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WO2024246018A1 - Agonistes de trem2 - Google Patents

Agonistes de trem2 Download PDF

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Publication number
WO2024246018A1
WO2024246018A1 PCT/EP2024/064557 EP2024064557W WO2024246018A1 WO 2024246018 A1 WO2024246018 A1 WO 2024246018A1 EP 2024064557 W EP2024064557 W EP 2024064557W WO 2024246018 A1 WO2024246018 A1 WO 2024246018A1
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Prior art keywords
pyrimidin
chloro
dimethyl
fluoro
phenyl
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Pending
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PCT/EP2024/064557
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English (en)
Inventor
Camille Christelle BELUZE
Stefan Berchtold
Linda BUI
Julie CHARPENTIER
Ludovic COLLIN
Maria Emilia Di Francesco
Guido Galley
Wolfgang Guba
Simon GUTBIER
Roland Johann HUMM
Alina LELKE
Xavier LUCAS CABRÉ
Adriana NEVES VIEIRA
Fionn Susannah O'HARA
Angélique PATINY-ADAM
Flore Marie Aude REGGIANI
Florian Wanke
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 WO2024246018A1 publication Critical patent/WO2024246018A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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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
    • 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, CNE/14.05.2024 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 7 , and R 8 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 (“C6-C10-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.
  • 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 H R N R N N N N R 5a 5b O R R5c R 4c R 6a N 6 c O R R 6b R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, C 1 - C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and halo-C 1 -C 6 -alkoxy; R 4a and R 5a are selected from hydrogen,
  • 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 N N N N N N N O N O N N N N N N;
  • R 1 , R 2 , and R 3 are each independently selected from hydrogen, halogen, cyano, C1- C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and halo-C1-C6-alkoxy;
  • R 7 is selected from C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, 3- to 10-membered heterocyclyl and C 3 -C 10 -cycloalkyl; wherein said C 3 -C 10 -cycloalkyl is optionally substituted with one substituent selected from halogen and C1-C6- alkyl; and
  • R 8 is selected from hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, 3- to 10-membered heterocyclyl, and C3-C10-cycloalkyl; wherein said C3-C10-cycloalkyl is optional
  • 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 2 and X 3 are N and X 1 is CH; or (iii) X 1 , X 2 and X 3 are all N; or (iv) X 2 and X 3 are CH and X 1 is N; or (v) X 1 and X 2 are N and X 3 is CH.
  • 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 2 and X 3 are CH and X 1 is N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkenyl, C 6 -C 10 -aryl, and 5- to 10-membered heteroaryl; R 1 is selected from hydrogen, halogen, cyano, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy; R 2 is selected from hydrogen, halogen, and C1-C6-alkyl; and R 3 is selected from hydrogen and halogen.
  • A is selected from C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkenyl, C 6 -C 10 -aryl, and 5- to 10-membered heteroaryl
  • R 1 is selected from hydrogen, halogen, cyano, C 1 -C 6
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl; R 1 is selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy; R 2 is selected from hydrogen, fluoro, and methyl; and R 3 is selected from hydrogen and fluoro.
  • A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl
  • R 1 is selected from hydrogen,
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C 3 -C 10 -cycloalkyl and C 6 -C 10 -aryl; R 1 is selected from halogen and halo-C1-C6-alkyl; 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 cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; R 1 is selected from fluoro, chloro, CHF2 and CF3; 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: B is selected from 4a 4 b H R N R N N N R 5a 5b O R R5c R 4c R 6a N 6 c O R R 6b R 4a and R 5a are selected from hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, and a group ; R 6a is selected from hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, and a group ; C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H- triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-
  • 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 N
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: B is selected from R 4b , R 5b , and R 6b are selected from hydrogen, halogen and C 1 -C 6 -alkyl; R 4c , R 5c , and R 6c are selected from hydrogen and halogen; R 9 is selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl; R 11 is selected from hydrogen, C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy; R 10 and R 12 are both hydrogen; C is selected from cyclopropyl, pyridyl and pyrazolyl; and D is selected from cyclopropyl and
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is In a further particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 7 is selected from C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl and C 3 -C 10 -cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one C1-C6-alkyl substituent; R 8 is selected from hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, and C 3 -C 10 - cycloalkyl; wherein said C3-C10-cycloalkyl is optionally
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 7 is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1- methylcyclopropyl, and cyclobutyl; R 8 is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1- difluoroethyl, cyclopropyl, 1-methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane; or R 7 and R 8 , taken together with the atoms to which they are attached, form a pyrrolidine ring.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 7 is C 1 -C 6 -alkyl; and R 8 is selected from C 1 -C 6 -alkyl and halo-C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are both methyl.
  • 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 2 and X 3 are N and X 1 is CH; or (iii) X 1 , X 2 and X 3 are all N; or (iv) X 2 and X 3 are CH and X 1 is N; or (v) X 1 and X 2 are N and X 3 is CH; A is selected from C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkenyl, C 6 -C 10 -aryl, and 5- to 10-membered heteroaryl; B is selected from 4a 4 b H R N R N N N R 5a O R 5b R5c R 4c R 6a N R 6c O R 6b R 1 is selected from hydrogen, halogen, cyano, 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 2 and X 3 are N and X 1 is CH; or (iii) X 1 , X 2 and X 3 are all N; or (iv) X 2 and X 3 are CH and X 1 is N; or (v) X 1 and X 2 are N and X 3 is CH; A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl; B is selected from
  • R 1 is selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy
  • R 2 is selected from hydrogen, fluoro, and methyl
  • R 3 is selected from hydrogen and fluoro
  • R 7 is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1- methylcyclopropyl, and cyclobutyl
  • R 8 is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1- difluoroethyl, cyclopropyl, 1-methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane; or R 7 and R 8 , taken together with the atoms to which they are attached, form a pyrrolidine ring.
  • 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 2 and X 3 are CH and X 1 is N; A is selected from C3-C10-cycloalkyl and C6-C10-aryl; B is selected from R 6a N 6 c O R R 6b R 1 is selected from halogen and halo-C1-C6-alkyl; R 2 is selected from hydrogen and halogen; R 3 is selected from hydrogen and halogen; R 4a and R 5a are a group R 6a is a group ; R 4b , R 5b , and R 6b are selected from hydrogen, halogen and C1-C6-alkyl; R 4c , R 5c , and R 6c are selected from hydrogen and
  • 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 2 and X 3 are CH and X 1 is N; A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; B is selected from R 1 is selected from fluoro, chloro, CHF 2 and CF 3 ; R 2 is selected from hydrogen and fluoro; R 3 is selected from hydrogen and fluoro; and R 7 and R 8 are both methyl.
  • 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 2 and X 3 are N and X 1 is CH; or (iii) X 1 , X 2 and X 3 are all N; or (iv) X 2 and X 3 are CH and X 1 is N; or (v) X 1 and X 2 are N and X 3 is CH; A is selected from C3-C10-cycloalkyl, C3-C10-cycloalkenyl, C6-C10-aryl, and 5- to 10-membered heteroaryl; B is selected from N N N N N N N O N O N N N N N N; R 1 is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy; R 2
  • 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 2 and X 3 are N and X 1 is CH; or (iii) X 1 , X 2 and X 3 are all N; or (iv) X 2 and X 3 are CH and X 1 is N; or (v) X 1 and X 2 are N and X 3 is CH; A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl; B is selected from N N N N N N N O N O N N N N N N; R 1 is selected from hydrogen, fluoro, chloro, cyano, CHF2, CF
  • 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 2 and X 3 are CH and X 1 is N; A is selected from C3-C10-cycloalkyl and C6-C10-aryl; B is selected from N N N N N N N O N O N N N N N R 1 is selected from halogen and halo-C 1 -C 6 -alkyl; R 2 is selected from hydrogen and halogen; R 3 is selected from hydrogen and halogen; R 4a and R 5a are a group ; R 6a is a group ; R 4b , R 5b , and R 6b are selected from hydrogen, halogen and C1-C6-alkyl; R 4c , R 5c , and R 6c are
  • 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 2 and X 3 are CH and X 1 is N; A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; B is selected from N N N N N N N O N O N N N N N R 1 is selected from fluoro, chloro, CHF 2 and CF 3 ; R 2 is selected from hydrogen and fluoro; R 3 is selected from hydrogen and fluoro; and R 7 and R 8 are both methyl.
