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WO2025128873A1 - Composés de pyridinone hétérocycliques en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation - Google Patents

Composés de pyridinone hétérocycliques en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation Download PDF

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WO2025128873A1
WO2025128873A1 PCT/US2024/059856 US2024059856W WO2025128873A1 WO 2025128873 A1 WO2025128873 A1 WO 2025128873A1 US 2024059856 W US2024059856 W US 2024059856W WO 2025128873 A1 WO2025128873 A1 WO 2025128873A1
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compound
tautomer
stereoisomer
solvate
pharmaceutically acceptable
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Jonathan B. Houze
Bhaumik PANDYA
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Vigil Neuroscience Inc
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Vigil Neuroscience Inc
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present disclosure provides compounds useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 (“TREM2”).
  • TEM2 Triggering Receptor Expressed on Myeloid Cells 2
  • This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a neurodegenerative disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula (I).
  • Microglia are resident innate immune cells in the brain and are important for the maintenance of homeostatic conditions in the central nervous system (Hickman et al. Nat Neurosci 2018, Li and Barres, Nat Rev Immunol. , 2018). These resident macrophages express a variety of receptors that allow them to sense changes in their microenvironment and alter their phenotypes to mediate responses to invading pathogens, proteotoxic stress, cellular injury, and other infarcts that can occur in health and disease. Id. Microglia reside in the parenchyma of the brain and spinal cord where they interact with neuronal cell bodies (Cserep et al. Science, 2019), neuronal processes (Paolicelli et al.
  • microglia More specialized functions of microglia include the ability to prune synapses from neurons and directly communicate with their highly arborized cellular processes that survey the area surrounding the neuronal cell bodies (Hong et al. Curr Opin Neurobiol, 2016; Sellgren et al. Nat Neurosci, 2019). [0004] The plasticity of microglia and their diverse states as described through single -cells RNASeq profding are thought to arise through the integration of signaling from a diverse array of cell surface receptors (Hickman et al. Nat Neurosci 2013).
  • microglial receptors Collectively known as the microglial “sensome,” these receptors are responsible for transducing activating or activation-suppressing intracellular signaling and include protein families such as Sialic acid-binding immunoglobulin-type lectins (“SIGLEC”), Toll-like receptors (“TLR”), Fc receptors, nucleotide -binding oligomerization domain (“NOD”) and purinergic G protein-coupled receptors.
  • SIGLEC Sialic acid-binding immunoglobulin-type lectins
  • TLR Toll-like receptors
  • Fc receptors Fc receptors
  • NOD nucleotide -binding oligomerization domain
  • purinergic G protein-coupled receptors Doens and Fernandez 2014, Madry and Attwell 2015, Hickman and El Khoury 2019.
  • TREM2 central nervous system
  • IgV immunoglobulin variable
  • TREM2/DAP12 complexes in particular act as a signaling unit that can be characterized as pro-activation on microglial phenotypes in addition to peripheral macrophages and osteoclasts (Otero et al. J Immunol, 2012; Kobayashi et al. J Neurosci, 2016; Jaitin et al., Cell, 2019.
  • signaling through TREM2 has been studied in the context of ligands such as phospholipids, cellular debris, apolipoproteins, and myelin (Wang et al.
  • mice lacking functional TREM2 expression or expressing a mutated form of the receptor a core observation is blunted microglial responses to insults such as oligodendrocyte demyelination, stroke -induced tissue damage in the brain, and proteotoxic inclusions in vivo (Cantoni et al., Acta Neuropathol, 2015, Wu et al., Mol Brain, 2017).
  • Coding variants in the TREM2 locus has been associated with late onset Alzheimer’s disease (“LOAD”) in human genome-wide association studies, linking a loss-of-receptor function to a gain in disease risk (Jonsson et al. N Engl J Med 2013, Sims et al. Nat Genet 2017).
  • LOAD late onset Alzheimer’s disease
  • CD33, PLCg2 and MS4A4A/6A have reached genome-wide significance fortheir association with LOAD risk (Hollingworth et al. Nat Genet 2011, Sims et al. Nat Genet 2017, Deming et al. Sci Transl Med 2019).
  • TREM2 In addition to human genetic evidence supporting a role of TREM2 in LOAD, homozygous loss-of-function mutations in TREM2 are causal for an early onset dementia syndrome known as Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (“PLOSL”) or Nasu-Hakola disease (“NHD”) (Golde et al. Alzheimers Res Ther 2013, Dardiotis et al. Neurobiol Aging 2017).
  • PLOSL Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy
  • NHS Nasu-Hakola disease
  • This progressive neurodegenerative disease typically manifests in the 3 rd decade of life and is pathologically characterized by loss of myelin in the brain concomitant with gliosis, unresolved neuroinflammation, and cerebral atrophy.
  • Typical neuropsychiatric presentations are often preceded by osseous abnormalities, such as bone cysts and loss of peripheral bone density (Bianchin et al. Cell Mol Neurobiol 2004; Madry et al. Clin Orthop Relat Res 2007, Bianchin et al. Nat Rev Neurol 2010).
  • osteoclasts of the myeloid lineage are also known to express TREM2
  • the PLOSL-related symptoms of wrist and ankle pain, swelling, and fractures indicate that TREM2 may act to regulate bone homeostasis through defined signaling pathways that parallel the microglia in the CNS (Paloneva et al. J Exp Med 2003, Otero et al. J Immunol 2012).
  • TREM2 function has illustrated the importance of the receptor in sustaining key physiological aspects of myeloid cell function in the human body.
  • Efforts have been made to model the biology of TREM2 in mice prompting the creation of TREM2 knock out (“KO”) mice in addition to the LOAD-relevant TREM2 R47H loss-of-function mutant transgenic mice (Ulland et al. Cell, 2017, Kang et al. Hum Mol Genet 2018). Although unable to recapitulate the neurological manifestations of PLOSL, TREM2 KO mice show abnormalities in bone ultrastructure (Otero et al. J Immunol 2012).
  • TREM2 KO or mutant mice have been crossed onto familial Alzheimer’s disease transgenic mouse background such as the 5XFAD amyloidogenic mutation lines, marked phenotypes have been observed (Ulrich et al. Neuron, 2017). These in vivo phenotypes of TREM2 loss-of-function in the CNS include elevated the plaque burden and lower levels of secreted microglial factors SPP1 and Osteopontin that are characteristic of the microglial response to amyloid pathology (Ulland et al. Cell, 2017). Other rodent studies have demonstrated that loss of TREM2 leads to decreased microglial clustering around plaques and emergence of less compact plaque morphology in familial AD amyloid models (Parhizkar et al.
  • TREM2 activators of TREM2 to address the genetics-implicated neuroimmune aspects of, for example, LOAD.
  • Such TREM2 activators may be suitable for use as therapeutic agents and remain in view of the significant continuing societal burden that remains unmitigated for diseases.
  • a pharmaceutical composition comprising a compound of Formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, and a pharmaceutically acceptable excipient.
  • Parkinson’s disease rheumatoid arthritis
  • Alzheimer’s disease Nasu-Hakola disease
  • frontotemporal dementia multiple sclerosis
  • prion disease or stroke.
  • the compound of Formula (I) is a compound of Formula (I’): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein Ring A, together with the 6-membered ring system to which it is fused, forms a bicyclic ring system selected from one of W is C(R 10 ) or N; X is C(R 11 ) or N; Y is C(R 12 ) or N; R 1 is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R 13 ; each R 2 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano
  • R 1 is selected from cyclopropyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with one or more R 13 .
  • R 1 is selected from cyclohexyl, 4,4-difluoro-cyclohexyl, 4-fluoro- cyclohexyl, 4-fluoromethyl-cyclohexyl, (spiro)-cyclopropyl-cyclopropyl-F 2 , bicyclo[1.1.1]- trifluoromethyl, bicyclo[1.1.1]-difluoromethyl, bicyclo[1.1.1]-CF-(CH 3 ) 2 , bicyclo[1.1.1]-CH 2 -CF 3 , bicyclo[1.1.1]-CH 2 -CHF 2 , bicyclo[1.1.1]-CF 2 -CH 3 , bicyclo[1.1.1]-chloro, or bicyclo[2.2.1]-CF 2 -CH 3
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with one or more R 13 .
  • R 1 is phenyl or thiazolyl, each of which is optionally substituted with one or more R 13 .
  • R 13 is deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, or halogen. [0019] In some embodiments, R 1 is selected from those shown below:
  • R 1 is -CH 2 CH 2 CF 3 , , , , , [0021] In some embodiments, R 1 is [0022] In some embodiments, R 1 is [0023] In some embodiments, R 1 is selected from cycloalkyl or heterocyclyl, each of which is optionally substituted with one or more R 13 . In some embodiments, R 1 is a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl or heterocyclyl, each of which is optionally substituted with optionally substituted with one or more R 13 .
  • R 1 is a 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered cycloalkyl, each of which is optionally substituted with one or more R 13 .
  • R 1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with optionally substituted with one or more R 13 .
  • R 1 is selected from [0024]
  • R 1 is -O(R A ), aryl, or heteroaryl, wherein aryl and heteroaryl are each optionally substituted with one or more R 13 .
  • R 1 is selected from phenyl, pyridyl, pyrimidyl, imidazolyl, oxadiaxolyl, isoxazolyl, oxazoleyl, isothiazolyl, thiazolyl, pyrazolyl, or pyrazyl, each of which is optionally substituted with one or more R 13 .
  • R 1 is phenyl or thiazolyl, each of which is optionally substituted with one or more R 13 .
