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WO2024246019A1 - Dérivés de pyrido[3,4-d]pyrimidin-4-one et pyrimido[5,4-d]pyrimidin-4-one utilisés en tant qu'agonistes de trem2 pour le traitement de la maladie de parkinson - Google Patents

Dérivés de pyrido[3,4-d]pyrimidin-4-one et pyrimido[5,4-d]pyrimidin-4-one utilisés en tant qu'agonistes de trem2 pour le traitement de la maladie de parkinson Download PDF

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Publication number
WO2024246019A1
WO2024246019A1 PCT/EP2024/064558 EP2024064558W WO2024246019A1 WO 2024246019 A1 WO2024246019 A1 WO 2024246019A1 EP 2024064558 W EP2024064558 W EP 2024064558W WO 2024246019 A1 WO2024246019 A1 WO 2024246019A1
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Prior art keywords
methyl
pyrimidin
chloro
fluoro
pyrimido
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Pending
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PCT/EP2024/064558
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English (en)
Inventor
Julie CHARPENTIER
Maria Emilia Di Francesco
Guido Galley
Wolfgang Guba
Fionn Susannah O'HARA
Flore Marie Aude REGGIANI
Stefan Berchtold
Roland Johann HUMM
Angélique PATINY-ADAM
Nicolas ZEIDAN
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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F Hoffmann La Roche AG
Hoffmann La Roche Inc
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Publication of WO2024246019A1 publication Critical patent/WO2024246019A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • TREM2 Triggering Receptor Expressed on Myeloid cells 2
  • 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.
  • Microglia express a multitude of receptors on their surface, which play a key role in sensing the environmental changes and enabling the complex crosstalk regulating their physiological functions.
  • TREM2 Triggering Receptor Expressed on Myeloid cells 2
  • TREM2 Triggering Receptor Expressed on Myeloid cells 2
  • 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.
  • Ig-SF Immunoglobulin superfamily
  • 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 A ⁇ oligomers. Stimulation of the TREM2/DAP12 complex induces in the phosphorylation of two tyrosine residues within the immunoreceptor tyrosine-based activation motif (ITAM) in the cytoplasmic domain of DAP12, which results in recruitment of Syk kinase to activate downstream signaling molecules.
  • ITAM immunoreceptor tyrosine-based activation motif
  • TREM2 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.
  • 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).
  • NBD Nasu-Hakola Disease
  • PLOSL Polycystic lipomembranous osteodysplasia with sclerosis leukoencephalopathy
  • TREM2 missense mutations of TREM2 have been associated with increased risk of Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
  • PD Parkinson’s disease
  • ALS amyotrophic lateral sclerosis
  • FTD frontotemporal dementia
  • GWAS genomic-wide association studies
  • the present invention provides compounds of formula (I) wherein A, B, R 1 , R 2 , R 3 , R 5 , and R 6 are as defined herein.
  • the invention provides compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I).
  • Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith.
  • alkyl refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms.
  • the alkoxy group contains 1 to 3 carbon atoms.
  • alkyl examples 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.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C 1-6 -alkoxy”).
  • the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms.
  • Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non- limiting example of alkoxy is methoxy.
  • halogen or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • halogen 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).
  • cycloalkyl refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C 3-10 -cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
  • 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.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1- bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl.
  • a particularly preferred, yet non-limiting example of cycloalkyl is cyclopropyl.
  • cycloalkenyl refers to a partially unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C3-10-cycloalkyl”).
  • the cycloalkenyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • “Bicyclic cycloalkenyl” refers to cycloalkenyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
  • the cycloalkenyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms.
  • Some non-limiting examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • aryl refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C 6 -C 10 -aryl”), wherein at least one ring in the system is aromatic.
  • aryl examples include phenyl and 9H-fluorenyl (e.g.9H-fluoren-9-yl).
  • a particularly preferred, yet non-limiting example of aryl is phenyl.
  • heterocyclyl and heterocycloalkyl are used herein interchangeably and refer to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, more preferably 3 to 6 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
  • ring atoms Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon.