  • 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 2 and X 3 are CH and X 1 is N; A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl; B is ; R 1 is selected from fluoro, chloro, CHF2 and CF3; R 2 is selected from hydrogen and fluoro; R 3 is selected from hydrogen and fluoro; and R 7 and R 8 are both methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 3 are N and X 2 is CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 2 and X 3 are N and X 1 is CH. In a preferred embodiment, 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 all N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 2 and X 3 are CH and X 1 is N. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are N and X 3 is CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from C3-C10- cycloalkyl, C 3 -C 10 -cycloalkenyl, C 6 -C 10 -aryl, and 5- to 10-membered heteroaryl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from H N N N 5a R R 5b R 5c wherein R 4a , R 4b , R 4c , R 5a , R 5b , and R 5c are as defined herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, halogen, and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen and halogen. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and a group , wherein R 9 , R 10 and C are as defined herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5a is selected from hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, and a group , wherein R 9 , R 10 and C are as defined herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6a is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and a group , wherein R 11 , R 12 and D are as defined herein.
  • 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, halogen, cyano, C 1 -C 6 -alkyl, and oxo.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6b is selected from hydrogen, halogen, cyano, C1-C6-alkyl, and oxo.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4c is selected from hydrogen, halogen, and C1-C6-alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6c is selected from hydrogen, halogen, and C1-C6-alkyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5b 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 5c is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from C1-C6- alkyl, halo-C1-C6-alkyl and C3-C10-cycloalkyl; wherein said C3-C10-cycloalkyl is optionally substituted with one C 1 -C 6 -alkyl substituent.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C10-cycloalkyl; wherein said C3-C10- cycloalkyl is optionally substituted with one C 1 -C 6 -alkyl substituent.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 , taken together with the atoms to which they are attached, form a 3- to 10-membered heterocycle.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10- cycloalkyl, and 3- to 10-membered heterocyclyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from hydrogen and C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydrogen, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and 3- to 10-membered heterocyclyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from hydrogen and C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl.
  • A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, fluoro, chloro, cyano, CHF 2 , CF 3 , methyl, and methoxy.
  • R 1 is selected from hydrogen, fluoro, chloro, cyano, CHF 2 , CF 3 , methyl, and methoxy.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, fluoro, and methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein 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 R 7 is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclpropyl, 1-methylcyclopropyl, and cyclobutyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1-difluoroethyl, cyclopropyl, 1- methlycyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 , taken together with the atoms to which they are attached, form a pyrrolidine ring.
  • 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 2 and X 3 are CH and X 1 is N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from C3-C10-cycloalkyl and C6-C10-aryl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from R 6a N R 6c O R 6b wherein R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6c are as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is ,wherein R 4a , R 4b , and R 4c are as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is ,wherein R 5a , R 5b , and R 5c are as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is ,wherein R 6a , R 6b , and R 6c are as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is ,wherein R 6a , R 6b , and R 6c are as described herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from halogen and halo-C1-C6-alkyl.
  • R 1 is selected from halogen and halo-C1-C6-alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 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 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 R 4a is a group , wherein R 9 , R 10 , and C are as defined herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5a is a group , wherein R 9 , R 10 , and C are as defined herein.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6a is a group , wherein R 11 , R 12 , and D are as defined herein.
  • 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, halogen and C 1 -C 6 -alkyl.
  • R 4b is selected from hydrogen, halogen and C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5b is selected from hydrogen, halogen and C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6b is selected from hydrogen, halogen and C1-C6-alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4c 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 R 5c 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 R 6c 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 R 7 is C1-C6-alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from C1-C6-alkyl and halo-C1-C6-alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, C1-C6-alkyl, C1-C6-alkoxy, and C3-C10-cycloalkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydrogen, C 1 -C 6 -alkyl, and C 1 -C 6 -alkoxy.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 12 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 cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is 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 . 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 . 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 .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from fluoro, chloro, CHF2 and CF3.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 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 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 C is selected from cyclopropyl, pyridyl and pyrazolyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein C is selected from cyclopropyl and pyridyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4b , R 5b , and R 6b are selected from hydrogen, fluoro and methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4c , R 5c , and R 6c are selected from hydrogen and fluoro.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is methyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 9 is selected from hydrogen, methyl, methoxy, and cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is selected from hydrogen, methyl and methoxy.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4- d]pyrimidin-4-one; 8-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one; 8-(4-chloro-2-fluoro-phenyl)
  • 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-diisopropyl ethylamine, triethylamine or the like in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone to form Ia (nucleophilic substitution).
  • a base like N,N-diisopropyl ethylamine, triethylamine or the like
  • a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone
  • 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
  • C-linked derivatives Ib the corresponding halogen derivatives R B -X 3 (VI) can be first transformed into organozinc compounds R B -Zn-X 3 (VII) by reacting with zinc under anhydrous conditions.
  • This organometallic reagent can then be reacted with intermediate IV using palladium-catalysed conditions to produce compounds of formula 1b using a metal-catalysed coupling (Scheme 1).
  • Scheme 2 Intermediates IIa can be prepared from compound VIII by coupling with amine IX using amide coupling reagents such as HATU, HBTU, EDC or the like followed by reaction of the formed intermediate X with an orthoester XI at elevated temperatures.
  • compound X can be reacted with an acid chloride XII (or an acid anhydride) and a base like N,N-diisopropyl ethylamine, triethylamine or pyridine to form intermediate XIII which is then cyclised by heating in presence of a base or a suitable solvent such as acetic acid (Scheme 2).
  • an acid chloride XII or an acid anhydride
  • a base like N,N-diisopropyl ethylamine, triethylamine or pyridine
  • Such processes include hydrogenation of a compound with a partially unsaturated carbocycle to give a saturated carbocycle in position R A or an alkylation of a suitable substituent R B with an alkylating agent and a base (Scheme 7)
  • 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. 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.
  • 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 168 or 169.
  • 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 1 3-amino-2,6-dichloro-isonicotinic acid To a suspension of 3-amino-2,6-dichloro-isonicotinic acid methyl ester (1000 mg, 4.52 mmol) in tetrahydrofuran (12 ml) and water (4 ml) was added at 0 °C lithiumhydroxide (325 mg, 13.57 mmol) and the mixture was stirred for one hour at 0 °C and after that at room temperature overnight. Water was added and the mixture was extracted once with ethyl acetate.
  • the aqueous phase was made acidic (pH 4) by addition of 3 M hydrochloric acid.
  • the formed precipitate was dried in vacuo to yield the title compound (592 mg, 60% yield) as a yellow solid, MS m/z: 205.1 [M-H]-, ESI pos.
  • Step 2 3-amino-2,6-dichloro-N-methyl-pyridine-4-carboxamide
  • methylamine hydrochloride 489 mg, 7.25 mmol
  • N,N-diisopropyl ethylamine 1873 mg, 14.5 mmol
  • HATU 2.76 g, 7.25 mmol
  • Step 3 6,8-dichloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one Trimethyl orthoformate (2.08 g, 19.6 mmol) was added to 3-amino-2,6-dichloro-N-methyl- pyridine-4-carboxamide (864.0 mg, 3.93 mmol) in 1,4-dioxane (5 ml). Toluene-4-sulfonic acid (676 mg, 3.93 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated, followed by addition of saturated NaHCO3 solution.
