Pyrido [3, 4-d] pyrimidin-4-one and pyrimidino [5, 4-d] pyrimidin-4-one derivatives as TREM2 agonists for treatment of parkinson's disease

Abstract

The present invention provides compounds having the general formula (I) wherein A, B, R1, R2, R3, R5 and R6 are as described herein; compositions comprising the compounds; methods of making the compounds; and said compounds for use in methods of treating or preventing diseases associated with TREM2, such as, for example, Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

Description

TECHNICAL FIELD

[0001] The present application 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 use in the treatment or prophylaxis of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease and stroke. BACKGROUND

[0002] Microglia are immune cells residing in the central nervous system (CNS) that play a crucial role in 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 disorders and neuropathological lesions, where they transform into an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to 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).

[0003] Microglia express a variety of receptors on their surface that play a key role in the complex crosstalk that senses environmental changes and modulates their physiological functions.

[0004] TREM2 (triggering receptor expressed on myeloid cells 2) is one of these cell surface receptors that is expressed on microglia in the brain and plays a key role in microglial survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445-453 (2003). https: / / doi.org / 10.1038 / nri1106). TREM2 is a single-pass transmembrane receptor that belongs to the immunoglobulin superfamily (Ig-SF). It is composed of a ligand-binding extracellular immunoglobulin variable-like domain (IgV) followed by a long stalk domain, a single transmembrane helix, and a short cytoplasmic tail that lacks signaling motifs. Downstream signaling is mediated through its interaction with the effector protein DAP12, a transmembrane disulfide-linked adaptor dimer whose expression and cellular localization at the plasma membrane is dependent on TREM2 and which associates with the TREM2 transmembrane helix via a lysine-aspartate interaction (K156-D50) to form a signaling complex (Zhong L. et al., J Biol Chem. 2015;290(25):15866-77). Given its short extracellular domain, DAP12 lacks ligand-binding capacity. Endogenous ligands for TREM2 include various molecules including phospholipids, glycolipids, lipoproteins, cellular debris, myelin, and Ab oligomers. Stimulation of the TREM2 / DAP12 complex induces phosphorylation of two tyrosine residues within an immunoreceptor-based tyrosine activation motif (ITAM) in the cytoplasmic domain of DAP12, which leads to the recruitment of Syk kinase to activate downstream signaling molecules.

[0005] Activation of TREM2 plays a key role in microglial signaling and function, including survival, migration, amyloid plaque sequestration, beta-amyloid phagocytosis, myelin debris clearance, and transition from a steady state to a disease-associated microglia (DAM) state in neurodegenerative environments (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).

[0006] Genetic variants of TREM2 have been linked to a number of neurodegenerative diseases (Hou J. et al. Molecular Neurodegeneration (2022) 17:84; doi: org / 10.1186 / s13024-022-00588-y). TREM2 variants that result in loss of expression of TREM2 were identified as the cause of Nasu-Hakola disease (NHD) or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), a fatal disease that presents as progressive presenile dementia and is characterized by myelin loss and skeletal 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 linked to impaired microglial function and decreased responsiveness to neurodegenerative disease (Kleinberger, G. et al., Sci. Transl. Med. 2014, 6, 243ra86).

[0007] Furthermore, genome-wide association studies (GWAS) have shown a strong link between some rare loss-of-function (LoF) variants of TREM2 and 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). Among these, the R47H variant is a LoF mutation associated with structural changes within the extracellular domain of TREM2 that results in impaired ability to bind endogenous ligands, associated with a ~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 lead to AD. Patients carrying these mutations can have impaired microglial function, including decreased clearance of extracellular aggregates (e.g., amyloid and myelin debris) and apoptotic neurons, ultimately leading to their decreased ability to fight the disease and increased susceptibility to neurodegeneration. Indeed, reduced microglial activation and failure to accumulate around amyloid plaques were observed in mouse models with defects in TREM2 or DAP12, confirming the central role of TREM2 signaling in microglial function and response to Alzheimer’s disease pathology hallmarks.

[0008] In view 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

[0009] In a first aspect, the present application provides a compound of Formula (I)

[0010] (I)

[0011] wherein A, B, R 1 , R 2 , R 3 , R 5 and R 6 are as defined herein.

[0012] In further aspects, the present application provides compositions comprising a compound of Formula (I), methods of making a compound of Formula (I), and methods of using a compound of Formula (I). DETAILED DESCRIPTION

[0013] Definitions

[0014] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment, or example of the application should be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features and / or steps disclosed in the specification (including any accompanying claims, abstract and drawings) can be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The application is not restricted to the details of any foregoing embodiments. The application extends to any novel one, or any novel combination, of the features disclosed in the specification (including any accompanying claims, abstract and drawings), or to any novel step or any novel combination of steps disclosed by any method or process disclosed.

[0015] The term "alkyl" means a monovalent or polyvalent (e.g., monovalent or divalent) straight-chain or branched-chain saturated hydrocarbon group of 1 to 6 carbon atoms ("C 1-6 -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 alkyl group contains 1 to 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, t-butyl, and 2,2-dimethylpropyl. Particularly preferred, but non-limiting, examples of alkyl groups are methyl, t-butyl, and 2,2-dimethylpropyl.

[0016] The term "alkoxy" means an alkyl group as previously defined attached to the parent molecular moiety through an oxygen atom. Unless otherwise indicated, 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 t-butoxy. A particularly preferred, but non-limiting, example of an alkoxy group is methoxy.

[0017] The term "halogen" or "halo" means fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halo" means fluorine (F), chlorine (Cl), or bromine (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluorine (F) and chlorine (Cl).

[0018] As used herein, the term "cycloalkyl" refers to a ring of 3 to 10 carbon atoms ("C10") 3-10 A saturated monocyclic or bicyclic hydrocarbon group consisting of a cycloalkyl group. In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group with 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic moiety (i.e., the two rings are connected by a common ring atom). Preferably, the cycloalkyl group is a monocyclic hydrocarbon group with 3 to 6 ring carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentyl, norbornelalkyl, and 1-bicyclo[2.2.2]octyl. A particularly preferred but non-limiting example of a cycloalkyl group is cyclopropyl.

[0019] As used in this article, the term "cycloalkenyl" refers to a ring of 3 to 10 carbon atoms ("C10"). 3-10 "Cycloalkyl" is a partially unsaturated monocyclic or bicyclic hydrocarbon group. In some preferred embodiments, the cycloalkenyl group is a monocyclic hydrocarbon group with 3 to 8 ring carbon atoms. "Bicyclic cycloalkenyl" refers to a cycloalkenyl moiety consisting of two saturated carbon rings having two common carbon atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic moiety (i.e., the two rings are connected by a common ring atom). Preferably, the cycloalkenyl group is a monocyclic hydrocarbon group with 3 to 6 ring carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms). Some non-limiting examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0020] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system ("C6-C") having a total of 6 to 10 ring members. 10 "-aryl", wherein at least one ring in the ring system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred but non-limiting example of aryl is phenyl.

[0021] The terms "heterocyclyl" and "heterocycloalkyl" as used herein are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic ring system having 3 to 10 ring atoms, preferably 3 to 8 ring atoms, more preferably 3 to 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, with the remainder of the ring atoms being carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, with the remainder of the ring atoms being carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings having two common ring atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) as well as 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-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 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]octane, and 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl.

[0022] The term "heteroaryl" refers to a monovalent or polyvalent 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 of the ring system is aromatic, and at least one ring of the ring system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl group comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl group comprising 1 to 2 heteroatoms independently selected from O, S, and N. Some preferred, but non-limiting examples of heteroaryl groups 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., imidazol-1-yl); benzoxazolyl (e.g., benzoxazol-2-yl), 2,3-dihydrobenzofuranyl; and oxazolo[5,4-c]pyridin-2-yl.

[0023] The term "cyano" refers to a -CN (nitrile) group.

[0024] The term "oxo" refers to the group =0.

[0025] 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 fluorine). 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 fluorine. Particularly preferred, but non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.

[0026] 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 fluorine). 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 fluorine. Particularly preferred, but 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.

[0027] The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effect and properties of the free bases or free acids, which are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, particularly 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 can be prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, 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.

[0028] 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 diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0029] The abbreviation "TREM2" refers to triggering receptor expressed on myeloid cells 2.

[0030] 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 its recurrence in case of maintenance treatment) of at least one clinical or subclinical symptom of the disease; and / or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of the clinical or subclinical symptoms). The benefit to a patient to be treated is statistically significant or at least perceptible to the patient or to the physician. However, it is understood that when a drug is administered to a patient to treat a disease, the outcome can not always be effective treatment.

[0031] The term "prevention" as used herein includes: preventing or delaying the appearance of clinical symptoms of a state, disorder or condition that develops in a mammal, especially in a human, which can be afflicted with or predisposed to the state, disorder or condition, but has not yet experienced or displayed clinical or subclinical symptoms of the state, disorder or condition.

[0032] Compounds of the invention

[0033] In a first aspect, the present application provides a compound of formula (I)

[0034] (I)

[0035] or a pharmaceutically acceptable salt thereof, wherein:

[0036] X 1 , X 2 and X 3 are each independently selected from N and CH;

[0037] A is selected from C3-C 10 -cycloalkyl, C3-C 10 -cycloalkenyl, C6-C 10 -aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclyl;

[0038] B is selected from

[0039]

[0040] R 1 , R 2 and R 3 are each independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy and halo-C1-C6-alkoxy;

[0041] R 4a is selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy and a group ;

[0042] R 4b and R 4c are each independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and oxo;

[0043] R 5 is selected from C1-C6-alkyl, halo-C1-C6-alkyl, 3- to 10-membered heterocyclyl, and C3-C 10 -cycloalkyl; wherein said C3-C 10 -cycloalkyl is optionally substituted with one substituent selected from halogen and C1-C6-alkyl;

[0044] R 6 is selected from hydrogen and fluorine;

[0045] R 7 and R 8 are each independently selected from hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, halo-C3-C 10 -cycloalkyl, and 3- to 10-membered heterocyclyl; and

[0046] C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H-triazole, 2H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl.

[0047] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0048] X 1 , X 2 , and X 3 are each independently selected from N and CH;

[0049] A is selected from C3-C 10 -cycloalkyl, C3-C 10 -cycloalkenyl, C6-C 10 -aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl;

[0050] B is selected from

[0051]

[0052] R1 , R 2 and R 3 are each independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy and halo-C1-C6-alkoxy;

[0053] R 4a is selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy and a group ;

[0054] R 4b and R 4c are each independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy and oxo;

[0055] R 5 is selected from C1-C6-alkyl, halo-C1-C6-alkyl, 3- to 10-membered heterocyclyl and C3-C 10 -cycloalkyl; wherein said C3-C 10 -cycloalkyl is optionally substituted with one substituent selected from halogen and C1-C6-alkyl;

[0056] R 6 is selected from hydrogen and fluorine;

[0057] R 7 and R 8 are each independently selected from hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, halo-C3-C 10 -cycloalkyl and 3- to 10-membered heterocyclyl; and

[0058] 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.

[0059] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0060] (i) X 1 and X 3 is N and X 2 is CH; or

[0061] (ii) X 1 , X 2 , and X 3 are all N; or

[0062] (iii) X 1 and X 2 are N and X 3 is CH; or.

[0063] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0064] (i) X 1 and X 3 are N and X 2 is CH; or

[0065] (ii) X 1 , X 2 , and X 3 are all N.

[0066] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0067] A is selected from C6-C 10 -aryl and C3-C 10 -cycloalkyl;

[0068] R 1 is selected from halo-Ci-C6-alkyl and halogen;

[0069] R 2 is selected from hydrogen and halogen; and

[0070] R 3 is selected from hydrogen and halogen.

[0071] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0072] A is selected from C6-C 10 -aryl and C3-C 10 -cycloalkyl;

[0073] R 1 is selected from halo-Ci-C6-alkyl and halogen;

[0074] R 2 is selected from hydrogen and halogen; and

[0075] R 3 is hydrogen.

[0076] In another preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0077] A is C6-C 10 -aryl;

[0078] R 1 is halogen;

[0079] R 2 is halogen; and

[0080] R 3 is hydrogen.

[0081] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0082] A is selected from phenyl, cyclohexyl and 1-bicyclo[1.1.1]pentanyl;

[0083] R 1 is selected from CF3, CHF2, fluorine and chlorine;

[0084] R 2 is selected from hydrogen and fluorine; and

[0085] R 3 is selected from hydrogen and fluorine.

