiazol-2-yl)morpholin- [M+H]⁺ 4-yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2- fluorophenyl)-2,3-dimethyl- 6-[(2R)-2-(5-methyl-1,3,4- 472.1 74 E35 oxadiazol-2-yl)morpholin- [M+H]⁺ 4-yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2- fluorophenyl)-2,3-dimethyl- 6-[(2S)-2-(5-methyl-1,3,4- 472.1 75 E35 oxadiazol-2-yl)morpholin- [M+H]⁺ 4-yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- 455.1 (1,2,4-triazol-1- E13 [M+H]⁺ yl)piperidino]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- 468.1 (2-methylpyrazol-3- E14 [M+H]⁺ yl)piperidino]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[3,3-dimethyl-4- (1-methylpyrazol-4- 482.2 E15 yl)pyrrolidino]-2,3- [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- (5-methyl-1,2,4-oxadiazol- 470.1 E16 3- [M+H]⁺ yl)piperidino]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[3-(3- methoxyphenyl)-3-methyl- 494.1 E17 pyrrolidino]-2,3-dimethyl- [M+H]⁺ pyrimido[5,4-d]pyrimidin- 4-one 6-[(3aR,6aR)-3a-phenyl- 3,4,6,6a-tetrahydro-1H- furo[3,4-c]pyrrol-5-yl]-8-(4- 492.1 E18 chloro-2-fluoro-phenyl)-2,3- [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[3-(3,5- dimethylpyrazol-1- 482.2 E19 yl)piperidino]-2,3-dimethyl- [M+H]⁺ pyrimido[5,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[6- (3-pyridyl)-3- 477.1 E20 azabicyclo[4.1.0]heptan-3- [M+H]⁺ yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-(2-cyclopropyl- 7,8-dihydro-5H-pyrido[4,3- 478.0 E21 d]pyrimidin-6-yl)-2,3- [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- 455.0 (triazol-1- E22 [M+H]⁺ yl)piperidino]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- (3-methyl-1,2,4-oxadiazol- 470.0 E23 5- [M+H]⁺ yl)piperidino]pyrimido[5,4- d]pyrimidin-4-one 6-(2-tert-butyl-6,7-dihydro- 4H-pyrazolo[1,5-a]pyrazin- 5-yl)-8-(4-chloro-2-fluoro- 482.0 E24 phenyl)-2,3-dimethyl- [M+H]⁺ pyrimido[5,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- 454.0 (1-methylpyrazol-4- E25 [M+H]⁺ yl)pyrrolidino]pyrimido[5,4 -d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-(7,8-dihydro-5H- 437.0 1,6-naphthyridin-6-yl)-2,3- E26 [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- (3-methyl-1,2,4-oxadiazol- 456.0 E27 5- [M+H]⁺ yl)pyrrolidino]pyrimido[5,4 -d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[3-keto-4-(p- 493.0 tolyl)piperazino]-2,3- E28 [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- 441.0 (1,2,4-triazol-1- E29 [M+H]⁺ yl)pyrrolidino]pyrimido[5,4 -d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-6-[3-(4- cyclopropyltriazol-1- 481.0 E30 yl)pyrrolidino]-2,3- [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-(7- methyl-2,6-dioxa-9- 460.0 E31 azaspiro[4.5]decan-9- [M+H]⁺ yl)pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- 478.0 methyl-3-(p- E32 [M+H]⁺ tolyl)pyrrolidino]pyrimido[ 5,4-d]pyrimidin-4-one 4-[8-(4-chloro-2-fluoro- phenyl)-4-keto-2,3- dimethyl-pyrimido[5,4- 454.0 E33 d]pyrimidin-6-yl]-1- [M+H]⁺ cyclopropyl-piperazine-2- carbonitrile 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[3- (5,6,7,8-tetrahydro- 495.0 97 [1,2,4]triazolo[4,3- E34 [M+H]⁺ a]pyridin-3- yl)pyrrolidino]pyrimido[5,4 -d]pyrimidin-4-one 8-(4-chloro-2- fluorophenyl)-2,3-dimethyl- 6-[2-(5-methyl-1,2,4- 472.1 98 E36 oxadiazol-3-yl)morpholin- [M+H]⁺ 4-yl]pyrimido[5,4- d]pyrimidin-4-one Example 99 and Example 100: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one and 8-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidin-4-one Step 1: bromo-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]zinc In an oven-dried flask zinc powder (4.0 g, 61.2 mmol) was added, then the flask was evacuated and backfilled with argon three times. A solution of lithium chloride (0.5 M in tetrahydrofuran, 40.8 ml, 20.4 mmol) was added, followed by 1,2-dibromoethane (192 mg, 88 µl, 1.02 mmol) and the reaction mixture was heated to 50 °C for 20 min. The flask was removed from the heating block and cooled down to room temperature. Trimethylsilyl chloride (111 mg, 130 µl, 1.02 mmol) was added and the reaction mixture was heated to 50 °C for 20 min. The flask was removed from the heating block and cooled down to room temperature. Iodine (104 mg, 408 µmol) was added as a solution in tetrahydrofuran (1.5 ml) and the reaction mixture was heated to 50 °C for 20 min. While still hot, a solution of 4-(4-bromotetrahydropyran-2-yl)-1-methyl- pyrazole (Intermediate D1, 5.0 g, 20.4 mmol) in tetrahydrofuran (25 ml) was added and the resulting mixture was stirred at 50 °C for 18 h. After cooling down to room temperature the reaction mixture was filtered to obtain a solution of the zinc reagent which was used directly for the following step. Step 2: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-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 Example 13 step 1, 100 mg, 0.296 mmol) in dry tetrahydrofuran (0.50 ml) was added Xantphos palladacycle G 3 (31 mg, 0.030 mmol, 0.10 eq) and the reaction mixture was purged and backfilled with argon. To this solution was added bromo-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]zinc (2.0 ml, 0.44 mmol, 1.5 eq) and the mixture was stirred at 50 °C for 1.5 h. The reaction mixture was diluted with 1M hydrochloric acid 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, methanol in dichloromethane 0-10%) to afford 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6- [2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one (140 mg) as an isomeric mixture. Separation was performed using chiral SFC (column Chiralcel OJ, 50 mm x 250 mm, 5-20% methanol) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one as first eluting enantiomer (t = 3.41 min), white solid, MS m/z: 466.2 [M-H]⁺, ESI neg. and 8-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidin-4-one as second eluting enantiomer (t = 3.51 min), white solid, MS m/z: 468.3 [M+H]⁺, ESI pos. The absolute stereochemistry was assigned arbitrarily. The following Examples 101-105 were prepared in analogy to Examples 99/100 by starting from the indicated intermediate instead of Intermediate A2 in step 2. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name Intermediate (ESI): m/z 8-(4-chloro-2-fluoro- phenyl)-2-ethyl-3-methyl-6- [(2R,4S)-2-(1- 482.3 101 methylpyrazol-4- A8 [M+H]⁺ yl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-3-methyl-6- [(2R,4S)-2-(1- 454.1 102 methylpyrazol-4- A3 [M+H]⁺ yl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidin- 4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6- [(2R,4S)-2-(1- 469.1 103 methylpyrazol-4- C2 [M+H]⁺ yl)tetrahydropyran-4- yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6- [(2S,4R)-2-(1- 469.1 104 methylpyrazol-4- C2 [M+H]⁺ yl)tetrahydropyran-4- yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6- [(2R,4R)-2-(1- 469.4 105 methylpyrazol-4- C2 [M+H]⁺ yl)tetrahydropyran-4- yl]pyrimido[5,4- d]pyrimidin-4-one Example 106: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-methyl-6-phenyl- tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 99 from (2S)-4-bromo-2-methyl-6- phenyl-tetrahydropyran (Intermediate D2) instead of 4-(4-bromotetrahydropyran-2-yl)-1-methyl- pyrazole (Intermediate D1) in step 1, white solid, MS m/z: 479.4 [M+H]⁺, ESI pos., mixture of diastereomers. Example 107: 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one Step 1: 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4- one To a solution of 6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A4, 2.05 g, 9.78 mmol) in tetrahydrofuran, extra dry (10 ml) under an atmosphere of nitrogen was added XantPhos Pd G3 (505 mg, 489 µmol, 0.05 eq) followed by the above mentioned solution of bromo-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]zinc (see Example 99, 67 ml, 14.67 mmol, 1.5 eq) and the mixture was stirred at 50 °C for 3 h. After evaporation of the solvent the residue was adsorbed on Isolute and purified by flash chromatography (silica gel, heptane / ethyl acetate = 50:50 to 0:100) to obtain 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidin-4-one (2.71 g, 77%) as yellow solid. MS m/z: 340.3 [M+H]⁺, ESI pos. Step 2: 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one 3-(Trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2 g, 11.1 mmol) was dissolved in 7.7 ml of a mixture of dimethyl sulfoxide and water (600/1) and 10 ml a solution of 2,3- dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one (500 mg, 1.38 mmol) in dimethyl sulfoxide/water (600/1) was added. The tube was placed under argon bubbling through the liquid. Next, 10 ml of a freshly prepared solution of ammonium persulfate (1.9 g, 8.31 mmol) in dimethyl sulfoxide/water (600/1, purged with argon) was added and the tube was sealed. The reaction mixture was stirred at 40 °C for 22 h. Ethyl acetate and a saturated solution of NaHCO3 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 reverse phase chromatography (column: YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to give the title compound (70 mg, 11% yield) as yellow solid, MS m/z: 474.2 [M+H]⁺, ESI pos. Example 108 and 109: 2,3-dimethyl-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 and 2,3-dimethyl- 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 The enantiomers of 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (see Example 107) were separated by SFC (Column chiral Lux C4, 5 um, 250 x 20 mm, 30% methanol + 0,2% diethylamine). The solvent was evaporated to give 2,3-dimethyl-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 (26.5 mg, 4% yield) as brown solid, first eluting isomer, MS m/z: 474.2 [M+H]⁺, ESI pos. and 2,3-dimethyl-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 (30 mg, 4.5%) as brown solid, second eluting isomer, MS m/z: 474.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 110: 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)cyclobutyl]pyrido[3,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 107 from 3-(trifluoromethyl)- cyclobutanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 2, yellow solid, MS m/z: 462.2 [M+H]⁺, ESI pos. Example 111, 112 and 113: 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one and 8-(4,4- difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidin-4-one and 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one The compounds were prepared in analogy to Example 107 from 4,4- difluorocyclohexanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1- carboxylic acid in step, 2 followed by chiral separation as described for Examples 108 and 109. 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidin-4-one: second eluting isomer with retention time = 3.62 min, yellow solid, MS m/z: 458.2 [M+H]⁺, ESI pos., and 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6- [(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one: third eluting isomer with retention time = 3.98 min, yellow solid, MS m/z: 458.2 [M+H]⁺, ESI pos., and 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one: fourth eluting isomer with retention time = 4.60 min, yellow solid, MS m/z: 458.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 114: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one Step 1: 6-chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4- d]pyrimidin-4-one A mixture of 6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A4, 260 mg, 1.24 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (670 mg, 3.72 mmol), Ir[dF(CF3)ppy]₂(dtbpy)(PF₆) (CAS: 870987-63-6, 3.0 mg, 0.01 mmol, 0.01 eq) and ammonium peroxodisulfate (183 mg, 4.96 mmol) in dimethyl sulfoxide (3 ml) was degassed and purged with oxygen, and then the mixture was stirred at 25°C for 16 h while irradiated with a 455 nm blue LED. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine (15 ml x 3) and dried over Na2SO4, then concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether/ ethyl acetate =1:0 to 2:1) to give 6-chloro-2,3-dimethyl-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (50 mg, 0.15 mmol, 12% yield) as light yellow solid, MS m/z: 344.1 [M+H]⁺, ESI pos. Step 2: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one To a solution of 6-chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl] pyrido[3,4-d]pyrimidin-4-one (40 mg, 0.12 mmol) in 1,4-dioxane (3 ml) were added (2R)-2-(1- methylpyrazol-4-yl)morpholine (23 mg, 0.14 mmol), cesium carbonate (95 mg, 0.29 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.01 mmol, 0.05 eq), Xantphos (6.5 mg, 0.01 mmol, 0.1 eq). Then the mixture was degassed by nitrogen three times and stirred at 100 °C for 12 h under nitrogen atmosphere. The reaction mixture was added into water (50 ml) and extracted with ethyl acetate (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na2SO4 and concentrated in vacuum. The residue was purified by preparative HPLC (column (Phenomenex luna C18, 150 x 25 mm x 10 um, water + 0.225% formic acid / acetonitrile, flow rate 25 ml/min) to give 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol- 4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4- one (4 mg, 7% yield) as a light green solid, MS m/z: 475.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 115-118 were prepared in analogy to Examples 114 by starting from the indicated carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1. The absolute stereochemistry was assigned arbitrarily. MS Carboxylic Ex. Structure Name (ESI): acid m/z 2,3-dimethyl-8-(3-methyl-1- bicyclo[1.1.1]pentanyl)-6- [(2R)-2-(1-methylpyrazol-4- CAS 65862- 421.1 115 yl)morpholin-4- 01-3 [M+H]⁺ yl]pyrido[3,4-d]pyrimidin- 4-one 8-[3-(difluoromethyl)-1- bicyclo[1.1.1]pentanyl]-2,3- dimethyl-6-[(2R)-2-(1- CAS 457.2 116 methylpyrazol-4- 2090481- [M+H]⁺ yl)morpholin-4- 18-6 yl]pyrido[3,4-d]pyrimidin- 4-one 3-[2,3-dimethyl-6-[(2R)-2- (1-methylpyrazol-4- yl)morpholin-4-yl]-4-oxo- CAS 83249- 432.3 117 pyrido[3,4-d]pyrimidin-8- 02-9 [M+H]⁺ yl]bicyclo[1.1.1]pentane-1- carbonitrile 8-(3-methoxy-1- bicyclo[1.1.1]pentanyl)-2,3- dimethyl-6-[(2R)-2-(1- CAS 437.4 118 methylpyrazol-4- 156329-86- [M+H]⁺ yl)morpholin-4- 1 yl]pyrido[3,4-d]pyrimidin- 4-one Example 119: 5-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4- yl)morpholino]-2,6-naphthyridin-1-one A solution of 2-(1-methylpyrazol-4-yl)morpholine (Intermediate E1, 2.5 g, 15 mmol), methyl 2,6-dichloropyridine-4-carboxylate (2.8 g, 13.6 mmol) and 7.1 ml, 40.8 mmol) in dry N- methylpyrrolidone (30 ml) was stirred at 100 °C overnight. The mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with water (3 x 25 ml), brine (30 ml), dried over Na2SO4 and evaporated under reduced pressure to give 2- chloro-6-[2-(1-methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester (2.5 g, 54% yield) as an orange solid, MS m/z: 337.2 [M+H]⁺, ESI pos. Step 2: 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester To a suspension of 2-chloro-6-[2-(1-methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester (675 mg, 2.0 mmol) in 1,4-dioxane (6.8 ml) was added at room temperature 4-chloro-2- fluorobenzeneboronic acid (367 mg, 2.1 mmol) followed by a solution of cesium carbonate (2 M in water, 3.0 ml, 6.0 mmol). The mixture was degassed by bubbling argon through the mixture for 10 min, then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (49 mg, 60 µmol, 0.030 eq) was added and degassing was done as described. The mixture was stirred at 22 °C for 1.5 h, then aqueous saturated NaHCO3 solution (50 ml) was added and the mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-100% [ethyl acetate/ethanol 3:1] in heptane) to give 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester (850 mg, 98% yield) as yellow solid. MS m/z: 431.2 [M+H]⁺, ESI pos. Step 3: 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4- yl)morpholino]isonicotinic acid methyl ester To a solution of 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino] isonicotinic acid methyl ester (850 mg, 1.97 mmol) in dichloromethane (17 ml) was added within 1.5 h in three portions at 22 °C N-bromosuccinimide (351 mg, 1.97 mmol). After complete addition the mixture was stirred at 22 °C for further 30 min. Another portion of N- bromosuccinimide (35 mg, 0.197 µmol) was added and stirring was continued for additional 30 min. The mixture was quenched with aqueous saturated NaHCO3 (50 ml) and extracted with dichloromethane (2 x 50 ml). