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WO2024233848A1 - Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation - Google Patents

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

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Publication number
WO2024233848A1
WO2024233848A1 PCT/US2024/028689 US2024028689W WO2024233848A1 WO 2024233848 A1 WO2024233848 A1 WO 2024233848A1 US 2024028689 W US2024028689 W US 2024028689W WO 2024233848 A1 WO2024233848 A1 WO 2024233848A1
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optionally substituted
ring
nitrogen
independently selected
sulfur
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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
    • 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
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • 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. Science, 2011, Ikegami et al. Neruopathology, 2019) in addition to other types of glial cells (Domingues et al. Front Cell Dev Biol, 2016; Liddelow et al. Nature, 2017, Shinozaki et al. Cell Rep., 2017), playing roles in a multitude of physiological processes.
  • microglia With the ability to rapidly proliferate in response to stimuli, microglia characteristically exhibit myeloid cell functions such as phagocytosis, cytokine/chemokine release, antigen presentation, and migration (Colonna and Butovsky, Annu Rev Immunol, 2017). 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).
  • microglial “sensome” 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 protein families such as Sialic acid-binding immunoglobulin-type lectins (“SIGLEC”), Toll-like receptors (“TLR”), Fc receptors, nucleotide-binding oligomerization domain (“NOD”)
  • TREM2 central nervous system
  • IgV immunoglobulin variable
  • TREM2 does not possess intracellular signal transduction-mediating domains
  • biochemical analysis has illustrated that interaction with adaptor proteins DAP10 and DAP12 mediate downstream signal transduction following ligand recognition (Peng et al. Sci Signal 2010; Jay et al. Mol Neurodegener, 2017).
  • 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.
  • 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 for their 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 Despite many attempts to alter disease progression by targeting the pathological hallmarks of LOAD through anti-amyloid and anti-Tau therapeutics, there is a need for 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, such as Alzheimer’s disease.
  • Y is C or N, as required by the bicyclic ring system formed by Ring A;
  • X 3 is CHR 3 , or NR 4 ;
  • X 4 is CHR 3 , NR 4 , O or S;
  • each Z 1 is independently CR 2 or N;
  • Z 2 is CR 3 or N;
  • a pharmaceutical composition comprising a compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.
  • a compound of Formula I, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition as described hereinabove for use in treating or preventing a condition associated with a loss of function of human TREM2.
  • a compound of Formula I I or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R 1 is an optionally substituted C1-6 aliphatic group, C1-6haloalkyl, optionally substituted OCH2- (C3-6cycloalkyl), optionally substituted O-phenyl, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-12 membered saturated or partially unsaturated bridged carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a
  • R 1 is an optionally substituted C 1-6 aliphatic group, C 1-6 haloalkyl, optionally substituted OCH 2 -(C 3- 6 cycloalkyl), or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-12 membered saturated or partially unsaturated bridged carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6- 12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6- 12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-2 heteroatoms independently selected from
  • a compound of Formula I-b I-b or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R 1 is an optionally substituted C 1-6 aliphatic group, C 1-6 haloalkyl, optionally substituted OCH 2 - (C 3-6 cycloalkyl), optionally substituted O-phenyl, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-12 membered saturated or partially unsaturated bridged carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6-12 membered saturated saturated
  • a compound of Formula I-c I-c or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R 1 is an optionally substituted C1-6 aliphatic group, C1-6haloalkyl, optionally substituted OCH2- (C3-6cycloalkyl), optionally substituted O-phenyl, or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 5-12 membered saturated or partially unsaturated bridged carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6-12 membered saturated or partially unsaturated bridged
  • the compound is a compound of Formula IIa1: IIa1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IIa2: IIa2 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IIb1: IIb1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IIb2: IIb2 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IIc1: IIc1 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IIc2: IIc2 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IIIa: or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IIIb: or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IIIc: IIIc or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IVa: or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IVb: IVb or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula IVc: IVc or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula Va: or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula Vb: Vb or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula Vc: Vc or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIa: VIa or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIb: VIb or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIc: VIc or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIIa: VIIa or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIIb: VIIb or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIIc: VIIc or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIIIa: VIIIa or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIIIb: VIIIb or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIIIc: VIIIc or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each variable is as defined above and described in embodiments herein both singly and in combination.
  • the compound is a compound of Formula VIIb-1 to VIIb-11:
  • the compound is a compound of Formula VIIb’-1 to VIIb’-11:
  • the compound is a compound of Formula VIIb’’-1 to VIIb’’-11:
  • R 1 is an optionally substituted C 1-6 aliphatic group, C 1-6 haloalkyl, optionally substituted OCH 2 -(C 3-6 cycloalkyl), or a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 6-12 membered saturated or partially unsaturated bridged carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6-12 membered saturated or partially unsaturated
  • R 1 is optionally substituted O-phenyl.
  • R 1 is an optionally substituted C 1-6 aliphatic group.
  • R 1 is -OR.
  • R 1 is -NR 2 .
  • R 2 is -SO 2 R.
  • R 1 is -SO 2 NR 2 .
  • R 1 is C 1-6 haloalkyl.
  • R 1 is an optionally substituted OCH 2 -(C 3-6 cycloalkyl). In some embodiments, R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1 is an optionally substituted 5-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 1 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 1 is an optionally substituted phenyl. In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.
  • R 1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 1 is a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 6-12 membered saturated or partially unsaturated bridged carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 6-12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen,
  • R 1 is phenyl, optionally substituted with 1-3 substituents independently selected from halogen, C 1–6 aliphatic, -OR ⁇ , or C 1-6 haloalkyl. In some embodiments, R 1 is phenyl, optionally substituted with 1-3 halogen. In some embodiments, R 1 is a 5-12 membered saturated or partially unsaturated bridged carbocyclic ring, optionally substituted with 1-3 substituents independently selected from halogen, C 1–6 aliphatic, -OR ⁇ , or C 1-6 haloalkyl.
  • R 1 is a C 5- 8tricycloalkyl ring, optionally substituted with 1-3 substituents independently selected from halogen, C1– 6 aliphatic, -OR ⁇ , or C1-6haloalkyl.
  • R 1 is 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 substituents independently selected from halogen, C1–6 aliphatic, -OR ⁇ , or C1- 6 haloalkyl.
  • R 1 is 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 halogen.
  • R 1 is optionally substituted C 3-6 cycloalkyl, optionally substituted spiro[3.3]heptanyl, optionally substituted spiro[5.2]octanyl, optionally substituted , optionally substituted cyclopent-1-en-1-yl, optionally substituted cyclohex-1-en-1-yl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted aziridine-1-yl, optionally substituted pyrrolidine-1- yl, optionally substituted azabicyclo[3.1.0]hexan-3-yl, optionally substituted piperidine-1-yl, or optionally substituted -OCH2-(C3-4cycloalkyl).
  • R 1 is optionally substituted C3-6cycloalkyl. In some embodiments, R 1 is optionally substituted spiro[3.3]heptanyl. In some embodiments, R 1 is some embodiments, R 1 is optionally substituted cyclopent-1-en-1-yl. In some embodiments, R 1 is optionally substituted cyclohex-1-en-1-yl. In some embodiments, R 1 is optionally substituted phenyl. In some embodiments, R 1 is optionally substituted pyridinyl. In some embodiments, R 1 is optionally substituted aziridine-1-yl. In some embodiments, R 1 is optionally substituted pyrrolidine-1-yl.
  • R 1 is optionally substituted azabicyclo[3.1.0]hexan-3-yl. In some embodiments, R 1 is optionally substituted piperidine-1-yl. In some embodiments, R 1 is optionally substituted -OCH 2 -(C 3- 4 cycloalkyl).
  • R 1 is a substituent selected from those shown below: [0053] In some embodiments, R 1 is . In some embodiments, R 1 is . In some embodiments, . some embodiments, . some embodiments, R 1 is selected from those depicted in Table A below. In some embodiments, R 1 is selected from those depicted in Table A3 below. [0054] As defined generally above, X 1 is CR 13 , CH or N. In some embodiments, X 1 is CH or N. In some embodiments, X 1 is CH. In some embodiments, X 1 is CR 13 . In some embodiments, X 1 is N. In some embodiments, X 1 is selected from those depicted in Table A below.
  • X 1 is selected from those depicted in Table A3 below.
  • X 2 is CR 14 , CH or N. In some embodiments, X 2 is CH or N. In some embodiments, X 2 is CH. In some embodiments, X 2 is CR 14 . In some embodiments, X 2 is N. In some embodiments, X 2 is selected from those depicted in Table A below. In some embodiments, X 2 is selected from those depicted in Table A3 below.
  • R 13 is hydrogen.
  • R 13 is an optionally substituted C1-6 aliphatic group.
  • R 13 is halogen.
  • R 13 is -OR.
  • R 13 is -CN.
  • R 13 is -NR2.
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula .
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system selected from: [0078] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system selected from: , [0079] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system . [0080] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system selected from those depicted in Table A below.
  • Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system selected from those depicted in Table A3 below.
  • X 3 is CHR 3 , or NR 4 .
  • X 3 is CHR 3 .
  • X 3 is NR 4 .
  • X 3 is NH.
  • X 3 is NMe.
  • X 3 is NCH(CH 3 ) 2 .
  • X 4 is CHR 3 , NR 4 , O or S. In some embodiments X 4 is CHR 3 .
  • X 4 is NR 4 . In some embodiments, X 4 is O. In some embodiments, X 4 is S. In some embodiments, X 4 is NH. In some embodiments, X 4 is NMe. In some embodiments, X 4 is NCH(CH3)2.
  • each Z 1 is independently CR 2 or N. In some embodiments, Z 1 is CR 2 . In some embodiments, Z 1 is N.
  • each Z 2 is independently CR 3 or N. In some embodiments, Z 2 is CR 3 . In some embodiments, Z 1 is N. [0085] As defined generally above, Z 11 is CHR 3 , C(R 3 )2, or NR 4 .
