Condensed pyrimidine derivates ALS TREM2 agonists

Abstract

The invention provides compounds having the general formula (I) wherein A, X1, X2, R1, R2, R3, R4, and R5 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 PYRIMIDINE DERIVATES ALS TREM2 AGONISTS

[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) wherein A, X1, X2, R1, R2, R3, R4, and R5are as defined herein.

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

[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, and l-bicyclo[2.2.2]octanyl. Particularly preferred, yet nonlimiting examples of cycloalkyl are cyclopropyl, bicyclofl. l.l]pentanyl 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 a pharmaceutically acceptable salt thereof, wherein:

[0032] A, X1, and X2are each independently selected from N and CH;

[0033] R1is selected from Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Cs-Cio-cycloalkyl, and 3- to 6- membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon;

[0034] 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;

[0035] 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;

[0036] R4is selected from hydrogen and Ci-Ce-alkyl; and

[0037] R5is selected from Ci-Ce-alkyl and 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon.

[0038] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0039] A and X1are each independently selected from N and CH; and X2is N.

[0040] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0041] A is CH;

[0042] X1is selected from N and CH; and

[0043] X2is N.

[0044] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0045] X1is selected from N and CH; and

[0046] X2is N.

[0047] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from N and CH.

[0048] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is N.

[0049] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is CH.

[0050] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X1is selected from N and CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X1is N.

[0051] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X1is CH.

[0052] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X2is selected from N and CH

[0053] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X2is N.

[0054] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X2is CH.

[0055] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is selected from methyl, CHF2, cyclopropyl, and oxetanyl.

[0056] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is Ci-Ce-alkyl.

[0057] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is methyl.

[0058] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from

[0059] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is Ce-Cio-aryl substituted with 1 to 2 substituents independently selected from halogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted with 1-2 substituents independently selected from fluoro and chloro.

[0060] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is

[0061] In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is

[0062] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from

[0063] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from a 5- membered heteroaryl comprising 2 nitrogen atoms, the remaining atoms being carbon; and a 6- membered heterocyclyl comprising 1 nitrogen atom, the remaining atoms being carbon; wherein said 3- to 6-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 1 Ci- Ce-alkyl substituent.

[0064] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from IH-pyrazole and lH-pyridin-2-one; wherein said IH-pyrazole is substituted with 1 substituent selected from methyl and cyclopropyl and said lH-pyridin-2-one is substituted with 1 methyl substituent.

[0065] In a particularly preferred embodiment, the present invention provides a compound of formula

[0066] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from

[0067] In a preferred embodiment, the present invention provides a compound of formula (I) 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.

[0068] In a preferred embodiment, the present invention provides a compound of formula (I) 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 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl.

[0069] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl. In a particularly preferred embodiment, the present invention provides a compound of formula

[0070] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is selected from

[0071] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen and methyl.

[0072] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

[0073] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is selected from methyl, ethyl, and oxetanyl.

[0074] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is Ci-Ce-alkyl.

[0075] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5is methyl.

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

[0077] R1is selected from methyl, CHF2, cyclopropyl, and oxetanyl; and

[0078] R5is selected from methyl, ethyl, and oxetanyl.

[0079] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1and R5are both Ci- Ce-alkyl.

[0080] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1and R5are both methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0081] R4is selected from hydrogen and methyl.

[0082] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0083] 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

[0084] R4is hydrogen.

[0085] In a further preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0086] 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 substituent selected from Ci-Ce-alkyl and Cs-Cio-cycloalkyl; and

[0087] R4is hydrogen.

[0088] In a particularly preferred embodiment, the present invention provides a compound of formula

[0089] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0090] R3is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl; and R4is hydrogen.

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

[0092] R3is selected from

[0093] R4is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0094] A, X1, and X2are each independently selected firom N and CH;

[0095] R1is selected from methyl, CHF2, cyclopropyl, and oxetanyl;

[0096] R4is selected from hydrogen and methyl; and

[0097] R5is selected from methyl, ethyl, and oxetanyl.

[0098] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0099] A and X1are each independently selected from N and CH;

[0100] X2is N;

[0101] R1is Ci-Ce-alkyl;

[0102] R2is Ce-Cio-aryl substituted with 1 to 2 substituents independently selected from halogen;

[0103] 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;

[0104] R4is hydrogen; and

[0105] R5is Ci-Ce-alkyl.

[0106] In a particularly preferred embodiment, the present invention provides a compound of formula

[0107] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0108] A and X1are each independently selected from N and CH;

[0109] X2is N;

[0110] R1is methyl; R2is phenyl substituted with 1-2 substituents independently selected from fluoro and chloro;

[0111] R3is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl;

[0112] R4is hydrogen; and

[0113] R5is methyl.

[0114] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from:

[0115] 8-(4-chloro-2-fluorophenyl)-6- [(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -1,3- dimethylpyrido[3,4-d]pyrimidine-2, 4-dione;

[0116] 8-(4-chloro-2-fluorophenyl)-6- [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -1,3- dimethylpyrido[3,4-d]pyrimidine-2, 4-dione;

[0117] 8-(4-chlorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4- d]pyrimidine-2, 4-dione;

[0118] 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidine-2, 4-dione;

[0119] 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidine-2, 4-dione;

[0120] 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione;

[0121] 8-(4-chloro-2-fluoro-phenyl)- 1 , 3 -dimethyl-6-[(2S,4R)-2-( 1 -cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione;

[0122] 8-(4-chlorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4- d]pyrimidine-2, 4-dione;

[0123] 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidine-2, 4-dione;

[0124] 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidine-2, 4-dione;

[0125] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- l,3-dimethyl-pyrimido[5,4-d]pyrimidine-2,4-quinone;

[0126] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-8-(4,4-difluorocyclohexyl)-l,3- dimethylpyrido[3,4-d]pyrimidine-2, 4-dione; 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(l-methylpyrazol-4-yl)tetrahydropyran- 4-yl]pyrido[3,4-d]pyrimidine-2,4-quinone;

[0127] 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidine-2,4-quinone;

[0128] 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidine-2,4-quinone;

[0129] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-l,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l. l.l]pentanyl]pyrido[3,4-d]pyrimidine-2, 4-dione;

[0130] 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,4R)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]- l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone;

[0131] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]- l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone;

[0132] 6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,3-dimethyl-8-[3-

[0133] (trifluoromethyl)- 1 -bicyclof 1.1. l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone; and 6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,3-dimethyl-8-[3- (trifluoromethyl)- 1 -bicyclof 1.1. l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone.

[0134] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from:

[0135] 8-(4-chloro-2-fluorophenyl)-6- f(2R,4 S)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -1,3- dimethylpyrido[3,4-d]pyrimidine-2, 4-dione;

[0136] 8-(4-chloro-2-fluorophenyl)-6- [(2 S,4R)-2-( 1 -cyclopropylpyrazol-4-yl)oxan-4-yl] -1,3- dimethylpyrido[3,4-d]pyrimidine-2, 4-dione;

[0137] 8-(4-chlorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4- d]pyrimidine-2, 4-dione;

[0138] 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidine-2, 4-dione; and

[0139] 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidine-2, 4-dione.

[0140] In a 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-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione;

[0141] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-

[0142] 1.3-dimethyl-pyrimido[5,4-d]pyrimidine-2,4-quinone; and

[0143] 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4-yl]-

[0144] 1.3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone.

[0145] In a 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-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]- l,3-dimethylpyrido[3,4-d]pyrimidine-2, 4-dione.

[0146] In a 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-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]- l,3-dimethylpyrido[3,4-d]pyrimidine-2, 4-dione.