  • R 1 is selected from [0025] In some embodiments, R 13 is deuterium, C 1-6 alkyl, C 1-6 heteroalkyl, cycloalkyl, C 1-6 haloalkyl, halogen, cyano, or -C(O)N(R B )(R C ). [0026] In some embodiments, R 1 is selected from those depicted in Table A below.
  • R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, or -O(R A ), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R 16 .
  • R 6 and R 7 are each independently C 1-6 alkyl (e.g., CH 3 ).
  • one of R 6 and R 7 is independently C 1-6 alkyl (e.g., CH 3 ) and the other of R 6 and R 7 is independently - O(R A ) (e.g., CH 3 ). In some embodiments, one of R 6 and R 7 is selected from those depicted in Table A below.
  • R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, or -O(R A ), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 16 .
  • one of R 6 and R 7 is independently C 1-6 alkyl (e.g., CH 3 ) and the other of R 6 and R 7 is independently C 1-6 alkyl or -O(R A ) (e.g., OCH 3 ).
  • one of R 6 and R 7 is CH 3 , and the other of R 6 and R 7 is OCH 3 .
  • R 6 and R 7 are each independently selected from [0029]
  • X is C(R 11 ) (e.g., CH 3 ).
  • X is N.
  • X is selected from those depicted in Table A below.
  • X is C(R 11 ) (e.g., CH).
  • Y is C(R 12 ).
  • Y is N.
  • Y is selected from those depicted in Table A below.
  • R 12 is hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, halogen, cyano, or -N(R B )(R C ), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R 16 .
  • R 12 is C 1-6 alkyl optionally substituted with one or more R 16 (e.g., CH 3 , CD 3 ).
  • R 12 is C 1-6 haloalkyl (e.g., CHF 2 , CF 3 ).
  • R 12 is cycloalkyl, heterocyclyl, or heteroaryl optionally substituted with one or more R 16 . In some embodiments, R 12 is selected from those depicted in Table A below. [0033] In some embodiments, Z is C(R 18 ) 2 . In some embodiments, R 18 is hydrogen or halogen. In some embodiments, R 18 is F. In some embodiments, Z is O.
  • R 2 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(R A ), or -N(R B )(R C ), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R 14 ; or two R 2 , taken together with the carbon atom to which they are attached, form an oxo group.
  • R 2 is selected from those depicted in Table A below.
  • R 3 is selected from those shown below:
  • R 3 is substituted with C 1-3 alkyl comprising one or more deuteriums. In some embodiments, R 3 is substituted with 1 to 3 substitutents selected from –CD 3 , - CHD 2 , and -CH 2 D.
  • R 3 is hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O(R A ), or -N(R B )(R C ), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 15 .
  • R 3 is selected from hydrogen, Cl, [0038]
  • R 4 and R 5 are each independently hydrogen or C 1-6 alkyl.
  • V 1 is N and V 2 is NR 8b .
  • W 1 and W 2 are each independently N.
  • R 8 is C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, cycloalkyl, heterocyclyl, or - N(R B )(R C ), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R 16 .
  • R 8 is -N(R B )(R C ).
  • R 8b is CH 3 .
  • Ring A is In some embodiments, W is C(R 10 ) or N, R 8a is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 haloalkyl, cycloalkyl, or heterocyclyl, wherein said alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R 16 .
  • each R 9a and R 9b is hydrogen.
  • each of R 9a and R 9b is hydrogen.
  • Ring A together with the 6-membered ring system to which it is fused is selected from [0048]
  • the compound of Formula (I) is a compound of Formula (I-a) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, R 1 , R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-b) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , R 13 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-c) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , R 13 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-d) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, R 1 , R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-f) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, R 2 , R 13 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-g) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-k) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-l) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-m) r a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-n) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , R 13 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-o) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , R 13 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-p) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-q) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 4 . R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-r) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 2 , R 13 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-s) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-t) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-u) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-v) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-w) or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-x): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 8b , W1, W 2 , W 3 , W 4 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-y): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 8b , W 1 , W 2 , W 3 , W 4 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-z): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 8b , W 3 , W 4 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-aa): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 8b , W1, W 2 , W 3 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-bb): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 8b , W 3 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-cc): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 8b , W 1 , W 2 , W 3 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-dd): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, Y, Z, R 1 , R 2 , R 3 , R 4 , R 5 , R 8b , W 1 , W 2 , W 4 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-ee): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of R 1 , R 2 , R 3 , R 8b , R 10 , W 3 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-ff): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of X, Y, Z, R 1 , R 2 , R 3 , R 8b , W 3 , W 4 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound of Formula (I-gg): or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, wherein each of Ring A, W 1 , W 2 , R 2 , R 13 , n and subvariables thereof are defined as for Formula (I).
  • the compound of Formula (I) is a compound provided in Table A.
  • a pharmaceutical composition comprising one or more of the compounds of Formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer disclosed herein and a pharmaceutically acceptable excipient.
  • the compound is a compound of any of the previous embodiments, or a pharmaceutical composition of the previous embodiments, for use in treating or preventing a condition associated with a loss of function of human TREM2.
  • a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound according to any one of the previous embodiments, or a pharmaceutical composition of the previous embodiments.
  • at least one hydrogen atom of the compound is a deuterium atom.
  • at least one C 1 -C 6 alkyl group of the compound is substituted with at least one deuterium atom.
  • R 6 is –CD 3 .
  • R 7 is –CD 3 .
  • R 6 and R 7 are both –CD 3 .
  • R 6 and R 7 are each independently selected from H, D, -CH 3 , –CD 3 , -CHD 2 , and -CH 2 D. In some embodiments, R 6 and R 7 are each independently selected from -CH 3 , –CD 3 , -CHD 2 , and -CH 2 D. In some embodiments, R 2 is deuterium. In some embodiments, the hydrogen atom attached to the same carbon as R 2 is deuterium. In some embodiments, R 3 is substituted with C 1-3 alkyl, comprising one or more deuteriums. In some embodiments, R 3 is substituted with 1 to 3 substitutents selected from –CD 3 , -CHD 2 , and -CH 2 D.
  • Exemplary compounds of the disclosure are set forth in Table A, below.
  • the compound is a compound set forth in Table A, or a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer thereof.
  • Table A Exemplary Compounds
  • FORMULATION AND ROUTE OF ADMINISTRATION While it may be possible to administer a compound disclosed herein alone in the uses described, the compound administered normally will be present as an active ingredient in a pharmaceutical composition.
  • a pharmaceutical composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants and the like, and, if desired, other active ingredients.
  • a pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.
  • the compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended.
  • the compounds and compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.
  • the pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension.
  • the pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.
  • compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically -transdermal patches may also be used.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this disclosure may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.
  • compositions of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.
  • the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • animals including horses, dogs, and cats may be treated with compounds provided herein.
  • TREM2 has been implicated in several myeloid cell processes, including phagocytosis, proliferation, survival, and regulation of inflammatory cytokine production. Ulrich and Holtzman 2016. In the last few years, TREM2 has been linked to several diseases. For instance, mutations in both TREM2 and DAP12 have been linked to the autosomal recessive disorder Nasu-Hakola Disease, which is characterized by bone cysts, muscle wasting and demyelination phenotypes. Guerreiro et al. 2013. More recently, variants in the TREM2 gene have been linked to increased risk for Alzheimer's disease (AD) and other forms of dementia including frontotemporal dementia.
  • AD Alzheimer's disease
  • the R47H variant has been identified in genome-wide studies as being associated with increased risk for late-onset AD with an overall adjusted odds ratio (for populations of all ages) of 2.3, second only to the strong genetic association of ApoE to Alzheimer's.
  • the R47H mutation resides on the extracellular 1g V-set domain of the TREM2 protein and has been shown to impact lipid binding and uptake of apoptotic cells and Abeta (W ang et al. 2015; Yeh et al. 2016), suggestive of a loss-of-function linked to disease.
  • TREM2 Toll-Like Receptor
  • the compounds disclosed herein are of particular use in disorders, such as those described above and in the embodiments that follow and in neurodegenerative disorders more generally.
  • the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating or preventing a condition associated with a loss of function of human TREM2.
  • the present disclosure features a compound of Formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof for use in treating a disease, disorder, or condition.
  • diseases, disorders, or conditions include proliferative diseases, cardiovascular diseases, metabolic diseases, inflammatory diseases, autoimmune disorders, neurodegenerative disorders, infectious diseases, and tissues injuries.
  • the proliferative disease is a benign condition, e.g., a benign neoplasm.
  • the proliferative disease is a cancer.
  • the cancer may be a cancer of any cell or tissue in the body, for example, a cancer of the brain, eye, thyroid, breast, lung, stomach, kidney, pancreas, bladder, colon, rectum, uterus, ovaries, prostate, skin, fibrous tissues, lympathic system, bone marrow, blood, or immune system.
  • the cancer may comprise a tumor or solid cancer (e.g., a carcinoma) or a non-mass cancer.
  • Exemplary cancers include glioblastoma, retinoblastoma, skin cancer, ocular cancer, gastrointestinal cancer, breast cancer, lung cancer, ductal carcinoma, lungadenocarcinoma, lymphoma, endometrial cancer, liver cancer, pancreatic cancer, renal cell cancer, ovarian cancer, fibrosarcoma, leukemia, myeloma, and polycythemia vera.
  • the disease, disorder, or condition is cardiovascular.
  • cardiovascular diseases, disorders, and conditions include stroke, coronary heart disease, cardiomyopathy, arrhythmia (e.g. atrial fibrillation), aortic aneurysms, and venous thrombosis.
  • the disease, disorder, or condition is metabolic disease.
  • exemplary metabolic diseases include diabetes (e.g., Type 1 diabetes or Type 2 diabetes), metabolic dysfunction- associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), and Gaucher’s disease.
