TREM2 agonists

Abstract

The invention provides compounds having the general formula (I), wherein A1, A2, R1, R2, R3, R3', R4, R4', and R7 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] F. Hoffmann-La Roche AG, CH-4070 Basel, Switzerland

[0002] Case: P39787

[0003] TREM2 AGONISTS

[0004] Field of the Invention

[0005] 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.

[0006] Background of the Invention

[0007] 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.

[0008] Neurobiol. 2010, 41(2-3): 115-28, doi: 10.1007 / sl2035-010-8106-8).

[0009] 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.

[0010] 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.

[0011] CNE / 09.10.2025 Downstream signal transduction is mediated through its interaction with the effector protein DAP12, a transmembrane disulphide-linked adapter dimer which expression and cellular localization at the plasma membrane are dependent on TREM2, and which is associated to TREM2 transmembrane helix via lysine-aspartic acid interaction (K156-D50) forming a signaling complex (Zhong L. et al., J Biol Chem. 2015;290(25): 15866-77). Given its short extracellular domain, DAP12 lacks ligand-binding capabilities. Endogenous ligands of TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cellular debris, myelin and Ap oligomers. Stimulation of the TREM2 / DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of DAP 12, which results in recruitment of Syk kinase to activate downstream signaling molecules.

[0012] 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:

[0013] 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).

[0014] 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 of TREM2 have been associated with increased risk of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Several of these TREM2 variants have been implicated with impaired microglia function and their reduced response to neurodegenerative diseases. (Kleinberger, G. et al., Sci. Transl. Med. 2014, 6, 243ra86). Moreover, genomic-wide association studies (GWAS) showed a strong link between a number of rare loss of function (LoF) variants of TREM2 and an increased risk of late onset Alzheimer’s disease (LOAD) (Guerreiro R. et al., N Engl J Med. 2013, 368(2): 117-27; Jonsson T. et al., N Engl J Med. 2013, 368(2): 107-16). Amongst those, the R47H variant, a LoF mutation associated with structural alterations within the extracellular domain of TREM2 resulting in impaired ability to bind endogenous ligands, was linked to a ca. 3 fold increased risk of LOAD (Sudom, A. et al., J Biol Chem. 2018 10;293(32): 12634-12646; doi: 10.1074 / jbc.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 DAP12, confirming the central role of TREM2 signalling in microglia function and response to Alzheimer’s pathological hallmarks.

[0015] 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. of the Invention

[0016] In a first aspect, the present invention provides compounds of formula (I) wherein A1, A2, R1, R2, R3, R3, R4, R4, and R7are as defined herein.

[0017] 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 of the Invention

[0018] Definitions

[0019] 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.

[0020] 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, tert-butyl, and 2,2-dimethylpropyl.

[0021] 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.

[0022] The term “alkoxyalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, preferably methoxy. Preferably, “alkoxyalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group, most preferably methoxy. A particularly preferred, yet non-limiting example of alkoxyalkyl is methoxymethyl.

[0023] 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).

[0024] 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, bicyclo[3.1.0]hexanyl, norbornanyl, and l-bicyclo[2.2.2]octanyl. Particularly preferred, yet non-limiting examples of cycloalkyl are cyclopropyl, bicyclo[l. l.l]pentanyl, bicyclo[3.1.0]hexanyl and cyclohexyl.

[0025] 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.

[0026] The term "heteroaryl" refers to a monocyclic aromatic ring having a total of 5 to 6 ring members, containing one or more heteroatoms. Preferably, the heteroaryl comprises 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. More preferably, the heteroaryl comprises 1 to 3 heteroatoms independently selected from O, S and N. Most preferably, the heteroaryl comprises 1 to 2 nitrogen atoms. Some preferred, yet non-limiting examples of heteroaryl include thiazolyl (e.g. thiazol-2-yl); oxazolyl (e.g. oxazol-2-yl); oxadiazolyl; l,2,4-oxadiazol-5- yl; pyridyl (e.g. 2-pyridyl); pyrazolyl (e.g. pyrazol-l-yl); triazolyl; tetrazolyl; pyrazinyl; and imidazolyl (e.g. imidazole- 1-yl). Some preferred, yet non-limiting examples of heteroaryl include pyridyl and pyrazolyl. The term “heterocyclyl” refers to a saturated or partly unsaturated monocyclic ring system of 3 to 6 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. Some non-limiting examples of heterocyclyl groups include azetidinyl, piperidyl, pyrrolidinyl, oxetanyl, piperidyl, 1,2-dihydropyridiynl, piperidyl, pyrrolidinyl, tetrahydrothiophenyl, and thietanyl. Preferred, yet non-limiting examples of heterocyclyl groups include 1,2-dihydropyridiynl and oxetanyl.

[0027] 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. Preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1 -difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl. A particularly preferred, yet non-limiting example of haloalkyl is tri fluoromethyl.

[0028] The term “haloalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 1,1- difluoroethoxy, 2,2-difluoroethoxy, and 2,2,2-trifluoroethoxy.

[0029] The term “halocycloalkyl” refers to a cycloalkyl group as defined herein, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “halocycloalkyl” refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of halocycloalkyl are 4,4-difluorocyclohexyl and 2,2-difluorocyclopropyl.

[0030] The term “haloheterocyclyl” refers to a heterocyclyl group as defined herein, wherein at least one of the hydrogen atoms of the heterocyclyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloheterocyclyl” refers to a heterocyclyl group wherein 1, 2 or 3 hydrogen atoms of the heterocyclyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloheterocyclyl are 4,4- difluoro- 1 -piperidine, 2-fluorooxiran-2-yl, 2-fluoroaziridin-2-yl, 3-fluorooxetan-3-yl, and 3- fluoroazeti din-3 -yl .

[0031] The term “cycloalkylalkyl” 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 cycloalkyl group, preferably cyclopropyl. Preferably, “cycloalkylalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by a cycloalkyl group, most preferably cyclopropyl. A particularly preferred, yet non-limiting example of cycloalkylalkyl is cyclopropylmethyl.

[0032] The term “cycloalkylalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group, preferably cyclopropyl. Preferably, “cycloalkylalkoxy” refers to an alkoxy group wherein 1 of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group, most preferably cyclopropyl. A particularly preferred, yet non-limiting example of cycloalkylalkoxy is cyclopropylmethoxy.

[0033] The term “cycloalkyloxy” refers to a cycloalkyl group as defined herein that is bound to the parent moiety via an oxygen atom. A preferred, yet non-limiting example of cycloalkyloxy is cyclopropoxy.