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 20- 100% ethyl acetate in heptane) to give 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(1- methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester (780 mg, 78% yield) as yellow foam. MS m/z: 509.0 [M+H]⁺, ESI pos. Step 4: 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino]-3-prop-1-ynyl- isonicotinic acid methyl ester In a microwave tube to a solution of 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(1- methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester (120 mg, 0.235 mmol) in N,N- dimethylformamide (1.2 ml) was added at room temperature tributyl(prop-1-ynyl)stannane (93 mg, 86 µl, 0.283 mmol) followed by tetrakis(triphenylphosphine) palladium(0) (8 mg, 7.0 µmol, 0.03 eq). The tube was filled with argon, sealed and irradiated using a microwave at 110 °C for 60 min. To the mixture was added further tributyl(prop-1-ynyl)stannane (78 mg, 72 µl l, 0.235 µl mol) and tetrakis(triphenylphosphine)palladium(0) (5.5 mg, 4.7 µmol, 0.02 eq) and irradiation was continued at 110 °C for another 30 min. The mixture was concentrated in vacuo and directly purified by flash column chromatography (RP18, compound adsorbed on Isolute HM-N, 30- 100% acetonitrile in water) to give 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4- yl)morpholino]-3-prop-1-ynyl-isonicotinic acid methyl ester (56 mg, 51% yield) as yellow oil, MS m/z: 469.0 [M+H]⁺, ESI pos. Step 5: 2-(4-chloro-2-fluoro-phenyl)-N-methyl-6-[2-(1-methylpyrazol-4-yl)morpholino]-3-prop- 1-ynyl-isonicotinamide In a reaction tube 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino]-3-prop- 1-ynyl-isonicotinic acid methyl ester (55 mg, 117 µmol) was dissolved in methylamine (40% solution in MeOH, 1.82 g, 2.39 ml, 23.5 mmol). The tube was sealed and heated to 50 °C for 2 h, then concentrated in vacuo. The residue was purified by flash column chromatography (RP18, compound adsorbed on Isolute HM-N, 10-100% acetonitrile in water) to give 2-(4-chloro-2- fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino]-3-prop-1-ynyl-isonicotinic acid methyl ester (36 mg, 66% yield) as light yellow solid. MS m/z: 468.2 [M+H]⁺, ESI pos. Step 6: 5-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one In a reaction tube 2-(4-chloro-2-fluoro-phenyl)-N-methyl-6-[2-(1-methylpyrazol-4- yl)morpholino]-3-prop-1-ynyl-isonicotinamide (15 mg, 32 µmol) was dissolved at room temperature in ethanol (3 ml) containing sodium ethoxide (22 mg, 320 µmol). The tube was sealed and the turbid mixture was heated to 80 °C for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography (RP18, compound adsorbed on Isolute HM-N, 30-100% acetonitrile in water with 0.1% HCOOH) to give 14 mg of a solid that was further purified by flash column chromatography (silica gel, 10- 80% [ethyl acetate / ethanol = 3:1] in heptane) to give 5-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]-2,6-naphthyridin-1-one (8.8 mg, 59% yield) as yellow solid, MS m/z: 468.2 [M+H]⁺, ESI pos. Example 120: 5-(4-chloro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one The tile compound was prepared in analogy to Example 119 from 4-chlorobenzeneboronic acid instead of 4-chloro-2-fluorobenzeneboronic acid in step 2, yellow solid, MS m/z: 450.2 [M+H]⁺, ESI pos. Example 121 and 122: 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]-2,6-naphthyridin-1-one and 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]-2,6-naphthyridin-1-one The enantiomers of 5-(4-chloro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]- 2,6-naphthyridin-1-one (Example 120, 44 mg) were separated by SFC (column chiral IK, 5 um, 150 x 4.6 mm, 40-60% methanol + 0,2% diethylamine). The solvent was evaporated to give 5- (4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholino]-2,6-naphthyridin- 1-one (20 mg, 46% yield) as yellow solid, first eluting isomer with retention time 5.09 min, MS m/z: 450.2 [M+H]⁺, ESI pos. and 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol- 4-yl)morpholino]-2,6-naphthyridin-1-one (18 mg, 42%) as yellow solid, second eluting isomer with retention time 5.92 min, MS m/z: 450.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 123: 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one To a solution of 8-bromo-6-chloro-2-ethyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A8, 468 mg, 1.55 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (270 mg, 1.55 mmol) in 1,4-dioxane (8.1 ml) and water (2.7 ml), was added cesium carbonate (1.51 g, 4.64 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. The mixture was purged and backfilled with argon three times and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted three 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 0-60%) and then triturated in diethyl ether to afford 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one (385 mg, 62% yield) as light yellow solid, MS m/z: 352.1 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one A flask was charged with (2S)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 47.5 mg, 38 µl l, 0.284 mmol), 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-pyrido[3,4- d]pyrimidin-4-one (50 mg, 0.142 mmol), N,N-diisopropyl ethylamine (55 mg, 74 µl l, 0.426 mmol) and dimethyl sulfoxide (1 ml) and the mixture was stirred at 120 °C for 16 h. The reaction mixture was filtered and directly separated by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford the title compound (22 mg, 32% yield) as yellow powder, MS m/z: 483.3 [M+H]⁺, ESI pos. The following Examples 124-126 were prepared in analogy to Examples 127 by starting from the indicated intermediates in steps 1 instead of intermediate A8 and in step 2 instead of intermediate (+)-E1. The absolute stereochemistry was assigned arbitrarily. MS Intermediate Ex. Structure Name (ESI): s m/z 8-(4-chloro-2-fluoro- phenyl)-2-ethyl-3-methyl-6- A8 and (-)- 483.3 124 [(2R)-2-(1-methylpyrazol-4- E1 [M+H]⁺ yl)morpholino]pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2-isopropyl-3- methyl-6-[(2S)-2-(1- A20 and 497.3 125 methylpyrazol-4- (+)-E1 [M+H]⁺ yl)morpholino]pyrido[3,4- d]pyrimidin-4-one 8-(4-chloro-2-fluoro- phenyl)-2-(1,1- difluoroethyl)-3-methyl-6- A18 and 519.2 126 [(2S)-2-(1-methylpyrazol-4- (+)-E1 [M+H]⁺ yl)morpholino]pyrido[3,4- d]pyrimidin-4-one Examples 127, 128, 129 and 130: 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-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]-2,3-dimethyl-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]-2,3-dimethyl-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]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one