  • “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
  • heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4- piperidyl, piperazinyl, pyrrolidinyl, oxazolidinyl, dihydropyrazinyl (e.g., 1,2-dihydropyrazin-6- yl), morpholinyl, 2-azaspiro[3.3]heptan-2-yl, 7-azaspiro[3.5]nonan-7-yl, 8- azabicyclo[3.2.1]octan-8-yl, 8-oxa-3-azabicyclo[3.2.1]octan, and 3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrol-2-yl.
  • dihydropyrazinyl e.g.
  • heteroaryl refers to a mono- or multivalent, monocyclic or bicyclic ring system having a total of 5 to 10 ring members, preferably 5 to 8 ring members, more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms.
  • heteroaryl refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O, S and N.
  • heteroaryl examples include thiazolyl (e.g. thiazol-2-yl); oxazolyl (e.g. oxazol-2-yl); oxadiazolyl; 5,6- dihydro-4H-cyclopenta[d]thiazol-2-yl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g.2-pyridyl); pyrazolyl (e.g. pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; imidazolyl (e.g. imidazole-1-yl); benzoxazolyl (e.g.
  • cyano refers to a –CN (nitrile) group.
  • 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.
  • 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.
  • haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, and 2,2,2-trifluoroethyl.
  • 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.
  • 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.
  • haloalkoxy are trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, (1,1,1-trifluoropropan-2-yl)oxy, and 2,2,2-trifluoroethoxy.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,
  • salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
  • Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like.
  • the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the abbreviation “TREM2” refers to Triggering Receptor Expressed on Myeloid cells 2.
  • treatment includes: (1) inhibiting the state, disorder or condition (e.g.
  • 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.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: X 1 , X 2 and X 3 are each independently selected from N and CH; A is selected from C3-C10-cycloalkyl, C3-C10-cycloalkenyl, C6-C10-aryl, 5- to 10- membered heteroaryl, and 3- to 10-membered heterocyclyl; B is selected from 4a 4 b R R N O R 4c R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, C1-C6- alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and halo-C 1 -C 6 -alkoxy; R 4a is selected from hydrogen, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy,
  • the present invention provides a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X 1 , X 2 and X 3 are each independently selected from N and CH; A is selected from C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkenyl, C 6 -C 10 -aryl, 5- to 10- membered heteroaryl, and 3- to 10-membered heterocyclyl; B is selected from 4a 4 b R R N O R 4c R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, C1-C6- alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and halo-C 1 -C 6 -alkoxy; R 4a is selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, hal
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; or (iii) X 1 and X 2 are N and X 3 is CH; or.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C6-C10-aryl and C3-C10-cycloalkyl; R 1 is selected from halo-C 1 -C 6 -alkyl and halogen; R 2 is selected from hydrogen and halogen; and R 3 is selected from hydrogen and halogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C6-C10-aryl and C3-C10-cycloalkyl; R 1 is selected from halo-C1-C6-alkyl and halogen; R 2 is selected from hydrogen and halogen; and R 3 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is C 6 -C 10 -aryl; R 1 is halogen; R 2 is halogen; and R 3 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R 1 is selected from CF 3 , CHF 2 , fluoro and chloro; R 2 is selected from hydrogen and fluoro; and R 3 is selected from hydrogen and fluoro.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R 1 is selected from CF 3 , CHF 2 , fluoro and chloro; R 2 is selected from hydrogen and fluoro; and R 3 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is phenyl; R 1 is chloro; R 2 is fluoro; and R 3 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group is selected from: In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group selected from: Cl F F F F In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the group In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 4b is selected from hydrogen and C1-C6-alkyl; R 4c is hydrogen; C is selected from pyridyl, pyrazolyl and 2H-triazole; R 7 is selected from C1-C6-alkyl, C1-C6-alkoxy and C3-C10-cycloalkyl; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 4b is selected from hydrogen and C1-C6-alkyl; R 4c is hydrogen; C is selected from pyridyl and pyrazolyl; R 7 is selected from C1-C6-alkyl and C3-C10-cycloalkyl; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from N N O N N N N N N O O N N N O
