Condensed pyrazines or pyrimidines ALS TREM2 agoonists

Abstract

The invention provides compounds having the general formula (I) or (II) (I) (II) wherein A, A1, X1, R1, R2, R3, R4, R5, and R6 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds in the treatment or prevention of diseases that are associated with TREM2.

Description

[0001] CONDENSED PYRAZINES OR PYRIMIDINES ALS TREM2 AGOONISTS

[0002] Field of the Invention

[0003] The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Triggering Receptor Expressed on Myeloid cells 2 (TREM2) agonists for the treatment or prevention of Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

[0004] Background of the Invention

[0005] Microglia are immune cells resident in the central nervous system (CNS) which play a crucial role in the CNS development and maintenance of brain homeostasis through synaptic pruning and removal of apoptotic neurons (Paolicelli R.C. et al., Science 2011, 9;333(6048):1456-8 doi: 10.1126 / science.1202529). Microglia are also key players in response to neurodegenerative conditions and neuropathological lesions, whereby they shift into an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to the lesion sites and phagocytosis of dead cells and debris. (Lue L.F. et al., Mol.

[0006] Neurobiol. 2010, 41(2-3): 115-28, doi: 10. 1007 / sl2035-010-8106-8).

[0007] Microglia express a multitude of receptors on their surface, which play a key role in sensing the environmental changes and enabling the complex crosstalk regulating their physiological functions.

[0008] TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is one of these cell surface receptors, which in brain is selectively expressed on microglia and plays a key role in their survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445-453 (2003). https: / / doi.org / 10.1038 / nril 106). TREM2 is a single-pass transmembrane receptor that belongs to the Immunoglobulin superfamily (Ig-SF). It is composed of a ligand binding extracellular immunoglobulin variable-like domain (IgV) followed by a long stalk domain, a single transmembrane helix and a short cytosolic tail that does not have signal transduction motifs. Downstream signal transduction is mediated through its interaction with the effector protein DAP 12, a transmembrane disulphide-linked adapter dimer which expression and cellular localization at the plasma membrane are dependent on TREM2, and which is associated to TREM2 transmembrane helix via lysine-aspartic acid interaction (K156-D50) forming a signaling complex (Zhong L. et al., J Biol Chem. 2015;290(25): 15866-77). Given its short extracellular domain, DAP 12 lacks ligand-binding capabilities. Endogenous ligands of TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cellular debris, myelin and Ap oligomers. Stimulation of the TREM2 / DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (IT AM) in the cytoplasmic domain of DAP 12, which results in recruitment of Syk kinase to activate downstream signaling molecules.

[0009] Activation of TREM2 plays a key role in microglia signaling and function, including survival, migration, amyloid plaque insulation, beta-amyloid phagocytosis, myelin debris clearance and the transition from the homeostatic to the disease-associated microglia (DAM) state in the context of a neurodegenerative environment (Condello, C. et al., Nat Commun 6, 6176, 2015, doi: org / 10.1038 / ncomms7176; Poliani et al., J Clin Invest, 2015 May;125(5):2161-70, doi: 10.1172 / JCI77983; Zhao et al., Neuron, 2018 Mar 7;97(5): 1023-103 l.e7, doi: 10.1016 / j.neuron.2018.01.031; Keren-Shaul H. et al., Cell, 2017 Jun 15;169(7): 1276-1290.el7. doi: 10. 1016 / j. cell.2017.05.018).

[0010] Genetic variants of TREM2 have been implicated in a multitude of neurodegenerative diseases (Hou J. et al. Molecular Neurodegeneration (2022) 17:84; doi: org / 10.1186 / sl3024-022-00588- y). TREM2 variants resulting in lack of TREM2 expression were identified as the cause of the Nasu-Hakola Disease (NHD), or Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy (PLOSL), a fatal condition manifesting with progressive pre-senile dementia and characterized by loss of myelin and bone abnormalities, consistent with TREM2 expression in myeloid cells microglia and osteoclasts (Paloneva, J. et al., Am J Hum Genet. 2002,71(3):656-62, doi: 10.1086 / 342259). Similarly, missense mutations ofTREM2 have been associated with increased risk of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several of these TREM2 variants have been implicated with impaired microglia function and their reduced response to neurodegenerative diseases. (Kleinberger, G. et al., Sci. Transl. Med. 2014, 6, 243ra86). Moreover, genomic-wide association studies (GW AS) showed a strong link between a number of rare loss of function (LoF) variants of TREM2 and an increased risk of late onset Alzheimer’s disease (LOAD) (Guerreiro R. et al., N Engl J Med. 2013, 368(2): 117-27; Jonsson T. et al., N Engl J Med. 2013, 368(2): 107-16). Amongst those, the R47H variant, a LoF mutation associated with structural alterations within the extracellular domain of TREM2 resulting in impaired ability to bind endogenous ligands, was linked to a ca. 3 fold increased risk of LOAD (Sudom, A. et al., J Biol Chem. 2018 10;293(32): 12634-12646; doi: 10. 1074 / jbc.RAl 18.002352). Studies are ongoing to elucidate the mechanism by which TREM2 LoF mutations contribute to AD. It is likely that patients carrying these mutations have impaired microglia function including reduced clearance of extracellular aggregates (e.g. amyloid and myelin debris) and apoptotic neurons, ultimately reducing their capacity to fight the disease and increasing their susceptibility to neurodegeneration. Indeed decreased microglia activation and failure to cluster around the amyloid plaque were observed in mouse models deficient for TREM2 or DAP 12, confirming the central role of TREM2 signalling in microglia function and response to Alzheimer’s pathological hallmarks.

[0011] In light of all this evidence, pharmacological activation of TREM2 appears to be a viable therapeutic intervention. The small molecules disclosed herein are potent and selective agonists of TREM2.

[0012] Summary of the Invention

[0013] In a first aspect, the present invention provides compounds of formula (I) or (II) wherein A, A1, X1, R1, R2, R3, R4, R5, and R6are as defined herein.

[0014] In further aspects, the invention provides compositions including the compounds of formula (I) or (II), processes of manufacturing the compounds of formula (I) or (II) and methods of using the compounds of formula (I) or (II). Detailed Description of the Invention

[0015] Definitions

[0016] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0017] The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“Ci-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some nonlimiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl are methyl and ethyl.

[0018] The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“Ci-6-alkoxy”). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet nonlimiting example of alkoxy is methoxy.

[0019] The term “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl). The term “oxo” refers to an oxygen atom bound to the parent molecule through a double bond (=0).

[0020] The term “cycloalkyl” as used herein refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-io-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1- bicyclo[l. l.l]pentanyl, norbornanyl, spiro[3.3]heptanyl, and l-bicyclo[2.2.2]octanyl. Particularly preferred, yet non-limiting examples of cycloalkyl are cyclopropyl, bicyclo [l. l.l]pentanyl, spiro[3.3]heptanyl, and cyclohexyl.

[0021] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“Ce-Cio-aryl”), wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g. 9H-fluoren-9-yl). A particularly preferred, yet non-limiting example of aryl is phenyl.

[0022] The term "heteroaryl" refers to a mono- or multivalent, monocyclic ring system having a total of 5 to 6 ring members, wherein the ring system is aromatic and contains 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon. Preferably, the heteroaryl comprises 1 to 3 heteroatoms, more preferably 1 to 2 heteroatoms independently selected from N, O, and S. Some preferred, yet non-limiting examples of heteroaryl include thiazolyl; oxazolyl; oxadiazolyl; l,2,4-oxadiazol-5-yl; pyridyl; pyrazolyl; triazolyl; tetrazolyl; pyrazinyl; and imidazolyl. Some further preferred, yet non-limiting examples of heteroaryl include pyridyl and pyrazolyl.

[0023] The term “heterocyclyl” as used herein refers to a saturated or partly unsaturated monocyclic ring system of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of said ring atoms are heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 3, more preferably 1 to 2 of said ring atoms are independently selected from N and O, the remaining ring atoms being carbon. Some non-limiting examples of heterocyclyl groups include azetidine, pyrrolidine, piperidine, piperazine, morpholine, oxetane and 1,2-dihydropyridine. A preferred, yet non-limiting example of heterocyclyl is oxetane.

[0024] The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1 -difluoroethyl, 2,2- difluoroethyl, and 2,2,2-trifluoroethyl.

[0025] The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.

[0026] The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0027] The abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2.

[0028] The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

[0029] The term “prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0030] Compounds of the Invention

[0031] In a first aspect, the present invention provides a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein:

[0032] A is selected from N and CH;

[0033] A1is selected from O and CR^R^;

[0034] X1is selected from N and CH;

[0035] R1is selected from Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0036] R2is selected from halo-Ci-Ce-alkyl, Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6- membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said Ce-Cio-aryl, C3-C10- cycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, Ci-Ce-alkyl, and halo-Ci- Ce-alkyl;

[0037] R3is selected from 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, and Cs-Cio-cycloalkyloxy; and wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from oxo, Ci-Ce-alkyl, Ci-Ce-alkoxy, and C3- Cio-cycloalkyl;

[0038] R4is selected from hydrogen and Ci-Ce-alkyl;

[0039] R5is selected from hydrogen and Ci-Ce-alkyl;

[0040] R6is selected from hydrogen and Ci-Ce-alkyl;

[0041] RA1is selected from hydrogen, halogen, and Ci-Ce-alkyl; and

[0042] RA2is selected from hydrogen, halogen, and Ci-Ce-alkyl.

[0043] In one embodiment, said compound of formula (I) or (II) is a compound of formula (lb) or (lib) or a pharmaceutically acceptable salt thereof, wherein:

[0044] A is selected from N and CH;

[0045] X1is selected from N and CH;

[0046] R1is selected from Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0047] R2is selected from halo-Ci-Ce-alkyl, Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and Cs-Cio-cycloalkyl are optionally substituted with 1 to 3 substituents independently selected from halogen, Ci-Ce-alkyl, and halo-Ci-Ce-alkyl;

[0048] R3is selected from 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl and wherein said 3- to 6- membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from oxo, Ci-Ce-alkyl, Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl;

[0049] R4is selected from hydrogen and Ci-Ce-alkyl; and R5is selected from hydrogen and Ci-Ce-alkyl. In one embodiment, said compound of formula (I) or (II) is a compound of formula (la) or (Ila) or a pharmaceutically acceptable salt thereof, wherein:

[0050] A is selected from N and CH;

[0051] X1is selected from N and CH;

[0052] R1is selected from Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0053] R2is selected from Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and C3- Cio-cycloalkyl are optionally substituted with 1 to 3 substituents independently selected from halogen, Ci-Ce-alkyl, and halo-Ci-Ce-alkyl;

[0054] R3is selected from 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl and wherein said 3- to 6- membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from oxo, Ci-Ce-alkyl, Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl; and

[0055] R4is selected from hydrogen and Ci-Ce-alkyl.

[0056] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0057] A1is selected from O and CRA1RA2;

[0058] RA1is halogen; and

[0059] RA2is halogen.

[0060] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0061] A1is selected from O and CRA1RA2;

[0062] RA1is fluoro; and

[0063] RA2is fluoro. In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein A1is O.

[0064] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0065] A is N;

[0066] A1is O; and

[0067] X1is selected from N and CH.

[0068] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0069] A is CH;

[0070] A1is O; and

[0071] X1is selected from N and CH.

[0072] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0073] A is N; and

[0074] X1is selected from N and CH.

[0075] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0076] A is CH; and

[0077] X1is selected from N and CH.

[0078] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is N.

[0079] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is CH.

[0080] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein X1is N.

[0081] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein X1is CH. In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from methyl, CHF2, and CF3.

[0082] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Ce-alkyl.

[0083] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is methyl.

[0084] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from halo- Ci-Ce-alkyl, Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6-membered heteroaryl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl.

[0085] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from halo- Ci-Ce-alkyl, Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and Cs-Cio-cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce- alkyl.

[0086] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from 3,3,3-trifluoropropyl, phenyl, cyclohexyl, spiro[3.3]heptane, bicyclo [1.1.1] pentane, and pyridyl, wherein said phenyl, cyclohexyl, spiro[3.3]heptane, bicyclo [1.1.1] pentane, and pyridyl are substituted with 1 to 3 substituents independently selected from chloro, fluoro, and CF3.

[0087] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from 3,3,3-trifluoropropyl, phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclo [1.1.1] pentane, wherein said phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclo[l. l.l]pentane are substituted with 1 to 3 substituents independently selected from chloro, fluoro, and CF3. In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from

[0088] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from

[0089] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from phenyl and Cs-Ce-cycloalkyl, wherein said phenyl and Cs-Ce-cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl. In a further preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and Cs-Cio-cycloalkyl are substituted with 1 to 2 halogen substituents. In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from phenyl, cyclohexyl, and bicyclo[l. l.l]pentane, wherein said phenyl, cyclohexyl, and bicyclofl. 1.1 ]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro, and CF3.

[0090] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from phenyl and cyclohexyl, wherein said phenyl and cyclohexyl are substituted with 1-2 substituents independently selected from fluoro and chloro.

[0091] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2

[0092] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2

[0093] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from 5- to 6-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, and Cs-Cio-cycloalkyloxy; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from Ci-Ce- alkyl and Cs-Cio-cycloalkyl. In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from 5- to 6-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl, and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from Ci-Ce-alkyl and C3- Cio-cycloalkyl.

[0094] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from

[0095] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from

[0096] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from

[0097] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from a 5- membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and a 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl and wherein said 6-membered heterocyclyl is substituted with oxo and a further substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl.

[0098] In a further preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is a 5- to 6- membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said 5- to 6-membered heteroaryl is substituted with 1-3 substituents independently selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl.

[0099] In a further preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is a 5- membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5-membered heteroaryl is substituted with 1 Ci-Ce-alkyl substituent.

[0100] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from IH-pyrazole and IH-pyridone, wherein said IH-pyrazole and IH-pyridone are substituted with 1 substituent selected from methyl and cyclohexyl.

[0101] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is IH-pyrazole substituted with 1 methyl substituent.

[0102] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from

[0103] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3 In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen and methyl.

[0104] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

[0105] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is selected from hydrogen and methyl.

[0106] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

[0107] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen.

[0108] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0109] R1is Ci-Ce-alkyl; and

[0110] R2is selected from halo-Ci-Ce-alkyl, Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and Cs-Cio-cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl.

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

[0112] R1is methyl; and

[0113] R2is selected from 3, 3, 3 -trifluoropropyl, phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclo [1.1.1] pentane, wherein said phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclofl. 1.1 ]pentane are substituted with 1 to 3 substituents independently selected from chloro, fluoro, and CF3.

[0114] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0115] R1is Ci-Ce-alkyl; and R2is selected from phenyl and Cs-Ce-cycloalkyl, wherein said phenyl and C3-C6- cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl.

[0116] In a particularly preferred embodiment, the present invention provides a compound of formula

[0117] (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0118] R1is methyl; and

[0119] R2is selected from phenyl, cyclohexyl, and bicyclofl .1. l]pentane, wherein said phenyl, cyclohexyl, and bicyclofl.1.1 ]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro, and CF3.

[0120] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0121] R1is selected from methyl, CHF2, and CF3; and

[0122] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0123] R1is Ci-Ce-alkyl; and

[0124] R2is selected from Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and C3-C10- cycloalkyl are substituted with 1 to 2 halogen substituents.

[0125] In a particularly preferred embodiment, the present invention provides a compound of formula

[0126] (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0127] R1is methyl; and

[0128] R2is selected from phenyl and cyclohexyl, wherein said phenyl and cyclohexyl are substituted with 1-2 substituents independently selected from fluoro and chloro.

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

[0130] R3is selected from 5- to 6-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl, and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl;

[0131] R4is hydrogen; and

[0132] R5is selected from hydrogen and Ci-Ce-alkyl.

[0133] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0134] R4is hydrogen; and

[0135] R5is selected from hydrogen and methyl.

[0136] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0137] R3is selected from a 5-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and a 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl and wherein said 6-membered heterocyclyl is substituted with oxo and a further substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl;

[0138] R4is hydrogen; and

[0139] R5is hydrogen.

[0140] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0141] R3is selected from IH-pyrazole and IH-pyridone, wherein said IH-pyrazole and 1H- pyridone are substituted with 1 substituent selected from methyl and cyclohexyl;

[0142] R4is hydrogen; and

[0143] R5is hydrogen. In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0144] R3is selected from

[0145] R4is selected from hydrogen and methyl.

[0146] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0147] R3is a 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said 5- to 6-membered heteroaryl is substituted with 1-3 substituents independently selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl; and

[0148] R4is hydrogen.

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

[0150] R3is a 5-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5-membered heteroaryl is substituted with 1 Ci-Ce-alkyl substituent; and

[0151] R4is hydrogen.

[0152] In a particularly preferred embodiment, the present invention provides a compound of formula

[0153] (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0154] R3is IH-pyrazole substituted with 1 methyl substituent; and

[0155] R4is hydrogen.

[0156] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0157] R4is hydrogen.

[0158] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from N and CH;

[0159] A1is selected from O and CR^R2;

[0160] X1is selected from N and CH;

[0161] R1is Ci-Ce-alkyl;

[0162] R2is selected from halo-Ci-Ce-alkyl, Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6- membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said Ce-Cio-aryl C3-C10- cycloalkyl, and 5- to 6-membered heteroaryl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl;

[0163] R3is selected from 5- to 6-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, and Cs-Cio-cycloalkyloxy; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from Ci-Ce- alkyl and Cs-Cio-cycloalkyl;

[0164] R4is hydrogen;

[0165] R5is selected from hydrogen and Ci-Ce-alkyl;

[0166] R6is hydrogen;

[0167] RA1is halogen; and

[0168] RA2is halogen.

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

[0170] A is selected from N and CH;

[0171] A1is selected from O and CRA1RA2;

[0172] X1is selected from N and CH;

[0173] R1is methyl;

[0174] R2is selected from 3, 3, 3 -trifluoropropyl, phenyl, cyclohexyl, spiro[3.3]heptane, bicyclo [1.1.1] pentane, and pyridyl, wherein said phenyl, cyclohexyl, spiro[3.3]heptane, bicyclo [1.1.1] pentane, and pyridyl are substituted with 1 to 3 substituents independently selected from chloro, fluoro, and CF3;

[0175] R4is hydrogen;

[0176] R5is selected from hydrogen and methyl;

[0177] R6is hydrogen;

[0178] RA1is fluoro; and RA2is fluoro.

[0179] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0180] A is selected from N and CH;

[0181] A1is O;

[0182] X1is selected from N and CH;

[0183] R1is Ci-Ce-alkyl;

[0184] R2is selected from phenyl and Cs-Ce-cycloalkyl, wherein said phenyl and C3-C6- cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl;

[0185] R3is selected from a 5-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and a 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl and wherein said 6-membered heterocyclyl is substituted with oxo and a further substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl;

[0186] R4is hydrogen;

[0187] R5is hydrogen; and

[0188] R6is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0189] A is selected from N and CH;

[0190] A1is O;

[0191] X1is selected from N and CH;

[0192] R1is methyl;

[0193] R2is selected from phenyl, cyclohexyl, and bicyclofl .1. l]pentane, wherein said phenyl, cyclohexyl, and bicyclofl.1.1 ]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro, and CF3;

[0194] R3is selected from IH-pyrazole and IH-pyridone, wherein said IH-pyrazole and 1H- pyridone are substituted with 1 substituent selected from methyl and cyclohexyl;

[0195] R4is hydrogen;

[0196] R5is hydrogen; and

[0197] R6is hydrogen.

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

[0199] A is selected from N and CH;

[0200] X1is selected from N and CH;

[0201] R1is Ci-Ce-alkyl;

[0202] R2is selected from halo-Ci-Ce-alkyl, Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and Cs-Cio-cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl;

[0203] R3is selected from 5- to 6-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl, and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl;

[0204] R4is hydrogen; and

[0205] R5is selected from hydrogen and Ci-Ce-alkyl.

[0206] In one embodiment, the present invention provides a compound of formula (lb) or (lib) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0207] A is selected from N and CH; X1is selected from N and CH;

[0208] R1is methyl;

[0209] R2is selected from 3, 3, 3 -trifluoropropyl, phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclo [1.1.1] pentane, wherein said phenyl, cyclohexyl, spiro[3.3]heptane, and bicyclofl. 1.1 ]pentane are substituted with 1 to 3 substituents independently selected from chloro, fluoro, and CF3;

[0210] R3is selected from

[0211] R4is hydrogen; and

[0212] R5is selected from hydrogen and methyl.

[0213] In a preferred embodiment, the present invention provides a compound of formula (lb) or (lib) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0214] A is selected from N and CH;

[0215] X1is selected from N and CH;

[0216] R1is Ci-Ce-alkyl;

[0217] R2is selected from phenyl and Cs-Ce-cycloalkyl, wherein said phenyl and C3-C6- cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl;

[0218] R3is selected from a 5-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and a 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl and wherein said 6-membered heterocyclyl is substituted with oxo and a further substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl;

[0219] R4is hydrogen; and

[0220] R5is hydrogen.

[0221] In a particularly preferred embodiment, the present invention provides a compound of formula (lb) or (lib) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from N and CH;

[0222] X1is selected from N and CH;

[0223] R1is methyl;

[0224] R2is selected from phenyl, cyclohexyl, and bicyclofl .1. l]pentane, wherein said phenyl, cyclohexyl, and bicyclofl.1.1 ]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro, and CF3;

[0225] R3is selected from IH-pyrazole and IH-pyridone, wherein said IH-pyrazole and 1H- pyridone are substituted with 1 substituent selected from methyl and cyclohexyl;

[0226] R4is hydrogen; and

[0227] R5is hydrogen.

[0228] In one embodiment, the present invention provides a compound of formula (la) or (Ila) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0229] A is selected from N and CH;

[0230] X1is selected from N and CH;

[0231] R1is selected from methyl, CHF2, and CF3;

[0232] R4is selected from hydrogen and methyl.

[0233] In a preferred embodiment, the present invention provides a compound of formula (la) or (Ila) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0234] A is N;

[0235] X1is selected from N and CH;

[0236] R1is Ci-Ce-alkyl; R2is selected from Ce-Cio-aryl and Cs-Cio-cycloalkyl, wherein said Ce-Cio-aryl and C3- Cio-cycloalkyl are substituted with 1 to 2 halogen substituents;

[0237] R3is a 5-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5-membered heteroaryl is substituted with 1 Ci-Ce-alkyl substituent; and

[0238] R4is hydrogen.

[0239] In a particularly preferred embodiment, the present invention provides a compound of formula (la) or (Ila) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0240] A is N;

[0241] X1is selected from N and CH;

[0242] R1is methyl;

[0243] R2is selected from phenyl and cyclohexyl, wherein said phenyl and cyclohexyl are substituted with 1-2 substituents independently selected from fluoro and chloro;

[0244] R3is IH-pyrazole substituted with 1 methyl substituent; and

[0245] R4is hydrogen.