  • R 2 and R 3 are each independently -NR-C(O)-R.
  • R 2 is hydrogen.
  • R 2 is an optionally substituted C 1-6 aliphatic group.
  • R 2 is halogen.
  • R 2 is -OR.
  • R 2 is -NR 2 .
  • R 2 is -SO 2 R.
  • R 2 is -SO 2 NR 2 .
  • R 2 is C 1-6 haloalkyl. In some embodiments, R 2 is C 1-6 haloalkoxy. In some embodiments, R 2 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 2 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 2 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 2 is an optionally substituted phenyl. In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.
  • R 2 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 2 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is selected from those depicted in Table A below. In some embodiments, R 2 is selected from those depicted in Table A3 below. [0089] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C1-6 aliphatic group. In some embodiments, R 3 is halogen. In some embodiments, R 3 is -OR.
  • R 3 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 3 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 3 is an optionally substituted phenyl. In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 3 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 3 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 3 is selected from those depicted in Table A below. In some embodiments, R 3 is selected from those depicted in Table A3 below. [0090]
  • R 2 is hydrogen. In some embodiments, R 2 is methyl. In some embodiments, R 2 is Cl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is a C1-3 haloalkyl. In some embodiments, R 2 is 3-8 membered saturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 2 is an azetidinyl group. In some embodiments, R 2 is optionally substituted ethyl.
  • R 2 is methoxy. In some embodiments, R 2 is -CH2F. In some embodiments, R 2 is -OCH2F. In some embodiments, R 2 is -CD3. [0091] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is methyl. In some embodiments, R 3 is Cl. In some embodiments, R 3 is isopropyl. In some embodiments, R 3 is a C1-3 haloalkyl. In some embodiments, R 3 is 3-8 membered saturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is an azetidinyl group.
  • R 3 is optionally substituted ethyl. In some embodiments, R 3 is methoxy. In some embodiments, R 3 is -CH2F. In some embodiments, R 3 is -OCH2F. In some embodiments, R 3 is -CD3. In some embodiments, R 3 is -N(CH3)-C(O)-CH3. In some embodiments, R 3 is - N(CH 3 ) 2 . In some embodiments, R 3 is -NH(CH 3 ). In some embodiments, R 3 is . In some .
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring.
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring.
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted phenyl. In some embodiments, R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 6-12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form a cyclopentane ring.
  • R 2 , R 2a , or R 2b are taken together with R 3 and their intervening atoms to form a pyrrolidine ring.
  • R 4 is hydrogen, an optionally substituted C 1-6 aliphatic group, an optionally substituted phenyl, an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring, an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or R 3 and R 4 are taken together with their intervening atoms to form a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8
  • R 4 is hydrogen. In some embodiments, R 4 is an optionally substituted C1- 6 aliphatic group. In some embodiments, R 4 is an optionally substituted phenyl. In some embodiments, R 4 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 4 is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 4 is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl. In some embodiments, R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.
  • R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 3 and R 4 are taken together with their intervening atoms to form an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0098] In some embodiments, R 3 and R 4 are taken together with their intervening atoms to form a cyclopentane ring. In some embodiments, R 3 and R 4 are taken together with their intervening atoms to form a pyrrolidine ring. [0099] As defined generally above, Ring .
  • Ring is .
  • Ring B is .
  • L is a bond or an optionally substituted straight chain or branched C1-6 alkylene. In some embodiments, L is a bond. In some embodiments, L is an optionally substituted straight chain or branched C1-6 alkylene. In some embodiments, L is optionally substituted ethylene. In some embodiments, L is optionally substituted methylene. In some embodiments, L is selected from those depicted in Table A below. In some embodiments, L is selected from those depicted in Table A3 below. [0102] As defined generally above, X 5 is CH, N or CR 5 . In some embodiments, X 5 is CH.
  • X 5 is N. In some embodiments, X 5 is CR 5 . In some embodiments, X 5 is selected from those depicted in Table A below. In some embodiments, X 5 is selected from those depicted in Table A3 below. [0103] As defined generally above, X 6 is CH, N or CR 6 . In some embodiments, X 6 is CH. In some embodiments, X 6 is N. In some embodiments, X 6 is CR 6 . In some embodiments, X 6 is selected from those depicted in Table A below. In some embodiments, X 6 is selected from those depicted in Table A3 below. [0104] In some embodiments, X 5 is N and X 6 is CH.
  • X 5 is N and X 6 is CR 6 . In some embodiments, X 5 is CH and X 6 is N. In some embodiments, X 5 is CR 5 and X 6 is N. In some embodiments, X 5 is CH and X 6 is CH. In some embodiments, X 5 is CH and X 6 is CR 6 . In some embodiments, X 5 is CR 5 and X 6 is CH.
  • R 16 is hydrogen.
  • R 16 is an optionally substituted C 1-6 aliphatic group.
  • R 16 is halogen.
  • R 13 is -OR.
  • R 16 is - CN.
  • m is 0, 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. [0107] In some embodiments, Ring . some embodiments, Ring B is . , . some embodiments, Ring B . , .
  • R 5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 5 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 5 is an optionally substituted phenyl. In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.
  • R 5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 5 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0110] In some embodiments, R 5 is F. In some embodiments, R 5 is Cl. In some embodiments, R 5 is - OCF3. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is selected from those depicted in Table A below. In some embodiments, R 5 is selected from those depicted in Table A3 below.
  • R 6 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 6 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 6 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 6 is an optionally substituted phenyl. In some embodiments, R 6 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring.
  • R 6 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 6 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 6 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 6 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 6 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0112] In some embodiments, R 6 is F. In some embodiments, R 6 is Cl. In some embodiments, R 6 is - OCF 3 . In some embodiments, R 6 is cyclopropyl. In some embodiments, R 6 is cyclobutyl. In some embodiments, R 6 is optionally substituted pyrazolyl.
  • R 6 is optionally substituted pyridinyl. In some embodiments, R 6 is optionally substituted pyrimidinyl. In some embodiments, R 6 is optionally substituted pyridazinyl. In some embodiments, R 6 is optionally substituted imidazolyl. In some embodiments, R 6 is optionally substituted triazolyl. In some embodiments, R 6 is optionally substituted oxazolyl. In some embodiments, R 6 is optionally substituted thiazolyl. In some embodiments, R 6 is optionally substituted oxadiazolyl. In some embodiments, R 6 is optionally substituted thiadiazolyl. In some embodiments, R 6 is optionally substituted oxetanyl.
  • R 6 is optionally substituted azetidinyl. In some embodiments, R 6 is optionally substituted piperidinyl. In some embodiments, R 6 is optionally substituted piperazinyl. In some embodiments, R 6 is selected from those depicted in Table A below. In some embodiments, R 6 is selected from those depicted in Table A3 below. [0113] In some embodiments, R 5 and R 6 are independently a substituent selected from hydrogen and those shown below:
  • R 5 and R 6 are taken together with their intervening atoms to form a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 7- 12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), a 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), and an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the cyclic group selected from a 3-8 member
  • R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted phenyl.
  • R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 6-12 membered saturated or partially unsaturated bridged heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 5 and R 6 are taken together with their intervening atoms to form an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 5 and R 6 are taken together with their intervening atoms to form a dioxole ring.
  • X 7 is N, CH, or CR 7 . In some embodiments, X 7 is N. In some embodiments, X 7 is CH. In some embodiments, X 7 is CR 7 . In some embodiments, X 7 is CCH 3 . In some embodiments, X 7 is COH. In some embodiments, X 7 is CF. In some embodiments, X 7 is selected from those depicted in Table A below. In some embodiments, X 7 is selected from those depicted in Table A3 below.
  • X 8 is O.
  • X 8 is NR 8 .
  • X 8 is C(R 8 ) 2 .
  • X 8 is CHR 8 .
  • X 8 is SO 2 .
  • X 8 is CH 2 .
  • X 8 is selected from those depicted in Table A below. In some embodiments, X 8 is selected from those depicted in Table A3 below.
  • X 9 is O.
  • X 9 is NR 9 .
  • X 9 is C(R 9 ) 2 .
  • X 9 is CHR 9 .
  • X 9 is SO 2 .
  • X 9 is CH 2 .
  • X 9 is selected from those depicted in Table A below. In some embodiments, X 9 is selected from those depicted in Table A3 below.
  • X 10 is O.
  • X 10 is NR 10 .
  • X 10 is C(R 10 )2.
  • X 10 is CHR 10 .
  • X 10 is SO2.
  • X 10 is CH2, CF2, or O.
  • X 10 is CH2.
  • X 10 is NR 10 , or O.
  • X 10 is NMe, NH, or O.
  • X 11 is selected from those depicted in Table A3 below.
  • X 12 is O.
  • X 12 is NR 12 .
  • X 12 is C(R 12 ) 2 .
  • X 12 is CHR 12 .
  • X 12 is CH 2 .
  • X 12 is SO 2 .
  • X 12 is - CH 2 CH 2 -. In some embodiments, X 12 is -OCH 2 -. In some embodiments, X 12 is a direct bond. In some embodiments, X 12 is selected from those depicted in Table A below. In some embodiments, X 12 is selected from those depicted in Table A3 below. [0123] In some embodiments, when any of X 7 , X 8 , X 9 , X 10 , X 11 , or X 12 is N, O or SO 2 , then neither of the neighboring positions in Ring B are N, O or SO 2 .
  • R 7 is an optionally substituted aliphatic group.
  • R 7 is selected from those depicted in Table A below. In some embodiments, R 7 is selected from those depicted in Table A3 below.
  • R 8 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 8 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 8 is an optionally substituted phenyl. In some embodiments, R 8 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 8 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 8 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 8 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 8 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 8 is methyl. In some embodiments, R 8 is -OH. In some embodiments, R 8 is F. In some embodiments, R 8 is methoxy.