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from N N O N N O
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 4b is hydrogen; R 4c is hydrogen; C is selected from pyridyl and pyrazolyl; R 7 is selected from C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 4b is hydrogen; R 4c is hydrogen; C is selected from pyridyl and pyrazolyl; R 7 is C1-C6-alkyl; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is C1-C6-alkyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; or (iii) X 1 and X 2 are N and X 3 is CH; A is selected from C6-C10-aryl and C3-C10-cycloalkyl; R 1 is selected from halo-C1-C6-alkyl and halogen; R 2 is selected from hydrogen and halogen; R 3 is selected from hydrogen and halogen; R 4b is selected from hydrogen and C 1 -C 6 -alkyl; R 4c is hydrogen; R 5 is C1-C6-alkyl; C is selected from pyridyl, pyrazolyl, and 2H-triazole; R 6 is selected from hydrogen and fluoro; R 7 is selected from C1-C6-alkyl,
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; or (iii) X 1 and X 2 are N and X 3 is CH; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R 1 is selected from CF 3 , CHF 2 , fluoro and chloro; R 2 is selected from hydrogen and fluoro; R 3 is selected from hydrogen and fluoro; B is selected from: N N O N N N N N N O O N N N O R 5 is methyl; and R 6 is selected from hydrogen and fluoro.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; A is selected from C 6 -C 10 -aryl and C 3 -C 10 -cycloalkyl; R 1 is selected from halo-C1-C6-alkyl and halogen; R 2 is selected from hydrogen and halogen; R 3 is hydrogen; R 4b is hydrogen; R 4c is hydrogen; C is selected from pyridyl and pyrazolyl; R 5 is C 1 -C 6 -alkyl; R 6 is selected from hydrogen and halogen; R 7 is selected from C1-C6-alkyl and C1-C6-alkoxy; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R 1 is selected from CF3, CHF2, fluoro and chloro; R 2 is selected from hydrogen and fluoro; R 3 is hydrogen; R 4b is hydrogen; R 4c is hydrogen; C is selected from pyridyl and pyrazolyl; R 5 is methyl; R 6 is selected from hydrogen and fluoro; R 7 is selected from methyl and methoxy; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl; R 1 is selected from CF3, CHF2, fluoro and chloro; R 2 is selected from hydrogen and fluoro; R 3 is hydrogen; R 5 is methyl; and R 6 is selected from hydrogen and fluoro.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; A is selected from C 6 -C 10 -aryl and C 3 -C 10 -cycloalkyl; R 1 is selected from halo-C1-C6-alkyl and halogen; R 2 is selected from hydrogen and halogen; R 3 is selected from hydrogen and halogen; R 4b is selected from hydrogen and C1-C6-alkyl; R 4c is hydrogen; R 5 is C 1 -C 6 -alkyl; C is selected from pyridyl and pyrazolyl; R 7 is selected from C 1 -C 6 -alkyl and C 3 -C 10 -cycloalkyl; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; A is phenyl; R 1 is selected from CF 3 , fluoro and chloro; R 2 is fluoro; R 3 is hydrogen; B is selected from: N N O
  • R 5 is C1-C6-alkyl
  • R 7 is selected from C 1 -C 6 -alkyl and C 3 -C 10 -cycloalkyl
  • R 8 is hydrogen
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; A is C6-C10-aryl; R 1 is halogen; R 2 is halogen; R 3 is hydrogen; R 4b is hydrogen; R 4c is hydrogen; C is selected from pyridyl and pyrazolyl; R 7 is C1-C6-alkyl; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X 1 and X 3 are N and X 2 is CH; or (ii) X 1 , X 2 and X 3 are all N; A is phenyl; R 1 is chloro; R 2 is fluoro; R 3 is hydrogen; B is selected from R 7 is C 1 -C 6 -alkyl; and R 8 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one;
  • the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein.
  • the present invention provides compounds according to formula (I) as described herein as free bases.
  • 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.
  • 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, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, 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.
  • a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed. Processes of Manufacturing The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.
  • 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.
  • Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.
  • 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.
  • the 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.
  • reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.
  • This intermediate can be reacted with amine R B -H (V) in presence of a base like N,N-diisopropylethylamine, triethylamine or the like in a dipolar aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone to form Ia (nucleophilic substitution).
  • a base like N,N-diisopropylethylamine, triethylamine or the like
  • a dipolar aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone to form Ia (nucleophilic substitution).