[0246] In one embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) or (II) is selected from:

[0247] 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrido[2,3- b]pyrazin-6-one;

[0248] 5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[2-( 1 -methylpyrazol-4-yl)morpholin-4-yl]pyrido [2,3- b]pyrazin-6-one;

[0249] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0250] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]pyrido[2,3-d]pyrimidine-4,7-quinone;

[0251] 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]pyrido[2,3- d]pyrimidine-4,7-quinone;

[0252] 6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3-dimethyl- pyrido[2,3-d]pyrimidine-4, 7-dione;

[0253] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione; 8-(4-chlorophenyl)-6- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2, 3 -dimethyl- pyrido^, 3-d]pyrimidine-4, 7-dione;

[0254] 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0255] 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[2,3- b]pyrazin-6-one;

[0256] 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0257] 8-(4-chlorophenyl)-2,3-dimethyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pteridine-4,7- dione;

[0258] 4-(4-chlorophenyl)-6,7-dimethyl-2-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[2,3- b]pyrazin-3-one;

[0259] 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0260] 2,3 -dimethyl-7-[2-( 1 -methylpyrazol-4-yl)morpholino] -5 -(3 ,3 , 3 -trifluoropropyl)pyrido [2,3- b]pyrazin-6-one;

[0261] 8-(4-chlorophenyl)-6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0262] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0263] 8-(4-chlorophenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0264] 6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-

[0265] 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0266] 8-(4,4-difluorocyclohexyl)-6-[rac-(2R,4S)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-

[0267] 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0268] 4-(4-chlorophenyl)-6,7-dimethyl-2-[rac-(2S,4R)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0269] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[2,3- b]pyrazin-3-one;

[0270] 5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0271] 5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[(2R,4 S)-2-( 1 -methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one; 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[rac-(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0272] 5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[rac-(2R,4 S)-2-(2-methyl-4-pyridyl)tetrahydropyran- 4-yl]pyrido [2,3 -b]pyrazin-6-one;

[0273] 8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pteridine-4, 7-dione;

[0274] 5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0275] 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0276] 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0277] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4-yl]pyrazino[2,3- b]pyrazin-3-one;

[0278] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methylpyrazol-4-yl)oxan-4-yl]pyrazino[2,3- b]pyrazin-3-one;

[0279] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0280] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0281] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0282] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0283] 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2R)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0284] 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0285] 4-(4-chlorophenyl)-2- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6, 7-dimethyl- pyrazino[2,3-b]pyrazin-3-one;

[0286] 7- [2-( 1 -cyclopropylpyrazol-4-yl)morpholino] -5 -(4,4-difluorocyclohexyl)-2, 3 -dimethyl- pyrido[2,3-b]pyrazin-6-one;

[0287] 7-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-5-(4,4-difluorocyclohexyl)-2,3- dimethylpyrido[2,3-b]pyrazin-6-one; 7- [(2 S)-2-( 1 -cyclopropy lpyrazol-4-y l)morpholin-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;

[0288] 6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0289] 7 - [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;

[0290] 7 - [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;

[0291] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pteridine-4, 7-dione;

[0292] 4-(4-chloro-2-fluoro-phenyl)-2-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0293] 4-(4-chloro-2-fluoro-phenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0294] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0295] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0296] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran- 4-yl]pyrazino[2,3-b]pyrazin-3-one;

[0297] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran- 4-yl]pyrazino[2,3-b]pyrazin-3-one;

[0298] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0299] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0300] 2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0301] 2-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0302] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pteridine-4, 7 -dione;

[0303] 8-(4-chlorophenyl)-6- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2, 3 -dimethyl- pteridine-4, 7 -dione; 8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-

[0304] 4-yl]pteridine-4, 7-dione;

[0305] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0306] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0307] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0308] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0309] 5-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0310] 2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0311] 2-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0312] 6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpteridine-4, 7-dione;

[0313] 6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpteridine-4, 7-dione;

[0314] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0315] 4-(4, 4-difluorocyclohexyl)-2- [(2 S ,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0316] 4-(4, 4-difluorocyclohexyl)-2- [(2R,4 S)-2-(2-methoxypyridin-4-yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0317] 4-(4, 4-difluorocyclohexyl)-2- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0318] 4-(4, 4-difluorocyclohexyl)-2- [(2 S ,4R)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0319] 6- [rac-(2R,4 S)-2-( 1 -cyclopropylpy razol-4-y l)tetrahydropyran-4-y 1] -2,3 -dimethyl-8- [3 - (trifluoromethyl)- 1 -bicyclo[ 1.1. l]pentanyl]pyrido[2,3-d]pyrimidine-4,7-quinone;

[0320] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l.l.l]pentanyl]pyrido[2,3-d]pyrimidine-4, 7-dione; 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l.l.l]pentanyl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0321] 8-(4, 4-difluorocyclohexyl)-6- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpteridine-4, 7-dione;

[0322] 4-(4-chlorophenyl)-2- [(2 S ,4R)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0323] 4-(4-chlorophenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0324] 4-(4-chlorophenyl)-2- [(2 S ,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0325] 4-(4-chlorophenyl)-2-[(2R,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0326] 8-(4-chloro-2-fluoro-phenyl)-6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0327] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0328] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0329] 5 -(4-chloro-2, 6-difluorophenyl)-7 - [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-b]pyrazin-6-one;

[0330] 8-(4,4-difluorocyclohexyl)-6-[(2S,4R)-2-(6-methoxy-3-pyridyl)-2-methyl-tetrahydropyran-4-yl]- 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0331] 5 -(4-chloro-2-fluorophenyl)-7- [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-b]pyrazin-6-one;

[0332] 5 -(4-chloro-2-fluorophenyl)-7- [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-b]pyrazin-6-one;

[0333] 8-(4-chlorophenyl)-6-[(2S,4R)-2-(6-methoxypyridin-3-yl)oxan-4-yl]-2,3-dimethylpyrido[2,3- d] pyrimidine-4, 7- dione ;

[0334] 8-(4-chlorophenyl)-6- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2, 3 -dimethylpyrido [2,3- d] pyrimidine-4, 7- dione ;

[0335] 8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0336] 6- [(2 S,4R)-2-( 1 -cyclopropyl-6-oxopyridin-3 -yl)oxan-4-yl] -8-(4, 4-difluorocyclohexyl)-2, 3 - dimethylpyrido [2, 3 -d]pyrimidine-4, 7-dione; 6-[(2R,4S)-2-(l-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0337] 8-(4, 4-difluorocyclohexyl)-6- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0338] 6-[2-(l-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0339] 8-(4-chlorophenyl)-6- [2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl]-2, 3 -dimethyl- pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0340] 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0341] 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0342] 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0343] 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0344] 8-(4, 4-difluorocyclohexyl)-6- [(2 S ,4R)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0345] 8-(4-chlorophenyl)-6-[(2S,4R)-2-(l-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0346] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0347] 6-[2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0348] 6- [(2 S,4R)-2-( 1 -cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl] -8-(4, 4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0349] 6-[(2R,4S)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0350] 2-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-4-(2,2-difluorospiro[3.3]heptan-6-yl)-6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0351] 2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-4-(2,2-difluorospiro[3.3]heptan-6-yl)-6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0352] 8-(4, 4-difluorocyclohexyl)-6- [2-(2-keto- 1 -methyl-4-pyridyl)tetrahydropyran-4-yl] -2, 3 -dimethyl- pyrido [2, 3 -d]pyrimidine-4, 7-quinone; 8-(4,4-difluorocyclohexyl)-6-[2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0353] 8-(4,4-difluorocyclohexyl)-6-[rac-(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-

[0354] 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;

[0355] 8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0356] 6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,2-difluorospiro[3.3]heptan-6-yl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0357] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,2-difluorospiro[3.3]heptan- 6-yl)-2, 3 -dimethyl-pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0358] 5 -(4, 4-difluorocyclohexyl)-7 - [(2 S ,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0359] 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0360] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0361] 4-(4-chloro-2,6-difluoro-phenyl)-2-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0362] 5 -(4, 4-difluorocyclohexyl)-7 - [(2 S ,4R)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0363] 5 -(4-chlorophenyl)-7 - [(2R,4 S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -2, 3 -dimethyl- pyrido[2,3-b]pyrazin-6-one;

[0364] 5 -(4-chlorophenyl)-7 - [(2 S ,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -2, 3 -dimethyl- pyrido[2,3-b]pyrazin-6-one;

[0365] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0366] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0367] 5 -(4-chlorophenyl)-7 - [(2R,4 S)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -2, 3 -dimethyl- pyrido[2,3-b]pyrazin-6-one;

[0368] 5 -(4-chlorophenyl)-7 - [(2 S ,4R)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -2, 3 -dimethyl- pyrido[2,3-b]pyrazin-6-one;

[0369] 5-(4-chlorophenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one; 5 -(4-chlorophenyl)-7 - [(2R,4 S)-2-(6-keto- 1 -methyl-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0370] 5 -(4-chlorophenyl)-7 - [(2 S ,4R)-2-(6-keto- 1 -methyl-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0371] 4-(4-chlorophenyl)-2-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-6,7-dimethyl- pyrazino[2,3-b]pyrazin-3-one;

[0372] 4-(4-chlorophenyl)-2- [(2 S ,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -6, 7-dimethyl- pyrazino[2,3-b]pyrazin-3-one;

[0373] 4-(4-chlorophenyl)-2-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-6,7-dimethyl- pyrazino[2,3-b]pyrazin-3-one;

[0374] 4-(4-chlorophenyl)-2- [(2 S ,4R)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -6, 7-dimethyl- pyrazino[2,3-b]pyrazin-3-one;

[0375] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0376] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0377] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0378] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyridin-4-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0379] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[2,3-d]pyrimidine-4,7-quinone;

[0380] 5-(4-chlorophenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0381] 5 -(4-chlorophenyl)-7 - [(2 S ,4R)-2-( 1 -cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0382] 5 -(4-chlorophenyl)-7 - [(2 S ,4R)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0383] 5 -(4-chlorophenyl)-7 - [(2R,4 S)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0384] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0385] 8-(4-chlorophenyl)-6-[(2S,4R)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone; 7 - [(2R,4 S)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl] -5 -(4,4-difluorocyclohexyl)-

[0386] 2,3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;

[0387] 7 - [(2 S,4R)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl] -5 -(4,4-difluorocyclohexyl)-

[0388] 2,3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;

[0389] 4-(4-chloro-2,6-difluoro-phenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0390] 4-(4-chloro-2, 6-difluoro-phenyl)-2- [(2 S ,4R)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0391] 8-(4,4-difluorocyclohexyl)-6-[(2S,4R)-2-(2-keto-l-methyl-4-pyridyl)-2-methyl-tetrahydropyran- 4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone;

[0392] 2- [(2R,4 S)-2-( 1 -cyclopropy lpyrazol-4-y l)tetrahydropyran-4-y 1] -4- [3 -(difluoromethyl)- 1 - bicyclo [1.1.1 ] pentanyl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0393] 5-(2,2-difluorospiro[3.3]heptan-6-yl)-7-[(2R,4S)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-

[0394] 4-yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;

[0395] 2- [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6, 7-dimethyl-4-[3 - (trifluoromethyl)-l -bicyclo [1.1. l]pentanyl]pyrazino[2,3-b]pyrazin-3-one;

[0396] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]pteridine-4, 7-dione;

[0397] 7 - [(2R,4 S)-2-( 1 -cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl] -5 -(4,4-difluorocyclohexyl)-

[0398] 2,3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;

[0399] 5-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;

[0400] 5 -(4-chloro-2, 6-difluoro-phenyl)-7 - [(2R,4 S)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0401] 7 - [(2R,4 S)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl] -5 -(2,2- difluorospiro[3.3]heptan-6-yl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0402] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-8-[6- (trifluoromethyl)-3-pyridyl]pyrido[2,3-d]pyrimidine-4,7-quinone;

[0403] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0404] 8-(4-chloro-2, 6-difluoro-phenyl)-6- [(2R,4S)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl]-2, 3 - dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0405] 8-(4-chloro-2, 6-difluoro-phenyl)-6- [(2R,4S)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl]-2, 3 - dimethyl-pteridine-4, 7-quinone; 8-(4,4-difluorocyclohexyl)-6-[(lS,3R)-4,4-difluoro-3-(6-keto-l-methyl-3-pyridyl)cyclohexyl]- 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;

[0406] 5 -(4-chloro-2, 6-difluoro-phenyl)-7 - [(2R,4 S)-2- [6-(cyclopropoxy)-3 -pyridyl]tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;

[0407] 5 -(4-chloro-2, 6-difluoro-phenyl)-7 - [(2R,4 S)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-

[0408] 4-yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;

[0409] 4-(4-chloro-2,6-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0410] 4-(4-chloro-2,6-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0411] 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]pteridine-4, 7-dione;

[0412] 8-(4-chloro-2, 6-difluoro-phenyl)-2, 3 -dimethyl-6-[(2R,4S)-2-( 1 -cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pteridine-4, 7-dione;

[0413] 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pteridine-4, 7-dione;

[0414] 2,3-dimethyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)- 1 -bicyclo[ 1.1. l]pentanyl]pteridine-4, 7-dione;

[0415] 5-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;

[0416] 5-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;

[0417] 4-(4-chloro-2,6-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0418] 4-(4-chloro-2,6-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0419] 4-(4-chloro-2, 6-difluoro-phenyl)-6, 7-dimethyl-2-[(2R,4S)-2-( 1 -methyl-6-oxo-3 - pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0420] 6-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l .1. l]pentanyl]pteridine-4, 7-dione;

[0421] 6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l .1. l]pentanyl]pteridine-4, 7-dione;

[0422] 8-(2,2-difluorospiro[3.3]heptan-6-yl)-6-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-

[0423] 2, 3-dimethyl-pteridine-4, 7-dione; and 8-(2,2-difluorospiro[3.3]heptan-6-yl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pteridine-4, 7-dione.

[0424] In a preferred embodiment, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) or (II) is selected from:

[0425] 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrido[2,3- b]pyrazin-6-one;

[0426] 5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[2-( 1 -methylpyrazol-4-yl)morpholin-4-yl]pyrido [2,3- b]pyrazin-6-one;

[0427] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0428] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]pyrido[2,3-d]pyrimidine-4,7-quinone;

[0429] 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]pyrido[2,3- d]pyrimidine-4,7-quinone;

[0430] 2,3 -dimethyl-7-[2-( 1 -methylpyrazol-4-yl)morpholino] -5 -(3 ,3 , 3 -trifluoropropyl)pyrido [2,3- b]pyrazin-6-one;

[0431] 8-(4-chlorophenyl)-6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0432] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0433] 8-(4-chlorophenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0434] 6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-

[0435] 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0436] 8-(4,4-difhrorocyclohexyl)-6-[rac-(2R,4S)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-

[0437] 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0438] 4-(4-chlorophenyl)-6,7-dimethyl-2-[rac-(2S,4R)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0439] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[2,3- b]pyrazin-3-one;

[0440] 5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one; 5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[(2R,4 S)-2-( 1 -methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0441] 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[rac-(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0442] 5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[rac-(2R,4 S)-2-(2-methyl-4-pyridyl)tetrahydropyran- 4-yl]pyrido [2,3 -b]pyrazin-6-one;

[0443] 8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pteridine-4, 7-dione;

[0444] 5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0445] 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0446] 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0447] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4-yl]pyrazino[2,3- b]pyrazin-3-one;

[0448] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methylpyrazol-4-yl)oxan-4-yl]pyrazino[2,3- b]pyrazin-3-one;

[0449] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0450] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0451] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0452] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0453] 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2R)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0454] 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0455] 4-(4-chlorophenyl)-2- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6, 7-dimethyl- pyrazino[2,3-b]pyrazin-3-one;

[0456] 7- [2-( 1 -cyclopropylpyrazol-4-yl)morpholino] -5 -(4,4-difluorocyclohexyl)-2, 3 -dimethyl- pyrido[2,3-b]pyrazin-6-one; 7-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-5-(4,4-difluorocyclohexyl)-2,3- dimethylpyrido[2,3-b]pyrazin-6-one;

[0457] 7- [(2 S)-2-( 1 -cyclopropy lpyrazol-4-y l)morpholin-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;

[0458] 6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0459] 7 - [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;

[0460] 7 - [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;

[0461] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pteridine-4, 7-dione;

[0462] 4-(4-chloro-2-fluoro-phenyl)-2-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0463] 4-(4-chloro-2-fluoro-phenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-

[0464] 6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0465] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0466] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0467] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran- 4-yl]pyrazino[2,3-b]pyrazin-3-one;

[0468] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran- 4-yl]pyrazino[2,3-b]pyrazin-3-one;

[0469] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0470] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0471] 2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0472] 2-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0473] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pteridine-4, 7 -dione; 8-(4-chlorophenyl)-6- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2, 3 -dimethyl- pteridine-4, 7 -dione;

[0474] 8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-

[0475] 4-yl]pteridine-4, 7-dione;

[0476] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0477] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0478] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0479] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0480] 5-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0481] 2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0482] 2-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0483] 6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpteridine-4, 7-dione;

[0484] 6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpteridine-4, 7-dione;

[0485] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0486] 4-(4, 4-difluorocyclohexyl)-2- [(2 S ,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0487] 4-(4, 4-difluorocyclohexyl)-2- [(2R,4 S)-2-(2-methoxypyridin-4-yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0488] 4-(4, 4-difluorocyclohexyl)-2- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0489] 4-(4, 4-difluorocyclohexyl)-2- [(2 S ,4R)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0490] 6- [rac-(2R,4 S)-2-( 1 -cyclopropylpy razol-4-y l)tetrahydropyran-4-y 1] -2,3 -dimethyl-8- [3 - (trifluoromethyl)- 1 -bicyclo[ 1.1. l]pentanyl]pyrido[2,3-d]pyrimidine-4,7-quinone; 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l.l.l]pentanyl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0491] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l.l.l]pentanyl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0492] 8-(4, 4-difluorocyclohexyl)-6- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpteridine-4, 7-dione;

[0493] 4-(4-chlorophenyl)-2- [(2 S ,4R)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0494] 4-(4-chlorophenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0495] 4-(4-chlorophenyl)-2- [(2 S ,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0496] 4-(4-chlorophenyl)-2-[(2R,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0497] 8-(4-chloro-2-fluoro-phenyl)-6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0498] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0499] 8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0500] 5 -(4-chloro-2, 6-difluorophenyl)-7 - [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-b]pyrazin-6-one;

[0501] 8-(4,4-difluorocyclohexyl)-6-[(2S,4R)-2-(6-methoxy-3-pyridyl)-2-methyl-tetrahydropyran-4-yl]- 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0502] 5 -(4-chloro-2-fluorophenyl)-7- [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-b]pyrazin-6-one;

[0503] 5 -(4-chloro-2-fluorophenyl)-7- [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-b]pyrazin-6-one;

[0504] 8-(4-chlorophenyl)-6-[(2S,4R)-2-(6-methoxypyridin-3-yl)oxan-4-yl]-2,3-dimethylpyrido[2,3- d] pyrimidine-4, 7- dione ;

[0505] 8-(4-chlorophenyl)-6- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2, 3 -dimethylpyrido [2,3- d] pyrimidine-4, 7- dione ;

[0506] 8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione; 6- [(2 S,4R)-2-( 1 -cyclopropyl-6-oxopyridin-3 -yl)oxan-4-yl] -8-(4, 4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0507] 6-[(2R,4S)-2-(l-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0508] 8-(4, 4-difluorocyclohexyl)-6- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0509] 6-[2-(l-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0510] 8-(4-chlorophenyl)-6- [2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl]-2, 3 -dimethyl- pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0511] 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0512] 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0513] 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0514] 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0515] 8-(4, 4-difluorocyclohexyl)-6- [(2 S ,4R)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0516] 8-(4-chlorophenyl)-6-[(2S,4R)-2-(l-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0517] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0518] 6-[2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0519] 6- [(2 S,4R)-2-( 1 -cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl] -8-(4, 4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0520] 6-[(2R,4S)-2-(l-cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;

[0521] 2-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-4-(2,2-difluorospiro[3.3]heptan-6-yl)-6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;

[0522] 2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-4-(2,2-difluorospiro[3.3]heptan-6-yl)-6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one; 8-(4, 4-difluorocyclohexyl)-6- [2-(2-keto- 1 -methyl-4-pyridyl)tetrahydropyran-4-yl] -2, 3 -dimethyl- pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0523] 8-(4 -difluorocyclohexyl)-6- [2-(6-keto- 1 -methyl-3 -pyridyl)tetrahydropyran-4-yl]-2, 3 -dimethyl- pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0524] 8-(4,4-difluorocyclohexyl)-6-[rac-(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]- 2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;

[0525] 8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0526] 6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,2-difluorospiro[3.3]heptan-6-yl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0527] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,2-difluorospiro[3.3]heptan- 6-yl)-2, 3 -dimethyl-pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0528] 5 -(4, 4-difluorocyclohexyl)-7 - [(2 S ,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0529] 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0530] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrido [2, 3 -d]pyrimidine-4, 7-quinone;

[0531] 4-(4-chloro-2,6-difluoro-phenyl)-2-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0532] 5 -(4, 4-difluorocyclohexyl)-7 - [(2 S ,4R)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one;

[0533] 5 -(4-chlorophenyl)-7 - [(2R,4 S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -2, 3 -dimethyl- pyrido[2,3-b]pyrazin-6-one; and

[0534] 5 -(4-chlorophenyl)-7 - [(2 S ,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -2, 3 -dimethyl- pyrido [2,3 -b]pyrazin-6-one .

[0535] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0536] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[2,3- b]pyrazin-3-one; 5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0537] 5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[(2R,4 S)-2-( 1 -methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;

[0538] 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrazino[2,3-b]pyrazin-3-one;

[0539] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4-yl]pyrazino[2,3- b]pyrazin-3-one;

[0540] 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;

[0541] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0542] 7 - [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;

[0543] 4-(4-chloro-2-fluoro-phenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-

[0544] 6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0545] 2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-(4,4-difluorocyclohexyl)-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;

[0546] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pteridine-4, 7 -dione;

[0547] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0548] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;

[0549] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l. l.l]pentanyl]pyrido[2,3-d]pyrimidine-4, 7-dione;

[0550] 5 -(4-chloro-2, 6-difluorophenyl)-7 - [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-b]pyrazin-6-one; and

[0551] 5 -(4-chloro-2-fluorophenyl)-7- [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-b]pyrazin-6-one.

[0552] In a particularly preferred embodiment, the present invention provides a compound of formula

[0553] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone.

[0554] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- y 1] pyrazino [2,3 -b] pyrazin-3 -one .

[0555] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one.

[0556] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one.

[0557] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4- yl)oxan-4-yl]pyrazino[2,3-b]pyrazin-3-one.

[0558] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4- yl] pyrazino [2,3 -b] pyrazin-3 -one .

[0559] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone.

[0560] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxopyridin-3- yl)oxan-4-yl]pyrido[2,3-d]pyrimidine-4, 7-dione. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-5-(4,4-difluorocyclohexyl)- 2,3 -dimethylpyrido [2,3 -b]pyrazin-6-one.

[0561] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 4-(4-chloro-2-fluoro-phenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one.

[0562] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-(4,4- difluorocyclohexyl)-6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one.

[0563] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2,3-dimethyl-pteridine-4, 7-dione.