  • MASH metabolic dysfunction-associated steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • Gaucher Gaucher’s disease.
  • the disease, disorder, or condition is an inflammatory disease.
  • Exemplary inflammatory diseases include arthritis, acute and chronic colitis, ulcerative colitis, inflammatory bowel disease, Behcet’s disease, and granulomatous disorders.
  • the disease, disorder, or condition is an autoimmune disease.
  • autoimmune diseases include diabetes (e.g., Type 1 diabetes), lupus, sarcoidosis, and multiple sclerosis.
  • the disease, disorder, or condition is a neurological disease.
  • the neurological disease is a neurodegenerative disease.
  • exemplary neurodegemative diseases include dementia, Alzheimer’s disease, Creutzfeldt- Jakob disease, Parkinson’s disease, demential with Lewy bodies, amyotrophic lateral sclerosis (ALS), Huntington’s disease, taupathy disease, Nasu-Hakola disease, dry age-related macular degeneration (dry AMD), multiple system atrophy (MSA), Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglionic degeneration, glaucoma, retinitis pigmentosa, and retinal degeneration,
  • the neurological condition is acute trauma, chronic trauma, acute disseminated encephalomyelitis, cognitive deficit and memory loss, essential tremor, central nervous system (CNS) lupus, normal pressure hydrocephalus, and seizures.
  • CNS central nervous system
  • the disease, disorder, or condition is an infectious disease.
  • An infectious disease may be local or systemic.
  • infectious diseases include eye infections, malaria, respiratory tract infections, sepsis, herpes (e.g., CNS herpes), parasitic infections, Trypanosome infection, Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningitidis infection, type I HIV, and Haemophilus influenza.
  • the disease, disorder, or condition is a tissue injury. Any tissues of the body may be injuried. Exemplary injuries include ocular (e.g. hyphoma), spinal cord injury, traumatic brain injury, hepatocellular, and wound repair in diabetes.
  • ocular e.g. hyphoma
  • spinal cord injury e.g. traumatic brain injury
  • hepatocellular e.g. hepatocellular
  • the disclosure provides a compound of Formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof for treating or preventing a disease, disorder or condition.
  • the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating or preventing Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.
  • the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing a condition associated with a loss of function of human TREM2.
  • the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.
  • the disclosure 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 the compound of the present disclosure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.
  • the disclosure provides a method of treating or preventing Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of the present disclosure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.
  • CSF1R is a cell-surface receptor primarily for the cytokine colony stimulating factor 1 (CSF-1), also known until recently as macrophage colony-stimulating factor (M-CSF), which regulates the survival, proliferation, differentiation and function of mononuclear phagocytic cells, including microglia of the central nervous system.
  • CSF1R is composed of a highly glycosylated extracellular ligand-binding domain, a trans-membrane domain and an intracellular tyrosine -kinase domain. Binding of CSF-1 to CSF1R results in the formation of receptor homodimers and subsequent auto-phosphorylation of several tyrosine residues in the cytoplasmic domain, notably Syk.
  • CSF1R is predominantly expressed in microglial cells. It has been found that microglia in CSF1R +/- patients are depleted and show increased apoptosis (Oosterhof et al., 2018).
  • TREM2 agonist can rescue the loss of microglia in cells having mutations in CSF1R. It has been previously shown that TREM2 agonist antibody 4D9 increases ATP luminescence (a measure of cell number and activity) in a dose dependent manner when the levels of M-CSF in media are reduced to 5 ng/mL (Schlepckow et al, EMBO Mol Med., 2020) and that TREM2 agonist AL002c increases ATP luminescence when M-CSF is completely removed from the media (Wang et al, J. Exp. Med.; 2020, 217(9): e20200785).
  • TREM2 agonism can compensate for deficiency in CSF1R signaling caused by a decrease in the concentration of its ligand.
  • doses of a CSF1R inhibitor that almost completely eliminate microglia in the brains of wild-type animals show surviving microglia clustered around the amyloid plaques (Spangenberg et al, Nature Communications 2019).
  • Plaque amyloid has been demonstrated in the past to be a ligand for TREM2, and it has been shown that microglial engagement with amyloid is dependent on TREM2 (Condello et al, Nat Comm., 2015).
  • the present dsiclosure relates to the unexpected discovery that it is activation of TREM2 that rescued the microglia in the presence of the CSF1R inhibitor, and that this effect is also observed in patients suffering from loss of microglia due to CSF1R mutation. This discovery has not been previously taught or suggested in the available art.
  • TREM2 agonism can rescue the loss of microglia in cells where mutations in the CSF1R kinase domain reduce CSF1R activity, rather than the presence of a CSF1R inhibitor or a deficiency in CSF1R ligand. Furthermore, no prior study has taught or suggested that reversal of the loss of microglia due to a CSF1R mutation through TREM2 agonism can be used to treat a disease or disorder caused by and/or associated with a CSF1R mutation.
  • the present disclosure relates to the surprising discovery that activation of the TREM2 pathway can rescue the loss of microglia in CSF1R +/- ALSP patients, preventing microglia apoptosis, thereby treating the ALSP condition.
  • the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating or preventing a condition associated with dysfunction of Colony stimulating factor 1 receptor (CSF1R, also known as macrophage colony -stimulating factor receptor / M-CSFR, or cluster of differentiation 115 / CD115).
  • CSF1R Colony stimulating factor 1 receptor
  • M-CSFR macrophage colony -stimulating factor receptor
  • CD115 Cluster of differentiation 115 / CD115
  • the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmentary orthochromatic leukodystrophy (POLD), pediatric -onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS).
  • ALSP adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
  • HDLS hereditary diffuse leukoencephalopathy with axonal spheroids
  • POLD pigmentary orthochromatic leukodystrophy
  • pediatric -onset leukoencephalopathy congenital absence of microglia, or brain abnormalities neuro
  • the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing adult -onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmentary orthochromatic leukodystrophy (POLD), pediatric-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS).
  • ALSP adult -onset leukoencephalopathy with axonal spheroids and pigmented glia
  • HDLS hereditary diffuse leukoencephalopathy with axonal spheroids
  • POLD pigmentary orthochromatic leukodystrophy
  • pediatric-onset leukoencephalopathy congenital absence of microgli
  • the disease or disorder is caused by a heterozygous CSF1R mutation. In some embodiments, the disease or disorder is caused by a homozygous CSF1R mutation. In some embodiments, the disease or disorder is caused by a splice mutation in the csflr gene. In some embodiments, the disease or disorder is caused by a missense mutation in the csflr gene. In some embodiments, the disease or disorder is caused by a mutation in the catalytic kinase domain of CSF1R. In some embodiments, the disease or disorder is caused by a mutation in an immunoglobulin domain of CSF1R. In some embodiments, the disease or disorder is caused by a mutation in the ectodomain of CSF1R.
  • the disease or disorder is a disease or disorder resulting from a change (e.g. increase, decrease or cessation) in the activity of CSF1R. In some embodiments, the disease or disorder is a disease or disorder resulting from a decrease or cessation in the activity of CSF1R.
  • CSF1R related activities that are changed in the disease or disorder include, but are not limited to: decrease or loss of microglia function; increased microglia apoptosis; decrease in Src signaling; decrease in Syk signaling; decreased microglial proliferation; decreased microglial response to cellular debris; decreased phagocytosis; and decreased release of cytokines in response to stimuli.
  • the disclosure provides a method of treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmentary orthochromatic leukodystrophy (POLD), pediatric-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.
  • a compound of the present disclosure or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.
  • the method treats or prevents ALSP, which is an encompassing and superseding name for both HDLS and POLD.
  • the disease or disorder is a homozygous mutation in CSF1R.
  • the method treats or prevents pediatric-onset leukoencephalopathy.
  • the method treats or prevents congenital absence of microglia.
  • the method treats or prevents brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS).
  • the disclosure provides a method of treating or preventing Nasu- Hakola disease, Alzheimer’s disease, frontotemporal dementia, multiple sclerosis, Guillain-Barre syndrome, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, traumatic brain injury, spinal cord injury, systemic lupus erythematosus, rheumatoid arthritis, prion disease, stroke, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysosteoplasia, Pyle disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, or metachromatic leukodystrophy wherein any of the aforementioned diseases or disorders are present in a patient exhibiting CSF1R dysfunction, or having a mutation in a
  • ABCD1 genes provides instructions for producing the adrenoleukodystrophy protein (ALDP).
  • ADP adrenoleukodystrophy protein
  • ABCD1 maps to Xq28.
  • ABCD1 is a member of the ATP -binding cassette (ABC) transporter superfamily.
  • the superfamily contains membrane proteins that translocate a wide variety of substrates across extra- and intracellular membranes, including metabolic products, lipids and sterols, and drugs. ALDP is located in the membranes of cell structures called peroxisomes.
  • Peroxisomes are small sacs within cells that process many types of molecules. ALDP brings a group of fats called very long-chain fatty acids (VLCFAs) into peroxisomes, where they are broken down.
  • VLCFAs very long-chain fatty acids
  • ABCD1 is highly expressed in microglia, it is possible that microglial dysfunction and their close interaction with other cell types actively participates in neurodegenerative processes (Gong et al., Annals of Neurology. 2017; 82(5): 813-827.) . It has been shown that severe microglia loss and damage is an early feature in patients with cerebral form of x-linked ALD (cALD) carrying ABCD1 mutations (Bergner et al., Glia. 2019; 67: 1196-1209).