  • R 9 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 9 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 9 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 9 is methyl. In some embodiments, R 9 is -OH. In some embodiments, R 9 is F. In some embodiments, R 9 is methoxy. In some embodiments, R 9 is -CH 2 OH. In some embodiments, wherein X 9 is C(R 9 ) 2 , each R 9 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X 9 is C(R 9 ) 2 , both R 9 are the same. In some embodiments, R 9 is selected from those depicted in Table A below.
  • R 9 is selected from those depicted in Table A3 below. [0129] In some embodiments, R 9 is optionally substituted pyrazolyl. In some embodiments, R 9 is optionally substituted pyridinyl. In some embodiments, R 9 is optionally substituted pyrimidinyl. In some embodiments, R 9 is optionally substituted pyridazinyl. In some embodiments, R 9 is optionally substituted imidazolyl. In some embodiments, R 9 is optionally substituted triazolyl. In some embodiments, R 9 is optionally substituted oxazolyl. In some embodiments, R 9 is optionally substituted thiazolyl.
  • R 9 is optionally substituted oxadiazolyl. In some embodiments, R 9 is optionally substituted thiadiazolyl. In some embodiments, R 9 is optionally substituted oxetanyl. In some embodiments, R 9 is optionally substituted azetidinyl. In some embodiments, R 9 is optionally substituted piperidinyl. In some embodiments, R 9 is optionally substituted piperazinyl. [0130] In some embodiments, R 9 is substituted with an optionally susbstituted 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • R 9 is substituted with an optionally substituted 5-8 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 9 is substituted with an optionally susbstituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring. In some embodiments, R 9 is substituted with an optionally susbstituted C1-6 aliphatic group. In some embodiments, R 9 is substituted with a methyl group. In some embodiments, R 9 is substituted with a -CD3 group. In some embodiments, R 9 is substituted with a methoxy group. In some embodiments, R 9 is substituted with a cyclopropyl group.
  • R 9 is substituted with an optionally substituted .
  • R 9 is -OR, wherein R is an an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 9 is -NHR, wherein R is an an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 9 is -N(CH 3 )R, wherein R is an an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 10 is C 1-6 haloalkoxy. In some embodiments, R 10 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 10 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 10 is an optionally substituted phenyl. In some embodiments, R 10 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 10 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 10 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 10 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 10 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 10 is methyl. In some embodiments, R 10 is -OH. In some embodiments, R 10 is F. In some embodiments, R 10 is methoxy.
  • R 10 is -CH 2 OH. In some embodiments, wherein X 10 is C(R 10 ) 2 , each R 10 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X 10 is C(R 10 ) 2 , both R 10 are the same. In some embodiments, R 10 is selected from those depicted in Table A below. In some embodiments, R 10 is selected from those depicted in Table A3 below. [0141] In some embodiments, R 11 is hydrogen. In some embodiments, R 11 is an optionally substituted C 1-6 aliphatic group. In some embodiments, R 11 -OR. In some embodiments, R 11 is -NR 2 .
  • R 11 is an optionally substituted phenyl. In some embodiments, R 11 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 11 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 11 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 11 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 11 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 11 is methyl. In some embodiments, R 11 is -OH. In some embodiments, R 11 is F. In some embodiments, R 11 is methoxy. In some embodiments, R 11 is -CH2OH. In some embodiments, wherein X 11 is C(R 11 )2, each R 11 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X 11 is C(R 11 )2, both R 11 are the same. In some embodiments, R 11 is selected from those depicted in Table A below.
  • R 11 is selected from those depicted in Table A3 below.
  • R 12 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 12 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R 12 is an optionally substituted phenyl. In some embodiments, R 12 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R 12 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • R 12 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 12 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 12 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 12 is methyl. In some embodiments, R 12 is -OH. In some embodiments, R 12 is F. In some embodiments, R 12 is methoxy.
  • R 12 is -CH 2 OH. In some embodiments, wherein X 12 is C(R 12 ) 2 , each R 12 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X 12 is C(R 12 ) 2 , both R 12 are the same. In some embodiments, R 12 is selected from those depicted in Table A below. In some embodiments, R 12 is selected from those depicted in Table A3 below. [0143] In some embodiments, Ring B is a substituent selected from those shown below: [0145] In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is .
  • Ring B is . [0146] In some embodiments, Ring . some embodiments, Ring B is some embodiments, Ring B is . In some embodiments, Ring . some embodiments, Ring B is . In some embodiments, Ring . some embodiments, Ring B is . In some embodiments, Ring . [0147] In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring B is . In some embodiments, Ring some embodiments, Ring B is . [0148] In some embodiments, Ring some embodiments, Ring B is . , . some embodiments, Ring B is .
  • Ring B is some embodiments, Ring . some embodiments, Ring . In some embodiments, Ring .
  • Ring . at least one hydrogen atom of the compound is a deuterium atom.
  • at least one C1-C6 aliphatic group of the compound is substituted with at least one deuterium atom.
  • at least one C1-C6alkyl group of the compound is substituted with at least one deuterium atom.
  • R 2 is –CD 3 .
  • R 3 is –CD 3 .
  • R 2 and R 3 are both –CD 3 .
  • R 4 is –CD 3 .
  • Exemplary compounds of the invention are set forth in Table A, below.
  • the compound is a compound set forth in Table A, or a pharmaceutically acceptable salt thereof. Table A.
  • Exemplary compounds of the invention are set forth in Table A2, below.
  • the compound is a compound set forth in Table A2, or a pharmaceutically acceptable salt thereof.
  • Table A2 Exemplary Compounds
  • Exemplary compounds of the invention are set forth in Table A3, below.
  • the compound is a compound set forth in Table A3, or a pharmaceutically acceptable salt thereof.
  • 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.
  • the invention provides a pharmaceutical composition comprising a compound of the present disclosure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.
  • the invention provides 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 comprising said compound, or said tautomer, or said salt, for use as a medicament.
  • Pharmaceutically acceptable compositions [0160] According to some embodiments, the present disclosure provides a composition comprising a compound of this disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • compositions of this disclosure are such that it is effective to measurably activate a TREM2 protein, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that it is effective to measurably activate a TREM2 protein, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this disclosure is formulated for oral administration to a patient.
  • compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di- glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • 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 corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration.
  • compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be affected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • provided pharmaceutically acceptable 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. [0170] Most preferably, pharmaceutically acceptable 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.
  • a compound of the present disclosure in the composition will also depend upon the particular compound in the composition.
  • METHODS OF USE As discussed herein (see, section entitled “Definitions”), the compounds described herein are to be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing or solvates of any of the foregoing. Accordingly, the scope of the methods and uses provided in the instant disclosure is to be understood to encompass also methods and uses employing all such forms. [0174] Besides being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
  • 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.
  • 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
  • other forms of dementia including frontotemporal dementia.
  • 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 lg V-set domain of the TREM2 protein and has been shown to impact lipid binding and uptake of apoptotic cells and Abeta (Wang et al.2015; Yeh et al.2016), suggestive of a loss-of-function linked to disease. Further, postmortem comparison of AD patients' brains with and without the R47H mutation are supportive of a novel loss-of-microglial barrier function for the carriers of the mutation, with the R47H carrier microglia putatively demonstrating a reduced ability to compact plaques and limit their spread. Yuan et al.2016.
  • TREM2 may play an important role in supporting microgliosis in response to pathology or damage in the central nervous system. Ulrich and Holtzman 2016. In addition, knockdown of TREM2 has been shown to aggravate a- syn–induced inflammatory responses in vitro and exacerbate dopaminergic neuron loss in response to AAV-SYN in vivo (a model of Parkinson’s disease), suggesting that impaired microglial TREM2 signaling exacerbates neurodegeneration by modulating microglial activation states. Guo et. al.2019.
  • TLR Toll-Like Receptor
  • the invention provides 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 for use in treating or preventing a condition associated with a loss of function of human TREM2.
  • the invention provides 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 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 invention provides 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 for use in the preparation of a medicament for treating or preventing a condition associated with a loss of function of human TREM2.
  • the invention provides 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 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 invention provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of 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 invention 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.
  • the present invention relates to the unexpected discovery that administration of a TREM2 agonist can rescue the loss of microglia in cells having mutations in CSF1R.
  • 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.
  • the present invention 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.
  • HALSP adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
  • HDLS hereditary diffuse leukoencephalopathy with axonal spheroids
  • POLD pigmentary orthochromatic leukodystrophy
  • ALSP is characterized by patchy cerebral white matter abnormalities visible by magnetic resonance imaging. However, the clinical symptoms and MRI changes are not specific to ALSP and are common for other neurological conditions, including Nasu-Hakola disease (NHD) and AD, making diagnosis and treatment of ALSP very difficult.
  • NBD Nasu-Hakola disease
  • ALSP is a Mendelian disorder in which patients carry a heterozygous loss of function mutation in the kinase domain of CSF1R, suggesting a reduced level of signaling on the macrophage colony-stimulating factor (M-CSF) / CSF1R axis (Rademakers et al, Nat Genet 2012; Konno et al, Neurology 2018).
  • M-CSF macrophage colony-stimulating factor
  • the present invention 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 invention provides 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 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
  • the invention provides 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 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 neurodegeneration
  • the invention provides 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 for use in the preparation of a medicament for treating or preventing a condition associated with dysfunction of CSF1R.
  • the invention provides 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 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 microglia,
  • the invention provides a method of treating or preventing a disease or disorder associated with dysfunction of CSF1R 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.
  • the subject is selected for treatment based on a diagnosis that includes the presence of a mutation in a CSF1R gene affecting the function of CSF1R.
  • the mutation in the CSF1R gene is a mutation that causes a decrease in CSF1R activity or a cessation of CSF1R activity.
  • 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 csf1r gene. In some embodiments, the disease or disorder is caused by a missense mutation in the csf1r 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 disease or disorder is caused by a loss-of-function mutation in CSF1R.
  • the loss-of-function mutation results in a complete cessation of CSF1R function.
  • the loss-of-function mutation results in a partial loss of CSF1R function, or a decrease in CSF1R activity.