[0086] In a particularly preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0087] A is selected from phenyl, cyclohexyl and 1-bicyclo[1.1.1]pentanyl;

[0088] R 1 is selected from CF3, CHF2, fluorine and chlorine;

[0089] R 2 is selected from hydrogen and fluorine; and

[0090] R 3 is hydrogen.

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

[0092] A is phenyl;

[0093] R 1 is chlorine;

[0094] R 2 is fluorine; and

[0095] R3 is hydrogen.

[0096] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group is selected from:

[0097]

[0098] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group is selected from:

[0099]

[0100] In one particularly preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group is .

[0101] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0102] B is selected from and ;

[0103] R 4a is a group ;

[0104] R 4b is selected from hydrogen and Ci-C6-alkyl;

[0105] R 4c is hydrogen;

[0106] C is selected from pyridyl, pyrazolyl and 2H-triazolyl;

[0107] R 7 is selected from Ci-C6-alkyl, Ci-C6-alkoxy and C3-C 10 -cycloalkyl; and

[0108] R 8 is hydrogen.

[0109] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0110] B is selected from and ;

[0111] R 4a is a group ;

[0112] R 4b is selected from hydrogen and Ci-C6-alkyl;

[0113] R 4c is hydrogen;

[0114] C is selected from pyridyl and pyrazolyl;

[0115] R 7 is selected from Ci-C6-alkyl and C3-C7-cycloalkyl; and 10 is cycloalkyl; and

[0116] R 8 is hydrogen.

[0117] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from

[0118]

[0119] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from

[0120]

[0121] In one preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0122] B is selected from and ;

[0123] R 4a is a group ;

[0124] R 4b is hydrogen;

[0125] R 4c is hydrogen;

[0126] C is selected from pyridyl and pyrazolyl;

[0127] R 7 is selected from Ci-C6-alkyl and Ci-C6-alkoxy; and

[0128] R 8 is hydrogen.

[0129] In one preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0130] B is selected from and ;

[0131] R 4a is a group ;

[0132] R 4b is hydrogen;

[0133] R 4c is hydrogen;

[0134] C is selected from pyridyl and pyrazolyl;

[0135] R 8 is C1-C6-alkyl; and

[0136] R 4a is a group

[0137] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0138] B is selected from and ;

[0139] R 4b is a group ;

[0140] R 4c is hydrogen;

[0141] R 7 is selected from methyl and methoxy; and

[0142] C is selected from pyridyl and pyrazolyl;

[0143] R 8 is hydrogen.

[0144] R 5 is hydrogen.

[0145] In a particularly preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from

[0146]

[0147] In a particularly preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from

[0148]

[0149] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5C1-C6-alkyl.

[0150] In a particularly preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.

[0151] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.

[0152] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen.

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

[0154] (i) X 1 and X 3 is N and X 2 is CH; or

[0155] (ii) X 1 , X 2 and X 3 are all N; or

[0156] (iii) X 1 and X 2 are N and X 3 is CH;

[0157] A is selected from C6-C 10 -aryl and C3-C 10 -cycloalkyl;

[0158] R 1 is selected from halo-Ci-C6-alkyl and halogen;

[0159] R 2 is selected from hydrogen and halogen;

[0160] R 3 is selected from hydrogen and halogen;

[0161] B is selected from and ;

[0162] R 4a is a group ;

[0163] R 4b is selected from hydrogen and Ci-C6-alkyl;

[0164] R 4c is hydrogen;

[0165] R 5 is Ci-C6-alkyl;

[0166] C is selected from pyridyl, pyrazolyl and 2H-triazolyl;

[0167] R 6 is selected from hydrogen and fluorine;

[0168] R 7 is selected from Ci-C6-alkyl, Ci-C6-alkoxy and C3-C 10 -cycloalkyl; and

[0169] R 8 is hydrogen.

[0170] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0171] (i) X 1 and X 3 is N and X 2 is CH; or

[0172] (ii) X 1 , X 2 and X 3 are all N; or

[0173] (iii) X 1 and X 2 are N and X 3 is CH;

[0174] A is selected from phenyl, cyclohexyl and 1 -bicyclo[1.1.1]pentanyl;

[0175] R 1 is selected from CF3, CHF2, fluorine and chlorine;

[0176] R 2 is selected from hydrogen and fluorine;

[0177] R 3 is selected from hydrogen and fluorine;

[0178] B is selected from:

[0179]

[0180] R 5 is methyl; and

[0181] R 6 is selected from hydrogen and fluorine.

[0182] In a preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0183] (i) X 1 and X 3 is N and X 2 is CH; or

[0184] (ii) X 1 , X 2 , and X 3 are all N;

[0185] A is selected from C6-C 10 -aryl and C3-C 10 -cycloalkyl;

[0186] R 1 is selected from halo-Ci-C6-alkyl and halogen;

[0187] R 2 is selected from hydrogen and halogen;

[0188] R 3 is hydrogen;

[0189] B is selected from and ;

[0190] R 4a is a group ;

[0191] R 4b is hydrogen;

[0192] R 4c is hydrogen;

[0193] C is selected from pyridyl and pyrazolyl;

[0194] R 5 is Ci-C6-alkyl;

[0195] R 6 is selected from hydrogen and halogen;

[0196] R 7 is selected from Ci-C6-alkyl and Ci-C6-alkoxy; and

[0197] R 8 is hydrogen.

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

[0199] (i)X 1 and X 3 Let N be the number of elements and X be the number of elements. 2 For CH; or

[0200] (ii)X 1 X 2 and X 3 All are N;

[0201] A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentyl;

[0202] R 1 Selected from CF3, CHF2, fluorine, and chlorine;

[0203] R 2 Selected from hydrogen and fluorine;

[0204] R 3 It is hydrogen;

[0205] B is selected from and ;

[0206] R 4a as a group ;

[0207] R 4b It is hydrogen;

[0208] R 4c It is hydrogen;

[0209] C is selected from pyridyl and pyrazolyl groups;

[0210] R 5 It is methyl;

[0211] R 6 Selected from hydrogen and fluorine;

[0212] R 7 Selected from methyl and methoxy; and

[0213] R 8 It is hydrogen.

[0214] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutical salt thereof, wherein:

[0215] (i)X 1 and X 3 Let N be the number of elements and X be the number of elements. 2 For CH; or

[0216] (ii)X 1 X 2 and X 3all N;

[0217] A is selected from phenyl, cyclohexyl and 1-bicyclo[1.1.1]pentanyl;

[0218] R 1 is selected from CF3, CHF2, fluorine and chlorine;

[0219] R 2 is selected from hydrogen and fluorine;

[0220] R 3 is hydrogen;

[0221] B is selected from

[0222]

[0223] R 5 is methyl; and

[0224] R 6 is selected from hydrogen and fluorine.

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

[0226] (i) X 1 and X 3 are N and X 2 is CH; or

[0227] (ii) X 1 , X 2 and X 3 are all N;

[0228] A is selected from C6-C 10 -aryl and C3-C 10 -cycloalkyl;

[0229] R 1 is selected from halo-Ci-C6-alkyl and halogen;

[0230] R 2 is selected from hydrogen and halogen;

[0231] R 3 is selected from hydrogen and halogen;

[0232] B is selected from and ;

[0233] R 4a is a group ;

[0234] R 4b is selected from hydrogen and Ci-C6-alkyl;

[0235] R 4c is hydrogen;

[0236] R 5 is C1-C6-alkyl;

[0237] C is selected from pyridinyl and pyrazolyl;

[0238] R 7 is selected from C1-C6-alkyl and C3-C 10 -cycloalkyl; and

[0239] R 8 is hydrogen.

[0240] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0241] (i) X 1 and X 3 is N and X 2 is CH; or

[0242] (ii) X 1 , X 2 , and X 3 are all N;

[0243] A is phenyl;

[0244] R 1 is selected from CF3, fluoro, and chloro;

[0245] R 2 is fluoro;

[0246] R 3 is hydrogen;

[0247] B is selected from:

[0248]

[0249] R 5 is C1-C6-alkyl;

[0250] R 7 is selected from C1-C6-alkyl and C3-C 10 -cycloalkyl; and

[0251] R 8 is hydrogen.

[0252] In one preferred embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0253] (i) X1 and X 3 is N and X 2 is CH; or

[0254] (ii) X 1 , X 2 and X 3 are all N;

[0255] A is C6-C 10 -aryl;

[0256] R 1 is halogen;

[0257] R 2 is halogen;

[0258] R 3 is hydrogen;

[0259] B is selected from and ;

[0260] R 4a is a group ;

[0261] R 4b is hydrogen;

[0262] R 4c is hydrogen;

[0263] C is selected from pyridyl and pyrazolyl;

[0264] R 7 is C1-C6-alkyl; and

[0265] R 8 is hydrogen.

[0266] In particularly preferred embodiments, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0267] (i) X 1 and X 3 is N and X 2 is CH; or

[0268] (ii) X 1 , X 2 and X 3 are all N;

[0269] A is phenyl;

[0270] R 1 is chloro;

[0271] R 2 is fluorine;

[0272] R 3 is hydrogen;

[0273] B is selected from

[0274]

[0275] R 7 is C1-C6-alkyl; and

[0276] R 8 is hydrogen.

[0277] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

[0278] 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0279] 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0280] 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0281] 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0282] 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0283] 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0284] 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0285] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0286] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0287] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0288] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0289] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0290] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0291] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0292] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0293] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one;

[0294] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3- methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0295] 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0296] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0297] 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0298] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0299] 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one;

[0300] 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetra- hydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one;

[0301] 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetra- hydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one;

[0302] 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl- 8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one;

[0303] 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-pyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-l-bicyclo[l. l. l]pentanyl]pyrido[3,4-d]pyrimidin-4-one;

[0304] 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-pyridin-4-yl)oxan-4- yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one;

[0305] 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-pyridin-4-yl)oxan-4- yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one;

[0306] 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(l-methylpyrazol-4- yl)oxan-4-yl]pyrimido[5,4-d]pyrimidin-4-one;

[0307] 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(l-methylpyrazol-4- yl)oxan-4-yl]pyrimido[5,4-d]pyrimidin-4-one;

[0308] 2-(difluoromethyl)-8-[3-(difluoromethyl)-l-bicyclo[l. l. l]pentanyl]-6-[(2S,4R)-2-(2-methoxy- pyridin-4-yl)oxan-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one;

[0309] 2-(difluoromethyl)-8-[3-(difluoromethyl)-l-bicyclo[l. l. l]pentanyl]-6-[(2R,4S)-2-(2-methoxy- pyridin-4-yl)oxan-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one;

[0310] 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-pyridin-4-yl)oxan-4-yl]-3-methyl-8-[3- (trifluoromethyl)-l-bicyclo[l. l. l]pentanyl]pyrido[3,4-d]pyrimidin-4-one;

[0311] 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxanyl-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one;

[0312] 2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one;

[0313] 2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one;

[0314] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one;

[0315] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one;

[0316] 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxanyl-4-yl]pyrido[3,4-d]pyrimidin-4-one;

[0317] 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)oxanyl-4-yl]pyrido[3,4-d]pyrimidin-4-one;

[0318] 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0319] 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0320] 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0321] 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0322] 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0323] 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one;

[0324] 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one;

[0325] 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one;

[0326] 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0327] 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0328] 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0329] 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0330] 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0331] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one;

[0332] 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0333] 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0334] 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0335] 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one;

[0336] 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one; and

[0337] 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one.

[0338] In one embodiment, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

[0339] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0340] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0341] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0342] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0343] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0344] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0345] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0346] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;

[0347] 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; and

[0348] 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one.

[0349] In a particular embodiment, the present application provides a pharmaceutically acceptable salt of a compound according to Formula (I) as described herein. In another particular embodiment, the present application provides a compound of Formula (I) as described herein as a free base.

[0350] In some embodiments, the compounds of Formula (I) are isotopically-labeled by replacement of one or more atoms by atoms having different atomic masses or mass numbers. Such isotopically-labeled (i.e., radiolabeled) compounds of Formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Certain isotopically-labeled compounds of Formula (I) (for example, those containing radioactive isotopes) are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C, 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 in 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0351] Substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0352] Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O, and 13N) Substitution can be used for positron emission tomography (PET) studies to examine occupancy of the substrate receptor. 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 herein below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0353] Preparation processes

[0354] The preparation of compounds of Formula (I) of the present application can be carried out in sequential or concurrent synthetic routes. Syntheses of the present application are illustrated by the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following description of the processes have the meanings provided herein unless indicated to the contrary.