[0147] In a 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-chlorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidine-2, 4-dione.

[0148] In a 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-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione.

[0149] In a 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-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-2, 4-dione.

[0150] In a 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-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione. In a 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-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-l,3-dimethyl-pyrimido[5,4-d]pyrimidine-2,4-quinone.

[0151] In a 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-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(6-keto-l-methyl-3- pyridyl)tetrahydropyran-4-yl]-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone.

[0152] In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein as free bases.

[0153] In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H,nC,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. Certain isotopically-labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0154] 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) wherein one or more hydrogen atoms, preferrably 1-3 hydrogen atoms have been replaced by deuterium.

[0155] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0156] Processes of Manufacturing

[0157] The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.

[0158] If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0159] If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0160] A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) - insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0161] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0162] In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0163] 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.

[0164] The following abbreviations are used in the present text: °C degrees Celsius

[0165] Ac = acetyl

[0166] CAS Chemical Abstracts Service registry number

[0167] CO2 carbon dioxide DCM dichloromethane

[0168] DIEA N,N-Diisopropylethylamine

[0169] EA ethyl acetate

[0170] ECso half maximal effective concentration eq equivalent

[0171] ESI electron spray ionization

[0172] Et ethyl

[0173] Ex. example

[0174] HPLC high performance liquid chromatography m / z mass-to-charge ratio mg milligram min minute ml milliliter mm millimeter mmol millimole

[0175] MS mass spectrometry

[0176] NMR nuclear magnetic resonance spectroscopy

[0177] PE petroleum ether pH potential of hydrogen pos. positive psi pounds per square inch

[0178] R Rectus according to the Cahn-Ingold-Prelog priority rules

[0179] RP reverse phase

[0180] RPM revolutions per minute s second

[0181] S Sinister according to the Cahn-Ingold-Prelog priority rules

[0182] SFC supercritical fluid chromatography tBME tert-butyl methyl ether

[0183] THF tetrahydrofuran

[0184] TLC thin layer chromatography pl microliter pm micrometer pmol micromoles

[0185] Scheme 1

[0186] The present compounds of formula I can be prepared by the synthesis of a (hetero)aryl core unit

[0187] (1) followed by successive functionalizations to install the various substituents around this core. The (hetero)aryl core 1 may be generated from a suitably functionalized amino-(hetero)aryl-ester

[0188] (2) (Wi, W2 = Cl, Br, I; R = small alkyl, such as Me or Et), via a cyclization reaction, e.g. using trichloroacetyl isocyanate, followed by ammonia (Scheme 1). The order in which the various substituents are installed around the core can be varied.

[0189] Typically the R1and R5groups may be installed via alkylation (e.g. using a base such as NaH, and a suitable alkyl-halide Rx-Y or R5-Y, where Y = Br, I). Alkylation typically proceeds preferentially at the R5 position, such that a mono-alkylated product may be isolated, and an independent alkylation reaction may be carried out to install an Ri group.

[0190] The R2group may be installed via a metal-catalyzed cross-coupling, such as a Suzuki or Buchwald reaction (e.g. where R2 = (hetero)aryl, a suitably functionalized-boronic acid R2- B(OH)2 could be coupled via a palladium-catalyzed Suzuki reaction). (Scheme 2, synthesis of 3).

[0191] Where A = N, the substituted morpholine may be installed via a Buchwald cross-coupling (e.g. using a palladium catalyst such as PdCl(crotyl)Qphos and a base such as CS2CO3). Alternatively, for pyrimidine-type cores (Xi = X2 = N), an SNAT reaction may be carried out (e.g. by heating in the presence of a base such as DIEA).

[0192] Where A = CH, the tetrahydropyran unit may be installed via Suzuki reaction with a suitable alkene-boronic acid or ester 4, to generate an alkene 5, which was then subjected to hydrogenation (e.g. using PtCh or RI1 / AI2O3 and H2 gas) to give 6. (Scheme 2) hydrogenation

[0193] Scheme 2

[0194] The required alkene-boronic esters (4) 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.

[0195] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the process is as described in any one of schemes 1 or 2.

[0196] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein.

[0197] TREM2 Agonistic Activity

[0198] Compounds of the present invention are TREM2 agonists. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for restoring the function of human TREM2 in a subject in need thereof.

[0199] In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of restoring the function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for restoring the function of human TREM2 in a subject in need thereof.

[0200] In a further aspect, the present invention provides a method for restoring the function of human TREM2 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) as described herein to the subject.

[0201] TREM2 agonist potency of the compounds of formula (I) according to the invention was measured using a HEK cell line expressing human TREM2 and DAP12. Upon binding of small molecule ligands to the TREM2 receptor, Syk kinase is recruited and activated by DAP12. The resulting increased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit.

[0202] 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.

[0203] 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 (IpM tool compound) controls were also added.

[0204] 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.

[0205] TREM2 agonistic potencies of the compounds of formula (I) according to the invention as measured in the assay described above are presented in Table 1.

[0206] Table 1

[0207] Using the Compounds of the Invention

[0208] In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein for use as a therapeutically active substance. In a further aspect, the present invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition described herein, in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.

[0209] In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof.

[0210] 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.

[0211] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Parkinson’s disease.

[0212] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is rheumatoid arthritis.

[0213] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Alzheimer’s disease.

[0214] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis.

[0215] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease.

[0216] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia.

[0217] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis.

[0218] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke.

[0219] Pharmaceutical Compositions and Administration

[0220] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0221] In one embodiment, there is provided a pharmaceutical composition according to Example 16 or 17.

[0222] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

[0223] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, 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.

[0224] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0225] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0226] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0227] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0228] 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.

[0229] 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.

[0230] Examples

[0231] 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.

[0232] 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.

[0233] The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers. According to the Cahn-Ingold- Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration. For the compounds described in the patent the absolute stereochemistry was arbitrarily assigned.

[0234] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0235] The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1.

[0236] Example 1

[0237] 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl] py rido [3, 4-d] pyrimidine-2, 4-dione and Example 2

[0238] 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(25',41?)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl] py rido [3, 4-d] pyrimidine-2, 4-dione

[0239] To a solution of 8-(4-chloro-2-fluoro-phenyl)-6-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone (100 mg, 199 pmol) in methanol (2 mL) was added Rh / AI2O3 5% (95.3 mg, 46.3 pmol). The mixture was stirred under H2 atmosphere at room temp for 6 h, and then overnight. The reaction mixture was filtered through a syringe-filter and washed with DCM:MeOH 9: 1. The filtrate was concentrated in vacuo. The crude material was purified by prep HPLC to obtain the title compound racemate (16.5 mg, 15.6%) as white solid. This material was purified by chiral SFC to obtain the title compounds Example 1 (4 mg, 3.98%) as white solid; MS (ESI): m / z = 510.2 [M+H]+, and Example 2 (3.5 mg, 3.49%) as white solid; MS (ESI): m / z = 510.2 [M+H]+. Enantiomers are arbitrarily assigned.

[0240] Step a) 6, 8-dichloro-lH-pyrido [ 3, 4-d]pyrimidine-2, 4-quinone

[0241] 3-amino-2,6-dichloro-isonicotinic acid methyl ester (CAS: 883107-62-8) (1.5 g, 6.79 mmol ) was dissolved in tetrahydrofiiran (19 mL) and trichloroacetyl isocyanate (1.92 g, 1.21 mL, 10.2 mmol) was added at rt. The mixture was stirred for 2 h at rt. The reaction mixture was concentrated to dryness. The crude material taken up with methanol (8 mL) and ammonia (7 N in MeOH) (763 mg, 969 pL, 6.79 mmol) was added. The mixture was stirred for 2 h at rt. Solids were filtered off, washed with MeOH and dried in vacuuo to obtain the crude title compound 6, 8-dichloro-lH-pyrido[3,4-d]pyrimidine-2, 4-quinone (1.61 g, 102%) as yellow solid, which was used directly without further purification. MS (ESI): m / z = 232.0 [M+H]+.

