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WO2024233848A1 - Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use - Google Patents

Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use 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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PCT/US2024/028689
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French (fr)
Inventor
Jonathan B. Houze
Bhaumik PANDYA
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Vigil Neuroscience, Inc.
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Publication of WO2024233848A1 publication Critical patent/WO2024233848A1/en

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  • 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.

Abstract

The present disclosure provides compounds useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 ("TREM2"). This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a neurodegenerative disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula (I).

Description

HETEROCYCLIC COMPOUNDS AS TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2 AGONISTS AND METHODS OF USE CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims priority benefit of U.S. Provisional Patent Application No. 63/501,386 filed May 10, 2023, which is hereby incorporated by reference in its entirety. FIELD [0002] The present disclosure provides compounds useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 (“TREM2”). This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a neurodegenerative disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula I. BACKGROUND [0003] 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. 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). [0004] The plasticity of microglia and their diverse states as described through single-cells RNASeq profiling are thought to arise through the integration of signaling from a diverse array of cell surface receptors (Hickman et al. Nat Neurosci 2013). 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. Doens and Fernandez 2014, Madry and Attwell 2015, Hickman and El Khoury 2019. Similar to other cells of the myeloid lineage, the composition of microglial sensomes is dynamically regulated and acts to recognize molecular pattern that direct phenotypic responses to homeostatic changes in the central nervous system (“CNS”). Id. One of the receptors selectively expressed by brain microglia is TREM2, composed of a single-pass transmembrane domain, an extracellular stalk region, and extracellular immunoglobulin variable (“IgV”)-like domain responsible for ligand interaction (Kleinberger et al. Sci Transl Med, 2014). As 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. In the CNS, signaling through TREM2 has been studied in the context of ligands such as phospholipids, cellular debris, apolipoproteins, and myelin (Wang et al. Cell, 2015; Kober and Brett, J Mol Biol, 2017; Shirotani et al., Sci Rep, 2019). In mice lacking functional TREM2 expression or expressing a mutated form of the receptor, a core observation is blunted microglial responses to insults such as oligodendrocyte demyelination, stroke-induced tissue damage in the brain, and proteotoxic inclusions in vivo (Cantoni et al., Acta Neuropathol, 2015, Wu et al., Mol Brain, 2017). [0005] 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). Genetic variation of other genes selectively expressed by microglia in the CNS, for example, 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). Together, these genetic findings link together in a putative biochemical circuit that highlights the importance of microglial innate immune function in LOAD. Additionally, increase or elevation in the soluble form of TREM2 (“sTREM2”) in the cerebrospinal fluid (CSF) of human subjects is associated with disease progression and emergence of pathological hallmarks of LOAD including phosphorylated Tau (Suarez-Calvet et al. Mol Neurodegener 2019). Furthermore, natural history and human biology studies indicate that baseline sTREM2 levels in the CSF can stratify the rate of temporal lobe volume loss and episodic memory decline in longitudinally monitored cohorts (Ewers et al. Sci Transl Med 2019). [0006] 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). This progressive neurodegenerative disease typically manifests in the 3rd 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). Given that 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). The link between TREM2 function and PLOSL has illustrated the importance of the receptor in sustaining key physiological aspects of myeloid cell function in the human body. [0007] 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). When the 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. Nat Neurosci 2019). With regards to the Tau protein pathology that is observed in LOAD, familial tauopathy models in mice demonstrated an enhanced spreading of pathological human Tau aggregates from point of injection into mouse brain in TREM2 KO mice (Leyns et al. Nat Neurosci 2019). Furthermore, single-cell RNASeq studies with the TREM2 KO mice in aged scenarios, 5XFAD familial Alzheimer’s disease model mice, and Amyotrophic Lateral Sclerosis SOD1 mutant mouse backgrounds indicate that TREM2 receptor function is critical for a conserved set of phenotypic transformations within microglial populations in response to CNS pathology (Keren-Shaul et al. Cell 2017). [0008] In rodent models where TREM2 expression levels are elevated, brain amyloid pathology in the 5XFAD transgenic mice displayed reduced plaque volume and altered morphology (Lee et al. Neuron, 2018). The changes in immunohistological markers relating to brain amyloid pathology were also accompanied by an attenuated presence of dystrophic neurites when TREM2 was overexpressed. Id. Therefore, the pharmacological activation of TREM2 is a target of interest for treating or preventing neurological, neurodegenerative and other diseases. 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. SUMMARY [0009] Provided herein is a compound of Formula I
Figure imgf000005_0001
or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R1 is an optionally substituted C1-6 aliphatic group, OR, -CN, -NR2, -C(=O)R, -C(=O)OR, - C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, optionally substituted OCH2-(C3-6cycloalkyl), 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 1-4 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, 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 is optionally substituted; X1 is CR13, CH or N; X2 is CR14, CH or N; Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000006_0001
Y is C or N, as required by the bicyclic ring system formed by Ring A; X3 is CHR3, or NR4; X4 is CHR3, NR4, O or S; each Z1 is independently CR2 or N; Z2 is CR3 or N; R2, R2a, R2b, and R3 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1- 6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or one of R2, R2a, R2b, and R3 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 is optionally substituted; R4 is hydrogen, an optionally substituted C1-6 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 R3 and R4 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 is optionally substituted;
Figure imgf000007_0001
L is a bond or an optionally substituted straight chain or branched C1-6 alkylene; X5 is CH, N or CR5; X6 is CH, N or CR6; provided that when one of X5 or X6 is N, the other is not N; R5 and R6 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C1-6haloalkyl, C1- 6haloalkoxy, or 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 is optionally substituted; or R5 and R6 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 is optionally substituted; X7 is N, CH, or CR7; X8 is O, NR8, C(R8)2, CHR8, SO2, or C=O; X9 is O, NR9, C(R9)2, CHR9, SO2, or C=O; X10 is O, NR10, C(R10)2, CHR10, SO2, or C=O; X11 is O, NR11, C(R11)2, CHR11, SO2, or C=O; X12 is a direct bond, O, NR12, C(R12)2, CHR12, -CH2CH2-, -OCH2-, SO2, or C=O; R7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, - C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; each of R8, R9, R10, R11, and R12 is independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1- 6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or any two of R7, R8, R9, R10, R11, and R12 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 is optionally substituted; R13 and R14 are each independently hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1- 6haloalkoxy; R16 is an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, - C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; m is 0, 1 or 2; each R is independently hydrogen, an optionally substituted C1-6 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 two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). [0010] Also provided herein is 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. [0011] Also provided herein is 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. [0012] Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure will be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION [0013] In one aspect, provided herein is a compound of Formula I:
Figure imgf000010_0001
I or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R1 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 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, 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 is optionally substituted; X1 is CR13, CH or N; X2 is CR14, CH or N; Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula ,
Figure imgf000010_0002
Y is C or N, as required by the bicyclic ring system formed by Ring A; X3 is CHR3, or NR4; X4 is CHR3, NR4, O or S; each Z1 is independently CR2 or N; Z2 is CR3 or N; Z11 is CHR3, C(R3)2, or NR4; Z12 is CHR2, C(R2)2, NR4, or C(=N-R4); R2, R2a, R2b, and R3 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -NR-C(O)-R, -C(=O)OR, -C(=O)NR2, -SO2R, - SO2NR2, C1-6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or one of R2, R2a, R2b, and R3 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 is optionally substituted; R4 is hydrogen, an optionally substituted C1-6 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 R3 and R4 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 is optionally substituted;
Figure imgf000012_0001
L is a bond or an optionally substituted straight chain or branched C1-6 alkylene; X5 is CH, N or CR5; X6 is CH, N or CR6; provided that when one of X5 or X6 is N, the other is not N; R5 and R6 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C1-6haloalkyl, C1- 6haloalkoxy, or 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 is optionally substituted; or R5 and R6 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 is optionally substituted; X7 is N, CH, or CR7; X8 is O, NR8, C(R8)2, CHR8, SO2, or C=O; X9 is O, NR9, C(R9)2, CHR9, SO2, or C=O; X10 is O, NR10, C(R10)2, CHR10, SO2, or C=O; X11 is O, NR11, C(R11)2, CHR11, SO2, or C=O; X12 is a direct bond, O, NR12, C(R12)2, CHR12, -CH2CH2-, -OCH2-, SO2, or C=O; R7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, - C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; each of R8, R9, R10, R11, and R12 is independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1- 6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or any two of R7, R8, R9, R10, R11, and R12 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 is optionally substituted; R13 and R14 are each independently hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1- 6haloalkoxy; R16 is an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, - C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; m is 0, 1 or 2; each R is independently hydrogen, an optionally substituted C1-6 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 two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). [0014] In another aspect, provided herein is a compound of Formula I-a
Figure imgf000014_0001
or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R1 is an optionally substituted C1-6 aliphatic group, C1-6haloalkyl, optionally substituted OCH2-(C3- 6cycloalkyl), 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 1-4 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, 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 is optionally substituted; X1 is CR13, CH or N; X2 is CR14, CH or N; Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula ,
Figure imgf000015_0001
Y is C or N, as required by the bicyclic ring system formed by Ring A; X3 is CHR3, or NR4; X4 is CHR3, NR4, O or S; each Z1 is independently CR2 or N; Z2 is CR3 or N; R2, R2a, R2b, and R3 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1- 6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or one of R2, R2a, R2b, and R3 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 is optionally substituted; R4 is hydrogen, an optionally substituted C1-6 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 R3 and R4 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 is optionally substituted;
Figure imgf000016_0001
L is a bond or an optionally substituted straight chain or branched C1-6 alkylene; X5 is CH, N or CR5; X6 is CH, N or CR6; provided that when one of X5 or X6 is N, the other is not N; R5 and R6 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C1-6haloalkyl, C1- 6haloalkoxy, or 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 is optionally substituted; or R5 and R6 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 is optionally substituted; X7 is N, CH, or CR7; X8 is O, NR8, C(R8)2, CHR8, SO2, or C=O; X9 is O, NR9, C(R9)2, CHR9, SO2, or C=O; X10 is O, NR10, C(R10)2, CHR10, SO2, or C=O; X11 is O, NR11, C(R11)2, CHR11, SO2, or C=O; X12 is a direct bond, O, NR12, C(R12)2, CHR12, -CH2CH2-, -OCH2-, SO2, or C=O; R7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, - C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; each of R8, R9, R10, R11, and R12 is independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1- 6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or any two of R7, R8, R9, R10, R11, and R12 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 is optionally substituted; R13 and R14 are each independently hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1- 6haloalkoxy; R16 is an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, - C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; m is 0, 1 or 2; each R is independently hydrogen, an optionally substituted C1-6 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 two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). [0015] In another aspect, provided herein is a compound of Formula I-b:
Figure imgf000018_0001
I-b or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R1 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 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, 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 is optionally substituted; X1 is CR13, CH or N; X2 is CR14, CH or N; Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula ,
Figure imgf000019_0001
Y is C or N, as required by the bicyclic ring system formed by Ring A; X3 is CHR3, or NR4; X4 is CHR3, NR4, O or S; each Z1 is independently CR2 or N; Z2 is CR3 or N; Z11 is CHR3, C(R3)2, or NR4; Z12 is CHR2, C(R2)2, NR4, or C(=N-R4); R2, R2a, R2b, and R3 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -NR-C(O)-R, -C(=O)OR, -C(=O)NR2, -SO2R, - SO2NR2, C1-6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or one of R2, R2a, R2b, and R3 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 is optionally substituted; R4 is hydrogen, an optionally substituted C1-6 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 R3 and R4 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 is optionally substituted;
Figure imgf000020_0001
L is a bond or an optionally substituted straight chain or branched C1-6 alkylene; X5 is CH, N or CR5; X6 is CH, N or CR6; provided that when one of X5 or X6 is N, the other is not N; R5 and R6 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C1-6haloalkyl, C1- 6haloalkoxy, or 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 is optionally substituted; or R5 and R6 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 is optionally substituted; X7 is N, CH, or CR7; X8 is O, NR8, C(R8)2, CHR8, SO2, or C=O; X9 is O, NR9, C(R9)2, CHR9, SO2, or C=O; X10 is O, NR10, C(R10)2, CHR10, SO2, or C=O; X11 is O, NR11, C(R11)2, CHR11, SO2, or C=O; X12 is a direct bond, O, NR12, C(R12)2, CHR12, -CH2CH2-, -OCH2-, SO2, or C=O; R7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, - C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; each of R8, R9, R10, R11, and R12 is independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1- 6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or any two of R7, R8, R9, R10, R11, and R12 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 is optionally substituted; R13 and R14 are each independently hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1- 6haloalkoxy; R16 is an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, - C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; m is 0, 1 or 2; each R is independently hydrogen, an optionally substituted C1-6 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 two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). [0016] In another aspect, provided herein is a compound of Formula I-c:
Figure imgf000023_0001
I-c or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R1 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 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, 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 is optionally substituted; X1 is CR13, CH or N; X2 is CR14, CH or N; Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000023_0002
Y is C or N, as required by the bicyclic ring system formed by Ring A; X3 is CHR3, or NR4; R2a, R2b, and R3 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -NR-C(O)-R, -C(=O)OR, -C(=O)NR2, -SO2R, - SO2NR2, C1-6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or one of R2a and R2b and R3 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 is optionally substituted; R4 is hydrogen, an optionally substituted C1-6 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 R3 and R4 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 is optionally substituted;
Figure imgf000025_0001
L is a bond or an optionally substituted straight chain or branched C1-6 alkylene; X5 is CH, N or CR5; X6 is CH, N or CR6; provided that when one of X5 or X6 is N, the other is not N; R5 and R6 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C1-6haloalkyl, C1- 6haloalkoxy, or 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 is optionally substituted; or R5 and R6 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 is optionally substituted; X7 is N, CH, or CR7; X8 is O, NR8, C(R8)2, CHR8, SO2, or C=O; X9 is O, NR9, C(R9)2, CHR9, SO2, or C=O; X10 is O, NR10, C(R10)2, CHR10, SO2, or C=O; X11 is O, NR11, C(R11)2, CHR11, SO2, or C=O; X12 is a direct bond, O, NR12, C(R12)2, CHR12, -CH2CH2-, -OCH2-, SO2, or C=O; R7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, - C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; each of R8, R9, R10, R11, and R12 is independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1- 6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or any two of R7, R8, R9, R10, R11, and R12 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 is optionally substituted; R13 and R14 are each independently hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1- 6haloalkoxy; R16 is an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, - C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; m is 0, 1 or 2; each R is independently hydrogen, an optionally substituted C1-6 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 two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). [0017] In some embodiments, the compound is a compound of Formula IIa1:
Figure imgf000027_0001
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. [0018] In some embodiments, the compound is a compound of Formula IIa2:
Figure imgf000027_0002
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. [0019] In some embodiments, the compound is a compound of Formula IIb1:
Figure imgf000027_0003
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. [0020] In some embodiments, the compound is a compound of Formula IIb2:
Figure imgf000028_0001
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. [0021] In some embodiments, the compound is a compound of Formula IIc1:
Figure imgf000028_0002
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. [0022] In some embodiments, the compound is a compound of Formula IIc2:
Figure imgf000028_0003
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. [0023] In some embodiments, the compound is a compound of Formula IIIa:
Figure imgf000028_0004
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. [0024] In some embodiments, the compound is a compound of Formula IIIb:
Figure imgf000029_0001
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. [0025] In some embodiments, the compound is a compound of Formula IIIc:
Figure imgf000029_0002
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. [0026] In some embodiments, the compound is a compound of Formula IVa:
Figure imgf000029_0003
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. [0027] In some embodiments, the compound is a compound of Formula IVb:
Figure imgf000029_0004
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. [0028] In some embodiments, the compound is a compound of Formula IVc:
Figure imgf000030_0001
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. [0029] In some embodiments, the compound is a compound of Formula Va:
Figure imgf000030_0002
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. [0030] In some embodiments, the compound is a compound of Formula Vb:
Figure imgf000030_0003
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. [0031] In some embodiments, the compound is a compound of Formula Vc:
Figure imgf000031_0001
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. [0032] In some embodiments, the compound is a compound of Formula VIa:
Figure imgf000031_0002
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. [0033] In some embodiments, the compound is a compound of Formula VIb:
Figure imgf000031_0003
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. [0034] In some embodiments, the compound is a compound of Formula VIc:
Figure imgf000031_0004
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. [0035] In some embodiments, the compound is a compound of Formula VIIa:
Figure imgf000032_0001
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. [0036] In some embodiments, the compound is a compound of Formula VIIb:
Figure imgf000032_0002
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. [0037] In some embodiments, the compound is a compound of Formula VIIc:
Figure imgf000032_0003
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. [0038] In some embodiments, the compound is a compound of Formula VIIIa:
Figure imgf000033_0001
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. [0039] In some embodiments, the compound is a compound of Formula VIIIb:
Figure imgf000033_0002
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. [0040] In some embodiments, the compound is a compound of Formula VIIIc:
Figure imgf000033_0003
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. [0041] In some embodiments, the compound is a compound of Formula VIIb-1 to VIIb-11:
Figure imgf000033_0004
Figure imgf000034_0001
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. [0042] In some embodiments, the compound is a compound of Formula VIIb’-1 to VIIb’-11:
Figure imgf000034_0002
Figure imgf000035_0001
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. [0043] In some embodiments, the compound is a compound of Formula VIIb’’-1 to VIIb’’-11:
Figure imgf000035_0002
Figure imgf000036_0001
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. [0044] As defined generally above, R1 is an optionally substituted C1-6 aliphatic group, C1-6haloalkyl, optionally substituted OCH2-(C3-6cycloalkyl), 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 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, 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 is optionally substituted. In some embodiments, R1 is optionally substituted O-phenyl. [0045] In some embodiments, R1 is an optionally substituted C1-6 aliphatic group. In some embodiments, R1 is -OR. In some embodiments, R1 is -NR2. In some embodiments, R1 is -C(=O)R. In some embodiments, R1 is -C(=O)OR. In some embodiments, R1 is -C(=O)NR2. In some embodiments, R2 is -SO2R. In some embodiments, R1 is -SO2NR2. In some embodiments, R1 is C1-6haloalkyl. In some embodiments, R1 is an optionally substituted OCH2-(C3-6cycloalkyl). In some embodiments, R1 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R1 is an optionally substituted 5-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R1 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R1 is an optionally substituted phenyl. In some embodiments, R1 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R1 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, R1 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, R1 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, R1 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0046] In some embodiments, R1 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, 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 is optionally substituted. [0047] In some embodiments, R1 is phenyl, optionally substituted with 1-3 substituents independently selected from halogen, C1–6 aliphatic, -OR ^, or C1-6haloalkyl. In some embodiments, R1 is phenyl, optionally substituted with 1-3 halogen. In some embodiments, R1 is a 5-12 membered saturated or partially unsaturated bridged carbocyclic ring, optionally substituted with 1-3 substituents independently selected from halogen, C1–6 aliphatic, -OR ^, or C1-6haloalkyl. In some embodiments, R1 is a C5- 8tricycloalkyl ring, optionally substituted with 1-3 substituents independently selected from halogen, C1– 6 aliphatic, -OR ^, or C1-6haloalkyl. In some embodiments, R1 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- 6haloalkyl. In some embodiments, R1 is 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), optionally substituted with 1-3 halogen. [0048] In some embodiments, R1 is optionally substituted C3-6cycloalkyl, optionally substituted spiro[3.3]heptanyl, optionally substituted spiro[5.2]octanyl, optionally substituted
Figure imgf000038_0001
, 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). In some embodiments, R1 is optionally substituted C3-6cycloalkyl. In some embodiments, R1 is optionally substituted spiro[3.3]heptanyl. In some embodiments, R1 is
Figure imgf000038_0002
some embodiments, R1 is optionally substituted cyclopent-1-en-1-yl. In some embodiments, R1 is optionally substituted cyclohex-1-en-1-yl. In some embodiments, R1 is optionally substituted phenyl. In some embodiments, R1 is optionally substituted pyridinyl. In some embodiments, R1 is optionally substituted aziridine-1-yl. In some embodiments, R1 is optionally substituted pyrrolidine-1-yl. In some embodiments, R1 is optionally substituted azabicyclo[3.1.0]hexan-3-yl. In some embodiments, R1 is optionally substituted piperidine-1-yl. In some embodiments, R1 is optionally substituted -OCH2-(C3- 4cycloalkyl). [0049] In some embodiments, R1 is optionally substituted with 1-3 groups that are independently halogen; –(CH2)0–6R ^; –(CH2)0–6OR ^; –O(CH2)0–6Ro, –O–(CH2)0–6C(O)OR°; –(CH2)0–6CH(OR ^)2; – (CH2)0–6SR ^; –(CH2)0–6Ph, which Ph may be substituted with R°; –(CH2)0–46O(CH2)0–1Ph which Ph may be substituted with R°; –CH=CHPh, which Ph may be substituted with R°; –(CH2)0–6O(CH2)0–1-pyridyl which pyridyl may be substituted with R°; –NO2; –CN; –N3; –(CH2)0–6N(R ^)2; –(CH2)0–6N(R ^)C(O)R ^; – N(R ^)C(S)R ^; –(CH2)0–6N(R ^)C(O)NR ^2; –N(R ^)C(S)NR ^2; –(CH2)0–6N(R ^)C(O)OR ^; – N(R ^)N(R ^)C(O)R ^; –N(R ^)N(R ^)C(O)NR ^2; –N(R ^)N(R ^)C(O)OR ^; –(CH2)0–6C(O)R ^; –C(S)R ^; – (CH2)0–6C(O)OR ^; –(CH2)0–6C(O)SR ^; –(CH2)0–6C(O)OSiR ^3; –(CH2)0–6OC(O)R ^; –OC(O)(CH2)0–6SR°,– (CH2)0–6SC(O)R ^; –(CH2)0–6C(O)NR ^2; –C(S)NR ^2; –C(S)SR°; –SC(S)SR°, –(CH2)0– 6OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH2C(O)R ^; –C(NOR ^)R ^; –(CH2)0–6SSR ^; – (CH2)0–6S(O)2R ^; –(CH2)0–6S(O)2OR ^; –(CH2)0–6OS(O)2R ^; –S(O)2NR ^2; –(CH2)0–6S(O)R ^; – N(R ^)S(O)2NR ^2; –N(R ^)S(O)2R ^; –N(OR ^)R ^; –C(NH)NR ^2; –P(O)2R ^; –P(O)R ^2; –P(O)(OR ^)2; – OP(O)(R ^)OR ^; –OP(O)R ^2; –OP(O)(OR ^)2; SiR ^3; –(C1–4 straight or branched alkylene)O–N(R ^)2; or – (C1–4 straight or branched alkylene)C(O)O–N(R ^)2, wherein each R ^ may be substituted as defined elsewhere herein and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, –CH2–(5- to 6- membered heteroaryl ring), or a 3- 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 occurrences of R ^, taken together with their intervening atom(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono– or bicyclic ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R1 is optionally substituted with one or more -SF5 groups.
Figure imgf000039_0001
Figure imgf000040_0001
[0052] In some embodiments, R1 is a substituent selected from those shown below:
Figure imgf000040_0002
Figure imgf000041_0001
[0053] In some embodiments, R1 is . In some embodiments, R1 is . In some embodiments,
Figure imgf000042_0001
. some embodiments,
Figure imgf000042_0002
. some embodiments, R1 is selected from those depicted in Table A below. In some embodiments, R1 is selected from those depicted in Table A3 below. [0054] As defined generally above, X1 is CR13, CH or N. In some embodiments, X1 is CH or N. In some embodiments, X1 is CH. In some embodiments, X1 is CR13. In some embodiments, X1 is N. In some embodiments, X1 is selected from those depicted in Table A below. In some embodiments, X1 is selected from those depicted in Table A3 below. [0055] As defined generally above, X2 is CR14, CH or N. In some embodiments, X2 is CH or N. In some embodiments, X2 is CH. In some embodiments, X2 is CR14. In some embodiments, X2 is N. In some embodiments, X2 is selected from those depicted in Table A below. In some embodiments, X2 is selected from those depicted in Table A3 below. [0056] As defined generally above, R13 and R14 are each independently hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, - SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy. [0057] In some embodiments, R13 is hydrogen. In some embodiments, R13 is an optionally substituted C1-6 aliphatic group. In some embodiments, R13 is halogen. In some embodiments, R13 is -OR. In some embodiments, R13 is -CN. In some embodiments, R13 is -NR2. In some embodiments, R13 is -C(=O)R. In some embodiments, R13 is -C(=O)OR. In some embodiments, R13 is -C(=O)NR2. In some embodiments, R13 is -SO2R. In some embodiments, R13 is -SO2NR2. In some embodiments, R13 is C1-6haloalkyl. In some embodiments, R13 is C1-6haloalkoxy. In some embodiments, R13 is methyl. [0058] In some embodiments, R14 is hydrogen. In some embodiments, R14 is an optionally substituted C1-6 aliphatic group. In some embodiments, R14 is halogen. In some embodiments, R14 is -OR. In some embodiments, R14 is -CN. In some embodiments, R14 is -NR2. In some embodiments, R14 is -C(=O)R. In some embodiments, R14 is -C(=O)OR. In some embodiments, R14 is -C(=O)NR2. In some embodiments, R14 is -SO2R. In some embodiments, R14 is -SO2NR2. In some embodiments, R14 is C1-6haloalkyl. In some embodiments, R14 is C1-6haloalkoxy. In some embodiments, R14 is methyl. [0059] As defined generally above, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000043_0001
[0060] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000043_0002
. [0061] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000043_0003
. [0062] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000043_0004
. [0063] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000044_0001
. [0064] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000044_0002
. [0065] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000044_0003
. [0066] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000044_0004
. [0067] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000044_0005
. [0068] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000044_0006
. [0069] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000044_0007
. [0070] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000045_0001
. [0071] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000045_0002
. [0072] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000045_0003
. [0073] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000045_0004
. [0074] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000045_0005
. [0075] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000045_0006
. [0076] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
Figure imgf000045_0007
, wherein Z11 is CHR3, C(R3)2, or NR4; and Z12 is CHR2, C(R2)2, NR4, or C(=N-R4), wherein each variable is independently as defined herein and as described in embodiments herein. [0077] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system selected from:
Figure imgf000046_0001
[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: ,
Figure imgf000046_0002
[0079] In some embodiments, Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system
Figure imgf000047_0001
. [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. 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 A3 below. [0081] As defined generally above, X3 is CHR3, or NR4. In some embodiments X3 is CHR3. In some embodiments, X3 is NR4. In some embodiments, X3 is NH. In some embodiments, X3 is NMe. In some embodiments, X3 is NCH(CH3)2. [0082] As defined generally above, X4 is CHR3, NR4, O or S. In some embodiments X4 is CHR3. In some embodiments, X4 is NR4. In some embodiments, X4 is O. In some embodiments, X4 is S. In some embodiments, X4 is NH. In some embodiments, X4 is NMe. In some embodiments, X4 is NCH(CH3)2. [0083] As defined generally above, each Z1 is independently CR2 or N. In some embodiments, Z1 is CR2. In some embodiments, Z1 is N. [0084] As defined generally above, each Z2 is independently CR3 or N. In some embodiments, Z2 is CR3. In some embodiments, Z1 is N. [0085] As defined generally above, Z11 is CHR3, C(R3)2, or NR4. In some embodiments, Z11 is CHR3. In some embodiments, Z11 is C(R3)2. In some embodiments, Z11 is NR4. [0086] As defined generally above, Z12 is CHR2, C(R2)2, NR4, or C(=N-R4). In some embodiments, Z12 is CHR2. In some embodiments, Z12 is C(R2)2. In some embodiments, Z12 is NR4. In some embodiments, Z12 is C(=N-R4). [0087] As defined generally above, R2 and R3 are each independently hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, - SO2NR2, C1-6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted, provided that at least one of R2 and R3 is not hydrogen; or R2 and R3 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 is optionally substituted. In some embodiments, R2 and R3 are each independently -NR-C(O)-R. [0088] In some embodiments, R2 is hydrogen. In some embodiments, R2 is an optionally substituted C1-6 aliphatic group. In some embodiments, R2 is halogen. In some embodiments, R2 is -OR. In some embodiments, R2 is -NR2. In some embodiments, R2 is -C(=O)R. In some embodiments, R2 is -C(=O)OR. In some embodiments, R2 is -C(=O)NR2. In some embodiments, R2 is -SO2R. In some embodiments, R2 is -SO2NR2. In some embodiments, R2 is C1-6haloalkyl. In some embodiments, R2 is C1-6haloalkoxy. In some embodiments, R2 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R2 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R2 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R2 is an optionally substituted phenyl. In some embodiments, R2 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R2 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, R2 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, R2 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, R2 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2 is selected from those depicted in Table A below. In some embodiments, R2 is selected from those depicted in Table A3 below. [0089] In some embodiments, R3 is hydrogen. In some embodiments, R3 is an optionally substituted C1-6 aliphatic group. In some embodiments, R3 is halogen. In some embodiments, R3 is -OR. In some embodiments, R3 is -NR2. In some embodiments, R3 is -NR-C(O)-R. In some embodiments, R3 is - C(=O)R. In some embodiments, R3 is -C(=O)OR. In some embodiments, R3 is -C(=O)NR2. In some embodiments, R3 is -SO2R. In some embodiments, R3 is -SO2NR2. In some embodiments, R3 is C1- 6haloalkyl. In some embodiments, R3 is C1-6haloalkoxy. In some embodiments, R3 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R3 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R3 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R3 is an optionally substituted phenyl. In some embodiments, R3 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R3 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, R3 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, R3 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, R3 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R3 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R3 is selected from those depicted in Table A below. In some embodiments, R3 is selected from those depicted in Table A3 below. [0090] In some embodiments, R2 is hydrogen. In some embodiments, R2 is methyl. In some embodiments, R2 is Cl. In some embodiments, R2 is isopropyl. In some embodiments, R2 is a C1-3 haloalkyl. In some embodiments, R2 is 3-8 membered saturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R2 is an azetidinyl group. In some embodiments, R2 is optionally substituted ethyl. In some embodiments, R2 is methoxy. In some embodiments, R2 is -CH2F. In some embodiments, R2 is -OCH2F. In some embodiments, R2 is -CD3. [0091] In some embodiments, R3 is hydrogen. In some embodiments, R3 is methyl. In some embodiments, R3 is Cl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is a C1-3 haloalkyl. In some embodiments, R3 is 3-8 membered saturated monocyclic heterocyclic ring (having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R3 is an azetidinyl group. In some embodiments, R3 is optionally substituted ethyl. In some embodiments, R3 is methoxy. In some embodiments, R3 is -CH2F. In some embodiments, R3 is -OCH2F. In some embodiments, R3 is -CD3. In some embodiments, R3 is -N(CH3)-C(O)-CH3. In some embodiments, R3 is - N(CH3)2. In some embodiments, R3 is -NH(CH3). In some embodiments, R3 is
Figure imgf000050_0001
. In some
Figure imgf000050_0002
. [0092] In some embodiments, R2, R2a, or R2b are taken together with R3 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, and sulfur), wherein the cyclic group is optionally substituted. [0093] In some embodiments R2, R2a, or R2b are taken together with R3 and their intervening atoms to form an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R2, R2a, or R2b are taken together with R3 and their intervening atoms to form an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R2, R2a, or R2b are taken together with R3 and their intervening atoms to form an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R2, R2a, or R2b are taken together with R3 and their intervening atoms to form an optionally substituted phenyl. In some embodiments, R2, R2a, or R2b are taken together with R3 and their intervening atoms to form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R2, R2a, or R2b are taken together with R3 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). In some embodiments R2, R2a, or R2b are taken together with R3 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). In some embodiments, R2, R2a, or R2b are taken together with R3 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). In some embodiments, R2, R2a, or R2b are taken together with R3 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). In some embodiments, R2, R2a, or R2b are taken together with R3 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). [0094] In some embodiments, R2, R2a, or R2b are taken together with R3 and their intervening atoms to form a cyclopentane ring. In some embodiments, R2, R2a, or R2b are taken together with R3 and their intervening atoms to form a pyrrolidine ring. [0095] As defined generally above, R4 is hydrogen, an optionally substituted C1-6 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 R3 and R4 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 is optionally substituted. [0096] In some embodiments, R4 is hydrogen. In some embodiments, R4 is an optionally substituted C1- 6 aliphatic group. In some embodiments, R4 is an optionally substituted phenyl. In some embodiments, R4 is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R4 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, R4 is an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0097] In some embodiments, R3 and R4 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, R3 and R4 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, R3 and R4 are taken together with their intervening atoms to form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R3 and R4 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, R3 and R4 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, R3 and R4 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, R3 and R4 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, R3 and R4 are taken together with their intervening atoms to form a cyclopentane ring. In some embodiments, R3 and R4 are taken together with their intervening atoms to form a pyrrolidine ring. [0099] As defined generally above, Ring
Figure imgf000052_0001
Figure imgf000052_0002
.