  • 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 2-(1-bicyclo[1.1.1]pentanyl)-8-bromo-6-chloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one
  • a solution of 3-(bicyclo[1.1.1]pentane-1-carbonylamino)-2-bromo-6-chloro-N-methyl-pyridine- 4-carboxamide (230 mg, 0.64 mmol) in acetic acid (3.0 ml) was stirred at 110 °C for 16 h.
  • the reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated.
  • Step 1 3-amino-2-bromo-6-chloro-N-cyclopropyl-isonicotinamide
  • 3-amino-2-bromo-6-chloro-isonicotinic acid (2 g, 7.56 mmol) in dry N,N- dimethylformamide (60 ml)
  • cyclopropylamine (1.29 g, 1.6 ml, 22.6 mmol
  • N-ethyl diisopropylamine 5.86 g, 7.84 ml, 45.4 mmol
  • reaction mixture was cooled at 0 °C and HATU (4.9 g, 12.9 mmol) was added and the reaction mixture was stirred at room temperature for 2 days.
  • the reaction mixture was diluted with saturated NaHCO3 solution and water, and was extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness.
  • Step 2 8-bromo-6-chloro-3-cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one
  • 3-amino-2-bromo-6-chloro-N-cyclopropyl-isonicotinamide 460 mg, 1.58 mmol
  • 1,1,1-trimethoxyethane 951 mg, 1.01 ml, 7.92 mmol
  • p-toluenesulfonic acid monohydrate 301 mg, 1.58 mmol
  • Step 2 3-amino-2-bromo-6-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide
  • N-bromosuccinimide 110 mg, 0.62 mmol
  • Step 3 8-bromo-6-chloro-2-methyl-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one
  • 3-amino-2-bromo-6-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide 150 mg, 0.45 mmol
  • 1,4-dioxane 5 ml
  • trimethyl orthoacetate 271 mg, 2.26 mmol
  • p-toluene sulfonic acid 155 mg, 0.9 mmol
  • Step 2 8-bromo-6-chloro-2-cyclobutyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one
  • 2-bromo-6-chloro-3-(cyclobutanecarbonylamino)-N-methyl-pyridine-4- carboxamide 120 mg, 0.35 mmol
  • acetic acid 4 ml
  • Step 2 8-bromo-6-chloro-3-methyl-pyrido[3,2-d]pyrimidin-4-one
  • sodium hydride 98 mg, 2.44 mmol
  • Iodomethane 433 mg, 191 ⁇ l, 3.05 mmol
  • the reaction mixture was poured in water and extracted two times with ethyl acetate.
  • Step 2 3-amino-4-bromo-6-chloro-N-methyl-picolinamide 3-Amino-4-bromo-6-chloro-picolinic acid (500 mg, 1.79 mmol) and methylamine hydrochloride (181 mg, 2.68 mmol) were dissolved in N,N-dimethylformamide (14 ml) and N,N-diisopropyl ethylamine (694 mg, 920 ⁇ l, 5.37 mmol) was added. After cooling the mixture to 0 °C HATU (817 mg, 2.15 mmol) was added. The reaction mixture was stirred at room temperature overnight, then diluted with water and ethyl acetate and extracted.
  • Step 3 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,2-d]pyrimidin-4-one
  • 3-amino-4-bromo-6-chloro-N-methyl-picolinamide 371 mg, 1.4 mmol
  • 1,1,1-trimethoxyethane 1.24 g, 1.31 ml, 10.3 mmol
  • acetic acid 84 mg, 80 ⁇ l, 1.4 mmol
  • the reaction mixture was concentrated to dryness and the crude material was purified by flash chromatography (silica gel, 100% dichloromethane) to yield the product which still contained some starting material.
  • Step 2 5-(ethoxymethyleneamino)-2,4-diketo-1H-pyrimidine-6-carboxylic acid methyl ester A suspension of 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylic acid methyl ester (440 mg, 2.38 mmol) in diethoxymethyl acetate (4.0 g, 4 ml, 24.5 mmol) was stirred for 2 h at 80 °C.
  • Step 3 3-methyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione
  • a suspension of 5-(ethoxymethyleneamino)-2,4-diketo-1H-pyrimidine-6-carboxylic acid methyl ester (400 mg, 1.66 mmol) in a 33% solution of methylamine in ethanol (4 ml, 32.1 mmol) was stirred over night at 80 °C. Solids were filtered off, washed with ethanol, then dried in vacuo to obtain the crude title compound 3-methyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (350 mg, 100%) as light yellow solid.
  • 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
  • dimethylformamide 181 mg, 192 ⁇ l, 2.48 mmol
  • Step 2 6-chloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one
  • 5-amino-2-chloro-N-methyl-pyrimidine-4-carboxamide 455 mg, 2.44 mmol
  • 1,1,1-trimethoxyethane 2.15 g, 2.25 ml, 17.88 mmol
  • acetic acid 146 mg, 140 ⁇ l, 2.44 mmol
  • Step 2 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanone
  • 2-chloro-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanone (3.60 g, 17.9 mmol) in dimethyl sulfoxide (60 ml) were added N-benzylethanolamine (2.71 g, 17.9 mmol), potassium carbonate (4.96 g, 35.9 mmol) and potassium iodide (2.98 g, 17.9 mmol). Then the mixture was stirred at 20 °C for 2 h.
  • Step 3 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanol
  • 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanone 5.0 g, 13.6 mmol
  • methanol 80 ml
  • sodium borohydride (2.06 g, 54.5 mmol
  • the reaction mixture was poured into aqueuous saturated NH4Cl solution (300 ml) and the aqueous layer was extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine (200 ml x 3), dried over Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: UniSil 10-120, C1870 x 250 mm, water + 0.1% formic acid / acetonitrile, flow rate 140ml/min). The pH of the eluent was adjusted to 8-9 with ammonium hydroxide and the mixture was extrated with ethyl acetate (200 ml x 3).
  • Step 4 4-benzyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine
  • 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazol-4-yl]ethanol 2.5 g, 7.88 mmol
  • diisopropyl azodicarboxylate 1.66 ml, 9.45 mmol
  • triphenylphosphine (2.48 g, 9.45 mmol) in portions.
  • Step 5 2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine
  • 4-benzyl-2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholine 1.2 g, 4.01 mmol
  • methanol 15 ml
  • Pd/C 10%, 213 mg
  • the reaction was stirred at 50 °C for 12 h under hydrogen (15 psi).
  • the reaction was cooled to room temperature and filtered through a pad of Celite.
  • (+)- 2-(1-methylpyrazol-4-yl)morpholine 2-(1-Methylpyrazol-4-yl)morpholine (Intermediate E1) was separated by chiral SFC (column AD-H, 5 ⁇ m, 100 x 4.6 mm, 20-40% MeOH + 0,2% diethylamine) to yield (+)- 2-(1- methylpyrazol-4-yl)morpholine as the first eluting enantiomer and (-)- 2-(1-methylpyrazol-4- yl)morpholine as the second eluting enantiomer.
  • 6-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one To a solution of 6,8-dichloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A1, 150 mg, 0.65 mmol) in a mixture of toluene (10 ml) and ethanol (5 ml) were added 4- chlor
  • Step 2 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one
  • 6-chloro-8-(4-chlorophenyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one 90 mg, 0.29 mmol
  • 2-(1-methylpyrazol-4-yl)morpholine (Intermediate E1, 74 mg, 0.44 mmol) in N- methyl pyrrolidone (3 ml) was added N,N-diisopropyl ethylamine (152 mg, 1.18 mmol) and the mixture was heated under microwave irradiation at 150 °C for 12 h.