[0242] Step b) 6, 8-dichloro-l, 3-dimethyl-pyrido[ 3, 4-d]pyrimidine-2, 4-quinone

[0243] 6,8-dichloro-lH-pyrido[3,4-d]pyrimidine-2,4-quinone (1 g, 4.31 mmol ) was suspended in N,N- dimethylformamide (17. 1 mL) and NaH (362 mg, 9.05 mmol) was added at 0 °C. The mixture was stirred for 30 min at 0 °C before iodomethane (1.35 g, 590 pL, 9.48 mmol) was added. The ice-bath was removed and the mixture was stirred over night at rt. The reaction mixture was quenched with water, and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over MgSCU and concentrated to dryness. The crude material was suspended with tBME and stirred for 2 min. Solids were filtered off, re-suspended with MeOH and stirred again for 2 min. Solids were filtered off again. The combined filtrates (tBME and MeOH solutions) were concentrated to dryness, and purified by flash chromatography on silica gel (EtOAc in Heptane 0-100%) to yield the title compound (569 mg, 21%) as white solid. MS (ESI): m / z = 260.0 [M+H]+.

[0244] Note: Filtered solids were isolated as pure side product 6,8-dichloro-3-methyl-lH-pyrido[3,4- d]pyrimidine-2,4-quinone (347 mg, 28.24%) as white solid. MS (ESI): m / z = 244.0 [M+H]+.

[0245] Step c) 6-chloro-8-( 4-chloro-2-fluoro-phenyl)-l, 3-dimethyl-pyrido[ 3, 4-d]pyrimidine-2, 4- quinone

[0246] 6,8-dichloro-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone (250 mg, 961 pmol) was dissolved in 1,4-dioxane (6 mL) and (4-chloro-2-fluoro-phenyl)boronic acid (335 mg, 1.92 mmol) and 2 M cesium carbonate solution (aq.) (1.44 mL, 2.88 mmol) were added at rt and degassed with Argon. l, r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (78.5 mg, 96.1 pmol) was added and the mixture was stirred overnight at 50 °C. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were dried over MgSO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (EtOAc in Heptane 0-100%) to obtain the title compound (222 mg, 54%) as white solid. MS (ESI): m / z = 354.1 [M+H]+.

[0247] Step d) 8-(4-chloro-2-fluoro-phenyl)-6-[6-(l-cyclopropylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4- yl -l, 3-dimethyl-pyrido[ 3, 4-d]pyrimidine-2, 4-quinone

[0248] 6-chloro-8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone (100 mg, 282 pmol) was suspended in 1,4-dioxane (2 mL). l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (A.1; CAS: 2738496-36-9) (179 mg, 565 pmol) and 3 M cesium carbonate solution (aq.) (282 pL, 847 pmol ) were added at rt. The mixture was degassed with Argon, then l, l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (23.3 mg, 28.2 pmol) was added. The mixture was stirred at 60 °C for 3 h. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were dried over MgSO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (EtOAc in Heptane 0-100%, then MeOH in DCM 0-10%) to obtain the title compound (100 mg, 66.24%) as light brown solid. MS (ESI): m / z = 508.2 [M+H]+.

[0249] Example 3

[0250] 8-(4-chlorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl] py rido [3, 4-d] pyrimidine-2, 4-dione

[0251] (2S)-2-(l-methylpyrazol-4-yl)morpholine (CAS: 2349914-19-6) (32.3 mg, 193 pmol) was dissolved in 1,4-dioxane (1 mL) and 6-chloro-8-(4-chlorophenyl)-l,3-dimethyl-pyrido[3,4- d]pyrimidine-2,4-quinone (50 mg, 149 pmol) and 2 M cesium carbonate solution (aq.) (223 pL, 446 pmol) were added at rt. The mixture was degased with Argon before PdCl(crotyl)QPhos (13.5 mg, 14.9 pmol) was added. The mixture was stirred for 4 h at 100 °C. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were dried over MgSO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (MeOH in DCM 0-5%) to yield the title compound as light yellow solid (13 mg, 17%, 89% purity). MS (ESI): m / z = 467.2 [M+H]+.

[0252] Step a) 6-chloro-8-(4-chlorophenyl)-l , 3-dimethyl-pyrido[ 3, 4-d]pyrimidine-2, 4-quinone

[0253] 6,8-dichloro-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone (synthesized in Examples 1 and 2, Step b) (250 mg, 961 pmol) was dissolved in 1,4-dioxane (3.81 mL) and (4- chlorophenyl)boronic acid (150 mg, 961 pmol) and 3 M cesium carbonate (aq.) (940 mg, 2.88 mmol) were added at rt. The mixture was degased with argon and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (78.5 mg, 96.1 pmol) was added at rt, and the mixture was stirred for 2 h. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were washed with water and brine, dried over Na?SO4 and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (Heptane: EtOAc 0-50%). To further improve purity the resulting crude was purified again with reverse phase chromatography to yield the title compound as white solid (109 mg, 29%, 86% purity). MS (ESI): m / z = 336.0 [M+H]+.

[0254] Example 4

[0255] 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- y 1] py rido [3, 4-d] pyrimidine-2, 4-dione

[0256] (2S)-2-(l-methylpyrazol-4-yl)morpholine (CAS: 2349914-19-6) (24.6 mg, 147 pmol) was dissolved in 1,4-dioxane (1.5 mL) and 6-chloro-8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl- pyrido[3,4-d]pyrimidine-2,4-quinone (made in Examples 1 and 2, Step c) (40 mg, 113 pmol) and 2 M cesium carbonate solution (aq.) (169 pL, 339 pmol) were added at rt. The mixture was degassed with Argon before PdCl(crotyl)QPhos (10.3 mg, 11.3 pmol) was added. The reaction mixture was stirred for 4 h at 100 °C. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were dried over MgSC and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (MeOH in DCM 0-5%), followed by a further purification by flash chromatography on silica gel (MeOH in DCM 0-3%) to obtain the title compound (29.3 mg, 43%) as light yellow solid. MS (ESI): m / z = 485.3 [M+H]+.

[0257] Example 5

[0258] 8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(25)-2-(l-methylpyrazol-4-yl)morpholin-4- yl] py rimido [5, 4-d] pyrimidine-2, 4-dione 4-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]-5H-pyrimido[5,4- d]pyrimidine-6, 8-quinone (40 mg, 87.4 pmol) was dissolved in N,N-dimethylformamide (1 mL) and NaH (7.34 mg, 183 pmol) was added at 0 °C. The mixture was stirred for 15 min at 0 °C before iodomethane (27.3 mg, 12.0 pL, 192 pmol) was added. After the addition, the ice-bath was removed and the mixture was stirred for 3 h at rt. The crude material was purified by prep- HPLC to obtain the title compound (13.2 mg, 31%) as yellow solid. MS (ESI): m / z = 486.2 [M+H]+.

[0259] Note: Side product 8-(4-chloro-2-fhioro-phenyl)-3-methyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholino]-lH-pyrimido[5,4-d]pyrimidine-2,4-quinone (13.1 mg, 32%) was also isolated as yellow solid. MS (ESI): m / z = 472.1 [M+H]+.