[0100] In some embodiments, Ring
Figure imgf000053_0001
. some embodiments, Ring B is
Figure imgf000053_0002
. [0101] As defined generally above, 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, X5 is CH, N or CR5. In some embodiments, X5 is CH. In some embodiments, X5 is N. In some embodiments, X5 is CR5. In some embodiments, X5 is selected from those depicted in Table A below. In some embodiments, X5 is selected from those depicted in Table A3 below. [0103] As defined generally above, X6 is CH, N or CR6. In some embodiments, X6 is CH. In some embodiments, X6 is N. In some embodiments, X6 is CR6. In some embodiments, X6 is selected from those depicted in Table A below. In some embodiments, X6 is selected from those depicted in Table A3 below. [0104] In some embodiments, X5 is N and X6 is CH. In some embodiments, X5 is N and X6 is CR6. In some embodiments, X5 is CH and X6 is N. In some embodiments, X5 is CR5 and X6 is N. In some embodiments, X5 is CH and X6 is CH. In some embodiments, X5 is CH and X6 is CR6. In some embodiments, X5 is CR5 and X6 is CH. [0105] As defined generally above, R16 is an optionally substituted C1-6 aliphatic group, halogen, -OR, - CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy. In some embodiments, R16 is hydrogen. In some embodiments, R16 is an optionally substituted C1-6 aliphatic group. In some embodiments, R16 is halogen. In some embodiments, R13 is -OR. In some embodiments, R16 is - CN. In some embodiments, R16 is -NR2. In some embodiments, R16 is -C(=O)R. In some embodiments, R16 is -C(=O)OR. In some embodiments, R16 is -C(=O)NR2. In some embodiments, R16 is -SO2R. In some embodiments, R16 is -SO2NR2. In some embodiments, R16 is C1-6haloalkyl. In some embodiments, R16 is C1-6haloalkoxy. In some embodiments, R16 is -CD3. In some embodiments, R16 is selected from those depicted in Table A below. In some embodiments, R16 is selected from those depicted in Table A3 below. [0106] As defined generally above, 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
Figure imgf000054_0001
. some embodiments, Ring B is
Figure imgf000054_0002
. , . some embodiments, Ring B
Figure imgf000054_0003
. , . [0108] As defined generally above, R5 and R6 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, - SO2NR2, halogen, C1-6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or R5 and R6 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 is optionally substituted. [0109] In some embodiments, R5 is an optionally substituted C1-6 aliphatic group. In some embodiments, R5 is -OR. In some embodiments, R5 is -NR2. In some embodiments, R5 is -C(=O)R. In some embodiments, R5 is -C(=O)OR. In some embodiments, R5 is -C(=O)NR2. In some embodiments, R5 is -SO2R. In some embodiments, R5 is -SO2NR2. In some embodiments, R5 is halogen. In some embodiments, R5 is C1-6haloalkyl. In some embodiments, R5 is C1-6haloalkoxy. In some embodiments, R5 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R5 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R5 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R5 is an optionally substituted phenyl. In some embodiments, R5 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R5 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, R5 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, R5 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, R5 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R5 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, R5 is F. In some embodiments, R5 is Cl. In some embodiments, R5 is - OCF3. In some embodiments, R5 is cyclopropyl. In some embodiments, R5 is selected from those depicted in Table A below. In some embodiments, R5 is selected from those depicted in Table A3 below. [0111] In some embodiments, R6 is an optionally substituted C1-6 aliphatic group. In some embodiments, R6 is -OR. In some embodiments, R6 is -NR2. In some embodiments, R6 is -C(=O)R. In some embodiments, R6 is -C(=O)OR. In some embodiments, R6 is -C(=O)NR2. In some embodiments, R6 is -SO2R. In some embodiments, R6 is -SO2NR2. In some embodiments, R6 is halogen. In some embodiments, R6 is C1-6haloalkyl. In some embodiments, R6 is C1-6haloalkoxy. In some embodiments, R6 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R6 is an optionally substituted 6-12 membered saturated or partially unsaturated bridged carbocyclic ring. In some embodiments, R6 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R6 is an optionally substituted phenyl. In some embodiments, R6 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R6 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, R6 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, R6 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, R6 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R6 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, R6 is F. In some embodiments, R6 is Cl. In some embodiments, R6 is - OCF3. In some embodiments, R6 is cyclopropyl. In some embodiments, R6 is cyclobutyl. In some embodiments, R6 is optionally substituted pyrazolyl. In some embodiments, R6 is optionally substituted pyridinyl. In some embodiments, R6 is optionally substituted pyrimidinyl. In some embodiments, R6 is optionally substituted pyridazinyl. In some embodiments, R6 is optionally substituted imidazolyl. In some embodiments, R6 is optionally substituted triazolyl. In some embodiments, R6 is optionally substituted oxazolyl. In some embodiments, R6 is optionally substituted thiazolyl. In some embodiments, R6 is optionally substituted oxadiazolyl. In some embodiments, R6 is optionally substituted thiadiazolyl. In some embodiments, R6 is optionally substituted oxetanyl. In some embodiments, R6 is optionally substituted azetidinyl. In some embodiments, R6 is optionally substituted piperidinyl. In some embodiments, R6 is optionally substituted piperazinyl. In some embodiments, R6 is selected from those depicted in Table A below. In some embodiments, R6 is selected from those depicted in Table A3 below. [0113] In some embodiments, R5 and R6 are independently a substituent selected from hydrogen and those shown below:
Figure imgf000056_0001
Figure imgf000057_0001
[0114] In some embodiments, R5 and R6 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 is optionally substituted. [0115] In some embodiments, R5 and R6 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, R5 and R6 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, R5 and R6 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, R5 and R6 are taken together with their intervening atoms to form an optionally substituted phenyl. In some embodiments, R5 and R6 are taken together with their intervening atoms to form an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R5 and R6 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, R5 and R6 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). In some embodiments, R5 and R6 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, R5 and R6 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, R5 and R6 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). [0116] In some embodiments, R5 and R6 are taken together with their intervening atoms to form a dioxole ring. [0117] As defined generally above, X7 is N, CH, or CR7. In some embodiments, X7 is N. In some embodiments, X7 is CH. In some embodiments, X7 is CR7. In some embodiments, X7 is CCH3. In some embodiments, X7 is COH. In some embodiments, X7 is CF. In some embodiments, X7 is selected from those depicted in Table A below. In some embodiments, X7 is selected from those depicted in Table A3 below. [0118] As defined generally above, X8 is O, NR8, C(R8)2, CHR8, SO2, or C=O. In some embodiments, X8 is O. In some embodiments, X8 is NR8. In some embodiments, X8 is C(R8)2. In some embodiments, X8 is CHR8. In some embodiments, X8 is SO2. In some embodiments, X8 is CH2. In some embodiments, X8 is C=O. In some embodiments, X8 is selected from those depicted in Table A below. In some embodiments, X8 is selected from those depicted in Table A3 below. [0119] As defined generally above, X9 is O, NR9, C(R9)2, CHR9, SO2, or C=O. In some embodiments, X9 is O. In some embodiments, X9 is NR9. In some embodiments, X9 is C(R9)2. In some embodiments, X9 is CHR9. In some embodiments, X9 is SO2. In some embodiments, X9 is CH2. In some embodiments, X9 is C=O. In some embodiments, X9 is selected from those depicted in Table A below. In some embodiments, X9 is selected from those depicted in Table A3 below. [0120] As defined generally above, X10 is O, NR10, C(R10)2, CHR10, SO2, or C=O. In some embodiments, X10 is O. In some embodiments, X10 is NR10. In some embodiments, X10 is C(R10)2. In some embodiments, X10 is CHR10. In some embodiments, X10 is SO2. In some embodiments, X10 is C=O. In some embodiments, X10 is CH2, CF2, or O. In some embodiments, X10 is CH2. In some embodiments, X10 is NR10, or O. In some embodiments, X10 is NMe, NH, or O. In some embodiments, X10 is selected from those depicted in Table A below. In some embodiments, X10 is selected from those depicted in Table A3 below. [0121] As defined generally above, X11 is O, NR11, C(R11)2, CHR11, SO2, or C=O. In some embodiments, X11 is O. In some embodiments, X11 is NR11. In some embodiments, X11 is C(R11)2. In some embodiments, X11 is CHR11. In some embodiments, X11 is SO2. In some embodiments, X11 is CH2. In some embodiments, X11 is C=O. In some embodiments, X11 is selected from those depicted in Table A below. In some embodiments, X11 is selected from those depicted in Table A3 below. [0122] As defined generally above, X12 is a direct bond, O, NR12, C(R12)2, CHR12, -CH2CH2-, -OCH2-, SO2, or C=O. In some embodiments, X12 is O. In some embodiments, X12 is NR12. In some embodiments, X12 is C(R12)2. In some embodiments, X12 is CHR12. In some embodiments, X12 is CH2. In some embodiments, X12 is SO2. In some embodiments, X12 is C=O. In some embodiments, X12 is - CH2CH2-. In some embodiments, X12 is -OCH2-. In some embodiments, X12 is a direct bond. In some embodiments, X12 is selected from those depicted in Table A below. In some embodiments, X12 is selected from those depicted in Table A3 below. [0123] In some embodiments, when any of X7, X8, X9, X10, X11, or X12 is N, O or SO2, then neither of the neighboring positions in Ring B are N, O or SO2. [0124] In some embodiments, when any one of X8, X9, X10, X11, or X12 is C=O, then neither of the neighboring positions in Ring B are C=O or SO2. [0125] As defined generally above, R7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy. In some embodiments, R7 is an optionally substituted aliphatic group. In some embodiments, R7 is halogen. In some embodiments, R7 is -OR. In some embodiments, R7 is -NR2. In some embodiments, R7 is -C(=O)R. In some embodiments, R7 is -C(=O)OR. In some embodiments, R7 is -C(=O)NR2. In some embodiments, R7 is -SO2R. In some embodiments, R7 is -SO2NR2. In some embodiments, R7 is C1-6haloalkyl. In some embodiments, R7 is C1-6haloalkoxy. In some embodiments, R7 is methyl. In some embodiments, R7 is OH. In some embodiments, R7 is F. In some embodiments, R7 is selected from those depicted in Table A below. In some embodiments, R7 is selected from those depicted in Table A3 below. [0126] As defined generally above, each of R8, R9, R10, R11, and R12 is independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, - C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or any two of R7, R8, R9, R10, R11, and R12 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 is optionally substituted. [0127] In some embodiments, R8 is hydrogen. In some embodiments, R8 is an optionally substituted C1- 6 aliphatic group. In some embodiments, R8 -OR. In some embodiments, R8 is -NR2. In some embodiments, R8 is -C(=O)R. In some embodiments, R8 is -C(=O)OR. In some embodiments, R8 is - C(=O)NR2. In some embodiments, R8 is -SO2R. In some embodiments, R8 is -SO2NR2. In some embodiments, R8 is C1-6haloalkyl. In some embodiments, R8 is