  • the invention 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 invention 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
  • ABCD1 [0194] The ABCD1 gene 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 invention 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.
  • 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 invention 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.
  • the invention provides 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 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 invention provides 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 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 Metachromatic leukodystrophy
  • CADASIL Cerebral autosomal dominant arteri
  • the invention provides 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 for use in the preparation of a medicament for treating or preventing a condition associated with dysfunction of ABCD1.
  • the invention provides 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 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 leukodystrophy
  • MLD Metachromatic leukodystrophy
  • CADASIL Cerebral
  • the invention 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, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said 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. In some embodiments, the disease or disorder is caused by a homozygous ABCD1 mutation. In some embodiments, the disease or disorder is caused by a splice mutation in the ABCD1 gene. In some embodiments, the disease or disorder is caused by a missense mutation in the ABCD1 gene. In some embodiments, the disease or disorder is a disease or disorder resulting from a change (e.g. increase, decrease or cessation) in the activity of ABCD1. In some embodiments, 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 ABCD1.
  • the disease or disorder is a neurodegenerative disorder.
  • the disease or disorder is a neurodegenerative disorder caused by and/or associated with an ABCD1 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 invention 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, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.
  • x-ALD Globoid cell leukodystrophy
  • MLD
  • any of the aforementioned diseases are present in a patient exhibiting ABCD1 dysfunction or having a mutation in a gene affecting the function of ABCD1.
  • 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 ABCD1.
  • the invention 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, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.
  • ALS amyotrophic lateral sclerosis
  • 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 invention relates to the unexpected discovery that activation of TREM2, using a compound of the present invention, 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, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said 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, 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 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, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said 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, or a pharmaceutically acceptable salt thereof 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 or a pharmaceutically acceptable salt thereof 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.
  • agents the combinations of this disclosure may also be combined with include, without limitation: treatments for Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu- Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.
  • 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 comprising a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents.
  • the therapeutic agent may be administered together with a provided compound or a pharmaceutically acceptable salt thereof, or may be administered prior to or following administration of a provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below.
  • a provided compound or a pharmaceutically acceptable salt thereof 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 or a pharmaceutically acceptable salt thereof 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.
  • Stereoisomers 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.
  • double-bond isomers i.e., geometric isomers (E/Z)
  • enantiomers e.e., 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 (1R,2R)-1-methyl-2-(trifluoromethyl)cyclohexane and (1R,2S)-1-methyl-2- (trifluoromethyl)cyclohexane.
  • 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.
  • This disclosure also encompasses the pharmaceutical 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. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents.
  • 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 [0226] 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.” [0228] 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 [0229] This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.
  • aliphatic or “aliphatic group”, as used herein, 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, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1 to 6 aliphatic carbon atoms.
  • aliphatic groups contain 1 to 5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 to 4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1 to 3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1 to 2 aliphatic carbon atoms.
  • “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C 3 -C 6 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 aliphatic 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.
  • the term “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.
  • 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.
  • 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 aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include: [0233]
  • Exemplary bridged bicyclics include: [0234]
  • the term “lower alkyl” refers to a C 1-4 straight or branched alkyl group.
  • lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C1-4 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.
  • alkylene refers to a bivalent alkyl group.
  • 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 aliphatic 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 aliphatic group.
  • halogen means F, Cl, Br, or I.
  • 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. Also included within the scope of the term “aryl,” as it is used herein, 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, cycloaliphatic, 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.
  • heterocycle As used herein, 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 includes a substituted nitrogen.
  • a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen.
  • 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 cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be monocyclic or bicyclic, bridged bicyclic, or spirocyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • 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.
  • Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH 2 ) 0–6 R ⁇ ; –(CH 2 ) 0–6 OR ⁇ ; –O(CH 2 ) 0–6 R o , –O–(CH 2 ) 0–6 C(O)OR°; – (CH 2 ) 0–6 CH(OR ⁇ ) 2 ; –(CH 2 ) 0–6 SR ⁇ ; –(CH 2 ) 0–6 Ph, which Ph may be substituted with R°; –(CH 2 ) 0–46 O(CH 2 ) 0– 1Ph which Ph may be substituted with R°; –
  • Suitable monovalent substituents on R ⁇ are independently halogen, –(CH2)0–2R ⁇ , – (haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 ; -O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , – (CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , –(CH 2 ) 0–
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, wherein each independent occurrence of R * is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, and an unsubstituted 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • Suitable substituents on the aliphatic group of R * include halogen, –R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or –NO2, wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include — R ⁇ , –NR ⁇ , –C(O)R ⁇ , –C(O) ⁇ ⁇ ⁇ ⁇ ⁇ 2 OR , –C(O)C(O)R , –C(O)CH2C(O)R , -S(O)2R , -S(O)2NR 2, –C(S)NR 2, – C(NH)NR ⁇ 2, or –N(R ⁇ )S(O)2R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or, notwithstanding the definition above, two independent
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R ⁇ , -(haloR ⁇ ), – OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or -NO2, wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5 to 6–membered saturated, partially unsaturated, or aryl ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur).
  • the term “provided compound” or “compound of the present disclosure” refers to any genus, subgenus, and/or species set forth herein.
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, which is incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
  • suitable inorganic and organic acids and bases include those derived from suitable inorganic and organic acids and bases.
  • pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.
  • patient and “subject” as used herein refer 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.
  • compositions of this disclosure refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxyprop
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily or degratorily active metabolite or residue thereof.
  • the terms “C 1- 3alkyl,” “C 1-5 alkyl,” and “C 1-6 alkyl” as used herein refer to a straight or branched chain hydrocarbon containing from 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively.
  • C1-3alkyl, C1-5alky, or C1-6alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • C2-4alkenyl 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.
  • C2-4alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.
  • C3-6cycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbon atoms.
  • Representative examples of C3-5cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • diC1-3alkylamino as used herein refer to –NR*R**, wherein R* and R** independently represent a C1-3alkyl as defined herein.
  • 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.
  • Representative examples of C 1-3 alkoxy or C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.
  • 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 C 6 heterocycloalkyl, 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.
  • pharmaceutically acceptable 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.
  • diluents colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
  • diluents as used herein 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 disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that 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 compounds of Formula (I) can be synthesized according to the following schemes. Any variables used in the following scheme are the variables as defined for Formula (I), unless otherwise noted. All starting materials are either commercially available, for example, from Merck Sigma-Aldrich Inc. and Enamine Ltd. or known in the art and may be synthesized by employing known procedures using ordinary skill.
  • Z is a leaving group, which can include but is not limited to, halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
  • Y is an organometal coupling reagent group, which can include but are not limited to, boronic acids and esters, organotin and organozinc reagents.
  • Condition A Column: Phenomenex luna C18150*25mm* 10 ⁇ m; Mobile Phase A: MeCN, Mobile Phase B: H 2 O (0.1% FA); Flow rate: 25 mL/min; Gradient 1: 48% B- 68% B in 10 min; Gradient 2: 80% B to 100% B in 9 min; Gradient 3: 0% B to 60% B; Gradient 4: 70% B to 100% B in 7 min; Gradient 5: 65% B to 95% B in 12 min; [0283] Condition B: Column: YMC-Gel SiL-HG 250mm*70mm*10 ⁇ m; Mobile Phase A: Hexanes, Mobile Phase B: EtOH (0.1% FA); [0284] Condition C: Column: Phenomenex luna C18250*50mm*10 ⁇ m; Mobile Phase A: MeCN, Mobile Phase B: H 2 O (0.225% FA); Flow rate: 25 mL/min; Gradient 1: 65% B- 90% B in 22 min; [0285] Condition D: Column:
  • Flash Chromatography Method [0287] 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).
  • Condition A Column: Chiralpak AD-350*4.6mm I.D., 3 ⁇ m; Mobile Phase A: CO2, Mobile Phase B: EtOH(0.05%DEA); Flow rate: 3mL/min; Gradient 1: 40% B to 40% B, Back Pressure: 100 Bar; Gradient 2: 40% B to 40% B in 23 min; [0291] Condition B: Column: Chiralpak IC (250mm*30mm,10 ⁇ m); Mobile Phase A: CO2, Mobile Phase B: MeCN/MeOH (0.1% NH3H2O); Flow rate: 120 mL/min; Gradient 1: 60% B to 60% B in 2.84 min; [0292] Condition C: Column: ChiralpakAD (250mm*30mm,10 ⁇ m; Mobile Phase A: CO2, Mobile Phase B: iPrOH (0.1% NH 3 H 2 O); Flow rate: 120 mL/min; Gradient 1: 60% B to 60% B in 5 min; [0293] Condition D: Column: Chiralpak AD (250mm*30mm,10 ⁇ m; Mobile Phase A
  • 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.
  • Proton NMR Spectra [0298] Unless otherwise indicated, all 1 H NMR spectra were collected on a Bruker NMR Instrument at 300, 400 or 500 Mhz or a Varian NMR Instrument at 400 Mhz.
  • Step 2 To a solution of ethyl 2-methyl-4-(trifluoromethylsulfonyloxy)thiazole-5-carboxylate (Int-B1, 1 eq, 6.7 g, 21 mmol) in 1,4-dioxane (80 mL) was added benzylurea (1.1 eq, 3467 mg, 23 mmol), Cs 2 CO 3 (2 eq, 13640 mg, 42 mmol), XantPhos (0.05 eq, 607 mg, 1.05 mmol) and Pd 2 (dba) 3 (0.025 eq, 480 mg, 0.53 mmol), the mixture was stirred at 60°C for 12h.
  • benzylurea 1.1 eq, 3467 mg, 23 mmol
  • Cs 2 CO 3 (2 eq, 13640 mg, 42 mmol
  • XantPhos 0.05 eq, 607 mg, 1.05 mmol
  • Pd 2 (dba) 3
  • Step 3 To a solution of 6-benzyl-2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione (Int-B2, 1 eq, 1.4 g, 5.1 mmol) in m-Xylene (20 mL) was added BBr 3 (4 eq, 1.9 mL, 21 mmol) at 25 °C, the mixture was stirred at 170 °C for 1h.