[0564] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one.

[0565] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one.

[0566] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-8-[3- (trifluoromethyl)-l -bicyclo [1.1. l]pentanyl]pyrido[2,3-d]pyrimidine-4, 7-dione.

[0567] In a particularly preferred embodiment, the present invention provides a compound of formula

[0568] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 5-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4- yl] -2, 3 -dimethylpyrido [2,3 -b]pyrazin-6-one.

[0569] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 5-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]- 2,3 -dimethylpyrido [2,3 -b]pyrazin-6-one.

[0570] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[2,3-b]pyrazin-6-one.

[0571] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[2,3-b]pyrazin-6-one.

[0572] In a particularly preferred embodiment, the present invention provides a compound of formula

[0573] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 4-(4-chloro-2-fhioro-phenyl)-6,7-dimethyl-2-[2-(l-methylpyrazol-4-yl)morpholin- 4-yl]pyrazino[2,3-b]pyrazin-3-one;

[0574] In a particularly preferred embodiment, the present invention provides a compound of formula

[0575] (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (II) is 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]pyrido [2,3 -d]pyrimidine-4, 7-quinone.

[0576] In a particularly preferred embodiment, the present invention provides a compound of formula (II) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (II) 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]pyrido [2,3 -d]pyrimidine-4, 7-quinone.

[0577] In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) or (II) as described herein. In a further particular embodiment, the present invention provides compounds according to formula (I) or (II) as described herein as free bases. In some embodiments, the compounds of formula (I) or (II) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) or (II) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) or (II) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H,nC,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Certain isotopically-labeled compounds of formula (I) or (II), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) or (II) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0578] Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Thus, the present invention encompasses compounds of formula (I) or (II) wherein one or more hydrogen atoms, preferrably 1-3 hydrogen atoms have been replaced by deuterium.

[0579] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) or (II) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0580] Processes of Manufacturing

[0581] The preparation of compounds of formula (I) or (II) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary. If one of the starting materials, intermediates or compounds of formula (I) or (II) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0582] If starting materials or intermediates contain stereogenic centers, compounds of formula (I) or (II) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) or (II) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I) or (II).

[0583] A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) or (II) - insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0584] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0585] In more detail, the compounds of formula (I) or (II) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0586] If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.

[0587] The following abbreviations are used in the present text: dba = dibenzylideneacetone, HPLC = high-performance liquid chromatography, DMF = N,N- dimethylformamide, MS = mass spectrometry, ESI = electrospray ionization, xantphos = (9,9- Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane), Me = methyl, FA = formic acid, NMP = N-methyl-2-pyrrolidone, DMSO = dimethylsulfoxide, tBuXPhos = 2-Di-tert-butylphosphino- 2',4',6'-triisopropylbiphenyl, G3 = generation 3, DCM = dichloromethane, Et = ethyl, Ac =acetyl, EtOAc = ethylacetate, aq = aqueous, eq = equivalence, DIEA = diisopropylethylamine, rt = room temperature, Ar = argon, sat. = saturated, IPA = Isopropyl alcohol, MeOH = Methanol,1H = proton, A = angstrom, CAS = Chemical Abstracts Service registry number, DIPEA = N,N- Diisopropylethylamine, DMEM = Dulbecco's modified eagle medium, ECso = half maximal effective concentration, Ex.= example, FBS = fetal bovine serum, HATU = hexafluorophosphate azabenzotriazole tetramethyl uranium, HBTU = hexafluorophosphate benzotriazole tetramethyl uranium, HEK = human embryonic kidney, m / z = mass-to-charge ratio, neg. = negative, pos. = positive, NMR = nuclear magnetic resonance spectroscopy, RP = reverse phase, SFC = supercritical fluid chromatography, TLC = thin layer chromatography. The present compounds of formula I, where Xi = CH, may be prepared by the route depicted in Scheme 1. A di-halogenated pyrazine derivative 1 (Wi, W2 = Cl, Br, I) is reacted with a suitable amine R2-NH2 to generate the amino pyrazine derivative 2. This may be carried out under SNAT conditions (e.g. heating in the presence of a base, such as ISfeCCh), or under palladium-catalyzed cross-coupling conditions (e.g. Buchwald reaction). Suzuki reaction with an alkene boronate 3 and cyclization generates the core structure 4 (if the E-alkene derivative is used, a nucleophilic catalyst such as sodium methanethiolate may be added to promote cyclization). Halogenation (e.g. bromination, using NBS) generates 5 (W = Br, I).

[0588] The six-membered ring may be installed by means of a metal-catalyzed cross-coupling reaction. Where A = N, the substituted morpholine may be installed via a Buchwald cross-coupling (e.g. using a palladium catalyst such as Pd2dba3 / Xantphos). Where A = CH, the tetrahydropyran unit may be installed via Suzuki reaction with a suitable alkene-boronic acid or ester 6, to generate an alkene 7, which was then subjected to hydrogenation (e.g. using RI1 / AI2O3 or PtCh and H2 gas). The required alkene-boronic esters (6) may be generated using literature techniques, e.g. via Miyaura-borylation of a trifluoromethanesulfonate derivative, which is in turn generated via a Prins-type cyclization.

[0589] Scheme 1 Compounds of formula II, where Xi = CH, may be prepared by the route depicted in Scheme 2. A chloro-substituted pyrimidin-4-one (8) can be reacted with a suitable amine R2-NH2 in the presence of a base such as DIEA, to generate 9. Halogenation (e.g. bromination using NBS) generates 10 (W = Br, I). Suzuki reaction with an alkene boronate 11 with in-situ cyclization promoted by addition of a nucleophilic catalyst such as sodium methanethiolate provides core structure 12, which can again be halogenated (e.g. bromination using NBS) to generate 13 (W = Br, I). The six-membered ring unit can then be installed via metal-catalyzed cross-coupling via either a 1 or 2 step process, as detailed above. Scheme 2

[0590] Alternatively, compounds of formula I, where X1= CH, may be generated as depicted in Scheme 3. A di-amino pyridine derivative 16 undergoes a condensation reaction with diketone 17 to form 18, which can then undergo deprotection (e.g. AcOH / HBr, heat) to release the free pyridone 19. The six-membered ring unit can then be installed via metal-catalyzed cross-coupling via either a 1 or 2 step process, as detailed above, to form 20. The R2group can then be installed via Chan-

[0591] Lam type coupling, alkylation, or Mitsunobu reaction.

[0592] 19 20

[0593] Scheme 3

[0594] Alternatively, compounds of formula II, where X1= N, may be generated as depicted in Scheme 4. Starting from pyrazine 21, the six-membered ring unit can be installed via metal-catalyzed cross-coupling via either a 1 or 2 step process, as detailed above to generate 22. Conversion of the ester to the amide (e.g. heating with MeNH2 in MeOH) gave 23, which could be condensed with an orthoester derivative 24 to give 25. Deprotection of the methoxy group (e.g. using NaSMe) released the free pyrazinone structure 26, which could be further functionalized to install the R2group (e.g. using Chan-Lam type conditions, to install an aryl group, or alkylation or Mitsunobu conditions)

[0595] Scheme 4 Alternatively, compounds of formula I, where X1= N, may be generated as depicted in Scheme

[0596] 5. A di-halogenated pyrazine derivative 1 (Wi, W2 = Cl, Br, I) is converted into amine 27 (e.g. by heating in MeOH / NHs). Reaction with a suitable amine R2-NH2 under Buchwald conditions (e.g. tBuXPhos-Pd-G3 / tBuXPhos) gave 28, which could be condensed with a suitable keto-ester 29 (e.g. by heating in AcOH) to give the target compound.

[0597] Scheme 5

[0598] The required ketoesters 29 can be generated as depicted in Scheme 6. A pyranone derivative 30 is reacted with a suitable HWE reagent to give target compound 31, which is hydrolyzed under basic conditions, for example in the presence of K2CO3. 30

[0599] Scheme 6

[0600] Alternatively, compounds of formula I, where X1= N, may be generated as depicted in Scheme 6. A di-halogenated pyrazine derivative 1 (Wi, W2 = Cl, Br, I) is converted into amine 27 (e.g. by heating in MeOH / NHs). Reaction with a suitable amine R2-NH2 under Buchwald conditions (e.g. tBuXPhos-Pd-G3 / tBuXPhos) gave 28, which can be condensed with oxalyl chloride to give target compound 32. Chlorination with a reagent like POCI3 gives 33. The six-membered ring unit can be installed via metal-catalyzed cross-coupling via either a 1 or 2 step process, as detailed above. Scheme 7

[0601] Alternatively, compounds of formula II, where X1= N, may be generated as depicted in Scheme 8. A pyrimididione with structure 34 is nitrated (e.g. using conditions such as HNO3, H2SO4) to give 35, which could be converted to 36 using reagents such as POCI3. Regioselective methylation under suitable conditions (e.g. Mel, NaH) gave N-methyl pyrimidinone, 37. Reaction with a suitable amine R2-NH2 under Buchwald conditions (e.g. tBuXPhos-Pd-G3 / tBuXPhos) or SNAT gave 38 which could be reduced to amine 39 (e.g. using Pd / C, H2). Condensation of amine 39 with a suitable keto-ester 29 (e.g. by heating in AcOH), gave the target compounds.

[0602]

[0603] Scheme 8

[0604] Alternatively, compounds of formula II, where X1= N, may be generated as depicted in Scheme 9. Intermediate 39 may be reacted with (COC1)2 to generate structures of formula 40, which when reacted with POCI3, gavecompounds with structure 41. The six-membered ring unit can be installed via metal-catalyzed cross-coupling via either a 1 or 2 step process, as detailed above (see e.g. Scheme 2).

[0605] Scheme 9 In one aspect, the present invention provides a process of manufacturing a compound of formula (I) or (II) described herein, or a pharmaceutically acceptable salt thereof, wherein the process is as described in any one of schemes 1 to 9.

[0606] In one aspect, the present invention provides a compound of formula (I) or (II) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein.

[0607] TREM2 Agonistic Activity

[0608] Compounds of the present invention are TREM2 agonists. Thus, in one aspect, the present invention provides the use of compounds of formula (I) or (II) as described herein for restoring the function of human TREM2 in a subject in need thereof.

[0609] In a further aspect, the present invention provides compounds of formula (I) or (II) as described herein for use in a method of restoring the function of human TREM2 in a subject in need thereof.

[0610] In a further aspect, the present invention provides the use of compounds of formula (I) or (II) as described herein for the preparation of a medicament for restoring the function of human TREM2 in a subject in need thereof.

[0611] In a further aspect, the present invention provides a method for restoring the function of human TREM2 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) or (II) as described herein to the subject.

[0612] TREM2 agonist potency of the compounds of formula (I) or (II) according to the invention was measured using a HEK cell line expressing human TREM2 and DAP12. Upon binding of small molecule ligands to the TREM2 receptor, Syk kinase is recruited and activated by DAP12. The resulting increased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit.

[0613] To perform the assay, frozen HEK293-TREM2 / DAP12 cells were thawed, adjusted and plated by using Certus at 20,000 cells per well in a 384 well plate, in 10 pL of DMEM media without Phenolred and supplemented with 5% FBS.

[0614] Compounds in dose response (1 :3) were diluted in DMSO (highest concentration lOrnM) and added to the cells from a Low Dead Volume plate using the ECHO (0-20 uM), diluting 500x (20 nL in 10 pl cell suspension; highest concentration 20uM, DMSO concentration 0.2% in all wells). Neutral (DMSO) and stimulator (I M tool compound) controls were also added.

[0615] Cells were incubated for 30 minutes at 37°C, 5% CO2 and 95% humidity. After compound addition and incubation, 2.5pL of lysis buffer was added by using the Certus. After a quick spin, plates were shaken for 30 minutes at 450 RPM, at room temperature and in the dark. After complete lysis, AlphaLisa reagents were added by Certus to the lysate, and fluorescence intensity was measured using a Pherastar plate reader (Excitation: 680nm / Emission: 615nm). EC50 values were calculated by using Genedata Screener, normalized to DMSO and 100% activity to the tool compound. TREM2 agonistic potencies of the compounds of formula (I) or (II) according to the invention as measured in the assay described above are presented in Table 1.

[0616] Table 1

[0617] Using the Compounds of the Invention

[0618] In one aspect, the present invention provides a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, as described herein for use as a therapeutically active substance.

[0619] In a further aspect, the present invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0620] In a further aspect, the present invention provides a compound of formula (I) or (II) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.

[0621] In a further aspect, the present invention provides the use of a compound of formula (I) or (II) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.

[0622] In a further aspect, the present invention provides the use of a compound of formula (I) or (II) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.

[0623] In one embodiment, said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

[0624] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Parkinson’s disease.

[0625] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is rheumatoid arthritis.

[0626] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Alzheimer’s disease.

[0627] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis.

[0628] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia.

[0629] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis.

[0630] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease.

[0631] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke.

[0632] Pharmaceutical Compositions and Administration

[0633] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) as described herein and a therapeutically inert carrier.

[0634] In one embodiment, there is provided a pharmaceutical composition according to Example 187 or 188.

[0635] The compounds of formula (I) or (II) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

[0636] The compounds of formula (I) or (II) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, com starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0637] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0638] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc. Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0639] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0640] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosityincreasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0641] The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.

[0642] Examples

[0643] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0644] In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.

[0645] The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers. According to the Cahn-Ingold- Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration. For the compounds described in the present patent application, the absolute stereochemistry was assigned arbitrarily.

[0646] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise. The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1.

[0647] Example 1

[0648] 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrido[2,3- b]pyrazin-6-one

[0649] Step a) 3-bromo-N-(4-chlorophenyl)-5, 6-dimethyl-pyrazin-2 -amine

[0650] Into a degassed mixture of 2,3-dibromo-5,6-dimethyl-pyrazine (CAS: 98142-06-4) (750 mg, 2.82 mmol), 4-chloroaniline (360 mg, 2.82 mmol) and cesium carbonate (1840 mg, 5.64 mmol) in 1,4-Dioxane (30 mL), xantphos (163 mg, 0.28 mmol) and Pd2(dba)s (258 mg, 0.28 mmol) were added. The resulting mixture was stirred at 25 °C for 120 h, filtered and evaporated. The residue was purified by HPLC (PHENYL SMB 100-5 column, using H2O / MeCN / 0.1% formic acid) to give the title compound (180 mg, 0.58 mmol, 19% yield) as a yellow solid. MS (ESI): m / z = 312.0 / 314.0 [M+H]+

[0651] Step b) 5-(4-chlorophenyl)-2, 3-dimethyl-pyrido[2, 3-b ]pyrazin-6-one

[0652] Into a degassed mixture of 3-bromo-N-(4-chlorophenyl)-5,6-dimethyl-pyrazin-2-amine (75.0 mg, 0.24 mmol), ethyl (Z)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-2-enoate (CAS: 219489-13-1) (108 mg, 0.48 mmol) and potassium carbonate (166 mg, 1.2 mmol) in DMF (2 mL), Pd(OAc)2 (5.37 mg, 0.02 mmol) was added. The resulting mixture was stirred at 100 °C for 16 h and filtered. The residue was purified by HPLC (PHENYL SMB 100-5 column, using H2O / MeCN / 0.1% formic acid) to give the title compound (27.0 mg, 0.09 mmol, 37% yield) as a white solid. MS (ESI): m / z = 286.2 / 288.2 [M+H]+

[0653] Step c) 7-bromo-5-( 4-chlorophenyl)-2, 3-dimethyl-pyrido[ 2,3-b ]pyrazin-6-one

[0654] Into a solution of 5-(4-chlorophenyl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one (27.0 mg, 0.09 mmol) in DMF (1 mL), N-bromosuccinimide (50.5 mg, 0.28 mmol) was added. The resulting mixture was stirred at 90 °C for 3 h and purified by HPLC (XB ridge BEH Cl 8 column, using EEO / MeOEl) to give the title compound (17.0 mg, 0.05 mmol, 47% yield) as a yellow solid. MS (ESI): m / z = 364.0 / 366.0 [M+H]+

[0655] Step d) 5-(4-chlorophenyl)-2, 3-dimethyl- 7-[ 2-(l -methylpyrazol-4-yl)morpholin-4-yl ]pyrido[ 2,3- b ]pyrazin-6-one

[0656] Into a degassed mixture of 7-bromo-5-(4-chlorophenyl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6- one (17.0 mg, 0.05 mmol), 2-(l-methylpyrazol-4-yl)morpholine (CAS: 1375963-52-2) (8.6 mg, 0.05 mmol) and cesium carbonate (30.4 mg, 0.09 mmol) in 1,4-Dioxane (1 mL), Pd2(dba)s (4.3 mg, 0.1 eq) and xantphos (2.7 mg, 0.1 eq) were added. The resulting mixture was stirred at 100 °C for 3 h. The reaction mixture was filtered, evaporated and the residue was purified by HPLC (MeCN / H2O / 0.1% formic acid) to give the title compound (2.3 mg, 0.01 mmol, 10% yield) as a yellow solid. MS (ESI): m / z = 451.2 / 453.2 [M+H]+ Example 2

[0657] 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholin-4- yl] py rido [2,3-b] pyrazin-6-one

[0658] Step a) 3-chloro-N-(4,4-difluorocyclohexyl)-5, 6-dimethyl-pyrazin-2-amine

[0659] A mixture of 2,3-dichloro-5,6-dimethyl-pyrazine (350 mg, 1.98 mmol), 4,4- difluorocyclohexylamine hydrochloride (407 mg, 2.37 mmol) and sodium carbonate (629 mg, 5.93 mmol) in NMP (10 mL) was stirred at 190 °C for 42 h and filtered. The mother liquor was evaporated and purified by HPLC (Chromatorex 18 SNB100-5T column, using H2O / MeOH) to give the title compound (285 mg, 1.03 mmol, 50% yield) as a yellow solid. MS (ESI): m / z = 276.2 / 278.2 [M+H]+

[0660] Step b) 5-(4, 4-difluorocyclohexyl)-2, 3-dimethyl-pyrido[ 2,3-b ]pyrazin-6-one

[0661] Into a degassed mixture of 3-chloro-N-(4,4-difluorocyclohexyl)-5,6-dimethyl-pyrazin-2-amine (80.0 mg, 0.29 mmol), ethyl (Z)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)prop-2-enoate (CAS: 219489-13-1) (131 mg, 0.58 mmol) and potassium carbonate (200 mg, 1.45 mmol) in DMF (2 mL), Pd(OAc)2 (6.5 mg, 0.03 mmol) was added. The resulting mixture was stirred at 100 °C for 16 h and filtered. The residue was purified by HPLC (Chromatorex 18 SMB 100-ST column, using H2O / MeCN / 0.1% formic acid) to give the title compound (21.0 mg, 0.07 mmol, 23% yield) as an orange solid. MS (ESI): m / z = 294.2 [M+H]+ Step c) 7-bromo-5-( 4, 4-difluorocyclohexyl)-2, 3-dimethyl-pyrido[ 2,3-b ]pyrazin-6-one

[0662] Into a solution of 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one (9.0 mg, 0.03 mmol) in DMF (1 mL), N-bromosuccinimide (7.1 mg, 0.04 mmol) was added. The resulting mixture was stirred at 90 °C for 2 h and purified by HPLC (XB ridge BEH Cl 8 column, using H2O / MeOH / 0.1% NH4OH) to give the title compound (5.0 mg, 0.01 mmol, 42% yield) as a yellow solid. MS (ESI): m / z = 372.0 / 374.0 [M+H]+

[0663] Step d) 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholin-4- yl ]pyrido[ 2,3-b ]pyrazin-6-one

[0664] Into a degassed mixture of 7-bromo-5-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3- b]pyrazin-6-one (11.0 mg, 0.03 mmol), 2-(l-methylpyrazol-4-yl)morpholine (9.88 mg, 0.06 mmol) and xantphos (1.7 mg, 0.1 eq) in 1,4-Dioxane (1 mL), Pd2(dba)s (2.7 mg, 0.1 eq) was added. The resulting mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered, evaporated, and the residue was purified by HPLC (XB ridge BEH Cl 8 column, using H2O / MeOH / NH4OH) to give the title compound (5.0 mg, 0.01 mmol, 36% yield) as a yellow solid. MS (ESI): m / z = 459.2 [M+H]+

[0665] Example 3

[0666] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[2-(l-methylpyrazol-4-yl)morpholin-4- yl] pyrazino [2,3-b] pyrazin-3-one

[0667] Step a) N3-(4-chloro-2-fluoro-phenyl)-5, 6-dimethyl-pyrazine-2, 3-diamine

[0668] To a mixture of 3-chloro-5,6-dimethyl-pyrazin-2-amine (1.0 g, 5.08 mmol), 4-chloro-2- fluoroaniline (813 mg, 5.58 mmol) in DMSO (4 mL), tBuXPhos (216 mg, 0.51 mmol) and tBuXPhos Pd G3 (403 mg, 0.51 mmol) were added under argon. The reaction was stirred at rt for 18 h. The reaction mixture was diluted with water (40 ml) and extracted with DCM (3*40 ml). The combined organic layers were washed with water (2*30 ml) and dried with Na2SO4. The solvent was removed in vacuo. The crude was purified by column chromatography to give the title compound (1.02 g, 3.83 mmol, 48% yield). MS (ESI): m / z = 267.2 [M+H]+

[0669] Step b) 4-(4-chloro-2-fluoro-phenyl)-6, 7-dimethyl-lH-pyrazino[2,3-b]pyrazine-2, 3-dione

[0670] Oxalyl chloride (0.11 mL, 1.25 mmol) was dissolved in 1,2-Dichlorobenzene (10.5 mL), the solution was heated to 60 °C and N3-(4-chloro-2-fluoro-phenyl)-5,6-dimethyl-pyrazine-2,3- diamine (350 mg, 1.14 mmol) was added in portions. The reaction was heated to 130 °C and stirred for 1 h. The reaction was passed through silica and eluted with petroleum ether. Then, the product was eluted with MeOH, the solvent was removed in vacuo to give the title compound (0.45 g, 1.4 mmol, 78% yield). MS (ESI): m / z = 321.0 [M+H]+

[0671] Step c) 2-chloro-4-(4-chloro-2-fluoro-phenyl)-6, 7-dimethyl-pyrazino[2,3-b]pyrazin-3-one

[0672] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-lH-pyrazino[2,3-b]pyrazine-2, 3-dione (450 mg, 0.94 mmol) was combined with phosphorus oxychloride (10 mL, 108 mmol) and the reaction was heated to 100 °C and stirred for 1 h. The reaction was concentrated in vacuo and the residue was triturated with ice (~80 g) and NaHCCh (3 g). An aqueous solution was extracted with EtOAc (4*50 ml) and washed with brine (1*50 ml). The combined organic fractions were dried with Na2SO4 and concentrated in vacuo to give the title compound (0.4 g, 1.18 mmol, 87% yield) MS (ESI): m / z = 339.2 [M+H]+

[0673] Step d) 4-(4-chloro-2-fluoro-phenyl)-6, 7-dimethyl-2-[2-(l-methylpyrazol-4-yl)morpholin-4- yl ]pyrazino[ 2,3-b ]pyrazin-3-one