  • This racemate was separated by SFC (column Daicel Chiralcel OD 250 mm*30 mm, 10 um, solvent: acetonitrile / isopropylalcohol / 0.1% ammonium hydroxide, flow rate 75 ml/min) to give 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1- methylpyrazol-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one as first eluting enantiomer with retention time 1.18 min (other enantiomer retention time 1.51 min), light yellow solid, MS m/z: 437.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 2 8-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the title compound was prepared in analogy to Example 1 from 2-fluoro-4- (trifluoromethyl)phenylboronic acid instead of 4-chlorophenylboronic acid in step 1 and (+)-2- (1-methylpyrazol-4-yl)morpholine instead of 2-(1-methylpyrazol-4-yl)morpholine in step 2 omitting the chiral SFC separation.
  • Example 3 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • 8-bromo-6-chloro-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A3, 834 mg, 3.04 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (530 mg, 3.04 mmol) in 1,4- dioxane (15 ml) and water (5 ml), was added cesium carbonate (2.97 g, 9.11 mmol).
  • reaction mixture was purged and backfilled with argon 3 times.
  • 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (124 mg, 152 ⁇ mol, 0.05 eq) was added and the mixture was purged and backfilled with argon 3 times.
  • the reaction mixture was stirred at room temperature for 16 h, then diluted with water and extracted two times with dichloromethane. The combined 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)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • 2-(1-methylpyrazol-4-yl)morpholine (Intermediate E1, 134 mg, 0.8 mmol)
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-pyrido[3,4-d]pyrimidin-4-one 130 mg, 0.4 mmol
  • N-methyl pyrrolidone 3 ml
  • N,N-diisopropyl ethylamine (0.21 ml, 1.2 mmol
  • This racemate was separated by SFC (column Daicel Chiralcel OD-3, 50 mm*4.6 mm, 3 um, mobile phase 50% acetonitrile / isopropylalcohol / 0.05% diethylamine, flow rate 3 ml/min) to give 8- (4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,4- d]pyrimidin-4-one as first eluting enantiomer with retention time 1.25 min (other enantiomer retention time 0.85 min), yellow solid, MS m/z: 455.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • 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 Na2SO4 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 E1, 89 mg, 0.53 mmol) in in N-methyl pyrrolidone (1 ml) was added N,N-diisopropyl ethylamine (138 mg, 1.06 mmol).
  • Example 14 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 Example 13, 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.
  • Example 15 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4- yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 13 from Intermediate E5 instead of Intermediate E1 in step 2, first eluting enantiomer with retention time 1.58 min, light yellow solid, MS m/z: 495.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 16 8-(4-chloro-2-fluoro-phenyl)-6-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4- yl]-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 13 from Intermediate E5 instead of Intermediate E1 in step 2, second eluting enantiomer with retention time 2.58 min, light yellow solid, MS m/z: 495.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 17 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H- pyrazolo[3,4-c]pyridin-6-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 (see Example 13, 25 mg, 74 ⁇ mol), 1-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine dihydrochloride (Intermediate E6, 16 mg, 74 ⁇ mol), tris(dibenzylideneacetone)dipalladium (3 mg, 3.7 ⁇ mol, 0.05 eq), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2 mg, 3.7
  • Example 18 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-2,3- dimethyl-pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 17 from Intermediate E8 instead of Intermediate E6, yellow powder, MS m/z: 436.2 [M+H] + , ESI pos.
  • Example 19 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
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4- one see Example 13, 30 mg, 0.09 mmol) in 1,4-dioxane (1.5 ml) were added 2-(2-methyl-4- pyridyl)morpholine (Intermediate E3, 24 mg, 0.13 mmol), cesium carbonate (87 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (6.5 mg, 0.01 mmol, 0.08 eq) and Xantphos (10 mg, 0.02 mmol, 0.2 eq) and the
  • This racemate was separated by SFC (column Daicel Chiralcel OD 250 mm*30 mm, 10 um, 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.
  • Example 20 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 Example 19, second eluting enantiomer with retention time 2.08 min, yellow solid, MS m/z: 480.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • the following Examples 21-30 were prepared in analogy to Example 19 and 20 by coupling the indicated intermediate instead of intermediate E3. The absolute stereochemistry was assigned arbitrarily.
  • reaction mixture was purged and backfilled with argon three times and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (42 mg, 0.052 mmol, 0.050 eq) was added.
  • the reaction mixture was purged and backfilled with argon three times.
  • the reaction mixture was stirred at room temperature for 16 hours.
  • 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 Na2SO4 and concentrated to dryness.
  • Step 2 3-fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-8-yl]benzonitrile
  • (2S)-2-(1-methylpyrazol-4-yl)morpholine Intermediate (+)-E1, 73 mg, 58 ⁇ l, 438 ⁇ mol
  • 4-(6-chloro-4-keto-2,3-dimethyl-pyrido[3,4-d]pyrimidin-8-yl)-3-fluoro- benzonitrile 100 mg, 219 ⁇ mol
  • N,N-diisopropyl ethylamine 85 mg, 115 ⁇ l, 657 ⁇ mol
  • dimethyl sulfoxide 1.5 ml.
  • reaction mixture was stirred at 120 °C for 16 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 to dryness.
  • the residue was purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to afford the title compound (24 mg, 24% yield) as yellow solid, MS m/z: 460.3 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 32 8-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 31 from 2-(4-chloro-2,6-difluoro- phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane at a reaction temperature of 80 °C instead of (4- chloro-2-fluoro-phenyl)boronic acid at room temperature in step 1, yellow solid, MS m/z: 487.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 33 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one
  • 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A2) 300 mg, 1.04 mmol) in 1,4-dioxane (10 ml) were added 2,4-difluorobenzeneboronic acid (164 mg, 1.04 mmol), sodium carbonate (331 mg, 3.12 mmol) and tetrakis(triphenylphosphine)- palladium(0) (60 mg, 0.05 mmol, 0.05 eq).
  • Step 2 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one
  • 6-chloro-8-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one 47 mg, 0.15 mmol
  • (2S)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-E1, 37 mg, 0.22 mmol), N,N-diisopropyl ethylamine (0.12 ml, 0.73 mmol) and the mixture heated under microwave irradiation at 150 °C for 12 h.
  • Example 34 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 33 from (2R)-2-(1-methylpyrazol-4- yl)morpholine instead of (2S)-2-(1-methylpyrazol-4-yl)morpholine in step 2, yellow solid, MS m/z: 453.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 35 8-(2-fluoro-4-methyl-phenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 33 from 2-fluoro-4- methylphenylboronic acid instead of 2,4-difluorobenzeneboronic acid in step 1 and (2R)-2-(1- methylpyrazol-4-yl)morpholine instead of (2S)-2-(1-methylpyrazol-4-yl)morpholine in step 2, yellow solid, MS m/z: 449.3 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 36 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p- tolyl)pyrido[3,4-d]pyrimidin-4-one
  • 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A2) 200 mg, 0.69 mmol) in 1,4-dioxane (6 ml) and were added 4-methylphenylboronic acid (94 mg, 0.69 mmol), cesium carbonate (678 mg, 2.08 mmol), bis(diphenylphosphino) ferrocene- palladium(II)dichloride dichloromethane complex (28 mg, 0.03 mmol, 0.05 eq) and water (2 ml).
  • reaction mixture was degassed with nitrogen three times and stirred at 25 °C for 12 h under nitrogen.
  • the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na 2 SO 4 and concentrated in vacuum.