[0034] The term “heterocyclylalkyl” 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 heterocyclyl group, preferably oxetanyl. Preferably, “heterocyclylalkyl” refers to an alkyl group wherein 1 of the hydrogen atoms of the alkyl group has been replaced by a heterocyclyl group, most preferably oxetanyl. A particularly preferred, yet non-limiting example of heterocyclylalkyl is oxetanylmethyl.

[0035] The term “heterocyclylalkoxy” refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclyl group, preferably oxetanyl, azetidinyl or piperidyl. Preferably, “heterocyclylalkoxy” refers to an alkoxy group wherein 1 of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclyl group, most preferably oxetanyl, azetidinyl or piperidyl. A particularly preferred, yet non-limiting example of heterocyclylalkoxy is oxetanylmethoxy.

[0036] The term “heterocyclyloxy” refers to a heterocyclyl group as defined herein that is bound to the parent moiety via an oxygen atom. A preferred, yet non-limiting example of heterocyclyloxy is oxetanyl oxy. 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.

[0037] 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.

[0038] The abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2.

[0039] 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.

[0040] 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.

[0041] Compounds of the Invention

[0042] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0043] A1is selected from the group consisting of N and CR8;

[0044] A2is selected from the group consisting of O and CR5R6;

[0045] R1is selected from the group consisting of Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0046] R2is selected from the group consisting of Ce-Cio-aryl, 5- to 6-membered heteroaryl,

[0047] Cs-Cio-cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said Ce-Cio-aryl, 5- to 6-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6-membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Ci-Ce-alkyl and halo-Ci-Ce-alkyl;

[0048] R3is selected from the group consisting of 5- to 6-membered heteroaryl, 9- to 10- membered fused bicyclic heteroaryl, and 3- to 6-membered heterocyclyl, wherein:

[0049] (i) said 5- to 6-membered heteroaryl and 9- to 10-membered fused bicyclic heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce- alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce- alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce- alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, Cs-Cio-cycloalkyloxy, 3- to 6- membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6- membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce- alkoxy and 3- to 6-membered heterocyclyloxy; and

[0050] (ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1-3 further substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce- alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio- cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, Cs-Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy;

[0051] R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0052] R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0053] R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0054] R5and R6are each independently selected from the group consisting of hydrogen and halogen;

[0055] R7is selected from the group consisting of hydrogen, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, and Cs-Cio-cycloalkyl; and

[0056] R8is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci-Ce- alkyl.

[0057] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0058] A1is selected from the group consisting of N and CR8;

[0059] A2is O; and

[0060] R8is hydrogen.

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

[0062] A1is CR8;

[0063] A2is O; and

[0064] R8is hydrogen.

[0065] 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.

[0066] 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.

[0067] In one 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 2-3 halogen substituents. 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 the group consisting of phenyl, cyclohexyl, bicyclo[l. l.l]pentane, spiro[3.3]heptane, bicyclo[3.1.0]hexane, and tetrahydropyrane wherein said phenyl, cyclohexyl, bicyclo[l. l.l]pentane, spiro[3.3]heptane, bicyclo[3.1.0]hexane, and tetrahydropyrane are substituted with 1-3 substituents independently selected from the group consisting of fluoro, chloro, cyano, methyl, CHF2, and CF3.

[0068] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted with 2-3 substituents independently selected from the group consisting of fluoro and chloro.

[0069] 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 2 halogen substituents.

[0070] 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 fluoro and chloro.

[0071] In one 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 substituted with 1 substituent selected from the group consisting of Ci-Ce-alkyl and C3-C10- cycloalkyl.

[0072] 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 pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, IH-triazolyl, 2H-triazolyl, 4H-l,2,4-triazolyl, pyrazolo[l,5-a]pyrimidine, [l,2,4]triazolo[l,5-a]pyridine, 1,2- dihydropyridine, 1,6-dihydropyridazine, 1,2-dihydropyrazine, 1,2-dihydropyrimidine, and 1,6- dihydropyrimidine, wherein said pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, 1,3,4- oxadiazolyl, 1,2,4-oxadiazolyl, IH-triazolyl, 2H-triazolyl, 4H-l,2,4-triazolyl, lH-l,2,4-triazolyl, pyrazolo[l,5-a]pyrimidine, and [l,2,4]triazolo[l,5-a]pyridine are optionally substituted with 1 substituent selected from the group consisting of methyl, ethyl, isopropyl, CHF2, CF3, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy, and wherein said 1,2-dihydropyridine, 1,6-dihydropyridazine, 1,2- dihydropyrazine, 1,2-dihydropyrimidine, and 1,6-dihydropyrimidine are substituted with oxo and optionally 1 further substituent selected from the group consisting of methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy .

[0073] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein, R3is pyrazolyl substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl.

[0074] 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 substituted with 1 Cs-Cio-cycloalkyl substituent.

[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 R3is pyrazolyl substituted with 1 cyclopropyl substituent.

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

[0077] R3is a 5-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkyl and Cs-Cio-cycloalkyl; and

[0078] R3is hydrogen.

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

[0080] R3is selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, IH-triazolyl, 2H-triazolyl, 4H-l,2,4-triazolyl, pyrazolo[l,5- a]pyrimidine, [l,2,4]triazolo[l,5-a]pyridine, 1,2-dihydropyridine, 1,6-dihydropyridazine, 1,2-dihydropyrazine, 1,2-dihydropyrimidine, and 1,6-dihydropyrimidine, wherein said pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadiazolyl, IH-triazolyl, 2H-triazolyl, 4H-l,2,4-triazolyl, pyrazolo[l,5-a]pyrimidine, and [l,2,4]triazolo[l,5-a]pyridine are optionally substituted with 1 substituent selected from the group consisting of methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy, and wherein said 1,2-dihydropyridine, 1,6-dihydropyridazine, 1,2-dihydropyrazine, 1,2- dihydropyrimidine, and 1,6-dihydropyrimidine are substituted with oxo and optionally 1 further substituent selected from the group consisting of methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, isopropoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy; and

[0081] R3is hydrogen.

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

[0083] R3is pyrazolyl substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl; and

[0084] R3is hydrogen.

[0085] In a 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 substituted with 1 Cs-Cio-cycloalkyl substituent; and

[0087] R3is hydrogen.

[0088] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0089] R3is pyrazolyl substituted with 1 cyclopropyl substituent; and

[0090] R3is hydrogen.

[0091] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

[0092] 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 the group consisting of hydrogen and methyl.

[0093] 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. 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.

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

[0095] R4is selected from the group consisting of hydrogen and methyl; and

[0096] R4is hydrogen.

[0097] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R4and R4are both hydrogen.

[0098] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R7is Ci-Ce-alkyl.

[0099] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R7is methyl.