[0355] If one of the starting materials, intermediates or compounds of Formula (I) contains one or more functional groups that are not stable or are reactive under the reaction conditions of one or more of the reaction steps, appropriate protecting groups (as described, for example, in T. W. Greene and P. G. M. Wutts, “Protective Groups in Organic Chemistry”, 5thedition, 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying the methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using the standard methods described in the literature.

[0356] If the starting materials or intermediates contain stereogenic centers, the compounds of Formula (I) can be obtained as a mixture 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 be separated into the corresponding enantiomers, for example, by separation of diastereomeric salt formed with an optically pure acid, or by using specific chromatography methods using a chiral adsorbent or chiral eluent to separate the enantiomers. Also, starting materials and intermediates containing stereogenic centers can be isolated to provide diastereomeric / enantiomeric enriched starting materials and intermediates. The use of such diastereomeric / enantiomeric enriched starting materials and intermediates in the synthesis of compounds of Formula (I) will generally result in the corresponding diastereomeric / enantiomeric enriched compounds of Formula (I).

[0357] The skilled person will recognize that in the synthesis of the compounds of formula (I) a "orthogonal protection group strategy" will be applied if not otherwise desired, which allows the cleavage of multiple protecting groups at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been reported 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).

[0358] The skilled person will recognize that the reaction sequence can vary depending on the reactivity and nature of the intermediates.

[0359] 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. Likewise, reaction conditions reported in the literature for affecting the described reactions are used, see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2ndEdition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999. It is also 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 used, 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 application. It can be convenient to carry out the above reactions in the temperature range from -78 °C to reflux. The time required for reactions can also vary widely, depending on many factors, in particular the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days is usually required to obtain the described intermediates and compounds. The reaction sequence is not limited to the sequence shown in the schemes, but the order of reaction steps can be freely varied depending on the starting materials and their respective reactivity.

[0360] If a starting material or an intermediate cannot be obtained commercially, or its synthesis has not been reported in the literature, it can be prepared using existing preparation methods analogous to close analogues or according to the outline in the experimental section.

[0361] The following abbreviations are used in the text:

[0362]

[0363] In the following scheme, R A refers to a group And R B refers to a group A, B, R 1 R 2 and R 3 As defined in this article.

[0364] Scheme 1

[0365]

[0366] Compound of general formula Ia can be prepared as described in Scheme 1 by first reacting intermediate II with an organoboronic acid (or an organoboronic acid derivative) III under palladium-catalyzed conditions (palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) or tetra(triphenylphosphine)palladium(O), and base such as cesium carbonate or sodium carbonate) to form compound IV. This intermediate can be reacted with amine R. B -H (V) reacts in a dipolar aprotic solvent (such as N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone) in the presence of a base (such as N,N-diisopropylethylamine, triethylamine, etc.) to form Ia (nucleophilic substitution). Alternatively, palladium-catalyzed coupling conditions (palladium source such as tris(diphenylmethyleneacetone)dipalladium(O), suitable ligand such as Xantphos, and base such as cesium carbonate or sodium tert-butoxide) can be used to react compound IV with amine R. B -H (V) reaction to form compound Ia (metal-catalyzed coupling).

[0367] Scheme 2

[0368]

[0369] Intermediate IIa can be prepared from compound VI by coupling amine VII with an amide coupling agent (such as HATU, HBTU, EDC, etc.), followed by reacting the resulting intermediate VIII with orthoester IX at an elevated temperature. Alternatively, compound VIII can be reacted with acyl chloride X (or anhydride) and a base (such as N,N-diisopropylethylamine, triethylamine, or pyridine) to form intermediate XI, which is then cyclized by heating in the presence of a base, in the presence of trimethylchlorosilane, or in a suitable additive-free solvent (such as acetic acid) (Scheme 2).

[0370] Scheme 3

[0371]

[0372] Intermediate IIb can be prepared from compound XII by coupling with amine VII using an amide coupling agent such as HATU, HBTU, EDC, etc., followed by halogenation using N-bromosuccinimide or N-chlorosuccinimide in a suitable solvent to give compound XV. This compound can be reacted with anhydride or orthoester IX at elevated temperature to form intermediate IIb (Scheme 3).

[0373] Scheme 4

[0374]

[0375] Intermediate IIc can be prepared from compound XVI by coupling with amine VII using an amide coupling reagent such as HATU, HBTU, EDC, etc., followed by reaction with orthoester IX to form compound XVIII. This compound is reacted with an inorganic halogenating reagent such as phosphorus oxychloride or phosphorus oxybromide XIX with or without additional base to give intermediate IIc (Scheme 4).

[0376] Scheme 5

[0377]

[0378] Compounds of general formula Ib can be prepared as described in Scheme 5 by reacting intermediate IV with an organoboronic acid derivative XIX using a palladium catalyst and a base to form intermediate XX, which can then be reduced by treatment with a suitable reagent such as hydrogen and a catalyst to form compound Ib. Preferred catalysts are palladium on carbon or platinum oxide in ethyl acetate, ethanol or methanol with or without additional reagents such as magnesium oxide or triethylamine.

[0379] Scheme 6

[0380]

[0381] Intermediate IVa (R ACompound XXII (obtainable from XXI by amide coupling) can be prepared from compound XXII (obtainable from XXI by amide coupling) by reacting it with carboxylic acid XXIII under oxidative coupling conditions (using ammonium persulfate in dimethylsulfoxide at temperatures between 0 °C and 50 °C, Minisci reaction, additional blue LED irradiation can be applied) to form compound XXIV. This intermediate is reacted with anhydride or orthoester IX at elevated temperatures to give intermediate IVa. Alternatively, compound XXII can first be cyclized using anhydride or orthoester IX to form intermediate XXV, which can then be reacted with carboxylic acid XXIII under oxidative coupling conditions (using ammonium persulfate in dimethylsulfoxide at temperatures between 0 °C and 50 °C, Minisci reaction, additional blue LED irradiation can be applied) to form intermediate IVa (Scheme 6).

[0382] Scheme 7

[0383]

[0384] Compound Ic can be prepared according to Scheme 7. Compound XXVI is reacted with organoboronic acid III under palladium catalysis to give compound XXVII. This intermediate is further reacted with amine V in the presence of a base such as N,N-diisopropylethylamine, triethylamine or the like in a dipolar aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidinone to form XXVIII. This compound is reacted with N-bromosuccinimide in a suitable solvent to form XXIX, which is converted to compound XXXI by palladium catalyzed reaction with tin derivative XXX. Ammonolysis of ester XXXI with amine IX in a solvent such as ethanol or methanol gives compound XXXII, which is treated with a base such as sodium methoxide to effect cyclization to compound XXXIII. Oxidation with a suitable reagent such as selenium dioxide gives aldehyde XXXVI, which can then be finally converted to compound Ic by using a fluorinating reagent such as DAST or Deoxo-fluor.

[0385] In one aspect, the present application provides a method of manufacturing a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the method is described in any one of Schemes 1 to 7.

[0386] In one aspect, the present application 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.

[0387] TREM2 agonistic activity

[0388] The compounds of the application are TREM2 agonists. Accordingly, in one aspect, the present application provides a compound of formula (I) as described herein for use in restoring human TREM2 function in a subject in need thereof.

[0389] In another aspect, the present application provides a compound of formula (I) as described herein for use in a method of restoring human TREM2 function in a subject in need thereof.

[0390] In another aspect, the present application provides a compound of formula (I) as described herein for use in the manufacture of a medicament for restoring human TREM2 function in a subject in need thereof.

[0391] In another aspect, the present application provides a method for restoring human TREM2 function in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I) as described herein.

[0392] TREM2 agonist efficacy of compounds of formula (I) according to the present application was measured using a HEK cell line expressing human TREM2 and DAP12. Upon binding of a small molecule ligand to the TREM2 receptor, DAP12 is recruited and activates Syk kinase. The resulting increase in phosphorylated Syk levels was measured in lysed cells with a commercial AlphaLisa kit.

[0393] To perform the assay, frozen HEK293-TREM2 / DAP12 cells were thawed, adjusted, and plated at 20,000 cells per well in 10 pL DMEM media without Phenolred but supplemented with 5% FBS in 384-well plates using Certus.

[0394] Dose responses (1 :3) of compounds were diluted in DMSO (10 mM maximum concentration) and added to cells from a low-dead-volume plate using ECHO (0 to 20 uM) diluted 500-fold (20 nL in 10 pL cell suspension; 20 uM maximum concentration, DMSO concentration 0.2% in all wells). Neutral (DMSO) and stimulant (1 pM tool compound) controls were also added.

[0395] Cells were incubated for 30 minutes at 37°C, 5% CO2 and 95% humidity. After compound addition and incubation, 2.5 pL lysis buffer was added using Certus. After a quick spin, the plate was shaken at 450 RPM for 30 minutes at room temperature and protected from light. After complete lysis, AlphaLisa reagents were added to the lysate by Certus and the fluorescence intensity was measured (excitation: 680 nm / emission: 615 nm) using a Pherastar FS plate reader. EC 50 values, normalized to DMSO and 100% activity for the tool compound.

[0396] TREM2 agonist efficacy of the reference compounds as measured in the above described assay are presented in Table 2.

[0397] Table 1

[0398]

[0399]

[0400]

[0401] Table 2

[0402]

[0403] Use of compounds of the invention

[0404] In one aspect, the present application provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0405] In another aspect, the present application provides a method of treating or preventing a disorder associated with loss of function of human TREM2 in a subject in need thereof, 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.

[0406] In another aspect, the present application 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 disorder associated with loss of function of human TREM2 in a subject in need thereof.

[0407] In another aspect, the present application provides the use of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for use in a method of treating or preventing a disorder associated with loss of function of human TREM2 in a subject in need thereof.

[0408] In another aspect, the present application provides the use of a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, in the manufacture of a medicament for use in a method of treating or preventing a disorder associated with loss of function of human TREM2 in a subject in need thereof.

[0409] In one embodiment, the disorder associated with 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.

[0410] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is Parkinson’s disease.

[0411] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is rheumatoid arthritis.

[0412] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is Alzheimer’s disease.

[0413] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is amyotrophic lateral sclerosis.

[0414] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is Nasu-Hakola disease.

[0415] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is frontotemporal dementia.

[0416] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is multiple sclerosis.

[0417] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is prion disease.

[0418] In one preferred embodiment, the disorder associated with loss of function of human TREM2 is stroke.

[0419] Pharmaceutical compositions and administration

[0420] In one aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0421] In one embodiment, there is provided a pharmaceutical composition according to either of Examples 60 or 61.

[0422] The compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, non-toxic, pharmaceutically acceptable salts such as water, air or anhydrous lactose, calcium phosphate or calcium carbonate, together with any chemically compatible, pharmaceutically acceptable excipients, i.e. technologically suitable, inert carriers, such as sodium crocetinate, as long as the purpose of the administration is not adversely affected by the excipient.

[0423] The compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, non-toxic, pharmaceutically acceptable salts such as water, air or anhydrous lactose, calcium phosphate or calcium carbonate, together with any chemically compatible, pharmaceutically acceptable excipients, i.e. technologically suitable, inert carriers, such as sodium crocetinate, as long as the purpose of the administration is not adversely affected by the excipient.

[0424] Suitable excipients for soft gel capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0425] Suitable excipients for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0426] Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0427] Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0428] Furthermore, 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.

[0429] The dosage can vary in wide limits and will, of course, have to be adjusted to the individual requirements in each particular case, and will necessarily be guided by the experiencing of the treating doctor. In general, however, a daily dosage of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amount, should be appropriate. It will, however, be clear to a person skilled in the art that upper limits given herein can be exceeded when indicated by the circumstances.

[0430] Examples

[0431] The present application will be more fully understood by reference to the following examples. The claims should not be construed as being limited to the examples.

[0432] In cases where the preparation examples are obtained as a mixture of enantiomers, the pure enantiomers can be isolated by the methods described herein or by methods known to one skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0433] The compounds of Formula I can contain several asymmetric centers and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereomers, or mixtures of diastereomers. According to the Cahn-Ingold-Prelog convention, the asymmetric carbon atom can be in the "R" or "S" configuration. The absolute stereochemistry is designated by the IUPAC rules. For compounds described in this patent, the absolute stereochemistry is arbitrarily designated.

[0434] Unless otherwise indicated, all reaction examples and intermediates were prepared under an argon atmosphere.

[0435] The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1.