  • Step 4 To a solution of 2-methylthiazolo[4,5-d]pyrimidine-5,7-diol (Int-B3, 1 eq, 1 g, 5.5 mmol) in POCl3 (24 eq, 12 mL, 128 mmol) was added N,N-dimethylaniline (0.7 eq, 0.5 mL, 3.8 mmol), the mixture was stirred at 130 oC for 4 h. The reaction mixture was poured into water (1000 mL) and stirred at 30°C for 30 min.
  • Example 1 Synthesis of Compounds 100-101 [0306] Step 1: A mixture of 2-(benzylamino)ethanol (1 eq, 2000 mg, 13 mmol) and 2-chloro-1-(1- cyclopropylpyrazol-4-yl)ethanone (1 eq, 2442 mg, 13 mmol), KI (1 eq, 2196 mg, 13 mmol), K2CO3 (3 eq, 5484 mg, 40 mmol) in Acetone (30 mL) was stirred at 25°C for 16 h. LCMS showed desired product was detected. The reaction mixture was quenched by H2O (50 mL), extracted with EtOAc (2x100 mL).
  • Step 2 To a solution of 2-[benzyl(2-hydroxyethyl)amino]-1-(1-cyclopropylpyrazol-4- yl)ethanone (Int-A1, 1 eq, 2.4 g, 8 mmol) in MeOH (40 mL) was added NaBH 4 (2 eq, 0.6 g, 16 mmol) at 0°C. The mixture was stirred at 25°C for 1h. LCMS showed desired product was detected.
  • Step 3 A mixture of 2-[benzyl(2-hydroxyethyl)amino]-1-(1-cyclopropylpyrazol-4-yl)ethanol (Int-A2, 1 eq, 1800 mg, 6 mmol) in HCl/dioxane (13 eq, 19 mL, 75 mmol) was stirred at 100°C for 1 h. LCMS showed desired product was detected. The mixture was concentrated under reduced pressure to give the 4-benzyl-2-(1-cyclopropylpyrazol-4-yl)morpholine (Int-A3, 1500 mg, 5.3 mmol, 89% yield) as an oil that was used in the next step directly.
  • Step 4 To a solution of 4-benzyl-2-(1-cyclopropylpyrazol-4-yl)morpholine (Int-A3, 1 eq, 800 mg, 2.8 mmol) in MeOH (10 mL) was added Pd/C (0.13 eq, 400 mg, 0.38 mmol) under N2 atmosphere. The mixture was purged with H2 (3x) and stirred at 25°C under H2 (15 psi) atmosphere for 2 h. LCMS showed desired product was detected.
  • Step 5 To a solution of 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5- d]pyrimidin-2-amine (Int-A4, 1 eq, 100 mg, 0.3 mmol) in DMSO (3 mL) was added 2-(1- cyclopropylpyrazol-4-yl) morpholine (3.3 eq, 195 mg, 1 mmol) and DIPEA (5 eq, 0.3 mL, 1.5 mmol). The mixture was stirred at 100°C for 1h. LCMS showed desired product was detected.
  • Step 6 The residue was purified by SFC (Condition A, Gradient 1) and lyophilized to give the 5-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5- d]pyrimidin-2-amine (Compound 100, 51 mg, 0.11 mmol, 52% yield) as a solid and 5-[(2R)-2-(1- cyclopropylpyrazol-4-yl)morpholin-4-yl]-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin- 2-amine (Compound 101, 40 mg, 0.08 mmol, 39% yield) as a solid.
  • Example 2 Synthesis of Compound 102 [0312] Step 1: To a mixture of 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1 eq, 500 mg, 2 mmol), 2-[4-(difluoromethyl)-2-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 eq, 546 mg, 2 mmol) and K 3 PO 4 (3 eq, 1278 mg, 6 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(Amphos)Cl2 (0.1 eq, 142 mg, 0.2 mmol) at 25°C under N2 atmosphere.
  • Pd(Amphos)Cl2 0.1 eq, 142 mg, 0.2 mmol
  • Step 2 A mixture of 5-chloro-7-[4-(difluoromethyl)-2-fluoro-phenyl]-N,N-dimethyl- thiazolo[4,5-d]pyrimidin-2-amine (Int-A6, 1 eq, 50 mg, 0.14 mmol), (2S,6R)-2-(1-cyclopropylpyrazol-4- yl)-6-methyl-morpholine (2.5 eq, 72 mg, 0.35 mmol), and DIEA (5 eq, 90 mg, 0.7 mmol) in DMSO (2.5 mL) was stirred at 100 o C for 2 h. LCMS showed desired product. The reaction mixture was combined with the material for further purification.
  • Example 3 Synthesis of Compound 103 [0314] Step 1: To a solution of 5-chloro-7-[4-(difluoromethyl)-2-fluoro-phenyl]-N,N-dimethyl- thiazolo[4,5-d]pyrimidin-2-amine (Int-A6, 1 eq, 70 mg, 0.2 mmol), 1-cyclopropyl-4-[(6R)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (1.5 eq, 93 mg, 0.3 mmol) and K2CO3 (3 eq, 81 mg, 0.6 mmol) in 1,4-dioxane (3 mL) and water (0.6 mL) was added Pd(dppf)Cl2 ⁇ DCM (0.15 eq, 21 mg, 0.03 mmol) at 25 °C under N2.
  • reaction mixture was stirred at 80 o C for 20 h. LCMS showed desired product. Then the reaction mixture was combined with the crude product in Page: XZ-2022-04-048-64, the mixture was filtered through a pad of celite. The filter cake was washed with EtOAc (100 mL), the combined filtrates were diluted with water (100 mL), and then extracted with EtOAc (3x100 mL).
  • Step 2 To a solution of 5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-7- [4-(difluoromethyl)-2-fluoro-phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Int-A7, 1 eq, 70 mg, 0.14 mmol) in MeOH (5 mL) was added PtO2 (2 eq, 62 mg, 0.3 mmol). The reaction mixture was stirred at 40 o C for 24 h under H2 (50 Psi) atmosphere. LCMS showed desired product.
  • reaction mixture was filtered through a pad of celite, the filter cake was washed with EtOH (60 mL), and the filtrate was concentrated under reduced pressure to afford a residue.
  • EtOH 60 mL
  • the residue was combined with YH- 2022-06-049-49 to work up.
  • Step 1 To a solution of 1-bromo-4-chloro-2,5-difluoro-benzene (1 eq, 1000 mg, 4.4 mmol) in THF (15 mL) was added n-BuLi (2 eq, 3.5 mL, 8.8 mmol) dropwise at -78 o C, then mixture was stirred at -78 o C under N2 atmosphere for 0.5 h. Triisopropyl borate (1.5 eq, 1.5 mL, 6.6 mmol) was added at - 78 o C, then the mixture was warmed to 25°C and stirred for 1 h.
  • Step 2 To a solution of 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1 eq, 730 mg, 2.9 mmol) and (4-chloro-2,5-difluoro-phenyl)boronic acid (Int-A8, 1.3 eq, 733 mg, 3.8 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was added Pd(dppf)Cl2 ⁇ DCM (0.15 eq, 322 mg, 0.44 mmol), K2CO3 (3 eq, 1215 mg, 8.8 mmol), then the mixture was stirred at 80 o C for 4 h under N2.
  • Step 3 To a solution of 1-cyclopropyl-4-[(6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydro-2H-pyran-6-yl]pyrazole (1.1 eq, 424 mg, 1.3 mmol), 5-chloro-7-(4-chloro-2,5-difluoro- phenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Int-A9, 1 eq, 440 mg, 1.2 mmol), and K 2 CO 3 (3 eq, 505 mg, 3.7 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl 2 ⁇ DCM (0.1 eq, 89 mg, 0.12 mmol) at 25°C under N 2 .
  • Step 4 To a solution of 7-(4-chloro-2,5-difluoro-phenyl)-N,N-dimethyl-5-[rac-(6R)-6-(1- cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (Int-A10, 1 eq, 330 mg, 0.5 mmol) in MeOH (5 mL) was added PtO 2 (2 eq, 225 mg, 0.99 mmol).
  • reaction mixture was stirred at 40 o C for 16 h under H 2 (50 Psi) atmosphere.
  • LCMS showed desired product.
  • the reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel chromatography (0-100% EtOAc/PE) and reversed-phase HPLC (0.1% FA condition) to give 7-(4-chloro-2,5-difluoro-phenyl)-N,N-dimethyl-5-[rac-(2R)-2-(1- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (Int-A11, 80 mg, 0.16 mmol, 31% yield) as a solid.
  • Step 5 The racemate 7-(4-chloro-2,5-difluoro-phenyl)-N,N-dimethyl-5-[(2R)-2-(1-cyclopropyl pyrazol-4-yl)tetrahydropyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (Int-A11, 1 eq, 120 mg, 0.23 mmol) was separated by SFC (Condition B, Gradient 1) to afford two enantiomers (Compounds 105 and 106).
  • Example 5 Synthesis of Compounds 107-108 [0321] Step 1: To a solution of 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1 eq, 1000 mg, 4 mmol), (2,3,4-trifluorophenyl)boronic acid (1 eq, 706 mg, 4 mmol), and K3PO4 (3 eq, 2556 mg, 12 mmol) in Toluene (20 mL) and water (2 mL) was added Pd(Amphos)Cl2 (0.1 eq, 284 mg, 0.4 mmol) under N2, the solution was stirred at 80 °C for 2 h.