[0100] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0101] A1is selected from the group consisting of N and CR8;

[0102] A2is O;

[0103] R3is a 5-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkyl and Cs-Cio-cycloalkyl;

[0104] R3is hydrogen;

[0105] R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0106] R4is hydrogen; and

[0107] R8is hydrogen.

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

[0109] A1is selected from the group consisting of N and CR8;

[0110] A2is O;

[0111] R3is selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, IH-triazolyl, 2H-triazolyl, 4H-l,2,4-triazolyl, pyrazolo[l,5- a]pyrimidine, [l,2,4]triazolo[l,5-a]pyridine, 1,2-dihydropyridine, 1,6-dihydropyridazine, 1.2-dihydropyrazine, 1,2-dihydropyrimidine, and 1,6-dihydropyrimidine, wherein said pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4- oxadiazolyl, IH-triazolyl, 2H-triazolyl, 4H-l,2,4-triazolyl, pyrazolo[l,5-a]pyrimidine, and [l,2,4]triazolo[l,5-a]pyridine are optionally substituted with 1 substituent selected from the group consisting of methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy, and wherein said 1,2-dihydropyridine, 1,6-dihydropyridazine, 1,2-dihydropyrazine, 1,2- dihydropyrimidine, and 1,6-dihydropyrimidine are substituted with oxo and optionally 1 further substituent selected from the group consisting of methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, isopropoxy, 2,2-difluoroethoxy,

[0112] 2.2.2-trifluoroethoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy;

[0113] R3is hydrogen;

[0114] R4is selected from the group consisting of hydrogen and methyl;

[0115] R4is hydrogen; and

[0116] R8is hydrogen.

[0117] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0118] A1is selected from the group consisting of N and CR8;

[0119] A2is O;

[0120] R3is pyrazolyl substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl;

[0121] R3is hydrogen;

[0122] R4is selected from the group consisting of hydrogen and methyl;

[0123] R4is hydrogen; and

[0124] R8is hydrogen.

[0125] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A1is CR8;

[0126] A2is O;

[0127] R3is a 5-membered heteroaryl substituted with 1 Cs-Cio-cycloalkyl substituent; R3is hydrogen;

[0128] R4is hydrogen;

[0129] R4is hydrogen; and

[0130] R8is hydrogen.

[0131] In a particularly preferred embodiment, the present invention provides a compound of formula

[0132] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0133] A1is CR8;

[0134] A2is O;

[0135] R3is pyrazolyl substituted with 1 cyclopropyl substituent;

[0136] R3is hydrogen;

[0137] R4is hydrogen;

[0138] R4is hydrogen; and

[0139] R8is hydrogen.

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

[0141] A1is selected from the group consisting of N and CR8;

[0142] A2is O;

[0143] R1is Ci-Ce-alkyl;

[0144] R2is Ce-Cio-aryl substituted with 2-3 halogen substituents;

[0145] R3is a 5-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkyl and Cs-Cio-cycloalkyl;

[0146] R3is hydrogen;

[0147] R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl;

[0148] R4is hydrogen;

[0149] R7is Ci-Ce-alkyl; and

[0150] R8is hydrogen.

[0151] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0152] A1is selected from the group consisting of N and CR8;

[0153] A2is O;

[0154] R1is methyl; R2is phenyl substituted with 2-3 substituents independently selected from the group consisting of fluoro and chloro;

[0155] R3is pyrazolyl substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl;

[0156] R3is hydrogen;

[0157] R4is selected from the group consisting of hydrogen and methyl;

[0158] R4is hydrogen;

[0159] R7is methyl; and

[0160] R8is hydrogen.

[0161] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0162] A1is CR8;

[0163] A2is O;

[0164] R1is Ci-Ce-alkyl;

[0165] R2is Ce-Cio-aryl substituted with 2 halogen substituents;

[0166] R3is a 5-membered heteroaryl substituted with 1 Cs-Cio-cycloalkyl substituent;

[0167] R3is hydrogen;

[0168] R4is hydrogen;

[0169] R4is hydrogen;

[0170] R7is Ci-Ce-alkyl; and

[0171] R8is hydrogen.

[0172] In a particularly preferred embodiment, the present invention provides a compound of formula

[0173] (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0174] A1is CR8;

[0175] A2is O;

[0176] R1is methyl;

[0177] R2is phenyl substituted with fluoro and chloro;

[0178] R3is pyrazolyl substituted with 1 cyclopropyl substituent;

[0179] R3is hydrogen;

[0180] R4is hydrogen;

[0181] R4is hydrogen;

[0182] R7is methyl; and

[0183] R8is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from:

[0184] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;

[0185] 4-(4-chloro-2-fluorophenyl)-2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7- dimethylpyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;

[0186] 4-(4-chloro-2-fluorophenyl)-2-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7- dimethylpyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;

[0187] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[rac-(2S,6S)-2-(l-cyclopropylpyrazol-4-yl)-6- methyl-morpholin-4-yl]pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;

[0188] 4-(4-chloro-2-fluoro-phenyl)-2-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-6,7-dimethyl-pyrimido[2,l-f][l,2,4]triazin-8-one;

[0189] 4-(4-chloro-2-fluoro-phenyl)-2-[(2R,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-6,7-dimethyl-pyrimido[2,l-f][l,2,4]triazin-8-one;

[0190] 4-(4-chloro-2,6-difluoro-phenyl)-2-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7- dimethyl-pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;

[0191] 4-(4-chloro-2,6-difluoro-phenyl)-2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7- dimethyl-pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one; and

[0192] 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one.

[0193] 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 or acids.

[0194] 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.

[0195] 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. Therefore, deuterated versions of the compounds disclosed herein are to be understood to be within the scope of the present invention. In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein 1-6, preferably 1-3, of the hydrogen atoms are replaced by deuterium atoms.

[0196] 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.

[0197] Processes of Manufacturing

[0198] 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.

[0199] If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature. If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0200] 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).

[0201] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0202] 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.

[0203] 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.