[0674] To a mixture of 2-chloro-4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3- one (0.4 g, 0.81 mmol), 2-(l-methylpyrazol-4-yl)morpholine;dihydrochloride (292 mg, 1.22 mmol) and cesium carbonate (793 mg, 2.43 mmol), xantphos (47.0 mg, 0.08 mmol) and Pd2(dba)s (74.3 mg, 0.08 mmol) were added under argon. The reaction was stirred at 100 °C for 18 h. Water (30 ml) was added and the solution was extracted with EtOAc (3*30 ml) combined organic fractions were washed with brine (1 *30 ml), dried with Na2SO4 and evaporated in vacuo. The crude was purified by HPLC (Chromatorex SMB Cl 8 column, using EEO / MeCN) to give the title compound (100 mg, 0.21 mmol, 25% yield). MS (ESI): m / z = 470.2 [M+H]+

[0675] Example 4

[0676] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]pyrido[2,3-d]pyrimidine-4,7-quinone

[0677] Step a) 6-chloro-2,3-dimethyl-pyrimidin-4-one

[0678] To a solution of 6-chloro-2-methyl-pyrimidin-4-ol (CAS: 17551-52-9)(2.6 g, 18.0 mmol) in N,N-dimethylformamide (130 mL) were added K2CO3 (4.97 g, 36.0 mmol) and iodomethane (3.1 g, 1.35 mL, 21.6 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel 0-100% EtOAc in n-Heptane) to provide the title compound (2.2 g, 75.4%) as white solid. MS (ESI): m / z = 159.0 [M+H]+

[0679] Step b) 6-[ ( 4, 4-difluorocyclohexyl)amino ]-2, 3-dimethyl-pyrimidin-4-one

[0680] In a pressure flask, 6-chloro-2,3-dimethyl-pyrimidin-4-one (1 g, 6.3 mmol), DIEA (3.3 g, 4.4 mL, 25.2 mmol) and (4,4-difluorocyclohexyl)amine (2.6 g, 2.4 mL, 18.9 mmol) were combined with ethanol (30 mL) to give a yellow solution. The reaction mixture was stirred at 130 °C for 2 hours. 6-chloro-2,3-dimethyl-pyrimidin-4-one (1 g, 6.31 mmol) and DIEA (3.26 g, 4.41 mL, 25.22 mmol) were added again. The reaction mixture was stirred at 130 °C for 2 hours. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography eluting from 0 % to 15 % MeOH in DCM to afford the title compound (1.29 g, 40%) as a yellow foam. MS (ESI): m / z = 258.2 [M+H]+

[0681] Step c) 5-bromo-6-[ ( 4, 4-difluorocyclohexyl)amino ]-2, 3-dimethyl-pyrimidin-4-one

[0682] 6-[(4,4-difluorocyclohexyl)amino]-2,3-dimethyl-pyrimidin-4-one (1.3 g, 5.01 mmol) was suspended in acetonitrile (40 mL) and N-bromosuccinimide (981.6 mg, 5.52 mmol) was added. The reaction mixture was stirred at rt for 1 hour. The reaction mixture was diluted with sat. NaHCCh-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (MeOH in DCM 0-10%) to afford the title compound (969 mg, 55%) as a white foam. MS (ESI): m / z = 338.1 [M+H]+

[0683] Step d) (E)-3-[ 4- [(4, 4-difluorocyclohexyl)amino ]-6-keto-l, 2-dimethyl-pyrimidin-5-yl acrylic acid ethyl ester

[0684] To a solution of 5-bromo-6-[(4,4-difluorocyclohexyl)amino]-2,3-dimethyl-pyrimidin-4-one (850 mg, 2.43 mmol) in N,N-dimethylformamide (25 mL) was added at 22 °C (E)-3-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)acrylic acid ethyl ester (823.1 mg, 3.64 mmol) followed by K2CO3 (1.01 g, 7.28 mmol). The mixture was purged and backfilled with argon (x3) followed by addition of [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), DCM adduct (198.2 mg, 242.7 pmol). The reaction mixture was warmed to 100 °C for 3 hours. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with EtOAc in Heptane 0-100% to afford the title compound (605 mg, 67%) as light brown oil. MS (ESI): m / z = 356.2 [M+H]+

[0685] Step e) 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7 -quinone

[0686] (E)-3-[4-[(4,4-difluorocyclohexyl)amino]-6-keto-l,2-dimethyl-pyrimidin-5-yl]acrylic acid ethyl ester (450 mg, 1.27 mmol) was dissolved in ethanol (9 mL) and sodium methanethiolate (97.6 mg, 1.39 mmol) was added. The reaction mixture was stirred at 23 °C for 5 days. The reaction mixture was diluted with sat. NaHCCh-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over ISfeSCU and concentrated to dryness. The crude material was purified by flash chromatography on silica gel using MeOH in DCM 0-10% to afford the title compound (327 mg, 81%) as an off-white solid. MS (ESI): m / z = 310.1 [M+H]+

[0687] Step f) 6-bromo-8-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7 -quinone

[0688] 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (256 mg, 802.8 pmol) was dissolved in N,N-dimethylformamide (5 mL) and N-bromosuccinimide (171.5 mg, 963.4 pmol) was added. The reaction mixture was stirred at rt for 4 hours. The reaction mixture was diluted with sat. NaHCCE-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel using MeOH in DCM 0-10% to afford the title compound (308 mg, 99%) as a light yellow solid. MS (ESI): m / z = 390. 1 [M+H]+

[0689] Step g) 8-(4, 4-difluorocyclohexyl)-2, 3 -dime thy 1-6- [ (2S)-2-( 1 -methylpyrazol-4- yl)morpholino ]pyrido[ 2, 3-d]pyrimidine-4, 7 -quinone

[0690] 6-bromo-8-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (50 mg, 128.8 pmol) was suspended in 1,4-dioxane (1 mL) and (2S)-2-(l-methylpyrazol-4-yl)morpholine (25.8 mg, 154.6 pmol), cesium carbonate (125.9 mg, 386.4 pmol) were added at rt. The mixture was degassed with argon before Pd2(dba)s (5.9 mg, 6.44 pmol) and xantphos (7.4 mg, 12.9 pmol) were added. The reaction was stirred for 2 hours at 100 °C. The reaction mixture was diluted with sat. NaHCOs- solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over ISfeSCU and concentrated to dryness. The crude material was purified by prep HPLC (Phenomenex Gemini NX Cl 8 column, using MeCN / H2O / 0.1% NEts) to afford the title compound (2.8 mg, 4.4%) as white lyophilized powder. MS (ESI): m / z = 475.2 [M+H]+

[0691] Example 5

[0692] 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]pyrido[2,3- d] pyrimidine-4,7-quinone

[0693] Step a) 6-(4-chloroanilino)-2, 3-dimethyl-pyrimidin-4-one

[0694] 6-chloro-2,3-dimethyl-pyrimidin-4-one (Example 4-Step a)(1.5 g, 9.5 mmol) was suspended in 1,4-dioxane (50 mL) and 4-chloroaniline (1.45 g, 11.4 mmol), cesium carbonate (9.25 g, 28.4 mmol) were added at rt. The mixture was degassed with argon before Pd2(dba)s (433.1 mg, 472.9 pmol) and xantphos (547.3 mg, 945.8 pmol) were added. The reaction was stirred for 2 hours at 100 °C. The reaction mixture was diluted with sat. NaHCCE-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel using MeOH in DCM 0-10% to afford the title compound (1.19 g, 35%) as a light yellow solid. MS (ESI): m / z = 250. 1 [M+H]+

[0695] Step b) 5-bromo-6-(4-chloroanilino)-2, 3-dimethyl-pyrimidin-4-one

[0696] 6-(4-chloroanilino)-2,3-dimethyl-pyrimidin-4-one (1.19 g, 4.77 mmol) was suspended in acetonitrile (35 mL) and N-bromosuccinimide (933.02 mg, 5.24 mmol) was added. The reaction mixture was stirred at rt for 1 hour. The reaction mixture was diluted with sat. NaHCCh-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel using MeOH in DCM (0-10%) to afford the title compound (880 mg, 52%) as a light yellow solid. MS (ESI): m / z = 330.0 [M+H]+

[0697] Step c) (E)-3-[4-(4-chloroanilino)-6-keto-l,2-dimethyl-pyrimidin-5-yl] acrylic acid ethyl ester

[0698] To a solution of 5-bromo-6-(4-chloroanilino)-2,3-dimethyl-pyrimidin-4-one (880 mg, 2.68 mmol) in N,N-dimethylformamide (25 mL) was added at 22 °C (E)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)acrylic acid ethyl ester (908.2 mg, 4.02 mmol) followed by K2CO3 (1.11 g, 8.03 mmol). The mixture was purged and backfilled with argon (x3) followed by addition of [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii), dem adduct (218.7 mg, 267.81 □ mol,). The reaction mixture was warmed to 100 °C for 3 hours. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel, eluting with EtOAc in Heptane (0-100%) to afford the title compound (580 mg, 62%) as an off-white solid. MS (ESI): m / z = 348.1 [M+H]+

[0699] Step d) 8-(4-chlorophenyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7-quinone

[0700] (E)-3-[4-(4-chloroanilino)-6-keto-l,2-dimethyl-pyrimidin-5-yl]acrylic acid ethyl ester (580 mg, 1.67 mmol) was dissolved in ethanol (12 mL) and sodium methanethiolate (128.57 mg, 1.83 mmol) was added. The reaction mixture was stirred at 23 °C for 5 days. The reaction mixture was diluted with sat. NaHCCh-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over ISfeSCU and concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with MeOH in DCM (0- 10%) to afford the title compound (403 mg, 80%) as a light yellow solid. MS (ESI): m / z = 302. 1 [M+H]+

[0701] Step e) 6-bromo-8-(4-chlorophenyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7 -quinone

[0702] 8-(4-chlorophenyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (200 mg, 642.96 pmol) was dissolved in N,N-dimethylformamide (4 mL) and N-bromosuccinimide (137.3 mg, 771.55 pmol) was added. The reaction mixture was stirred at rt for 4 hours. The reaction mixture was diluted with sat. NaHCOs- solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel eluting with MeOH in DCM (0-10%) to afford the title compound (212 mg, 84%) as a white solid. MS (ESI): m / z = 382.0 [M+H]+ Step f) 8-( 4-chlorophenyl)-2, 3 -dime thy 1-6- [ (2S)-2-( I -methylpyrazol-4- yl)morpholino ]pyrido[ 2, 3-d]pyrimidine-4, 7 -quinone

[0703] 6-bromo-8-(4-chlorophenyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (100 mg, 262.7 pmol) was suspended in 1,4-dioxane (2 mL) and (2S)-2-(l-methylpyrazol-4-yl)morpholine (52.7 mg, 315.3 pmol), cesium carbonate (256.8 mg, 788.2 pmol) were added at rt. The mixture was degassed with argon before Pd2(dba)s (12.0 mg, 13.1 pmol) and xantphos (15.2 mg, 26.3 pmol) were added. The reaction was stirred for 2 hours at 100 °C. The reaction mixture was diluted with sat. NaHCCh-solution and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by prep HPLC (YMC-Triart C18 column, eluting with MeCN / water+0.1% formic acid) to afford the title compound (3.1 mg, 2%) as white lyophilized powder. MS (ESI): m / z = 467.2 [M+H]+

[0704] Example 16

[0705] 2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholino]-5-(3,3,3-trifluoropropyl)pyrido[2,3- b]pyrazin-6-one oxy-pyridine-2, 3-diamine

[0706] To a solution of 5-bromo-6-methoxy-3-nitro-pyridin-2-amine (1.8 g, 7.26 mmol), Raney nickel

[0707] (425.91 mg, 7.26 mmol) was added. The reaction mixture was stirred under hydrogen -n - atmosphere for 16 h . LCMS of the RM showed -60% conversion. Raney nickel (425.9 mg, 7.3 mmol) was added to the RM. An aliqout was taken after stirring for 34 h, LCMS showed complete conversion. The RM was filtered, the filtrate was concentrated in vacuo, to afford the title compound (1.55 g, 7.1 mmol, 90.5% yield). MS (ESI): m / z = 218 [M+H]+

[0708] Step b) 7 -bromo-6-methoxy-2,3-dimethyl-pyrido [2,3-b] pyrazine

[0709] The mixture of 5-bromo-6-methoxy-pyridine-2,3-diamine (1.55 g, 7.11 mmol) , 2,3 -butanedione (0.68 mL, 7.82 mmol) and sodium acetate (0.05 mL, 0.71 mmol) in Acetic acid (80 mL) was heated to 70 °C and stirred for 1 h . LCMS of an evaporated aliqout showed complete conversion. The RM was concentrated in vacuo. NaHCO3 saturated (40 ml) was added to the residue, an alcali aqueous solution was extracted with MTBE (4*50 ml). Organic fractions were combined, dried with Na2SO4 and concentrated in vacuo, to afford the title compound (1.5 g, 5.59 mmol, 70.83% yield) MS (ESI): m / z = 268 [M+H]+

[0710] Step c) 4-( 6-methoxy-2, 3-dimethyl-pyrido[ 2,3-b Jpyrazin- 7-yl)-2-( 1 -methylpyrazol-4- yl)morpholine

[0711] 7-bromo-6-methoxy-2,3-dimethyl-pyrido[2,3-b]pyrazine (1.5 g, 5.59 mmol) was dissolved in dry 1,4-Dioxane (60 mL) . 2-(l-methylpyrazol-4-yl)morpholine (1.4 g, 8.39 mmol), cesium carbonate (3.65 g, 11.19 mmol), Xantphos (0.32 g, 0.56 mmol), and Pd2(dba)3 (0.51 g, 0.56 mmol) were added to the obtained solution in that order. The mixture was purged with argon and left while stirring at 100 °C for 18 h. After that, the mixture was analyzed by LC-MS, which showed complete conversion. The mixture was concentrated in vacuo. The residue was diluted with EtOAc (600 mL), filtered through anhydrous sodium sulfate, and evaporated in vacuo to obtain crude (3 g), which was combined with a previous experiment and purified by column chromatography (ISCO® : Interchim 80 g SiO2, MTBE / methanol with methanol from 0-100%, flow rate = 60 mL / min). The title compound was obtained (1.2 g, 3.39 mmol, 54.57% yield) and used in the next step. MS (ESI): m / z = 355.2 [M+H]+ Step d) 2, 3-dimethyl- 7-[ 2-(l -methylpyrazol-4-yl)morpholin-4-yl ]-5H-pyrido[ 2, 3-b ]pyrazin-6- one

[0712] Hydrobromic acid (0.52 mL, 4.2 mmol) was added to a stirred solution of 4-(6-methoxy-2,3- dimethyl-pyrido[2,3-b]pyrazin-7-yl)-2-(l-methylpyrazol-4-yl)morpholine (500.0 mg, 1.4 mmol) in acetic acid (12.5 mL) . After stirring at 20 °C for 18 h, the mixture was analyzed by LC-MS, which showed complete conversion. So the mixture was quenched (carefully!) with a saturated solution ofNaHCO3 (150 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to obtain crude (0.45 g), which was combined with previous experiments and purified by column chromatography (ISCO® : Interchim 40 g SiO2, MTBE / methanol with methanol from 0-100%, flow rate = 40 mL / min). The title compound was obtained (200.0 mg, 0.59 mmol, 37.5% yield). MS (ESI): m / z = 341.2 [M+H]+

[0713] Step e) 2, 3-dimethyl- 7-[ 2-(l -methylpyrazol-4-yl)morpholino ]-5-( 3, 3, 3- trifluoropropyl)pyrido[2, 3-b ]pyrazin-6-one

[0714] 2,3 -dimethyl-7-[2-( 1 -methylpyrazol-4-yl)morpholino] -5H-pyrido [2,3 -b]pyrazin-6-one (50 mg, 146.9 umol) was dissolved in N,N-dimethylformamide, extra dry (1.88 mL) under argon atmosphere. NaH (11.75 mg, 293.8 umol) was added at 0 °C. Gas formation observed. The resulting mixture was stirred at 0 °C for 40 minutes. The milky light orange suspesion turned into a brown solution. 1,1, 1 -trifluoro-3 -iodo-propane (65.8 mg, 34.4 uL, 293.8 umol) was added at 0 °C. The reaction mixture was stirred at room temperature for 3.5 hours. LC-MS showed 50% conversion to product. The reaction mixture was quenched with water and ethylacetate. The organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography to give the title compound (30 mg, 46.8%) as a light yellow solid. 437.3 [M+H]+, ESI pos

[0715] Example 17

[0716] 8-(4-chlorophenyl)-6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone

[0717] Step a) 8-(4-chlorophenyl)-6-[ 6-(l -cyclopropylpyrazol-4-yl) -3, 6-dihydro-2H-pyran-4-yl ]-2, 3- dimethyl-pyrido[ 2, 3-d]pyrimidine-4, 7 -quinone

[0718] To a solution of 6-bromo-8-(4-chlorophenyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (0.100 g, 262.7 umol, See example 5, Step E) in 1,4-dioxane (3 mL) was added at 22 °C 1- cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyrazole (124.6 mg, 394.1 umol, Made in analogy to Example 24-Step D-E except using 1- cyclopropylpyrazole-4-carbaldehyde instead of l-methylpyrazole-4-carbaldehyde in Step D) followed by a solution of potassium carbonate (108.9 mg, 788.2 umol) in water (600 uL) . The mixture was purged and backfilled with argon (x3) followed by addition of 1 , 1 '- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (21.4 mg, 26.3 umol). purging with argon. The reaction mixture was warmed to 60 °C for 1 h. The mixture was treated with aq. sat. NaHCO3 and extracted with ethyl acetate. The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 25g, dissolved in DCM, 0-10% MeOH in DCM) to afford the title compound (128 mg, 99.44%) as light brown foam , 490.3 [M+H]+, ESI pos Step b) 8-( 4-chlorophenyl)-6-[rac-(2R, 4S)-2-( I -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl ]- 2, 3-dimethyl-pyrido[2, 3-d]pyrimidine-4, 7 -quinone

[0719] 8-(4-chlorophenyl)-6- [6-( 1 -cyclopropylpyrazol-4-yl)-3 ,6-dihydro-2H-pyran-4-yl]-2, 3 -dimethyl - pyrido[2,3-d]pyrimidine-4,7-quinone (128 mg, 0.26 mmol) was dissolved in Toluene:MeOH (2 mL) and palladium / C 10% (27.8 mg, 26.1 umol) was added under argon. The flask was evacuated and backfilled with argon 3X, and then with H2. the reaction mixture was stirred at RT for 22 hours. The reaction mixture was filtered on decalite and mother liquors were concentrated on vaccuo.

[0720] The crude material was purified by prep HPLC to afford the title compound (25 mg, 19.3%) as white lyoph powder, 492.1803 [M+H]+, ESI pos

[0721] Example 18 and Example 19

[0722] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone and 8-(4-chlorophenyl)-6-[(2S,4R)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7- quinone

[0723] The racemic Example 17 (25 mg) was resolved by SFC using a chiral IB column using a mixture of MeOH:EtOH:iPrOH (1:1:1) mixture up to 35% to obtain 8-(4-chlorophenyl)-6-[(2R,4S)-2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -2, 3 -dimethyl-pyrido [2, 3 -d]pyrimidine-4,7- quinone (5.3 mg, 20.1%) as white lyoph powder , 492.3 [M+H]+, ESI pos and 8-(4- chlorophenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl- pyrido[2,3-d]pyrimidine-4,7-quinone (3.4 mg, 12.92%) as white lyoph powder , 492.3 [M+H]+, ESI pos.

[0724] Example 22

[0725] 4-(4-chlorophenyl)-6,7-dimethyl-2-[rac-(2S,4R)-2-(l-methylpyrazol-4-yl)tetrahydropyran- 4-yl] pyrazino [2,3-b] pyrazin-3-one

[0726] 2,3-dichloro-5,6-dimethyl-pyrazine (3.0 g, 16.95 mmol) in methanol (15 mL) with liquid ammonia (50.0 mL, 1761.6 mmol) was stirred into the high pressure autoclave at 110 °C at the pressure of 30000 mmHg for 72 h . The RM was concentrated under reduced pressure, the residue was diluted with water (50 ml). An aqueous solution was extracted with EtOAc (3*50 ml), the combined organic fractions were dried with Na2SO4 and evaporated in vacuo to afford the target compound (2.5 g, 15.86 mmol, 65.5% yield) which was used in the next step without purification.

[0727] Step b) N3-(4-chlorophenyl)-5, 6-dimethyl-pyrazine-2, 3-diamine

[0728] To a mixture of 3-chloro-5,6-dimethyl-pyrazin-2-amine (0.5 g, 2.2 mmol) , 4-chloroaniline (0.31 g, 2.4 mmol) and MTBD (0.64 mL, 4.4 mmol) in DMSO (10 mL) ,tBuXPhos (0.14 g, 0.33 mmol) and tBuXPhos Pd G3 (0.26 g, 0.33 mmol) were added under argon. The RM was stirred at rt for 18 h. LCMS of the RM showed complete conversion. The reaction mixture was diluted with water and aqueous solution was extracted with EtOAc (3*50 ml), combined organic fractions were washed with brine (20 mL), dried with Na2SO4 and evaporated in vacuo. The crude material was purified by HPLC (0-2-7 min 33-40-65% H2O / ACN, flow 30ml / min (loading pump 4ml / min ACN), column: Chromatorex C18 SMB100-5T 100* 19mm, 5microM) to afford the target compound (170.0 mg, 0.68 mmol, 29.8% yield). 249.2 [M+H]+, ESI pos.

[0729] Step c) ethyl (2E)-2-[tert-butyl(dimethyl)silyl]oxy-2-[2-(l-methylpyrazol-4-yl)tetrahydropyran- 4-ylidene ] acetate

[0730] To a solution of ethyl 2-[tert-butyl(dimethyl)silyl]oxy-2-diethoxyphosphoryl-acetate (1.95 g, 5.49 mmol) in THF (25 mL) was added a solution of lithium bis(trimethylsilyl)amide (5.83 mL, 5.99 mmol) at -70 °C under Ar. After the reaction mixture was stirred at -70 °C for 1 h, a solution of 2-(l-methylpyrazol-4-yl)tetrahydropyran-4-one (0.9 g, 4.99 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -70 °C for 30 min, warmed to room temperature overnight, quenched with saturated aqueous NH4C1 solution (50 mL), extracted with EtOAc (3 x 50 mL), washed with brine (50 mL), dried over Na2SO4, filtered, concentrated to dryness. The residue was puriefed by FC (eluente hexan:EtOAc 1 :1) afford to afford the target compound (1.51 g, 3.97 mmol, 75.5% yield) as mixture of isomers. 381.2 [M+H]+, ESI pos.

[0731] Step d) ethyl 2-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-oxo-acetate

[0732] Caesium fluoride (0.6 g, 3.97 mmol) and acetic acid (1.19 g, 19.84 mmol) were added to a solution of ethyl (2E)-2-[tert-butyl(dimethyl)silyl]oxy-2-[2-(l-methylpyrazol-4- yl)tetrahydropyran-4-ylidene]acetate (1.51 g, 3.97 mmol) in ACN (25 mL). The reaction mixture was stirred at 20 °C for 18 h. Then the reaction mixture was quenched with saturated aqueous NaHCO3 (20 mL), extracted with EtOAc, washed with saturated aqueous NaHCO3 and concentrated to dryness to afford the target compound (0.8 g, 3.0 mmol, 64.4% yield) that was used in the next step without further purification. 267.0 [M+H]+, ESI pos.