C1-6haloalkoxy. In some embodiments, R8 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R8 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R8 is an optionally substituted phenyl. In some embodiments, R8 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R8 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, R8 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, R8 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R8 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R8 is methyl. In some embodiments, R8 is -OH. In some embodiments, R8 is F. In some embodiments, R8 is methoxy. In some embodiments, R8 is -CH2OH. In some embodiments, wherein X8 is C(R8)2, each R8 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X8 is C(R8)2, both R8 are the same. In some embodiments, R8 is selected from those depicted in Table A below. In some embodiments, R8 is selected from those depicted in Table A3 below. [0128] In some embodiments, R9 is hydrogen. In some embodiments, R9 is an optionally substituted C1- 6 aliphatic group. In some embodiments, R9 -OR. In some embodiments, R9 is -NR2. In some embodiments, R9 is -C(=O)R. In some embodiments, R9 is -C(=O)OR. In some embodiments, R9 is - C(=O)NR2. In some embodiments, R9 is -SO2R. In some embodiments, R9 is -SO2NR2. In some embodiments, R9 is C1-6haloalkyl. In some embodiments, R9 is C1-6haloalkoxy. In some embodiments, R9 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R9 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R9 is an optionally substituted phenyl. In some embodiments, R9 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R9 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, R9 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, R9 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R9 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R9 is methyl. In some embodiments, R9 is -OH. In some embodiments, R9 is F. In some embodiments, R9 is methoxy. In some embodiments, R9 is -CH2OH. In some embodiments, wherein X9 is C(R9)2, each R9 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X9 is C(R9)2, both R9 are the same. In some embodiments, R9 is selected from those depicted in Table A below. In some embodiments, R9 is selected from those depicted in Table A3 below. [0129] In some embodiments, R9 is optionally substituted pyrazolyl. In some embodiments, R9 is optionally substituted pyridinyl. In some embodiments, R9 is optionally substituted pyrimidinyl. In some embodiments, R9 is optionally substituted pyridazinyl. In some embodiments, R9 is optionally substituted imidazolyl. In some embodiments, R9 is optionally substituted triazolyl. In some embodiments, R9 is optionally substituted oxazolyl. In some embodiments, R9 is optionally substituted thiazolyl. In some embodiments, R9 is optionally substituted oxadiazolyl. In some embodiments, R9 is optionally substituted thiadiazolyl. In some embodiments, R9 is optionally substituted oxetanyl. In some embodiments, R9 is optionally substituted azetidinyl. In some embodiments, R9 is optionally substituted piperidinyl. In some embodiments, R9 is optionally substituted piperazinyl. [0130] In some embodiments, R9 is substituted with an optionally susbstituted 3-6 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R9 is substituted with an optionally substituted 5-8 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R9 is substituted with an optionally susbstituted 3-6 membered saturated or partially unsaturated monocyclic heterocyclic ring. In some embodiments, R9 is substituted with an optionally susbstituted C1-6 aliphatic group. In some embodiments, R9 is substituted with a methyl group. In some embodiments, R9 is substituted with a -CD3 group. In some embodiments, R9 is substituted with a methoxy group. In some embodiments, R9 is substituted with a cyclopropyl group. In some embodiments, R9 is substituted with an optionally substituted
Figure imgf000061_0001
. [0131] In some embodiments, R9 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). In some embodiments, R9 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). In some embodiments, R9 is -N(CH3)R, wherein R is an an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R9 is -C(=O)N(CH3)R, wherein R is an an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R9 is -C(=O)NHR, wherein R is an an optionally substituted 5-6 membered heteroaryl ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0132] In some embodiments, R9 is a substituent selected from those shown below:
Figure imgf000062_0001
Figure imgf000063_0001
[0134] In some embodiments, R9 is methyl, tetrahydrofuran-3-yl,
Figure imgf000064_0001
, ,
Figure imgf000064_0002
[0136] In some embodiments,
Figure imgf000064_0003
[0137] In some embodiments,
Figure imgf000064_0004
. [0138] In some embodiments,
Figure imgf000064_0005
. [0139] In some embodiments,
Figure imgf000064_0006
. [0140] In some embodiments, R10 is hydrogen. In some embodiments, R10 is an optionally substituted C1-6 aliphatic group. In some embodiments, R10 -OR. In some embodiments, R10 is -NR2. In some embodiments, R10 is -C(=O)R. In some embodiments, R10 is -C(=O)OR. In some embodiments, R10 is - C(=O)NR2. In some embodiments, R10 is -SO2R. In some embodiments, R10 is -SO2NR2. In some embodiments, R10 is C1-6haloalkyl. In some embodiments, R10 is C1-6haloalkoxy. In some embodiments, R10 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R10 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R10 is an optionally substituted phenyl. In some embodiments, R10 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R10 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, R10 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, R10 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R10 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R10 is methyl. In some embodiments, R10 is -OH. In some embodiments, R10 is F. In some embodiments, R10 is methoxy. In some embodiments, R10 is -CH2OH. In some embodiments, wherein X10 is C(R10)2, each R10 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X10 is C(R10)2, both R10 are the same. In some embodiments, R10 is selected from those depicted in Table A below. In some embodiments, R10 is selected from those depicted in Table A3 below. [0141] In some embodiments, R11 is hydrogen. In some embodiments, R11 is an optionally substituted C1-6 aliphatic group. In some embodiments, R11 -OR. In some embodiments, R11 is -NR2. In some embodiments, R11 is -C(=O)R. In some embodiments, R11 is -C(=O)OR. In some embodiments, R11 is - C(=O)NR2. In some embodiments, R11 is -SO2R. In some embodiments, R11 is -SO2NR2. In some embodiments, R11 is C1-6haloalkyl. In some embodiments, R11 is C1-6haloalkoxy. In some embodiments, R11 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R11 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R11 is an optionally substituted phenyl. In some embodiments, R11 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R11 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, R11 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, R11 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R11 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R11 is methyl. In some embodiments, R11 is -OH. In some embodiments, R11 is F. In some embodiments, R11 is methoxy. In some embodiments, R11 is -CH2OH. In some embodiments, wherein X11 is C(R11)2, each R11 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X11 is C(R11)2, both R11 are the same. In some embodiments, R11 is selected from those depicted in Table A below. In some embodiments, R11 is selected from those depicted in Table A3 below. [0142] In some embodiments, R12 is hydrogen. In some embodiments, R12 is an optionally substituted C1-6 aliphatic group. In some embodiments, R12 -OR. In some embodiments, R12 is -NR2. In some embodiments, R12 is -C(=O)R. In some embodiments, R12 is -C(=O)OR. In some embodiments, R12 is - C(=O)NR2. In some embodiments, R12 is -SO2R. In some embodiments, R12 is -SO2NR2. In some embodiments, R12 is C1-6haloalkyl. In some embodiments, R12 is C1-6haloalkoxy. In some embodiments, R12 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R12 is an optionally substituted 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, R12 is an optionally substituted phenyl. In some embodiments, R12 is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R12 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, R12 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, R12 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R12 is an optionally substituted 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R12 is methyl. In some embodiments, R12 is -OH. In some embodiments, R12 is F. In some embodiments, R12 is methoxy. In some embodiments, R12 is -CH2OH. In some embodiments, wherein X12 is C(R12)2, each R12 is independently selected from any of the aforementioned substituents. In some embodiments, wherein X12 is C(R12)2, both R12 are the same. In some embodiments, R12 is selected from those depicted in Table A below. In some embodiments, R12 is selected from those depicted in Table A3 below. [0143] In some embodiments, Ring B is a substituent selected from those shown below:
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0002
Figure imgf000068_0001
[0145] In some embodiments, Ring B is
Figure imgf000069_0001
. In some embodiments, Ring B is . In some embodiments, Ring B is
Figure imgf000069_0002
. In some embodiments, Ring B is
Figure imgf000069_0003
. In some embodiments, Ring B is
Figure imgf000069_0004
. [0146] In some embodiments, Ring
Figure imgf000069_0005
. some embodiments, Ring B is
Figure imgf000069_0006
some embodiments, Ring B is . In some embodiments, Ring
Figure imgf000069_0007
. some embodiments, Ring B is . In some embodiments, Ring
Figure imgf000069_0009
. some embodiments, Ring B is
Figure imgf000069_0008
. In some embodiments, Ring
Figure imgf000069_0010
. [0147] In some embodiments, Ring B is
Figure imgf000069_0011
. In some embodiments, Ring B is . In some embodiments, Ring B is
Figure imgf000069_0012
. In some embodiments, Ring B is
Figure imgf000069_0013
. In some embodiments, Ring
Figure imgf000069_0014
some embodiments, Ring B is
Figure imgf000070_0004
. [0148] In some embodiments, Ring
Figure imgf000070_0001
some embodiments, Ring B is
Figure imgf000070_0002
. , . some embodiments, Ring B is
Figure imgf000070_0003
Figure imgf000071_0001
Figure imgf000071_0002
ents, Ring B is
Figure imgf000071_0003
some embodiments, Ring
Figure imgf000072_0002
. some embodiments, Ring
Figure imgf000072_0001
. In some embodiments, Ring
Figure imgf000072_0003
. [0150] In some embodiments, at least one hydrogen atom of the compound is a deuterium atom. In some embodiments, at least one C1-C6 aliphatic group of the compound is substituted with at least one deuterium atom. In some embodiments, at least one C1-C6alkyl group of the compound is substituted with at least one deuterium atom. In some embodiments, R2 is –CD3. In some embodiments, R3 is –CD3. In some embodiments, R2 and R3 are both –CD3. In some embodiments, R4 is –CD3. [0151] Exemplary compounds of the invention are set forth in Table A, below. In some embodiments, the compound is a compound set forth in Table A, or a pharmaceutically acceptable salt thereof. Table A. Exemplary Compounds
Figure imgf000072_0004
Figure imgf000072_0005
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000076_0003
[0152] Exemplary compounds of the invention are set forth in Table A2, below. In some embodiments, the compound is a compound set forth in Table A2, or a pharmaceutically acceptable salt thereof. Table A2. Exemplary Compounds
Figure imgf000076_0002
Figure imgf000076_0004
Figure imgf000077_0002
Figure imgf000077_0001
[0153] Exemplary compounds of the invention are set forth in Table A3, below. In some embodiments, the compound is a compound set forth in Table A3, or a pharmaceutically acceptable salt thereof.