[0204] The following abbreviations are used in the present text:

[0205] °C degrees Celsius

[0206] 'H proton

[0207] A angstrom

[0208] Aik alkyl c concentration

[0209] CAS Chemical Abstracts Service registry number

[0210] CH3CN acetonitrile

[0211] CO2 carbon dioxide

[0212] DIPEA N,N-Diisopropylethylamine

[0213] DMEM Dulbecco's modified eagle medium

[0214] DMF N,N-Dimethylformamide

[0215] DMSO dimethylsulfoxide

[0216] DMSO-d6 hexadeuterodimethyl sulfoxide

[0217] EC50 half maximal effective concentration eq equivalent

[0218] ESI electron spray ionization

[0219] Ex. example

[0220] FBS fetal bovine serum g gram g / L gram per liter h hour

[0221] HATU hexafluorophosphate azabenzotri azole tetramethyl uronium

[0222] HBTU hexafluorophosphate benzotriazole tetramethyl uronium

[0223] HCOOH formic acid

[0224] HEK human embryonic kidney HPLC high performance liquid chromatography

[0225] J coupling constant kg kilogram

[0226] M molar m / z mass-to-charge ratio

[0227] MeOH methanol mg milligram

[0228] MgSO4 magnesium sulfate

[0229] MHz megahertz min minute ml milliliter mm millimeter mmol millimole

[0230] MPLC medium pressure liquid chromatography

[0231] MS mass spectrometry

[0232] Na2SOs sodium sulfite

[0233] Na2SO4 sodium sulfate

[0234] NaHCCh sodium bicarbonate neg. negative

[0235] NH4CI ammonium chloride nm nanometer

[0236] NMR nuclear magnetic resonance spectroscopy pH potential of hydrogen pos. positive psi pounds per square inch

[0237] R Rectus according to the Cahn-Ingold-Prelog priority rules

[0238] RP reverse phase

[0239] RPM revolutions per minute s second

[0240] S Sinister according to the Cahn-Ingold-Prelog priority rules

[0241] SFC supercritical fluid chromatography

[0242] TLC thin layer chromatography pl microliter pm micrometer pmol micromoles

[0243] Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) aD specific rotation at 589 nm

[0244] 5 chemical shift in parts per million

[0245] Scheme 1

[0246] R1, R2, R3, R3', R4, R4', R7, A2according to claim definition

[0247] Aik = alkyl chain like Me, Et

[0248] Compounds of general formula la (I with A1=N) can be prepared as described in Scheme 1 by first reacting triazinone II with ketoester III in presence of an acid like polyphosphoric acid or a Lewis acid such as bismuth trichloride at elevated temperatures to form intermediate IV. This compound can further be reacted with phosphorous oxychloride or a related reagent to give the chlorinated heterocycle V which can be transformed with a boronic acid (or a boronic acid derivative) VI under palladium catalysed conditions (a palladium source such as (1,T- bis(diphenylphosphino)ferrocene)palladium(II) dichloride, bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) or tetrakis(triphenylphosphine)- palladium(O) and a base such as potassium phosphate, cesium carbonate or sodium carbonate) to form compound VII. Next, compound VII is reacted with an oxidating agent such as metachloroperoxybenzoic acid to form intermediate VIII. This intermediate can be reacted with amine IX in presence of a base like N,N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone at elevated temperatures to form la.

[0249] Scheme 2

[0250]

[0251] R1, R2, R3, R3', R4, R4', R7, A2according to claim definition

[0252] Aik = alkyl chain like Me, Et

[0253] Furthermore, compounds of general formula la can be prepared as described in Scheme 2. Commercial compound X can first be transformed into compound XI by reacting with a boronic acid (or a boronic acid derivative) VI under palladium catalysed conditions (a palladium source such as (l,l'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) or tetrakis(triphenylphosphine)- palladium(O) and a base such as potassium phosphate, cesium carbonate or sodium carbonate). This compound XI can be reacted with amine IX in presence of a base like N,N-diisopropyl ethylamine, triethylamine or the like in a protic solvent such as butanol or a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone at elevated temperatures to form Intermediate XII. This ester can then be saponified by treatment with a base such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a mixture of tetrahydrofurane and water to form acid XIII. Treatment of XIII with dipenylphosphoryl azide and a base like triethylamine in presence of water gives rise to amino compound XIV which then can be cyclised with ketoester III in presence of an acid like polyphosphoric acid or p- toluenesulfonic acid or a Lewis acid such as bismuth trichloride at elevated temperatures to form compound la.

[0254] Scheme 3

[0255]

[0256] The synthesis of C-linked derivatives lb (I with A1=CH) can be performed as illustrated in Scheme 3. Intermediate XI is reacted with ammonia in methanol at room temperature to give compound XV which can be transformed into chloro derivative XVI by a Sandmeyer reaction using for instance isoamyl nitrite or tert-butyl nitrite in presence of a copper salt at elevated temperatures. This derivative can be reacted with boronic acid derivative XVII using a palladium catalyst and a base to form intermediate XVIII, which can then be reduced by treatment with a suitable agent like hydrogen and a catalyst to form compound XIX. Preferred reaction conditions for the reduction step are palladium on charcoal or platinum oxide in ethyl acetate, ethanol or methanol with or without the addition of further reagents like magnesium oxide or tri ethylamine.

[0257] Ester XIX can then be saponified by treatment with a base such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a mixture of tetrahydrofurane and water followed by treatment of the resulting acid with dipenylphosphoryl azide and a base like triethylamine in presence of water leading to amino compound XX. Treatment of this compound with reagent XXI under elevated temperatures leads to intermediate XXI which can be further reacted with acid chloride XXIII and a base like tri ethylamine to form desired compound lb.

[0258] In one aspect, the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the process is as described in any one of schemes 1 to 3. 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.

[0259] TREM2 Agonistic Activity

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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.

[0266] Compounds in dose response (1 :3) were diluted in DMSO (highest concentration lOmM) 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.

[0267] 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). ECso values were calculated by using Genedata Screener, normalized to DMSO and 100% activity to the tool compound.

[0268] 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.

[0269] Table 1 of the Invention

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Parkinson’s disease.

[0276] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is rheumatoid arthritis.

[0277] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Alzheimer’s disease.

[0278] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis.

[0279] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease.

[0280] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia.

[0281] In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis.

[0282] 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.

[0283] Pharmaceutical Compositions and Administration

[0284] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0285] In one embodiment, there is provided a pharmaceutical composition according to Example 10 or 11.

[0286] 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).

[0287] 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, corn 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.

[0288] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0289] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0290] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0291] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0292] 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.

[0293] 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.

[0294] 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.

[0295] 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.

[0296] 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.

[0297] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0298] The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure controls.

[0299] The following intermediates were prepared according to the procedures provided herein, are commercially available or can be prepared according to literature procedures.

[0300] Example 1 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one

[0301]

[0302] 6-Amino-3-methylsulfanyl-4H-l,2,4-triazin-5-one (CAS 89730-56-3, 4.25 g, 21.5 mmol) and ethyl 2-methylacetoacetate (12.2 ml, 86 mmol) were added to warm polyphosphoric acids (21.0 g, 215 mmol). After stirring at 120 °C for 2 h the mixture was cooled to room temperature, quenched with ice water (300 ml) and the precipitate was filtered off. The filter cake was washed with water (3 x 100 ml), ethyl acetate (100 ml) and then air-dried to obtain 6,7-dimethyl-2- methylsulfanyl-3H-pyrimido[2,l-f][l, 2, 4]triazine-4, 8-dione (4.8 g, 70% yield) as a grey solid, MS m / z: 239.2 [M+H]+, ESI pos.