[0260] Step a) 2, 4-dichloro-5H-pyrimido[ 5, 4-d]pyrimidine-6, 8-quinone

[0261] 5-amino-2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (CAS: 502184-51-2) (2 g, 9.01 mmol) was dissolved in tetrahydrofuran (24 mL) and trichloroacetyl isocyanate (2.55 g, 1.61 mL, 13.5 mmol) was added at rt. The mixture was stirred for 90 min at rt, and concentrated to dryness. The residue was taken up with methanol (8 mL) and ammonia (7 N in MeOH) (1.01 g, 1.29 mL, 9.01 mmol) was added. The mixture was stirred for 2 h at rt. Solids were filtered off, washed with MeOH and dried in vacuuo to obtain the title compound (1.9 g, 91%) as yellow solid. MS (ESI): m / z = 232.9 [M+H]+.

[0262] Step b) 2-chloro-4-( 4-chloro-2-fluoro-phenyl)-5H-pyrimido[ 5, 4-d]pyrimidine-6, 8-quinone

[0263] 2.4-dichloro-5H-pyrimido[5,4-d]pyrimidine-6, 8-quinone (500 mg, 2.15 mmol) was dissolved in

[0264] 1.4-dioxane (12 mL) and (4-chloro-2-fluoro-phenyl)boronic acid (449 mg, 2.58 mmol) and 2 M cesium carbonate solution (aq.) (3.22 mL, 6.44 mmol) were added at rt, and the mixture was degassed with Argon. 1, l'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (175 mg, 215 pmol) was added and the mixture was stirred at 60 °C for 2 h, then stirred at 80 °C for 1 h. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were dried over MgSCh and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (EtOAc in heptane 0- 100%) to obtain the title compound (280 mg, 40%) as light yellow solid. MS (ESI -): m / z = 325.0 [M-H]-.

[0265] Step c) 4-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholino]-5H- pyrimido[ 5, 4-d]pyrimidine-6, 8-quinone (2S)-2-(l-methylpyrazol-4-yl)morpholine (130 mg, 775 pmol) was dissolved in N,N- dimethylformamide (3 mL) and 2-chloro-4-(4-chloro-2-fluoro-phenyl)-5H-pyrimido[5,4- d]pyrimidine-6, 8-quinone (195 mg, 596 pmol ) were added at rt. The mixture was degassed with Argon before DIEA (154 mg, 208 pL, 1.19 mmol) was added. The mixture was stirred for 4 h at 100 °C. The reaction mixture was diluted with water and extracted two times with EtOAc. The organic layers were dried over MgSCU and concentrated to dryness. The crude material was purified by flash chromatography on silica gel (MeOH in DCM 0-5%), followed by further purification by flash chromatography on silica gel (MeOH in DCM 0-3%) to obtain the title compound (86 mg, 31%) as yellow solid. MS (ESI): m / z = 458.1 [M+H]+.

[0266] Example 6

[0267] 8-(4-chloro-2-fluoro-phenyl)-6-[(21?,45)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-l,3-dimethyl-pyrimido[5,4-d]pyrimidine-2,4-quinone

[0268] To a solution of 8-(4-chloro-2-fluoro-phenyl)-6-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]-l,3-dimethyl-pyrimido[5,4-d]pyrimidine-2,4-quinone (95 mg, 187 pmol) in ethyl acetate (3 mL) and triethylamine (22.6 mg, 31 pL, 224 pmol) at room temperature was added magnesium oxide (75.2 mg, 1.87 mmol) and Pd / C 10% (40 mg). The mixture was stirred under H2 atmosphere at room temperature for 20 min. The reaction mixture was filtered through a syringe filter and washed with DCM / MeOH 9: 1. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel Cl 8, acetonitrile in water 10-100%) to obtain rac-8-(4-chloro-2-fluoro-phenyl)-6-[(27?,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-l,3-dimethyl-pyrimido[5,4-d]pyrimidine-2,4-quinone (18 mg). This material was separated by chiral SFC (column Chiral OD, CCL / MeOH) to obtain the title compound as second eluting enantiomer (5.6 mg, 5.7% yield), light brown solid, MS m / z: 511.2 [M+H]+, ESI pos. Enantiomers are arbitrarily assigned.

[0269] Step a) 4-(4-chloro-2-fluoro-phenyl)-2-[6-(l-cyclopropylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4- yl ]-5H-pyrimido[ 5, 4-d]pyrimidine-6, 8-quinone The title compound was prepared in analogy to Example 1 and 2, step d) from 2-chloro-4-(4- chloro-2-fluoro-phenyl)-5H-pyrimido[5,4-d]pyrimidine-6,8-quinone (see Example 5, step b) instead of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4- quinone. Light yellow solid, MS m / z: 481.1 [M+H]+, ESI pos.

[0270] Step b) 8-(4-chloro-2-fluoro-phenyl)-6-[6-(l-cyclopropylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4- yl -l, 3-dimethyl-pyrimido[ 5, 4-d]pyrimidine-2, 4-quinone

[0271] 4-(4-Chloro-2-fluoro-phenyl)-2- [6-( 1 -cyclopropylpyrazol-4-yl)-3 , 6-dihydro-2H-pyran-4-yl]-5H- pyrimido[5,4-d]pyrimidine-6,8-quinone (135 mg, 281 pmol) was dissolved in N,N- dimethylformamide (2 mL) and sodium hydride (23.6 mg, 590 pmol) was added at 0 °C. The mixture was stirred for 15 min at 0 °C before iodomethane (87.7 mg, 38.5 pL, 618 pmol) was added. After the addition, the ice-bath was removed and the mixture was stirred during 3 h at room temperature. The reaction mixture was quenched by adding it to water at 0 °C. It was extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSCU and concentrated to dryness. The crude material was purified by column chromatography (silica gel, ethyl acetate in heptane 0-100%) to obtain 8-(4-chloro-2- fluoro-phenyl)-6- [6-( 1 -cyclopropylpyrazol-4-yl)-3 , 6-dihydro-2H-pyran-4-yl] -1,3 -dimethyl- pyrimido[5,4-d]pyrimidine-2, 4-quinone (108 mg, 64.2% yield) as light yellow solid, MS m / z: 509.2 [M+H]+, ESI pos.

[0272] Example 7

[0273] 6-[(21?,45)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-8-(4,4-difluorocyclohexyl)-l,3- dimethylpyrido [3, 4-d] pyrimidine-2, 4-dione

[0274] To a solution of 6-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-8-(4,4- difluorocyclohexyl)-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2, 4-dione (90.0 mg, 0.18 mmol) in ethyl acetate (9 mL) was added Pd / C (77 mg) under N2. The reaction mixture was degassed and filled with H2 three times, then stirred at 30 °C for 50 min under H2 atmosphere (15 Psi). The crude mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to and the residue was purified by preparative HPLC (column Phenomenex luna Cl 8 150 x 25 mm x 10 pm, water with 0.1% formic acid / acetonitrile) to give 6-[2-( 1 - cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-(4,4-difluorocyclohexyl)-l,3-dimethyl- pyrido[3,4-d]pyrimidine-2, 4-dione (40 mg) as white solid. This material was separated by chiral SFC (column Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, CO2 / acetonitrile / i-PrOH / 0.1% ammonium hydroxide) to obtain the title compound as first eluting enantiomer (9.9 mg, 24.6% yield), white solid, MS m / z: 500.2 [M+H]+, ESI pos. Enantiomers are arbitrarily assigned.