Table A3. Exemplary Compounds
Figure imgf000078_0002
Figure imgf000078_0001
Figure imgf000079_0001
[0154] The foregoing merely summarizes certain aspects of this disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way. FORMULATION AND ROUTE OF ADMINISTRATION [0155] 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. Thus, in one embodiment, provided herein is 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. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol.1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, a pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein. [0156] 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. [0157] 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. [0158] In one aspect, 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. [0159] In another aspect, 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. 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, 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. [0161] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. [0162] For this purpose, 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. [0163] Pharmaceutically acceptable 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. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When 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. [0164] Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. [0165] Pharmaceutically acceptable 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. [0166] 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. [0167] For topical applications, provided pharmaceutically acceptable 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. Alternatively, 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. [0168] For ophthalmic use, 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. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. [0169] Pharmaceutically acceptable 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. [0171] The amount of compounds 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. Preferably, 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. [0172] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present disclosure in the composition will also depend upon the particular compound in the composition. METHODS OF USE [0173] 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. For example, animals including horses, dogs, and cats may be treated with compounds provided herein. [0175] Without wishing to be bound by any particular theory, the following is noted: TREM2 has been implicated in several myeloid cell processes, including phagocytosis, proliferation, survival, and regulation of inflammatory cytokine production. Ulrich and Holtzman 2016. In the last few years, TREM2 has been linked to several diseases. For instance, mutations in both TREM2 and DAP12 have been linked to the autosomal recessive disorder Nasu-Hakola Disease, which is characterized by bone cysts, muscle wasting and demyelination phenotypes. Guerreiro et al.2013. More recently, variants in the TREM2 gene have been linked to increased risk for Alzheimer's disease (AD) and other forms of dementia including frontotemporal dementia. Jonsson et al.2013, Guerreiro, Lohmann et al.2013, and Jay, Miller et al.2015. In particular, 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. Impairment in microgliosis has been reported in animal models of prion disease, multiple sclerosis, and stroke, suggesting that 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. A variety of animal models also suggest that Toll-Like Receptor (TLR) signaling is important in the pathogenesis of Rheumatoid Arthritis (RA) via persistent expression of pro-inflammatory cytokines by macrophages. Signaling through TREM2/DAP12 inhibits TLR responses by reducing MAPK (Erk1/2) activation, suggesting that TREM2 activation may act as a negative regulator of TLR driven RA pathogenesis. Huang and Pope 2009. [0176] In view of the data indicating that deficits in TREM2 activity affect macrophage and microglia function, the compounds disclosed herein are of particular use in disorders, such as those described above and in the embodiments that follow and in neurodegenerative disorders more generally. [0177] In one aspect, 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. [0178] In one aspect, 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. [0179] In one aspect, 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. [0180] In one aspect, 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. [0181] In another aspect, 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. [0182] In another aspect, 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 [0183] CSF1R is a cell-surface receptor primarily for the cytokine colony stimulating factor 1 (CSF-1), also known until recently as macrophage colony-stimulating factor (M-CSF), which regulates the survival, proliferation, differentiation and function of mononuclear phagocytic cells, including microglia of the central nervous system. CSF1R is composed of a highly glycosylated extracellular ligand-binding domain, a trans-membrane domain and an intracellular tyrosine-kinase domain. Binding of CSF-1 to CSF1R results in the formation of receptor homodimers and subsequent auto-phosphorylation of several tyrosine residues in the cytoplasmic domain, notably Syk. In the brain, CSF1R is predominantly expressed in microglial cells. It has been found that microglia in CSF1R +/- patients are depleted and show increased apoptosis (Oosterhof et al., 2018). [0184] 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. It has been previously shown that TREM2 agonist antibody 4D9 increases ATP luminescence (a measure of cell number and activity) in a dose dependent manner when the levels of M-CSF in media are reduced to 5 ng/mL (Schlepckow et al, EMBO Mol Med., 2020) and that TREM2 agonist AL002c increases ATP luminescence when M-CSF is completely removed from the media (Wang et al, J. Exp. Med.; 2020, 217(9): e20200785). This finding suggests that TREM2 agonism can compensate for deficiency in CSF1R signaling caused by a decrease in the concentration of its ligand. In a 5xFAD murine Alzheimer’s disease model of amyloid pathology, doses of a CSF1R inhibitor that almost completely eliminate microglia in the brains of wild-type animals show surviving microglia clustered around the amyloid plaques (Spangenberg et al, Nature Communications 2019). Plaque amyloid has been demonstrated in the past to be a ligand for TREM2, and it has been shown that microglial engagement with amyloid is dependent on TREM2 (Condello et al, Nat Comm., 2015). The present 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. [0185] Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously recognized as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD), is an autosomal-dominant central nervous system disease that manifests in the form of variable behavioral, cognitive and motor function changes in patients suffering from the disease. 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. [0186] Recent studies have discovered that 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). In one aspect, 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. [0187] In one aspect, 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). [0188] In one aspect, 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). [0189] In one aspect, 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. [0190] In one aspect, 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). [0191] In another aspect, 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. In some embodiments, 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. In some embodiments, the mutation in the CSF1R gene is a mutation that causes a decrease in CSF1R activity or a cessation of CSF1R activity. In some embodiments, 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. 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 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. In some embodiments, the disease or disorder is caused by a loss-of-function mutation in CSF1R. In some embodiments, the loss-of-function mutation results in a complete cessation of CSF1R function. In some embodiments, the loss-of-function mutation results in a partial loss of CSF1R function, or a decrease in CSF1R activity. [0192] In another aspect, 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. In some embodiments, the method treats or prevents ALSP, which is an encompassing and superseding name for both HDLS and POLD. In some embodiments, the disease or disorder is a homozygous mutation in CSF1R. In some embodiments, the method treats or prevents pediatric-onset leukoencephalopathy. In some embodiments, the method treats or prevents congenital absence of microglia. In some embodiments, the method treats or prevents brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS). [0193] In yet another aspect, 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 a gene affecting the function of CSF1R, 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. ABCD1 [0194] The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein (ALDP). ABCD1 (ALDP) 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. As 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). It has also been shown that ABCD1-deficiency leads to an impaired plasticity of myeloid lineage cells that is reflected in incomplete establishment of anti-inflammatory responses, thus possibly contributing to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy (Weinhor et al., BRAIN 2018: 141; 2329–2342). These findings emphasize microglia/ monocytes/ macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy. [0195] 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. It has been previously shown that TREM2 agonist antibody 4D9 increases ATP luminescence (a measure of cell number and activity) in a dose dependent manner when the levels of M-CSF in media are reduced to 5 ng/mL (Schlepckow et al, EMBO Mol Med., 2020) and that TREM2 agonist AL002c increases ATP luminescence when M-CSF is completely removed from the media (Wang et al, J. Exp. Med.; 2020, 217(9): e20200785). This finding suggests that 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. [0196] In one aspect, 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). [0197] In one aspect, 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). [0198] In one aspect, 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. [0199] In one aspect, 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). [0200] In yet another aspect, 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. In some embodiments, 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. In some embodiments, the mutation in the ABCD1 gene is a mutation that causes a decrease in ABCD1 activity or a cessation of ABCD1 activity. In some embodiments, 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). In some embodiments, the disease or disorder is caused by a loss- of-function mutation in ABCD1. In some embodiments, the loss-of-function mutation results in a complete cessation of ABCD1 function. In some embodiments, the loss-of-function mutation results in a partial loss of ABCD1 function, or a decrease in ABCD1 activity. In some embodiments, the disease or disorder is caused by a homozygous mutation in ABCD1. In some embodiments, the disease or disorder is a neurodegenerative disorder. In some embodiments, the disease or disorder is a neurodegenerative disorder caused by and/or associated with an 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. [0201] In yet another aspect, 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. In some embodiments, 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. In some embodiments, the method treats or prevents X-linked adrenoleukodystrophy (x-ALD). In some embodiments, the x-ALD is a cerebral form of x-linked ALD (cALD). In some embodiments, 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. In some embodiments, the method treats or prevents Addison disease, wherein the patient has a loss-of-function mutation in ABCD1. [0202] In yet another aspect, 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. Autism Spectrum Disorders [0203] It has been found that 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.). Further studies have shown that increased dendritic spin density detected in post-mortem ASD brains, likely caused by defective synaptic pruning, results in circuit hypoconnectivity and behavioral defects and are a potential origin of a number of neurodevelopmental diseases (Tang, et al., Neuron, 2014, 83, 1131-1143). Without intending to be limited to any particular theory, these findings suggest that 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. [0204] In another aspect, 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. [0205] In yet another aspect, 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. [0206] In yet another aspect, 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. In some embodiments, the method treats autism. In some embodiments, the method treats Asperger syndrome. [0207] In some embodiments, 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. In some embodiments, the contacting takes place in vitro. In some embodiments, the contacting takes place in vivo. In some embodiments, the TREM2 is human TREM2. Combination Therapies [0208] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure. As used herein, 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.” [0209] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent. [0210] In some embodiments, 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. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. [0211] Examples of 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. [0212] As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, 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. [0213] 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. Preferably 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. [0214] 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. Alternatively, 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. If administered as a multiple dosage regime, 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. In some embodiments, 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. [0215] In one embodiment, 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. In certain embodiments, 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. In other embodiments, 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. DEFINITIONS [0216] The following definitions are provided to assist in understanding the scope of this disclosure. [0217] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification or claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements. [0218] As used herein, if any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. If the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. [0219] As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 101st Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2005, and “March’s Advanced Organic Chemistry: Reactions Mechanisms and Structure”, 8th Ed., Ed.: Smith, M.B., John Wiley & Sons, New York: 2019, the entire contents of which are hereby incorporated by reference. Stereoisomers [0220] The compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers. Accordingly, 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. [0221] If the 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. For example, (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. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This is not to be confused with a wavy line drawn perpendicular to a bond which indicates the point of attachment of a group to the rest of the molecule. [0222] The term “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. For example, 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. [0223] 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. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). Tautomers [0224] As known by those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because one chemical structure may only be used to represent one tautomeric form, it will be understood that for convenience, referral to a compound of a given structural formula includes other tautomers of said structural formula. Accordingly, the scope of the instant disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein. Isotopically-Labelled Compounds [0225] Further, the scope of the present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of the compounds disclosed herein, such as the compounds of Formula I, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S. Certain isotopically-labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium (3H) and carbon-14 (14C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with isotopes such as deuterium (2H 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 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. 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. [0227] The term “solvate” as used herein 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. [0230] Compounds of this present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 101st Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2005, and “March’s Advanced Organic Chemistry: Reactions Mechanisms and Structure”, 8th Ed., Ed.: Smith, M.B., John Wiley & Sons, New York: 2019, the entire contents of which are hereby incorporated by reference. [0231] The term “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. Unless otherwise specified, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, 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. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-C6 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. [0232] As used herein, 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. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” 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. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, 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). In some embodiments, 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. Unless otherwise specified, 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:
Figure imgf000097_0001
[0233] Exemplary bridged bicyclics include:
Figure imgf000097_0002
[0234] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. [0235] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms. [0236] The term “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. [0237] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. [0238] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. [0239] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., –(CH2)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. [0240] The term “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. [0241] The term “halogen” means F, Cl, Br, or I. [0242] The term “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. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present disclosure, “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. [0243] The terms “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. The term “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. The terms “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. A heteroaryl ring may include one or more oxo (=O) or thioxo (=S) substituent. 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. [0244] 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. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring (having 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. [0245] 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. Examples of such 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. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are 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. A heterocyclic ring may include one or more oxo (=O) or thioxo (=S) substituent. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. [0246] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “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. [0247] As described herein, compounds of the present disclosure may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, 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. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. [0248] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–6R ^; –(CH2)0–6OR ^; –O(CH2)0–6Ro, –O–(CH2)0–6C(O)OR°; – (CH2)0–6CH(OR ^)2; –(CH2)0–6SR ^; –(CH2)0–6Ph, which Ph may be substituted with R°; –(CH2)0–46O(CH2)0– 1Ph which Ph may be substituted with R°; –CH=CHPh, which Ph may be substituted with R°; –(CH2)0– 6O(CH2)0–1-pyridyl which pyridyl may be substituted with R°; –NO2; –CN; –N3; –(CH2)0–6N(R ^)2; – (CH2)0–6N(R ^)C(O)R ^; –N(R ^)C(S)R ^; –(CH2)0–6N(R ^)C(O)NR ^2; –N(R ^)C(S)NR ^2; –(CH2)0– 6N(R ^)C(O)OR ^; –N(R ^)N(R ^)C(O)R ^; –N(R ^)N(R ^)C(O)NR ^2; –N(R ^)N(R ^)C(O)OR ^; –(CH2)0– 6C(O)R ^; –C(S)R ^; –(CH2)0–6C(O)OR ^; –(CH2)0–6C(O)SR ^; –(CH2)0–6C(O)OSiR ^3; –(CH2)0–6OC(O)R ^; – OC(O)(CH2)0–6SR°,–(CH2)0–6SC(O)R ^; –(CH2)0–6C(O)NR ^2; –C(S)NR ^2; –C(S)SR°; –SC(S)SR°, – (CH2)0–6OC(O)NR ^2; -C(O)N(OR ^)R ^; –C(O)C(O)R ^; –C(O)CH2C(O)R ^; –C(NOR ^)R ^; –(CH2)0–6SSR ^; –(CH2)0–6S(O)2R ^; –(CH2)0–6S(O)2OR ^; –(CH2)0–6OS(O)2R ^; –S(O)2NR ^2; –(CH2)0–6S(O)R ^; – N(R ^)S(O)2NR ^2; –N(R ^)S(O)2R ^; –N(OR ^)R ^; –C(NH)NR ^2; –P(O)2R ^; –P(O)R ^2; –P(O)(OR ^)2; – OP(O)(R ^)OR ^; –OP(O)R ^2; –OP(O)(OR ^)2; SiR ^3; –(C1–4 straight or branched alkylene)O–N(R ^)2; or – (C1–4 straight or branched alkylene)C(O)O–N(R ^)2, wherein each R ^ may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, –CH2–(5- to 6-membered heteroaryl ring), or a 3- 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 occurrences of R ^, taken together with their intervening atom(s), form a 3- to 12- membered saturated, partially unsaturated, or aryl mono– or bicyclic ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), which may be substituted as defined below. [0249] Suitable monovalent substituents on R ^ (or the ring formed by taking two independent occurrences of R ^ together with their intervening atoms), are independently halogen, –(CH2)0–2R ^, – (haloR ^), –(CH2)0–2OH, –(CH2)0–2OR ^, –(CH2)0–2CH(OR ^)2; -O(haloR ^), –CN, –N3, –(CH2)0–2C(O)R ^, – (CH2)0–2C(O)OH, –(CH2)0–2C(O)OR ^, –(CH2)0–2SR ^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR ^, – (CH2)0–2NR^2, –NO2, –SiR ^ 3, –OSiR ^ 3, -C(O)SR ^ , –(C1–4 straight or branched alkylene)C(O)OR ^, or – SSR ^ wherein each R ^ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from 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 divalent substituents on a saturated carbon atom of R ^ include =O and =S. [0250] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR* 2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R* 2))2–3O–, or –S(C(R* 2))2–3S–, 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 divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR* 2)2–3O–, 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). [0251] 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). [0252] 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 occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3 to 12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring (having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur). [0253] 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). [0254] As used herein, the term “provided compound” or “compound of the present disclosure” refers to any genus, subgenus, and/or species set forth herein. [0255] As used 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. Examples of 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. Other pharmaceutically acceptable 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, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. [0256] 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. [0257] Unless otherwise stated, 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. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-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. [0258] The terms “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. [0259] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” 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-polyoxypropylene-block polymers, polyethylene glycol and wool fat. [0260] 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. [0261] The terms “C1-3alkyl,” “C1-5alkyl,” and “C1-6alkyl” 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. Representative examples of 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. [0262] The term “C2-4alkenyl” as used herein refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight and branched moieties. Representative examples of C2-4alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl. [0263] The term “C3-6cycloalkyl” as used herein 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. [0264] The terms “diC1-3alkylamino” as used herein refer to –NR*R**, wherein R* and R** independently represent a C1-3alkyl as defined herein. Representative examples of diC1-3alkylamino include, but are not limited to, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH2CH2CH3)2, and – N(CH(CH3)2)2. [0265] The term “C1-3alkoxy” and “C1-6alkoxy” as used herein refer to –OR#, wherein R# represents a C1-3alkyl and C1-6alkyl group, respectively, as defined herein. Representative examples of C1-3alkoxy or C1-6alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy. [0266] The term “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. Representative examples of a 6-membered heteroaryl include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl. [0267] The term “C3-6heterocycloalkyl” as used herein 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 C3-6heterocycloalkyl group is a C6heterocycloalkyl, one or two carbon atoms are substituted with a heteroatom independently selected from N, O, and S. Representative examples of C3-6heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. [0268] The term “C5-8spiroalkyl” as used herein refers a bicyclic ring system, wherein the two rings are connected through a single common carbon atom. Representative examples of C5-8spiroalkyl 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. [0269] The term “C5-8tricycloalkyl” as used herein refers a tricyclic ring system, wherein all three cycloalkyl rings share the same two ring atoms. Representative examples of C5-8tricycloalkyl include, but are not limited to, tricyclo[1.1.1.01,3]pentanyl,
Figure imgf000104_0001
, tricyclo[2.1.1.01,4]hexanyl, tricyclo[3.1.1.01,5]hexanyl, and tricyclo[3.2.1.01,5]octanyl. [0270] The term “pharmaceutically acceptable excipient” as used herein 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. Typically, 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. [0271] The term “therapeutically effective amount” 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. GENERAL SYNTHETIC PROCEDURES [0272] The compounds provided herein can be synthesized according to the procedures described in this and the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. 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. [0273] Generally, 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. Starting material may also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as, solvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in the examples provided herein. As used below, 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. As used below, in certain embodiments Y is an organometal coupling reagent group, which can include but are not limited to, boronic acids and esters, organotin and organozinc reagents.