[0733] Step e) 4-(4-chlorophenyl)-6, 7-dimethyl-2-[rac-(2S,4R)-2-(l-methylpyrazol-4- yl) tetrahydropyran-4-yl ]pyrazino[ 2,3-b ]pyrazin-3-one

[0734] N3-(4-chlorophenyl)-5,6-dimethyl-pyrazine-2,3-diamine (100.0 mg, 0.4 mmol) was added to ethyl 2-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-oxo-acetate (226.74 mg, 0.72 mmol) in acetic acid (241.45 mg, 4.02 mmol) and heated at 90 °C for 18 h. The reaction was purified by HPLC (23-35-55% 0-2-8 min H2O / ACN flow 30 ml / min ((loading pump 4 ml ACN), column : Chromatorex C18 SMB100-5T 100*19mm, 5 microM) to afford the target compound (21.5 mg, 0.05 mmol, 11.9% yield). 451.2 [M+H]+, ESI pos.

[0735] Example 32 and Example 33

[0736] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4- yl] py razino [2,3-b] pyrazin-3-one and 4-(4-chlorophenyl)-6,7-dimethyl-2- [(2S,4R)-2-(l- methylpyrazol-4-yl)oxan-4-yl]pyrazino[2,3-b]pyrazin-3-one

[0737] The racemic mixture was separated by SFC using a chiral OZ column, eluting with CO2 / MeOH+0.2% DEA to give 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-3-one (4 mg, 37.88%) as off- white solid 451. 19 [M+H]+, ESI pos and 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one (4 mg, 37.88%) as off-white solid 451.23 [M+H]+, ESI pos.

[0738] Example 24

[0739] 5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-

[0740] 4-yl] pyrido [2,3-b] pyrazin-6-one

[0741] To a solution of 5-bromo-6-methoxy-3-nitro-pyridin-2-amine (5.0 g, 20.2 mmol) in THF (50 mL), Raney nickel (1183.1 mg, 20.2 mmol) and Methanol (10 mL) were added. The RM was stirred at rt for 18 h under hydrogen atmosphere. The RM was filtered and the filtrate was concentrated in vacuo to afford the title compound (4.4 g, 20.2 mmol, 100% yield). 218.0 220.0 [M+H]+, ESI pos.

[0742] Step b) 7-bromo-6-methoxy-2,3-dimethyl-pyrido[2,3-b]pyrazine

[0743] To a solution of 5-bromo-6-methoxy-pyridine-2, 3-diamine (4.4 g, 20. 18 mmol) in acetic acid (180 mL), sodium acetate (0.17 g, 2.02 mmol) and 2, 3 -butanedione (1.93 mL, 22.2 mmol) were added. The RM was heated to 70 °C and stirred for 1 h. The RM was concentrated in vacuo, diluted with saturated NaHCO3 solution (80 ml) and extracted with MTBE (6*80 ml). Combined organic fractions were dried with Na2SO4 and evapotrated in vacuo to afford the title compound (4.4 g, 16.4 mmol, 73.2% yield). 268.0270.0 [M+H]+, ESI pos.

[0744] Step c) 7-bromo-2,3-dimethyl-5H-pyrido[2,3-b]pyrazin-6-one

[0745] To a solution of 7-bromo-6-methoxy-2,3-dimethyl-pyrido[2,3-b]pyrazine (2.0 g, 6.71 mmol) in acetic acid (20 mL) was added hydrogen bromide (7.6 mL, 67. 14 mmol) solution. The RM was stirred at 100 °C for 18 h. The RM was concentrated to dryness, the residue was triturated with ethanol (2*30 ml) and MTBE (1*30 ml). The precipitate was then dried in vacuo to afford the title compound (1.6 g, 6.3 mmol, 89.1% yield). 254.0 256.0 [M+H]+, ESI pos.

[0746] Step d) trifluoromethanesulfonic acid [6-(l-methylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4-yl] ester l-methylpyrazole-4-carbaldehyde (2 g, 18.2 mmol) was dissolved in dichloro methane, extra dry (36 mL) and 3-butyn-l-ol (1.97 g, 2.14 mL, 27.3 mmol) was added at rt. trifluoromethane sulfonic acid (8.18 g, 4.84 mL, 54.5 mmol) was added dropwise (dropping funnel) at -10 °C. The mixture was stirred for 30 min at -10 °C before it was warmed to room temp and stirred over night. The reaction mixture was quenched with sat. NaHCO3 -solution and extracted two times with DCM. The organic layers were dried over MgSO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (80g, EtOAc in heptane 0-100%) to obtain the title compound (2.79 g, 47.7%) as light yellow oil. 313.1 [M+H]+, ESI pos.

[0747] Step e) l-methyl-4-[ 4-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-3, 6-dihydro-2H-pyran-6- yl]pyrazole potassium acetate (0.98 g, 10.02 mmol) was added to a stirred solution of [6-(l-methylpyrazol-4- yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (1.7 g, 4.4 mmol) and bis(pinacolato)diboron (1.3 g, 5.2 mmol) in dry 1,4-dioxane (30 mL) . The mixture was degassed, filled with argon, and l, T-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.36 g, 0.44 mmol) was added. The reaction was stirred at 85 °C for 18 h then evaporated in vacuo, and the crude residue was purified on SiO2 with MTBE as eluent. The target compound was obtained (2.5 g, 8.62 mmol, 79.1% yield) and used in the next step without additional purification. 291.2 [M+H]+, ESI pos.

[0748] Step f) 2, 3-dimethyl- 7-[ 6-(l -methylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4-yl ]-5H-pyrido[ 2,3- b ]pyrazin-6-one potassium carbonate (0.65 g, 4.7 mmol) was added to a stirred solution of l-methyl-4-[4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (1.99 g, 2.7 mmol) and 7-bromo-2,3-dimethyl-5H-pyrido[2,3-b]pyrazin-6-one (0.8 g, 3.2 mmol) in dry 1,4- dioxane (20 mL). The mixture was degassed, filled with argon, and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.26 g, 0.31 mmol) was added. After stirring at 65 °C for 18 h the mixture was evaporated in vacuo, the crude residue was diluted with brine (150 mL), and extracted with EtOAc (2 x 150 mL). The combined organic layer was dried over anhydrous sodium sulfate, and evaporated in vacuo to obtain crude (2.5 g). The product was purified by FC (ISCO® : Interchim 120 g SiO2, CHC13 / MeOH with MeOH from 0-100%, flow rate = 46 mL / min). The target compound was obtained (0.5 g, 1.48 mmol, 42.4% yield) was obtained and used in the next step. 338.2 [M+H]+, ESI pos.

[0749] Step g) 2, 3-dimethyl- 7-[ rac-(2R, 4S)-2-( I -methylpyrazol-4-yl)tetrahydropyran-4-yl J-5H- pyrido[ 2,3-b ]pyrazin-6-one Palladium (5% on activated charcoal) (1.58 g, 0.74 mmol) was added to a solution of 2,3- dimethyl-7-[6-(l-methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5H-pyrido[2,3-b]pyrazin-6- one (0.5 g, 1.48 mmol) in a mixture of THF (12 mL) and methanol (12 mL), and the resulting mixture was hydrogenated at 760 mmHg and ambient temperature. The catalyst was filtered off, washed with a mixture of methanol and THF, and the combined filtrate was evaporated under reduced pressure to afford crude (0.38 g). The product was purified by FC, and was obtained as an off-white solid (69.0 mg, 0.2 mmol, 13.03% yield). 340.2 [M+H]+, ESI pos.

[0750] Step h) 5-( 4-chlorophenyl)-2, 3-dimethyl- 7-[rac-(2R, 4S)-2-( 1 -methylpyrazol-4- yl) tetrahydropyran-4-yl ]pyrido[ 2, 3-b ]pyrazin-6-one

[0751] Cupric acetate (75.73 mg, 0.42 mmol) was added to a stirred solution of 4-chlorophenylboronic acid (65.19 mg, 0.42 mmol) and 2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5H-pyrido[2,3-b]pyrazin-6-one (28.3 mg, 0.08 mmol) in solution of DCM (2 mL) and Pyridine (2 mL) . After stirring at 20 °C for 18 h, the mixture was evaporated in vacuo and sent for HPLC purification (0.6-7 min 20-50% water-ACN 30ml / min (loading pump 4ml ACN) target mass 450 column CROMATOREX SMB Cl 8 100* 19mm, 5 microM). The target compound was obtained (3.0 mg, 0.01 mmol, 7.6% yield). 450.2 [M+H]+, ESI pos.

[0752] Example 25 and Example 26

[0753] 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl] py rido [2, 3-b] pyrazin-6-one and

[0754] 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl] py rido [2, 3-b] pyrazin-6-one

[0755] Step a) 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4- yl) tetrahydropyran-4-yl ]pyrido[ 2, 3-b ]pyrazin-6-one diisopropyl azodicarboxylate (0.19 mL, 0.96 mmol) was added dropwise to a precooled stirred solution of 2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-5H- pyrido[2,3-b]pyrazin-6-one (54.5 mg, 0.16 mmol, See Example 24-Step g) , 4,4- difluorocyclohexanol (80.89 mg, 0.59 mmol) , and triphenylphosphine (252.7 mg, 0.96 mmol) in dry THF (6 mL) . After stirring at 20 °C for 18 h, the mixture was purified by HPLC (0.6-6.6 min 25-50% water-ACN 30ml / min (loading pump 4ml ACN) column CROMATOREX SMB C18 100*19mm, 5 microM). The racemic title compound (Example 26) was obtained (12.7 mg, 0.03 mmol, 14.7% yield). 458.2 [M+H]+, ESI pos.

[0756] Step b) 5-(4, 4-difluorocyclohexyl)-2, 3-dimethyl- 7-[ (2S, 4R)-2-( 1 -methylpyrazol-4- yl) tetrahydropyran-4-yl ]pyrido[ 2, 3-b ]pyrazin-6-one and 5-(4, 4-difluorocyclohexyl)-2, 3- dimethyl- 7-[ ( 2R, 4S)-2-( I -methylpyrazol-4-yl)tetrahydropyran-4-yl ]pyrido[ 2, 3-b ]pyrazin-6-one.

[0757] The enantiomers of 5-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol- 4-yl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one (30.0 mg, 0.07 mmol) were resolved by chromatography: Column: Chiralpak IG II (250 * 20 mm, 5 mkm); Mobile phase : IPA-MeOH, 50-50. Flow Rate: 12 mL / min; Column Temperature: 21'C; Wavelength: 205 nm. RetTime (isomer A) = 30.37 min; RetTime (isomer B) = 44.09 min. As a result, 2 pure enantiomers with arbitrary CIS configuration were obtained. Isomer A: (8.0 mg, 0.02 mmol, 25.3% yield) (RT = 30.37 min) 458.2 [M+H]+, ESI pos. Isomer B: (8.6 mg, 0.02 mmol, 27.2% yield) (RT = 44.09 min). 458.2 [M+H]+, ESI pos.

[0758] Example 28

[0759] 8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran- 4-yl]pteridine-4,7-dione

[0760] S 6-chloro-5-methoxy-pyrazine-2-carboxylate

[0761] Potassium carbonate (7.1 g, 51.4 mmol) was added to a stirred solution of methyl 3-amino-5,6- dichloro-pyrazine-2-carboxylate (3.8 g, 17.1 mmol) in dry methanol (90 mL). After stirring at 20 °C for 18 h, the mixture was concentrated in vacuo, the residue was diluted with water (100 mL), and filtered. The filter cake was washed with water (30 mL) and air-dried to obtain crude (2.9 g). The crude dark brown solids were refluxed with EtOAc (100 mL) and filtered without cooling. This procedure was repeated 4 times. The combined filtrate was evaporated in vacuo to obtain the target compound (2.6 g, 11.95 mmol, 59.3% yield), which was used in the next step without additional purification. 218.2 [M+H]+, ESI pos.

[0762] Step b) methyl 3-amino-5-methoxy-6-[6-(l-methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4- yl ]pyrazine-2-carboxylate

[0763] Sodium carbonate (1.49 g, 14.06 mmol) was added to a stirred solution of methyl 3-amino-6- chloro-5-methoxy-pyrazine-2-carboxylate (0.9 g, 3.52 mmol) and 1 -methyl-4-[4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (2.55 g, 2.64 mmol, see Example 24- Step e) in a mixture of 1,4-dioxane (50 mL) and water (10 mL) . The mixture was degassed, filled with argon, and l, l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.34 g, 0.42 mmol) was added. After stirring at 80 °C for 18 h, the mixture was evaporated in vacuo, the crude residue was diluted with EtOAc (250 mL), and washed with brine (2 x 250 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to obtain crude (2.45 g), which was purified by FC (ISCO® : Interchim; SiO2 80g mtbe-methanol 20% 6.5-7.5CV). The target compound was obtained (0.5 g, 1.45 mmol, 33% yield) and used in the next step without additional purification. 346.2 [M+H]+, ESI pos.

[0764] Step c) methyl 3-amino-5-methoxy-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazine-2- carboxylate

[0765] Palladium (5% on activated charcoal) (1232.6 mg, 0.58 mmol) was added to a solution of methyl 3-amino-5-methoxy-6-[6-(l-methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]pyrazine-2- carboxylate (0.5 g, 1.16 mmol) in a mixture of THF (10 mL) and methanol (10 mL), and the resulting mixture was hydrogenated at 760 mmHg and ambient temperature. The catalyst was filtered off, washed with methanol and the combined filtrate was evaporated under reduced pressure to afford the target compound (0.45 g, 1.3 mmol, 78.3% yield), which was used in the next step without additional purification. 348.2 [M+H]+, ESI pos.

[0766] Step d) 3-amino-5-methoxy-N-methyl-6-[2-( I -methylpyrazol-4-yl)tetrahydropyran-4- yl ]pyrazine-2-carboxamide

[0767] Methyl 3-amino-5-methoxy-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazine-2- carboxylate (0.45 g, 0.91 mmol) was dissolved in methanol (15 mL) and monomethylamine (20% solution in MeOH) (15.1 mL, 76.2 mmol) was added. After stirring at 50 °C for 18 h, the mixture was concentrated in vacuo to obtain the title compound (0.43 g, 1.24 mmol, 68.45% yield) , which was used in the next step without additional purification. 347.2 [M+H]+, ESI pos.

[0768] Step e) 7-methoxy-2, 3 -dime thy 1-6- [ 2-( 1 -methylpyrazol-4-yl)tetrahydropyran-4-yl ]pteridin-4-one

[0769] To a suspension of 3-amino-5-methoxy-N-methyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran- 4-yl]pyrazine-2-carboxamide (0.43 g, 0.62 mmol) in triethyl orthoacetate (11.38 mL, 62.1 mmol) was added acetic acid (0.71 mL, 12.4 mmol). After stirring at 120 °C for 18 h, the mixture was evaporated in vacuo and the residue was purified by HPLC (0.6-6.6 minO-25% water-ACN 30 ml / min (loading pump 4ml ACN) column CROMATOREX Cl 8 100*19 mm, 5 microM). The title compound was obtained (144.3 mg, 0.39 mmol, 56.49% yield). 371.2 [M+H]+, ESI pos.

[0770] Step f) 2,3-dimethyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8H-pteridine-4, 7-dione

[0771] Sodium hydride (77.91 mg, 1.95 mmol) was suspended in dry DMF (4 mL) and cooled to 0 °C. methyl mercaptan (gas) (93.7 mg, 1.95 mmol) (freshly prepared from aq. NaSMe solution and cone. H3PO4) was bubbled through a pre-cooled suspension until it became a clear solution, and then 7-methoxy-2,3-dimethyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]pteridin-4- one (144.3 mg, 0.39 mmol) was added. After stirring at 80 °C for 18 h, the reaction mixture was acidified with acetic acid, and evaporated in vacuo to obtain the title compound (0.34 g, 0.95 mmol, 98% yield) (with DMF), which was used in the next step without additional purification.

[0772] 357.2 [M+H]+, ESI pos.

[0773] Step g) 8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2R, 4S)-2-(l-methylpyrazol-4- yl) tetrahydropyran-4-yl ]pteridine-4, 7 -dione

[0774] Copper(II) acetate (346.55 mg, 1.91 mmol) was added to a stirred suspension of 4- chlorophenylboronic acid (298.36 mg, 1.91 mmol), and 2,3-dimethyl-6-[2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]-8H-pteridine-4, 7-dione (340.0 mg, 0.38 mmol) in a mixture of dry DCE (10 mL) and Pyridine (10 mL). After stirring at 60 °C for 6 h under active air bubbling (solvents were added periodically), the mixture was concentrated in vacuo and purified by HPLC (0.6-6.6 min 20-30%-water-acetonitrile 30ml / min (loading pump 4m acetonitrile) column cromatorex C18 100*19mm, 5 microM). The title compound was obtained (2.2 mg, 0.005 mmol, 1.17% yield). 467.2 [M+H]+, ESI pos.

[0775] Example 47 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl] pteridine-4, 7-dione thyl-5-nitro-lH-pyrimidin-6-one To a cooled suspension of 4,6-dihydroxy-2-methylpyrimidine (4.8 g, 38.1 mmol) in acetic acid (90 mL), fuming nitric acid (10.0 mL, 38.06 mmol) was added dropwise at 15 °C. The RM was stirred at rt for 18 h. The RM was filtered and the precipitate was washed with MTBE (2*50 ml). The precipitate was dried in vacuo to obtain the title compound (5.1 g, 29.81 mmol, 74.4% yield) 'H NMR (500 MHz, DMSO-d6) 5 ppm 2.30 (s, 3 H) 12.32 - 13.54 (m, 2 H).

[0776] Step b) 6-chloro-2-methyl-5-nitro-pyrimidin-4-ol

[0777] To a cooled solution of 2-methyl-5-nitro-pyrimidine-4,6-diol (5.1 g, 29.81 mmol) in DMF (2 mL) phosphorus oxychloride (2.92 mL, 31.3 mmol) was added at 0 °C. The RM was stirred at rt for 6 h. The RM was poured onto ice (-150 g) with brine (50 ml) and extracted with EtOAc (3*100 ml), EtOAc solution was washed with water (3*100 ml), the organic solution was dried with Na2SO4 and evaporated in vacuo to obtain the title compound (2.23 g, 11.76 mmol, 33.6% yield). 188.0 [M-H]-, ESI pos.

[0778] Step c) 6-chloro-2,3-dimethyl-5-nitro-pyrimidin-4-one

[0779] To a solution of 4-chloro-2-methyl-5-nitro-lH-pyrimidin-6-one (2.23 g, 10.0 mmol) in ACN (50 mL), potassium carbonate (2764.12 mg, 20.0 mmol) and iodomethane (3.74 mL, 60.0 mmol) were added. The RM was stirred at rt for 18 h, then was concentrated in vacuo and the residue was triturated with EtOAc (2*50 ml). The organic solution was concentrated in vacuo to obtain the title compound (1.71 g, 8.4 mmol, 76% yield). 204.0 [M+H]+, ESI pos.

[0780] Step d) 6-[ ( 4, 4-difluorocyclohexyl)amino ]-2, 3-dimethyl-5-nitro-pyrimidin-4-one To a solution of 6-chloro-2,3-dimethyl-5-nitro-pyrimidin-4-one (1.71 g, 8.4 mmol) in ACN (40 mL) 4,4-difluorocyclohexylamine hydrochloride (1585.7 mg, 9.24 mmol), then N,N- diisopropylethylamine (4.39 mL, 25.2 mmol) was added and the RM was heated to 90 °C and stirred for 1 h. The solvent was removed in vacuo, then the compound was triturated in MTBE (200 ml) while using an ultrasonic bath. The solution was separated using decantation and the undissolved residue was dissolved in DCM (150 ml) and washed with water (20 ml). The DCM solution was dried with Na2SO4 and evaporated in vacuo to obtain the title compound (2.91 g, 9.63 mmol, 91.7% yield). 303.2 [M+H]+, ESI pos.

[0781] Step e) 5-amino-6-[ ( 4, 4-difluorocyclohexyl) amino ]-2, 3-dimethyl-pyrimidin-4-one

[0782] To a solution of 6-[(4,4-difhiorocyclohexyl)amino]-2,3-dimethyl-5-nitro-pyrimidin-4-one (2.91 g, 9.63 mmol) in DMF (8 mL), 4,4 '-Dipyridyl (451.06 mg, 2.89 mmol) was added. The mixture was cooled with an ice bath and tetrahydroxydiboron (2675.44 mg, 29.84 mmol) was added in three portions (5 min between each portion). The RM was stirred under cooling for 10 min after the last portion was added, then the RM was heated to r.t. and stirred for 20 min. The RM was poured onto an ice-cold K2CO3 solution (50 ml, 5% in water). Then the aqueous solution was extracted with EtOAc (4*50 ml). The organic layer was washed with water (3*50 ml) and then brine (50 ml). The organic solution was dried with Na2SO4 and evaporated in vacuo to obtain the title compound (1.44 g, 5.29 mmol, 49.4% yield). 273.2 [M+H]+, ESI pos.

[0783] Step f) 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl] pteridine -4, 7 -dione 5-amino-6-[(4,4-difluorocyclohexyl)amino]-2,3-dimethyl-pyrimidin-4-one (50.0 mg, 0.18 mmol) was mixed with ethyl 2-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-oxo-acetate (88.02 mg, 0.33 mmol, see Example 22-Step d) in dry 1,2-dichloroethane (2 mL). Freshly dried magnesium sulfate (110.51 mg, 0.92 mmol) was added, and the resulting mixture was stirred at room temperature for 40 h. l,3,4,6,7,8-hexahydro-2H-pyrimido[l,2-a]pyrimidine (51.12 mg, 0.37 mmol) was added and the mixture was stirred at 90 °C for 60 h. The reaction mixture was purified by HPLC (0.6-6.9 min20-45% water-ACN 30ml / min (loading pump 4ml ACN) column cromatorex C18 100* 19mm, 5 microM) to obtain the title compound (13.3 mg, 0.03 mmol, 14.5% yield). 475.2 [M+H]+, ESI pos.