To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin- 4-one (see Example 67, 100 mg, 0.29 mmol) in dimethyl sulfoxide (2 ml) were added N,N- diisopropyl ethylamine (0.15 ml, 0.88 mmol) and 2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholine (Intermediate E10, 73 mg, 0.35 mmol) and the mixture was stirred at 30 °C for 16 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (50 ml x 2) and dried over Na₂SO₄, then concentrated in vacuum. The residue was purified by chromatography (column: Phenomenex Luna C18, 150*25 mm*10 um, water + 0.225% formic acid / acetonitrile, flow rate 25 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-6-[2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (130 mg). The isomers were separated by chiral SFC (column Daicel Chiralpak AD, 250 mm*30 mm, 10 um, ethanol + 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4- one (21 mg, 30% yield) as 1st eluting isomer with retention time 0.75 min, light yellow solid, MS m/z: 510.2 [M+H]⁺, ESI pos., 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4- one (23 mg, 14% yield) as 2nd eluting isomer with retention time 1.03 min, light yellow solid, MS m/z: 510.1 [M+H]⁺, ESI pos., 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4- one (38 mg, 54% yield) as 3rd eluting isomer with retention time 1.28 min, light yellow solid, MS m/z: 510.1 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4- one (36 mg, 21% yield) as 4th eluting isomer with retention time 1.47 min, light yellow solid, MS m/z: 510.1 [M+H]⁺, ESI pos. The absolute stereochemistry was assigned arbitrarily. Examples 131 and 132: 8-(4-chloro-2-fluoro-phenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazol- 4-yl)-1-piperidyl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro- phenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidyl]-2,3-dimethyl-pyrimido[5,4- d]pyrimidin-4-one The tile compounds were prepared in analogy to Example 127-130 from Intermediate E9 instead of Intermediate E10, light yellow gum, MS m/z: 504.1 [M+H]⁺, ESI pos. and MS m/z: 504.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 133: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 127 from Intermediate E39 instead of Intermediate E10, first eluting enantiomer, light yellow gum, MS m/z: 512.1 [M+H]⁺, ESI pos. absolute stereochemistry arbitrarily assigned. Example 134: 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol- 4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one Step 1: 6-chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin- 4-one To a solution of 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (Intermediate C2, 50 mg, 0.2 mmol) in 1,4-dioxane (1.5 ml) and water (0.5 ml) was added 2-[2-fluoro-4- (trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 1073353-68-0, 59 mg, 0.2 mmol). Then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (17 mg, 0.02 mmol, 0.1 eq) and cesium carbonate (199 mg, 0.61 mmol) were added, and the mixture was degassed with nitrogen three times and stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was poured into water (50 ml), the aqueous layer was separated and extracted with ethyl acetate (30 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to give 6-chloro-8-[2-fluoro-4- (trifluoromethyl)phenyl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (65 mg, 85% yield) as off-white solid, MS m/z: 373.0 [M+H]⁺, ESI pos. Step 2: 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one To a solution of 6-chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrimido[5,4- d]pyrimidin-4-one (55 mg, 0.15 mmol) in dimethyl sulfoxide (1 ml) were added N,N-diisopropyl ethylamine (0.08 ml, 0.44 mmol) and (2R)-2-(1-methylpyrazol-4-yl)morpholine (30 mg, 0.18 mmol) and the mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 ml x 2) and dried over Na₂SO₄, then concentrated in vacuum. The residue was purified by preparative HPLC (column Phenomenex luna C18150x 25mm x 10um, water + 0.225% formic acid / acetonitrile, flow rate 25 ml/min) to give the title compound (50 mg, 67% yield) as yellow solid, MS m/z: 504.2 [M+H]⁺, ESI pos., absolute stereochemistry assigned arbitrarily. The following Examples 135-137 were prepared in analogy to Example 134 by coupling the indicated boronic acid derivative instead of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane. The absolute stereochemistry was assigned arbitrarily. Boronic MS Ex. Structure Name acid (ESI): derivative m/z 2,3-dimethyl-6-[(2R)-2-(1- methylpyrazol-4- CAS 486.2 135 yl)morpholin-4-yl]-8-[4- 214360-65- [M+H]⁺ (trifluoromethyl)phenyl]pyri 3 mido[5,4-d]pyrimidin-4-one 8-(2,4-difluorophenyl)-2,3- dimethyl-6-[(2R)-2-(1- CAS methylpyrazol-4- 454.3 136 288101-48- yl)morpholin-4- [M+H]⁺ 4 yl]pyrimido[5,4- d]pyrimidin-4-one 2,3-dimethyl-6-[(2R)-2-(1- methylpyrazol-4- CAS yl)morpholin-4-yl]-8-[6- 487.3 137 1218790- (trifluoromethyl)-3- [M+H]⁺ 39-6 pyridyl]pyrimido[5,4- d]pyrimidin-4-one Examples 138 and 139: 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4- pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro- phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimido[5,4- d]pyrimidin-4-one To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin- 4-one (see Example 67, 50 mg, 0.15 mmol) in dimethyl sulfoxide (1.5 ml) were added N,N- diisopropyl ethylamine (0.13 ml, 0.74 mmol) and 2-(2-methoxy-4-pyridyl)morpholine hydrochloride (Intermediate E4, 41 mg, 0.18 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 2). Organic phase was washed with brine (50 ml x 2), dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (column: Spherical C18, 20- 45 um, 100A, water + 0.1% formic acid / acetonitrile, flow rate 40 ml/min). The eluent was extracted with ethyl acetate (50 ml × 2), the combined organic layers were dried over Na₂SO₄ and concentrated to give 8-(4-chloro-2-fluoro-phenyl)-6-[2-(2-methoxy-4-pyridyl)morpholin-4- yl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (65 mg). The enantiomers were separated by chiral SFC (column Daicel Chiralpak AD, 250 mm × 30 mm, 10um, ethanol + 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]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (25 mg, 42% yield) as first eluting enantiomer with a retention time of 1.21 min, yellow solid, MS m/z: 497.2 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one (26 mg, 40% yield) as second eluting enantiomer enantiomer with a retention time of 1.48 min, yellow solid, MS m/z: 497.1 [M+H]⁺, ESI pos. Examples 140 and 141: 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 The tile compounds were prepared in analogy to Example 144 and 145 from Intermediate E3 instead of Intermediate E4, light yellow solids, MS m/z: 481.2 [M+H]⁺, ESI pos. and MS m/z: 481.