  • cALD x-linked ALD
  • the present disclosure relates to the unexpected discovery that administration of a TREM2 agonist can rescue the loss of microglia in cells having mutations in the ABCD1 gene. It has been previously shown that TREM2 agonist antibody 4D9 increases ATP luminescence (a measure of cell number and activity) in a dose dependent manner when the levels of M-CSF in media are reduced to 5 ng/mL (Schlepckow et al, EMBO Mol Med., 2020) and that TREM2 agonist AL002c increases ATP luminescence when M-CSF is completely removed from the media (Wang et al, J. Exp. Med.; 2020, 217(9): e20200785).
  • TREM2 agonism can compensate for deficiency in ABCD1 function leading to sustained activation, proliferation, chemotaxis of microglia, maintenance of anti-inflammatory environment and reduced astrocytosis caused by a decrease in ABCD1 and accumulation of VLCFAs.
  • the present disclosure relates to the unexpected discovery that activation of TREM2 can rescue the microglia in the presence of the ABCD1 mutation and an increase in VLCFA, and that this effect may be also observed in patients suffering from loss of microglia due to ABCD1 mutation. This discovery has not been previously taught or suggested in the available art.
  • TREM2 agonism can rescue the loss of microglia in cells where mutations in the ABCD1 and a VLCFA increase is present.
  • No prior study has taught or suggested that reversal of the loss of microglia due to an ABCD 1 mutation through TREM2 agonism can be used to treat a disease or disorder caused by and/or associated with an ABCD1 mutation.
  • the disclosure provides a compound of Formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof for use in treating or preventing a condition associated with dysfunction of ATP -binding cassette transporter 1 (ABCD1).
  • ABCD1 ATP -binding cassette transporter 1
  • the disclosure provides a compound of Formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof for use in treating or preventing X-linked adrenoleukodystrophy (x-ALD), Globoid cell leukodystrophy (also known as Krabbe disease), Metachromatic leukodystrophy (MLD), Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Vanishing white matter disease (VWM), Alexander disease, fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).
  • x-ALD Globoid cell leukodystrophy
  • MLD Meta
  • the disclosure provides a compound of Formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing a condition associated with dysfunction of ABCD 1.
  • the invention provides a compound of Formula (I), a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing X-linked adrenoleukodystrophy (x-ALD), Globoid cell leukodystrophy (also known as Krabbe disease), Metachromatic leukodystrophy (MLD), Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Vanishing white matter disease (VWM), Alexander disease, fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).
  • x-ALD Globoid cell leukodys
  • the disclosure provides a method of treating or preventing a disease or disorder associated with dysfunction of ABCD1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof.
  • the patient is selected for treatment based on a diagnosis that includes the presence of a mutation in an ABCD1 gene affecting the function of ABCD1.
  • the mutation in the ABCD1 gene is a mutation that causes a decrease in ABCD1 activity or a cessation of ABCD1 activity.
  • the disease or disorder is caused by a heterozygous ABCD1 mutation.
  • the disease or disorder is caused by a homozygous ABCD1 mutation.
  • the disease or disorder is caused by a splice mutation in the ABCD1 gene.
  • the disease or disorder is caused by a missense mutation in the ABCD1 gene.
  • the disease or disorder is a disease or disorder resulting from a change (e.g. increase, decrease or cessation) in the activity of ABCD1.
  • the disease or disorder is a disease or disorder resulting from a decrease or cessation in the activity of ABCD1.
  • ABCD1 related activities that are changed in the disease or disorder include, but are not limited to peroxisomal import of fatty acids and/or fatty acyl-CoAs and production of adrenoleukodystrophy protein (ALDP).
  • the disease or disorder is caused by a loss-of-function mutation in ABCD1.
  • the loss-of-function mutation results in a complete cessation of ABCD1 function.
  • the loss-of- function mutation results in a partial loss of ABCD1 function, or a decrease in ABCD1 activity.
  • the disease or disorder is caused by a homozygous mutation in ABCD 1. In some embodiments, the disease or disorder is a neurodegenerative disorder. In some embodiments, the disease or disorder is a neurodegenerative disorder caused by and/or associated with an ABCD 1 dysfunction. In some embodiments, the disease or disorder is an immunological disorder. In some embodiments, the disease or disorder is an immunological disorder caused by and/or associated with an ABCD1 dysfunction.
  • the disclosure provides a method of treating or preventing X-linked adrenoleukodystrophy (x-ALD), Globoid cell leukodystrophy (also known as Krabbe disease), Metachromatic leukodystrophy (MLD), Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Vanishing white matter disease (VWM), Alexander disease, fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or t
  • x-ALD Glo
  • any of the aforementioned diseases are present in a patient exhibiting ABCD 1 dysfunction or having a mutation in a gene affecting the function of ABCDf .
  • the method treats or prevents X- linked adrenoleukodystrophy (x-ALD).
  • x-ALD is a cerebral form of x- linked ALD (cALD).
  • the method treats or prevents Addison disease wherein the patient has been found to have a mutation in one or more ABCD1 genes affecting ABCD1 function.
  • the method treats or prevents Addison disease, wherein the patient has a loss-of-function mutation in ABCD 1.
  • the disclosure provides a method of treating or preventing Nasu- Hakola disease, Alzheimer’s disease, frontotemporal dementia, multiple sclerosis, Guillain-Barre syndrome, amyotrophic lateral sclerosis (ALS), or Parkinson’s disease, wherein any of the aforementioned diseases or disorders are present in a patient exhibiting ABCD1 dysfunction, or having a mutation in a gene affecting the function of ABCD1, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof.
  • a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof.
  • TREM2 deficient mice exhibit symptoms reminiscent of autism spectrum disorders (ASDs) (Filipello et al., Immunity, 2018, 48, 979-991). It has also been found that microglia depletion of the autophagy Aatg7 gene results in defective synaptic pruning and results in increased dendritic spine density, and abnormal social interaction and repetitive behaviors indicative of ASDs (Kim, et al., Molecular Psychiatry, 2017, 22, 1576-1584.).
  • TREM2 activation can reverse microglia depletion, and therefore correct the defective synaptic pruning that is central to neurodevelopmental diseases such as ASDs.
  • the present disclosure relates to the unexpected discovery that activation of TREM2, using a compound of the present disclosure, can rescue microglia in subjects suffering from an ASD. This discovery has not been previously taught or suggested in the available art.
  • the present invention provides a compound of the present disclosure, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof for use in treating autism or autism spectrum disorders.
  • the present invention provides a compound of the present disclosure, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating autism or autism spectrum disorders.
  • the present invention provides a method of treating autism or autism spectrum disorders in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or a pharmaceutical composition thereof.
  • the method treats autism.
  • the method treats Asperger syndrome.
  • the disclosure provides a method of increasing the activity of TREM2, the method comprising contacting a compound of the present disclosure, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer with the TREM2.
  • the contacting takes place in vitro.
  • the contacting takes place in vivo.
  • the TREM2 is human TREM2.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated.”
  • a provided combination, or composition thereof is administered in combination with another therapeutic agent.
  • the present disclosure provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure.
  • a combination of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the amount of additional therapeutic agent present in the compositions of this disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • One or more other therapeutic agent may be administered separately from a compound or composition of the present disclosure, as part of a multiple dosage regimen.
  • one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition.
  • one or more other therapeutic agent and a compound or composition of the present disclosure may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours from one another.
  • one or more other therapeutic agent and a compound or composition of the present disclosure are administered as a multiple dosage regimen within greater than 24 hours a parts.
  • the present disclosure provides a composition
  • a composition comprising a provided compound, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer and one or more additional therapeutic agents.
  • the therapeutic agent may be administered together with a provided compound a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer, or may be administered prior to or following administration of a provided compound, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer.
  • Suitable therapeutic agents are described in further detail below.
  • a provided compound, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent.
  • a provided compound, a pharmaceutically acceptable salt, solvate, stereoisomer, or tautomer thereof, or a pharmaceutically acceptable salt and/or solvate of said compound, stereoisomer, or tautomer may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.
  • any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound.
  • the compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers.
  • the scope of the instant disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.
  • stereoisomerically pure form for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure
  • stereoisomeric mixtures for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated.
  • (1R)-1 -methyl -2- (trifluoromethyl)cyclohexane is meant to encompass (lR,2R)-l-methyl-2- (trifluoromethyl)cyclohexane and (IR,2S)-I-methyl-2-(trifluoromethyl)cyclohexane.
  • a bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule.
  • stereoisomer or “stereoisomerically pure” compound as used herein refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound.
  • a typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.
  • compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein. Further, this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein.
  • isotopically-Labelled Compounds [0170] Further, the scope of the present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of the compounds disclosed herein, such as the compounds of Formula (I), wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of Formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with isotopes such as deuterium ( 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances.
  • 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 example, for examining target occupancy.
  • PET Positron Emission Topography
  • Isotopically-labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying General Synthetic Schemes and Examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • Solvates [0171] As discussed above, the compounds disclosed herein and the stereoisomers, tautomers, and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing may exist in solvated or unsolvated forms.
  • solvate refers to a molecular complex comprising a compound or a pharmaceutically acceptable salt thereof as described herein and a stoichiometric or non- stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. If the solvent is water, the solvate is referred to as a “hydrate.” [0173] Accordingly, the scope of the instant disclosure is to be understood to encompass all solvents of the compounds disclosed herein and the stereoisomers, tautomers and isotopically-labelled forms thereof or a pharmaceutically acceptable salt of any of the foregoing. Miscellaneous Definitions [0174] This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.
  • alkyl means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, that has a single point of attachment to the rest of the molecule.