  • compound IV can be reacted with amine R B -H (V) using palladium-catalysed coupling conditions (a palladium source such as tris(dibenzylideneacetone) dipalladium(0), a suitable ligand such as Xantphos and a base such as cesium carbonate or sodium tert.-butoxide to form compound Ia (metal-catalysed coupling).
  • a palladium source such as tris(dibenzylideneacetone) dipalladium(0)
  • a suitable ligand such as Xantphos
  • a base such as cesium carbonate or sodium tert.-butoxide
  • Scheme 2 Intermediates IIa can be prepared from compound VI by coupling with amine VII using amide coupling reagents such as HATU, HBTU, EDC or the like followed by reaction of the formed intermediate VIII with an orthoester IX at elevated temperatures.
  • compound VIII can be reacted with an acid chloride X (or an acid anhydride) and a base like N,N- diisopropylethylamine, triethylamine or pyridine to form intermediate XI which is then cyclised by heating in presence of a base, in presence of trimethylsilyl chloride or in a suitable solvent without additive such as acetic acid (Scheme 2).
  • an acid chloride X or an acid anhydride
  • a base like N,N- diisopropylethylamine, triethylamine or pyridine
  • intermediate XI which is then cyclised by heating in presence of a base, in presence of trimethylsilyl chloride or in a suitable solvent without additive such as acetic acid (Scheme 2).
  • Intermediates IIb can be prepared from compound XII by coupling with amine VII using amide coupling reagents such as HATU, HBTU, EDC or the like, followed by halogenation using N- bromosuccinimide or N-chlorosuccinimide in a suitable solvent to give compound XV.
  • This compound can be reacted with an acid anhydride or an orthoester IX at elevated temperatures to form intermediate IIb (Scheme 3).
  • compound XXII can be first cyclised using anhydride or orthoester IX to form intermediate XXV which can then be reacted with carboxylic acid XXIII under oxydative coupling conditions (using for example ammonium persulfate in dimethylsulfoxide at temperatures of 0 °C to 50 °C, Minisci reaction, additional blue LED irradiation can be applied) to form intermediate IVa (Scheme 6).
  • Compounds Ic can be prepared according to Scheme 7.
  • Compound XXVI is reacted with boronic acid III under palladium catalysed conditions to give compound XXVII.
  • This intermediate is further reacted with amine V in presence of a base like N,N-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone to form XXVIII.
  • the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the process is as described in any one of schemes 1 to 7.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein.
  • TREM2 Agonistic Activity Compounds of the present invention are TREM2 agonists.
  • 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.
  • 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.
  • 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.
  • the present invention provides a method for restoring the function of human TREM2 in a subject in need thereof, which method comprises administering an effective amount of a compound of formula (I) as described herein to the subject.
  • TREM2 agonist potency of the compounds of formula (I) according to the invention was measured using a HEK cell line expressing human TREM2 and DAP12.
  • Syk kinase Upon binding of small molecule ligands to the TREM2 receptor, Syk kinase is recruited and activated by DAP12. The resulting increased levels of phosphorylated Syk were measured in lysed cells with a commercial AlphaLisa reagent kit. To perform the assay, frozen HEK293-TREM2/DAP12 cells were thawed, adjusted and plated by using Certus at 20,000 cells per well in a 384 well plate, in 10 ⁇ L of DMEM media without Phenolred and supplemented with 5% FBS.
  • 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.
  • TREM2 agonistic potencies of reference compounds as measured in the assay described above are presented in table 2.
  • EC 50 ( ⁇ M) EC 50 ( ⁇ M) 1 0.007 17 0.015 2 0.003 18 0.002 3 0.125 19 0.103 4 0.023 20 0.015 5 0.007 21 0.245 6 0.119 22 0.665 7 0.002 23 0.020 8 0.014 24 0.237 9 0.001 25 0.024 10 0.005 26 2.143 11 0.026 27 0.019 12 0.010 28 0.144 13 0.025 29 0.647 14 0.046 30 0.962 15 0.004 31 0.052 16 0.165 32 0.109 hTREM2 hTREM2 Ex. Ex.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • said condition associated with a loss of function of human TREM2 is Parkinson’s disease.
  • said condition associated with a loss of function of human TREM2 is rheumatoid arthritis.
  • said condition associated with a loss of function of human TREM2 is Alzheimer’s disease.