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 142: 13-(4-chloro-2-fluoro-phenyl)-11-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]- 2,7,10,12-tetrazatricyclo[7.4.0.0^3,7]trideca-1(9),2,10,12-tetraen-8-one Step 1: 11-chloro-13-(4-chloro-2-fluoro-phenyl)-2,7,10,12-tetrazatricyclo[7.4.0.0^3,7]trideca- 1(9),2,10,12-tetraen-8-one To a stirred solution of 11,13-dichloro-2,7,10,12-tetrazatricyclo[7.4.0.0^3,7]trideca-1(9),2,10,12- tetraen-8-one (Intermediate C3, 200 mg, 0.74 mmol) and 4-chloro-2-fluorophenylboronic acid (129 mg, 0.74 mmol) in a mixture of toluene (12 ml) and water (1.2 ml) was added K3PO4 (471 mg, 2.22 mmol). The mixture was degassed, filled with argon, and bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (52 mg, 0.07 mmol, 0.1 eq) was added. After stirring at 20 °C for 18 h, the mixture was diluted with water (60 ml) and extracted with ethyl acetate (3 x 60 ml). The combined organic layers were dried (sodium sulfate) and evaporated to obtain crude 11-chloro-13-(4-chloro-2-fluoro-phenyl)-2,7,10,12- tetrazatricyclo[7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one (187 mg, 25% yield), which was used in the next step without additional purification, brown gum, MS m/z: 351.0 [M+H]⁺, ESI pos. Step 2: 13-(4-chloro-2-fluoro-phenyl)-11-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2,7,10,12- tetrazatricyclo[7.4.0.0^3,7]trideca-1(9) tetraen-8-one To a solution of 11-chloro-13-(4-chloro-2-fluoro-phenyl)-2,7,10,12-tetrazatricyclo- [7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one (187 mg, 0.2 mmol) and 2-(1-methylpyrazol-4- yl)morpholine (Intermediate E1, 66 mg, 0.39 mmol) in dry dimethyl sulfoxide (6 ml) was added N,N-diisopropyl ethylamine (0.17 ml, 0.99 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was purified by preparative HPLC as DMSO solution (column: XBridge 19*100 mm, 30 ml/min water / acetonitrile +ammonia) to give the title compound (42 mg, 41% yield) as a yellow solid, MS m/z: 482.2 [M+H]⁺, ESI pos. The following Examples 143-146 were prepared in analogy to Examples 146 / 147 using the boronic acid derivative as in Example 140 and indicated in the following table. The absolute stereochemistry was assigned arbitrarily. Boronic MS Ex. Structure Name acid (ESI): derivative m/z 8-[2-fluoro-4- (trifluoromethyl)phenyl]- 2,3-dimethyl-6-[(2S)-2-(2- CAS 515.2 143 methyl-4- 1073353- [M+H]⁺ pyridyl)morpholin-4- 68-0 yl]pyrimido[5,4- d]pyrimidin-4-one 8-[2-fluoro-4- (trifluoromethyl)phenyl]- 2,3-dimethyl-6-[(2R)-2-(2- CAS 515.2 144 methyl-4- 1073353- [M+H]⁺ pyridyl)morpholin-4- 68-0 yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2,6-difluoro- phenyl)-2,3-dimethyl-6- CAS [(2S)-2-(2-methyl-4- 499.2 145 1165935- pyridyl)morpholin-4- [M+H]⁺ 84-1 yl]pyrimido[5,4- d]pyrimidin-4-one 8-(4-chloro-2,6-difluoro- phenyl)-2,3-dimethyl-6- CAS [(2R)-2-(2-methyl-4- 499.2 146 1165935- pyridyl)morpholin-4- [M+H]⁺ 84-1 yl]pyrimido[5,4- d]pyrimidin-4-one The following Examples 147-150 were prepared in analogy to Examples 127 - 130 using 6- chloro-8-(2,4-difluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (as in Example 142) instead of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4- one. The absolute stereochemistry was assigned arbitrarily. MS Ex. Structure Name (ESI): m/z 6-[(2S,6S)-2-(1- cyclopropylpyrazol-4-yl)-6- methyl-morpholin-4-yl]-8- 494.2 147 (2,4-difluorophenyl)-2,3- [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one F 6-[(2R,6R)-2-(1- cyclopropylpyrazol-4-yl)-6- F methyl-morpholin-4-yl]-8- 4 148 _N N 94.2 N N N (2,4-difluorophenyl)-2,3- [M+H]⁺ N N O O dimethyl-pyrimido[5,4- d]pyrimidin-4-one 6-[(2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6- methyl-morpholin-4-yl]-8- 494.2 149 (2,4-difluorophenyl)-2,3- [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one 6-[(2R,6S)-2-(1- cyclopropylpyrazol-4-yl)-6- methyl-morpholin-4-yl]-8- 494.2 150 (2,4-difluorophenyl)-2,3- [M+H]⁺ dimethyl-pyrimido[5,4- d]pyrimidin-4-one Example 151: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 127 from Intermediate E39 instead of Intermediate E10, second eluting enantiomer, light yellow gum, MS m/z: 512.1 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 152-153 were prepared in analogy to Example 134 by coupling the indicated boronic acid derivative instead of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane. The absolute stereochemistry was assigned arbitrarily. Boronic MS Ex. Structure Name acid (ESI): derivative m/z 8-(5-chloro-2-fluoro- phenyl)-2,3-dimethyl-6- CAS [(2R)-2-(1-methylpyrazol-4- 470.2 152 1190129- yl)morpholin-4- [M+H]⁺ 77-1 yl]pyrimido[5,4- d]pyrimidin-4-one 8-[2-fluoro-5- (trifluoromethyl)phenyl]- 2,3-dimethyl-6-[(2R)-2-(1- CAS 504.1 153 methylpyrazol-4- 1192045- [M+H]⁺ yl)morpholin-4- 31-0 yl]pyrimido[5,4- d]pyrimidin-4-one Example 154: 8-(4-chloro-2-fluoro-phenyl)-6-[3-(difluoromethyl)pyrrolidino]-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin- 4-one (see Example 67, 40 mg, 0.10 mmol) in N,N-dimethylformamide (1.5 ml) were added 3- (difluoromethyl)pyrrolidine hydrochloride (Intermediate E37, 32 mg, 0.20 mmol) and N,N- diisopropyl ethylamine (65 mg, 88 µl, 0.50 mmol) at room temperature and the mixture was stirred for 2 h at 120 °C. The reaction mixture was directly submitted to preparative HPLC (column: YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford the title compound (28 mg, 66% yield) as yellow solid, MS m/z: 424.2 [M+H]⁺, ESI pos. Example 155: 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 154 from Intermediate E8 instead of Intermediate E37, yellow solid, MS m/z: 437.2 [M+H]⁺, ESI pos. Example 156: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 154 from Intermediate E11 instead of Intermediate E37, yellow solid, MS m/z: 456.2 [M+H]⁺, ESI pos. Examples 157 and 158: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl- 6-[(2R)-2-(1H-pyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one The enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (Example 156, 49 mg) were separated by chiral SFC (column: chiral IJ, 5 um, 250 x 20 mm, 20% methanol). The solvent was evaporated to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (21 mg, 43% yield), first eluting isomer (t = 1.64 min), as yellow solid, MS m/z: 456.2 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-6-[(2R)-2-(1H-pyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (19 mg, 38% yield), second eluting isomer (t = 1.82 min), as yellow solid, MS m/z: 456.