[0275] Step a) 6-chloro-l, 3-dimethyl-pyrido[ 3, 4-d]pyrimidine-2, 4-dione

[0276] A suspension of potassium carbonate (12.59 g, 91.1 mmol) and 6-chloro-lH-pyrido[3,4- d]pyrimidine-2, 4-dione (CAS: 2190512-63-9, 4.50 g, 18.22 mmol) in DMF (100 mL) was stirred under nitrogen at room temperature for 30 min. Then iodomethane (5.67 mL, 91.1 mmol) was added and the mixture was stirred at room temperature for 12 h. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with petroleum ether (20 mL) at room temperature for 30 min, then it was filtered and the filter cake was dried under reduced pressure to give 6-chloro-l, 3 -dimethyl- pyrido[3,4-d]pyrimidine-2, 4-dione (4.1 g, 99.7% yield) as light yellow solid, MS m / z: 226.0 [M+H]+, ESI pos.

[0277] Step b) 6-chloro-8-(4, 4-difluorocyclohexyl)-l, 3-dimethyl-pyrido[ 3, 4-d]pyrimidine-2, 4-dione

[0278] To a solution of 6-chloro-l, 3-dimethyl-pyrido[3,4-d]pyrimidine-2, 4-dione (0.8 g, 3.55 mmol) in DMSO / water (600: 1, 24 ml) was added 4,4-difluorocyclohexane carboxylic acid (5.82 g, 35.46 mmol). The mixture was degassed and filled with N2 three times, then a solution of ammonium persulfate (4.85 g, 21.27 mmol) in DMSO / water (600: 1, 24 ml) was added under N2 and the reaction was stirred at 45 °C for 16 h under N2. The reaction mixture was diluted with aqueous saturated sodium bicarbonate solution (300 mL) and extracted with ethyl acetate (400 mL x ). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex luna C18 150 x 25 mm x 10 pm, water with 0.1% formic acid / acetonitrile) to give 6-chloro-8-(4,4-difluorocyclohexyl)-l,3-dimethyl-pyrido[3,4-d]pyrimidine- 2,4-dione (300 mg, 19.7% yield) as yellow solid, MS m / z: 344.1 [M+H]+, ESI pos., 'H NMR (400 MHz, CDCh) 5 = 7.87 (s, 1H), 3.69 (s, 3H), 3.47 (s, 3H), 3.19 (br t, J = 11.3 Hz, 1H), 2.30 - 2.12 (m, 5H), 1.96 - 1.85 (m, 4H) and 6-chloro-5-(4,4-difluorocyclohexyl)-l,3-dimethyl- pyrido[3,4-d]pyrimidine-2, 4-dione (120 mg, 9.8% yield) as minor regoisomer.

[0279] Step c) 6-[6-(l-cyclopropylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4-yl]-8-(4,4-difluorocyclohexyl)~ 1, 3-dimethyl-pyrido[ 3, 4-d]pyrimidine-2, 4-dione

[0280] The title compound was prepared in analogy to Example 1 and 2, step d) from 6-chloro-8-(4,4- difluorocyclohexyl)-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2, 4-dione instead of 6-chloro-8-(4- chloro-2-fluoro-phenyl)-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone. Yellow solid, MS m / z: 498.2 [M+H]+, ESI pos.

[0281] Example 8

[0282] 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(21?,45)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl] py rido [3, 4-d] pyrimidine-2,4-quinone

[0283] The title compound was prepared in analogy to Example 1 and 2 by using building block A.2 instead of building block A.l in step d). First eluting enantiomer, light yellow solid, MS m / z: 484.2 [M+H]+, ESI pos. Enantiomers are arbitrarily assigned.

[0284] Example 9

[0285] 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(21?,45)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2,4-quinone and

[0286] Example 10

[0287] 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(25',41?)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2,4-quinone

[0288] To a solution of the 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[6-(2-methyl-4-pyridyl)-3,6- dihydro-2H-pyran-4-yl]pyrido[3,4-d]pyrimidine-2,4-quinone (100 mg, 193 pmol) in ethyl acetate (16.5 mL) were added triethylamine (24.6 mg, 34 pl, 243 pmol), magnesium oxide (81.7 mg, 2.03 mmol) and platinum oxide (9.2 mg) under argon. The reaction mixture was stirred under H2 atmosphere at room temperature for 21 h. The mixture was filtered through a syringe filter and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica RP18, 0% to 60% acetonitrile in water) to afford rac-8-(4-chloro-2- fluoro-phenyl)-l,3-dimethyl-6-[(2A,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrido[3,4- d]pyrimidine-2,4-quinone (42 mg). This material was separated by chiral SFC (column Chiral OJ 250 mm x 20 mm, 5 pm, CO2 / methanol / 0.2% diethylamine) to obtain 8-(4-chloro-2-fluoro- phenyl)-l,3-dimethyl-6-[(2A,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrido[3,4- d]pyrimidine-2,4-quinone (Example 9) as first eluting enantiomer (13 mg, 33% yield), white solid, MS m / z: 495.2 [M+H]+, ESI pos. and 8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6- [(25, 4A)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2, 4-quinone (Example 10) as second eluting enantiomer (14 mg, 35% yield), white solid, MS m / z: 495.2 [M+H]+, ESI pos. Enantiomers are arbitrarily assigned.

[0289] Step a) 8-(4-chloro-2-fluoro-phenyl)-6-[ 6-(2-chloro-4-pyridyl)-3, 6-dihydro-2H-pyran-4-yl]-l, 3- dimethyl-pyrido[ 3, 4-d]pyrimidine-2, 4-quinone

[0290] The title compound was prepared in analogy to Example 1 and 2, step d) by using Building block A.3 instead of Building block A.l. White solid, MS m / z: 513.1 [M+H]+, ESI pos.

[0291] Step b) 8-( 4-chloro-2-fluoro-phenyl)-l , 3 -dime thy 1-6- [ 6-( 2-methyl-4-pyridyl)-3, 6-dihydro-2H- pyran-4-yl ]pyrido[ 3, 4-d]pyrimidine-2, 4-quinone

[0292] To a solution of 8-(4-chloro-2-fluoro-phenyl)-6-[6-(2-chloro-4-pyridyl)-3,6-dihydro-2H-pyran-4- yl]-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2, 4-quinone (169 mg, 296 pmol) in 1,4-dioxane (4 mL) were added under argon 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (3.5 M in THF, 145 pL, 506.5 pmol), potassium carbonate (161.5 mg, 1.17 mmol) and 1,1 - bis(diphenylphosphino)ferrocene-palladium(II)dichloride (28.9 mg, 38.96 umol) and the reaction mixture was heated to 90 °C for 2 h. After cooling to room temperature, the reaction mixture was filtered over celite and washed with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (silica RP18, 0% to 60% acetonitrile in water) to afford 8-(4-chloro-2-fluoro-phenyl)-l,3- dimethyl-6-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrido[3,4-d]pyrimidine-2,4- quinone (100 mg, 65%) as light grey foam, MS m / z: 493.2 [M+H]+, ESI pos.