  • Pd(Amphos)Cl2 0.1 eq, 284 mg, 0.4 mmol
  • Step 2 To a solution of 5-chloro-N,N-dimethyl-7-(2,3,4-trifluorophenyl)thiazolo[4,5-d] pyrimidin-2-amine (Int-A12, 1 eq, 430 mg, 1.3 mmol) in 1,4-dioxane (22 mL) and water (2.2 mL) was added 1-cyclopropyl-4-[(6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6- yl]pyrazole (2.5 eq, 986 mg, 3.1 mmol), K 2 CO 3 (3 eq, 517 mg, 3.7
  • Step 3 To a solution of 5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]- N,N-dimethyl-7-(2,3,4-trifluorophenyl)thiazolo[4,5-d]pyrimidin-2-amine (Int-A13, 1 eq, 500 mg, 1 mmol) in MeOH (25 mL) and EtOAc (10 mL) was added PtO2 (2 eq, 455 mg, 2 mmol) under N2. The reaction mixture was stirred at 40°C for 12 h under H2 (50 psi) atmosphere.
  • Step 1 A mixture of 2-chlorothiazolo[4,5-d]pyrimidine-5,7-diol (1 eq, 1000 mg, 4.9 mmol) in DMSO (8 mL) was added (2R)-2-methylpyrrolidine (1 eq, 418 mg, 4.9 mmol) and DIEA (3 eq, 2.4 mL, 15 mmol), then stirred at 100°C for 1h. LCMS showed desired product.
  • Step 2 A mixture of 2-[(2R)-2-methylpyrrolidin-1-yl]thiazolo[4,5-d]pyrimidine-5,7-diol (Int- A14, 1 eq, 1100 mg, 4.4 mmol) in POCl3 (30 eq, 11 mL, 131 mmol), then stirred at 100°C for 12 h. LCMS showed desired product. The reaction mixture was concentrated under reduced pressure to give a crude residue that was partitioned between EtOAc (2x100 mL) and NaHCO3 (aq., 100 mL).
  • Step 3 A mixture of 5,7-dichloro-2-[(2R)-2-methylpyrrolidin-1-yl]thiazolo[4,5-d]pyrimidine (Int-A15, 1 eq, 1200 mg, 4.2 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was added (2,4- difluorophenyl)boronic acid (1 eq, 655 mg, 4.2 mmol), K3PO4 (3 eq, 2643 mg, 12.4 mmol) and PdCl2(amphos) (0.1 eq, 294 mg, 0.42 mmol), then stirred at 60 °C for 16 h under N2 atmosphere.
  • Step 4 A mixture of 5-chloro-7-(2,4-difluorophenyl)-2-[(2R)-2-methylpyrrolidin-1- yl]thiazolo[4,5-d]pyrimidine (Int-A16, 1 eq, 80 mg, 0.22 mmol) in DMSO (1 mL) was added (2S,6R)-2- (1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (2 eq, 90 mg, 0.44 mmol) and DIEA (3 eq, 0.11 mL, 0.66 mmol), then stirred at 100 °C for 2 h. LCMS showed desired product.
  • reaction mixture was adjusted to pH ⁇ 7 with formic acid, purified by prep-HPLC (Condition A, Gradient 2) to give 50 mg the YT-2022-04-030-37-1(90 purity) which was then purified by prep-TLC (50% EtOAc/PE) and lyophilized to give (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-(2,4-difluorophenyl)-2-((R)-2-methylpyrrolidin- 1-yl)thiazolo[4,5-d]pyrimidin-5-yl)-6-methylmorpholine (Compound 109, 29 mg, 0.05 mmol, 24% yield) as a solid.
  • Step 1 To a solution of 5,7-dichloro-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1 eq, 100 mg, 0.4 mmol), (2-fluoro-4-methyl-phenyl)boronic acid (1 eq, 62 mg, 0.4 mmol), and K 3 PO 4 (3 eq, 256 mg, 1.2 mmol) in toluene (2 mL) and water (0.2 mL) was added Pd(Amphos)Cl2 (0.1 eq, 28 mg, 0.04 mmol) under N2 atmosphere.
  • Step 2 To a solution of 5-chloro-7-(2-fluoro-4-methyl-phenyl)-N,N-dimethyl-thiazolo[4,5- d]pyrimidin-2-amine (Int-A17, 1 eq, 30 mg, 0.09 mmol) in DMSO (1 mL) was added (2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1 eq, 19 mg, 0.09 mmol) and DIEA (3 eq, 36 mg, 0.28 mmol). The mixture was stirred at 100 oC for 8 h, monitored by LCMS. LCMS showed starting material remained and 75% of desired product was detected.
  • Example 8 Synthesis of Compound 111 [0330] Step 1: A mixture of 5,7-dichlorothieno[3,2-b]pyridine (1 eq, 1000 mg, 4.9 mmol) in 1,4- dioxane (8mL) was added (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1 eq, 1016 mg, 4.9 mmol), Cs 2 CO 3 (3 eq, 4790 mg, 14.7 mmol), Pd(OAc) 2 (0.05 eq, 55 mg, 0.25 mmol), and dppf (0.1 eq, 272 mg, 0.5 mmol), then stirred at 100 °C for 12 h under N 2 atmosphere.
  • Step 2 A mixture of (2S,6R)-4-(7-chlorothieno[3,2-b]pyridin-5-yl)-2-(1-cyclopropylpyrazol-4- yl)-6-methyl-morpholine (Int-A18, 1 eq, 500 mg, 1.3 mmol) in THF (5 mL) and water (0.5 mL) was added (2,4-difluorophenyl)boronic acid (2 eq, 421 mg, 2.7 mmol), K3PO4 (3 eq, 849 mg, 4 mmol), Sphos-Pd-G3 (0.1 eq, 104 mg, 0.13 mmol), then stirred at 60 °C for 12 h under N2 atomsphere.
  • (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-4-[7-(2,4-difluorophenyl)thieno[3,2-b]pyridin-5- yl]-6-methyl-morpholine (Compound 111, 1 eq, 5.0 mg, 0.01 mmol) was purified by prep-TLC (33% EtOAc/PE) and lyophilized to give (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-(2,4-difluorophenyl) thieno[3,2-b]pyridin-5-yl)-6-methylmorpholine (2.5 mg, 0.005 mmol, 47% yield) as a solid.
  • Example 9 Synthesis of Compounds 113-114 [0332] Step 1: To a solution of 5-chloro-7-(2,4-difluorophenyl)-2-(methylthio)thiazolo[4,5- d]pyrimidine (1 eq, 300 mg, 0.77 mmol) and (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6- methylmorpholine (1.1 eq, 176 mg, 0.85 mmol) in DMSO (6 mL) was added DIEA (5 eq, 0.6 mL, 3.9 mmol) and stirred at 100 o C for 1 h. LCMS showed the starting material was consumed completely and desired product was detected.
  • DIEA 5 eq, 0.6 mL, 3.9 mmol
  • Step 2 To a solution of (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-(2,4-difluorophenyl)- 2-(methylthio)thiazolo[4,5-d]pyrimidin-5-yl)-6-methylmorpholine (1 eq, 170 mg, 0.34 mmol) and Pd(dppf)Cl2 ⁇ DCM (0.2 eq, 50 mg, 0.07 mmol) in dry THF (3 mL) under N2 was added isopropylzinc(II) chloride (15 eq, 16 mL, 5.1 mmol) under N2.
  • reaction mixture was stirred at 80 o C for 2 h. LCMS showed that the starting material was consumed completely and 21% of the desired mass was detected.
  • the reaction mixture with HW-2022-05-053-30 was quenched with the addition of H2O (50 mL) at 0°C, extracted with EtOAc (2x30 mL).
  • Example 10 Synthesis of Compounds 115-116 [0334] Step 1: Zinc (3 eq, 919 mg, 14 mmol) was suspened in LiCl (0.5 M in THF) (1 eq, 9.0 mL, 4.7 mmol), 1,2-dibromoethane (0.05 eq, 0.02 mL, 0.23 mmol) was added and the suspension was stirred at 55°C for 20 min. The reaction was cooled to room temperature, then TMSCl (0.05 eq, 0.03 mL, 0.23 mmol) was introduced and the mixture was stirred for another 20 min.
  • LiCl 0.5 M in THF
  • 1,2-dibromoethane 0.05 eq, 0.02 mL, 0.23 mmol
  • Step 2 To a suspension of C-Phos (0.05 eq, 40 mg, 0.09 mmol) and 5-chloro-7-(2,4- difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1 eq, 600 mg, 1.8 mmol) in THF (5 mL) (99.5%, dried over Molecular Sieves) was added Pd(OAc) 2 (0.1 eq, 41 mg, 0.18 mmol).
  • Step 2 To a solution of [5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]- 7-[2-fluoro-4-(trifluoromethyl)phenyl]thiazolo[4,5-d]pyrimidin-2-yl]hydrazine (Int-A21, 1 eq, 90 mg, 0.17 mmol) in DCE (3 mL) was added SOCl 2 (5 eq, 100 mg, 0.84 mmol) and then stirred for 16 h at 25 °C. LCMS showed raw material was consumed and the major peak showed desired.
  • Step 3 To a solution of (2S,6R)-4-[2-chloro-7-[2-fluoro-4- (trifluoromethyl)phenyl]thiazolo[4,5-d]pyrimidin-5-yl]-2-(1-cyclopropylpyrazol-4-yl)-6-methyl- morpholine (Int-A22, 1 eq, 60 mg, 0.11 mmol) and NaOiPr (2 eq, 18 mg, 0.2 mmol) (powder) in the Isopropanol (1 mL) (extra dry) and then stirred for 1 h at 25°C.
  • Example 12 Synthesis of Compounds 119-122 [0339] Step 1: Zinc (3 eq, 865 mg, 13 mmol) was suspended in LiCl (0.5 M in THF) (1 eq, 9.0 mL, 4.4 mmol), 1,2-Dibromoethane (0.05 eq, 0.02 mL, 0.22 mmol) was added and the suspension was stirred at 55 °C for 20 min. Cooled down, then TMSCl (0.05 eq, 0.03 mL, 0.22 mmol) was introduced and the mixture was stirred for another 20 min.