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. The following Examples 159-160 were prepared in analogy to Example 107 by starting from the indicated carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1. MS Carboxylic Ex. Structure Name (ESI): acid m/z 8-(6,6-difluoro-3- bicyclo[3.1.0]hexanyl)-2,3- dimethyl-6-[2-(1- CAS 456.2 159 methylpyrazol-4- 1093751- [M+H]⁺ yl)tetrahydropyran-4- 02-0 yl]pyrido[3,4-d]pyrimidin- 4-one 8-[4- (difluoromethyl)cyclohexyl] -2,3-dimethyl-6-[2-(1- CAS 472.2 160 methylpyrazol-4- 1378852- [M+H]⁺ yl)tetrahydropyran-4- 94-8 yl]pyrido[3,4-d]pyrimidin- 4-one Example 161: 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholino]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one Step 1: 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4- one To a solution of 6-chloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (Intermediate C4, 530 mg, 2.52 mmol) in dimethyl sulfoxide (33 ml) were added 2-(1-methylpyrazol-4-yl)morpholine (842 mg, 5.03 mmol) and N,N-diisopropyl ethylamine (1.63 g, 2.2 ml, 12.58 mmol) at room temperature. The reaction mixture was stirred at 120 °C for 3 h. 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. Because the residue contained dimethyl sulfoxide a complete conversion was assumed for calculation of the amount and the solution was used as is for the next step. Step 2: 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholino]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one To a solution of 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholino]pyrimido[5,4- d]pyrimidin-4-one (aliquot of the dimethyl sulfoxide solution prepared above assuming 50 mg, 0.146 µmol) in DMSO/Water (600/1), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (264 mg, 1.46 mmol) was added. The reaction mixture was degassed while bubbling argon through it. A freshly prepared solution of ammonium persulfate (200 mg, 0.88 µmol) in purged DMSO/Water (600/1) was added under argon. The reaction mixture was stirred at 40 °C for 21 h. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by reversed-phase HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm) using a acetonitrile gradient 20%-98% in Water + 0.1% formic acid) to give the title compound (4.5 mg, 5% yield) as yellow solid, MS m/z: 476.2 [M+H]⁺, ESI pos. Examples 162 and 163: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(2-methylpyrazol-3- yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)- 2,3-dimethyl-6-[8-(1-methylpyrazol-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin- 4-one Step 1: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(1H-pyrazol-3-yl)-6-azaspiro[3.4]octan- 6-yl]pyrimido[5,4-d]pyrimidin-4-one To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin- 4-one (see Example 67, 45 mg, 0.118 mmol) in N,N-dimethylformamide (1.63 ml) were added 8-(1H-pyrazol-3-yl)-6-azaspiro[3.4]octane dihydrochloride (Intermediate E38, 59 mg, 0.235 mmol) and N,N-diisopropyl ethylamine (106 mg, 144 µl, 0.824 mmol) at room temperature and 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 0-10%) to obtain 8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-6-[8-(1H-pyrazol-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4- d]pyrimidin-4-one (55 mg, 97% yield) as yellow oil, MS m/z: 480.2 [M+H]⁺, ESI pos. Step 2: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(2-methylpyrazol-3-yl)-6- azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-6-[8-(1-methylpyrazol-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one To a solution of 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(1H-pyrazol-3-yl)-6- azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one (55 mg, 0.115 mmol) in N,N- dimethylformamide (1 ml) under argon at 0 °C, was added sodium hydride (60% in mineral oil, 5.5 mg, 0.137 mmol), then the mixture was stirred at 0 °C for 20 min. Iodomethane (19 mg, 8.6 µl, 0.137 mmol) was added and the mixture was stirred at 0 °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 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6- [8-(2-methylpyrazol-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one (10 mg, 17% yield) as yellow solid, MS m/z: 494.2 [M+H]⁺, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)- 2,3-dimethyl-6-[8-(1-methylpyrazol-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin- 4-one (12 mg, 20% yield) as yellow solid, MS m/z: 494.2 [M+H]⁺, ESI pos. Example 164: 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one The tile compound was prepared in analogy to Example 119 from methyl 2,6-dichloro- pyrimidine-4-carboxylate instead of methyl 2,6-dichloropyridine-4-carboxylate and Intermediate (+)-E1 instead of Intermediate E1 in step 1, yellow solid, MS m/z: 469.2 [M+H]⁺, ESI pos., absolute stereochemistry arbitrarily assigned. Example 165: 8-(4-chloro-2-fluoro-phenyl)-6-[2-[1-(2,2-difluoroethyl)pyrazol-4- yl]morpholino]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one A solution of trifluoromethanesulfonic acid 2,2-difluoroethyl ester (37 mg, 0.175 mmol) in N,N- dimethylformamide (0.8 mL) was added to 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H- pyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (see Example 156, 40 mg, 0.0877 mmol) and cesium carbonate (114 mg, 0.351 mmol). The vial was sealed and the reaction was stirred for 4 h at 90 °C. The mixture was diluted with saturated ammonium chloride and ethyl acetate. The product was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (silica gel, 50 - 100 % ethyl acetate in heptane) to give the title compound (23 mg, 48% yield) as yellow solid, MS m/z: 520.2 [M+H]⁺, ESI pos. Example 166: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-[1-(2,2,2-trifluoroethyl)pyrazol- 4-yl]morpholino]pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 165 from trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester instead of trifluoromethanesulfonic acid 2,2-difluoroethyl ester, yellow oil, MS m/z: 538.2 [M+H]⁺, ESI pos. Example 167: 8-(4-chloro-2-fluoro-phenyl)-6-[2-[1-(2,2-difluorocyclopropyl)pyrazol-4- yl]morpholino]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one The tile compound was prepared in analogy to Example 165 from 2-bromo-1,1-difluoro- cyclopropane instead of trifluoromethanesulfonic acid 2,2-difluoroethyl ester, yellow oil, MS m/z: 532.2 [M+H]⁺, ESI pos. Example 168 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 169 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 N N ^{N N} N N O _N O N _N N 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; R⁷ 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; and R⁸ is selected from hydrogen, 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; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10- membered heterocycle.