  • Step 2 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4- d]pyrimidin-4-one
  • 6-chloro-2,3-dimethyl-8-(p-tolyl)pyrido[3,4-d]pyrimidin-4-one 60 mg, 0.2 mmol
  • N-methyl pyrrolidone (2 ml)-2-(1-methylpyrazol-4-yl)morpholine (50 mg, 0.3 mmol) and N,N-diisopropyl ethylamine (0.1 ml, 0.6 mmol)
  • Example 37 2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-(p- tolyl)pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 36 from (2S)-2-(1-methylpyrazol-4- yl)morpholine instead of (2R)-2-(1-methylpyrazol-4-yl)morpholine in step 2, yellow solid, MS m/z: 431.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 38 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • Step 1 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-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 see Example 13, 300 mg, 0.89 mmol) in N-methylpyrrolidone (4 ml) were added 2-(1H- pyrazol-4-yl)morpholine (Intermediate E11,
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4-yl)morpholin-4- yl]pyrido[3,4-d]pyrimidin-4-one 35 mg, 0.08 mmol
  • 3-iodooxetane 28 mg, 0.15 mmol
  • cesium carbonate 75 mg, 0.23 mmol
  • the enantiomers were separated by SFC (column Daicel Chiralpak AD, 250 mm x 30 mm, 10 um, solvent ethanol + 0.1% ammonium hydroxide, flow rate 70 ml/min) to give as first eluting compound (retention time 1.08 min) 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6- [(2R)-2-[1-(oxetan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (2.8 mg, 10%) as light yellow gum, MS m/z: 511.1 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 39 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 38, step 2 second eluting compound (retention time 1.62 min) light yellow gum, MS m/z: 511.1 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 40 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one 500 mg, 1.73 mmol
  • ethanol ethanol
  • 2-(4,4- dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane CAS 859217-67-7, 409 mg, 1.73 mmol
  • sodium carbonate 551 mg, 5.2 mmol
  • tetrakis(triphenylphosphine)palladium(0) 100 mg, 0.09 mmol
  • Step 2 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one
  • 6-chloro-8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin- 4-one 130 mg, 0.41 mmol
  • 2-(2-methyl-4-pyridyl)morpholine (Intermediate E3, 109 mg, 0.615 mmol)
  • cesium carbonate 400 mg, 1.23 mmol
  • tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol, 0.08 eq)
  • Xantphos 47 mg, 0.08 mmol, 0.2 eq
  • the enantiomers were separated by SFC (column Daicel Chiralpak AD, 250 mm x 30 mm, 10 um, solvent ethanol + 0.1% ammonium hydroxide, flow rate 75 ml/min) to give as first eluting compound (retention time 2.1 min), MS m/z: 460.4 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 41 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidin-4-one
  • Step 1 6-chloro-2,3-dimethyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidin-4- one
  • 8-bromo-6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A2) 500 mg, 1.73 mmol) in 1,4-dioxane (12 ml) were added 4,4,5,5-tetramethyl-2-[4- (trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane (CAS 683242-93-5, 478 mg, 1.73
  • Step 2 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[4- (trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidin-4-one
  • 6-chloro-2,3-dimethyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4- d]pyrimidin-4-one (170 mg, 0.48 mmol) in 1,4-dioxane (1 ml) were added (2R)-2-(1- methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 119 mg, 0.71 mmol), cesium carbonate (387 mg, 1.19 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.02 mmol, 0.05 eq), Xantphos (27.5 mg, 0.05
  • Examples 42-45 were prepared in analogy to Example 41 by coupling the indicated boronic acid derivative instead of 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)- cyclohexen-1-yl]-1,3,2-dioxaborolane.
  • the absolute stereochemistry was assigned arbitrarily. Boronic MS Ex.
  • Step 2 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]oct-6-en-6- yl-pyrido[3,4-d]pyrimidin-4-one
  • (2R)-2-(1-methylpyrazol-4- yl)morpholine Intermediate (+)-E1, 107 mg, 0.64 mmol
  • tris(dibenzylideneacetone)dipalladium 31 mg, 0.03 mmol, 0.08 eq)
  • cesium carbonate (418 mg, 1.28 mmol
  • Xantphos (49.5 mg, 0.09 mmol, 0.2
  • Step 3 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-spiro[2.5]octan-6-yl- pyrido[3,4-d]pyrimidin-4-one
  • methanol 2 ml
  • palladium on charcoal 10%, 10 mg
  • Example 47 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 46 from 2-(4,4-difluorocyclohex-1-en-1- yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 1227068-84-9) instead of 4,4,5,5-tetramethyl- 2-spiro[2.5] oct-6-en-6-yl-1,3,2-dioxaborolane in step 1 and hydrogenation for 16 h at 50 °C and atmospheric pressure in step 3, light yellow solid, MS m/z: 459.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 48 8-(4,4-dimethylcyclohexyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 46 from 8-(4,4-dimethylcyclohexen-1- yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one (Example 40) instead of 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8- spiro[2.5]oct-6-en-6-yl-pyrido[3,4-d]pyrimidin-4-one using atmospheric pressure for 16 h at room temperature in step 3, light yellow solid, MS m/z:
  • Example 49 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrido[3,4-d]pyrimidin-4-one
  • Step 1 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-ethyl-pyrido[3,4-d]pyrimidin-4-one
  • 4-chloro-2-fluorophenylboronic acid 189 mg, 1.08 mmol
  • sodium carbonate 314 mg, 2.95 mmol
  • tetrakis(triphenylphosphine) palladium(0) 91 mg, 0.08 mmol
  • reaction mixture was stirred at 80 °C for 16 h under nitrogen atmosphere. After cooling down to room temperature the reaction was added into water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (100 ml) and dried over Na2SO4, then concentrated under reduce pressure.
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-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)-3-ethyl-pyrido[3,4-d]pyrimidin-4-one 110 mg, 0.33 mmol
  • 2-(1-methylpyrazol-4- yl)morpholine (Intermediate E1, 82 mg, 0.49 mmol) and N,N-diisopropyl ethylamine (126 mg, 0.98 mmol).
  • reaction was heated under microwave irradiation at 150 °C for 16 h. After cooling down to room temperature the reaction mixture was added into water (50 ml) and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (50 ml x 2) and dried over Na2SO4, then concentrated in vacuum.
  • This racemate was separated by SFC (column Daicel Chiralpak OD 250 mm*30 mm, 10 um, solvent: acetonitrile/methanol/0.1% ammonium hydroxide, flow rate 70 ml/min) to give the title compound (8 mg, 12% yield) as second eluting enantiomer with retention time 0.99 min (other enantiomer retention time 0.71 min), yellow solid, MS m/z: 469.1 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 50 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-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 Example 49 from 6,8-dichloro-3-cyclopropyl- pyrido[3,4-d]pyrimidin-4-one (Intermediate A6) instead of 6,8-dichloro-3-ethyl-pyrido[3,4- d]pyrimidin-4-one (Intermediate A5) in step 1, light yellow solid, MS m/z: 481.1 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 51 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-3- (2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 49 from 6,8-dichloro-3-(2,2,2- trifluoroethyl)pyrido[3,4-d]pyrimidin-4-one (Intermediate A7) instead of 6,8-dichloro-3-ethyl- pyrido[3,4-d]pyrimidin-4-one (Intermediate A5) in step 1, yellow solid, MS m/z: 523.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 52 8-(4-chloro-2-fluoro-phenyl)-3-cyclobutyl-2-methyl-6-[(2R)-2-(1-methylpyrazol- 4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • Step 1 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-cyclobutyl-2-methyl-pyrido[3,4-d]pyrimidin-4- one
  • 8-bromo-6-chloro-3-cyclobutyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A12, 200 mg, 0.61 mmol) in 1,4-dioxane (6 ml) were added 4-chloro-2- fluorophenylboronic acid (106 mg, 0.61 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)d
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-3-cyclobutyl-2-methyl-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)-3-cyclobutyl-2-methyl-pyrido[3,4- d]pyrimidin-4-one 60 mg, 0.16 mmol
  • (2R)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 32 mg, 0.19 mmol) in 1,4-dioxane (3 ml) were added cesium carbonate (65 mg, 0.48 mmol), XantPhos (9 mg, 0.02 mmol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (7 mg, 0.01
  • reaction mixture was purged and backfilled with argon three times. Then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (58 mg, 0.071 mmol, 0.05 eq) was added. The mixture was purged and backfilled with argon three times and stirred at 30 °C for 1 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 Na2SO4 and concentrated to dryness.