Scheme 1
Figure imgf000106_0001
Figure imgf000106_0002
Figure imgf000106_0003
[0274] As can be appreciated by the skilled artisan, the above synthetic scheme and representative examples are not intended to comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be performed in an alternate sequence or order to give the desired compounds. [0275] Purification methods for the compounds described herein are known in the art and include, for example, crystallization, chromatography (for example, liquid and gas phase), extraction, distillation, trituration, and reverse phase HPLC. [0276] The disclosure further encompasses “intermediate” compounds, including structures produced from the synthetic procedures described, whether isolated or generated in-situ and not isolated, prior to obtaining the finally desired compound. These intermediates are included in the scope of this disclosure. Exemplary embodiments of such intermediate compounds are set forth in the Examples below. EXAMPLES [0277] This section provides specific examples of compounds of Formula (I) and methods of making the same. List of Abbreviations
Figure imgf000106_0004
Figure imgf000107_0001
General Analytical and Purification Methods [0278] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific compounds provided herein. Chromatography: [0279] Unless otherwise indicated, crude product-containing residues were purified by passing the crude material or concentrate through either a Biotage brand silica gel column pre-packed with flash silica (SiO2) or reverse phase flash silica (C18) and eluting the product off the column with a solvent gradient as indicated. For example, a description of silica gel (0-40% EtOAc/hexane) means the product was obtained by elution from the column packed with silica using a solvent gradient of 0% to 40% EtOAc in hexanes. Preparative HPLC Method: [0280] Where so indicated, the compounds described herein were purified via reverse phase HPLC using Waters Fractionlynx semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenominex Gemini column (5 micron, C18, 150x30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100x30 mm). [0281] A typical run through the instrument included: eluting at 45 mL/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v formic acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separations. [0282] Condition A: Column: Phenomenex luna C18150*25mm* 10μm; Mobile Phase A: MeCN, Mobile Phase B: H2O (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*10μm; Mobile Phase A: Hexanes, Mobile Phase B: EtOH (0.1% FA); [0284] Condition C: Column: Phenomenex luna C18250*50mm*10 μm; Mobile Phase A: MeCN, Mobile Phase B: H2O (0.225% FA); Flow rate: 25 mL/min; Gradient 1: 65% B- 90% B in 22 min; [0285] Condition D: Column: DAICEL CHIRALCEL OJ (250mm*50mm,10 μm); Mobile Phase A: 0.1%NH3·H2O EtOH; Flow rate: 150 mL/min; Gradient 1: 100% in 8.5 min; Analytical HPLC Method: [0286] Where so indicated, the compounds described herein were analyzed using an Aglilent 1100 series instrument with DAD detector. Flash Chromatography Method: [0287] Where so indicated, flash chromatography was performed on Teledyne Isco instruments using pre-packaged disposable SiO2 stationary phase columns with eluent flow rate range of 15 to 200 mL/min, UV detection (254 and 220 nm). [0288] Condition A: Column: 20g Flash Column; Mobile Phase A: MeCN, Mobile Phase B: H2O (0.1% FA); Gradient 1: 40% B to 50% B in 5 min; Preparative Chiral Supercritical Fluid Chromatography (SFC) Method: [0289] Where so indicated, the compounds described herein were purified via chiral SFC using one of the two following chiral SFC columns: (a) Chiralpak IG 2x25 cm, 5 µm or (b) Chiralpak AD-H 2x15 cm, 5μm. Detector: PDA; [0290] Condition A: Column: Chiralpak AD-350*4.6mm I.D., 3μm; 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,10μm); 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,10μm; Mobile Phase A: CO2, Mobile Phase B: iPrOH (0.1% NH3H2O); Flow rate: 120 mL/min; Gradient 1: 60% B to 60% B in 5 min; [0293] Condition D: Column: Chiralpak AD (250mm*30mm,10 μm); Mobile Phase A: CO2, Mobile Phase B: EtOH (0.1% NH3H2O); Flow rate: 70 mL/min; Gradient 1: 50% B to 50% B in 10 min; [0294] Condition E: Column: Chiralpak AD (250mm*30mm,10 μm); Mobile Phase A: CO2, Mobile Phase B: MeCN/MeOH (0.1% NH3H2O); Flow rate: 100 mL/min; Gradient 1: 100% B in 8.2 min; [0295] Some CP Analytical-SFC experiments were run on SFC Method Station (Thar, Waters) with the following conditions: Column temperature: 40 ºC, Mobile phase: CO2/ MeOH (0.2% MeOH Ammonia) = Flow: 4.0 ml/min, Back Pressure: 120 Bar, Detection wavelength: 214 nm. [0296] Some CP Analytical-SFC experiments were run on SFC-80 (Thar, Waters) with the following conditions: Column temperature: 35 ºC, Mobile phase (example): CO2/ MeOH (0.2% MeOH Ammonia) = Flow rate: 80 g/min, Back pressure: 100 bar, Detection wavelength: 214 nm. [0297] Preparative CP Method: Acidic reversed phase MPLC: Instrument type: Reveleris™ prep MPLC; Column: Phenomenex LUNA C18(3) (150x25 mm, 10μ); 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 1H NMR spectra were collected on a Bruker NMR Instrument at 300, 400 or 500 Mhz or a Varian NMR Instrument at 400 Mhz. Where so characterized, all observed protons are reported as parts-per-million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as reference. All NMR were collected at about 25°C. Mass Spectra (MS) [0299] Unless otherwise indicated, all mass spectral data for starting materials, intermediates and/or exemplary compounds are reported as mass/charge (m/z), having an [M+H]+ molecular ion. The molecular ion reported was obtained by electrospray detection method (commonly referred to as an ESI MS) utilizing a Waters Acquity UPLC/MS system or a Gemini-NX UPLC/MS system. Compounds having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic pattern, as appreciated by those skilled in the art. Compound Names [0300] The compounds disclosed and described herein have been named using the IUPAC naming function of ChemDraw Professional 17.0. Specific Examples [0301] Provided in this section are the procedures to synthesize specific examples of the compounds provided herein. All starting materials are either commercially available from Sigma-Aldrich Inc., unless otherwise noted, or known in the art and may be synthesized by employing known procedures using ordinary skill. Synthesis of Intermediates Example A1: Synthesis of Intermediates B1-4
Figure imgf000110_0001
[0302] Step 1: To a solution of ethyl 4-hydroxy-2-methyl-thiazole-5-carboxylate (1 eq, 4.9 g, 26 mmol) in DCM (60mL) was added TEA (1.5 eq, 5.4 mL, 39 mmol) and trifluoromethanesulfonic anhydride (1.1 eq, 4.9 mL, 29 mmol) at -78°C, the mixture was stirred at -78oC for 4 h. The mixture was concentrated to give a crude product that was purified by column chromatography on silica gel eluted with (0-10% EtOAc/PE). Ethyl 2-methyl-4-(trifluoromethylsulfonyloxy)thiazole-5-carboxylate (Int-B1, 6.7 g, 21 mmol, 80% yield) was obtained as an oil. LC-MS: m/z: 320.0 [M+H]+.
Figure imgf000110_0002
Figure imgf000110_0003
[0303] 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), Cs2CO3 (2 eq, 13640 mg, 42 mmol), XantPhos (0.05 eq, 607 mg, 1.05 mmol) and Pd2(dba)3 (0.025 eq, 480 mg, 0.53 mmol), the mixture was stirred at 60°C for 12h. The mixture was poured into water, stirred for 15 min, filtered, and the filtrate was collected and concentrated in vacuo to approximately one-third. Then the solution was adjusted to pH=7 with HCl aq (1 M). The resultant precipitate was collected by filtration, washed with EtOAc and dried in vacuo to give a crude product that was carried to the next step without further purification.6-benzyl-2-methyl-4H-thiazolo[4,5-d]pyrimidine-5,7-dione (Int-B2, 2.4 g, 8 mmol, 38% yield) was obtained as a solid. LCMS: m/z: 274.1 [M+H]+.
Figure imgf000111_0001
[0304] 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 BBr3 (4 eq, 1.9 mL, 21 mmol) at 25 °C, the mixture was stirred at 170 °C for 1h. After the mixture was cooled to room temperature, the mixture was poured into MeOH (100 mL) at 0°C, filtered, and the filter cake was washed with MeOH and H2O, dried in vacuo to give a crude product that used for next step without further purification.2-methylthiazolo[4,5- d]pyrimidine-5,7-diol (Int-B3, 780 mg, 4.3 mmol, 83% yield) was obtained as a solid.1H NMR (400 MHz, DMSO-d6) δ: 12.27 (s, 1H), 11.32 (s, 1H), 2.74 (s, 3H).
Figure imgf000111_0002
[0305] 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. The aqueous phase was extracted with DCM (3x1000 mL), and the combined organic phase was washed with brine (3x1000 mL), dried with anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude product that was purified by column chromatography (0-25% EtOAc/PE).5,7-dichloro-2-methyl-thiazolo[4,5-d]pyrimidine (Int-B4, 350 mg, 1.6 mmol, 29% yield) was obtained as a solid.1H NMR (400 MHz, CDCl3) δ: 2.99 (s, 3H). Example 1: Synthesis of Compounds 100-101
Figure imgf000111_0003
[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). The organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue that was purified by silica gel column (0-33% EtOAc/PE) to give 2-[benzyl(2- hydroxyethyl)amino]-1-(1-cyclopropylpyrazol-4-yl)ethanone (Int-A1, 2.4 g, 8 mmol, 61% yield) as an oil. LCMS: [M+H]+ = 330.2.
Figure imgf000112_0001
[0307] 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 NaBH4 (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. The reaction mixture was quenched by saturated NH4Cl (100 mL), extracted with EtOAc (2x300 mL), the combine organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the 2-[benzyl(2-hydroxyethyl)amino]-1-(1-cyclopropylpyrazol-4-yl)ethanol (Int-A2, 1800 mg, 6 mmol, 75% yield) as an oil that was used in the next step without purification. LCMS: [M+H]+ = 330.2.
Figure imgf000112_0002
[0308] 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. LCMS: [M+H]+ = 284.1.
Figure imgf000112_0003
[0309] 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. The residue was filtered and the filter cake was washed with MeOH (3x20 mL), the combine organic layers was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the 2-(1-cyclopropylpyrazol-4-yl)morpholine (Int-A4, 400 mg, 2.1 mmol, 73% yield) as an oil. LCMS: [M+H]+ = 241.2.
Figure imgf000113_0001
[0310] 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. The mixture was quenched by H2O (10mL), extracted with EtOAc (3x20 mL), and the combine organic layers was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the residue. The residue was purified by Prep-TLC (100% EtOAc) give the 5-[2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-7- (2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Int-A5, 100 mg, 0.2 mmol, 65% yield) as a solid. LCMS: [M+H]+ = 484.2.
Figure imgf000113_0002
[0311] 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. Compound 100: LCMS: [M+H]+ = 484.2.1H NMR (400 MHz, CDCl3) δ: 7.81 - 7.70 (m, 1H), 7.53 (d, J = 5.8 Hz, 2H), 7.05 - 6.99 (m, 1H), 6.98 - 6.90 (m, 1H), 4.86 (br d, J = 13.6 Hz, 1H), 4.68 (br d, J = 12.9 Hz, 1H), 4.55 (dd, J = 2.6, 10.4 Hz, 1H), 4.05 (dd, J = 1.7, 11.6 Hz, 1H), 3.78 (dt, J = 2.8, 11.5 Hz, 1H), 3.58 (tt, J = 3.8, 7.3 Hz, 1H), 3.41 - 3.20 (m, 6H), 3.20 - 3.09 (m, 2H), 1.13 - 1.08 (m, 2H), 1.04 - 0.97 (m, 2H) ppm. Compound 101: LCMS: [M+H]+ = 484.2.1H NMR: (400 MHz, CDCl3) δ: 7.80 - 7.72 (m, 1H), 7.53 (d, J = 5.4 Hz, 2H), 7.06 - 6.99 (m, 1H), 6.98 - 6.91 (m, 1H), 4.90 - 4.83 (m, 1H), 4.68 (br d, J = 13.4 Hz, 1H), 4.55 (dd, J = 2.7, 10.3 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.84 - 3.72 (m, 1H), 3.58 (tt, J = 3.7, 7.3 Hz, 1H), 3.41 - 3.21 (m, 6H), 3.20 - 3.09 (m, 2H), 1.15 - 1.08 (m, 2H), 1.05 - 0.98 (m, 2H) ppm. Example 2: Synthesis of Compound 102
Figure imgf000114_0001
[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 K3PO4 (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℃ under N2 atmosphere. The reaction mixture was stirred at 90oC for 12h under N2 atmosphere. LCMS showed desired product. The reaction solution was diluted with water (50 mL), extracted with DCM (3x50 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (17% EtOAc/DCM) to afford 5-chloro-7-[4- (difluoromethyl)-2-fluoro-phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Int-A6, 242 mg, 0.5 mmol, 26% yield) as a solid. LCMS: [M+H]+ = 358.8.
Figure imgf000115_0001
[0313] 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 oC for 2 h. LCMS showed desired product. The reaction mixture was combined with the material for further purification. The reaction solution was diluted with water (50 mL), extracted with EtOAc (3x50 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by prep-TLC (60% EtOAc/DCM) to afford the product 5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]- 7-[4-(difluoromethyl)-2-fluoro-phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Compound 102, 60 mg, 0.1 mmol, 81% yield) as a solid. LCMS: [M+H]+ = 530.1.1H NMR (400 MHz, CDCl3) δ: 0.96 - 1.04 (m, 2H), 1.08 - 1.15 (m, 2H), 1.30 (d, J = 6.13 Hz, 3H), 2.73 (dd, J = 13.13, 10.76 Hz, 1H), 2.96 (dd, J = 13.07, 11.07 Hz, 1H), 3.28 (br s, 6H), 3.57 (tt, J = 7.19, 3.69 Hz, 1H), 3.75 - 3.86 (m, 1H), 4.58 (dd, J = 10.88, 2.38 Hz, 1H), 4.80 (br d, J = 13.01 Hz, 1H), 4.91 (br d, J = 13.13 Hz, 1H), 6.53 - 6.86 (m, 1H), 7.36 (br d, J = 10.38 Hz, 1H), 7.42 (br d, J = 8.00 Hz, 1H), 7.53 (d, J = 5.13 Hz, 2H), 7.85 (t, J = 7.44 Hz, 1H) ppm. Example 3: Synthesis of Compound 103
Figure imgf000115_0002
[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. the reaction mixture was stirred at 80 oC 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). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (70% EtOAc/DCM) to afford 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, 130 mg, 0.23 mmol, 118% yield crude) as a solid. LCMS: [M+H]+ = 513.1.