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) X² and X³ are N and X¹ is CH; or (iii) X¹, X² and X³ are all N; or (iv) X² and X³ are CH and X¹ is N; or (v) X¹ and X² are N and X³ is CH.

3. The compound of formula (I) according to claim 2, 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) X² and X³ are CH and X¹ is 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 C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkenyl, C₆-C₁₀-aryl, and 5- to 10-membered heteroaryl; R¹ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy; R² is selected from hydrogen, halogen, and C₁-C₆-alkyl; and R³ is selected from hydrogen and halogen.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein: A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl; R¹ is selected from hydrogen, fluoro, chloro, cyano, CHF₂, CF₃, methyl, and methoxy; R² is selected from hydrogen, fluoro, and methyl; and R³ is selected from hydrogen and fluoro.

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

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

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein B is .

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: R⁷ is selected from C1-C6-alkyl, halo-C1-C6-alkyl and C3-C10-cycloalkyl; wherein said C₃-C₁₀-cycloalkyl is optionally substituted with one C₁-C₆-alkyl substituent; R⁸ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C10- cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one C₁-C₆-alkyl substituent; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10- membered heterocycle.

10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein: R⁷ is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1- methylcyclopropyl, and cyclobutyl; R⁸ is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1- difluoroethyl, cyclopropyl, 1-methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a pyrrolidine ring.

11. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein: R⁷ is C₁-C₆-alkyl; and R⁸ is selected from C₁-C₆-alkyl and halo-C₁-C₆-alkyl.

12. The compound of formula (I) according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R⁷ and R⁸ are both methyl.

13. 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) X² and X³ are N and X¹ is CH; or (iii) X¹, X² and X³ are all N; or (iv) X² and X³ are CH and X¹ is N; or (v) X¹ and X² are N and X³ is CH; A is selected from C₃-C₁₀-cycloalkyl, C₃-C₁₀-cycloalkenyl, C₆-C₁₀-aryl, and 5- to 10-membered heteroaryl; B is selected from N N ^{N N} N N O _N O ^N _N N R¹ is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy; R² is selected from hydrogen, halogen, and C1-C6-alkyl; R³ is selected from hydrogen and halogen; R⁷ is selected from C1-C6-alkyl, halo-C1-C6-alkyl and C3-C10-cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one C1-C6-alkyl substituent; and R⁸ is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C10- cycloalkyl; wherein said C₃-C₁₀-cycloalkyl is optionally substituted with one C₁-C₆-alkyl substituent; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a 3- to 10- membered heterocycle.

14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein: (i) X¹ and X³ are N and X² is CH; or (ii) X² and X³ are N and X¹ is CH; or (iii) X¹, X² and X³ are all N; or (iv) X² and X³ are CH and X¹ is N; or (v) X¹ and X² are N and X³ is CH; A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl; B is selected from N N ^{N N} N N O _N O ^N _N N R¹ is selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy; R² is selected from hydrogen, fluoro, and methyl; R³ is selected from hydrogen and fluoro; R⁷ is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1- methylcyclopropyl, and cyclobutyl; and R⁸ is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1- difluoroethyl, cyclopropyl, 1-methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane; or R⁷ and R⁸, taken together with the atoms to which they are attached, form a pyrrolidine ring.