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-cyclopropyl-3-methyl-pyrido[3,4- d]pyrimidin-4-one (30 mg, 0.082 mmol) in 1,4-dioxane (3 ml) was added at room temperature (2S)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1, 18 mg, 0.107 mmol) followed by cesium carbonate (81 mg, 0.247 mmol) in water (1 ml).
  • the mixture was degassed for 10 min by bubbling argon through the mixture. Then was added PdCl(crotyl)QPhos (CAS 1252598-33- 6, 7.5 mg, 0.0082 mmol, 0.10 eq) and degassing was continued for 5 min. The tube was sealed and heated to 60 °C for 18 h. The mixture was treated with aqueous saturated NaHCO3 solution (10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • Example 61 8-(4-chloro-2-fluoro-phenyl)-3-ethyl-2-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 60 from 8-bromo-6-chloro-3-ethyl-2- methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A19) instead of 6,8-dichloro-3-cyclopropyl- pyrido[3,4-d]pyrimidin-4-one (Intermediate A16) in step 1, yellow solid, MS m/z: 483.0 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 62 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazol- 4-yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • Step 1 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin- 4-one
  • To a solution of 8-bromo-6-chloro-3-cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A10, 440 mg, 1.4 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (244 mg, 1.4 mmol) in 1,4-dioxane (6 ml) and water (2 ml) was added cesium carbonate (1.37 g, 4.2 mmol
  • reaction mixture was purged and backfilled with argon three times. Then 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (57 mg, 0.07 mmol, 0.050 eq) was added. After purging and backfilling with argon the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness.
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • (2S)-2-(1-methylpyrazol-4-yl)morpholine Intermediate (+)-E1, 46 mg, 36 ⁇ l, 0.275 mmol
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-cyclopropyl-2-methyl-pyrido[3,4- d]pyrimidin-4-one 50 mg, 0.137 mmol
  • N,N-diisopropyl ethylamine 53 mg, 72 ⁇ l, 0.412 mmol
  • dimethyl sulfoxide 1 ml
  • Example 63 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 66 from 8-bromo-6-chloro-2,3- dimethyl-pyrido[3,2-d]pyrimidin-4-one (Intermediate B2) instead of 8-bromo-6-chloro-3- cyclopropyl-2-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A10) in step 1 and 2-(1- methylpyrazol-4-yl)morpholine (Intermediate E1) instead of (2S)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (+)-E1) in step 2, light brown solid, MS m/z: 469.3 [M+H] + , ESI pos.,
  • Example 64 and 65 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6- [(2R)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[3,2-d]pyrimidin-4-one
  • the enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one (Example 63, 42 mg) were separated by chiral SFC (column chiral OD-H, 5 um, 250 x 20 mm, 45% methanol + 0,2%
  • Example 66 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one
  • (4-chloro-2-fluoro-phenyl)boronic acid (19 mg, 0.11 mmol)
  • 8-bromo-6-chloro- 3-methyl-pyrido[3,2-d]pyrimidin-4-one (Intermediate B1, 30 mg, 0.11 mmol) and cesium carbonate (105 mg, 0.321 mmol), 1,4-dioxane (480 ⁇ l) and water (144 ⁇ l) were added.
  • the tube was set under argon atmosphere and tetrakis(triphenylphosphine)palladium (6 mg, 0.0054 mmol, 0.050 eq) was added. The mixture was heated to 55°C overnight. The reaction mixture was extracted two times with ethyl acetate. The combined organic layers were washed with water an ⁇ d brine, dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane / 0-50% ethyl acetate) to give the title compound (14 mg, 40% yield) as a white solid, MS m/z: 324.1 [M+H] + , ESI pos.
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-3-methyl-pyrido[3,2-d]pyrimidin-4-one 50 mg, 0.148 mmol
  • toluene 2 ml
  • argon 2-(1-methylpyrazol-4- yl)morpholine Intermediate E1, 30 mg, 0.178 mmol
  • sodium tert-butylate (19 mg, 0.193 mmol)
  • XPhos-Pd-G3 9 mg, 0.010 ⁇ mol, 0.070 eq
  • reaction mixture was diluted with saturated NaHCO 3 solution and extracted two times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by reverse phase chromatography (column: YMC-Triart C18, 12 nm, 5 um, 100 x 30 mm, acetonitrile / water + 0.1% formic acid) to give 8-(4-chloro-2-fluoro-phenyl)-3-methyl-6-[2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,2-d]pyrimidin-4-one (19 mg).
  • Example 67 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
  • Step 1 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one 6,8-Dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (Intermediate C2, 850 mg, 3.47 mmol) was dissolved in 1,4-dioxane (20 ml) and (4-chloro-2-fluoro-phenyl)boronic acid (605 mg, 3.47 mmol) and 2 M cesium carbonate in water (5.2 ml, 10.41 mmol) were added at room temperature.
  • 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 (+)-E1, 25 mg, 0.174 mmol) and N,N-diisopropyl ethylamine (48 mg, 64 ⁇ l, 0.369 mmol) were added at room temperature.
  • Example 68 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazol-4-yl)morpholin- 4-yl]pyrimido[5,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 67 from 6,8-dichloro-3-methyl- pyrimido[5,4-d]pyrimidin-4-one (Intermediate C1) instead of 6,8-dichloro-2,3-dimethyl- pyrimido[5,4-d]pyrimidin-4-one (Intermediate C2) in step 1, yellow solid, MS m/z: 456.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 69 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 67 from (2R)-2-(1-methylpyrazol-4- yl)morpholine (Intermediate (-)-E1) instead of (2S)-2-(1-methylpyrazol-4-yl)morpholine (Intermediate (+)-E1) in step 2, yellow solid, MS m/z: 470.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 70 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazol-5- 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 (see Example 67, 25 mg, 0.074 mmol) was dissolved in N,N-dimethylformamide (0.5 ml).
  • Example 71 and 72 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(3-methyl-1,2,4- oxadiazol-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2- fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazol-5-yl)morpholin-4- yl]pyrimido[5,4-d]pyrimidin-4-one
  • the enantiomers of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazol-5- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one (Example 70, 16 mg) were separated by chiral SFC (col
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazol-4- yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4- one To a solution of 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4- one (see Example 13 step 1) was added Xantphos palladacycle G
  • Example 107 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one
  • Step 1 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4- one
  • 6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A4, 2.05 g, 9.78 mmol) in tetrahydrofuran, extra dry (10 ml) under an atmosphere of nitrogen was added XantPhos Pd G3 (505 mg, 489 ⁇ mol, 0.05 eq) followed by the above mentioned solution of bromo-[2-(1-methylpyrazol-4-yl]
  • Step 2 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one 3-(Trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2 g, 11.1 mmol) was dissolved in 7.7 ml of a mixture of dimethyl sulfoxide and water (600/1) and 10 ml a solution of 2,3- dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one (500 mg, 1.38 mmol) in dimethyl sulfoxide/water (600/1) was added.
  • Example 108 and 109 2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]- 8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one and 2,3-dimethyl- 6-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one
  • Example 110 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)cyclobutyl]pyrido[3,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 107 from 3-(trifluoromethyl)- cyclobutanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 2, yellow solid, MS m/z: 462.2 [M+H] + , ESI pos.