[0436] The following intermediates were prepared according to the procedures provided herein, or were commercially available, or were prepared according to literature procedures.

[0437] Intermediate Al: 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one

[0438]

[0439] Step 1: 5-amino-2-chloro-N-methyl-isonicotinamide

[0440]

[0441] To a solution of 5-amino-2-chloro-isonicotinic acid (800 mg, 4.64 mmol) in dichloromethane (10 ml) at room temperature were added methylamine hydrochloride (438 mg, 6.49 mmol), N,N-diisopropylethylamine (1.8 g, 2.43 ml, 13.9 mmol), l-(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 over Na2S04, filtered 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, yield 84%) as a light yellow solid, MS m / z: 186.0 [M+H] + , ESI pos.

[0442] Step 2: 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide

[0443]

[0444] 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 at room temperature overnight. 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 Na2S04, filtered and evaporated. The crude mixture was purified by flash chromatography (silica gel, gradient: heptane / ethyl acetate 100 / 0 to 50 / 50) to give 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (961 mg, yield 96%) as a light yellow solid, MS m / z: 264.0 [M+H] + , ESI pos.

[0445] Step 3: 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one

[0446]

[0447] 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 at 135 °C for 20 h. As the reaction was not complete, 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 at 135 °C overnight. After evaporation of the 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 a light yellow solid, MS m / z: 290.0 [M+H] + , ESI pos.

[0448] Intermediate A2: 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one

[0449]

[0450] Step 1: 2-bromo-6-chloro-3-[(2,2-difluoroacetyl)amino]-N-methyl-isonicotinamide

[0451]

[0452] To a solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see Intermediate A1, 0.600 g, 2.27 mmol) in dry tetrahydrofuran (15 ml) was added 2,2-difluoroacetic anhydride (395 mg, 282 µl, 2.27 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated and triturated in diethyl ether to give 2-bromo-6-chloro-3-[(2,2-difluoroacetyl)amino]-N-methyl-isonicotinamide (678 mg, yield 88%) as a white solid, MS m / z: 344.0 [M+H] + , ESI pos.

[0453] Step 2: 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one

[0454] A solution of 2-bromo-6-chloro-3-[(2,2-difluoroacetyl)amino]-N-methyl- isonicotinamide (678 mg, 1.98 mmol) in acetic acid (8 ml) was heated at 110 °C for 3 h. The reaction mixture was concentrated in vacuo and triturated in diethyl ether to give 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4- d]pyrimidin-4-one (510 mg, yield 79%) as a white solid, MS m / z: 326.0 [M+H] + , ESI pos.

[0455] Intermediate A3: 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one

[0456]

[0457] The title compound was prepared in analogy to Intermediate Al by replacing 2,2- difluoroacetic anhydride with trifluoroacetic anhydride in Step 1. Yellow solid, MS m / z: 344.0 [M+H] + , ESI pos.

[0458] Intermediate A4: 6,8-dichloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one

[0459]

[0460] Step 1: 5-amino-2,4-diketone-N-methyl-1H-pyrimidine-6-carboxamide

[0461]

[0462] To a solution of 5-amino-2,4-diketo-lH-pyrimidine-6-carboxylic acid (CAS 7164-43-4, 5 g, 29.2 mmol) in N,N-dimethylformamide (120 ml) at room temperature was added N,N-diisopropylethylamine (15.1 g, 20.4 ml, 117 mmol) and methylamine hydrochloride (3.95 g, 58.4 mmol). HATU (14.4 g, 38 mmol) was added portionwise and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to remove most of the solvent and the residue was suspended in 150 ml of a mixture methanol / methyl-tert-butyl ether = 1 : 1. The suspension was stirred for 10 min, then it was filtered off and washed with methanol / methyl-tert-butyl ether. The obtained solid was dried in vacuo to give 5-amino-2,4-diketo-N-methyl-lH-pyrimidine-6-carboxamide (4.0 g, yield 67%) as a yellow solid. MS m / z: 185.0 [M+H] + ESI pos.

[0463] Step 2: 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione

[0464]

[0465] A suspension of 5-amino-2,4-diketo-N-methyl-lH-pyrimidine-6-carboxamide (3 g, 16.3 mmol) in ortho-acetic anhydride (13.2 g, 15 ml, 81.5 mmol) and acetic acid (980 mg, 933 µl, 16.3 mmol) was stirred at 130 °C for 5 h. The reaction mixture was diluted with methyl-tert-butyl ether and stirred for additional 5 min, then the solid was filtered off and washed with methyl-tert-butyl ether. The solid was dried in vacuo to obtain the title compound 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (3.26 g, yield 86.5%) as a yellow solid, MS m / z: 209.0 [M+H] + ESI pos.

[0466] Step 3: 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one

[0467]

[0468] 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) at room temperature was added dropwise a mixture of N,N-diisopropylethylamine (2.0 g, 2.68 ml, 15.4 mmol) and N,N-dimethylformamide (181 mg, 192 µl, 2.48 mmol). The mixture was stirred at 130 °C overnight, then concentrated to dryness. The residue was taken up in dichloromethane. Water was added, and the mixture was extracted twice 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% to 100%) to obtain the title compound 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (1.44 g, yield 38%) as a brown solid, MS m / z: 245.0 [M+H] + ESI pos.

[0469] Intermediate A5: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one

[0470]

[0471] To a solution of 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4- d]pyrimidin-4-one (Intermediate A2, 500 mg, 1.54 mmol) and (4-chloro-2- fluoro-phenyl)boronic acid (269 mg, 1.54 mmol) in 1,4-dioxane (9 ml) and water (3 ml) was added cesium carbonate (1.51 g, 4.62 mmol). The reaction mixture was purged and backfilled with argon three times before adding 1,1'- bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (63 mg, 0.077 mmol, 0.050 eq). After purging and refilling 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 organic layer was washed with water and brine, dried over Na2S04 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 30%) then triturated in diethyl ether to give 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl- pyrido[3,4-d]pyrimidin-4-one (235 mg, yield 41%) as an off-white solid, MS m / z: 374.1 [M+H] + , ESI pos.

[0472] Intermediate A6: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4- d]pyrimidin-4-one

[0473]

[0474] To a solution of 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4- d]pyrimidin-4-one (Intermediate A3, 250 mg, 0.73 mmol) in 1,4-dioxane (3 ml) was added water (1 ml), 4-chloro-2-fluorophenylboronic acid (127 mg, 0.73 mmol), 1,1'- bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (30 mg, 0.04 mmol, 0.05 eq) and cesium carbonate (713 mg, 2.19 mmol). The mixture was then degassed with nitrogen three times and stirred at 30 °C for 16 h under nitrogen atmosphere. The reaction mixture was added to water (20 ml) and extracted with dichloromethane (20 ml x 3). The combined organic layers were washed with brine (50 ml) and dried over Na2S04, then concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 1:1) to give 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one (60 mg, yield 21%) as a light yellow solid, MS m / z: 392.0 [M+H] ESI pos. + , ESI pos.

[0475] Intermediate A7: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrimido[5,4- d]pyrimidin-4-one

[0476]

[0477] Step 1: 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid ethyl ester

[0478]

[0479] A solution of (4-chloro-2-fluoro-phenyl)-boronic acid (1.33 g, 7.63 mmol) and 5-amino-2,6-dichloro-pyrimidine-4-carboxylic acid ethyl ester (1.5 g, 6.35 mmol) in 1,4-dioxane (28.85 mL) was purged with argon. Then 1,1'-bis(diphenylphosphino)ferrocene- dichloropalladium(ll) dichloromethane complex (525 mg, 0.635 mmol, 0.10 eq) and 3 M aqueous cesium carbonate (6.35 ml, 19.1 mmol) were added and the reaction was heated to 60°C overnight while stirring under argon. The reaction mixture was filtered over celite, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04 and evaporated. The product was purified by flash chromatography (silica gel, 10% to 50% ethyl acetate in heptane) to give 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid ethyl ester (1.64 g, yield 74%) as a yellow powder, MS m / z: 330.0 [M+H] + , ESI pos.

[0480] Step 2: 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid

[0481]

[0482] To a solution of 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4- carboxylic acid ethyl ester (1.64 g, 4.97 mmol) in tetrahydrofuran (20 ml) and water (20 ml) was added aqueous lithium hydroxide (0.5 M, 14.9 ml, 7.45 mmol) and the mixture was stirred at room temperature for 1 h. Then hydrochloric acid (2 M, 8 ml) was added, the volatiles were evaporated and the formed precipitate was filtered, washed with water and dried under high vacuum to give 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid (1.49 g, yield 95%) as a yellow solid, MS m / z: 302.0 [M+H] + , ESI pos.

[0483] Step 3: 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4-carboxamide

[0484]

[0485] Dissolve 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid (1.0 g, 3.18 mmol) in N,N-dimethylformamide (15 ml). Add N,N-diisopropylethylamine (1.64 g, 2.2 ml, 12.7 mmol) and methylamine hydrochloride (429 mg, 6.36 mmol), then HATU (1.57 g, 4.13 mmol) portionwise and stir the mixture overnight. Dilute the reaction with water and extract twice with ethyl acetate. Wash the combined organic layers with NH4CI solution and brine, dry over Na2S04 and evaporate. Purify the residue by flash column chromatography (silica gel, 50% ethyl acetate in heptane) to give 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4-carboxamide (429 mg, yield 42%) as a yellow solid, MS m / z: 315.0 [M+H] + , ESI pos.

[0486] Step 4: 2-chloro-6-(4-chloro-2-fluoro-phenyl)-5-[(2,2-difluoroacetyl)amino]-N-methyl-pyrimidine- 4-carboxamide

[0487]

[0488] To a solution of 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4- carboxamide (272 mg, 0.846 mmol) in tetrahydrofuran (5 ml) at 0°C add 2,2-difluoroacetic anhydride (147 mg, 105 µl, 0.846 mmol). Stir the reaction at room temperature overnight. Evaporate the volatiles to give 2-chloro-6-(4-chloro-2-fluoro-phenyl)-5-[(2,2-difluoroacetyl)amino]-N-methyl- pyrimidine-4-carboxamide (332 mg, yield 97%) as a yellow solid, MS m / z: 393.1 [M+H] + , ESI pos.

[0489] Step 5: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrimido[5,4-d]pyrimidine- 4-one

[0490]

[0491] A solution of 2-chloro-6-(4-chloro-2-fluoro-phenyl)-5-[(2,2-difluoroacetyl)amino]- N-methyl-pyrimidine-4-carboxamide (332 mg, 0.819 mmol) in acetic acid (4.1 ml) was stirred at 110 °C for 1 h. The volatiles were evaporated and the product was purified by flash column chromatography (silica gel, 5% to 50% ethyl acetate in heptane) to give 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl- pyrimido[5,4-d]pyrimidin-4-one (98 mg, 32% yield) as an off-white solid, MS m / z: 375.1 [M+H] + , ESI pos.

[0492] Intermediate A8: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one

[0493]

[0494] Step 1: 2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine- 4-carboxamide

[0495]

[0496] To a solution of 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4- carboxamide (see Intermediate A7, 2.2 g, 6.98 mmol) in tetrahydrofuran (30 ml) at 0 °C was added 4-dimethylaminopyridine (85 mg, 0.7 mmol) and trifluoroacetic anhydride (1.48 ml, 10.5 mmol). The reaction was stirred at 30 °C for 16 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine, dried over Na2S04and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 5:1) to give 2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2,2,2- trifluoroacetyl)amino]pyrimidine-4-carboxamide (2.2 g, 75% yield) as a light yellow gum.

[0497] Step 2: 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine- 4-one

[0498]

[0499] To a solution of 2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2,2,2- trifluoroacetyl)amino]pyrimidine-4-carboxamide (1.4 g, 3.41 mmol) in dichloromethane (20 ml) at 0 °C was added triethylamine (14.2 ml, 102.15 mmol) and trimethylsilyl chloride (4.33 ml, 34.1 mmol) and the mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine, dried over Na2S04 and concentrated in vacuo to give 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (1.34 g, yield 100%) as a light yellow solid. MS m / z: 393.0 [M+H] + , ESI pos.