  • alkyl groups contain 1 to 6 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 5 alkylcarbon atoms. In other embodiments, alkylgroups contain 1 to 4 alkylcarbon atoms. In still other embodiments, alkylgroups contain 1 to 3 alkylcarbon atoms, and in yet other embodiments, alkylgroups contain 1 to 2 alkylcarbon atoms.
  • cycloalkyl or “carbocyclic” as used herein, means a hydrocarbon ring, substituted or unsubstituted that is completely saturated or that contains one or more units of unsaturation but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • cycloalkyl refers to a monocyclic or bicyclic, bridged bicyclic, or spirocyclic ring, C3-12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable cycloalkyl groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bicyclic ring or “bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle.
  • Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphonates and phosphates), boron, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom.
  • a bridged bicyclic group is optionally substituted with one or more substituents as set forth for alkyl groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include:
  • Exemplary bridged bicyclics include:
  • lower alkyl refers to a C 1-4 straight or branched alkyl group.
  • exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • C 1-6 haloalkyl refers to a C 1-6 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or an oxygen, sulfur, nitrogen, phosphorus, or silicon atom in a heterocyclic ring.
  • unsaturated means that a moiety has one or more units of unsaturation.
  • bivalent C1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 )n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted alkyl group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted alkyl group.
  • the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7 to 10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms, as defined above.
  • nitrogen When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring (having 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. [0188] A heterocyclic ring can be attached to a provided compound at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloalkyl rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be monocyclic or bicyclic, bridged bicyclic, or spirocyclic.
  • C 1-3 alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively.
  • Representative examples of C 1-3 alkyl, C 1-5 alky, or C 1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • C 2-4 alkenyl refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight and branched moieties. Representative examples of C 2-4 alkenyl include, but are not limited to, 1- propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.
  • C 3-6 cycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbon atoms.
  • C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • diC 1-3 alkylamino refer to –NR*R**, wherein R* and R** independently represent a C 1-3 alkyl as defined herein.
  • diC 1-3 alkylamino include, but are not limited to, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 2 CH 3 ) 2 , and – N(CH(CH 3 ) 2 ) 2 .
  • C 1-3 alkoxy and “C 1-6 alkoxy” as used herein refer to –OR # , wherein R # represents a C 1-3 alkyl and C 1-6 alkyl group, respectively, as defined herein.
  • C 1-3 alkoxy or C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.
  • halogen refers to –F, -CI, -Br, or -I.
  • halo as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein. The halogen is independently selected at each occurrence.
  • C 1-6 haloalkyl refers to a C 1-6 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.
  • Representative examples of C 1-6 haloalkyl include, but are not limited to, -CH 2 F, -CHF 2 , -CF 3 , -CHFCl, -CH 2 CF 3 , -CFHCF 3 , -CF 2 CF 3 , -CH(CF 3 ) 2 , -CF(CHF 2 ) 2 , and - CH(CH 2 F)(CF 3 ).
  • C 1-6 haloalkoxy refers to a C 1-6 alkoxy as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.
  • Representative examples of C 1-6 haloalkoxy include, but are not limited to, -OCH 2 F, -OCHF 2 , -OCF 3 , -OCHFCl, -OCH 2 CF 3 , - OCFHCF 3 , -OCF 2 CF 3 , -OCH(CF 3 ) 2 , -OCF(CHF 2 ) 2 , and -OCH(CH 2 F)(CF 3 ).
  • 5-membered heteroaryl or “6-membered heteroaryl” as used herein refers to a 5 or 6-membered carbon ring with two or three double bonds containing one ring heteroatom selected from N, S, and O and optionally one or two further ring N atoms instead of the one or more ring carbon atom(s).
  • Representative examples of a 5-membered heteroaryl include, but are not limited to, furyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl.
  • C 3-6 heterocycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbons and wherein one carbon atom is substituted with a heteroatom selected from N, O, and S. If the C 3-6 heterocycloalkyl group is a C6heterocycloalkyl, one or two carbon atoms are substituted with a heteroatom independently selected from N, O, and S.
  • C 3-6 heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.
  • C 5-8 spiroalkyl refers a bicyclic ring system, wherein the two rings are connected through a single common carbon atom.
  • C 5-8 spiroalkyl include, but are not limited to, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, and spiro[2.5]octanyl.
  • C 5-8 tricycloalkyl refers a tricyclic ring system, wherein all three cycloalkyl rings share the same two ring atoms.
  • C 5-8 tricycloalkyl include, but are not limited to, tricyclo[1.1.1.0 1,3 ]pentanyl, , tricyclo[2.1.1.0 1,4 ]hexanyl, tricyclo[3.1.1.0 1,5 ]hexanyl, and tricyclo[3.2.1.0 1,5 ]octanyl.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • aryl may be used interchangeably with the term “aryl ring”.
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom in the context of “heteroaryl” particularly includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cyclo alkyl, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin–3(4H)–one.
  • a heteroaryl group may be monocyclic or bicyclic.
  • the term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • the term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. [0203] As described herein, compounds of the present disclosure may contain “substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • pharmaceutically acceptable refers to generally recognized for use in subjects, particularly in humans.
  • pharmaceutically acceptable salt refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-
  • excipient refers to a broad range of ingredients that may be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation.
  • excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
  • subject refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment the subject is a human.
  • therapeutically effective amount refers to that amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, a system, or subject that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • the compounds provided herein can be synthesized according to the procedures described in this and the following sections.
  • the synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art.
  • the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.
  • the above synthetic scheme and representative examples are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds.
  • Purification methods for the compounds described herein include, for example, crystallization, chromatography (for example, liquid and gas phase), extraction, distillation, trituration, and reverse phase HPLC.
  • the disclosure further encompasses “intermediate” compounds, including structures produced from the synthetic procedures described, whether isolated or generated in-situ and not isolated, prior to obtaining the finally desired compound. These intermediates are included in the scope of this disclosure. Exemplary embodiments of such intermediate compounds are set forth in the Examples below.
  • Preparative HPLC or Reverse Phase Flash Chromatography purification [0215] Where so indicated, the compounds described herein were purified via reverse phase HPLC using Waters Fractionlynx semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenominex Gemini column (5 micron, C18, 150x30 mm) or (b) Waters X- select CSH column (5 micron, C18, 100x30 mm). [0216] A typical run through the instrument included: eluting at 45 mL/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v formic acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separations.
  • Condition 1 Column: Phenomenex luna C18250 ⁇ 50 mm ⁇ 10 ⁇ m; Mobile Phase A: [H 2 O] (conditions: [water (0.225% NH 3 ⁇ H 2 O(FA))]); Mobile Phase B: acetonitrile (ACN); Gradient a: 65% B to 90% B; [0219] Condition 2: Column: Phenomenex luna C18250 ⁇ 50 mm ⁇ 10 ⁇ m; Mobile Phase A: [H 2 O] (conditions: [water (0.225% FA)]); Mobile Phase B: ACN; Gradient a: 65% B to 90% B; [0220] Condition 3: Column: Phenomenex luna C18150 ⁇ 25 mm ⁇ 10 ⁇ m; Mobile Phase A: [H 2 O] (conditions: [water (0.225% FA]); Mobile Phase B: ACN; Gradient a: 55% B to 85% B;
  • Flash Chromatography Method [0239] Where so indicated, flash chromatography was performed on Teledyne Isco instruments using pre-packaged disposable SiO 2 stationary phase columns with eluent flow rate range of 15 to 200 mL/min, UV detection (254 and 220 nm).
  • Preparative Chiral Supercritical Fluid Chromatography (SFC) Method [0240] Where so indicated, the compounds described herein were purified via chiral SFC using one of the two following chiral SFC columns: (a) Chiralpak IG 2x25 cm, 5 ⁇ m or (b) Chiralpak AD-H 2x15 cm, 5 ⁇ m.
  • Acidic reversed phase MPLC Instrument type: RevelerisTM prep MPLC; Column: Phenomenex LUNA C18(3) (150x25 mm, 10 ⁇ ); Flow: 40 mL/min; Column temp: room temperature; Eluent A: 0.1% (v/v) Formic acid in water, Eluent B: 0.1% (v/v) Formic acid in acetonitrile; using the indicated gradient and wavelength.
  • Condition 1 Column: Chiralcel OJ-3, 50 ⁇ 4.6mm, 3 ⁇ m; Mobile Phase A: CO 2 ; Mobile Phase B: methanol (MeOH) (0.05% diethanolamine (DEA)); Flow Rate: 3 mL/min; Column Temp: 35 °C; Back Pressure: 100 Bar; Gradient a: 5% B to 40% B; Gradient a-1: 5% B to 40% B, Mobile Phase B: EtOH (0.05% DEA); Gradient a-2: 5% B to 40% B, Mobile Phase B: isopropyl alcohol (iPOH) (0.05% DEA); [0245] Condition 2: Column: Chiralpak AD-3, 50 ⁇ 4.6 mm, 3 ⁇ m; Mobile Phase A: CO 2 ; Mobile Phase B: MeOH (0.05% DEA); Flow Rate: 3 mL/min; Column Temp: 35 °C; Back Pressure: 100 Bar; Gradient a: 40% B; [0246] Condition 3: Column: DAICEL Chiralpak IG
  • reaction mixture was agitated at 0 ⁇ 5 °C for 0.5 h under N 2 atmosphere, then sodium methanolate (3 equiv., 115 mg, 2.14 mmol) was added into the solution at 0 ⁇ 5 °C. The resulting mixture was agitated for 1 hour at 0 ⁇ 5 °C under N 2 protection. LCMS showed 21% desired product.