  • LiCl 0.5 M in THF
  • 1,2-Dibromoethane 0.05 eq, 0.02 mL, 0.22 mmol
  • TMSCl 0.05 eq, 0.03 mL, 0.22 mmol
  • Step 2 To a suspension of Cphos (0.1 eq, 80 mg, 0.18 mmol), Pd(OAc) 2 (0.05 eq, 21 mg, 0.09 mmol) and 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1 eq, 600 mg, 1.8 mmol) in THF (6 mL) was purged with N 2 (x4), bromo-[2-(1-methyl-6-oxo-3- pyridyl)tetrahydropyran-4-yl]zinc (Int-A23, 1.2 eq, 744 mg, 2.2 mmol) was added and stirred at 55 °C for 2 h.
  • Step 3 1-methyl-5-[rac-(2R,4S)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5-d]- pyrimidin-5-yl]tetrahydropyran-2-yl]pyridin-2-one (Int-A24a, 150 mg) was purified with SFC (Condition E, Gradient 1), evaporated under reduced pressure to give crude P1 (60 mg) and crude P2(60 mg).
  • Example 13 Synthesis of Compound 123 [0342] Step 1: A solution of (2R,6S)-2-methyl-6-(2-methyl-4-pyridyl) morpholine (1 eq, 40 mg, 0.042 mmol) and 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (1.1 eq, 15 mg, 0.046 mmol) in DMSO (1 mL) was added DIEA (5 eq, 27 mg, 0.21 mmol), then stirred at 100 °C for 1 h. LCMS showed 2% of desired mass. The reaction mixture was extracted with EtOAc (3x20 mL).
  • Example 14 Synthesis of Compounds 124-125 [0343] Step 1: In a flame dried 10 mL microwave vial, (2R)-2-methylpyrrolidine;hydrochloride (2.5 eq, 32 mg, 0.27 mmol) and DIPEA (5.4 eq, 100 uL, 0.57 mmol) were added to a stirring solution of 8- chloro-2-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6-(2,4-difluorophenyl)-7-methyl- purine (Int-A25, 1 eq, 50 mg, 0.11 mmol) in DMSO (1.25 mL).
  • Example 15 Synthesis of Compound 126 [0344] Step 1: NaH (60% dispersion in mineral oil) (2 eq., 0.88 g, 22 mmol) was added to a solution of 2,6-dichloro-9H-purine (1 eq, 2.0 g, 11 mmol) in DMF (40 mL) at 0 °C. The reaction mixture was stirred for 30 min at room temperature and re-cooled to 0 °C, followed by the addition of SEM-Cl (1.5 eq, 2.9 mL, 16.5 mmol). The reaction was then stirred at room temperature of 1 h, at which point the reaction was judged complete by LC-MS.
  • the reaction mixture was cooled to 0 °C and was carefully quenched with the drop-wise addition of a saturated aqueous solution of NH 4 Cl (100 mL).
  • the mixture was warmed to room temperature and extracted with EtOAc (3x100 mL).
  • the combined extracts were washed with brine (3x50 mL), dried over MgSO 4 and filtered via vacuum filtration.
  • the solvents were removed under reduced pressure and the residue was directly purified by flash chromatography (5-40% EtOAc/Hexanes).
  • Step 2 A round-bottom flask equipped with a Teflon-coated magnetic stirring bar was charged with 2,6-dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (Int-A26, 1 eq, 1.95 g, 5.7 mmol), [2- fluoro-4-(trifluoromethyl)phenyl]boronic acid (1.01 eq, 1.2 g, 5.7 mmol), K2CO3 (3 eq, 2.4 g, 17 mmol) and Pd(dppf)Cl2 (0.05 eq, 208 mg, 0.28 mmol).
  • the flask was sealed, purged under Argon and supplemented with 1,4-dioxane (24 mL) and water (6 mL).
  • the resulting solution was degassed under Ar for 5 min and heated to 85 °C with stirring. After 16 h, the reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL). The resulting solution was washed with water and brine. The organic layer was collected, dried over anhydrous Na2SO4, filtered via vacuum filtration, and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography (10-30% EtOAc/Hexanes).
  • Step 3 A flame-dried round-bottomed flask equipped with a Teflon-coated magnetic stirring bar was charged with 2-chloro-6-(2-fluoro-4-(trifluoromethyl)phenyl)-9-((2- (trimethylsilyl)ethoxy)methyl)-9H-purine (Int-A27, 1 eq, 894 mg, 2 mmol), (2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.5 eq, 622 mg, 3 mmol) and anhydrous DMSO (10 mL).
  • the flask was sealed, purged under Ar and supplemented with DIPEA (3 eq, 1.0 mL, 6 mmol) while stirring at room temperature.
  • the reaction mixture was heated to 100 °C with stirring for 6 h, at which point the reaction was judged complete by LC-MS.
  • the reaction mixture was cooled to room temperature and diluted with EtOAc (100 mL).
  • the resulting solution was washed with aqueous saturated NH4Cl and brine.
  • the organic layer was collected, dried over anhydrous Na2SO4, filtered via vacuum filtration, and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography (20-50% EtOAc/Hexanes).
  • Step 4 A flame-dried round-bottomed flask equipped with a Teflon-coated magnetic stirring bar was charged with (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(6-(2-fluoro-4- (trifluoromethyl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)-6-methylmorpholine (Int- A28, 1 eq, 775 mg, 1.25 mmol), sealed, and purged under Ar.
  • Step 5 A flame dried microwave vial equipped with a Teflon-coated magnetic stirring bar was purged under Ar and charged with (2S,6R)-4-(8-bromo-6-(2-fluoro-4-(trifluoromethyl)phenyl)-9-((2- (trimethylsilyl)ethoxy)methyl)-9H-purin-2-yl)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (Int-A29, 1 eq, 320 mg, 0.46 mmol), anhydrous DMSO (5 mL), DIPEA (3 eq, 0.24 mL, 1.4 mmol) and dimethylamine (2.0 M in THF) (1.5 eq, 0.34 mL, 0.69 mmol).
  • the vial was sealed and irradiated in a microwave at 120 °C for 45 min.
  • the reaction was judged complete by LC-MS, cooled to room temperature, and diluted with EtOAc (100 mL).
  • the resulting solution was washed with aqueous sat. NH4Cl and brine.
  • the organic layer was collected, dried over anhydrous Na2SO4, filtered via vacuum filtration, and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography (20-40% EtOAc/Hexanes).
  • Step 6 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-6-(2-fluoro-4- (trifluoromethyl)phenyl)-N,N-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-8-amine (Int-A30, 1 eq, 291 mg, 0.42 mmol) was dissolved in TFA (310 eq, 10 mL, 130 mmol) at room temperature and stirred vigorously for 16 h. The reaction was judged complete by LC-MS and was concentrated under reduced pressure.
  • Step 1 To a solution of Int-A31 (1 eq, 50 mg, 0.1 mmol) and zinc difluoromethanesulfinate (2.7 eq, 82 mg, 0.28 mmol) in ⁇ , ⁇ , ⁇ -trifluorotoluene (1 mL) and Water (0.4 mL), was added TFA (1 eq, 79 ⁇ L, 0.10 mmol) followed by slow addition of tert-butyl hydroperoxide (5 eq, 50 ⁇ L, 50 mmol).
  • the reaction mixture was stirred with vigorous stirring at room temperature for 16 h, then the reaction was partitioned between CH2Cl2 (2.0 mL) and sat. NaHCO3 (2.0 mL). The organic layer was collected, and the aqueous layer was extracted with CH2Cl2 (3x2 mL). The combined organic phase was washed with brine, dried over MgSO4, and filtered and the solvents were removed under reduced pressure.
  • the crude material was purified by flash chromatography (0-100% EtOAc/DCM). The selected fractions were evaporated to provide Compound 127 as a mixture of diastereoisomers (40.4 mg, d.r.2:1).
  • Example 17 Synthesis of Compounds 128-129 [0351]
  • Step 1 In a flame dried 10 mL microwave vial, 2-[(2R,4S)-2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimidine-4,5-diamine (Int- A32, 1 eq, 150 mg, 0.35 mmol) was dissolved in DCE (2 mL).
  • Step 2 To a 20 mL round bottom flask equipped with a stir bar was added 2-[(2R,4S)-2-(1- cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-N,N-dimethyl-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1] pentanyl]-7H-purin-8-amine (Compound 129, 1 eq, 40 mg, 0.08 mmol) and MeMgCl (1.1 eq, 30 uL, 0.09 mmol) at room temperature in THF (2.0 mL). The mixture was stirred at room temperature for 30 minutes.
  • Example 18 Synthesis of Compound 130 [0353] Step 1: To a solution of 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-6-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimidine-4,5-diamine (Int-A33, 1 eq, 120 mg, 0.27 mmol) and iodomethane (1.1 eq, 18 uL, 0.29 mmol) in DMF (2 mL) was added potassium carbonate (2 eq, 74 mg, 0.53 mmol) at 0 °C.
  • the resulting mixture was stirred at room temperature for 3 h under argon atmosphere.
  • the mixture was transferred into a separatory funnel and partitioned between the saturated solution of brine (20 mL) and EtOAc (20 mL).
  • the organic layer was washed with brine (30 mL), dried with Na2SO4, filtered, and concentrated.
  • the obtained solid was purified by reverse phase purification (10-45% MeCN in 10 mM aqueous AMF).
  • Step 2 To a solution of 2-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]- N5-methyl-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimidine-4,5-diamine (Int-A34, 1 eq, 90 mg, 0.194 mmol) in DCE (2 mL) was added DIPEA (3 eq, 101 uL, 0.58 mmol) followed by dichloromethylene(dimethyl)ammonium;chloride (1.3 eq, 41 mg, 0.25 mmol) and the resulting mixture was refluxed for 3 h.
  • Step 1 To a solution of 5,7-dichloro-[1,2,4]triazolo[1,5-a]pyrimidine (1 eq, 0.21 g, 1.13 mmol) in 1,4-dioxane (6 mL) was added (2,4-difluorophenyl)boronic acid (1.2 eq, 215 mg, 1.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.05 eq, 46 mg, 0.06 mmol) and Na2CO3 (2M in water) (3 eq, 1.7 mL, 3.4 mmol).