[0500] Intermediate A9: 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one

[0501]

[0502] Step 1: 5-amino-2-chloro-N-methyl-pyrimidine-4-carboxamide

[0503]

[0504] To a solution of 5-amino-2-chloro-pyrimidine-4-carboxylic acid (3 g, 17.3 mmol) in N,N-dimethylformamide (50 ml) at room temperature was added methylamine hydrochloride (1.75 g, 25.9 mmol) and N,N-diisopropylethylamine (6.7 g, 9.06 ml, 51.9 mmol). Then HATU (7.89 g, 20.74 mmol) was added and the mixture was stirred at room temperature for 3 days. The solvent was evaporated and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na2S04 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give 5-amino-2-chloro-N-methyl-pyrimidine-4-carboxamide (2.6 g, yield 81%) as a pink solid, MS m / z: 187.0 [M+H] + , ESI pos.

[0505] Step 2: 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-pyrimidine-4-carboxamide

[0506]

[0507] To a solution of 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl- pyrimidine-4-carboxamide (322 mg, 1.22 mmol) in dimethyl sulfoxide / water (600:1) was added 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2.19 g, 12.17 mmol). The reaction mixture was bubbled with argon. A freshly prepared solution of ammonium persulfate (1.67 g, 7.3 mmol) in bubbled dimethyl sulfoxide / water (600:1) was added under argon and the reaction mixture was stirred at 40 °C for 18 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide (240 mg, yield 44%) as a light yellow solid, MS m / z: 397.1 [M-H] + , ESI pos.

[0508] Step 3: 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1-bicyclo [1.1.1]pentanyl]pyrimidine-4-carboxamide

[0509]

[0510] To a solution of 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl- pyrimidine-4-carboxamide (322 mg, 1.22 mmol) in dimethyl sulfoxide / water (600:1) was added 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2.19 g, 12.17 mmol). The reaction mixture was bubbled with argon. A freshly prepared solution of ammonium persulfate (1.67 g, 7.3 mmol) in bubbled dimethyl sulfoxide / water (600:1) was added under argon and the reaction mixture was stirred at 40 °C for 18 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide (240 mg, yield 44%) as a light yellow solid, MS m / z: 397.1 [M-H] - , ESI neg.

[0511] Step 4: 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl] pyrimido[5,4-d]pyrimidin-4-one

[0512]

[0513] To a solution of 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide (230 mg, 0.49 mmol) in toluene (5 ml) was added p-toluenesulfonic acid monohydrate (9 mg, 49 µmol) and the mixture was heated to 110 °C for 1 h. The reaction mixture was diluted with a saturated NaHCO3 solution and extracted twice 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% to 100%) to give the title compound (120 mg, yield 61%) as a white foam, MS m / z: 381.1 [M+H] + , ESI pos.

[0514] Intermediate A10: 6-chloro-8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-pyrimido[5,4- d]pyrimidin-4-one

[0515]

[0516] The title compound was prepared in analogy to Intermediate A9, replacing 3- (trifluoromethyl)bicyclo[1.1.1]pentane-1 -carboxylic acid by 3-(difluoromethyl)- bicyclo[1.1.1]pentane-1 -carboxylic acid in step 3. White solid, MS m / z: 363.2 [M+H] + , ESI pos.

[0517] Intermediate A11: 6-chloro-2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3- methyl-pyrimido[5,4-d]pyrimidin-4-one

[0518]

[0519] The title compound was prepared in analogy to Intermediate A9, replacing 3- (trifluoromethyl)bicyclo[1.1.1]pentane-1 -carboxylic acid by 3-(difluoromethyl)- bicyclo[1.1.1]pentane-1 -carboxylic acid in step 3. White solid, MS m / z: 363.2 [M+H] + , ESI pos.

[0520] Intermediate A12: 6-chloro-2-(difluoromethyl)-8-(2,4-difluorophenyl)-3-methyl-pyrimido[5,4- d]pyrimidin-4-one

[0521]

[0522] The title compound was prepared in analogy to Intermediate A7, replacing (4-chloro-2-fluoro-phenyl)-boronic acid by (2,4-difluorophenyl)boronic acid in step 1. Yellow foam, MS m / z: 359.1 [M+H] + , ESI pos.

[0523] Intermediate A13: 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl] pyrimido[3,4-d]pyrimidin-4-one

[0524]

[0525] Step 1: 6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one

[0526]

[0527] In a flask was added 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrimido[3,4- d]pyrimidin-4-one (Intermediate A2, 1 g, 3.08 mmol) and palladium on carbon (10%, 100 mg) and the flask was purged with argon. Ethyl acetate (15 ml) and triethylamine (468 mg, 644 µl, 4.62 mmol) were added and the argon balloon was replaced with hydrogen. The reaction was stirred for 3 h. The product was purified by flash column chromatography (silica gel, 2% to 10% ethyl acetate in heptane) to give 6-chloro-2-(difluoromethyl)-3-methyl-pyrimido[3,4-d]pyrimidin-4-one (283 mg, 37% yield) as a white solid. MS m / z: 246.0 [M+H] + , ESI pos.

[0528] Step 2: 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one Step 3: 6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrido[5,4- d]pyrimidin-4-one

[0529]

[0530] To a degassed solution of 6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4- d]pyrimidin-4-one (450 mg, 1.83 mmol) in 12 ml dimethylsulfoxide / water (600:1) was added a solution of ammonium persulfate (2.51 g, 11 mmol) in the same dimethylsulfoxide / water mixture (24 ml) and the reaction was stirred at 40 °C for 18 h. The reaction was diluted with ethyl acetate and washed with water then brine. The product was purified by flash chromatography (silica gel, heptane / ethyl acetate) to give the title compound (130 mg, yield 16%) as a white solid. MS m / z: 380.2 [M+H] + , ESI pos.

[0531] Step 1: 2-chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide 6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one

[0532]

[0533] Step 2: 6-chloro-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

[0534]

[0535] To a solution of 5-amino-2-chloro-N-methyl-pyrimidine-4-carboxamide (see Intermediate A9, step 1, 6.0 g, 32.2 mmol) and 4-dimethylaminopyridine (393 mg, 3.22 mmol) in tetrahydrofuran (60 ml) at 0 °C was added trifluoroacetic anhydride (5.35 ml, 38.6 mmol). The mixture was then stirred at 25 °C for 12 h. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 ml) and dried over Na2S04and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 2:1) to give 2-chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (8.0 g, yield 88%) as an off-white solid. MS m / z: 283.1 [M+H] + , ESI pos.

[0536] Step 3: 6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrido[5,4- d]pyrimidin-4-one

[0537]

[0538] To a solution of 2-chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4- carboxamide (7.0 g, 24.77 mmol, 1.0 eq) in dichloromethane (100 ml) was added triethylamine (34.4 ml, 248 mmol) at 0 °C under nitrogen, followed by dropwise addition of trimethylchlorosilane (15.8 ml, 124 mmol). The mixture was then stirred at 25 °C for 2 h under nitrogen. To the mixture was added 1 M aqueous hydrochloric acid solution dropwise until pH = 3 to 4, which was then extracted with dichloromethane (100 ml x 2). The combined organic layers were washed with brine (100 ml), dried over Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 1:1) to give 6-chloro-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (3.8 g, yield 58%) as a light yellow solid. MS m / z: 265.2 [M+H] + ESI pos.

[0539] Step 1: [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate Step 2: 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]pyridine

[0540]

[0541] To a solution of 6-chloro-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one (1.0 g, 3.78 mmol) in dimethyl sulfoxide (75 ml) was added 4,4-difluorocyclohexanecarboxylic acid (1.86 mg, 11.3 mmol), ammonium persulfate (3.45 g, 15.12 mmol) and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate (CAS 870987-63-6, 42 mg, 0.04 mmol, 0.01 eq). The mixture was degassed and purged with nitrogen, then the mixture was stirred at 25 °C for 16 h and irradiated with 455 nm blue LED. The reaction mixture was purified by preparative MPLC (column: Spherical C18, 20 to 45 µm, 100 A, water / acetonitrile containing 0.1% formic acid, flow rate 100 ml / min) and the eluate was lyophilized to give the product 6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (1.0 g, yield 69%) as a light brown solid. MS m / z: 383.1 [M+H] + , ESI pos.

[0542] Step 1: 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[6-(2-methoxy-4-pyridyl)-3,6- dihydro-2H-pyran-4-yl]-3-methyl-pyrido[5,4-d]pyrimidin-4-one 6-chloro-8-(4-chlorophenyl)-3-methyl-2-(trifluoromethyl)pyridino[3,4-d]pyrimidin-4-one

[0543]

[0544] The title compound was prepared in analogy to Intermediate A6, replacing 4-chloro-2-fluorophenylboronic acid by 4-chlorophenylboronic acid in step 1. Yellow solid, MS m / z: 374.0 [M+H] + , ESI pos.

[0545] Step 2: 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran- 4-yl]-3-methyl-pyrido[5,4-d]pyrimidin-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6- [(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[5,4-d]pyrimidin-4- one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetra- hydropyran-4-yl]-3-methyl-pyrido[5,4-d]pyrimidin-4-one 6-chloro-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

[0546]

[0547] The title compound was prepared in analogy to Intermediate A14 by replacing 4,4-difluorocyclohexanecarboxylic acid by 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 3. Yellow solid, MS m / z: 374.0 [M+H] + , ESI pos.

[0548] Step 1: 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3- methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one 6-chloro-8-(4-chlorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one

[0549]

[0550] The title compound was prepared in analogy to Intermediate A7 by replacing (4-chloro-2-fluoro-phenyl)-boronic acid by 4-chlorophenylboronic acid in step 1 and trifluoroacetic anhydride by 2,2-difluoroacetic anhydride in step 4 as a light yellow gum, MS m / z: 375.0 [M+H] + , ESI pos.

[0551]

[0552] Chiral separation of Intermediate B1 :

[0553] Intermediate B1 was separated by chiral SFC (column: AD-H, 5 µm, 100 x 4.6 mm, 20% to 40% MeOH + 0.2% diethylamine) to give (+)-2-(1-methylpyrazol-4-yl)morpholine (+)-B1 as the first eluting enantiomer and (-)-2-(1-methylpyrazol-4-yl)morpholine (-)-B1 as the second eluting enantiomer. (+)-2-(1-methylpyrazol-4-yl)morpholine: yellow oil, aD (589 nm) 20 °C = +13.36° (c = 0.1 g / L, MeOH).

[0554] Step 2: 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxanyl-4-yl]-3-methyl-8- [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one and 2-(difluoro- methyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxanyl-4-yl]-3-methyl-8-[3-(trifluoromethyl)- 1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridine

[0555]

[0556] Step 2: 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxanyl-4-yl]-3-methyl-8- [3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one and 2-(difluoro- methyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxanyl-4-yl]-3-methyl-8-[3-(trifluoromethyl)- 1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one

[0557]

[0558] To a solution of 2-methoxyisonicotinaldehyde (1.0 g, 7.29 mmol) in dichloromethane (10 ml) under argon was added 3-butyn-1-ol (767 mg, 0.833 ml, 10.94 mmol). The mixture was then cooled to -10 °C and trifluoromethanesulfonic acid (3.28 g, 1.92 ml, 21.9 mmol) was added. After stirring at -10 °C for 30 min, the mixture was allowed to warm to room temperature and stirring was continued overnight. The reaction mixture was diluted with saturated NaHCO3 solution and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (870 mg, yield 32%) as a colourless oil, MS m / z: 340.1 [M+H] + , ESI pos.

[0559] ​ ​

[0560]

[0561] To a solution of [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (870 mg, 2.31 mmol) in 1,4-dioxane (15 ml) was added bis(pinacolato)diboron (1.17 g, 4.62 mmol), potassium acetate (906 mg, 9.23 mmol) and 1,1'-bis(diphenylphosphino)ferrocene- dichloropalladium(ll) dichloromethane complex (189 mg, 0.231 mmol, 0.10 eq). The mixture was purged and backfilled with argon three times, then stirred at 90 °C for 2 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 80%) to give 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (656 mg, yield 81%) as a colourless oil, MS m / z: 318.3 [M+H] + , ESI pos.

[0562] ​ 2-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]triazole

[0563]

[0564] The title compound was prepared in analogy to Intermediate B6, replacing 2- methoxyisonicotinaldehyde by 2-methyl-2H-1,2,3-triazole-4-carbaldehyde (CAS 1104078-88-7). Light yellow oil, MS m / z: 292.1 [M+H] + ESI pos.

[0565] Example 1: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one

[0566]

[0567] A solution of 2-(2-methyl-4-pyridyl)morpholine (Intermediate B2, 48 mg, 0.267 mmol), 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl- pyrido[3,4-d]pyrimidin-4-one (Intermediate A5, 50 mg, 0.134 mmol) and N,N- diisopropylethylamine (52 mg, 70 µl, 401 µmol) in dimethyl sulfoxide (1 ml) was stirred at 120 °C for 2 h. The reaction mixture was diluted with water and extracted twice 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 give the title compound (47 mg, yield 66%) as a yellow powder, MS m / z: 516.2 [M+H] + ESI pos.