[0293] Example 11

[0294] 6-[(21?,45)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-l,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo [1.1.1] pentanyl] pyrido [3,4- d] pyrimidine-2, 4-dione

[0295] To a solution of 6-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-l,3-dimethyl-8- [3-(trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]pyrido[3,4-d]pyrimidine-2, 4-dione (130 mg, 0.25 mmol) in ethyl acetate (13 mL) was added Pd / C 10% (108 mg) under N2. The reaction mixture was degassed and filled with H2 three times, then stirred at 30 °C for 1 h under H2 atmosphere (15 Psi). The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex luna C18 150 x 25 mm x 10 pm, water with 0. 1% formic acid / acetonitrile) to give 6-[2-(l- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 , 3 -dimethyl-8-[3 -(trifluoromethyl)- 1 - bicyclofl. l.l]pentanyl]pyrido[3,4-d]pyrimidine-2, 4-dione (90 mg). This material was separated by chiral SFC (column Daicel Chiralpak AD 250 mm x 30 mm, 10 pm, CO2 / acetonitrile / i- PrOH / 0.1% ammonium hydroxide) to obtain the title compound as first eluting enantiomer (25.9 mg, 28.8% yield), off-white solid, MS m / z: 516.4 [M+H]+, ESI pos. Enantiomers are arbitrarily assigned. Step a) methyl 3-amino-6-bromo-2-[ 3-(trifluoromethyl)-l-bicyclo [ 1.1. l]pentanyl]pyridine-4- carboxylate

[0296] To a solution of methyl 5-amino-2-bromo-pyridine-4-carboxylate (800 mg, 3.46 mmol) in DMSO / water (600: 1, 24 ml) was added 3-(trifluoromethyl)bicyclo[l. l.l]pentane-l-carboxylic acid (6.24 g, 34.62 mmol). The mixture was degassed and filled with lSh three times, then a solution of ammonium persulfate (4.74 g, 20.77 mmol) in DMSO / water (600: 1, 24 ml) was added under N2. The reaction was stirred at 40 °C for 20 h under N2. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (400 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex luna C18 150 x 25 mm x 10 pm, water with 0. 1% formic acid / acetonitrile) to give methyl 3-amino-6-bromo-2-[3-(trifluoromethyl)-l- bicyclo[l. l.l]pentanyl]pyridine-4-carboxylate (400 mg, 31.6% yield) as yellow solid, MS m / z: 365.0 [M+H]+, ESI pos., 'H NMR (400 MHz, CDCI3) 8 = 7.62 (s, 1H), 5.73 (br s, 2H), 3.78 (s, 4H), 2.32 (s, 6H).

[0297] Step b) methyl 6-bromo-3-[(2,2,2-trichloroacetyl)carbamoylamino]-2-[3-(trifluoromethyl)-l- bicyclo[ 1.1.1 ]pentanyl]pyridine-4-carboxylate

[0298] To a solution of methyl 3-amino-6-bromo-2-[3-(trifhioromethyl)-l-bicyclo[l. l.l]pentanyl]- pyridine-4-carboxylate (420 mg, 1.15 mmol) in THF (5 mL) was added trichloroacetyl isocyanate (217 mg, 1.15 mmol) and the mixture was stirred at 20 °C for 2 h. The mixture was concentrated in vacuo to give the crude product, brown solid, MS m / z: 553.9 [M+H]+, ESI pos.

[0299] Step c) 6-bromo-8-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-lH-pyrido[3,4-d]pyrimidine- 2, 4-dione

[0300] To a solution of methyl 6-bromo-3-[(2,2,2-trichloroacetyl)carbamoylamino]-2-[3- (trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]pyridine-4-carboxylate (600 mg, 1.08 mmol) in methanol (3 mL) was added NH3 in methanol (7 M, 3.0 mL, 21.0 mmol) and the mixture was stirred at 20 °C for 2 h under N2. The mixture was concentrated in vacuo to give the crude product, yellow solid, MS m / z: 376.0; 378.0 [M+H]+, ESI pos.

[0301] Step d) 6-bromo-l, 3-dimethyl-8-[ 3-( trifluoromethyl)-! -bicyclo [ 1.1.1 ]pentanyl ]pyrido[ 3, 4- d]pyrimidine-2, 4-dione A suspension of potassium carbonate (441 mg, 3.19 mmol) and 6-bromo-8-[3-(trifluoromethyl)- 1 -bicyclofl. l.l]pentanyl]-lH-pyrido[3,4-d]pyrimidine-2, 4-dione (600 mg, 1.6 mmol) in DMF (6 mL) was stirred under nitrogen at room temperature for 30 min. Then iodomethane (0.3 mL, 4.79 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenomenex luna Cl 8 150 x 25 mm x 10 pm, water with 0. 1% formic acid / acetonitrile) to give 6-bromo-l,3-dimethyl-8-[3- (trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]pyrido[3,4-d]pyrimidine-2, 4-dione (280 mg, 43.4% yield) as yellow solid, MS m / z: 404.0; 406.0 [M+H]+, ESI pos.

[0302] Step e) 6-[6-(l-cyclopropylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4-yl]-l,3-dimethyl-8-[3- ( trifluoromethyl)-! -bicyclo [ 1.1.1 ]pentanyl]pyrido[ 3, 4-d]pyrimidine-2, 4-dione

[0303] To a solution of 6-bromo-l,3-dimethyl-8-[3-(trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]- pyrido[3,4-d]pyrimidine-2, 4-dione (290 mg, 0.72 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added l-cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro- 2H-pyran-6-yl]pyrazole (Building block A.l, 302.5 mg, 0.86 mmol), cesium carbonate (701 mg, 2.15 mmol) and l, l'-bis(diphenylphosphino)ferrocene-palladium(II)di chloride (58.6 mg, 0.07 mmol). Then the reaction was degassed with N2 three times and the reaction mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The reaction mixture was added into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over Na2SO4, and concentrated in vacuum. The residue was purified by flash chromatography (silica gel, ethyl acetate in petroleum ether 0 to 60%) to give 6- [6-(l - cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-l,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l. l.l]pentanyl]pyrido[3,4-d]pyrimidine-2, 4-dione (170 mg, 0.33 mmol, 46.1% yield) as yellow solid, MS m / z: 514.2 [M+H]+, ESI pos.

[0304] Example 12

[0305] 8-(4-chloro-2-fluoro-phenyl)-6-[(25,41?)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4- yl]-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone and Example 13

[0306] 8-(4-chloro-2-fluoro-phenyl)-6-[(21?,45)-2-(6-keto-l-methyl-3-pyridyl)tetrahydropyran-4- yl]-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone

[0307] The title compounds were prepared in analogy to Example 1 and 2 by using building block A.4 instead of building block A.l in step d), off-white solids, MS m / z: 511.2 [M+H]+, ESI pos. Enantiomers are arbitrarily assigned.

[0308] Example 14

[0309] 6-[(21?,45)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,3-dimethyl-8-[3- (trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone and

[0310] Example 15

[0311] 6-[(25,41?)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,3-dimethyl-8-[3-

[0312] (trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone

[0313] To a suspension of 6-[6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-l,3-dimethyl- 8-[3-(trifhroromethyl)-l-bicyclo[l .1. l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone (65 mg, 126.3 pmol) in ethyl acetate (5 mL) and ethanol (2.5 mL) was added triethylamine (15.3 mg, 21 pL, 151.6 umol) and magnesium oxide (50.9 mg, 1.26 mmol). The flask was evacuated and back-filled with nitrogen (3 x), then palladium on carbon, 10% (27 mg, 25.3 pmol) was added. Evacuation and back-filling with nitrogen was repeated, followed by evacuation and back-filling with hydrogen. The mixture was vigorously stirred with a connected hydrogen balloon at 22 °C for 4 h. The catalyst was filtered off, washed with ethyl acetate (2 x 2 mL) and the solution was concentrated in vacuo. The residue (93 mg) was purified by flash column chromatography (silica, 20-60% [EtOAc / EtOH 3: 1] in heptane) to give 6-[2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]- 1 , 3 -dimethyl-8-[3 -(trifluoromethyl)- 1 - bicyclofl. l.l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone (48 mg). ). This material was separated by chiral SFC (column Chiral OZ 250 mm x 20 mm, 5 pm, CO2 / methanol) to obtain 6-[(2A,45)-2-( 1 -cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 1 , 3 -dimethyl-8-[3 - (trifluoromethyl)-l -bicyclo [1.1. l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone (Example

[0314] 14) as first eluting enantiomer (17 mg, 35% yield), white solid, MS m / z: 517.3 [M+H]+, ESI pos. and 6-[(25,4A)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,3-dimethyl-8-[3- (trifluoromethyl)-l -bicyclo [1.1. l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone (Example

[0315] 15) as second eluting enantiomer (17.5 mg, 36% yield), white solid, MS m / z: 517.3 [M+H]+, ESI pos. Enantiomers are arbitrarily assigned.