[0303] Step 2: 4-chloro-6,7-dimethyl-2-methylsulfanyl-pyrimidor2,l-firE2,41triazin-8-one

[0304] A suspension of 6,7-dimethyl-2-methylsulfanyl-3H-pyrimido[2,l-f][l,2,4]triazine-4,8-dione (1.5 g, 4.72 mmol) in phosphorus oxychloride (24.2 ml, 260 mmol) was stirred at 100 °C for 0.25 h. The mixture was quenched carefully with ice water (120 ml) and extracted with chloroform (3 x 100 ml). The combined organic layers were dried over anhydrous sodium sulfate and evaporated in vacuo to obtain crude 4-chloro-6,7-dimethyl-2-methylsulfanyl-pyrimido[2,l-f][l,2,4]triazin-8- one (0.52 g, 26% yield), which was used in the next step without additional purification, MS m / z: 257.0 [M+H]+, ESI pos. 3 : 4-(4-chloro-2-fluoro- i-6,7-dimethvl-2-methvlsulfanvl-l .,1- ,41triazin-8-one

[0305] To a stirred solution of 4-chloro-6,7-dimethyl-2-methylsulfanyl-pyrimido[2,l-f][l,2,4]triazin-8- one (520 mg, 1.22 mmol, 1.0 eq) in a mixture of toluene (26 ml) and water (2.6 ml) was added potassium phosphate (1.29 g, 6.08 mmol) and 4-chloro-2-fhiorophenylboronic acid (706 mg, 4.05 mmol). The mixture was degassed, filled with argon, and bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (143 mg, 0.2 mmol, 0.17 eq) was added. After stirring at 20 °C for 6 h, the mixture was diluted with ethyl acetate (160 ml) and washed with brine (3 x 120 ml). The organic layer was filtered through anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by chromatography (silica gel, methanol in acetonitrile 0 to 100%) to afford 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-methylsulfanyl- pyrimido[2,l-f][l,2,4]triazin-8-one (235 mg, 55% yield), MS m / z: 351.0 [M+H]+, ESI pos. i-6,7-dimethvl-2-methvlsulfonvl-pvrimidor2,l-

[0306] ,2,4]triazin-8-one

[0307] To a solution of 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-methylsulfanyl-pyrimido[2,l- f][l,2,4]triazin-8-one (100 mg, 0.26 mmol) in dry dichloromethane (20 ml) was added 3- chloroperoxybenzoic acid (190 mg, 0.77 mmol). After stirring for 18 h at 25 °C , the mixture was evaporated in vacuo to obtain crude 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2- methylsulfonyl-pyrimido[2,l-f][l,2,4]triazin-8-one which was used in next step without additional purification. MS m / z: 383.2 [M+H]+, ESI pos. Step 5: 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-r(2S)-2-(l-methylpyrazol-4-yl)morpholin-

[0308] 4-yl1pyrimidol2,l-f]rE2,41triazin-8-one

[0309] The crude 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-methylsulfonyl-pyrimido[2,l- f][l,2,4]triazin-8-one was dissolved in dry dimethylsulfoxide (5 ml), then (2S)-2-(l- methylpyrazol-4-yl)morpholine (98 mg, 0.59 mmol) and N,N-diisopropylethylamine (0.23 ml, 1.31 mmol) were added. After stirring for 18 h at 100 °C, the mixture was evaporated and the residue was purified by HPLC (column: XBridge, 100 mm x 19 mm, 30% water / acetonitrile, flow rate 4 ml) to give the title compound (29 mg, 45% yield) as light-brown solid. MS m / z: 470.2 [M+H]+, ESI pos.

[0310] Example 2 and 3 4-(4-chloro-2-fluorophenyl)-2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin- 4-yl]-6,7-dimethylpyrimido[2,l-f][l,2,4]triazin-8-one (2) and 4-(4-chloro-2-fluorophenyl)-2- [(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7-dimethylpyrimido[2,l-f][l,2,4]triazin- 8-one (3)

[0311] Step 1: ethyl 5-(4-chloro-2-fluoro-phenyl)-3-methylsulfanyl-E2,4-triazine-6-carboxylate

[0312] To a solution of 4-chloro-2-fluorophenylboronic acid (746 mg, 4.28 mmol) in 1,2- dimethoxyethane (15 ml) was added at room temperature ethyl 5-chloro-3-(methylthio)-l,2,4- triazine-6-carboxylate (CAS 75824-03-2, 1.0 g, 4.28 mmol), tripotassium phosphate (1.36 g, 6.42 mmol) and tetrakis(triphenylphosphine)palladium(0) (495 mg, 0.43 mmol, 0.1 eq). Then the mixture was stirred at 100 °C for 16 h under nitrogen atmosphere. After cooling the reaction mixture to room temperature, water (100 ml) was added and it was extracted with ethyl acetate (100 ml x 2). The combined organic layers were washed with brine (100 ml), dried over ISfeSCU and concentrated in vacuum. Then the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 : 1 to 1 : 1) to give ethyl 5-(4-chloro-2-fluoro-phenyl)-3- methylsulfanyl-l,2,4-triazine-6-carboxylate (400 mg, 29% yield) as yellow oil, MS m / z: 328.1 [M+H]+, ESI pos.

[0313] Step 2: 5-(4-chloro-2-fluoro-phenyl)-3-r2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl1-E2,4- triazine-6-carboxylic acid

[0314] To a solution of ethyl 5-(4-chloro-2-fluoro-phenyl)-3-methylsulfanyl-l,2,4-triazine-6- carboxylate (500 mg, 1.3 mmol) in 1-butanol (5 ml) was added triethylamine (262 mg, 2.59 mmol) and 2-(l-cyclopropylpyrazol-4-yl)morpholine (376 mg, 1.95 mmol) at room temperature, then the mixture was stirred at 120 °C for 72 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 3 : 1 to 1 : 1) and evaporated to give a mixture of ethyl 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol- 4-yl)morpholin-4-yl]-l,2,4-triazine-6-carboxylate and butyl 5-(4-chloro-2-fluoro-phenyl)-3-[2- (l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-l,2,4-triazine-6-carboxylate. This mixture of esters was dissolved in tetrahydrofuran (6 ml) and a solution of lithium hydroxide hydrate (67 mg, 1.6 mmol) in water (2 ml) was added. The reaction mixture was stirred at 20 °C for 3 h, then the pH was adjusted with hydrochloric acid (1 M in water) and poured into water (50 ml). It was extracted with ethyl acetate (50 ml x 3) and the combined organic layers were washed by brine (50 ml), dried over Na2SO4 and concentrated under reduced pressure to give the 5-(4-chloro-2- fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-l,2,4-triazine-6-carboxylic acid (350 mg, 76% yield) as yellow solid, MS m / z: 445.2 [M+H]+, ESI pos. in-4-yl]-l,2,4- triazin-6-amine