15. The compound of formula (I) according to claim 13, 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) X² and X³ are CH and X¹ is N; A is selected from C3-C10-cycloalkyl and C6-C10-aryl; B is selected from N N ^{N N} N N O _N O N _N N R¹ is selected from halogen and halo-C₁-C₆-alkyl; R² is selected from hydrogen and halogen; R³ is selected from hydrogen and halogen; R^4a and R^5a are a group ; R^6a is a group ; R^4b, R^5b, and R^6b are selected from hydrogen, halogen and C1-C6-alkyl; R^4c, R^5c, and R^6c are selected from hydrogen and halogen; R⁷ is C₁-C₆-alkyl; R⁸ is selected from C1-C6-alkyl and halo-C1-C6-alkyl; R⁹ is selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; R¹¹ is selected from hydrogen, C1-C6-alkyl, and C1-C6-alkoxy; R¹⁰ and R¹² are both hydrogen; C is selected from cyclopropyl, pyridyl and pyrazolyl; and D is selected from cyclopropyl and pyrazolyl.

16. The compound of formula (I) according to claim 15, 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) X² and X³ are CH and X¹ is N; A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; B is selected from N N ^{N N} N N O _N O N _N N R¹ is selected from fluoro, chloro, CHF₂ and CF₃; R² is selected from hydrogen and fluoro; R³ is selected from hydrogen and fluoro; and R⁷ and R⁸ are both methyl.

17. 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-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]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]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(3R)-3-(1-methylpyrazol-4-yl)-1- piperidyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]- 3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]- 3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4- c]pyridin-6-yl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(trifluoromethyl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-3-methyl- pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1- piperidyl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1- piperidyl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one; 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; 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; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]- 2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]- 2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H- pyrazolo[3,4-c]pyridin-6-yl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one; 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; 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; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(3S)-3-(1-methylpyrazol-4-yl)-1- piperidyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(3R)-3-(1-methylpyrazol-4-yl)-1- piperidyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1- piperidyl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1- piperidyl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one; 3-fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-8-yl]benzonitrile; 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(2-fluoro-4-methyl-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p- tolyl)pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p- tolyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)phenyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-methyl-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]octan-6- yl-pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-dimethylcyclohexyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-3- (2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-cyclobutyl-2-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-methyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-cyclobutyl-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2-(1-bicyclo[1.1.1]pentanyl)-8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-cyclopentyl-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2-tert-butyl-8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(1-methylcyclopropyl)-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-methyl-3-(1-methylcyclopropyl)-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-2-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one; 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; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(3-methyl-1,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(5-methyl-1,3,4-oxadiazol-2- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(1,2,4-triazol-1- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(2-methylpyrazol-3- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3,3-dimethyl-4-(1-methylpyrazol-4-yl)pyrrolidino]- 2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(5-methyl-1,2,4-oxadiazol-3- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-(3-methoxyphenyl)-3-methyl-pyrrolidino]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 6-[(3aR,6aR)-3a-phenyl-3,4,6,6a-tetrahydro-1H-furo[3,4-c]pyrrol-5-yl]-8-(4-chloro- 2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-(3,5-dimethylpyrazol-1-yl)piperidino]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[6-(3-pyridyl)-3- azabicyclo[4.1.0]heptan-3-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(2-cyclopropyl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(triazol-1- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(3-methyl-1,2,4-oxadiazol-5- yl)piperidino]pyrimido[5,4-d]pyrimidin-4-one; 6-(2-tert-butyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-8-(4-chloro-2-fluoro- phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(1-methylpyrazol-4- yl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(7,8-dihydro-5H-1,6-naphthyridin-6-yl)-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(3-methyl-1,2,4-oxadiazol-5- yl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-keto-4-(p-tolyl)piperazino]-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(1,2,4-triazol-1- yl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-(4-cyclopropyltriazol-1-yl)pyrrolidino]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-(7-methyl-2,6-dioxa-9- azaspiro[4.5]decan-9-yl)pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-methyl-3-(p- tolyl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 4-[8-(4-chloro-2-fluoro-phenyl)-4-keto-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-6- yl]-1-cyclopropyl-piperazine-2-carbonitrile; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[3-(5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyridin-3-yl)pyrrolidino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(5-methyl-1,2,4-oxadiazol-3- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-methyl-6-phenyl- tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-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; 2,3-dimethyl-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; 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)cyclobutyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-8-(3-methyl-1-bicyclo[1.1.1]pentanyl)-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 3-[2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-4-oxo-pyrido[3,4- d]pyrimidin-8-yl]bicyclo[1.1.1]pentane-1-carbonitrile; 8-(3-methoxy-1-bicyclo[1.1.1]pentanyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 5-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]- 2,6-naphthyridin-1-one; 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one; 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one; 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one; 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-isopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(1,1-difluoroethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-2,3-dimethyl-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]-2,3-dimethyl-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]-2,3-dimethyl-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]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1- piperidyl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1- piperidyl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)phenyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[6- (trifluoromethyl)-3-pyridyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 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; 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; 13-(4-chloro-2-fluoro-phenyl)-11-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]- 2,7,10,12-tetrazatricyclo[7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-8-(2,4- difluorophenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(5-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-[2-fluoro-5-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[3-(difluoromethyl)pyrrolidino]-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one; 8-(6,6-difluoro-3-bicyclo[3.1.0]hexanyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-[4-(difluoromethyl)cyclohexyl]-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one; 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholino]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(2-methylpyrazol-3-yl)-6- azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(1-methylpyrazol-3-yl)-6- azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one; 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one; 8-(4-chloro-2-fluoro-phenyl)-6-[2-[1-(2,2-difluoroethyl)pyrazol-4-yl]morpholino]- 2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-[1-(2,2,2-trifluoroethyl)pyrazol-4- yl]morpholino]pyrimido[5,4-d]pyrimidin-4-one; and 8-(4-chloro-2-fluoro-phenyl)-6-[2-[1-(2,2-difluorocyclopropyl)pyrazol-4- yl]morpholino]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one.

18. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

19. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

20. 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 17, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19.

21. The method according to claim 20, 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.

22. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, for use in a method according to claim 20 or 21.

23. Use of a compound according to any one of claims 1 to 17, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to claim 19, in a method according to claim 20 or 21.

24. Use of a compound according to any one of claims 1 to 17, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to claim 20 or 21.

25. The invention as described hereinbefore.