  • Zinc (5.54 equiv., 2.0 g, 30.6 mmol) was suspended in LiCl (0.5 M in THF) (1 equiv., 20 mL, 5.52 mmol), 1,2-dibromoethane (0.05 equiv., 0.024 mL, 0.28 mmol) was added and the suspension was stirred at 55 °C for 20 min, cooled down, then TMSCl (0.05 equiv., mg, 0.276 mmol) was introduced and the mixture was stirred at 55 °C for additional 20 min.
  • LiCl 0.5 M in THF
  • 1,2-dibromoethane 0.05 equiv., 0.024 mL, 0.28 mmol
  • Batch 1 3-(1-hydroxy-1-methyl- ethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Int-A24, 2.0 g, 12.3 mmol, 42% yield) as a solid and batch 2: 3-(1-hydroxy-1-methyl-ethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (Int-A24, 2.1 g, 12.3 mmol, 40% yield) as a solid.
  • N,N-diisopropylethylamine (2 equiv., 4.1 mL, 23.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.2 equiv., 1375 mg, 14.1 mmol) were added and the reaction mixture was continued to stirred at 20 °C for 12 h.
  • LCMS showed starting material was consumed completely and a peak with desired mass was detected.
  • the reaction was combined with a second batch. The final mixture was concentrated under reduced pressure to give a crude.
  • n- BuLi (1.6 equiv., 194 mL, 484 mmol) was added slowly to the mixture below -60 °C, after, the mixture was stirred at -78 °C for 1 hour. Then MeI (3 equiv., 57 mL, 908 mmol) was added slowly below -60 °C, the reaction was stirred at -60 °C for 1 h and warmed to 20 °C for 1 h. The reaction mixture was poured into saturated NH 4 Cl aqueous solution (200 mL) and then extracted with DCM (3 ⁇ 200 mL). The combined organic layers were dried over Na 2 SO 4 , filtered.
  • reaction mixture was stirred vigorously under air for 2 h. TLC showed one new spot formed, which had fluorescence under 254 nm.
  • the reaction mixture was filtered through a pad of Celite. The filter cake was washed with DCM (100 mL). The filtrates was diluted with water (100 mL) and then extracted with DCM (3 ⁇ 50 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 . Then the organic layers was combined with another batch and purified by distillation. Then crude product (9 g) was given (760 mmHg, b.p. > 90 °C) as an oil. Then it was further purified by distillation under reduced pressure.
  • TMPMgCl ⁇ LiCl (1.3 equiv., 0.78 mL, 0.775 mmol) was added dropwise at -20 °C, and the mixture was stirred at -20 °C for 1 h.
  • LCMS showed most of starting material remained.
  • TMPMgCl•LiCl (1.2 equiv., 0.72 mL, 0.716 mmol) was added at -20 °C and stirred at -20 °C for 1 h.
  • LCMS showed 29% of desired product. TLC showed the starting material was consumed completed and one new spot found.
  • reaction mixture was added to NH 4 Cl (aq, 10 mL), partitioned between EtOAc (2 ⁇ 40 mL) and water (40 mL) and extracted. The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue.
  • the mixture was degassed with H 2 for 3 times and cooled to 0 °C.
  • the mixture was stirred at 0 °C for 30 min under H 2 (15 psi) atmosphere.
  • LCMS showed the starting material was consumed completely and a peak with desired MS was detected.
  • the mixture was filtered and washed with EtOH (50 mL).
  • the filtrate was concentrated under reduced pressure to give a crude product.
  • the crude product was purified by reversed-phase flash (0.1% FA condition) and concentrated to remove CH 3 CN, then adjusted pH to about 9 ⁇ 10 by using Na 2 CO 3 solid, followed by extracted with EtOAc (3 ⁇ 40 mL).
  • diphenylphosphinic chloride (1 equiv., 1.00 g, 4.23 mmol) and DCM (6 mL) were added under N 2 atmosphere. This solution was added dropwise to the hydroxylamine solution over 30 min, such that the internal temperature of the reaction solution was kept below 0 °C. After 1 h, the mixture was allowed to warm above 10 °C and an aqueous solution of citric acid (5% wt., 2.5 mL) was added over 5 min. The phases were separated and the organic layer was concentrated under reduced pressure until the product began to precipitate. Heptanes (30 mL) was added to the resulting slurry and the solvent was removed under reduced pressure.
  • reaction mixture was stirred at room temperature until full conversion was observed by LC-MS.
  • the reaction mixture was partitioned between DCM (10 mL) and sat. NaHCO 3 (aq) (10 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 ⁇ 10 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • reaction mixture was cooled down to -78 °C, NaHMDS (1.0 M in THF, 1.5 equiv., 4.3 mL, 4.25 mmol) was added dropwise, and the mixture was stirred at -78 °C for 30 min. After 30 min, a solution of iodoethane (1.7 equiv., 0.39 mL, 4.82 mmol) in anhydrous THF (4.5 mL) was added dropwise to the reaction mixture. The reaction mixture was allowed to slowly warm up to r.t. and stirred for 24 h. The reaction was quenched by addition of sat. NH 4 Cl (aq.) (10 mL) and extracted with EtOAc (3 ⁇ 40 mL).
  • reaction vial was cycled with H 2 (g) and vacuum three times, equipped with a H 2 (g) balloon, and stirred under 1 atm of H 2 (g) for 30 min.
  • the reaction mixture was then filtered through a pad of Celite, washed with DCM, and concentrated under reduced pressure to afford 5-((2S,6R)-6-methylmorpholin-2-yl)pyridin-2(1H)-one (Int-C17, 124 mg, 0.64 mmol, 91% yield) as an oil.
  • the reaction flask was fitted with a reflux condenser and stirred at 60 °C for 16 h.
  • the reaction mixture was cooled to r.t. and diluted with EtOAc (150 mL).
  • the resulting suspension was washed with sat. ammonium choride (aq) and brine.
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure onto Celite (15 g).
  • the reaction mixture was stirred at r.t. for 16 h.
  • the reaction mixture was concentrated in vacuo and diluted with EtOAc (150 mL).
  • the resulting solution was washed with sat. NaHCO 3 (aq) and brine.
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo onto Celite (20 g).
  • the reaction mixture was stirred at r.t. for 18 h.
  • the reaction mixture was concentrated in vacuo and diluted with EtOAc (150 mL).
  • the resulting solution was washed with sat. ammonium chloride (aq), sat. NaHCO 3 (aq) and brine.
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo onto Celite (20 g).
  • the vial was sealed, purged with argon, and heated at 90 °C for 18 h. Another portion of allyl bromide (2 equiv., 2.0 mL, 23.0 mmol) was added, and the vial stirred at 90 °C for a further 5 hours. The reaction mixture was filtered through a Celite pad, rinsing with MeCN, and the filtrate was concentrated under reduced pressure.
  • reaction mixture was refluxed, and five portions of trimethyl(trifluoromethyl)silane (3.5 equiv, 340 ⁇ L, 2.3mmol) were added over 24 h.
  • the reaction mixture was concentrated under reduced pressure and purified by flash chromatography (24 g SiO 2 column) using an elution gradient of 10-60% EtOAc:EtOH (3:1) in hexanes to yield methyl (2R,4S)-2-[1-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-6-oxo-3- pyridyl]tetrahydropyran-4-carboxylate (Int-D9, 105 mg, 0.15 mmol, 22% yield) as a solid.
  • the vial was sealed, purged three times with argon, and anhydrous DMSO (28 mL) was added.
  • the reaction was placed in a Penn PhD photoreactor M2 and irradiated at 450 nm for 2 h. Then the reaction mixture was diluted with DCM, washed with sat. NaHCO 3 (aq.), and the aqueous phase was extracted twice with DCM. The combined organic phases were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the reaction flask was degassed and refilled with N 2 , repeatedly for three cycles.
  • the mixture was stirred at 80 °C for 2 h.
  • the mixture was cooled to 25 °C, added into sat. KF (aq., 800 mL) and stirred for 2 h at 25 °C.
  • the mixture was extracted with ethyl acetate (500 mL ⁇ 3), washed with saturated brine solution (500 mL), and dried (Na 2 SO 4 ) before concentration to dryness.
  • reaction solution was added into water (20 mL), extracted with EtOAc (20 mL ⁇ 3). The organics was washed with 20 mL saturated brine solution. The organics were then separated and dried (Na 2 SO 4 ) before concentration to dryness.
  • reaction mixture was stirred at -5 °C for 1 h and then quenched with sat. NH 4 Cl (aq) (2 mL) and warmed to r.t..
  • the reaction mixture was diluted with EtOAc and washed with 5% citric acid (aq) and brine.
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • reaction mixture was cooled to 0 °C in an ice bath, and pivaloyl chloride (1.2 equiv., 2.1 mL, 17.0 mmol) was added, and the reaction mixture was allowed to warm to r.t. and stirred overnight.
  • the reaction mixture was diluted with DCM (50 mL) washed with sat. NH 4 Cl (aq.), and the aqueous layer was extracted with DCM (2 ⁇ 50 mL). The combined organic layers were dried with anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • the system was purged with hydrogen, and the mixture was stirred at 25 °C for 4 h under a balloon of hydrogen.
  • the reaction was then purged with nitrogen, diluted with DCM, filtered thought celite and evaporated under vacuum.
  • the residue was diluted in DCM (10 mL) and manganese dioxide (10 eq, 2.7 g, 11.7 mmol) was added. The resulting mixture was stirred at room temperature overnight then filtered through celite and evaporated.