[0315] To a mixture of 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]- l,2,4-triazine-6-carboxylic acid (350 mg, 0.79 mmol) in toluene (10 ml) were added diphenylphosphoryl azide (433 mg, 1.57 mmol), water (0.06 ml, 3.15 mmol) and triethylamine (159 mg, 1.57 mmol) at room temperature and the mixture was stirred at 90 °C for 2 h. The solvent was evaporated and the residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 : 1 to 0 : 1) to give 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l- cyclopropylpyrazol-4-yl)morpholin-4-yl]-l,2,4-triazin-6-amine (160 mg, 41% yield) as yellow oil, MS m / z: 416.1 [M+H]+, ESI pos. -4-yl)morpholin-4-yl]-6,7- riazin-8-one and 4-(4-chl oro-2- i-2-F(2S)-2-(l- in-4-vl]-6,7-di in-8-one

[0316] To a solution of 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]- l,2,4-triazin-6-amine (160 mg, 0.38 mmol) in toluene (5 ml) was added ethyl 2- methyl acetoacetate (277 mg, 1.92 mmol) and p-toluenesulfonic acid (13 mg, 0.08 mmol). The reaction was stirred at 120 °C for 16 h under nitrogen, then concentrated under reduced pressure. The residue was purified by preparative HPLC (column Phenom enex Luna, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.225% formic acid - acetonitrile, 0-100%, flow rate 25 ml / min) to afford 4-(4-chloro-2-fluoro-phenyl)-2-[2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7- dimethyl-pyrimido[2,l-f][l,2,4]triazin-8-one (120 mg, 0.24 mmol, 63% yield). This racemate was separated by chiral SFC (Daicel Chiralcel OD 250 mm x 30 mm, 10 pm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 70 ml / min) to give 4-(4-chloro-2- fluorophenyl)-2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7-dimethylpyrimido[2,l- f][l,2,4]triazin-8-one (31 mg, 26% yield), yellow solid as the first eluting enantiomer and 4-(4- chloro-2-fluorophenyl)-2-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7- dimethylpyrimido[2,l-f][l,2,4]triazin-8-one (27 mg, 22% yield), yellow solid as the second eluting enantiomer, MS m / z: 496.1 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[0317] Examples 4, 5, and 6 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[rac-(2S,6S)-2-(l- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]pyrimido[2, 1 -f] [1 ,2,4]triazin-8-one (4), 4-(4- chloro-2-fluoro-phenyl)-2-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]- 6,7-dimethyl-pyrimido[2,l-f][l,2,4]triazin-8-one (5), and 4-(4-chloro-2-fluoro-phenyl)-2- [(2R,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-6,7-dimethyl-pyrimido[2,l- f][l,2,4]triazin-8-one (6)

[0318] The title compounds was prepared in analogy to Example 2 and 3 using 2-(l- cyclopropylpyrazol-4-yl)-6-methyl-morpholine instead of 2-(l-cyclopropylpyrazol-4- yl)morpholine in step 2, yellow solids, MS m / z: 510.1 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[0319] Example 7 and Example 8 4-(4-chloro-2,6-difluoro-phenyl)-2-[(2S)-2-(l-cyclopropylpyrazol- 4-yl)morpholin-4-yl]-6,7-dimethyl-pyrimido[2,l-f][l,2,4]triazin-8-one (7) and 4-(4-chloro-2,6- difluoro-phenyl)-2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]-6,7-dimethyl- pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one (8)

[0320] The title compounds was prepared in analogy to Example 2 and 3 using 4-chloro-2,6- difluorophenylboronic acid instead of 4-chloro-2-fluorophenylboronic acid in step 2, yellow solids, MS m / z: 514.3 [M+H]+, ESI pos. The absolute stereochemistry was assigned arbitrarily.

[0321] Example 9 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[rac-(2R,4S)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one

[0322]

[0323] Ethyl 5-(4-chloro-2-fluoro-phenyl)-3-methylsulfanyl-l,2,4-triazine-6-carboxylate (see Example 2, 36.0 g, 109.8 mmol) was dissolved in a solution of ammonia in methanol (7 M, 150 ml, 1050 mmol) and the mixture was stirred at 20 °C for 1 h. Then pH of mixture was adjusted to 6 with hydrochloric acid (3 M, around 100 ml), the precipitate was filtered off and dried by adding toluene and removing the volatiles in vacuo (twice) to give ethyl 3-amino-5-(4-chloro-2-fluoro- phenyl)-l,2,4-triazine-6-carboxylate (25.0 g, 77% yield) as off-white solid, MS m / z: 297.0 [M+H]+, ESI pos.

[0324] Step 2: ethyl 3-chloro-5-(4-chloro-2-fluoro-phenyl)-E2,4-triazine-6-carboxylate

[0325] To a solution of ethyl 3-amino-5-(4-chloro-2-fluoro-phenyl)-l,2,4-triazine-6-carboxylate (7.0 g, 23.6 mmol) in acetonitrile (100 ml) was added copper(II)-chloride (4.76 g, 35.4 mmol) and the mixture was degassed by nitrogen three times. Then tert-butyl nitrite (10.5 g, 47.2 mmol) was added and the mixture was stirred at 60 °C for 1 h. The mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 15% ethyl acetate in petroleum ether) to afford ethyl 3- chloro-5-(4-chloro-2-fluoro-phenyl)-l,2,4-triazine-6-carboxylate (5.5 g, 74% yield) as yellow solid, MS m / z: 470.2 [M+H]+, ESI pos.

[0326] Step 3: ethyl 5-(4-chloro-2-fluoro-phenyl)-3-r6-(l-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H- pyran-4-yl]- 1 ,2,4-triazine-6-carboxylate

[0327] To a solution of ethyl 3-chloro-5-(4-chloro-2-fluoro-phenyl)-l,2,4-triazine-6-carboxylate (1.0 g, 3.16 mmol) in 1,4-dioxane (10 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 (CAS 2738495-81-1, 2.0 g, 6.33 mmol), potassium carbonate (1.31 g, 9.49 mmol) and l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (258 mg, 0.32 mmol, 0.1 eq). After adding water (1 ml), the mixture was degassed by nitrogen three times, then stirred at 20 °C for 2 h. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (30 ml x 3) and the combined organic layers were washed by brine (50 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1 : 0 to 1 : 1) to give ethyl 5-(4-chloro-2-fluoro-phenyl)-3-[6-(l- cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-l,2,4-triazine-6-carboxylate (317 mg, 21% yield) as orange oil, MS m / z: 470.2 [M+H]+, ESI pos.