[0568] Example 2 and 3: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one

[0569]

[0570] The enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one (Example 1) were separated by chiral SFC (Column: Daicel IH, 5 µm, 250 x 20 mm, 20% methanol + 0.2% diethylamine). The solvent was evaporated to give 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one (15 mg, 36% yield) as the second eluting isomer (t = 1.64 min) as a yellow solid, MS m / z: 516.1 [M+H] + , ESI pos.; and 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one (15 mg, 36%) as the first eluting isomer (t = 1.22 min) as a yellow solid, MS m / z: 516.1 [M+H] + , ESI pos. with the absolute stereochemical structure arbitrarily assigned.

[0571] Example 4: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morphol-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one

[0572]

[0573] To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one (Intermediate A6, 50 mg, 0.13 mmol) in 1,4-dioxane (2 ml) was added tris(dibenzylideneacetone)dipalladium (6 mg, 0.01 mmol, 0.05 eq), Xantphos (7.5 mg, 0.01 mmol, 0.1 eq) and (2R)-2-(1-methylpyrazol-4-yl)morpholine (32 mg, 0.19 mmol). The mixture was degassed with nitrogen three times and stirred at 100 °C under nitrogen for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, water / acetonitrile containing 0.1% formic acid, flow rate 25 ml / min) to give the title compound (4.5 mg, yield 7%) as a light yellow solid. MS m / z: 523.1 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.

[0574] Examples 5 and 6 below were prepared in analogy to Example 1 by starting from the indicated intermediates instead of Intermediate B2. The absolute stereochemistry is arbitrarily assigned.

[0575]

[0576] Example 7: 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridinyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one

[0577]

[0578] To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3- methyl- pyrimido[5,4-d]pyrimidin-4-one (Intermediate A7, 62 mg, 0.15 mmol) and 2-(2-methyl-4- pyridyl)morpholine (Intermediate B2, 54 mg, 0.30 mmol) in N,N-dimethylformamide (1 ml) was added N,N-diisopropylethylamine (97 mg, 131 µl, 0.75 mmol) and the mixture was heated to 120 °C for 90 min. The solution was directly purified by preparative HPLC (Gemini NX, 12 nm, 5 µm, 100 x 30 mm, acetonitrile / water + 0.1% triethylamine) to give the title compound (27 mg, yield 35%) as a yellow solid, MS m / z: 517.2 [M+H] ESI pos. + , ESI pos.

[0579] Examples 8 and 9: 8-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2- methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-Chloro-2-fluoro- phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4- d]pyrimidin-4-one

[0580]

[0581] The enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2- methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (Example 7, 23 mg) were separated by chiral SFC (Column: Chiral IC, 5 µm, 250 x 20 mm, 40% methanol + 0.2% diethylamine). The solvent was evaporated to give 8-(4-chloro-2-fluoro-phenyl)-2- (difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidin- 4-one (9 mg, yield 39%) as the first eluting isomer (t = 4.19 min) as a yellow solid, MS m / z: 517.2 [M+H] +, ESI pos.; and 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (9 mg, 39%) as the second eluting isomer (t = 5.25 min) as a yellow solid, MS m / z: 517.2 [M+H] + , ESI pos., arbitrary assigned absolute stereochemistry.

[0582] Example 10: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one

[0583]

[0584] The title compound was prepared in analogy to Example 7, replacing intermediate (+)-B1 for intermediate B2, as a yellow solid, MS m / z: 506.2 [M+H] + , ESI pos., arbitrary assigned absolute stereochemistry.

[0585] Example 11: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

[0586]

[0587] To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (intermediate A8, 60 mg, 0.15 mmol) in dimethyl sulfoxide (2 ml) was added N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) and (2S)-2-(1-methylpyrazol-4-yl)morpholine (intermediate (+)-B1, 38 mg, 0.23 mmol) and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was acidified with formic acid until pH = 5 to 7. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, water / acetonitrile containing 0.225% formic acid, flow rate 25 ml / min) to give the title compound (14 mg, yield 17%) as a light yellow solid. MS m / z: 524.1 [M+H]+ ESI pos.

[0588] The following Examples 12 to 14 were prepared in analogy to Example 7 by starting from the indicated intermediates. The absolute stereochemistry is arbitrarily assigned.

[0589]

[0590] Examples 15 and 16: 8-(4-Chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-Chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

[0591]

[0592] The title compound was prepared in analogy to Example 11 by replacing intermediate (+)-B1 by intermediate B3, followed by separation of the enantiomers by chiral SFC (column: Daicel Chiralpak AD 250 mm x 30 mm, 10 µm, isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 70 ml / min) to give 8-(4-Chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one as the first eluting enantiomer as a light yellow solid, MS m / z: 551.1 [M+H] + ESI pos.; and 8-(4-Chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one as the second eluting enantiomer as a light yellow solid, MS m / z: 551.1 [M+H] + ESI pos. with arbitrarily assigned absolute stereochemistry.

[0593] Example 17, Example 18, Example 19, and Example 20: 8-(4-Chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-Chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-Chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-Chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

[0594]

[0595] The title compound was prepared in analogy to Example 11 by replacing intermediate (+)-B1 by intermediate B4, followed by separation of the diastereomers by preparative HPLC (column: Phenomenex Synergi C18, 150 x 25 mm x 10 µm, water / acetonitrile containing 0.225% formic acid, flow rate 25 ml / min), followed by chiral SFC (column: Daicel Chiralpak AD 250 mm x 30 mm, 10 µm, ethanol / 0.1% ammonium hydroxide, flow rate 70 ml / min) to yield 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6- methyl-morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro- 2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one as light yellow gels, MS m / z: 564.3 [M+H] + , ESI pos. arbitrarily assigned absolute stereochemistry.

[0596] Example 21 and Example 22 and Example 23: 2-(Difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one and 2-(Difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one and 2-(Difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one

[0597]

[0598] ​ ​

[0599]

[0600] A mixture of 6-chloro-2-(difluoromethyl)-8-(2,4-difluorophenyl)-3-methyl- pyrimido[5,4-d]pyrimidin-4-one (Intermediate A12, 110 mg, 0.245 mmol), 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]pyridine (Intermediate B6, 117 mg, 0.368 mmol), potassium carbonate (102 mg, 0.74 mmol) and l,l'-bis(diphenylphosphino)ferrocene- dichloropalladium(ll) dichloromethane complex (20 mg, 24 pmol, 0.10 eq) in 1,4- dioxane (2.5 ml) and water (0.5 ml) was flushed with argon and stirred at 60 °C for 2 h. The reaction mixture was diluted with saturated NaHC03solution and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2S04and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one (111 mg, yield 86%) as a light yellow foam, MS m / z: 514.3 [M+H] + ESI pos.

[0601] ​ ​ ​ ​ ​

[0602]

[0603] To a solution of 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[6-(2-methoxy-4- pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one (105 mg, 0.204 mmol) in ethyl acetate (2 ml) under argon was added palladium on carbon (10%, 44 mg). The flask was evacuated and backfilled with argon three times, then filled with hydrogen. The reaction mixture was stirred under hydrogen at room temperature for 3 h, then it was filtered over celite and washed with ethyl acetate. The combined organic layers were concentrated. The residue was purified by preparative HPLC (column: YMC Triart, C18, 100 mm x 30 mm, 5 µm, mobile phase: water / 0.1% formic acid - acetonitrile, 0% to 100%) to give 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one (48 mg, 45% yield) as a white powder, MS m / z: 516.3 [M+H] + , ESI pos. 44 mg of this compound was separated by chiral SFC (column: Chiral Lux C4, 5 µm, 250 x 20 mm, 40% methanol + 0.2% diethylamine, flow rate 90 ml / min) to give 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one (17 mg, 39% yield) as the first eluting enantiomer as a white powder, MS m / z: 516.3 [M+H] + , ESI pos. and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one (18 mg, 41% yield) as the second eluting enantiomer as a white powder, MS m / z: 516.3 [M+H] + , ESI pos. with the absolute stereochemistry arbitrarily assigned.

[0604] Examples 24 to 31 were prepared in analogy to Examples 21 to 23 by starting from the indicated intermediates. The absolute stereochemistry is arbitrarily assigned.

[0605]

[0606]

[0607] Example 32 and Example 33: 2-(Difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-pyridin-4- yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4- d]pyrimidin-4-one and 2-(Difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-pyridin-4-yl)oxan-4- yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4- one

[0608] ​ ​

[0609]

[0610] To a flask containing 1,1’-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (14 mg, 17 µmol, 0.10 eq), 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyran-6-yl]pyridine (Intermediate B6, 71 mg, 222 µmol), 6-chloro-2- (difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4- d]pyrimidin-4-one (Intermediate A13, 65 mg, 171 µmol) and potassium carbonate (71 mg, 514 µmol) under argon was added toluene (1.43 ml) and water (0.28 ml). The reaction vessel was sealed and heated to 60 °C for 1 h. The reaction was cooled and diluted with saturated sodium bicarbonate solution. The product was extracted with ethyl acetate, washed with water and brine and concentrated in vacuo. The residue was purified by column chromatography to give 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3- methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (82.5 mg, 78% yield) as a light brown solid. MS m / z: 535.3 [M+H] + ESI pos.

[0611] ​ ​ ​ 1 -Bicyclo[1.1.1]pentanylpyrido[3,4-d]pyrimidin-4-one

[0612]

[0613] To a vial containing 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4- d]pyrimidin-4-one (82 mg, 0.154 mmol) and palladium on carbon (10%, 8 mg) under argon was added ethanol (2 ml). The argon balloon was replaced with a hydrogen balloon, the reaction mixture was bubbled and purged, and the mixture was stirred overnight. The reaction was filtered through a pad of silica, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 20% to 40% ethyl acetate in heptane) to give 2-(difluoromethyl)-6-[(rac)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (70 mg, 84% yield) as a colourless oil. The cis enantiomer was separated by chiral SFC to give 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-pyridin-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (13 mg, 16% yield) as the second eluting enantiomer as a pale yellow oil, MS m / z: 537.2 [M+H] + , ESI pos.; and 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-pyridin-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one (13 mg, 16% yield) as the first eluting enantiomer as a pale yellow oil, MS m / z: 537.2 [M+H] + , ESI pos. The absolute stereochemical structure is arbitrarily assigned.

[0614] Examples 34 to 39 were prepared in analogy to Examples 21 to 23 by starting from the indicated intermediates. The absolute stereochemistry is arbitrarily assigned.

[0615]

[0616]

[0617] Example 40 and Example 41 and Example 42: 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

[0618]

[0619] Step 1 : 8-(4-Chloro-2-fluoro-phenyl)-3-methyl-6-[6-(2-methyltriazol-4-yl)-3,6- dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one Step 2: 8-(4-Chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahy dro pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-Chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahy dro pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

[0620]

[0621] To a suspension of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (Intermediate A8, 250 mg, 0.64 mmol) and 2-methyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-6-yl]triazole (Intermediate B7, 444 mg, 0.76 mmol) in 1,4-dioxane (10 ml) and water (1 ml), cesium carbonate (518 mg, 1.59 mmol) and l,l'-bis(diphenylphosphino) ferrocene-palladium(II) dichloromethane complex (26 mg, 0.03 mmol, 0.05 eq) were added. After degassing with nitrogen three times, the resulting mixture was stirred at 25 °C under nitrogen atmosphere for 2 h. The reaction mixture was added into 0.1 M hydrochloric acid (150 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na2S04and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100: 1 to 1: 2) to give 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[6-(2-methyltriazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (240 mg, yield 72%) as a light yellow oil. MS m / z: 522.1 [M+H] + , ESI pos.