  • said condition associated with a loss of function of human TREM2 is amyotrophic lateral sclerosis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is Nasu-Hakola disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is frontotemporal dementia. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is multiple sclerosis. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is prion disease. In a preferred embodiment, said condition associated with a loss of function of human TREM2 is stroke.
  • the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.
  • a pharmaceutical composition according to Example 60 or 61.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories).
  • the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi- solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi- solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • the upper limit given herein can be exceeded when this is shown to be indicated. Examples
  • the invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.
  • the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.
  • the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers.
  • the asymmetric carbon atom can be of the "R" or "S" configuration.
  • Step 2 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide
  • N-bromosuccinimide 806 mg, 4.53 mmol
  • Step 3 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one
  • 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide 961 mg, 3.63 mmol
  • 1,1,1-trimethoxyethane 3.2 g, 3.35 ml, 26.6 mmol
  • acetic acid 218 mg, 208 ⁇ l, 3.63 mmol
  • Step 2 8-bromo-6-chloro-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one
  • acetic acid 8 ml
  • Step 2 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione
  • a suspension of 5-amino-2,4-diketo-N-methyl-1H-pyrimidine-6-carboxamide (3 g, 16.3 mmol) in triethyl orthoacetate (13.2 g, 15 ml, 81.5 mmol) and acetic acid (980 mg, 933 ⁇ l, 16.3 mmol) was stirred for 5 h at 130 °C.
  • the reaction mixture was diluted with methyl tert-butyl ether and stirred for another 5 min before solids were filtered off and washed with methyl tert-butyl ether.
  • Step 3 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one
  • 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione 3.2 g, 15.4 mmol
  • phosphorus oxychloride 49.35 g, 30 ml, 322 mmol
  • N,N-diisopropyl ethylamine 2.0 g, 2.68 ml, 15.4 mmol
  • N,N-dimethylformamide 181 mg, 192 ⁇ l, 2.48 mmol
  • reaction mixture was purged and backfilled with argon three times, then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (63 mg, 0.077 mmol, 0.050 eq) was added. After purging and filling with argon again, the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were washed with water and brine, dried over Na 2 SO 4 and concentrated to dryness.
  • 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex 525 mg, 0.635 mmol, 0.10 eq
  • 3 M aqueous cesium carbonate solution (6.35 ml, 19.1 mmol) were added, and the reaction was heated overnight to 60 °C while stirring under argon.
  • the reaction mixture was filtered over Celite, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na 2 SO 4 and evaporated.
  • Step 2 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid
  • aqueous lithium hydroxide solution 0.5 M, 14.9 ml, 7.45 mmol
  • Step 3 5-amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-pyrimidine-4-carboxamide
  • 5-Amino-2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid (1.0 g, 3.18 mmol) was dissolved in N,N-dimethylformamide (15 ml).
  • N,N-diisopropylethylamine (1.64 g, 2.2 ml, 12.7 mmol) and methylamine hydrochloride (429 mg, 6.36 mmol) were added, then HATU (1.57 g, 4.13 mmol) was added portionwise and the mixture was stirred overnight.
  • Step 2 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one
  • 2-chloro-6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-[(2,2,2- trifluoroacetyl)amino]pyrimidine-4-carboxamide 1. g, 3.41 mmol
  • dichloromethane 20 ml
  • triethylamine (14.2 ml, 102.15 mmol)
  • trimethylsilyl chloride (4.33 ml, 34.1 mmol
  • Step 2 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-pyrimidine-4-carboxamide 2,2-Difluoroacetic acid anhydride (1.03 g, 0.73 ⁇ l, 5.89 mmol) was added to a solution of 5- amino-2-chloro-N-methyl-pyrimidine-4-carboxamide (1.1 g, 5.89 mmol) in tetrahydrofuran (33 ml) at 0 °C. The reaction mixture was stirred for 30 minutes at 0 °C, then the cooling bath was removed and the reaction mixture was warmed to room temperature over 1 h.
  • Step 3 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide
  • 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-pyrimidine-4-carboxamide 322 mg, 1.22 mmol
  • 3-(trifluoromethyl)- bicyclo[1.1.1]pentane-1-carboxylic acid (2.19 g, 12.17 mmol).