  • Step 2 To a solution of 5-chloro-7-(2,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidine (Int- A35, 1 eq, 100 mg, 0.094 mmol) in THF (1 mL) was added (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6- methyl-morpholine (1.1 eq, 21 mg, 0.1 mmol) and DIPEA (1.5 eq, 0.024 mL, 0.14 mmol). The reaction was stirred at 80 °C for 16 h. After completion, the reaction was cooled down to room temperature and diluted with EtOAc.
  • Step 3 To a -78 °C solution of (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-4-[7-(2,4- difluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-6-methyl-morpholine (Compound 131, 1 eq, 15 mg, 0.03 mmol) in THF (0.5 mL) was added n-BuLi (2.5M in hexanes, 1.2 eq, 0.016 mL, 0.041 mmol).
  • the reaction mixture was degassed for 5 minutes under N2 and Pd(PPh3)4 (0.3 eq, 811 mg, 0.7 mmol), and copper(I) thiophene-2-carboxylate (2 eq, 892 mg, 4.7 mmol) were introduced.
  • the vial was degassed, and sealed and the mixture was stirred at 100 °C overnight.
  • the obtained product was quenched with water (20 mL).
  • the organic phase was extracted with EtOAc, washed with brine, dried with Na2SO4, and concentrated.
  • the crude material was purified by flash chromatography (0-10% DCM/EtOAc).
  • Step 2 To a solution of 7-chloro-5-[2-fluoro-4-(trifluoromethyl)phenyl]-2-methyl-imidazo[1,2- c]pyrimidine (Int-A36, 1 eq, 100 mg, 0.3 mmol) in 1,4-dioxane (3 mL) was added 1-cyclopropyl-4-[(6R)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole (1.1 eq, 106 mg, 0.33 mmol) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.05 eq, 12 mg, 0.015 mmol) and Na 2 CO 3 (2M in water, 3 eq, 0.45 mL, 0.91 mmol).
  • Step 3 To a solution of 7-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5- [2-fluoro-4-(trifluoromethyl)phenyl]-2-methyl-imidazo[1,2-c]pyrimidine (Int-A37, 1 eq, 75 mg, 0.16 mmol) in EtOH (2 mL), was added, under an argon atmosphere, PtO2 (0.8 eq, 28 mg, 0.124 mmol). The mixture was purged with hydrogen and stirred overnight under H2. The mixture was then purged with Argon and filtered through a pad of Celite and concentrated under reduced pressure.
  • Step 1 To a room temperature solution of 7-chloro-2-methyl-5-methylsulfanyl-imidazo[1,2- c]pyrimidine (1 eq, 400 mg, 1.9 mmol) and (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.1 eq, 427 mg, 2.1 mmol) in 1,4-dioxane (8 mL) was added Cs 2 CO 3 (3 eq, 1830 mg, 5.6 mmol) and XantPhos Pd G3 (0.1 eq, 161 mg, 0.19 mmol).
  • Step 2 To a degassed solution of (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-4-(2-methyl- 5-methylsulfanyl-imidazo[1,2-c]pyrimidin-7-yl)morpholine (Int-A38, 1 eq, 122 mg, 0.32 mmol) and chloro-(4-chloro-2-fluoro-phenyl)zinc (0.17M in THF, 2 eq, 3.8 mL, 0.64 mmol) in MeCN (3 mL) was added PEPPSITM-SIPr (0.2 eq, 73 mg, 0.064 mmol).
  • Step 1 A solution of 4,6-dichloro-2-methyl-3H-pyrrolo[3,4-c]pyridin-1-one (1 eq, 750 mg, 3.46 mmol), 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane (1 eq, 954 mg, 3.46 mmol) and Cs2CO3 (2 eq, 2252 mg, 6.91 mmol) in 1,4-Dioxane (15 mL)/Water (1.5 mL) was added Pd(dppf)Cl2 ⁇ DCM (0.1 eq, 280 mg, 0.346 mmol) under N2 atmosphere.
  • Step 2 A mixture of 6-chloro-2-methyl-4-[4-(trifluoromethyl)cyclohexen-1-yl]-3H- pyrrolo[3,4-c]pyridin-1-one (Int-A39, 1 eq, 450 mg, 1.36 mmol), (2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.5 eq, 423 mg, 2.04 mmol), Brettphos-Pd-G3 (0.1 eq, 123 mg, 0.136 mmol) and t-BuONa (3 eq, 392 mg, 4.08 mmol) in 1,4-Dioxane (18 mL) was stirred at 80 °C for 2 hours.
  • Step 3 To a solution of 6-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin- 4-yl]-2-methyl-4-[4-(trifluoromethyl)cyclohexen-1-yl]-3H-pyrrolo[3,4-c]pyridin-1-one (Int-A40, 1 eq, 100 mg, 0.199 mmol) in Methanol (2 mL) was added PtO2 (1 eq, 45 mg, 0.199 mmol) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times.
  • Step 1 A solution of ethyl 2,6-dichloro-3-methyl-pyridine-4-carboxylate (1 eq, 3000 mg, 12.8 mmol) in Carbon tetrachloride (72 mL) was added NBS (1 eq, 2281 mg, 12.8 mmol), BPO (0.05 eq, 155 mg, 0.641 mmol). The solution was stirred at 80 °C for 4 h. LCMS showed 30% of the starting material was still remained.
  • Step 2 A solution of ethyl 3-(bromomethyl)-2,6-dichloro-pyridine-4-carboxylate (Int- A41, 1 eq, 3900 mg, 12.5 mmol) in THF (30 mL) was added ammonium hydroxide (1 eq, 7.5 mL, 12.5 mmol) and the solution was stirred at 25 o C for 2 h.
  • ESI-MS (m/z+): 202.9 [M+H] + showed 81% of desired product.
  • the reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 3 A solution of 4,6-dichloro-2,3-dihydropyrrolo[3,4-c]pyridin-1-one (Int-A42, 1 eq, 1000 mg, 4.93 mmol), [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (1 eq, 1024 mg, 4.93 mmol) and Cs2CO3 (2 eq, 3.21 g, 9.85 mmol) in 1,4-Dioxane (10 mL) / Water (1 mL) was added Pd(dppf)Cl2 ⁇ DCM (0.1 eq, 399 mg, 0.493 mmol) under N2 atmosphere.
  • Step 4 A solution of 6-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3- dihydropyrrolo[3,4-c]pyridin-1-one (Int-A43, 1 eq, 400 mg, 1.21 mmol) in 1,4-Dioxane (10 mL) was added 3-iodo-1-methyl-pyrazole (1.5 eq, 377 mg, 1.81 mmol), K2CO3 (3 eq, 502 mg, 3.63 mmol), DMEDA (0.6 eq, 64 mg, 0.726 mmol), CuI (0.5 eq, 115 mg, 0.605 mmol) and KI (2 eq, 402 mg, 2.42 mmol), then the mixture was stirred at 100 °C under N2 atmosphere for 12 h.
  • Step 5 A mixture of 6-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-2-(1- methylpyrazol-3-yl)-3H-pyrrolo[3,4-c]pyridin-1-one (Int-A44, 1 eq, 70 mg, 0.170 mmol) in 1,4- Dioxane (4 mL) was added (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1 eq, 35 mg, 0.170 mmol), Cs2CO3 (3 eq, 167 mg, 0.511 mmol) and SPhos Pd G3 (0.1 eq, 12 mg, 0.0170 mmol), then stirred at 90 °C for 12 h under N2 atmosphere.
  • 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 [0371] 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% CO2 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.
  • Compounds designated as “B” demonstrated an EC50 > 0.05 ⁇ M and ⁇ 0.5 ⁇ M.
  • Compounds designated as “C” demonstrated an EC50 > 0.5 ⁇ M and ⁇ 3.0 ⁇ M.
  • Compounds designated as “D” demonstrated an EC50 > 3.0 ⁇ M and ⁇ 100 ⁇ M.
  • Compounds designated as “ -” had not been tested as of the filing of the present application, but can be tested using the methods described herein.
  • hTREM2 EC50 Data (HEK293 Cells) Cmpd hTREM2 No. EC50 ⁇ M 100 A 101 B 102 A 103 B 104 B 105 A 106 D 107 A 108 B 109 A 110 A 111 C 112 A 113 A 114 A 115 C 116 A 117 B Table D-2.
  • hTREM2 EC50 Data (HEK293 Cells) Cmpd hTREM2 No.

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Abstract

La présente invention concerne des composés utiles pour l'activation du récepteur de déclenchement exprimé sur des cellules myéloïdes 2 ("TREM2"). La présente invention concerne également des compositions pharmaceutiques comprenant les composés, des utilisations des composés, et des compositions pour le traitement, par exemple, d'un trouble neurodégénératif. En outre, l'invention concerne des intermédiaires utiles dans la synthèse de composés de formule (I).
PCT/US2024/028689 2023-05-10 2024-05-09 Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation Pending WO2024233848A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025157993A1 (fr) * 2024-01-24 2025-07-31 Muna Therapeutics Aps Modulateurs de trem2
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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US20120142673A1 (en) * 2006-08-23 2012-06-07 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
WO2022236272A2 (fr) * 2021-05-04 2022-11-10 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation
US20230002390A1 (en) * 2020-05-04 2023-01-05 Amgen Inc. Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use

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Publication number Priority date Publication date Assignee Title
US20120142673A1 (en) * 2006-08-23 2012-06-07 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
US20230002390A1 (en) * 2020-05-04 2023-01-05 Amgen Inc. Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use
WO2022236272A2 (fr) * 2021-05-04 2022-11-10 Vigil Neuroscience, Inc. Composés hétérocycliques utilisés en tant que récepteur de déclenchement exprimé sur des agonistes de cellules myéloïdes 2 et procédés d'utilisation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2025157993A1 (fr) * 2024-01-24 2025-07-31 Muna Therapeutics Aps Modulateurs de trem2

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