[0328] Step 4: ethyl 5-(4-chloro-2-fluoro-phenyl)-3-r2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yll- 1 ,2,4-triazine-6-carboxylate

[0329] To a suspension of palladium on charcoal (208 mg) in ethyl acetate (5 ml) under nitrogen was added a solution of ethyl 5-(4-chloro-2-fluoro-phenyl)-3-[6-(l-cyclopropylpyrazol-4-yl)-3,6- dihydro-2H-pyran-4-yl]-l,2,4-triazine-6-carboxylate (460 mg, 0.98 mmol) in ethyl acetate (45 ml) at room temperature under nitrogen. The reaction mixture was degassed and filled with hydrogen three times, then stirred at 20 °C for 22 h under hydrogen atmosphere (15 Psi). Then the reaction 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, Cl 8, 150 x 25 mm x 10 pm, mobile phase: water / 0.225% formic acid - acetonitrile, 0- 100%, flow rate 60 ml / min) to give ethyl 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropyl- pyrazol-4-yl)tetrahydropyran-4-yl]-l,2,4-triazine-6-carboxylate (220 mg, 48% yield) as yellow solid, MS m / z: 472.2 [M+H]+, ESI pos.

[0330] Step 5: 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- l,2,4-triazine-6-carboxylic acid

[0331] To a solution of ethyl 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-l,2,4-triazine-6-carboxylate (220 mg, 0.47 mmol) in tetrahydrofuran (6 ml) and water (2 ml) was added lithium hydroxide monohydrate (59 mg, 1.4 mmol) at room temperature and the mixture was stirred at 20 °C for 2 h. Then the reaction mixture was adjusted to pH 3 with hydrochloric acid (1 M in water), poured into water (10 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed by brine (20 ml) and dried over Na2SO4, filtered and concentrated under reduced pressure to give 5-(4-chloro-2-fluoro- phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,2,4-triazine-6-carboxylic acid (200 mg, 97% yield) as yellow solid, MS m / z: 444.1 [M+H]+, ESI pos.

[0332] Step 6: 5-(4-chloro-2-fluoro-phenyl)-3-r2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl1-

[0333] 1 ,2,4-triazin-6-amine

[0334] To a mixture of 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran- 4-yl]-l,2,4-triazine-6-carboxylic acid (100 mg, 0.23 mmol) in toluene (3 ml) was added diphenylphosphoryl azide (124 mg, 0.45 mmol), water (0.02 ml, 0.9 mmol) and triethylamine (46 mg, 0.45 mmol) at room temperature, then the mixture was stirred at 90 °C for 1 h under nitrogen atmosphere. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 3), the combined organic layers were washed by brine (50 ml), dried over Na2SO4 and concentrated under reduce pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1 : 0 to 1 : 2) to give 5-(4-chloro-2- fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l,2,4-triazin-6-amine (54 mg, 29% yield) as brown solid, MS m / z: 415.1 [M+H]+, ESI pos.

[0335] Step 7: N'-r5-(4-chloro-2-fluoro-phenyl)-3-r2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl1- E2,4-triazin-6-yl]-N,N-dimethyl-acetamidine

[0336] A solution of 5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4- yl]-l,2,4-triazin-6-amine (50 mg, 0.09 mmol) in 1,1 -dimethoxy -N,N-dimethylethan-l -amine (304 mg, 2.28 mmol) was stirred in a microwave oven at 110 °C for 15 min. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed by brine (20 ml) and dried over ISfeSCU and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, ethyl acetate) to give N'-[5-(4-chloro-2-fluoro-phenyl)-3-[2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- l,2,4-triazin-6-yl]-N,N-dimethyl-acetamidine (26 mg, 59% yield) as yellow solid, MS m / z: 484.2 [M+H]+, ESI pos.

[0337] -4-

[0338] To a solution of N'-[5-(4-chloro-2-fluoro-phenyl)-3-[rac-(2R,4S)-2-(l-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-l,2,4-triazin-6-yl]-N,N-dimethyl-acetamidine (16 mg, 0.03 mmol) in dichloromethane (3 ml) was added propionyl chloride (3.1 mg, 0.03 mmol) and triethylamine (0.01 ml, 0.06 mmol) and the mixture was stirred at 20 °C for 2 h under nitrogen atmosphere. The reaction mixture was poured into water (20 ml) and extracted with dichloromethane (20 ml x 3), then the combined layers were washed by brine (20 ml) and 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, mobile phase: water / 0.225% formic acid - acetonitrile, 0-100%, flow rate 25 ml / min) to give the title compound (5 mg, 36% yield) as yellow solid, MS m / z: 495.1 [M+H]+, ESI pos.

[0339] Example 10

[0340] 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:

[0341] Per tablet

[0342] Active ingredient 200 mg

[0343] Microcrystalline cellulose 155 mg

[0344] Com starch 25 mg

[0345] Talc 25 mg Hydroxypropylmethylcellulose 20 mg

[0346] 425 mg

[0347] Example 11

[0348] 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:

[0349] Per capsule

[0350] Active ingredient 100.0 mg

[0351] Com starch 20.0 mg

[0352] Lactose 95.0 mg Talc 4.5 mg

[0353] Magnesium stearate 0.5 mg

[0354] 220.0 mg

Claims

1. Claims1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:A1is selected from the group consisting of N and CR8;A2is selected from the group consisting of O and CR5R6;R1is selected from the group consisting of Ci-Ce-alkyl and halo-Ci-Ce-alkyl;R2is selected from the group consisting of Ce-Cio-aryl, 5- to 6-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6-membered heterocyclyl, wherein said Ce-Cio-aryl, 5- to 6-membered heteroaryl, Cs-Cio-cycloalkyl, and 3- to 6- membered heterocyclyl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, Ci-Ce- alkyl and halo-Ci-Ce-alkyl;R3is selected from the group consisting of 5- to 6-membered heteroaryl, 9- to 10- membered fused bicyclic heteroaryl, and 3- to 6-membered heterocyclyl, wherein:(i) said 5- to 6-membered heteroaryl and 9- to 10-membered fused bicyclic heteroaryl are optionally substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, Cs-Cio-cycloalkyl, halo-Cs-Cio-cycloalkyl, C3-C10- cycloalkyl-Ci-Ce-alkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkoxy, C3-C10- cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6- membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy; and(ii) said 3- to 6-membered heterocyclyl is substituted with oxo and 1-3 further substituents independently selected from the group consisting of halogen, cyano, amino, hydroxy, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, C3-C10- cycloalkyl, halo-Cs-Cio-cycloalkyl, Cs-Cio-cycloalkyl-Ci-Ce-alkyl, C3- Cio-cycloalkyl-Ci-Ce-alkoxy, Cs-Cio-cycloalkyloxy, 3- to 6-membered heterocyclyl, halo-3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkyl, 3- to 6-membered heterocyclyl-Ci-Ce-alkoxy and 3- to 6-membered heterocyclyloxy;R3is selected from the group consisting of hydrogen and Ci-Ce-alkyl;R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl;R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl;R5and R6are each independently selected from the group consisting of hydrogen and halogen;R7is selected from the group consisting of hydrogen, Ci-Ce-alkyl, halo-Ci-Ce- alkyl, and Cs-Cio-cycloalkyl; andR8is selected from the group consisting of hydrogen, halogen, hydroxy, and Ci- Ce-alkyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A1is selected from the group consisting of N and CR8;A2is O; andR8is hydrogen.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A1is CR8;A2is O; andR8is hydrogen.

4. 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.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R1is methyl.

6. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2is Ce-Cio-aryl substituted with 2-3 halogen substituents.

7. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2is selected from the group consisting of phenyl, cyclohexyl, bicyclo[l. l.l]pentane, spiro[3.3]heptane, bicyclo[3.1.0]hexane, and tetrahydropyrane wherein said phenyl, cyclohexyl, bicyclo[l.l. l]pentane, spiro[3.3]heptane, bicyclo[3.1.0]hexane, and tetrahydropyrane are substituted with 1-3 substituents independently selected from the group consisting of fluoro, chloro, cyano, methyl, CHF2, and CF3.

8. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted with 2-3 substituents independently selected from the group consisting of fluoro and chloro.

9. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2is Ce-Cio-aryl substituted with 2 halogen substituents.

10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted with fluoro and chloro.

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3is a 5-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkyl and Cs-Cio-cycloalkyl.

12. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3is selected from pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, IH-triazolyl, 2H-triazolyl, 4H-l,2,4-triazolyl, lH-l,2,4-triazolyl, pyrazolo[l,5- a]pyrimidine, [l,2,4]triazolo[l,5-a]pyridine, 1,2-dihydropyridine, 1,6- dihydropyridazine, 1,2-dihydropyrazine, 1,2-dihydropyrimidine, and 1,6- dihydropyrimidine, wherein said pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, IH-triazolyl, 2H-triazolyl, 4H-1,2,4-triazolyl, pyrazolo[l,5-a]pyrimidine, and [l,2,4]triazolo[l,5-a]pyridine are optionally substituted with 1 substituent selected from the group consisting of methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2- methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy, and wherein said1.2-dihydropyridine, 1,6-dihydropyridazine, 1,2-dihydropyrazine, 1,2- dihydropyrimidine, and 1,6-dihydropyrimidine are substituted with oxo and optionally 1 further substituent selected from the group consisting of methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, isopropoxy,2.2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclopropylmethoxy, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy.

13. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3is pyrazolyl substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl.

14. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3is a 5-membered heteroaryl substituted with 1 Cs-Cio-cycloalkyl substituent.

15. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3is pyrazolyl substituted with 1 cyclopropyl substituent.

16. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

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

18. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

19. The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen.

20. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R7is Ci-Ce-alkyl.

21. The compound of formula (I) according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R7is methyl.

22. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A1is selected from the group consisting of N and CR8;A2is O;R1is Ci-Ce-alkyl;R2is Ce-Cio-aryl substituted with 2-3 halogen substituents;R3is a 5-membered heteroaryl substituted with 1 substituent selected from the group consisting of Ci-Ce-alkyl and Cs-Cio-cycloalkyl;R3is hydrogen;R4is selected from the group consisting of hydrogen and Ci-Ce-alkyl;R4is hydrogen;R7is Ci-Ce-alkyl; andR8is hydrogen.

23. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A1is selected from the group consisting of N and CR8;A2is O;R1is methyl;R2is phenyl substituted with 2-3 substituents independently selected from the group consisting of fluoro and chloro;R3is pyrazolyl substituted with 1 substituent selected from the group consisting of methyl and cyclopropyl;R3is hydrogen;R4is selected from the group consisting of hydrogen and methyl;R4is hydrogen;R7is methyl; andR8is hydrogen.

24. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A1is CR8;A2is O;R1is Ci-Ce-alkyl;R2is Ce-Cio-aryl substituted with 2 halogen substituents;R3is a 5-membered heteroaryl substituted with 1 Cs-Cio-cycloalkyl substituent;R3is hydrogen;R4is hydrogen;R4is hydrogen;R7is Ci-Ce-alkyl; andR8is hydrogen.

25. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:A1is CR8;A2is O;R1is methyl;R2is phenyl substituted with fluoro and chloro;R3is pyrazolyl substituted with 1 cyclopropyl substituent;R3is hydrogen;R4is hydrogen;R4is hydrogen;R7is methyl; andR8is hydrogen.

26. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(l-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;4-(4-chloro-2-fluorophenyl)-2-[(2R)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]- 6,7-dimethylpyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;4-(4-chloro-2-fluorophenyl)-2-[(2S)-2-(l-cyclopropylpyrazol-4-yl)morpholin-4-yl]- 6,7-dimethylpyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[rac-(2S,6S)-2-(l-cyclopropylpyrazol- 4-yl)-6-methyl-morpholin-4-yl]pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;4-(4-chloro-2-fluoro-phenyl)-2-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-6,7-dimethyl-pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;4-(4-chloro-2-fluoro-phenyl)-2-[(2R,6S)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl- morpholin-4-yl]-6,7-dimethyl-pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one;4-(4-chl oro-2, 6-difluoro-phenyl)-2-[(2S)-2-(l-cy cl opropylpyrazol-4-yl)morpholin-4- yl]-6,7-dimethyl-pyrimido[2,l-f][l,2,4]triazin-8-one;4-(4-chl oro-2, 6-difluoro-phenyl)-2-[(2R)-2-(l-cy cl opropylpyrazol-4-yl)morpholin-4- yl]-6,7-dimethyl-pyrimido[2,l-f][l,2,4]triazin-8-one; and4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[rac-(2R,4S)-2-(l-cyclopropylpyrazol- 4-yl)tetrahydropyran-4-yl]pyrimido[2, 1 -f] [ 1 ,2,4]triazin-8-one.

27. The compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

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

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

30. The method according to claim 30, 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.

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

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

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

34. The invention as described hereinbefore.

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