  • the reaction mixture was sparged with argon.
  • Step 4 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one
  • 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide 230 mg, 0.49 mmol
  • p-toluenesulfonic acid monohydrate 9 mg, 49 ⁇ mol
  • Step 2 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one
  • a solution of ammonium persulfate (2.51 g, 11 mmol) in the same dimethylsulfoxide / water mixture (24 ml) was added and the reaction was stirred at 40 °C for 18 h.
  • Step 2 6-chloro-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one
  • 2-chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide 7.0 g, 24.77 mmol, 1.0 eq
  • dichloromethane 100 ml
  • triethylamine 34.4 ml, 248 mmol
  • trimethylsilyl chloride 15.8 ml, 124 mmol
  • Step 3 6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one
  • 4-4-difluorocyclohexane carboxylic acid (1.86 mg, 11.3 mmol)
  • ammonium persulfate (3.45 g, 15.12 mmol)
  • [4,4′-bis(1,1- dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl- N]phenyl-C]Iridium(III) hexafluorophosphate CAS
  • the mixture was degassed and purged with nitrogen, then the mixture was stirred at 25 °C for 16 h and irradiated with a 455 nm blue LED.
  • the reaction mixture was purified by preparative MPLC (column: Spherical C18, 20-45 ⁇ m, 100 A, water + 0.1% formic acid / acetonitrile, flow rate 100ml/min) and the eluent was lyophilized to give a product 6-chloro-8-(4,4- difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (1.0 g, 69% yield) as light brown solid.
  • Step 2 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyridine
  • [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate 870 mg, 2.31 mmol
  • 1,4-dioxane 15 ml
  • bis(pinacolato)diboron (1.17 g, 4.62 mmol)
  • potassium acetate 906 mg, 9.23 mmol
  • 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex 189 mg, 0.231 mmol, 0.10 eq).
  • the mixture was purged and backfilled with argon three times, then stirred at 90 °C for 2 h.
  • the reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na 2 SO 4 and concentrated.
  • Example 1 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • 2-(2-methyl-4-pyridyl)morpholine (Intermediate B2, 48 mg, 0.267 mmol)
  • 6- chloro-8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A5, 50 mg, 0.134 mmol) and N,N-diisopropylethylamine (52 mg, 70 ⁇ l, 401 ⁇ mol ) in dimethyl sulfoxide (1 ml) was stirred at 120 °C for 2 h.
  • Example 2 and 3 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2- methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2- (difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4- one
  • the enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrido[3,4-d]pyrimidin-4-one were separated by chiral SFC (column Daicel IH, 5 ⁇ m, 250 x 20
  • Example 4 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-one
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4- d]pyrimidin-4-one (Intermediate A6, 50 mg, 0.13 mmol) in 1,4-dioxane (2 ml) was added tris(dibenzylideneacetone)dipalladium (6 mg, 0.01 mmol, 0.05 eq), Xantphos (7.5 mg, 0.01 mmol, 0.1 eq) and (2R)-2-(1-methylpyrazol-4-yl)morpholine (32 mg, 0.19 mmol).
  • Example 8 and 9 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2- methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)- 2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4- d]pyrimidin-4-one
  • the enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4- pyridyl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (Example 7, 23 mg) were separated by chiral SFC (column: chiral IC, 5
  • Example 10 8-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 7 from Intermediate (+)-B1 instead of Intermediate B2, yellow solid, MS m/z: 506.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 11 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-2-(trifluoromethyl)- pyrimido[5,4-d]pyrimidin-4-one (Intermediate A8, 60 mg, 0.15 mmol) in dimethylsulfoxide (2 ml) was added N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) and (2S)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-B1, 38 mg, 0.23 mmol) and the resulting mixture was stirred at 25 °C for 2 h.
  • Example 17 and Example 18 and Example 19 and Example 20 8-(4-chloro-2-fluoro-phenyl)- 6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6-[(2R,6S)- 2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-6-[(2S,6S)-2- (1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-3-methyl-2- (trifluoromethyl)pyrimid
  • Example 21 and Example 22 and Example 23 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6- [2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one and 2- (difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6- [(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one
  • Step 2 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4- yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6- [(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4- one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4- pyridyl)tetrahydropyran-4-yl]-3-methyl-pyrimido[5,4-d]pyrimidin-4-one To a solution of 2-(difluoromethyl
  • the flask was evacuated and backfilled with argon three times and then filled with hydrogen.