[0784] Example 54 and Example 55

[0785] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl] py razino [2,3-b] pyrazin-3-one and 4-(4-chloro-2-fluoro-phenyl)- 6,7-dimethyl-2-[(2S,4R)-2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]pyrazino[2,3- b]pyrazin-3-one

[0786] To a stirred solution of 4-(4-chloro-2-fluoro-phenyl)-2-[2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one (500.0 mg, 0.96 mmol, made in analogy to Example 22, except using 2-(2-methoxy-4-pyridyl)tetrahydropyran-4- one instead of 2-(l-methylpyrazol-4-yl)tetrahydropyran-4-one in Step D, and 4-chloro-2-fluoro- aniline instead of 4-chloroaniline in Step B) in ACN (10 mL), sodium iodide (538.37 mg, 3.59 mmol) and trimethylsilyl chloride (455.84 uL, 3.59 mmol) were added. The resulting mixture was heated at 60 °C for 16 h. The reaction was evaporated and purified by HPLC (13-20-70% 0- 2-8 min H2O / ACN / flow 30 ml / min (loading pump 4 ml ACN) column : XBridge BEH Cl 8 100* 19mm, 5 microM), then chiral separation (Column: CHIRALPAK IC (250x20 mm, 5 mkm)— 834VJ002-DA181—11 Mobile Phase: IPAMeOH, 50:50 Flow Rate: 11 ml / min) to obtain 4-(4- chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one (15.5 mg, 0.03 mmol, 3.36% yield) 482.0 [M+H]+, ESI pos. and 4-(4-chloro-2-fluoro-phenyl)-6, 7-dimethyl-2-[ (2 S, 4R)-2-(2-oxo- 1 H-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-3-one (8.7 mg, 0.02 mmol, 1.88% yield). 482.0 [M+H]+, ESI pos.

[0787] Example 61 and Example 62

[0788] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl] pyrazino [2,3-b] pyrazin-3-one and 4-(4-chloro-2-fluoro- phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4- yl] pyrazino [2,3-b] pyrazin-3-one

[0789] Cyclopropylboronic acid (249.55 mg, 2.91 mmol), cupric acetate (461.71 mg, 2.54 mmol) and sodium carbonate (153.95 mg, 1.45 mmol) were added to a stirred solution of 4-(4-chloro-2- fluoro-phenyl)-6,7-dimethyl-2-[2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]pyrazino[2,3- b]pyrazin-3-one (350.0 mg, 0.73 mmol, see Example 54) in DCE (30 mL) and pyridine (0.59 mL, 7.26 mmol). After stirring at 70 °C for 16 h the reaction mixture was cooled to room temperature and filtered, the precipitate was washed with DCE (50 mL) and evaporated to obtain crude product, which was subjected to HPLC (23-30-55% 0-2-8 min H2O / ACN / flow 30 ml / min ((loading pump 4 ml ACN), column : XB ridge BEH Cl 8 100* 19mm, 5 microM) and then to chiral separation (Column: Chiralpak IB (250 * 20 mm, 5 mkm); Mobile phase : Hexane-IPA- MeOH, 95-2.5-2.5. Flow Rate: 15 mL / min; Column Temperature: 24'C; Wavelength: 205 nm. RetTime (isomer A) = 16.84 min; RetTime (isomer B) = 22.54 min) to afford 4-(4-chloro-2- fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one (20.1 mg, 0.04 mmol, 5.3% yield) 522.0 [M+H]+, ESI pos. and 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-3-one (19.4 mg, 0.04 mmol, 5.12% yield). 522.0 [M+H]+, ESI pos. Example 63 and Example 64

[0790] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl] pyrazino [2,3-b] pyrazin-3-one and 4-(4-chloro-2-fluoro- phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4- y 1] pyrazino [2,3-b] pyrazin-3-one

[0791] Diisopropyl azodicarboxylate (0.61 mL, 3.11 mmol) was added to a precooled (0

[0792] °C) stirred solution of methanol (0.11 mL, 2.59 mmol), 4-(4-chloro-2-fluoro-phenyl)-6,7- dimethyl-2-[2-(2-oxo-lH-pyridin-4-yl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-3-one (250.0 mg, 0.52 mmol, see Example 54) and triphenylphosphine (816.39 mg, 3.11 mmol) in dry THF (5 mL). After stirring at 20 °C for 16 h, the reaction was evaporated to obtain crude product, which was purified by HPLC (28-35-80% 0-2-8 minH2O / ACN / flow 30 ml / min ((loading pump 4 mlACN) column : XBridge BEH Cl 8 100* 19mm, 5 microM) and then chiral separation (Column: CHIRALPAK IC (250x20 mm, 5 mkm)-834VJ002-DA181-II Mobile Phase: IPA:MeOH, 50:50 Flow Rate: 14 ml / min) to afford 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-

[0793] 2-[(2R,4S)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-3-one (19.1 mg, 0.04 mmol, 7.42% yield). Also isolated was 4-(4-chloro-2-fluoro-phenyl)-6,7- dimethyl-2-[(2S,4R)-2-(l-methyl-2-oxo-4-pyridyl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-

[0794] 3-one (19.1 mg, 0.04 mmol, 7.42% yield). 496.0 [M+H]+, ESI pos.

[0795] Example 68 and Example 69

[0796] 6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpteridine-4, 7-dione and 6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8- (4, 4-difluorocyclohexyl)-2,3-dimethylpteridine-4, 7-dione

[0797] Step a) 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-5H-pteridine-4,6, 7-trione

[0798] To a solution of 5-amino-6-[(4,4-difluorocyclohexyl)amino]-2,3-dimethyl-pyrimidin-4-one (1.0 g, 3.31 mmol, see Example 47-Step e) in hydrochloric acid (25.0 mL, 50.0 mmol) (2 M aqueous solution) oxalic acid (476.1 mg, 5.29 mmol) was added. The RM was stirred at 110 °C for 60 h. The RM was concentrated in vacuo to dryness, then the residue was evaporated with MeOH (3*30 ml) to give 1.46 g of the crude. The product was purified by FC (SiO2 40g chloroformacetonitrile 70% 17-23CV) to obtain the title compound (0.48 g, 1.48 mmol, 42.5% yield).JH NMR (400 MHz, DMSO-t / 6) 8 ppm 1.69 (br d, 7=12.70 Hz, 2 H) 1.85 - 2.06 (m, 2 H) 2.07 - 2.18 (m, 2 H) 2.53 (s, 3 H) 2.66 - 2.85 (m, 2 H) 3.49 (s, 3 H) 4.96 - 5.39 (m, 1 H) 11.04 - 12.00 (m, 1 H).

[0799] Step b) 6-chloro-8-(4,4-difluorocyclohexyl)-2,3-dimethyl-pteridine-4, 7 -dione Phosphorus oxychloride (15.0 mL, 160.94 mmol) was added to a 8-(4,4-difluorocyclohexyl)-2,3- dimethyl-5H-pteridine-4, 6, 7-trione (0.48 g, 1.48 mmol). The RM was stirred at 100 °C for 1 h. The RM was concentrated in vacuo, and to the residue was added ice (40 g) and K2CO3 (3 g). The aqueous solution was extracted with chloroform (4*20 ml), dried with Na2SO4 and evaporated in vacuo to obtain the title compound (350.7 mg, 1.02 mmol, 65.4% yield). 345.2 [M+H]+, ESI pos.

[0800] Step c) 6-[ 2-(l -cyclopropylpyrazol-4-yl)morpholino ]-8-(4, 4-difluorocyclohexyl)-2, 3-dimethyl- pteridine-4, 7-quinone

[0801] In a sealed vial, 6-chloro-8-(4,4-difluorocyclohexyl)-2,3-dimethyl-pteridine-4,7-quinone (49 mg, 142.13 umol), cesium carbonate (92.62 mg, 284.26 umol) and 2-(l-cyclopropylpyrazol-4- yl)morpholine (39.24 mg, 198.98 umol) were dissolved in 1,4-dioxane, extra dry (783.75 uL). The mixture was degased and refilled with Nitrogen (3 times) before adding XantPhos Pd G3 (3.53 mg, 5.8 umol). The reaction mixture was again degased and refilled with nitrogen (3 times) and heated to 100 °C. The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was quenched by adding water and ethylacetate. The reaction mixture was extracted with ethylacetate and the aqueous phase was reextracted with ethylacetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness. The product was purified by flash chromatography (solid deposite, 12g, EtOAc / EtOH(3: l) in Heptane 0-100 %, run length 35 minutes) to obtain the title compound (64.7 mg, 86.2%) as an orange solid. 502.5 [M+H]+, ESI pos.

[0802] Step d) 6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpteridine-4, 7-dione and 6- [(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl] -8-(4,4- difluorocyclohexyl)-2, 3-dimethylpteridine-4, 7 -dione

[0803] A sample of 6-[2-(l-cyclopropylpyrazol-4-yl)morpholino]-8-(4,4-difluorocyclohexyl)-2,3- dimethyl-pteridine-4,7-quinone (60 mg) was purified by chiral SFC, using MeOH as a modifier on a chiral OZ column to obtain 6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4- difluorocyclohexyl)-2,3-dimethylpteridine-4, 7-dione (25 mg, 41%) 502.5 [M+H]+, ESI pos and 6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)-2,3- dimethylpteridine-4, 7-dione (24.8 mg, 40%) 502.5 [M+H]+, ESI pos. Example 71 and Example 72

[0804] 4-(4,4-difluorocyclohexyl)-2-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-6,7- dimethylpyrazino[2,3-b]pyrazin-3-one and 4-(4,4-difluorocyclohexyl)-2-[(2R,4S)-2-(2- methoxypyridin-4-yl)oxan-4-yl]-6,7-dimethylpyrazino[2,3-b]pyrazin-3-one

[0805] Step a) 4-(4,4-difluorocyclohexyl)-2-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-6, 7- dimethyl-pyrazino[2, 3-b ]pyrazin-3-one

[0806] To a degassed solution of 2-methoxy-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyridine (324. 19 mg, 1.02 mmol, made in analogy to Example 24-Step e, except using 2-methoxypyridine-4-carbaldehyde instead of l-methylpyrazole-4- carbaldehyde), 2-chloro-4-(4,4-difluorocyclohexyl)-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one (96 mg, 292.02 umol, Made in analogy to Example 3 -Step C, except using 4,4- difluorocyclohexanamine instead of 4-chloro-2-fluoroaniline in Step A), K2CO3 (121.08 mg, 876.05 umol) in 1,4-dioxane (3.52 mL) was added l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (24.14 mg, 29.2 umol). The mixture was degassed again with N2 with sonication, then water (352.27 uL) was added and the reaction was left stirring at 60 °C for 1 hr. The solvent was removed under reduced pressure. The material was purified using column chromatography (25g, 0-20-50-100%) to obtain the title compound (68 mg, 48.2%) as an orange oil. 484.44 [M+H]+, ESI pos. Step b) 4-(4,4-difluorocyclohexyl)-2-[(2S,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-6, 7- dimethylpyrazino[2, 3-b ]pyrazin-3-one and 4-(4, 4-difluorocyclohexyl)-2-[(2R, 4S)-2-(2- methoxypyridin-4-yl)oxan-4-yl]-6, 7-dimethylpyrazino[2, 3-b]pyrazin-3-one

[0807] To a solution of 4-(4,4-difluorocyclohexyl)-2-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran- 4-yl]-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one (68 mg, 0.14 mmol) in ethyl acetate (2.2 mL) was added platinum (IV) oxide (31.9 mg, 140.6 umol) and Et3N (17.08 mg, 23.5 uL, 168.8 umol ). The flask was evacuated with argon three times and with hydrogen 3 times. The reaction was stirred at r.t. for 4 h under 1 atm of H2. The over hydrogenated product was isolated by filtration, washing with EtOAc, and concentration in vaccuo. To the crude residue was added 1,2- dichloroethane (4.5 mL) and manganese dioxide (242.52 mg, 2.79 mmol). The reaction vial was capped and stirred at 50 °C for 12 hr. The crude was partially purified using normal phase column chromatography (0-100% EtOAc in heptane). The product was further purified by chiral SFC to obtain 4-(4,4-difhiorocyclohexyl)-2-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one (0.800 mg, 1.18%) 486.4 [M+H]+, ESI pos as an off-white solid and 4-(4,4-difluorocyclohexyl)-2-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one (0.500 mg, 0.738%) as an off-white solid. 486.3 [M+H]+, ESI pos.

[0808] Example 78

[0809] 8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(6-methoxypyridin-3-yl)oxan-4-yl]-2,3- dimethylpteridine-4, 7-dione Step a) 8-(4,4-difluorocyclohexyl)-6-[6-(6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3- dimethyl-pteridine-4, 7-quinone

[0810] To a degassed solution of 2-methoxy-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6- dihydro-2H-pyran-6-yl]pyridine (483.03 mg, 1.52 mmol, made in analogy to Example 24-Step e, except using 6-methoxypyridine-3-carbaldehyde instead of l-methylpyrazole-4-carbaldehyde), 6-chloro-8-(4,4-difluorocyclohexyl)-2, 3 -dimethyl-pteridine-4, 7-quinone (150 mg, 435.1 umol, See Example 68-Step B), K2CO3 (180.4 mg, 1.31 mmol) in 1,4-dioxane (5.49 mL) was added l,r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (35.97 mg, 43.51 umol). The mixture was degassed again with N2 and sonication then water (549.12 uL) and the reaction was left stirring at 60 °C for 1 hr. The solvent was removed under reduced pressure. The material was purified using column chromatography (25g, eluting with 0- 100% EtOAc in Heptane) to obtain the title compound (123 mg, 54%) as a light brown solid. 500.46 [M+H]+, ESI pos.

[0811] Step b) 8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(6-methoxypyridin-3-yl)oxan-4-yl]-2,3- dimethylpteridine-4, 7-dione

[0812] 8-(4,4-difluorocyclohexyl)-6- [6-(6-methoxy-3 -pyridyl)-3 , 6-dihydro-2H-pyran-4-yl]-2,3 - dimethyl-pteridine-4, 7-quinone (123 mg, 0.236 mmol), magnesium oxide (95.26 mg, 2.36 mmol ), platinum (IV) oxide (53.68 mg, 236.39 umol), were degassed and put under N2. Ethyl acetate (3.69 mL) and Et3N (28.7 mg, 39.54 uL, 283.66 umol) were added and the suspension was degassed again. The H2 atmosphere was established through 3 H2 / vacuum cycles and the mixture was left stirring at r.t. The mixture was filtered through celite and concentrated. The racemic product was isolated by SFC using an achiral P4VP column, and MeOH as a modifier up to 10%. The enantiomers were resolved by chiral separation on SFC using an OD-H column and MeOH as the modifier up to 25% to obtain two peaks at 2.33 min and 2.78 min. The target compound was obtained as the second eluting compound (7.1 mg, 5.87%) as an off-white solid. 502.2 [M+H]+, ESI pos.

[0813] Example 90

[0814] 5-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3- dimethylpyrido [2, 3-b] pyrazin-6-one

[0815] S uoro-phenyl)-(3-chloro-5, 6-dimethyl-pyrazin-2-yl)amine

[0816] A mixture of (4-chloro-2,6-difluoro-phenyl)amine (1.39 g, 8.47 mmol), 2,3-dichloro-5,6- dimethyl-pyrazine (1 g, 5.65 mmol), NaOtBu (1.63 g, 16.95 mmol), P(tBu)3 Pd G2 (231.55 mg, 451.9 umol) in toluene, extra dry (20 mL) was heated to 80 °C for 24 hr. The reaction material was filtered over decalite. Washed with ethyl acetate. The filtrate was extracted with 50 ml H2O. The layers were separated. The aq. layer was extracted with two 50 ml portions of ethyl acetate. The combined org. layers were washed with one 50 ml portion of sat. NaCl, dried over anh. sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (loaded as an impregnate on ISOLUTE-N; (SiO2, 80g / 15-40 um, cartridge), n- heptane / ethyl acetate: 100 : 0 - > 85 : 15, detection at 254 nm) to obtain the title compound (1.5 g, 78.58%) as light red solid. MS: 304.1 ([M+H]+), ESI pos.

[0817] Step b) 7-bromo-5-( 4-chloro-2, 6-difluoro-phenyl)-2, 3-dimethyl-pyrido[ 2, 3-b ]pyrazin-6-one

[0818] Target compound was obtained in analogy to Example 1-Step B and Step C, using (4-chloro-2,6- difluoro-phenyl)-(3-chloro-5,6-dimethyl-pyrazin-2-yl)amine instead of 3-bromo-N-(4- chlorophenyl)-5,6-dimethyl-pyrazin-2-amine in Step B. 7-bromo-5-(4-chloro-2,6-difluoro- phenyl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one (53 mg, 9.31%) as a white solid 400 / 402.1 ([M+H]+), ESI pos.

[0819] Step c) 5-(4-chloro-2, 6-difluoro-phenyl)- 7-[ 6-( 1 -cyclopropylpyrazol-4-yl)-3, 6-dihydro-2H- pyran-4-yl -2, 3-dimethyl-pyrido[ 2, 3-b ]pyrazin-6-one

[0820] Into a degassed mixture of 7-bromo-5-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrido[2,3- b]pyrazin-6-one (77.4 mg, 173.88 umol) , l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (57.73 mg, 182.58 umol, made in analogy to Example 24-Step D-E except using l-cyclopropylpyrazole-4-carbaldehyde instead of l-methylpyrazole-4-carbaldehyde) and SODIUM CARBONATE (64.07 mg, 604.5 umol) in 1,4- dioxane, extra dry (1.1 mL) was added l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (29.99 mg, 36.27 umol) at RT. The resulting mixture was stirred at 80 °C for 4 h. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (40 ml). The layers were separated. The aqueous layer was extracted with two 40 ml portions of ethyl acetate. The combined organic layers were washed with one 40 ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (loaded as an impregnate on ISOLUTE-N; (SiO2, 25g / 15-40 um, cartridge), n-heptane / ethyl acetate: 100 : 0 - > 15 : 85, detection at 254 nm) to obtain the title compound (35 mg, 37.5%) as light yellow solid. MS: 510.4 ([M+H]+), ESI pos. Step d) 5-(4-chloro-2, 6-difluorophenyl)- 7-[(2R, 4S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl]-2, 3- dimethylpyrido[2, 3-b ]pyrazin-6-one

[0821] A suspension of 5-(4-chloro-2,6-difhioro-phenyl)-7-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro- 2H-pyran-4-yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one (35 mg, 67.95 umol) in THF (550 uL) was treated with ethanol (2.6 mL). TRIETHYLAMINE (8.25 mg, 11.36 uL, 81.54 umol ) and magnesium oxide (27.38 mg, 679.49 umol) were added, inerted by evacuation and backfilling with nitrogen (3 x). Then was added Pd / C (1.45 mg, 13.59 umol) and again inerted as described. H2 -balloon was set and evacuation and back-filling with hydrogen. This procedure was repeated (5 x). The mixture was vigorously stirred at 22 °C for 6 h. The catalyst was removed by filtration over a Satorius filter system. Washed with ethyl acetate and the filtrate was concentrated in vacuo to obtain the crude solid mixture. The enantiomers were purified by chiral SFC on an OD column (5 pm, 250 x 20 mm), waters 44 °C 100ml 25%MeOH 90BPR 220nm to obtain the title compounds. Fraction A: 9.6 mg, off-white solid

[0822] 5 -(4-chloro-2, 6-difluoro-phenyl)-7 - [(2 S ,4R)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one (9.6 mg, 25.39%) as off-white solid MS: 512.4 ([M+H]+), ESI pos. 5-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one (7 mg, 19.72%) as off-white solid 512.4 ([M+H]+), ESI pos.

[0823] Example 130 and Example 131

[0824] 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl] py razino [2,3-b] pyrazin-3-one and 4-(4-chlorophenyl)-6,7-dimethyl-2- [(2S,4R)-2-(2- methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-3-one

[0825] Step a) 4-(4-chlorophenyl)-2-[2-(2-chloro-4-pyridyl)tetrahydropyran-4-yl]-6, 7-dimethyl- pyrazino[2, 3-b ]pyrazin-3-one

[0826] A solution of N3-(4-chlorophenyl)-5,6-dimethyl-pyrazine-2,3-diamine (80 mg, 0.32 mmol, made in analogy to Example 22-Step b), ethyl 2-[2-(2-chloro-4-pyridyl)tetrahydropyran-4-yl]-2-oxo- acetate (143.65 mg, 0.48 mmol, made in analogy to Example 22-Step C-D except using 2-(2- chloro-4-pyridyl)tetrahydropyran-4-one instead of 2-(l-methylpyrazol-4-yl)tetrahydropyran-4- one in Step C) in HO Ac (0.18 mL, 3.22 mmol) was stirred at 90 °C for 16 h.The reaction mixture was cooled to the room temperature, then quenched with saturated NaHCCh (5 mL), added into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL) and dried over Na2SO4, then concentrated in vacuum to give a residue. The residue was purified by flash chromatography on silica using petroleum ether: ethylacetate from 0-100% to obtain the title compound 4-(4-chlorophenyl)-2-[2-(2-chloro-4- pyridyl)tetrahydropyran-4-yl]-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one (55.0 mg, 0.11 mmol, 35.45% yield) as orange solid. MS: 482.3 ([M+H]+), ESI pos.

[0827] Step b) 4-(4-chlorophenyl)-6, 7-dimethyl-2-[2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl ]pyrazino[ 2, 3-b ]pyrazin-3-one To a brown solution of 4-(4-chlorophenyl)-2-[2-(2-chloro-4-pyridyl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino[2,3-b]pyrazin-3-one (50 mg, 0.1 mmol) in 1,4-Dioxane (1 mL) were added trimethylboroxine (104.1 mg, 0.41 mmol), l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride (7.7 mg, 0.01 mmol) and K2CO3 (42.9 mg, 0.31 mmol) at room temperature. The flask was purged with N2 three times. The reaction mixture was stirred at 90 °C for 2 h under N2. The reaction was cooled to room temperature, water (10 mL) was added, and the product was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (10 mL x 3) and dried over Na2SO4, then concentrated in vacuum to give a residue. The residue was purified by preparative TLC (petroleum ether :EtOAc=0: 1) to afford 4- (4-chlorophenyl)-6, 7-dimethyl-2- [2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino [2,3- b]pyrazin-3-one (35 mg, 0.08 mmol, 73% yield) as a yellow solid. MS: 462.3 ([M+H]+), ESI pos.

[0828] Step c) 8-(4-chlorophenyl)-6-[(2R, 4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]~ 2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7-quinone and 8-(4-chlorophenyl)-6-[(2S,4R)-2-(6- cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2, 3-dimethyl-pyrido[2, 3-d]pyrimidine-4, 7- quinone

[0829] The enantiomers of 4-(4-chlorophenyl)-6,7-dimethyl-2-[2-(2-methyl-4-pyridyl)tetrahydropyran- 4-yl]pyrazino[2,3-b]pyrazin-3-one were separated by chiral SFC on a CHIRALPAK AD column, eluting with 60% isocratic IPA(0.1%NH3H2O) as the modifier to obtain the title compounds 4- (4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one (11 mg, 0.02 mmol, 31% yield, 462.1 ([M+H]+), ESI pos) as white solid and 4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-3-one (11 mg, 0.02 mmol, 31% yield, 462.1 ([M+H]+), ESI pos) as white solid. Example 150 and Example 151

[0830] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone and 8-(4-chlorophenyl)-6-[(2S,4R)-2-(6- cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-

[0831] 4,7-quinone

[0832] Step a) ethyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2- carboxylate

[0833] To a solution of 4-ketotetrahydropyran-2-carboxylic acid ethyl ester (12 g, 73 mmol, CAS: 287193-07-1) and 2,6-di-tert-butyl-4-methylpyridine (17.9 g, 87.2 mmol) in dichloromethane, extra dry (150 mL) at 0°C under N2 was added trifluoromethanesulfonic anhydride (41.0 g, 24.4 mL, 145.3 mmol). The reaction mixture was stirred under N2 at r.t. for 2 hr and then at 45 °C overnight. The reaction mixture was quenched with H2O (250 ml), the aqueous layer was separated and extracted with DCM (3 x 250 ml). The combined organic layers were washed with brine (100 ml) and concentrated under reduced pressure. Crude product was purified by flash column chromatography on silica eluting with Heptane:EtOAc from 0-40% to obtain 4- triflyloxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (15.35 g, 70%) as light brown oil which was used in the following step.