Figure imgf000116_0001
[0315] 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 oC for 24 h under H2 (50 Psi) atmosphere. LCMS showed desired product. The 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. The residue was combined with YH- 2022-06-049-49 to work up. The combined residues were dissolved in MeOH (1.5 mL), and then purified by prep-HPLC (Condition A, Gradient 1) to afford 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]-7-[4-(difluoromethyl)-2-fluoro-phenyl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin- 2-amine (Compound 103, 24 mg, 0.05 mmol, 33% yield) as a solid. LCMS: [M+H]+ = 515.4; 1H NMR (400 MHz, CDCl3) δ: 0.94 - 1.02 (m, 2H), 1.06 - 1.12 (m, 2H), 2.04 - 2.23 (m, 3H), 2.34 (dt, J = 13.23, 1.64 Hz, 1H), 3.34 (ddt, J = 15.71, 7.90, 3.77, 3.77 Hz, 7H), 3.55 (tt, J = 7.30, 3.77 Hz, 1H), 3.77 (td, J = 11.85, 2.44 Hz, 1H), 4.20 - 4.26 (m, 1H), 4.51 (dd, J = 11.38, 2.00 Hz, 1H), 6.57 - 6.87 (m, 1H), 7.37 - 7.50 (m, 4H), 7.90 (t, J = 7.57 Hz, 1H) ppm. Example 4: Synthesis of Compounds 104-106
Figure imgf000117_0001
[0316] 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 oC, then mixture was stirred at -78 oC under N2 atmosphere for 0.5 h. Triisopropyl borate (1.5 eq, 1.5 mL, 6.6 mmol) was added at - 78 oC, then the mixture was warmed to 25℃ and stirred for 1 h. TLC showed all of starting material was consumed and one new spot was formed. The mixture was quenched by NH4Cl, diluted with water (50 mL), and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. To the residue was added THF (10 mL) and HCl (10 mL, 3M) to stirred at 25 ℃ for 12 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (4-chloro-2,5-difluoro- phenyl)boronic acid (Int-A8, 840 mg, 4.1 mmol, 94% yield) as a solid.
Figure imgf000117_0002
[0317] 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 oC for 4 h under N2. LCMS showed desired product. The reaction mixture was combined with the crude product in Page: XZ-2022- 04-048-72 to work up. The combined mixture was diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (40% EtOAc/PE) to afford 5-chloro-7-(4-chloro-2,5-difluoro-phenyl)-N,N-dimethyl-1,3-benzothiazol-2- amine (Int-A9, 520 mg, 1 mmol, 35% yield) as a solid. LCMS: [M+H]+ = 360.7.
Figure imgf000118_0001
[0318] 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 K2CO3 (3 eq, 505 mg, 3.7 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added Pd(dppf)Cl2·DCM (0.1 eq, 89 mg, 0.12 mmol) at 25°C under N2. The reaction mixture was stirred at 80oC for 12 h. LCMS showed desired product. The reactions were diluted with water (50 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue that was purified by silica gel chromatography (88% EtOAc/PE) to afford the title compound 7-(4-chloro-2,5-difluoro-phenyl)-5-[(6R)-6-(1-cyclopropylpyrazol-4-yl)-3,6- dihydro-2H-pyran-4-yl]-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Int-A10, 330 mg, 0.6 mmol, 48% yield) as a solid. LCMS: [M+H]+ = 514.9.
Figure imgf000118_0002
[0319] 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 PtO2 (2 eq, 225 mg, 0.99 mmol). The reaction mixture was stirred at 40 oC for 16 h under H2 (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. The residue was purified by column chromatography on silica gel chromatography (50% EtOAc/PE) to afford a crude residue which was purified by reversed phase flash chromatography (Condition A, Gradient 1) to afford 7-(2,5-difluorophenyl)-N,N-dimethyl-5-[rac-(2R)-2- (1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (Compound 104, 22 mg, 0.05 mmol, 89% yield) as a solid. Compound 104: LCMS: [M+H]+ = 483.0.1H NMR (400 MHz, CDCl3) δ: 0.97 - 1.07 (m, 2H), 1.08 - 1.17 (m, 2H), 2.02 - 2.47 (m, 5H), 2.66 - 2.76 (m, 1H), 3.15 - 3.52 (m, 7H), 3.58 (ddt, J = 10.83, 7.21, 3.49, 3.49 Hz, 2H), 3.79 (td, J = 11.66, 1.69 Hz, 1H), 3.89 - 3.95 (m, 1H), 4.21 - 4.28 (m, 1H), 4.54 (br d, J = 11.01 Hz, 1H), 4.93 (dd, J = 7.88, 3.13 Hz, 1H), 7.22 (br t, J = 6.32 Hz, 2H), 7.49 - 7.57 (m, 3H) ppm.
Figure imgf000119_0001
[0320] 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). Compound 105: 7-(4-chloro-2,5-difluoro-phenyl)-N,N-dimethyl-5-[(2R,4S)-2-(1-cyclopropylpyrazol-4- yl)tetrahydropyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (81 mg, 0.16 mmol, 67% yield) as a solid. LCMS: [M+H]+ = 516.9. 1H NMR (400 MHz, CDCl3) δ: 0.96 - 1.04 (m, 2H), 1.05 - 1.13 (m, 2H), 2.04 - 2.20 (m, 3H), 2.33 (dt, J = 13.13, 1.69 Hz, 1H), 3.12 - 3.50 (m, 7H), 3.56 (tt, J = 7.30, 3.71 Hz, 1H), 3.78 (td, J = 11.79, 2.44 Hz, 1H), 4.19 - 4.27 (m, 1H), 4.52 (dd, J = 11.38, 2.00 Hz, 1H), 7.32 (dd, J = 9.38, 5.88 Hz, 1H), 7.49 (d, J = 1.63 Hz, 2H), 7.65 (dd, J = 8.94, 6.19 Hz, 1H) ppm. Compound 106: 7-(4-chloro-2,5-difluoro-phenyl)-N,N-dimethyl-5-[rac-(2R,4R)-2-(1-cyclopropylpyrazol -4-yl)tetrahydropyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (29 mg, 0.06 mmol, 24% yield) as a solid. LCMS: [M+H]+ = 517. 1H NMR (400 MHz, CDCl3) δ: 0.96 - 1.05 (m, 2H), 1.07 - 1.16 (m, 2H), 2.05 - 2.15 (m, 1H), 2.25 (ddd, J = 13.29, 7.97, 4.88 Hz, 1H), 2.34 - 2.43 (m, 1H), 2.64 - 2.73 (m, 1H), 3.11 - 3.49 (m, 6H), 3.51 - 3.62 (m, 2H), 3.89 (t, J = 5.38 Hz, 2H), 4.90 (dd, J = 7.57, 3.31 Hz, 1H), 7.33 (dd, J = 9.51, 5.88 Hz, 1H), 7.49 (s, 2H), 7.64 (dd, J = 8.94, 6.19 Hz, 1H) ppm. Example 5: Synthesis of Compounds 107-108
Figure imgf000120_0001
[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. LCMS showed starting material was remained and a major peak with desired was detected. The mixture was added silica gel and concentrated under reduced process to give a residue that was purified by flash chromatography (50% EtOAc/DCM) and concentrated under vacuum to give 5-chloro-N,N-dimethyl-7-(2,3,4-trifluorophenyl)thiazolo[4,5- d]pyrimidin-2-amine (Int-A12, 490 mg, 1.3 mmol, 31% yield) as a solid. LCMS: [M+H]+ = 345.0.1H NMR (400 MHz, CDCl3) δ: 7.63 - 7.46 (m, 1H), 7.22 - 7.06 (m, 1H), 3.55 - 3.14 (m, 6H) ppm.
Figure imgf000120_0002
[0322] 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), K2CO3 (3 eq, 517 mg, 3.7 mmol), and Pd(dppf)Cl2·DCM (0.1 eq, 91 mg, 0.13 mmol) under N2, and the solution was stirred at 100 °C for 4 h. LCMS showed starting material was consumed completely and a major peak with desired MS was detected. The mixture was added silica gel and concentrated under reduced process to give the residue. The residue was purified by flash column (100% EtOAc) and concentrated under vacuum to give 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, 500 mg, 1 mmol, 80% yield) as a solid. LCMS: [M+H]+ = 499.1. 1H NMR (400 MHz, CDCl3) δ: 7.60 - 7.56 (m, 1H), 7.53 (s, 1H), 7.41 - 7.40 (m, 1H), 7.43 - 7.38 (m, 1H), 7.19 - 7.10 (m, 1H), 7.20 - 7.10 (m, 1H), 4.68 (br d, J = 3.3 Hz, 1H), 4.63 - 4.49 (m, 2H), 3.62 - 3.53 (m, 1H), 3.51 - 3.12 (m, 7H), 2.96 - 2.76 (m, 1H), 1.17 - 1.07 (m, 2H), 1.07 - 0.94 (m, 2H) ppm.
Figure imgf000121_0001
[0323] 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. LCMS showed starting material was remained and a peak with desired MS was found and the mixture was cooled to 25 °C and degassed with N2 (3x). The mixture was filtered, and the filtrate was concentrated under vacuum to give the crude. The crude was purified by normal phase preparative HPLC (Condition B) to afford the product and recycle starting material. Then the product was purified by reversed-phase chromatography (60% MeCN/Water(FA)) and lyophilized to give 5-[(2R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- N,N-dimethyl-7-(2,3,4-trifluorophenyl)thiazolo[4,5-d]pyrimidin-2-amine (190 mg, 0.37 mmol, 37%
Figure imgf000121_0002
190 mg product was purified by SFC separation (Condition C, Gradient 1) and lyophilized to give Compound 107 and Compound 108. Compound 107: 5-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-N,N-dimethyl-7-(2,3,4- trifluorophenyl)thiazolo[4,5-d]pyrimidin-2-amine (25 mg, 0.05 mmol, 5% yield) as a solid. LCMS: [M+H]+ = 501.4. 1H NMR (400 MHz, CDCl3) δ: 7.59 - 7.53 (m, 1H), 7.53 - 7.49 (m, 1H), 7.49 - 7.46 (m, 1H), 7.20 - 7.10 (m, 1H), 4.89 (dd, J = 3.4, 7.7 Hz, 1H), 4.03 - 3.81 (m, 2H), 3.61 - 3.52 (m, 2H), 3.52 - 3.09 (m, 6H), 2.74 - 2.58 (m, 1H), 2.37 (td, J = 4.5, 9.1 Hz, 1H), 2.28 - 2.19 (m, 1H), 2.14 - 2.04 (m, 1H), 1.15 - 1.07 (m, 2H), 1.04 - 0.95 (m, 2H) ppm. Compound 108: 5-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-N,N-dimethyl-7-(2,3,4- trifluorophenyl)thiazolo[4,5-d]pyrimidin-2-amine (89 mg, 0.18 mmol, 18% yield) as a solid. LCMS: [M+H]+ = 501.2. 1H NMR (400 MHz, CDCl3) δ: 7.55 (br d, J = 6.9 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.20 - 7.10 (m, 1H), 4.51 (dd, J = 1.9, 11.4 Hz, 1H), 4.29 - 4.15 (m, 1H), 3.82 - 3.71 (m, 1H), 3.58 - 3.51 (m, 1H), 3.49 - 3.03 (m, 7H), 2.38 - 2.27 (m, 1H), 2.20 - 2.14 (m, 1H), 2.14 - 2.09 (m, 1H), 2.08 - 2.01 (m, 1H), 1.14 - 1.03 (m, 2H), 1.03 - 0.93 (m, 2H) ppm. Example 6: Synthesis of Compound 109
Figure imgf000122_0001
[0324] 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. The crude product was purified by reversed-phase HPLC (0.1% FA condition) and lyophilized to give (R)-2-(2-methylpyrrolidin-1- yl)thiazolo[4,5-d]pyrimidine-5,7-diol (Int-A14, 1200 mg, 4.8 mmol, 97% yield) as a solid. LCMS: [M+H]+ = 253.2.1H NMR (400 MHz, CDCl3) δ: 2.28 - 2.15 (m, 2H), 2.04 (s, 2H), 2.02 (s, 1H), 1.87 - 1.77 (m, 2H), 1.44 (d, J = 6.7 Hz, 3H) ppm.
Figure imgf000122_0002
[0325] 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). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by column chromatography on silica gel chromatography (0-100% EtOAc-PE) to give (R)-5,7-dichloro-2-(2-methylpyrrolidin-1-yl)thiazolo[4,5-d]pyrimidine (Int-A15, 1200 mg, 4 mmol, 95% yield) as a solid. LCMS: [M+H]+ = 288.9.1H NMR (400 MHz, CDCl3) δ: 4.62 - 3.33 (m, 3H), 2.35 - 1.75 (m, 4H), 1.41 (br d, J = 6.0 Hz, 3H) ppm.
Figure imgf000123_0001
[0326] 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. LCMS showed desired product. The reaction mixture was purified by column chromatography on silica gel chromatography (0-100% EtOAc/PE) to give (R)-5-chloro-7-(2,4-difluorophenyl)-2-(2-methylpyrrolidin- 1-yl)thiazolo[4,5-d]pyrimidine (Int-A16, 1200 mg, 3.3 mmol, 79% yield) as a solid. LCMS: [M+H]+ = 367.0.1H NMR (400 MHz, CDCl3) δ: 7.85 - 7.77 (m, 1H), 7.06 (dt, J = 2.2, 8.2 Hz, 1H), 7.00 - 6.94 (m, 1H), 3.97 - 3.84 (m, 1H), 3.76 - 3.34 (m, 2H), 2.32 - 2.07 (m, 4H), 1.42 (br s, 3H) ppm.