[0316] Step a) 5-amino-2-chloro-6-[ 3-( trifluoromethyl)-! -bicyclo [ 1.1.1 ]pentanyl ]pyrimidine-4- carboxylic acid ethyl ester

[0317] A flask was charged with 5-amino-2-chloro-pyrimidine-4-carboxylic acid ethyl ester (1.5 g, 7.44 mmol) and 3-(trifluoromethyl)bicyclo[l. l.l]pentane-l-carboxylic acid (8.04 g, 44.64 mmol), then dimethyl sulfoxide (30 mL) and water (50 pL) were added. The mixture was degassed at 22 °C by bubbling argon through the mixture for 10 min and a degassed solution of ammonium persulfate (10. 19 g, 44.64 mmol) in dimethyl sulfoxide (60 mL) and water (100 pL) was added. Argon was bubbling through the solution for 5 min, then the mixture was stirred at 45 °C for 24 h. Saturated NaHCOs solution (300 mL) was carefully added and the mixture was extracted with ethyl acetate (2 x 300 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica RP18, 10 to 100% acetonitrile in water) and re-purified by flash column chromatography (silica, 0-30% ethyl acetate in heptane) to give 5-amino-2-chloro-6-[3-(trifluoromethyl)-l- bicyclo[l. l.l]pentanyl]pyrimidine-4-carboxylic acid ethyl ester (345 mg, 13%) as light yellow solid, MS m / z: 336.1 [M+H]+, ESI pos.

[0318] Step b) 2-chloro-5-[(2, 2, 2-trichloroacetyl)carbamoylamino ]-6-[ 3-( trifluoromethyl)-!- bicyclo[l.l. l]pentanyl]pyrimidine-4-carboxylic acid ethyl ester To a solution of 5-amino-2-chloro-6-[3-(trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]pyrimidine-4- carboxylic acid ethyl ester (255 mg, 760 pmol) in tetrahydrofiiran (2.5 mL) was added at 22 °C trichloroacetyl isocyanate (214.6 mg, 136 pL, 1.14 mmol) and the mixture was stirred at 22 °C for 30 min. The mixture was concentrated in vacuo to give the crude title compound (530 mg) as off-white solid.

[0319] Step c) 2-chloro-4-[3-(trifluoromethyl)-l-bicyclo[l.l. l]pentanyl]-5H-pyrimido[5,4- d]pyrimidine-6, 8-quinone

[0320] To a solution of 2-chloro-5-[(2,2,2-trichloroacetyl)carbamoylamino]-6-[3-(trifluoromethyl)-l- bicyclo[l. l.l]pentanyl]pyrimidine-4-carboxylic acid ethyl ester (530 mg, 758 pmol) in methanol (5.3 mL) was added at 22 °C a solution of ammonia, 7 M in MeOH (100 mg, 130 pL, 910 pmol) and the mixture was stirred at 22 °C for 30 min. The mixture was concentrated in vacuo to get the crude title compound (255 mg) which was used directly for the next step, white solid, MS m / z: 333.1 [M+H]+, ESI pos.

[0321] Step d) 6-chloro-l, 3-dimethyl-8-[ 3-( trifluoromethyl)-! -bicyclo [ 1.1.1 ]pentanyl ]pyrimido[5, 4- d]pyrimidine-2, 4-quinone

[0322] To a solution of 2-chloro-4-[3-(trifluoromethyl)-l-bicyclo[l. l.l]pentanyl]-5H-pyrimido[5,4- d]pyrimidine-6, 8-quinone (255 mg, 766 pmol) in N,N-dimethylformamide (5 mL) was added at 22 °C sodium hydride, 60% in oil (85.8 mg, 2.15 mmol) followed after 5 min by iodomethane (435 mg, 191 pL, 3.07 mmol) and the mixture was stirred at 22 °C for 16 h. To the reaction mixture was added saturated NaHCCL solution (25 mL), and it was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0- 40% ethyl acetate in heptane) to give 6-chloro-l,3-dimethyl-8-[3-(trifhioromethyl)-l- bicyclo[l. l.l]pentanyl]pyrimido[5,4-d]pyrimidine-2, 4-quinone (178 mg, 64%) as off-white solid, MS m / z: 361.1 [M+H]+, ESI pos.

[0323] Step e) 6-[6-(l-cyclopropylpyrazol-4-yl)-3, 6-dihydro-2H-pyran-4-yl]-l,3-dimethyl-8-[3- ( trifluoromethyl)-! -bicyclo [ 1.1.1 ]pentanyl]pyrimido[ 5, 4-d]pyrimidine-2, 4-quinone

[0324] A reaction tube was charged with 6-chloro-l,3-dimethyl-8-[3-(trifhioromethyl)-l- bicyclo[l. l.l]pentanyl]pyrimido[5,4-d]pyrimidine-2, 4-quinone (70 mg, 194 pmol) and 1- cyclopropyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyrazole (Building block A.l, 122.7 mg, 388 pmol) followed by 1,4-dioxane (2 mL) and potassium carbonate (80.5 mg, 582 pmol) in water (400 pL). The mixture was degassed by bubbling argon through the mixture for 10 min. Then l, l'-bis(diphenylphosphino)ferrocene- palladium(II) dichloride dichloromethane complex (15.8 mg, 19.4 pmol) was added and degassing was repeated for 5 min. The vial was sealed and heated to 60 °C for 2 h. After cooling down to room temperature the reaction mixture was poured into saturated NaHCCh solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0-60% [EtOAc / EtOH 3: 1] in heptane) to give 6-[6-(l- cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-l,3-dimethyl-8-[3-(trifluoromethyl)-l- bicyclo[l. l.l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4-quinone (73 mg, 73% yield) as off-white solid, MS m / z: 515.3 [M+H]+, ESI pos.

[0325] Synthesis of non-commercial building blocks

[0326] A.1 l-cyclopropyl-4-|4-(4.4.5.5-tetraniethyl-l .3.2-dioxaborolan-2-yl)-3.6-dihydro-2 / / -pyran-6- yljpyrazole

[0327] To a solution of [6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (680 mg, 2.01 mmol) in 1,4-dioxane (10 mL) was added bis(pinacolato)diboron (613 mg, 2.41 mmol) , potassium acetate (592 mg, 6.03 mmol) and Pd(dppf)C12*CH2C12 (82.0 mg, 0.1 mmol). The solution was degassed with N2 three times and the reaction was stirred at 90 °C for 2 h under N2. The mixture was poured into water (40mL) and extracted with ethyl acetate (20 mL x 3). Organic phase was washed with brine (20 mL x 3) and dried over Na2SO4, then concentrated in vacuum to give a residue which was purified by reversed phase HPLC to yield the title compound (380 mg, 1.2 mmol, 59% yield) as brown oil. MS (ESI): m / z = 317.2 [M+H]+; *HNMR (400 MHz, CHLOROFORM-d) 5 = 7.46 (s, 1H), 7.43 (s, 1H), 6.57 (d, J = 2.0 Hz, 1H), 5.17 (br d, J = 2.3 Hz, 1H), 3.96 - 3.85 (m, 1H), 3.73 (ddd, J = 4.4, 7.4, 11.6 Hz, 1H), 3.55 (td, J = 3.6, 7.2 Hz, 1H), 2.29 (tdd, J = 2.4, 4.9, 7.4 Hz, 1H), 2.25 - 2.13 (m, 1H), 1.29 (s, 9H), 1.12 - 1.08 (m, 2H), 1.01 - 0.97 (m, 2H). Step a) [6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate

[0328] To a solution of l-cyclopropylpyrazole-4-carbaldehyde (4.5 g, 33.1 mmol) and 3-butyn-l-ol (3.47 g, 49.6 mmol) in DCM (80 mL) was added dropwise trifluoromethane sulfonic acid (7.93 mL, 99.2 mmol) at -10 °C. After addition, the mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into water (400 mL) and extracted with DCM (200 mL x 3). The combined organics were washed with brine, dried over Na2SO4, filtered, and purified by column on silica gel plate (PE:EA=1 : 1 ) and concentrated under reduced pressure to give the title compound (7.0 g, 20.7 mmol, 63% yield) as light yellow oil. MS (ESI): m / z = 339.1 [M+H]+.