  • the reaction mixture was stirred at room temperature under hydrogen for 3 h, then it was filtered on dicalite and washed with ethyl acetate. The combined organic layers were concentrated.
  • the reaction vessel was sealed the heated to 60 °C for 1 h.
  • the reaction was cooled and diluted with saturated sodium bicarbonate solution.
  • the product was extracted with ethyl acetate, washed with water and brine, and concentrated in vacuo.
  • the residue was purified by column chromatography to give 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H- pyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4- one (82.5 mg, 78% yield) as light brown solid.
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2- fluoro-phenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6- [rac-(2R,4R)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one To a
  • the mixture was degassed with hydrogen three times, then stirred at 25 °C for 2 h under hydrogen atmosphere (15 Psi).
  • the reaction mixture was filtered through a pad of Celite.
  • the filtrate was diluted with ethyl acetate (100 ml) and washed with 1M hydrochloric acid (50 ml x 2) and brine (50 ml), then dried over Na2SO4, filtered and concentrated in vacuo.
  • This diasteromeric racemate was separated by chiral SFC (column Daicel Chiralpak AD 250 mm ⁇ 30 mm, 10 ⁇ m, isopropanol / 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro- phenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazol-4-yl)tetrahydropyran-4-yl]-2- (trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (12 mg, 4% yield), first eluting enantiomer, white solid, MS m/z: 546.3 [M+Na] + , ESI pos.
  • Example 54 and Example 55 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6- [(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4- d]pyrimidin-4-one and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2- (1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one (difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1- 4-yl)- 2H-pyran-4-yl]-2- d]pyrimidin-4-one and 6-[3- 2H
  • Step 2 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide
  • Step 4 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4-one Racemic 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]-2-(trifluor
  • the title compounds were prepared in analogy to
  • Example 59 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one
  • Step 1 methyl 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylate
  • 2,6-dichloropyrimidine-4-carboxylic acid methyl ester 1.0 g, 4.83 mmol
  • 1,4-dioxane 32 ml
  • 4-chloro-2-fluoro-phenyl)boronic acid 842 mg, 4.83 mmol
  • cesium carbonate 4.72 g, 14.5 mmol
  • Step 2 methyl 6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimidine-4-carboxylate
  • 2-chloro-6-(4-chloro-2-fluoro-phenyl)pyrimidine-4-carboxylic acid methyl ester 235 mg, 0.780 mmol
  • (2S)-2-(1-methylpyrazol- 4-yl)morpholine (Intermediate (+)-B1, 144 mg, 0.858 mmol) and N,N-diisopropyl ethylamine (202 mg, 272 ⁇ l, 1.56 mmol)
  • the mixture was stirred for 2 h at 110°C.
  • Step 3 methyl 5-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate
  • a solution of methyl 6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate 275 mg, 0.637 mmol
  • dichloromethane 6 ml
  • N-bromosuccinimide 125 mg, 0.70 mmol
  • Step 4 methyl 6-(4-chloro-2-fluoro-phenyl)-5-prop-1-ynyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate
  • methyl 5-bromo-6-(4-chloro-2-fluoro-phenyl)-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxylate 190 mg, 0.372 mmol
  • N,N-dimethylformamide 3 tributyl(prop-1-ynyl)stannane (184 mg, 170 ⁇ l, 0.558 mmol) at room temperature.
  • the mixture was degassed with argon before tetrakis(triphenylphosphine) palladium(0) (43 mg, 37 ⁇ mol, 0.10 eq) was added.
  • the mixture was stirred for 1 h at 110 °C in a microwave.
  • the reaction mixture was diluted with water and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated to dryness.
  • Step 5 6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-prop-1-ynyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimidine-4-carboxamide
  • Methyl 6-(4-chloro-2-fluoro-phenyl)-5-prop-1-ynyl-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrimidine-4-carboxylate (180 mg, 0.383 mmol) was dissolved in a solution of methylamine (40% in methanol, 4.77 ml, 38.3 mmol) at room temperature and the mixture was stirred for 2 h at 50 °C.