[0622] Step 2: 8-(4-Chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahy dro pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-Chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahy dro pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one Step 2: 8-(4-Chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahy dro pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-Chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahy dro pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide

[0623]

[0624] To a solution of 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[6-(2-methyltriazol-4-yl)- 3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (150 mg, 0.29 mmol) in ethyl acetate (8 ml) was added magnesium oxide (116 mg, 2.87 mmol), triethylamine (35 mg, 0.34 mmol) and palladium on carbon (10%, 61 mg). The mixture was degassed with hydrogen gas three times and then stirred under hydrogen atmosphere (15 psi) at 25 °C for 2 h. The reaction mixture was filtered through a pad of celite. The filtrate was diluted with ethyl acetate (100 ml) and washed with 1 M hydrochloric acid (50 ml x 2) and brine (50 ml) then dried over r Na2S04, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 pm, water / acetonitrile containing 0.225% formic acid, flow rate 25 ml / min) to give 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one. This diastereomeric racemate was separated by chiral SFC (Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 70 ml / min) to give 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (12 mg, 4% yield) as the first eluting enantiomer as a white solid, MS / z: 546.3 [M+Na] + ESI pos.; and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (17 mg, 6% yield) as the second eluting enantiomer as a white solid, MS m / z: 524.3 [M+H] +, ESI pos.; and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[rac-(2R,4R)-2-(2- methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one (6 mg, 2% yield) as an off-white solid, MS m / z: 524.3 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.

[0625] Examples 43 to 52 were prepared in analogy to Examples 21 to 23 by starting from the indicated intermediates. The absolute stereochemistry is arbitrarily assigned.

[0626]

[0627]

[0628] Example 53: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidin-4-one

[0629]

[0630] The title compound was prepared in analogy to Example 21 by replacing intermediate A12 by intermediate A7 and intermediate B6 by intermediate B5 as a light brown solid, MS m / z: 505.3 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.

[0631] Examples 54 and 55: 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6- [(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6- [(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one

[0632]

[0633] Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide

[0634]

[0635] To a suspension of 6-chloro-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (Intermediate A16, 200 mg, 0.53 mmol) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (Intermediate B5, 366 mg, 0.63 mmol) in 1,4-dioxane (5 ml) and water (0.5 ml), cesium carbonate (513 mg, 1.58 mmol) and 1,1’-bis(diphenylphosphino)ferrocene- dichloropalladium(ll) dichloromethane complex (21 mg, 0.03 mmol, 0.05 eq) were added. After degassed with nitrogen for three times, the resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The mixture was poured into water (100 ml), the aqueous layer was separated and extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100: 1 to 1: 3) to give a mixture of 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1-methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1-methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidin-4-carboxamide (210 mg, 51:44), and it was used directly in the next step.

[0636] Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide Step 1 : 8-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 6-[3-(Difluoromethyl)-1 -bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1 -methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide

[0637]

[0638] To a solution of 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1- methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one and 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1- methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine- 4-carboxamide (190 mg, 0.37 mmol) in ethyl acetate (15 ml) was added magnesium oxide (150 mg, 3.74 mmol), triethylamine (45 mg, 0.45 mmol) and palladium on carbon (10%, 60 mg). The reaction mixture was degassed with hydrogen gas three times and then stirred under hydrogen gas (15 psi) at 25 °C for 2 h. The mixture was filtered through a pad of celite. The filtrate was diluted with ethyl acetate (100 ml) and washed with hydrochloric acid (1M, 30 ml) and brine (30 ml) then dried over Na2S04and concentrated to give crude 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4- carboxamide (190 mg, 96% yield) as a light yellow oil. MS m / z: 529.2 [M+H] + ESI pos.

[0639] ​ ​

[0640]

[0641] To a solution of 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4- carboxamide (190 mg, 0.36 mmol) in dichloromethane (8 ml) at 25 °C was added triethylamine (0.5 ml, 3.6 mmol). Then trimethylchlorosilane (0.23 ml, 1.8 mmol) was added dropwise at 0 °C under nitrogen and the reaction was stirred at 25 °C for 2 h. Hydrochloric acid (1 M) was added to the reaction mixture to adjust the pH to 3 to 5 and the aqueous mixture was extracted with dichloromethane (50 ml x 3). The combined organic layers were washed with brine (50 ml x 3) and dried over Na2SO4, then concentrated in vacuo. The residue was combined and purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 µm, water / acetonitrile containing 0.225% formic acid, flow rate 25 ml / min) to give 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (105 mg, yield 57%) as a light yellow solid. MS m / z: 511.3 [M+H] + , ESI pos.

[0642] ​ ​ ​ ​

[0643]

[0644] Racemic 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin- 4-one (105 mg) was separated by chiral SFX (column: Daicel Chiralcel OX 250 mm x 30 mm, 10 µm, solvent: acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 70 ml / min) to give 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4- one (41 mg, yield 39%) as the first eluting enantiomer as a white solid, MS m / z: 511.2 [M+H] + , ESI pos.; and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4- one (35 mg, yield 33%) as the second eluting enantiomer as a white solid, MS m / z: 511.2 [M+H] + , ESI pos.

[0645] Example 56, Example 57 and Example 58: 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4- one and 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran- 4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chlorophenyl)-3- methyl-6-[rac-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one

[0646]

[0647] The title compound was prepared in analogy to Example 54 and 55, replacing intermediate A16 by intermediate A17, which was a light yellow solid, MS m / z: 505.2 [M+H] + , ESI pos. arbitrary specified absolute stereochemical structure.

[0648] Example 59: 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one

[0649]

[0650] ​

[0651]

[0652] To a solution of 2,6-dichloropyrimidine-4-carboxylic acid methyl ester (1.0 g, 4.83 mmol) in 1,4-dioxane (32 ml) was added (4-chloro-2-fluoro-phenyl)boronic acid (842 mg, 4.83 mmol) and cesium carbonate (4.72 g, 14.5 mmol) at room temperature. The mixture was degassed, then 1,1’-bis(diphenylphosphino)ferrocene- dichloropalladium(ll) dichloromethane complex (395 mg, 0.483 µmol, 0.10 eq) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 50%) to give 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid methyl ester (983 mg, 60%) as a light yellow solid, MS m / z: 301.0 [M+H] + ESI pos.

[0653] Step 2: 6-(4-Chloro-2-fluoro-phenyl)-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrimidine-4-carboxylic acid methyl ester 4-methyl carboxylate

[0654]

[0655] To a solution of 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid methyl ester (235 mg, 0.780 mmol) in N,N-dimethylformamide (4 ml) was added (2S)-2-(1-methylpyrazol-4-yl)morpholine (intermediate (+)-B1, 144 mg, 0.858 mmol) and N,N-diisopropylethylamine (202 mg, 272 µl, 1.56 mmol) at room temperature and the mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with water and extracted twice 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% to 100%) to give 6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylic acid methyl ester (304 mg, yield 90%) as a yellow solid. MS m / z: 432.1 [M+H] ESI pos. + , ESI pos.

[0656] Step 3: 5-Bromo-6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin- 4-yl]pyrimidine-4-carboxylic acid methyl ester pyrimidine-4-carboxylic acid methyl ester

[0657]

[0658] To a solution of 6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylic acid methyl ester (275 mg, 0.637 mmol) in dichloromethane (6 ml) was added N-bromosuccinimide (125 mg, 0.70 mmol) at room temperature and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give 5-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylic acid methyl ester (225 mg, yield 65%) as a yellow solid, MS m / z: 512.1 [M+H] + , ESI pos.

[0659] Step 4: 6-(4-Chloro-2-fluoro-phenyl)-5-prop-l-ynyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpho lin-4-yl]pyrimidine-4-carboxylic acid methyl ester Step 5: 6-(4-Chloro-2-fluoro-phenyl)-N-methyl-5-prop-l-ynyl-2-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxamide

[0660]

[0661] To a solution of 5-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylic acid methyl ester (190 mg, 0.372 mmol) in N,N-dimethylformamide (3 ml) was added tributyl(prop-1-ynyl)stannane (184 mg, 170 µl, 0.558 mmol) at room temperature. The mixture was degassed with argon, then tetrakis(triphenylphosphine)palladium(0) (43 mg, 37 µmol, 0.10 eq) was added. The mixture was stirred in the microwave at 110 °C for 1 h. The reaction mixture was diluted with water and extracted twice 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% to 100%) to give 6-(4-chloro-2-fluoro-phenyl)-5-prop-1-ynyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylic acid methyl ester (182 mg, yield 97%) as a light yellow solid, MS m / z: 470.2 [M+H] + ESI pos.

[0662] Step 6: 4-(4-Chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-8-one Step 7: 4-(4-Chloro-2-fluoro-phenyl)-7-methyl-8-oxo-2-[(2S)-2-(l-methylpyrazol-4-yl)morpho lin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde

[0663]

[0664] Methyl 6-(4-chloro-2-fluoro-phenyl)-5-prop-1-ynyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (180 mg, 0.383 mmol) was dissolved in methylamine solution (40% in methanol, 4.77 ml, 38.3 mmol) at room temperature and the mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated to dryness. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give 6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-prop-1-ynyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxamide (160 mg, yield 80%) as a yellow solid, MS m / z: 469.2 [M+H] + ESI pos.

[0665] Step 8: 4-(4-Chloro-2-fluoro-phenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(l-methylpyrazol- 4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one Step 1: 6-Chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one

[0666]

[0667] To a solution of 6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-prop-1-ynyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxamide (160 mg, 0.341 mmol) in ethanol (2.5 ml) was added sodium ethoxide (232 mg, 3.41 mmol) at room temperature and the mixture was stirred at 80 °C overnight. The reaction mixture was diluted with water and extracted with dichloromethane four times. The combined organic layers were dried over MgS04and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0% to 5%) to give 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one (71 mg, yield 42%) as a yellow solid, MS m / z: 469.1 [M+H] + ESI pos.

[0668] Step 2: 8-(4-Chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(l-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one Step 1: 6-Chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[5,4-d]pyrimidin-4-one

[0669]

[0670] To a solution of 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one (20 mg, 43 pmol) in 1,4- dioxane (1 ml) was added selenium dioxide (9.5 mg, 85.3 pmol) at room temperature and the mixture was stirred at 100 °C for 2 h. The reaction mixture was concentrated to dryness and the residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0% to 8%) to give 4-(4-chloro-2-fluoro-phenyl)-7-methyl-8-oxo-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde (18 mg, yield 83%) as a yellow solid, MS m / z: 483.1 [M+H] + ESI pos.

[0671] Step 2: 8-(4-Chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[5,4-d]pyrimidin-4-one ​

[0672]

[0673] To a solution of 4-(4-chloro-2-fluoro-phenyl)-7-methyl-8-oxo-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde (7 mg, 14.5 µmol) in dichloromethane (1 ml) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (2.7 M in toluene, 54 µl, 145 µmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with a saturated NaHCO3 solution and extracted twice with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by preparative HPLC (Gemini NX C-18, 5µm, 100 x 30 mm, acetonitrile / water) to give the title compound (2 mg, yield 26%) as a yellow solid, MS m / z: 505.1 [M+H] ESI pos. + , ESI pos.

[0674] Reference Example

[0675] Reference Example 1: 8-(4-Chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one

[0676]

[0677] ​

[0678]

[0679] To a solution of 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate Al, 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- dichloropalladium(ll) 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 layer was 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% to 60%) then triturated in diethyl ether to give 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (556 mg, yield 62%) as a light yellow solid, MS m / z: 338.1 [M+H] + , ESI pos.,1H NMR (300MHz, 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).

[0680] ​ ​

[0681]

[0682] To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4- d]pyrimidin-4-one (120 mg, 0.35 mmol) and 2-(1-methylpyrazol-4-yl)morpholine (Intermediate B1, 89 mg, 0.53 mmol) in N-methylpyrrolidine (1 ml) was added N,N- diisopropylethylamine (138 mg, 1.06 mmol). The mixture was heated under microwave irradiation at 150 °C for 12 h, then purified by preparative HPLC (column: Phenomenex Luna C18 150 x25mm x 10 µm, water / acetonitrile with 0.1% formic acid, flow rate 25 ml / min) to give the product 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (50 mg). This racemate was separated by SFC (column: Daicel Chiralcel OD 250 mm*30 mm, 10 µm, solvent: acetonitrile / isopropanol / 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 the first eluting enantiomer with retention time 2.06 min (other enantiomer retention time 2.46 min) as a light yellow solid, MS m / z: 469.3 [M+H] ESI pos. arbitrarily assigned absolute stereochemistry.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). + , ESI pos. arbitrarily assigned absolute stereochemistry.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).

[0683] Reference Example 2: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one

[0684]

[0685] The title compound, which is the second eluting enantiomer having a retention time 2.46 min, was prepared in analogy to Reference Example 1 as a light yellow solid, MS m / z: 469.3 [M+H] Example 2: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one + , ESI pos., arbitrarily assigned absolute stereochemistry.