  • Example A2 Synthesis of Exemplary Compounds Method 1: Synthesis of Example 7, 16, and 62
  • Example 7 5-[(2S,6R)-4-[4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridin-2-yl]-6- methyl-morpholin-2-yl]-1-methyl-pyridin-2-one [0451]
  • 2-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pteridine (1 equiv., 50 mg, 0.14 mmol) and 1-methyl-5-[(2S,6R)-6-methylmorpholin-2-yl]pyridin-2-one (Int- A5, 2 equiv., 58 mg, 0.28 mmol) in DMSO (0.5 mL), was added DIPEA (5 equiv., 0.12 mL, 0.7 mmol), and the reaction was stirred at 100 °C
  • Example 38 Synthesis of Example 38, 40, 42, 43, 44, 46, 48, 50, and 52
  • Example 38 5-[(2R,4S)-4-[4-[3-(1,1-difluoroethyl)-1-bicyclo[1.1.1]pentanyl]-6,7-dimethyl- pteridin-2-yl]tetrahydropyran-2-yl]-1-methyl-pyridin-2-one [0474] To a solution of (2R,4S)-N-[3-[3-(1,1-difluoroethyl)bicyclo[1.1.1]pentane-1-carbonyl]- 5,6-dimethyl-pyrazin-2-yl]-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-carboxamide (Int-A23, 1 equiv., 350 mg, 0.699 mmol) in 1-butanol (15 mL) was added ammoni
  • reaction mixture was stirred at 115 °C for 2 hours. LCMS showed starting material was consumed completely and desired mass was detected.
  • the reaction mixture was diluted with water 10 mL and extracted with EtOAc (20 mL ⁇ 2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a crude residue.
  • Example 88 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]-1-[1,2,2,2-tetradeuterio-1- (trideuteriomethyl)ethyl]pyridin-2-one [0476] To a solution of 2-bromo-1,1,1,2,3,3,3-heptadeuterio-propane (1.5 equiv., 83 mg, 0.636 mmol) and 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pteridin-2- yl]tetrahydropyran-2-yl]-1H-pyridin-2-one (Example 34, 1 equiv.,
  • Example 104 5-((2R)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo-[1.1.1]pentan-1-yl)pteridin- 2-yl)tetrahydro-2H-pyran-2-yl)-1-(5-methylthiophen-3-yl)pyridin-2(1H)-one [0480] To a solution of 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)pteridin-2-yl)tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one (Example 34, 1 equiv., 150 mg, 0.318 mmol) in DMF (5 mL) was added 4-bromo-2-methylthiophene (
  • Example 105 5-((2R,4S)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)pteridin-2-yl)tetrahydro-2H-pyran-2-yl)-1-(5-methylthiophen-3-yl)pyridin-2(1H)-one [0481] 5-((2R)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pteridin-2- yl)tetrahydro-2H-pyran-2-yl)-1-(5-methylthiophen-3-yl)pyridin-2(1H)-one (Example 104, 1 equiv., 83 mg, 0.146 mmol) was purified by SFC (Condition 3, Gradient a) to give 60 mg the desired product, LCMS showed 95% purity.
  • Crude B was purified by SFC (Condition 4, Gradient a), concentrated under reduced pressure, and further purified by Prep-HPLC (Condition 5) and lyophilized to give 1-(1- bicyclo[1.1.1]pentanyl)-5-[(2S,4R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]- pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]pyridine-2-one (Example 121, 1.3 mg, 0.0024 mmol, 1% yield) as a solid.
  • Example 126 5-[(2R,4S)-4-[6-(difluoromethyl)-4-[2-fluoro-4- (trifluoromethyl)phenyl]-7-methyl-pteridin-2-yl]tetrahydropyran-2-yl]-1-methyl-pyridin-2-one
  • Example 127 5-[(2S,4R)-4-[6-(difluoromethyl)-4-[2-fluoro-4-(trifluoromethyl) phenyl]-7- methyl-pteridin-2-yl]tetrahydropyran-2-yl]-1-methyl-pyridin-2-one [0490] The crude (Example 128) was separated by SFC (Condition 14, Gradient a) to afford 5- [(2R,4S)-4-[6-(difluoromethyl)
  • Example 140 5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]-1-methyl-pyridin-2-one [0495] To a mixture of 5-[(2R,4S)-4-[6-methoxy-7-methyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]-1H-pyridin-2-one (Example 143, 1 equiv., 40 mg, 0.0821 mmol) and Cs 2 CO 3 (2 equiv., 53 mg, 0.164 mmol) in MeCN (2 mL) was added MeI (5 equiv., 0.026 mL
  • Example 136 5-[(2R)-4-(4-cyclohexyl-6-methoxy-7-methyl-pteridin-2-yl)tetrahydropyran-2-yl]- 1-methyl-pyridin-2-one [0501] To a solution of [6-methoxy-7-methyl-2-[(2R)-2-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]pteridin-4-yl] 4-methylbenzenesulfonate (Int-B17, 1 equiv., 30 mg, 0.056 mmol) and Pd(Amphos) 2 Cl 2 (0.1 equiv., 4.0 mg, 0.006 mmol) in
  • Example 167-170 The crude (Example 171) was purified by Prep-HPLC (Condition 7, Gradient c) to give Crude A (40 mg) and Crude B (30 mg, 85% purity). [0505] Crude A (40 mg) was purified by SFC (Condition 11, Gradient d) and lyophilized to get the 1-methyl-5-[(2R,4S)-4-[2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl] pyrido[2,3- b]pyrazin-6-yl]tetrahydropyran-2-yl]pyridin-2-one (Example 167, 9.3 mg, 0.0188 mmol, 6% yield) as a solid and 1-methyl-5-[(2S,4R)-4-[2,3-dimethyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrid
  • Crude B (30 mg, 85% purity) was purified by Prep-HPLC (Condition 7, Gradient d) to give the Crude B (17 mg, 95% purity) which was purified by SFC (Condition 11, Gradient e) and lyophilized to afford 1-methyl-5-[(2R,4R)-4-[2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo- [1.1.1]pentanyl]pyrido[2,3-b]pyrazin-6-yl]tetrahydropyran-2-yl]pyridin-2-one (Example 169, 5.9 mg, 0.012 mmol, 4% yield) as a solid and 1-methyl-5-[(2S,4S)-4-[2,3-dimethyl-8-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[2,3-b]pyrazin-6-yl]tetrahydropyran-2-yl
  • Example 173 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5-d]pyrimidin- 5-yl]-6-methyl-morpholin-2-yl]-1H-pyridin-2-one [0511] To a solution of 5-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-7-(2,4- difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Int-C3, 1 equiv., 90 mg, 0.157 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1.0 mL) was added MsOH (0.10 mL), and then the mixture was stirred for 12 h at 20 °C and then for another 12 h at 25 °
  • Example 174 1-amino-5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5- d]pyrimidin-5-yl]-6-methyl-morpholin-2-yl]pyridin-2-one [0512] To a mixture of 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5- d]pyrimidin-5-yl]-6-methyl-morpholin-2-yl]-1H-pyridin-2-one (Example 173, 1 equiv., 30 mg, 0.0619 mmol) and Cs 2 CO 3 (3.5 equiv., 71 mg, 0.217 mmol) in DMF (1 mL) was added O- diphenylphosphorylhydroxylamine (2 equiv., 29 mg, 0.124
  • NaBH 3 CN (2.5 equiv., 18 mg, 0.293 mmol) was added at 0 °C, and then the mixture was stirred for 1 h at 20 °C.
  • the reaction solution was added into NH 4 Cl aqueous solution (10 mL) and then extracted with DCM (15 mL ⁇ 3). The organics were washed with 10 mL saturated brine solution, separated, and dried (Na 2 SO 4 ) before concentration to dryness.
  • Example 176 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5-d]pyrimidin- 5-yl]-6-methyl-morpholin-2-yl]-1-methyl-pyridin-2-one [0515] To a solution of 5-[(2S,6R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5- d]pyrimidin-5-yl]-6-methyl-morpholin-2-yl]-1H-pyridin-2-one (Example 173, 1 equiv., 20 mg, 0.0413 mmol) and K 2 CO 3 (2 equiv., 11 mg, 0.0826 mmol) in DMF (0.50 mL) was added MeI (1.5 equiv., 8.8 mg, 0.0619 mmol), and then the mixture was
  • Example 179 5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]-1-(methylamino)pyridin-2-one [0518] A flame-dried MW vial was charged with 5-[(2R,4S)-4-[6,7-dimethyl-4-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]-1H-pyridin-2-one (Example 34, 1 equiv., 100 mg, 0.21 mmol), cesium carbonate (4 equiv., 276 mg, 0.85 mmol), N- diphenylphosphoryloxymethanamine (Int-C6, 4 equiv., 210 mg, 0.
  • reaction mixture was cooled to 0 °C and water was added.
  • the aqueous suspension formed was extracted with EtOAc (4 ⁇ 20 mL).
  • the combined organic phases were washed with water and brine.
  • the organic layer was dried with anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • Example 180 5-[(2S,6R)-4-[6-(difluoromethyl)-7-methyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pteridin-2-yl]-6-methyl-morpholin-2-yl]-1-methyl-pyridin-2-one [0520] A MW vial was charged with 2-chloro-6-(difluoromethyl)-7-methyl-4-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pteridine (Int-C7, 1 equiv., 70 mg, 0.146 mmol) and 1- methyl-5-[(2S,6R)-6-methylmorpholin-2-yl]pyridin-2-one (3) (1.05 equiv., 32 mg, 0.153 mmol) in anhydrous THF (1 mL).