  • Step 6 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-8-one
  • 6-(4-chloro-2-fluoro-phenyl)-N-methyl-5-prop-1-ynyl-2-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrimidine-4-carboxamide 160 mg, 0.341 mmol
  • sodium ethoxide 232 mg, 3.41 mmol
  • Step 7 4-(4-chloro-2-fluoro-phenyl)-7-methyl-8-oxo-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde
  • 4-(4-chloro-2-fluoro-phenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one (20 mg, 43 ⁇ mol) in 1,4-dioxane (1 ml) was added selenium dioxide (9.5 mg, 85.3 ⁇ mol) at room temperature and the mixture was stirred for 2 h at 100 °C.
  • Step 8 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one
  • 4-(4-chloro-2-fluoro-phenyl)-7-methyl-8-oxo-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde 7 mg, 14.5 ⁇ mol) in dichloromethane (1 ml) was added [bis(2-methoxyethyl)amino]sulfur trifluoride (2.7 M in toluene, 54 ⁇ l, 145 ⁇ mol) and the mixture was stirred overnight at room temperature.
  • reaction mixture was purged and backfilled with argon 3 times and 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (106 mg, 130 ⁇ mol, 0.05 eq) was added.
  • the reaction mixture was purged and backfilled with argon 3 times and stirred at room temperature for 16 h.
  • the mixture was diluted with water and extracted 3 times with ethyl acetate. The organic layers were washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo.
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4- one 120 mg, 0.35 mmol
  • 2-(1-methylpyrazol-4-yl)morpholine (Intermediate B1, 89 mg, 0.53 mmol) in in N-methyl pyrrolidone (1 ml) was added N,N-diisopropyl ethylamine (138 mg, 1.06 mmol).
  • Reference Example 2 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol- 4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Reference Example 1, second eluting enantiomer with retention time 2.46 min, light yellow solid, MS m/z: 469.3 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • This racemate was separated by SFC (column Daicel Chiralcel OD 250 mm*30 mm, 10 ⁇ m, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 80 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl- 6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one as first eluting enantiomer with retention time 1.02 min (other enantiomer retention time 2.08 min), yellow solid, MS m/z: 480.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Reference Example 4 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Reference Example 3, second eluting enantiomer with retention time 2.08 min, yellow solid, MS m/z: 480.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Step 2 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one 6-Chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (25 mg, 0.074 mmol) was dissolved in dimethyl sulfoxide (1 ml) and (2S)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-B1, 25 mg, 0.174 mmol) and N,N-diisopropyl ethylamine (48 mg, 64 ⁇ l, 0.369 mmol) were added at room temperature.
  • the enantiomers were separated by chiral SFC (column Daicel Chiralpak AD, 250 mm ⁇ 30 mm, 10 ⁇ m, ethanol + 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (19 mg, 42% yield) as first eluting enantiomer with a retention time of 1.05 min, light yellow solid, MS m/z: 481.2 [M+H] + , ESI pos.
  • Example 60 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg
  • Example 61 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

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Abstract

L'invention concerne des composés de formule générale (I) dans laquelle A, B, R1, R2, R3, R5 et R6 sont tels que décrits dans la description, des compositions comprenant les composés, des procédés de fabrication des composés et des composés destinés à être utilisés dans des méthodes de traitement ou de prévention de maladies qui sont associées à TREM2, telles que, par exemple, la maladie de Parkinson, la polyarthrite rhumatoïde, la maladie d'Alzheimer, la sclérose latérale amyotrophique, la maladie de Nasu-Hakola, la démence frontotemporale, la sclérose en plaques, la maladie à prion et l'accident vasculaire cérébral.
PCT/EP2024/064558 2023-05-30 2024-05-28 Dérivés de pyrido[3,4-d]pyrimidin-4-one et pyrimido[5,4-d]pyrimidin-4-one utilisés en tant qu'agonistes de trem2 pour le traitement de la maladie de parkinson Pending WO2024246019A1 (fr)

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US12459953B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators
US12459952B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators

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US12459953B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators
US12459952B2 (en) 2024-01-04 2025-11-04 Muna Therapeutics Aps TREM2 modulators

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