[0686] Reference Example 3: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2- methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one

[0687]

[0688] To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4- d]pyrimidin-4-one (see Reference Example 1, 30 mg, 0.09 mmol) in 1,4-dioxane (1.5 ml) were added 2-(2-methyl-4-pyridyl)morpholine (Intermediate B2, 24 mg, 0.13 mmol), cesium carbonate (87 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (6.5 mg, 0.01 mmol, 0.08 eq) and Xantphos (10 mg, 0.02 mmol, 0.2 eq) and the mixture was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by chromatography (silica gel plate, dichloromethane / ethyl acetate = 10:1) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(2-methyl-4-pyridyl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one (30 mg). This racemate was separated by SFC (column: Daicel Chiralcel OD 250 mm*30 mm, 10 µm, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 80 ml / min) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one as the first eluting enantiomer with retention time 1.02 min (other enantiomer retention time 2.08 min) as a yellow solid, MS m / z: 480.2 [M+H] ESI pos., absolute stereochemistry arbitrarily assigned. + , ESI pos., absolute stereochemistry arbitrarily assigned.

[0689] Reference Example 4: 8-(4-Chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one

[0690]

[0691] The title compound was prepared in analogy to Reference Example 3 as the second eluting enantiomer with retention time 2.08 min as a yellow solid, MS m / z: 480.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.

[0692] Reference Example 5: 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one

[0693]

[0694] ​

[0695]

[0696] Dissolve 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (Intermediate A4, 850 mg, 3.47 mmol) in 1,4-dioxane (20 ml) at room temperature and add (4-chloro-2-fluoro-phenyl)boronic acid (605 mg, 3.47 mmol) and 2 M aqueous cesium carbonate solution (5.2 ml, 10.41 mmol). Degass the mixture and then add 1,1’-bis(diphenylphosphino)ferrocene- dichloropalladium(ll) dichloromethane complex (283 mg, 347 µmol, 0.10 eq). Stir the mixture at room temperature for 2 h. Dilute the reaction mixture with water and extract twice with ethyl acetate. Wash the combined organic layers with water and brine, dry over MgSO4 and concentrate to dryness. Purify the residue by flash chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (928 mg, yield 76%) as a light brown solid, MS m / z: 339.0 [M+H] + ESI pos.

[0697] ​ ​

[0698]

[0699] (2S)-2-(l-methylpyrazol-4-yl)morpholine (Intermediate (+)-B1, 25 mg, 0.174 mmol) and N,N-diisopropylethylamine (48 mg, 64 μΐ, 0.369 mmol) were added at room temperature. The mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgS04and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol in dichloromethane 0% to 4%) to give the title compound (30 mg, 85%) as a yellow solid, MS m / z: 470.2 [M+H] ESI pos., absolute stereochemistry arbitrarily assigned. + , ESI pos., absolute stereochemistry arbitrarily assigned.

[0700] Reference Examples 6 and 7: 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2- methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2- fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4- d]pyrimidin-4-one

[0701]

[0702] To a solution of 2-(2-methyl-4-pyridyl)morpholine (Intermediate B2, 43 mg, 0.24 mmol) in dimethyl sulfoxide (1 ml) was added 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one (see Reference Example 5, 55 mg, 0.16 mmol) and N,N- diisopropylethylamine (23 mg, 0.18 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (40 ml x 2). The organic phase was washed with brine (100 ml x 3), dried over Na2S04and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / ether = 1:0) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (44 mg). The enantiomers were separated by chiral SFC (column: Daicel Chiralpak AD, 250 mm x 30 mm, 10 µm, ethanol + 0.1% ammonium hydroxide, flow rate 70 ml / min) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (19 mg, 42% yield) as the first eluting enantiomer with retention time 1.05 min as a light yellow solid, MS m / z: 481.2 [M+H] + , ESI pos.; and 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (21 mg, 47% yield) as the second eluting enantiomer with retention time 1.44 min as a light yellow solid, MS m / z: 481.2 [M+H] + , ESI pos. of any specified absolute stereochemistry.

[0703] Example 60

[0704] The compounds of the formula (I) can be used as active ingredients for the production of tablets of the following composition in a manner known per se:

[0705]

[0706] Example 61

[0707] The compounds of formula (I) can be used as active ingredients in the production of capsules of the following composition in a manner known per se:

[0708] .

Claims

1. A compound of formula (I) (I) Or its medicinal salt, wherein: X 1 X 2 and X 3 Each is independently selected from N and CH; A is selected from C3-C 10 -Cycloalkyl, C3-C 10 -cycloalkenyl, C6-C 10 -Aryl, 5- to 10-membered heteroaryl and 3- to 10-membered heterocyclic groups; B is selected from ； R 1 R 2 and R 3 Each is independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy and halo-C1-C6-alkoxy; R 4a Selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy and groups ; R 4b and R 4c Each is independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and oxo; R 5 Selected from C1-C6-alkyl, halo-C1-C6-alkyl, 3- to 10-membered heterocyclic groups and C3-C 10 -cycloalkyl; wherein the C3-C 10 -The cycloalkyl group is optionally substituted with a substituent selected from halogens and C1-C6-alkyl groups; R 6 Selected from hydrogen and fluorine; R 7 and R 8 Each is independently selected from hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -cycloalkyl groups and 3- to 10-membered heterocyclic groups; and C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H-triazole, 2H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein: (i)X 1 and X 3 Let N be the number of elements and X be the number of elements. 2 For CH; or (ii)X 1 X 2 and X 3 All are N; or (iii)X 1 and X 2 Let N be the number of elements and X be the number of elements. 3 For CH; or.

3. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein: (i)X 1 and X 3 Let N be the number of elements and X be the number of elements. 2 For CH; or (ii)X 1 X 2 and X 3 All are N.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein: A is selected from C6-C 10 -Aryl and C3-C 10 -cycloalkyl; R 1 Selected from halogenated-C1-C6-alkyl groups and halogens; R 2 Selected from hydrogen and halogens; and R 3 Selected from hydrogen and halogens.

5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein: A is selected from C6-C 10 -Aryl and C3-C 10 -cycloalkyl; R 1 Selected from halogenated-C1-C6-alkyl groups and halogens; R 2 Selected from hydrogen and halogens; and R 3 It is hydrogen.

6. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein: A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentyl; R 1 Selected from CF3, CHF2, fluorine, and chlorine; R 2 Selected from hydrogen and fluorine; and R 3 Selected from hydrogen and fluorine.

7. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein: A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentyl; R 1 Selected from CF3, CHF2, fluorine, and chlorine; R 2 Selected from hydrogen and fluorine; and R 3 It is hydrogen.

8. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutical salt thereof, wherein the group Selected from: 。 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutical salt thereof, wherein: B is selected from and ; R 4a as a group ; R 4b Selected from hydrogen and C1-C6-alkyl; R 4c It is hydrogen; C is selected from pyridinyl, pyrazolyl, and 2H-triazole; R 7 Selected from C1-C6-alkyl, C1-C6-alkoxy and C3-C 10 -cycloalkyl; and R 8 It is hydrogen.

10. The compound of formula (I) according to claim 9, or a pharmaceutical salt thereof, wherein B is selected from... 。 11. The compound of formula (I) according to claim 9, or a pharmaceutical salt thereof, wherein: B is selected from and ; R 4a as a group ; R 4b It is hydrogen; R 4c It is hydrogen; C is selected from pyridyl and pyrazolyl groups; R 7 Selected from C1-C6-alkyl and C1-C6-alkoxy; and R 8 It is hydrogen.

12. The compound of formula (I) according to claim 9, or a pharmaceutical salt thereof, wherein: B is selected from and ; R 4a as a group ; R 4b It is hydrogen; R 4c It is hydrogen; C is selected from pyridyl and pyrazolyl groups; R 7 Selected from methyl and methoxy; and R 8 It is hydrogen.

13. The compound of formula (I) according to claim 9, or a pharmaceutical salt thereof, wherein B is selected from... 。 14. The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutical salt thereof, wherein R 5 It is a C1-C6-alkyl group.

15. The compound of formula (I) according to claim 14, or a pharmaceutical salt thereof, wherein R 5 It is a methyl group.

16. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein: (i)X 1 and X 3 Let N be the number of elements and X be the number of elements. 2 For CH; or (ii)X 1 X 2 and X 3 All are N; or (iii)X 1 and X 2 Let N be the number of elements and X be the number of elements. 3 For CH; A is selected from C6-C 10 -Aryl and C3-C 10 -cycloalkyl; R 1 Selected from halogenated-C1-C6-alkyl groups and halogens; R 2 Selected from hydrogen and halogens; R 3 Selected from hydrogen and halogens; B is selected from and ; R 4a as a group ; R 4b Selected from hydrogen and C1-C6-alkyl; R 4c It is hydrogen; R 5 It is a C1-C6-alkyl group; C is selected from pyridinyl, pyrazolyl, and 2H-triazole; R 6 Selected from hydrogen and fluorine; R 7 Selected from C1-C6-alkyl, C1-C6-alkoxy and C3-C 10 -cycloalkyl; and R 8 It is hydrogen.

17. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein: (i)X 1 and X 3 Let N be the number of elements and X be the number of elements. 2 For CH; or (ii)X 1 X 2 and X 3 All are N; or (iii)X 1 and X 2 Let N be the number of elements and X be the number of elements. 3 For CH; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentyl; R 1 Selected from CF3, CHF2, fluorine, and chlorine; R 2 Selected from hydrogen and fluorine; R 3 Selected from hydrogen and fluorine; B is selected from: ； R 5 It is methyl; and R 6 Selected from hydrogen and fluorine.

18. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein: (i)X 1 and X 3 Let N be the number of elements and X be the number of elements. 2 For CH; or (ii)X 1 X 2 and X 3 All are N; A is selected from C6-C 10 -Aryl and C3-C 10 -cycloalkyl; R 1 Selected from halogenated-C1-C6-alkyl groups and halogens; R 2 Selected from hydrogen and halogens; R 3 It is hydrogen; B is selected from and ; R 4a as a group ; R 4b It is hydrogen; R 4c It is hydrogen; C is selected from pyridyl and pyrazolyl groups; R 5 It is a C1-C6-alkyl group; R 6 Selected from hydrogen and halogens; R 7 Selected from C1-C6-alkyl and C1-C6-alkoxy; and R 8 It is hydrogen.

19. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein: (i)X 1 and X 3 Let N be the number of elements and X be the number of elements. 2 For CH; or (ii)X 1 X 2 and X 3 All are N; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentyl; R 1 Selected from CF3, CHF2, fluorine, and chlorine; R 2 Selected from hydrogen and fluorine; R 3 It is hydrogen; B is selected from ； R 5 It is methyl; and R 6 Selected from hydrogen and fluorine.

20. The compound of formula (I) according to claim 1, or a pharmaceutical salt thereof, wherein the compound of formula (I) is selected from: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimidino[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimidino[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidino[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimidino[5,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxacyclohexane-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyridino[3,4-d]pyrimidin-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxacyclohexane-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyridino[3,4-d]pyrimidin-4-one; 2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[3,4-d]pyrimidin-4-one; 2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[racemic-(2R,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[racemic-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxacyclohexane-4-yl]-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxacyclohexane-4-yl]-3-methyl-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[racemic-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimidino[5,4-d]pyrimidin-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-Chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; 8-(4-chlorophenyl)-3-methyl-6-[racemic-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimidino[5,4-d]pyrimidin-4-one; and 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one.

21. The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutical salt thereof, used as a therapeutically active substance.

22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20 or a pharmaceutical salt thereof, and a therapeutically inert carrier.

23. A method for treating or preventing a condition in a subject of need related to loss of function of human TREM2, the method comprising administering to the subject a therapeutically effective amount of a compound or a pharmaceutical salt thereof according to any one of claims 1 to 20, or a pharmaceutical composition according to claim 22.

24. The method of claim 23, wherein the condition associated with 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 diseases, and stroke.

25. The compound or pharmaceutical salt thereof according to any one of claims 1 to 20, or the pharmaceutical composition according to claim 23, for use in the method according to claim 23 or 24.

26. Use of the compound or pharmaceutical salt thereof according to any one of claims 1 to 20, or the pharmaceutical composition according to claim 22, in the method according to claim 23 or 24.

27. Use of the compound or a pharmaceutical salt thereof according to any one of claims 1 to 20 in the preparation of a medicament, wherein the medicament is used in the method according to claim 23 or 24.

28. The present invention as described above.

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