  • Example 190 5-[1-[4-(2,4-difluorophenyl)-6,7-dimethyl-pteridin-2-yl]-4,4-difluoro-3-piperidyl]- 1-methyl-pyridin-2-one [0522] Cs 2 CO 3 (3 equiv, 61 mg, 0.19 mmol) was added to a solution of 5-[1-[4-(2,4- difluorophenyl)-6,7-dimethyl-pteridin-2-yl]-4,4-difluoro-3-piperidyl]-1H-pyridin-2-one (Compound 189, 1 equiv, 30 mg, 0.062 mmol) and methyl iodide (2 equiv, 7.7 ⁇ L, 0.12 mmol) in THF (2.0 mL).
  • Example 191 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-b]pyrazin-7-yl)-6- methylmorpholin-2-yl)-1-methylpyridin-2(1H)-one [0524] From 1-methyl-5-((2S,6R)-6-methylmorpholin-2-yl)pyridin-2(1H)-one and 7-chloro-5- (2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-b]pyrazine, a coupling procedure analogous to Method 5 from WO 2022/236272 was utilized to obtain 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3- dimethylpyrido[3,4-b]pyrazin-7-yl)-6-methylmorpholin-2-yl)-1-
  • Example 196 5-((2S,6R)-4-(5-(2,4-difluorophenyl)-2,3-dimethyl-1,6-naphthyridin-7-yl)-6- methylmorpholin-2-yl)-1-methylpyridin-2(1H)-one [0525] From 1-methyl-5-((2S,6R)-6-methylmorpholin-2-yl)pyridin-2(1H)-one and7-chloro-5- (2,4-difluorophenyl)-2,3-dimethyl-1,6-naphthyridine, a coupling procedure analogous to Method 4 from WO 2022/236272 was utilized to obtain 5-((2S,6R)-4-
  • Example 201 5-((2R,4S)-4-(6,7-bis(methyl-d 3 )-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)pteridin-2-yl)tetrahydro-2H-pyran-2-yl)-1-cyclopropylpyridin-2(1H)-one [0527] 1-Cyclopropyl-5-((2R,4S)-4-(4,5-diamino-6-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)pyrimidin-2-yl)tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one (In
  • Example 205 3-[6,7-dimethyl-2-[(2R,6S)-2-methyl-6-(1-methyl-6-oxo-3-pyridyl)morpholin-4- yl]pteridin-4-yl]bicyclo[1.1.1]pentane-1-carbonitrile [0531] TFAA (1 equiv., 0.015 mL, 0.11 mmol) was added dropwise to a solution of 3-[6,7- dimethyl-2-[(2R,6S)-2-methyl-6-(1-methyl-6-oxo-3-pyridyl)morpholin-4-yl]pteridin-4- yl]bicyclo[1.1.1]pentane-1-carboxamide (Example 204, 1 equiv., 50 mg, 0.11 mmol) and pyridine (2 equiv., 0.017 mL, 0.21 mmol) in DCM (1 mL), and the resulting mixture was
  • Example 206 1-(diallylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]pyridin-2-one; and Example 207: 1- (allylamino)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pteridin- 2-yl]tetrahydropyran-2-yl]pyridin-2-one [0532] A 20 mL microwave vial was charged with 1-amino-5-[(2R,4S)-4-[6,7-dimethyl-4-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pteridin-2-yl]t
  • Example 208 5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-pyran-2- yl)-1-(propan-2-ylideneamino)pyridin-2(1H)-one [0536] To a stirring solution of 1-amino-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-pyran-2- yl)pyridin-2(1H)-one (Example 332, 1 equiv, 15 mg, 0.026 mmol)
  • Example 210 1-(2,5-dihydropyrrol-1-yl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]pyridin-2-one [0537] DCM (1 mL) was added to a round bottomed flask containing 1-(diallylamino)-5- [(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pteridin-2- yl]tetrahydropyran-2-yl]pyridin-2-one (Example 206, 1 equi
  • the vial was sealed and stirred at 80 °C for 2 h.
  • the reaction mixture was heated to 80 °C for 16 h.
  • the reaction mixture was cooled down to r.t., water was added, and the aqueous phase was extracted three times with EtOAc. Organic phases were combined, dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure.
  • Example 216 2,3-dimethyl-6-[rac-(2R,4S)-2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]-8-[3- (trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidin-4-one [0539]
  • Pd/C 10 wt%, 0.1 equiv., 13 mg, 0.013 mmol
  • the resulting solution was stirred at 60 °C for 6 h.
  • the reaction mixture was cooled to r.t., degassed with Ar, and charged with 10 wt% Pd/C (0.1 equiv., 17 mg, 0.02 mmol).
  • the reaction mixture was stirred under an atmosphere of H 2 , at r.t. for 4 h.
  • the reaction mixture was degassed with Ar and filtered through a short pad of Celite, washing with EtOH.
  • Example 230 2-((2R,4S)-2-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)tetrahydro-2H-pyran- 4-yl)-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimido[4,5-d]pyridazin-8(7H)- one [0541] To a stirring solution of 7-methyl-2-((2R,4S)-2-(6-oxo-1,6-dihydropyridin-3- yl)tetrahydro-2H-pyran-4-yl)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimido[4,5- d]pyridazin-8(
  • the resulting mixture was purged with oxygen for 5 min, capped, and stirred at 70 °C for 72 h.
  • the reaction mixture was cooled to r.t. and diluted with EtOAc and water. The layers were separated, and the organic layer was washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo.
  • Example 336 1-(dimethylamino)-5-((2R,4S)-4-(7-methyl-6-(trifluoromethyl)-4-(3- (trifluoromethyl)bicyclo-[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-pyran-2- yl)pyridin-2(1H)-one; and Example 338: 1-(methylamino)-5-((2R,4S)-4-(7-methyl-6- (trifluoromethyl)-4-(3-(trifluoromethyl)bicyclo-[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidin-2-
  • reaction mixture was stirred at this temperature for 2 days.
  • the reaction mixture was diluted with EtOAc, and the resulting solution was washed with sat. NaHCO 3 (aq), and brine.
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • Example 336 ESI-MS: [M+H] + 568.3.
  • Example 311 5-((2R,4S)-4-(6-chloro-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-pyran-2-yl)-1-(methyl-d 3 )pyridin-2(1H)-one; and
  • Example 322 1-(methyl-d 3 )-5-((2R,4S)-4-(7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan- 1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one [0546]
  • Example 309 1-(difluoromethyl)-5-((2R,4S)-4-(6-fluoro-7-methyl-4-(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-pyran-2- yl)pyridin-2(1H)-one [0550] 5-[(2R,4S)-4-[6-fluoro-7-methyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pyrido[2,3-d]pyrimidin-2-yl]tetrahydropyran-2-yl]-1H-pyridin-2-one (Int-E24, 1 equiv., 45 mg, 0.1 mmol) and sodium tert-butoxide (2.2 equiv., 1.1 mmol, 106 mg) were added
  • Example 305 7-methyl-2-((2R,4S)-2-(1-(methyl-d 3 )-6-oxo-1,6-dihydropyridin-3-yl)tetrahydro- 2H-pyran-4-yl)-4-(3-(trifluoromethyl)bicyclo [1.1.1] pentan-1-yl)pyrido[2,3-d]pyrimidine-6- carbonitrile [0552] 5-((2R,4S)-4-(6-bromo-7-methyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)pyrido[2,3-d]pyrimidin-2-yl)tetrahydro-2H-pyran-2-yl)-1-(methyl-d 3 )pyridin-2(1H)-one (Example 303, 1 equiv., 60 mg, 0.11 mmol), Zn(CN) 2 (2
  • Example 118 1-(1-deuteriocyclopropyl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-1- bicyclo[1.1.1]pentanyl]pteridin-2-yl]tetrahydropyran-2-yl]pyridin-2-one [0555] To a microwave vial equipped with a Teflon-coated magnetic stirring bar was added bipyridyl (2.0 equiv., 46 mg, 0.30 mmol) and the vial was flame-dried under vacuum.5-[(2R,4S)-4- [6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pteridin-2-yl
  • Example A3 In vitro Assay Data In vitro Measurement of Triggering Receptor Expressed on Myeloid Cells 2 activity using cellular phosphorylation of Spleen Tyrosine Kinase (“Syk”) Assays [0556] Measurement of TREM2 agonist potency was done using a HEK cell line expressing human TREM2 and DAP12 (HEK293T-hTREM2 cells). Binding of small molecules to, and activation of, TREM2 increases the phosphorylation of Syk. The resultant levels of Syk phosphorylation are measured using a commercial AlphaLisa reagent kit.
  • HEK- hTREM2 cells were plated at 14,000 cells per well in a 384 well plate, in 25 ⁇ L of complete growth media and incubated at 37 °C, 5% CO 2 for 20-24 hours.
  • test compounds Prior to the assay, test compounds were diluted in the 384 well plates in assay buffer and allowed to equilibrate for 30 minutes. Growth media was removed from cell plates by inversion on blotting paper, and 25 ⁇ L of test articles in assay buffer was added to cells. Cells were incubated for 45 minutes at room temperature. After 45 minutes, assay buffer was removed and 10 ⁇ L of lysis buffer was added. Plates were shaken for 20 minutes at 350 RPM at room temperature.

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Abstract

La présente divulgation concerne des composés de Formule (I), utiles pour l'activation d'un récepteur de déclenchement exprimé sur des cellules myéloïdes 2 (" TREM2 "). Cette divulgation concerne également des compositions pharmaceutiques comprenant les composés, des utilisations des composés, ainsi que des compositions pour le traitement, par exemple, d'un trouble neurodégénératif. En outre, la divulgation concerne des intermédiaires utiles dans la synthèse de composés de Formule (I).
PCT/US2024/059856 2023-12-12 2024-12-12 Composés de pyridinone hétérocycliques en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation Pending WO2025128873A1 (fr)

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

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

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