[0834] To a solution of 4-triflyloxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (15.33 g, 50.4 mmol) in 1,4-dioxane, extra dry (200 mL) was added potassium acetate (14.8 g, 151.2 mmol) and bis(pinacolato)diboron (13.4 g, 52.9 mmol). The mixture was degassed with Ar, 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.25 g, 1.51 mmol) was added and reaction mixture was degassed with Ar again. The reaction mixture was stirred at 80 °C for 2 hr. The reaction mixture was quenched with H2O (250 ml). The resulting solution was extracted three times with EtOAc (3 x 250 ml). The organic layers were combined, washed with brine and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica eluting with Heptane:EtOAc from 0-100% to obtain the title compound 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- pyran-2-carboxylic acid ethyl ester (10.43 g, 73%) as light brown oil. 283.4 [M+H]+ ESI pos.

[0835] Step b) rac-4-[8-(4-chlorophenyl)-4, 7-diketo-2, 3-dimethyl-pyrido[2, 3-d]pyrimidin-6-yl]-3, 6- dihydro-2H-pyran-2-carboxylic acid ethyl ester

[0836] To a suspension of 6-bromo-8-(4-chlorophenyl)-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7- quinone (650 mg, 1.71 mmol, see Example 5-Step E) in 1,4-dioxane (20 mL) was added at 22 °C 4-(4, 4, 5 , 5-tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)-3 , 6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (626 mg, 2.22 mmol) followed by potassium carbonate (708 mg, 5.12 mmol) and water (4 mL). The mixture was degassed with argon for 10 min followed by addition of 1 , 1 bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (139.5 mg, 170.77 umol). Degassing with argon was continued for 5 min. The mixture was warmed to 60 °C for 30 min. The mixture was cooled to 22 °C, treated with aq. sat. NaHCO3 (100 mL) and extracted with ethyl acetate (2 x 100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 40 g, dissolved in DCM, 10-70% [EtOAc / EtOH 3 : 1] in heptane) to obtain the title compound (630 mg, 81%) as light yellow solid. 456.3 / 458.3 [M+H]+ ESI pos.

[0837] Step c) rac-(2R, 4S)-4-[8-(4-chlorophenyl)-4, 7-diketo-2, 3-dimethyl-pyrido[2, 3-d]pyrimidin-6- yl]tetrahydropyran-2-carboxylic acid ethyl ester

[0838] A suspension of 4-[8-(4-chlorophenyl)-4,7-diketo-2,3-dimethyl-pyrido[2,3-d]pyrimidin-6-yl]- 3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (50 mg, 109.7 umol) in ethyl acetate (5 mL) was treated with triethylamine (13.3 mg, 18.3 uL, 131.6 umol) and ethanol (2.5 mL), magnesium oxide (44.2 mg, 1.1 mmol) was added. The flask was purged with nitrogen (3x). Then palladium on carbon, 10% (23.3 mg, 21.9 umol) was added and again purged with ntirogen. H2-balloon was set and evacuation and back-filling with hydrogen was repeated (5 x). The mixture was vigorously stirred at 22 °C for 3 h. The mixture was filtered from catalyst, washed with ethyl acetate (3 x 5 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (RP18, 5.5 g, dissolved in ACN / water+DMSO, 10-80% acetonitrile in water) to obtain the titled compound (43 mg, 86%, 90% purity) as white solid. The product was further purified by flash column chromatography (silica, 4 g, dissolved in DCM, 0-60% [EtOAcZEtOH 3 : 1] in heptane) to obtain the title compound (22 mg, 44%) as white solid. 458.4 / 460.4 [M+H]+ ESI pos.

[0839] Step d) rac-(2R,4S)-4-[8-(4-chlorophenyl)-4, 7-diketo-2,3-dimethyl-pyrido[2,3-d]pyrimidin-6- yl ]tetrahydropyran-2-carboxylic acid

[0840] To a suspension of rac-(2R,4S)-4-[8-(4-chlorophenyl)-4,7-diketo-2,3-dimethyl-pyrido[2,3- d]pyrimidin-6-yl]tetrahydropyran-2-carboxylic acid ethyl ester (266 mg, 580.9 umol) in tetrahydrofiiran (4 mL) and ethanol (2 mL) was added lithium hydroxide monohydrate (73.1 mg, 1.7 mmol) in water (1.74 mL). The mixture was stirred at 22 °C. HC1 (1 M, 1.74 mL) was added to the mixture and was left overnight at 22°C. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20ml). The organic layer was washed with brine. The - I l l - organic layers were dried over sodium sulfate (245mg, 98%) as an off-white solid. 430.2 / 432.2 [M+H]+ ESI pos.

[0841] Step e) rac-(2R, 4S)-4-[8-(4-chlorophenyl)-4, 7-diketo-2, 3-dimethyl-pyrido[2, 3-d]pyrimidin-6-yl]~

[0842] N-methoxy-N-methyl-tetrahydropyran-2-carboxamide

[0843] To a solution of rac-(2S)-4-[8-(4-chlorophenyl)-4,7-diketo-2,3-dimethyl-pyrido[2,3-d]pyrimidin- 6-yl]tetrahydropyran-2-carboxylic acid (225 mg, 523.4 umol) in N,N-dimethylformamide, extra dry (4.52 mL) were added HATU (238.8 mg, 628.1 umol), N,O-dimethylhydroxylamine hydrochloride (56.2 mg, 575.8 umol) and DIEA (270.6 mg, 365.7 uL, 2. 1 mmol). The solution was stirred at rt. The reaction mixture was poured into aq. sat. NaHCO3 (20 mL) and extracted with ethyl acetate (2X 20ml). The combined organic layers were washed with brine dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40g ethyl acetate +EtOH 3 / 1 - Heptane 0% to 80%) to to obtain the title compound as a light yellow crystalline (229 mg, 92%). 473.4 / 475.4 [M+H]+ ESI pos.

[0844] Step j) rac-8-(4-chlorophenyl)-6-[(2R, 4S)-2-(3-cyclopropylpropioloyl)tetrahydropyran-4-yl]~ 2, 3-dimethyl-pyrido[2, 3-d]pyrimidine-4, 7 -quinone

[0845] To a cooled solution of ethynylcyclopropane (38.4 mg, 581.5 umol) in tetrahydro furan, extra dry (2.11 mL) at -78 °C was added 1.6 M BuLi (330.4 uL, 528.6 umol) dropwise and the mixture left for 30 min at this temp. This solution was then added to a cooled -78°C, stirred solution of rac- (2R,4S)-4-[8-(4-chlorophenyl)-4,7-diketo-2,3-dimethyl-pyrido[2,3-d]pyrimidin-6-yl]-N- methoxy-N-methyl-tetrahydropyran-2-carboxamide (50 mg, 105.7 umol) in tetrahydrofiiran, extra dry (2.11 mL) and the reaction mixture was stirred for 30 min at -78°C. The reaction mixture was quenched with 1 M KHSO4 solution at -78 °C, diluted with water and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo.

[0846] The product was purified by chromatography (silica gel, 25g, solid loading, 0% to 60% ethyl acetate / EtOH 3: 1 in heptane) to obtain the title compound (27.3 mg, 67%) as white solid.

[0847] Step g) rac-8-( 4-chlorophenyl)-6-[ (2R, 4S)-2-( 6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4- yl -2, 3-dimethyl-pyrido[ 2, 3-d]pyrimidine-4, 7 -quinone

[0848] 8-(4-chlorophenyl)-6-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (56 mg, 53.11%) as white solid

[0849] To a suspension of 8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2R,4S)-2-(3- cyclopropylpropioloyl)tetrahydropyran-4-yl]pyrido[2,3-d]pyrimidine-4,7-quinone (97 mg, 203 umol) in acetonitrile (2.9 mL) was added at 22 °C formamidine acetate (63.4 mg, 608.9 umol) followed by sodium carbonate (129.1 mg, 1.22 mmol) and heated to 80 °C for 2 h. The reaction was treated with aq. sat. NaHCO3 (20 mL) and extracted with ethyl acetate (3 x 20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). All organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 12 g, dissolved in DCM, 0-40% [EtOAc / EtOH 3: 1] in heptane) to obtain the title compound (80 mg, 78%) as a white solid. 504.2 / 506.2 [M+H]+ ESI pos.

[0850] Step h) 8-(4-chlorophenyl)-6-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]~ 2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7-quinone and 8-(4-chlorophenyl)-6-[(2S,4R)-2-(6- cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2, 3-dimethyl-pyrido[2, 3-d]pyrimidine-4, 7- quinone

[0851] The enantiomers were separated by chiral SFC on a OJ column, eluting with MeOH as the modifier up to 20% to obtain the title compounds 8-(4-chlorophenyl)-6-[(2R,4S)-2-(6- cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7- quinone (18 mg, 32%, 504.2 / 506.2 [M+H]+ ESI pos.) as white solid and 8-(4-chlorophenyl)-6- [(2 S ,4R)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4-yl] -2,3 -dimethyl-pyrido [2,3 - d]pyrimidine-4,7-quinone (19 mg, 34%, 504.2 / 506.2 [M+H]+ ESI pos.) as white solid.

[0852] Example 134

[0853] 5-(4-chlorophenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one

[0854] 5 -(4-chlorophenyl)-7 - [2-(2-keto- 1 H-pyridi n-4-yl )tetrahydropyran-4-y 1] -2, 3 -dimethyl-pyrido [2,3 - b]pyrazin-6-one (90 mg, 175 umol, made in analogy to Example 54 except using Example 126 instead of 4-(4-chloro-2-fluoro-phenyl)-2-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino[2,3-b]pyrazin-3-one) was weighed in a 10 mL Chemvial and dissolved with N,N-dimethylformamide (2 mL). To this solution was added cesium carbonate (114 mg, 350 umol) and iodomethane (37.2 mg, 262.5 umol) at 0 °C. The reaction mixture was stirred at r.t. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (25g, Hept / (EtOAcZEtOH 3: 1) 0-100%) to afford 5-(4-chlorophenyl)-7-[2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4- yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one (82 mg, 89.41%) as light brown oil , 477.3 [M+H]+, ESI pos. The enantiomers were separated by chiral SFC on an OD column, eluting with MeOH as the modifier to give 5-(4-chlorophenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one (19.7 mg, 24.82%) as white lyoph powder , 477.2 [M+H]+, ESI pos.

[0855] Example 169

[0856] 8-(4,4-difluorocyclohexyl)-6-[(lS,3R)-4,4-difluoro-3-(6-keto-l-methyl-3- pyridyl)cyclohexyl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone

[0857] S ridyl)-l,4-dioxaspiro[4.5]decan-8-one

[0858] To a solution of sodium tert-butoxide (11.2 g, 116.8 mmol) in THF (110 mL) were added 1,4- dioxaspiro[4.5]decan-8-one (7.3 g, 46.7 mmol) and 5-bromo-2-methoxypyridine (8.8 g, 46.7 mmol). After 5 min, tri-tert-butylphosphine (11 mL, 4.7 mmol) and palladium (II) acetate (1.05 g, 4.7 mmol) were added to the reaction mixture. The air of the flask was changed with N2. The reaction was stirred for 1 hr. The reaction mixture was poured into water (400 mL), and then extracted with ethyl acetate (200 mL x 3), the organic phase was washed with saturated brine (100 mL x 3), and the combined organic phases were dried over anhydrous Na2SO4, then concentrated under vacuum to give a residue. The residue was purified by silica column(SiO2, 80 g, PE / EtOAc=l / 0-0 / l) and concentrated to obtain the title compound (4.5 g, 17.1 mmol, 36% yield) as yellow solid. LCMS: 264.0 [M+H]+, ESI+

[0859] Step b) 5-(8,8-difluoro-l ,4-dioxaspiro [4.5]decan-7-yl)-2-methoxy-pyridine

[0860] To a yellow solution of 7-(6-methoxy-3-pyridyl)-l,4-dioxaspiro[4.5]decan-8-one (4.5 g, 17. 1 mmol) in DCM (50 mL) was added diethylamino sulfur trifluoride (DAST) (4.24 mL, 34.2 mmol) at 0 °C by dropwise. The reaction mixture was stirred at 20 °C for 16 h. The reaction mixture was poured into saturated NaHCO3 (100 mL) at 0 °C, and then extracted with ethyl acetate (100 mL x 3), the organic phase was washed with saturated brine (100 mL x 3), and the combined organic phases were dried over anhydrous Na2SO4, then concentrated under vacuum to give a residue. The residue was purified by silica column(SiO2, 80 g, PE / EtOAc=l / 0-3 / l) and concentrated to obtain the title compound (4.1 g, 14.4 mmol, 84% yield) as white solid. LCMS: 286.1 [M+H]+, ESI+

[0861] Step c) 4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexanone

[0862] To a colorless solution of 5-(8,8-difluoro-l,4-dioxaspiro[4.5]decan-7-yl)-2-methoxy-pyridine (80.0 mg, 0.28 mmol) in THF (1 mL) was added HC1 (1 M) (1.0 mL, 1.0 mmol, 3.6 eq). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution (20 mL) at room temperature, and extracted with EtOAc(20 mL x 3). Organic phase was washed with brine (20 mL x 3) and dried over Na2SO4, then concentrated in vacuum to give the crude. The crude was purified by Prep-TLC(PE:EtOAc=2: 1) to obtain the title compound (37 mg, 0.15 mmol, 55% yield) as yellow oil. LCMS: 242.1 [M+H]+, ESI+

[0863] Step d) [4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexen-l-yl] trifluoromethanesulfonate To a solution of 4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexanone (3000 mg, 12.4 mmol) and THF (30 mL) was added LiHMDS (16.2 mL, 16.2 mmol) at -78 °C under N2. The mixture was stirred at -78 °C for 0.5 h, then dropped added N,N-bis(trifhioromethylsulfonyl)aniline (4.9 g, 13.7 mmol) in THF (10 mL). The reaction was stirred at -78°C for 0.5 h,then warmed to and stirred at 25 °C for 16 h under N2.

[0864] The mixture was combined with WUX004527-540 and quenched with water(200 mL), the aqueous layer was separated and extracted with DCM(100 mL x 3). The organic layers were washed with brine(100 mL x 2), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica column(SiO2, 40 g, PE / EtOAc=l / 0-5 / l) and concentrated to obtain the title compound (1.95 g, 5.2 mmol, 42% yield) as yellow oil. LCMS: 374.0 [M+H]+ ESI+.

[0865] Step e) 5-[6, 6-difluoro-3-(4, 4,5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)cyclohex-2-en-l-yl]-2- methoxy-pyridine

[0866] To a yellow solution of 7-chloro-9-(4,4-difluorocyclohexen-l-yl)-2,3-dimethyl-pyrimido[l,2- b]pyridazin-4-one (300.0 mg, 0.92 mmol) in 1,4-dioxane (4 mL) were added bis(pinacolato)diboron (281 mg, 1.11 mmol), potassium acetate (271.2 mg, 2.8 mmol) and 1, 1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (75.2 mg, 0.09 mmol). The reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was poured into water (20 mL), and then extracted with ethyl acetate (20 mL x 3), the organic phase was washed with saturated brine (20 mL x 3), and the combined organic phases were dried over anhydrous Na2SO4, then concentrated under vacuum to give a residue. The residue was purified by silica column(SiO2, 20 g, PE / EtOAc=l / 0-5 / l) to obtain the title compound (340 mg, 0.97 mmol, 82% yield) as yellow oil. LCMS: 352.1 [M+H]+, ESI+.

[0867] Step j) 8-(4, 4-difluorocyclohexyl)-6-[ 4, 4-difluoro-3-( 6-methoxy-3-pyridyl) cyclohexen-l-yl -2, 3- dimethyl-pyrido[ 2, 3-d]pyrimidine-4, 7 -quinone

[0868] To a white suspension of 6-bromo-8-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3- d]pyrimidine-4,7-quinone (300 mg, 772.8 umol) in 1,4-dioxane (6 mL) under nitrogen at room temperature, was added 5-[6,6-difhioro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)cyclohex-2-en-l-yl]-2-methoxy-pyridine (508.9 mg, 1.2 mmol) and a solution of potassium carbonate (320.4 mg, 2.3 mmol) in water (1.2 mL). The reaction mixture was purged and backfilled with nitrogen (3 times), followed by addition of 1, l'-bis(diphenylphosphino)ferrocene- palladium(ii)dichloride dichloromethane complex (63.1 mg, 77.3 umol). The reaction mixture was stirred at 60 °C for 2 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. Sat. NaHCO3 was added and both layers were separated. The aqueous one was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude brown oil was purified with flash column chromatography on silica (40 g) eluting with a gradient formed from n-heptane and ethyl acetate (0% to 60% in 15 minutes). The resulting light brown oil was triturated with ethyl acetate and some drops of diethyl ether until precipitation. The resulting off-white solid was triturated 3 times with diethyl ether and then dried to obtain the title compound (266 mg, 62%) as off-white solid MS: 531.3 [M-H]-, ESI neg.

[0869] Step g) 8-(4, 4-difluorocyclohexyl)-6-[ 4, 4-difluoro-3-( 6-methoxy- 3 -pyridyl) cyclohexyl -2, 3- dimethyl-pyrido[ 2, 3-d]pyrimidine-4, 7 -quinone

[0870] To a solution of 8-(4,4-difluorocyclohexyl)-6-[4,4-difluoro-3-(6-methoxy-3-pyridyl)cyclohexen- l-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (265 mg, 497.6 umol) in ethyl acetate (15.8 mL) under nitrogen at room temperature, were added magnesium oxide (243.8 mg, 6.1 mmol) , TRIETHYLAMINE (60.1 mg, 82.8 uL, 594.3 umol) and finally palladium / C 10% (106.5 mg, 100.1 umol) . The reaction mixture was well stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was flushed with argon. The mixture was filtered over a sartorius filter and well rinsed to obtain the title compound (269 mg, 92%) as off- white foam. MS: 535.5 [M+H]+, ESI pos

[0871] Step h) 8-(4, 4-difluorocyclohexyl)-6-[ 4, 4-difluoro-3-( 6-hydroxy-3-pyridyl)cyclohexyl -2, 3- dimethyl-pyrido[ 2, 3-d]pyrimidine-4, 7 -dione

[0872] To a light yellow solution of 8-(4,4-difluorocyclohexyl)-6-[4,4-difluoro-3-(6-methoxy-3- pyridyl)cyclohexyl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (268 mg, 501.4 umol) in acetonitrile (9.9 mL) under nitrogen at room temperature, was added sodium iodide (112.7 mg, 752.0 umol), followed by TMS-C1 (81.7 mg, 96.1 uL, 752.0 umol). The resulting yellow suspension was stirred at 65 °C for 20 hours. The mixture was cooled to room temperature and quenched with water. Ethyl acetate was added. Both layers were separated. The aqueous one was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude yellow oil was purified with flash column chromatography on silica (40 g) eluting with a gradient formed from n-heptane and ethyl acetate (0% to 100% in 15 minutes) and then with ethyl acetate / ethanol (3 : 1) to obtain the title compound (225 mg, 78%) as yellow foam MS: 521.4 [M+H]+, ESI pos

[0873] Step i) 8-(4, 4-difluorocyclohexyl)-6-[ 4, 4-difluoro-3-( 6-keto-l-methyl-3-pyridyl)cyclohexyl -2, 3- dimethyl-pyrido[ 2, 3-d]pyrimidine-4, 7 -quinone To a yellow suspension of 8-(4,4-difluorocyclohexyl)-6-[4,4-difluoro-3-(6-keto-lH-pyridin-3- yl)cyclohexyl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone (70 mg, 134.5 umol) in acetonitrile, extra dry (2.5 mL) under nitrogen at room temperature, were added cesium carbonate (131.4 mg, 403.4 umol) and iodomethane (38.2 mg, 16.8 uL, 269.0 umol). The reaction mixture was stirred at 80 °C for 50 minutes. The mixture was cooled to room temperature and quenched with water. Ethyl acetate was added and both layers were separated. The aqueous one was extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude yellow semi-solid was purified with flash column chromatography on silica (12 g) eluting with a gradient formed from n- heptane and ethyl acetate / ethanol 3 : 1 (0% to 50% in 15 minutes) to obtain the title compound (78 mg, >99%) as light yellow solid MS: 535.4 [M+H]+, ESI pos.

[0874] Step j) 8-(4, 4-difluorocyclohexyl)-6-[ (IS, 3R)-4, 4-difluoro-3-( 6-keto-l-methyl-3- pyridyl) cyclohexyl] -2, 3-dimethyl-pyrido[2, 3-d]pyrimidine-4, 7-quinone

[0875] The racemic compound from Step I was asymmetrically resolved by SFC on a chiral ID column, eluting with MeOH as the modifier up to 50% to obtain the title compound (20.6 mg, 27%) as light yellow solid. MS: 535.32 [M+H]+, ESI pos.

[0876] The following Examples were prepared in analogy to the Examples described above. Specific deviations to the procedures are noted in the “procedure column”. Unless otherwise stated, all enantiomerically pure compounds were obtained by chiral separation on SFC using standard columns and methods known to those skilled in the art. The absolute configuration was assigned arbitraritly.

[0877]

[0878] Example 187

[0879] A compound of formula (I) or (II) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

[0880] Per tablet

[0881] Active ingredient 200 mg

[0882] Microcrystalline cellulose 155 mg

[0883] Corn starch 25 mg

[0884] Talc 25 mg

[0885] Hydroxypropylmethylcellulose 20 mg

[0886] 425 mg

[0887] Example 188

[0888] A compound of formula (I) or (II) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

[0889] Per capsule

[0890] Active ingredient 100.0 mg

[0891] Corn starch 20.0 mg

[0892] Lactose 95.0 mg

[0893] Talc 4.5 mg

[0894] Magnesium stearate 0.5 mg

[0895] 220.0 mg

Claims

Claims1. A compound of formula (I) or (II)or a pharmaceutically acceptable salt thereof, wherein:A is selected from N and CH;A1is selected from O and CR^R2;X1is selected from N and CH;R1is selected from Ci-Ce-alkyl and halo-Ci-Ce-alkyl;R2is selected from halo-Ci-Ce-alkyl, Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6- membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halogen, cyano, Ci-Ce- alkyl, and halo-Ci-Ce-alkyl;R3is selected from 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is optionally substituted with 1-3 substituents independently selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, C3-C10- cycloalkyl, and Cs-Cio-cycloalkyloxy; and wherein said 3- to 6-membered heterocyclyl is optionally substituted with 1-3 substituents independently selected from oxo, Ci-Ce-alkyl, Ci-Ce-alkoxy, and Cs-Cio-cycloalkyl;R4is selected from hydrogen and Ci-Ce-alkyl;R5is selected from hydrogen and Ci-Ce-alkyl;R6is selected from hydrogen and Ci-Ce-alkyl;RA1is selected from hydrogen, halogen, and Ci-Ce-alkyl; and RA2is selected from hydrogen, halogen, and Ci-Ce-alkyl.

2. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A is N;A1is O; andX1is selected from N and CH.

3. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A is CH;A1is O; andX1is selected from N and CH.

4. The compound of formula (I) or (II) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is selected from methyl, CHF2, and CF3.

5. The compound of formula (I) or (II) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Ce-alkyl.

6. The compound of formula (I) or (II) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R1is methyl.

7. The compound of formula (I) or (II) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2is selected from halo-Ci-Ce- alkyl, Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6-membered heteroaryl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl.

8. The compound of formula (I) or (II) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2is selected from 3,3,3- trifluoropropyl, phenyl, cyclohexyl, spiro[3.3]heptane, bicyclo [1.1.1] pentane, and pyridyl, wherein said phenyl, cyclohexyl, spiro[3.3]heptane, bicyclofl . l. l]pentane, and pyridyl are substituted with 1 to 3 substituents independently selected from chloro, fluoro, and CF3.The compound of formula (I) or (II) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2is selected from 3,3,3-10. The compound of formula (I) or (II) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2is selected from phenyl and C3- Ce-cycloalkyl, wherein said phenyl and Cs-Ce-cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl.

11. The compound of formula (I) or (II) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R2is selected from phenyl, cyclohexyl, and bicyclo [1.1.1] pentane, wherein said phenyl, cyclohexyl, and bicyclo [1.1.1] pentane are substituted with 1-3 substituents independently selected from fluoro, chloro, and CF3.

12. The compound of formula (I) or (II) according to claim 11, or a pharmaceuticallyacceptable salt thereof, wherein R2is selected from, and13. The compound of formula (I) or (II) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3is selected from 5- to 6-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, C3-C10- cycloalkyl, and Cs-Cio-cycloalkyloxy; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from Ci-Ce- alkyl and Cs-Cio-cycloalkyl.

14. The compound of formula (I) or (II) according to any one of claims 1 to 12, or apharmaceutically acceptable salt thereof, wherein R3is selected from15. The compound of formula (I) or (II) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3is selected from a 5-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and a 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl and wherein said 6-membered heterocyclyl is substituted with oxo and a further substituent selected from Ci-Ce- alkyl and Cs-Cio-cycloalkyl.

16. The compound of formula (I) or (II) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3is selected from IH-pyrazole and IH-pyridone, wherein said IH-pyrazole and IH-pyridone are substituted with 1 substituent selected from methyl and cyclohexyl.

17. The compound of formula (I) or (II) according to claim 16, or a pharmaceutically18. The compound of formula (I) or (II) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen and methyl.

19. The compound of formula (I) or (II) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

20. The compound of formula (I) or (II) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R5is selected from hydrogen and methyl.

21. The compound of formula (I) or (II) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen.

22. The compound of formula (I) or (II) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R6is hydrogen.

23. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A is selected from N and CH;A1is selected from O and CRA1RA2;X1is selected from N and CH;R1is Ci-Ce-alkyl;R2is selected from halo-Ci-Ce-alkyl, Ce-Cio-aryl, Cs-Cio-cycloalkyl, and 5- to 6- membered heteroaryl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon; wherein said Ce-Cio-arylCs-Cio-cycloalkyl, and 5- to 6-membered heteroaryl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl;R3is selected from 5- to 6-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and 3- to 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 3- to 6-membered heteroaryl is substituted with 1 substituent selected from Ci-Ce-alkyl, Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, and Cs-Cio-cycloalkyloxy; and wherein said 3- to 6-membered heterocyclyl is substituted with oxo and 1 further substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl;R4is hydrogen;R5is selected from hydrogen and Ci-Ce-alkyl;R6is hydrogen;RA1is halogen; andRA2is halogen.

24. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A is selected from N and CH;A1is selected from O and CR^R^;X1is selected from N and CH;R1is methyl;R2is selected from 3, 3, 3 -trifluoropropyl, phenyl, cyclohexyl, spiro[3.3]heptane, bicyclo [1.1.1] pentane, and pyridyl, wherein said phenyl, cyclohexyl, spiro[3.3]heptane, bicyclo [1.1.1] pentane, and pyridyl are substituted with 1 to 3 substituents independently selected from chloro, fluoro, and CF3;R4is hydrogen;R5is selected from hydrogen and methyl;R6is hydrogen;RA1is fluoro; andRA2is fluoro.

25. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A is selected from N and CH;A1is O;X1is selected from N and CH;R1is Ci-Ce-alkyl;R2is selected from phenyl and Cs-Ce-cycloalkyl, wherein said phenyl and C3-C6- cycloalkyl are substituted with 1 to 3 substituents independently selected from halogen and halo-Ci-Ce-alkyl;R3is selected from a 5-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; and a 6-membered heterocyclyl comprising 1 to 2 nitrogen atoms, the remaining atoms being carbon; wherein said 5- membered heteroaryl is substituted with 1 substituent selected from Ci-Ce- alkyl and Cs-Cio-cycloalkyl and wherein said 6-membered heterocyclyl is substituted with oxo and a further substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl;R4is hydrogen;R5is hydrogen; andR6is hydrogen.

26. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A is selected from N and CH;A1is O;X1is selected from N and CH;R1is methyl;R2is selected from phenyl, cyclohexyl, and bicyclofl .

1. l]pentane, wherein said phenyl, cyclohexyl, and bicyclo[l. l.l]pentane are substituted with 1-3 substituents independently selected from fluoro, chloro, and CF3;R3is selected from IH-pyrazole and IH-pyridone, wherein said IH-pyrazole and IH-pyridone are substituted with 1 substituent selected from methyl and cyclohexyl;R4is hydrogen;R5is hydrogen; andR6is hydrogen.

27. The compound of formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) or (II) is selected from:5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[2,3-b]pyrazin-6-one;5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[2-( 1 -methylpyrazol-4-yl)morpholin-4- yl]pyrido[2,3-b]pyrazin-6-one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[2,3-b]pyrazin-3-one;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]pyrido [2,3 -d]pyrimidine-4, 7-quinone;8-(4-chlorophenyl)-2,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]pyrido [2,3 -d]pyrimidine-4, 7-quinone;6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)- 2, 3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7-dione;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrido[2,3-d]pyrimidine-4, 7-dione;8-(4-chlorophenyl)-6- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2, 3 - dimethyl-pyrido [2,3 -d]pyrimidine-4,7-dione;5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[2-( 1 -methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[2,3-b]pyrazin-6-one;5-(4,4-difhrorocyclohexyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)tetrahydropyran- 4-yl]pyrido[2,3-b]pyrazin-6-one;8-(4-chlorophenyl)-2,3-dimethyl-6-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pteridine-4, 7-dione;4-(4-chlorophenyl)-6,7-dimethyl-2-[2-(l-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrazino[2,3-b]pyrazin-3-one;4-(4, 4-difluorocyclohexyl)-6, 7-dimethyl-2-[2-( 1 -methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;2,3 -dimethyl-7-[2-( 1 -methylpyrazol-4-yl)morpholino] -5 -(3 ,3 , 3 - trifluoropropyl)pyrido[2,3-b]pyrazin-6-one;8-(4-chlorophenyl)-6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;8-(4-chlorophenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;8-(4, 4-difluorocyclohexyl)-6- [rac-(2R,4 S)-2-(6-keto- 1 -methyl-3 - pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7-quinone;4-(4-chlorophenyl)-6,7-dimethyl-2-[rac-(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrazino[2,3-b]pyrazin-3-one;5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[(2R,4 S)-2-( 1 -methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[rac-(2S,4R)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;5 -(4, 4-difluorocyclohexyl)-2, 3 -dimethyl-7-[rac-(2R,4 S)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2R,4S)-2-(l-methylpyrazol-4- y l)tetrahydropyran-4-yl] pteridine-4, 7 - dione ;5-(4-chlorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan- 4-yl]pyrazino[2,3-b]pyrazin-3-one;4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methylpyrazol-4-yl)oxan- 4-yl]pyrazino[2,3-b]pyrazin-3-one;4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrazino[2,3-b]pyrazin-3-one;4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methylpyrazol-4-yl)oxan-4- yl]pyrazino[2,3-b]pyrazin-3-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(l-methyl-6-oxopyridin-3- yl)oxan-4-yl]pyrido [2,3 -d]pyrimidine-4, 7-dione;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxopyridin-3- yl)oxan-4-yl]pyrido [2,3 -d]pyrimidine-4, 7-dione;4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2R)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrazino[2,3-b]pyrazin-3-one;4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrazino[2,3-b]pyrazin-3-one;4-(4-chlorophenyl)-2- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6, 7 - dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;7- [2-( 1 -cyclopropylpyrazol-4-yl)morpholino] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethyl-pyrido[2,3-b]pyrazin-6-one;7-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-5-(4,4-difluorocyclohexyl)-2,3 -dimethylpyrido [2,3 -b]pyrazin-6-one;7-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-5-(4,4-difluorocyclohexyl)-2,3 -dimethylpyrido [2,3 -b]pyrazin-6-one;6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)- 2, 3-dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;7 - [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;7 - [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -5 -(4,4-difluorocyclohexyl)-2, 3 - dimethylpyrido[2,3-b]pyrazin-6-one;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[2-(l-methylpyrazol-4- y l)tetrahydropyran-4-yl] pteridine-4, 7 - dione ;4-(4-chloro-2-fluoro-phenyl)-2-[(2S,4R)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-oxo-lH-pyridin-4- yl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-(4,4- difluorocyclohexyl)-6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;2- [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -4-(4,4- difluorocyclohexyl)-6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2,3-dimethyl-pteridine-4, 7-dione;8-(4-chlorophenyl)-6- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2, 3 - dimethyl-pteridine-4, 7 -dione;8-(4-chlorophenyl)-2,3-dimethyl-6-[rac-(2S,4R)-2-(l-cyclopropylpyrazol-4- y l)tetrahydropyran-4-yl] pteridine-4, 7 - dione ;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-cyclopropyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;5-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrido[2,3-b]pyrazin-6-one;2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-4-(4,4-difluorocyclohexyl)-6, 7-dimethylpyrazino [2,3 -b]pyrazin-3 -one;2-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-4-(4,4-difluorocyclohexyl)-6.7-dimethylpyrazino [2,3 -b]pyrazin-3 -one;6-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)- 2, 3-dimethylpteridine-4, 7-dione;6-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-8-(4,4-difluorocyclohexyl)- 2, 3-dimethylpteridine-4, 7-dione;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methylpyrazol-4-yl)oxan- 4-yl]pyrido[2,3-d]pyrimidine-4, 7-dione;4-(4, 4-difluorocyclohexyl)-2- [(2 S ,4R)-2-(2-methoxypyridin-4-yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;4-(4, 4-difluorocyclohexyl)-2- [(2R,4 S)-2-(2-methoxypyridin-4-yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;4-(4, 4-difluorocyclohexyl)-2- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;4-(4, 4-difluorocyclohexyl)-2- [(2 S ,4R)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -6,7- dimethylpyrazino [2,3 -b]pyrazin-3 -one;6-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-8- [3-(trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]pyrido[2,3-d]pyrimidine-4,7- quinone;6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-8-[3- (trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]pyrido[2,3-d]pyrimidine-4, 7-dione;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-8-[3- (trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]pyrido[2,3-d]pyrimidine-4, 7-dione;8-(4, 4-difluorocyclohexyl)-6- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpteridine-4, 7-dione;4-(4-chlorophenyl)-2- [(2 S ,4R)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6.7-dimethyl-pyrazino[2,3-b]pyrazin-3-one;4-(4-chlorophenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one;4-(4-chlorophenyl)-2- [(2 S ,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] - 6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one;4-(4-chlorophenyl)-2-[(2R,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7-dimethyl-pyrazino[2,3-b]pyrazin-3-one;8-(4-chloro-2-fluoro-phenyl)-6-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone;5-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4- yl] -2, 3 -dimethylpyrido [2,3 -b]pyrazin-6-one;8-(4,4-difluorocyclohexyl)-6-[(2S,4R)-2-(6-methoxy-3-pyridyl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone;5 -(4-chloro-2-fluorophenyl)-7 - [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3 -dimethylpyrido [2,3 -b]pyrazin-6-one;5 -(4-chloro-2-fluorophenyl)-7 - [(2 S ,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -2,3 -dimethylpyrido [2,3 -b]pyrazin-6-one;8-(4-chlorophenyl)-6-[(2S,4R)-2-(6-methoxypyridin-3-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;8-(4-chlorophenyl)-6-[(2R,4S)-2-(6-methoxypyridin-3-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(2-methoxypyridin-4-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;6- [(2 S,4R)-2-( 1 -cyclopropyl-6-oxopyridin-3 -yl)oxan-4-yl] -8-(4, 4- difluorocyclohexyl)-2, 3 -dimethylpyrido [2,3 -d]pyrimidine-4, 7-dione;6- [(2R,4 S)-2-( 1 -cyclopropyl-6-oxopyridin-3 -yl)oxan-4-yl] -8-(4, 4- difluorocyclohexyl)-2, 3 -dimethylpyrido [2,3 -d]pyrimidine-4, 7-dione;8-(4, 4-difluorocyclohexyl)-6- [(2R,4 S)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;6-[2-(l-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;8-(4-chlorophenyl)-6- [2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl]-2, 3 - dimethyl-pyrido [2, 3 -d]pyrimidine-4, 7-quinone;8-(4-chlorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxopyridin-3-yl)oxan-4- yl]pyrido[2,3-d]pyrimidine-4, 7-dione;5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;8-(4, 4-difluorocyclohexyl)-6- [(2 S ,4R)-2-(6-methoxypyridin-3 -yl)oxan-4-yl] -2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;8-(4-chlorophenyl)-6- [(2 S ,4R)-2-( 1 -cyclopropyl-6-oxopyridin-3 -yl)oxan-4-yl] -2, 3 - dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;8-(4-chlorophenyl)-6-[(2R,4S)-2-(l-cyclopropyl-6-oxopyridin-3-yl)oxan-4-yl]-2,3- dimethylpyrido[2,3-d]pyrimidine-4, 7-dione;6-[2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl]-8-(4,4- difluorocyclohexyl)-2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;6- [(2 S,4R)-2-( 1 -cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl] -8-(4, 4- difluorocyclohexyl)-2, 3 -dimethylpyrido [2,3 -d]pyrimidine-4, 7-dione;6- [(2R,4 S)-2-( 1 -cyclopropyl-2-oxopyridin-4-yl)oxan-4-yl] -8-(4, 4- difluorocyclohexyl)-2, 3 -dimethylpyrido [2,3 -d]pyrimidine-4, 7-dione;2- [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -4-(2,2-difluorospiro [3.3 ]heptan- 6-yl)-6, 7-dimethylpyrazino [2,3 -b]pyrazin-3 -one;2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-4-(2,2-difluorospiro[3.3]heptan- 6-yl)-6, 7-dimethylpyrazino [2,3 -b]pyrazin-3 -one;8-(4,4-difluorocyclohexyl)-6-[2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;8-(4,4-difluorocyclohexyl)-6-[2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;8-(4,4-difluorocyclohexyl)-6-[rac-(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7-quinone;8-(4,4-difluorocyclohexyl)-6-[(2R,4S)-2-(2-keto-l-methyl-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4, 7-quinone;-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,2- difluorospiro[3.3 ]heptan-6-yl)-2, 3 -dimethyl-pyrido[2,3 -d]pyrimidine-4,7- quinone; -[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(2,2- difluorospiro[3.3 ]heptan-6-yl)-2, 3 -dimethyl-pyrido[2,3 -d]pyrimidine-4,7- quinone; -(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one; -(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran- 4-yl]pyrido[2,3-b]pyrazin-6-one; -(4-chlorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3- dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone; -(4-chloro-2, 6-difluoro-phenyl)-2- [2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran- 4-yl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one; -(4, 4-difluorocyclohexyl)-7 - [(2 S ,4R)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one; -(4-chlorophenyl)-7 - [(2R,4 S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one; -(4-chlorophenyl)-7 - [(2 S ,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one; -(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran- 4-yl]pyrazino[2,3-b]pyrazin-3-one; -(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[2,3-b]pyrazin-3-one; -(4-chlorophenyl)-7 - [(2R,4 S)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one; -(4-chlorophenyl)-7 - [(2 S ,4R)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -2,3- dimethyl-pyrido[2,3-b]pyrazin-6-one; -(4-chlorophenyl)-7-[(2R,4S)-2-(2-keto-l-methyl-4-pyridyl)tetrahydropyran-4-yl]-2,3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one; -(4-chlorophenyl)-7-[(2R,4S)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one; -(4-chlorophenyl)-7 - [(2 S ,4R)-2-(6-keto- 1 -methyl-3 -pyridyl)tetrahydropyran-4-yl] -2,3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;4-(4-chlorophenyl)-2-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;4-(4-chlorophenyl)-2- [(2 S ,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl] -6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;4-(4-chlorophenyl)-2-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;4-(4-chlorophenyl)-2- [(2 S ,4R)-2-(6-methoxy-3 -pyridyl)tetrahydropyran-4-yl] -6,7- dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chlorophenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chlorophenyl)-6,7-dimethyl-2-[(2S,4R)-2-(l-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyridin-4-yl)oxan- 4-yl]pyrido[2,3-d]pyrimidine-4, 7-dione;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrido[2,3-d]pyrimidine-4,7-quinone;5-(4-chlorophenyl)-7-[(2R,4S)-2-(l-cyclopropyl-2-keto-4-pyridyl)tetrahydropyran- 4-yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;5 -(4-chlorophenyl)-7 - [(2 S ,4R)-2-( 1 -cyclopropyl-2-keto-4-pyridyl)tetrahydropyran- 4-yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;5 -(4-chlorophenyl)-7 - [(2 S ,4R)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran- 4-yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;5-(4-chlorophenyl)-7-[(2R,4S)-2-(l-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran- 4-yl] -2, 3 -dimethyl-pyrido [2,3 -b]pyrazin-6-one;8-(4-chlorophenyl)-6-[(2R,4S)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;8-(4-chlorophenyl)-6-[(2S,4R)-2-(6-cyclopropylpyrimidin-4-yl)tetrahydropyran-4- yl] -2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4,7-quinone;7 - [(2R,4 S)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl] -5 -(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;7 - [(2 S,4R)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl] -5 -(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;4-(4-chloro-2,6-difluoro-phenyl)-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;4-(4-chloro-2, 6-difluoro-phenyl)-2- [(2 S ,4R)-2-( 1 -cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl] -6, 7-dimethyl-pyrazino [2,3 -b]pyrazin-3 -one;8-(4,4-difluorocyclohexyl)-6-[(2S,4R)-2-(2-keto-l-methyl-4-pyridyl)-2-methyl- tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone;2- [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -4- [3 -(difluoromethyl)- 1 -bicyclo[ 1.

1. l]pentanyl]-6,7-dimethyl-pyrazino[2,3-b]pyrazin- 3 -one;5-(2,2-difluorospiro[3.3]heptan-6-yl)-7-[(2R,4S)-2-(6-keto-l-methyl-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;2- [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] -6, 7-dimethyl-4-[3 - (trifluoromethyl)-l -bicyclo [1.

1. l]pentanyl]pyrazino[2,3-b]pyrazin-3-one;8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pteridine-4, 7-dione;7 - [(2R,4 S)-2-( 1 -cyclopropyl-2-keto-4-pyridyl)tetrahydropyran-4-yl] -5 -(4,4- difluorocyclohexyl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;5 -(4-chloro-2, 6-difluoro-phenyl)-7 - [(2R,4 S)-2-(6-keto- 1 -methyl-3 - pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;5 -(4-chloro-2, 6-difluoro-phenyl)-7 - [(2R,4 S)-2-(6-methoxy-3 - pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;7 - [(2R,4 S)-2-( 1 -cyclopropyl-6-keto-3 -pyridyl)tetrahydropyran-4-yl] -5 -(2,2- difluorospiro[3.3]heptan-6-yl)-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-8-[6- (trifluoromethyl)-3-pyridyl]pyrido[2,3-d]pyrimidine-4,7-quinone;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-d]pyrimidine-4,7-quinone;8-(4-chloro-2,6-difluoro-phenyl)-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pteridine-4,7-quinone;8-(4,4-difluorocyclohexyl)-6-[(lS,3R)-4,4-difluoro-3-(6-keto-l-methyl-3- pyridyl)cyclohexyl] -2, 3 -dimethyl-pyrido [2,3 -d]pyrimidine-4, 7-quinone;5 -(4-chloro-2, 6-difluoro-phenyl)-7 - f(2R,4 S)-2- [6-(cyclopropoxy)-3 - pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;5 -(4-chloro-2, 6-difluoro-phenyl)-7 - f(2R,4 S)-2-( 1 -cyclopropyl-6-keto-3 - pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[2,3-b]pyrazin-6-one;4-(4-chloro-2,6-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-cyclopropyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2,6-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pteridine-4, 7-dione;8-(4-chloro-2, 6-difluoro-phenyl)-2, 3 -dimethyl-6-[(2R,4S)-2-( 1 -cyclopropylpyrazol- 4-yl)tetrahydropyran-4-y 1] pteridine-4, 7- dione ;8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pteridine-4, 7-dione;2,3-dimethyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)- 1 -bicyclof 1.

1. l]pentanyl]pteridine-4, 7-dione;5-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;5-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrido[2,3-b]pyrazin-6-one;4-(4-chloro-2,6-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(l-methyl-2-oxo-4- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2,6-difluoro-phenyl)-6,7-dimethyl-2-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;4-(4-chloro-2, 6-difluoro-phenyl)-6, 7-dimethyl-2-[(2R,4S)-2-( 1 -methyl-6-oxo-3 - pyridyl)tetrahydropyran-4-yl]pyrazino[2,3 -b]pyrazin-3 -one;6-[(2R,4S)-2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-8-[3- (trifluoromethyl)- 1 -bicyclof 1.

1. l]pentanyl]pteridine-4, 7-dione;6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)- 1 -bicyclof 1.

1. l]pentanyl]pteridine-4, 7-dione;8-(2,2-difluorospiro[3.3]heptan-6-yl)-6-[(2R,4S)-2-(6-methoxy-3- pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pteridine-4, 7-dione; and28. 8-(2,2-difluorospiro[3.3]heptan-6-yl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]pteridine-4, 7-dione. The compound of formula (I) or(II) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

29. A pharmaceutical composition comprising a compound of formula (I) or (II) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

30. A method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28.

31. The method according to claim 29, wherein said condition associated with a loss of function of human TREM2 is selected from Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

32. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28, for use in a method according to claim 29 or 30.

33. Use of a compound according to any one of claims 1 to 26, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to claim 28, in a method according to claim 29 or 30.

34. Use of a compound according to any one of claims 1 to 26, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to claim 29 or 30.

35. The invention as described hereinbefore.

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