  • Example 111, 112 and 113 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one and 8-(4,4- difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4- yl]pyrido[3,4-d]pyrimidin-4-one and 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1- methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidin-4-one
  • the compounds were prepared in analogy to
  • Example 114 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one
  • Step 1 6-chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4- d]pyrimidin-4-one
  • a mixture of 6-chloro-2,3-dimethyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A4, 260 mg, 1.24 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (670 mg, 3.72 mmol), Ir[dF(CF3)ppy] 2 (dtbpy)(PF 6 ) (CAS: 870987-63-6
  • Step 2 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidin-4-one
  • 6-chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl] pyrido[3,4-d]pyrimidin-4-one 40 mg, 0.12 mmol) in 1,4-dioxane (3 ml) were added (2R)-2-(1- methylpyrazol-4-yl)morpholine (23 mg, 0.14 mmol), cesium carbonate (95 mg, 0.29 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.01 mmol, 0.05 eq), Xantphos (6.5 mg, 0.01 m
  • Examples 115-118 were prepared in analogy to Examples 114 by starting from the indicated carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1.
  • the absolute stereochemistry was assigned arbitrarily.
  • Step 2 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester
  • 2-chloro-6-[2-(1-methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester (675 mg, 2.0 mmol) in 1,4-dioxane (6.8 ml) was added at room temperature
  • 4-chloro-2- fluorobenzeneboronic acid (367 mg, 2.1 mmol) followed by a solution of cesium carbonate (2 M in water, 3.0 ml, 6.0 mmol).
  • the mixture was degassed by bubbling argon through the mixture for 10 min, then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (49 mg, 60 ⁇ mol, 0.030 eq) was added and degassing was done as described.
  • the mixture was stirred at 22 °C for 1.5 h, then aqueous saturated NaHCO3 solution (50 ml) was added and the mixture was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 3 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4- yl)morpholino]isonicotinic acid methyl ester
  • 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino] isonicotinic acid methyl ester 850 mg, 1.97 mmol
  • dichloromethane 17.17 ml
  • N- bromosuccinimide 35 mg, 0.197 ⁇ mol was added and stirring was continued for additional 30 min. The mixture was quenched with aqueous saturated NaHCO3 (50 ml) and extracted with dichloromethane (2 x 50 ml). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo.
  • Step 4 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino]-3-prop-1-ynyl- isonicotinic acid methyl ester
  • 3-bromo-2-(4-chloro-2-fluoro-phenyl)-6-[2-(1- methylpyrazol-4-yl)morpholino]isonicotinic acid methyl ester 120 mg, 0.235 mmol
  • N,N- dimethylformamide 1.2 ml
  • tributyl(prop-1-ynyl)stannane 93 mg, 86 ⁇ l, 0.283 mmol
  • tetrakis(triphenylphosphine) palladium(0) 8 mg, 7.0 ⁇ mol, 0.03 eq).
  • the tube was filled with argon, sealed and irradiated using a microwave at 110 °C for 60 min.
  • To the mixture was added further tributyl(prop-1-ynyl)stannane (78 mg, 72 ⁇ l l, 0.235 ⁇ l mol) and tetrakis(triphenylphosphine)palladium(0) (5.5 mg, 4.7 ⁇ mol, 0.02 eq) and irradiation was continued at 110 °C for another 30 min.
  • Step 5 2-(4-chloro-2-fluoro-phenyl)-N-methyl-6-[2-(1-methylpyrazol-4-yl)morpholino]-3-prop- 1-ynyl-isonicotinamide
  • 2-(4-chloro-2-fluoro-phenyl)-6-[2-(1-methylpyrazol-4-yl)morpholino]-3-prop- 1-ynyl-isonicotinic acid methyl ester 55 mg, 117 ⁇ mol
  • the tube was sealed and heated to 50 °C for 2 h, then concentrated in vacuo.
  • Step 6 5-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one
  • 2-(4-chloro-2-fluoro-phenyl)-N-methyl-6-[2-(1-methylpyrazol-4- yl)morpholino]-3-prop-1-ynyl-isonicotinamide 15 mg, 32 ⁇ mol
  • ethanol ml
  • sodium ethoxide 22 mg, 320 ⁇ mol
  • Example 120 5-(4-chloro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]-2,6- naphthyridin-1-one
  • the tile compound was prepared in analogy to Example 119 from 4-chlorobenzeneboronic acid instead of 4-chloro-2-fluorobenzeneboronic acid in step 2, yellow solid, MS m/z: 450.2 [M+H] + , ESI pos.
  • Example 121 and 122 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]-2,6-naphthyridin-1-one and 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1- methylpyrazol-4-yl)morpholino]-2,6-naphthyridin-1-one
  • the enantiomers of 5-(4-chloro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholino]- 2,6-naphthyridin-1-one (Example 120, 44 mg) were separated by SFC (column chiral IK, 5 um, 150 x 4.6 mm, 40-60% methanol + 0,2% diethylamine).
  • Example 123 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • 8-bromo-6-chloro-2-ethyl-3-methyl-pyrido[3,4-d]pyrimidin-4-one (Intermediate A8) 468 mg, 1.55 mmol) and (4-chloro-2-fluoro-phenyl)boronic acid (270 mg, 1.55 mmol) in 1,4-dioxane (8.1 ml) and water (2.7 ml), was added cesium carbonate (1.51 g, 4.64 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. The mixture was purged and backfilled with argon three times and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated to dryness.
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazol-4- yl)morpholino]pyrido[3,4-d]pyrimidin-4-one
  • (2S)-2-(1-methylpyrazol-4-yl)morpholine Intermediate (+)-E1, 47.5 mg, 38 ⁇ l l, 0.284 mmol
  • 6-chloro-8-(4-chloro-2-fluoro-phenyl)-2-ethyl-3-methyl-pyrido[3,4- d]pyrimidin-4-one 50 mg, 0.142 mmol
  • N,N-diisopropyl ethylamine 55 mg, 74 ⁇ l l, 0.426 mmol
  • dimethyl sulfoxide 1 ml
  • reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (50 ml x 2) and dried over Na 2 SO 4 , then concentrated in vacuum.
  • Examples 131 and 132 8-(4-chloro-2-fluoro-phenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazol- 4-yl)-1-piperidyl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro- phenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidyl]-2,3-dimethyl-pyrimido[5,4- d]pyrimidin-4-one
  • the tile compounds were prepared in analogy to Example 127-130 from Intermediate E9 instead of Intermediate E10, light yellow gum, MS m/z: 504.1 [M+H] + , ESI pos.
  • Example 133 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazol-4- yl]morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 127 from Intermediate E39 instead of Intermediate E10, first eluting enantiomer, light yellow gum, MS m/z: 512.1 [M+H] + , ESI pos. absolute stereochemistry arbitrarily assigned.
  • Example 134 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol- 4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one
  • Step 1 6-chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin- 4-one
  • To a solution of 6,8-dichloro-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (Intermediate C2, 50 mg, 0.2 mmol) in 1,4-dioxane (1.5 ml) and water (0.5 ml) was added 2-[2-fluoro-4- (trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 1073353-68-0
  • Step 2 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one
  • 6-chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrimido[5,4- d]pyrimidin-4-one 55 mg, 0.15 mmol
  • dimethyl sulfoxide (1 ml) were added N,N-diisopropyl ethylamine (0.08 ml, 0.44 mmol) and (2R)-2-(1-methylpyrazol-4-yl)morpholine (30 mg, 0.18 mmol) and the mixture was stirred at 20 °C for 2 h.
  • Examples 135-137 were prepared in analogy to Example 134 by coupling the indicated boronic acid derivative instead of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane.
  • the absolute stereochemistry was assigned arbitrarily. Boronic MS Ex.
  • reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 2). Organic phase was washed with brine (50 ml x 2), dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (column: Spherical C18, 20- 45 um, 100A, water + 0.1% formic acid / acetonitrile, flow rate 40 ml/min).
  • the enantiomers were separated by chiral SFC (column Daicel Chiralpak AD, 250 mm ⁇ 30 mm, 10um, ethanol + 0.1% ammonium hydroxide, flow rate 70 ml/min) to give 8-(4-chloro-2-fluoro-phenyl)-6-[(2S)-2-(2-methoxy-4- pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one (25 mg, 42% yield) as first eluting enantiomer with a retention time of 1.21 min, yellow solid, MS m/z: 497.2 [M+H] + , ESI pos.
  • Examples 140 and 141 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4- pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidin-4-one
  • the tile compounds were prepared in analogy to Example 144 and 145 from Intermediate E3 instead of Intermediate E4, light yellow solids, MS m/z: 481.2 [M+H] + , ESI pos.
  • Example 142 13-(4-chloro-2-fluoro-phenyl)-11-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]- 2,7,10,12-tetrazatricyclo[7.4.0.0 3,7 ]trideca-1(9),2,10,12-tetraen-8-one
  • Step 1 11-chloro-13-(4-chloro-2-fluoro-phenyl)-2,7,10,12-tetrazatricyclo[7.4.0.0 3,7 ]trideca- 1(9),2,10,12-tetraen-8-one
  • the mixture was degassed, filled with argon, and bis(di-tert-butyl(4- dimethylaminophenyl)phosphine)dichloropalladium(II) (52 mg, 0.07 mmol, 0.1 eq) was added. After stirring at 20 °C for 18 h, the mixture was diluted with water (60 ml) and extracted with ethyl acetate (3 x 60 ml).
  • Step 2 13-(4-chloro-2-fluoro-phenyl)-11-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]-2,7,10,12- tetrazatricyclo[7.4.0.0 3,7 ]trideca-1(9) tetraen-8-one
  • 11-chloro-13-(4-chloro-2-fluoro-phenyl)-2,7,10,12-tetrazatricyclo- [7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one (187 mg, 0.2 mmol) and 2-(1-methylpyrazol-4- yl)morpholine (Intermediate E1, 66 mg, 0.39 mmol) in dry dimethyl sulfoxide (6 ml) was added N,N-diisopropyl ethylamine (0.17 ml, 0.99 mmol) and the mixture was stirred at room temperature for
  • Examples 152-153 were prepared in analogy to Example 134 by coupling the indicated boronic acid derivative instead of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane.
  • the absolute stereochemistry was assigned arbitrarily. Boronic MS Ex.
  • Example 155 8-(4-chloro-2-fluoro-phenyl)-6-(3,4-dihydro-1H-2,7-naphthyridin-2-yl)-2,3- dimethyl-pyrimido[5,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 154 from Intermediate E8 instead of Intermediate E37, yellow solid, MS m/z: 437.2 [M+H] + , ESI pos.
  • Example 156 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 154 from Intermediate E11 instead of Intermediate E37, yellow solid, MS m/z: 456.2 [M+H] + , ESI pos.
  • Examples 157 and 158 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl- 6-[(2R)-2-(1H-pyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one
  • the enantiomers of 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H-pyrazol-4- yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (Example 156, 49 mg) were separated by chiral SFC (column: chiral IJ, 5 um, 250 x 20 mm, 20% methanol
  • the reaction mixture was stirred at 120 °C for 3 h. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na 2 SO 4 , filtrated and evaporated. Because the residue contained dimethyl sulfoxide a complete conversion was assumed for calculation of the amount and the solution was used as is for the next step.
  • Step 2 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholino]-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one
  • 2,3-dimethyl-6-[2-(1-methylpyrazol-4-yl)morpholino]pyrimido[5,4- d]pyrimidin-4-one aliquot of the dimethyl sulfoxide solution prepared above assuming 50 mg, 0.146 ⁇ mol) in DMSO/Water (600/1), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (264 mg, 1.46 mmol) was added.
  • reaction mixture was degassed while bubbling argon through it.
  • a freshly prepared solution of ammonium persulfate (200 mg, 0.88 ⁇ mol) in purged DMSO/Water (600/1) was added under argon.
  • the reaction mixture was stirred at 40 °C for 21 h.
  • the reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated.
  • Examples 162 and 163 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(2-methylpyrazol-3- yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)- 2,3-dimethyl-6-[8-(1-methylpyrazol-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin- 4-one
  • Step 1 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(1H-pyrazol-3-yl)-6-azaspiro[3.4]octan- 6-yl]pyrimido[5,4-d]pyrimidin-4-one
  • Step 1 8-(4-chloro-2-flu
  • Step 2 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(2-methylpyrazol-3-yl)-6- azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one and 8-(4-chloro-2-fluoro-phenyl)-2,3- dimethyl-6-[8-(1-methylpyrazol-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one To a solution of 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[8-(1H-pyrazol-3-yl)-6- azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidin-4-one (55 mg, 0.115 mmol) in N,N- dimethylform
  • Example 164 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazol-4- yl)morpholin-4-yl]pyrido[3,4-d]pyrimidin-8-one
  • the tile compound was prepared in analogy to Example 119 from methyl 2,6-dichloro- pyrimidine-4-carboxylate instead of methyl 2,6-dichloropyridine-4-carboxylate and Intermediate (+)-E1 instead of Intermediate E1 in step 1, yellow solid, MS m/z: 469.2 [M+H] + , ESI pos., absolute stereochemistry arbitrarily assigned.
  • Example 165 8-(4-chloro-2-fluoro-phenyl)-6-[2-[1-(2,2-difluoroethyl)pyrazol-4- yl]morpholino]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one
  • a solution of trifluoromethanesulfonic acid 2,2-difluoroethyl ester (37 mg, 0.175 mmol) in N,N- dimethylformamide (0.8 mL) was added to 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-(1H- pyrazol-4-yl)morpholino]pyrimido[5,4-d]pyrimidin-4-one (see Example 156, 40 mg, 0.0877 mmol) and cesium carbonate (114 mg, 0.351 mmol).
  • Example 166 8-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-6-[2-[1-(2,2,2-trifluoroethyl)pyrazol- 4-yl]morpholino]pyrimido[5,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 165 from trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester instead of trifluoromethanesulfonic acid 2,2-difluoroethyl ester, yellow oil, MS m/z: 538.2 [M+H] + , ESI pos.
  • Example 167 8-(4-chloro-2-fluoro-phenyl)-6-[2-[1-(2,2-difluorocyclopropyl)pyrazol-4- yl]morpholino]-2,3-dimethyl-pyrimido[5,4-d]pyrimidin-4-one
  • the tile compound was prepared in analogy to Example 165 from 2-bromo-1,1-difluoro- cyclopropane instead of trifluoromethanesulfonic acid 2,2-difluoroethyl ester, yellow oil, MS m/z: 532.2 [M+H] + , ESI pos.
  • Example 168 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 169 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, R7 et R8 sont tels que décrits dans la description, des compositions comprenant les composés, des procédés de fabrication des composés et des procédés d'utilisation des composés dans le traitement ou la prévention de maladies qui sont associées à TREM2.
PCT/EP2024/064557 2023-05-30 2024-05-28 Agonistes de trem2 Pending WO2024246018A1 (fr)

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WO2025128848A1 (fr) * 2023-12-12 2025-06-19 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés comme agonistes du récepteur de déclenchement exprimé sur les cellules myéloïdes 2 et méthodes d'utilisation
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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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025128848A1 (fr) * 2023-12-12 2025-06-19 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés comme agonistes du récepteur de déclenchement exprimé sur les cellules myéloïdes 2 et méthodes d'utilisation
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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