[0329] A.2 l-niethyl-4-|4-(4.4.5.5-tetraniethyl-l .3.2-diox:iborol:in-2-yl)-3.6-dihydro-2 / / -pyran-6- yljpyrazole

[0330] 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, l'-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 silica gel 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. MS m / z: 291.2 [M+H]+, ESI pos.

[0331] Step a) [6-(l-methylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate l-Methylpyrazole-4-carbaldehyde (2 g, 18.2 mmol) was dissolved in dichloromethane, extra dry (36 mL) and 3-butyn-l-ol (1.97 g, 2.14 mL, 27.3 mmol) was added at room temperature 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 saturated NaHCCL solution and extracted two times with DCM. The organic layers were dried over MgSCU 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. MS m / z: 313.1 [M+H]+, ESI pos.

[0332] A.3

[0333] 2-chloro-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl] pyridine

[0334] The title compound was prepared in analogy to Building Block A.2 from 2- chloroisonicotinaldehyde instead of l-methylpyrazole-4-carbaldehyde in step a). Light yellow oil, MS m / z: 322.2 [M+H]+, ESI pos.

[0335] A.4 l-methyl-5-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridin-2-one

[0336] The title compound was prepared in analogy to Building Block A.2 from 2-keto-l-methyl- isonicotinaldehyde instead of l-methylpyrazole-4-carbaldehyde in step a). Brown oil, MS m / z: 318.2 [M+H]+, ESI pos.

[0337] Example 16

[0338] A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition:

[0339] Per tablet

[0340] Active ingredient 200 mg

[0341] Microcrystalline cellulose 155 mg

[0342] Corn starch 25 mg

[0343] Talc 25 mg Hydroxypropylmethylcellulo se 20 mg

[0344] 425 mg

[0345] Example 17

[0346] A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

[0347] Per capsule

[0348] Active ingredient 100.0 mg

[0349] Corn starch 20.0 mg

[0350] Lactose 95.0 mg Talc 4.5 mg

[0351] Magnesium stearate 0.5 mg

[0352] 220.0 mg

Claims

Claims1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:A, X1, and X2are each independently selected from N and CH;R1is selected from Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Cs-Cio-cycloalkyl, and 3- to 6- membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon;R2is selected from 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;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 C3- 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;R4is selected from hydrogen and Ci-Ce-alkyl; andR5is selected from Ci-Ce-alkyl and 3- to 6-membered heterocyclyl comprising 1 to 4 heteroatoms independently selected from N, O, and S, the remaining atoms being carbon.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A and X1are each independently selected from N and CH; and X2is N.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A is CH;X1is selected from N and CH; andX2is N.

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

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

7. The compound of formula (I) according to any one of claims 1 to 6, or a8. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R2is Ce-Cio-aryl substituted with 1 to 2 substituents independently selected from halogen.

9. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted with 1-2 substituents independently selected from fluoro and chloro.

10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3is selected from12. The compound of formula (I) according to any one of claims 1 to 10, 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 C3- Cio-cycloalkyl.

13. The compound of formula (I) according to claim 12, 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 substituent selected from Ci-Ce-alkyl and C3-C10- cycloalkyl.

14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R3is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl.

15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R3is selected from16. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R4is selected from hydrogen and methyl.

17. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

18. The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R5is selected from methyl, ethyl, and oxetanyl.

19. The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R5is Ci-Ce-alkyl.

20. The compound of formula (I) according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R5is methyl.

21. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A, X1, and X2are each independently selected from N and CH;R1is selected from methyl, CHF2, cyclopropyl, and oxetanyl;R4is selected from hydrogen and methyl; andR5is selected from methyl, ethyl, and oxetanyl.

22. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A and X1are each independently selected from N and CH;X2is N;R1is Ci-Ce-alkyl;R2is Ce-Cio-aryl substituted with 1 to 2 substituents independently selected from halogen;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;R4is hydrogen; andR5is Ci-Ce-alkyl.

23. The compound of formula (I) according to claim 22, or a pharmaceutically acceptable salt thereof, wherein:A and X1are each independently selected from N and CH;X2is N;R1is methyl;R2is phenyl substituted with 1-2 substituents independently selected from fluoro and chloro;R3is IH-pyrazole substituted with 1 substituent selected from methyl and cyclopropyl;R4is hydrogen; andR5is methyl.

24. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]- l,3-dimethylpyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]- l,3-dimethylpyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chlorophenyl)- 1 , 3 -dimethyl-6-[(2S)-2-( 1 -methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluoro-phenyl)- 1 , 3 -dimethyl-6-[(2S,4R)-2-( 1 -cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chlorophenyl)- 1 , 3 -dimethyl-6-[(2S)-2-( 1 -methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluorophenyl)-l,3-dimethyl-6-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-l,3-dimethyl-pyrimido[5,4-d]pyrimidine-2,4-quinone;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-8-(4,4-difluorocyclohexyl)-l,3- dimethylpyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(l-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2,4-quinone;8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2R,4S)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2,4-quinone;8-(4-chloro-2-fluoro-phenyl)-l,3-dimethyl-6-[(2S,4R)-2-(2-methyl-4- pyridyl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-2,4-quinone;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)oxan-4-yl]-l,3-dimethyl-8-[3- (trifluoromethyl)-l -bicyclo [1.

1. l]pentanyl]pyrido[3,4-d]pyrimidine-2, 4-dione;8-(4-chloro-2-fluoro-phenyl)-6-[(2S,4R)-2-(6-keto-l-methyl-3- pyridyl)tetrahydropyran-4-yl]-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone;8-(4-chloro-2-fluoro-phenyl)-6-[(2R,4S)-2-(6-keto-l-methyl-3- pyridyl)tetrahydropyran-4-yl]-l,3-dimethyl-pyrido[3,4-d]pyrimidine-2,4-quinone;6-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,3-dimethyl-8-[3- (trifluoromethyl)- 1 -bicyclof 1.

1. l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4- quinone; and6-[(2S,4R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,3-dimethyl-8-[3- (trifluoromethyl)- 1 -bicyclof 1.

1. l]pentanyl]pyrimido[5,4-d]pyrimidine-2,4- quinone.

25. The compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

26. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

27. 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 24, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 26.

28. The method according to claim 27, 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.

29. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 26, for use in a method according to claim 27 or 28.

30. Use of a compound according to any one of claims 1 to 24, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition according to claim 26, in a method according to claim 27 or 28.

31. Use of a compound according to any one of claims 1 to 24, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to claim 27 or 28.

32. The invention as described hereinbefore.

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