Figure imgf000123_0002
[0327] 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. The 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. LCMS: [M+H]+ = 538.3.1H NMR (400 MHz, CDCl3) δ: 7.75 (dt, J = 6.6, 8.4 Hz, 1H), 7.53 (d, J = 4.9 Hz, 2H), 7.04 - 6.89 (m, 2H), 4.95 - 4.76 (m, 2H), 4.58 (dd, J = 2.6, 10.8 Hz, 1H), 3.80 (ddd, J = 2.5, 6.3, 10.5 Hz, 1H), 3.57 (tt, J = 3.7, 7.3 Hz, 1H), 2.95 (dd, J = 10.9, 13.2 Hz, 1H), 2.72 (dd, J = 10.6, 13.1 Hz, 1H), 2.22 - 2.03 (m, 3H), 1.85 - 1.76 (m, 1H), 1.67 - 1.55 (m, 2H), 1.35 (br d, J = 5.3 Hz, 3H), 1.30 (d, J = 6.1 Hz, 3H), 1.13 - 1.08 (m, 2H), 1.00 (dd, J = 2.4, 7.1 Hz, 2H) ppm. The above procedure was followed to prepare the below compound:
Figure imgf000124_0002
Example 7: Synthesis of Compound 110
Figure imgf000124_0001
[0328] 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 K3PO4 (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. The mixture was stirred at 80 oC for 1 h. LCMS showed starting material remained and desired product was detected. The mixture was quenched by H2O (30mL), extracted with EtOAc (3x30 mL), the combined organic layers was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by Prep-HPLC (Condition A, Gradient 3) to give 5-chloro-7-(2-fluoro-4-methyl-phenyl)-N,N-dimethyl-thiazolo[4,5- d]pyrimidin-2-amine (Int-A17, 42 mg, 0.13 mmol, 32% yield) as a solid. LCMS: [M+H]+= 323.2.1H NMR (400 MHz, CDCl3) δ: 7.68 (t, J = 7.9 Hz, 1H), 7.17 - 7.07 (m, 1H), 7.02 (d, J = 11.6 Hz, 1H), 3.53 - 3.09 (m, 6H), 2.43 (s, 3H) ppm.
Figure imgf000125_0001
[0329] 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. The reaction was quenched by H2O (25 mL), extracted with EtOAc (3x15 mL), the combine organic layers was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by Prep-TLC (33% EtOAc/PE) to give crude product (20 mg). The crude product was purified by Prep-HPLC (Condition A, Gradient 4) and lyophilized to give the 5-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4- yl]-7-(2-fluoro-4-methyl-phenyl)-N,N-dimethyl-thiazolo[4,5-d]pyrimidin-2-amine (Compound 110, 4.3 mg, 0.01 mmol, 9% yield) as a solid. LCMS: [M+H]+ = 494.4.1H NMR (400 MHz, CDCl3) δ: 7.63 (br t, J = 7.8 Hz, 1H), 7.52 (br d, J = 5.8 Hz, 2H), 7.07 (br d, J = 7.9 Hz, 1H), 6.99 (br d, J = 11.6 Hz, 1H), 4.91 (br d, J = 13.0 Hz, 1H), 4.80 (br d, J = 13.1 Hz, 1H), 4.57 (br d, J = 9.1 Hz, 1H), 3.79 (br s, 1H), 3.62 - 3.49 (m, 1H), 3.25 (br s, 6H), 2.94 (br t, J = 12.0 Hz, 1H), 2.76 - 2.62 (m, 1H), 2.41 (s, 3H), 1.28 (br d, J = 6.1 Hz, 3H), 1.10 (br s, 2H), 0.99 (br d, J = 5.9 Hz, 2H) ppm. The above procedure was followed to make the following compounds:
Figure imgf000126_0002
Example 8: Synthesis of Compound 111
Figure imgf000126_0001
[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), Cs2CO3 (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 N2 atmosphere. LCMS showed desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a crude residue that was purified by column chromatography on silica gel chromatography (0-100% EtOAc/PE) to give (2S,6R)-4-(7-chlorothieno[3,2-b]pyridin-5-yl)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6- methylmorpholine (Int-A18, 840 mg, 2.2 mmol, 46% yield) as a solid. LCMS: [M+H]+ = 375.2.1H NMR (400 MHz, CDCl3) δ: 7.67 (d, J = 5.5 Hz, 1H), 7.55 (s, 2H), 7.31 (d, J = 5.4 Hz, 1H), 6.78 (s, 1H), 4.65 (dd, J = 2.6, 10.9 Hz, 1H), 4.30 (br d, J = 12.6 Hz, 1H), 4.21 - 4.16 (m, 1H), 3.92 - 3.84 (m, 1H), 3.58 (tt, J = 3.8, 7.3 Hz, 1H), 2.94 (dd, J = 10.9, 12.7 Hz, 1H), 2.72 (dd, J = 10.6, 12.6 Hz, 1H), 1.34 (d, J = 6.3 Hz, 3H), 1.15 - 1.11 (m, 2H), 1.01 (s, 2H) ppm.
Figure imgf000127_0001
[0331] 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. LCMS showed desired product. The reaction mixture with the YT-2022-04-030-51 was purified by column chromatography on silica gel chromatography (0-100% EtOAc/PE) to give (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7- (2,4-difluorophenyl)thieno[3,2-b]pyridin-5-yl)-6-methyl-morpholine (Crude, 520 mg, 1.2 mmol, 86% yield) as an oil. (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. LCMS: [M+H]+ = 453.1.
Figure imgf000127_0002
NMR (400 MHz, CDCl3) δ: 7.67 - 7.54 (m, 4H), 7.37 (d, J = 5.5 Hz, 1H), 7.07 - 6.97 (m, 2H), 6.75 (s, 1H), 4.69 (dd, J = 2.5, 10.9 Hz, 1H), 4.38 - 4.21 (m, 2H), 3.91 (ddd, J = 2.5, 6.3, 10.5 Hz, 1H), 3.58 (td, J = 3.6, 7.3 Hz, 1H), 3.01 - 2.69 (m, 2H), 1.35 (d, J = 6.3 Hz, 3H), 1.15 - 1.10 (m, 2H), 1.04 - 0.98 (m, 2H) ppm.
Example 9: Synthesis of Compounds 113-114
Figure imgf000128_0001
[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 oC for 1 h. LCMS showed the starting material was consumed completely and desired product was detected. The mixture was quenched by H2O (30 mL) and extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue that was purified by column chromatography (0-100% EtOAc/PE) to give (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 (Int-A19, 380 mg, 0.6 mmol, 81% yield) as a solid. LCMS: [M+H]+ = 501.1.1H NMR (400 MHz, CDCl3) δ: 7.77 (dt, J = 6.4, 8.4 Hz, 1H), 7.55 (d, J = 4.4 Hz, 2H), 7.04 (dt, J = 2.2, 8.3 Hz, 1H), 6.97 (ddd, J = 2.4, 8.6, 10.7 Hz, 1H), 5.01 - 4.77 (m, 2H), 4.59 (dd, J = 2.6, 10.9 Hz, 1H), 3.89 - 3.73 (m, 1H), 3.58 (tt, J = 3.8, 7.3 Hz, 1H), 3.02 (dd, J = 10.9, 13.3 Hz, 1H), 2.85 (s, 3H), 2.79 (dd, J = 10.7, 13.2 Hz, 1H), 1.32 (d, J = 6.3 Hz, 3H), 1.15 - 1.10 (m, 2H), 1.05 - 0.99 (m, 2H) ppm. Preparing isopropylzinc(II) chloride: A 40 mL sealed tube was heated and purged with N2 (3x), a solution of iPrMgCl·LiCl (1 eq, 5 mL, 6.5 mmol) (in THF) was added with syringe. Then, ZnCl2 (1.2 eq, 16 mL, 7.8 mmol) (in THF) was added slowly with syringe at 25oC under N2 and stirred for 1 h to give the reaction mixture (solution of isopropylzinc(II) chloride (935 mg, 6.5 mmol, 100% yield) in THF was ~0.32 M) was used directly in the next step.
Figure imgf000129_0001
[0333] 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. The reaction mixture was stirred at 80 oC 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). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude residue that was purified by column chromatography (0-100% EtOAc/PE) to give 100 mg impure product that was purified by prep-HPLC (Condition A, Gradient 5) to give 30 mg the desired product (pure, checked by LCMS).30 mg the desired product was purified by prep-TLC (50% EtOAc/PE) to give 25 mg the desired product, HNMR showed no change.25 mg the desired product was purified by SFC (Condition D, Gradient 1) to give (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-(2,4-difluorophenyl)-2-isopropylthiazolo[4,5- d]pyrimidin-5-yl)-6-methylmorpholine (Compound 113, 13 mg, 0.025 mmol, 7% yield) as a solid, and (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-(2,4-difluorophenyl)-2-propylthiazolo[4,5-d]pyrimidin- 5-yl)-6-methylmorpholine (Compound 114, 2.1 mg, 0.0038 mmol, 1% yield) as a solid. Compound 113: LCMS: [M+H]+ = 497.1. 1H NMR (400 MHz, CDCl3) δ: 7.78 (dt, J = 6.5, 8.4 Hz, 1H), 7.54 (d, J = 3.8 Hz, 2H), 7.09 - 7.02 (m, 1H), 6.98 (ddd, J = 2.4, 8.6, 10.6 Hz, 1H), 4.96 (br d, J = 13.0 Hz, 1H), 4.85 (br d, J = 13.3 Hz, 1H), 4.60 (dd, J = 2.6, 10.8 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.58 (tt, J = 3.5, 7.2 Hz, 1H), 3.40 (td, J = 6.9, 13.8 Hz, 1H), 3.02 (dd, J = 11.0, 13.2 Hz, 1H), 2.79 (dd, J = 10.7, 13.3 Hz, 1H), 1.49 (d, J = 6.8 Hz, 6H), 1.32 (d, J = 6.2 Hz, 3H), 1.16 - 1.09 (m, 2H), 1.06 - 0.98 (m, 2H) ppm. Compound 114: LCMS: [M+H]+ = 497.2. 1H NMR (400 MHz, CDCl3) δ: 7.79 (dt, J = 6.5, 8.5 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.05 (dt, J = 1.7, 8.3 Hz, 1H), 6.98 (ddd, J = 2.4, 8.5, 10.7 Hz, 1H), 4.96 (br d, J = 12.3 Hz, 1H), 4.84 (br d, J = 13.0 Hz, 1H), 4.60 (dd, J = 2.6, 10.8 Hz, 1H), 3.87 - 3.76 (m, 1H), 3.66 - 3.53 (m, 1H), 3.09 (t, J = 7.5 Hz, 2H), 3.02 (dd, J = 11.0, 13.2 Hz, 1H), 2.79 (dd, J = 10.6, 13.3 Hz, 1H), 1.95 (sxt, J = 7.4 Hz, 2H), 1.32 (d, J = 6.2 Hz, 3H), 1.15 - 1.09 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H), 1.01 (br d, J = 5.4 Hz, 2H) ppm. Example 10: Synthesis of Compounds 115-116
Figure imgf000130_0001
[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. Cooled down, then iodine (0.02 eq, 24 mg, 0.09 mmol) in THF (0.4 mL) was introduced and the reaction was stirred at 55°C for another 20 min, 4-[(2R)-4-bromotetrahydropyran-2-yl]-2-methyl-pyridine (1 eq, 1200 mg, 4.7 mmol) in THF (9 mL) was then added to the warm suspension of activated zinc. The reaction solution was stirred at 55°C for 12 h. LCMS showed reactant was consumed and major De-Br mass, the reaction solution was used directly in the next step. Int-A20: LCMS: [M+H]+ = 178.2.
Figure imgf000130_0002
[0335] 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). The mixture was purged with N2 (3x), followed by 5-chloro-7-(2,4-difluorophenyl)-N,N-dimethyl-thiazolo[4,5- d]pyrimidin-2-amine (1 eq, 600 mg, 1.8 mmol), and the mixture was then stirred at 55°C for 2 h. LCMS showed excess zinc reagent and desired mass, the reaction mixture was poured into H2O (50 mL), extracted with EtOAc (3x50 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude residue was then purified with flash chromatography (9% MeOH/EtOAc) and evaporated under reduced pressure to give 400 mg product as a solid that was purified with Prep-HPLC and lyophilized to give ~140 mg racemate product, which was then purified with SFC and lyophilized to give 7-(2,4-difluorophenyl)- N,N-dimethyl-5-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (Compound 115, 54 mg, 0.12 mmol, 6% yield) as a solid and 7-(2,4-difluorophenyl)-N,N-dimethyl-5- [(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]thiazolo[4,5-d]pyrimidin-2-amine (Compound 116, 60 mg, 0.13 mmol, 7% yield) as a solid. Compound 115: LCMS: [M+H]+ = 468.3. 1H NMR (400 MHz, CDCl3) δ: 8.43 (d, J = 5.1 Hz, 1H), 7.78 (dt, J = 6.6, 8.4 Hz, 1H), 7.22 (s, 1H), 7.11 (d, J = 5.1 Hz, 1H), 7.06 (dt, J = 2.4, 8.3 Hz, 1H), 7.01 - 6.94 (m, 1H), 4.53 - 4.46 (m, 1H), 4.33 (dd, J = 3.3, 11.6 Hz, 1H), 3.79 (dt, J = 2.5, 11.8 Hz, 1H), 3.48 - 3.09 (m, 7H), 2.55 (s, 3H), 2.33 (br d, J = 13.5 Hz, 1H), 2.26 - 2.07 (m, 2H), 2.06 - 1.93 (m, 1H) ppm. Compound 116: LCMS: [M+H]+ = 468.3. 1H NMR (400 MHz, CDCl3) δ: 8.44 (d, J = 5.1 Hz, 1H), 7.78 (dt, J = 6.5, 8.4 Hz, 1H), 7.23 (s, 1H), 7.12 (br d, J = 5.1 Hz, 1H), 7.06 (dt, J = 2.4, 8.1 Hz, 1H), 7.01 - 6.94 (m, 1H), 4.50 (dd, J = 1.6, 11.3 Hz, 1H), 4.38 - 4.29 (m, 1H), 3.79 (dt, J = 2.7, 11.9 Hz, 1H), 3.45 - 3.14 (m, 7H), 2.56 (s, 3H), 2.38 - 2.28 (m, 1H), 2.25 - 2.08 (m, 2H), 2.06 - 1.93 (m, 1H) ppm. Example 11: Synthesis of Compound 118
Figure imgf000131_0001
[0336] Step 1: To a solution of (2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-4-[7-[2-fluoro-4- (trifluoromethyl)phenyl]-2-methylsulfanyl-thiazolo[4,5-d]pyrimidin-5-yl]-6-methyl-morpholine (1 eq, 100 mg, 0.18 mmol) and N2H4·H2O (1.2 eq, 11 mg, 0.22 mmol) in EtOH (1 mL) was added and then the mixture was stirred for 3 h at 25°C. LCMS showed raw material consumed and the major peak showed desired. The reaction was then extracted with EtOAc (2x2 mL) and the organics washed with sat. brine solution (5 mL), the organics were then separated and dried over Na2SO4, filtered and concentrated under reduced pressure to give [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, 90 mg, 0.17 mmol, 93% yield) as a solid. LCMS: [M+H]+ = 535.2.
Figure imgf000132_0001
[0337] 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 SOCl2 (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. The reaction solution was poured into ice NaHCO3 (aq.10 mL) slowly and then extracted with EtOAc (2x10 mL), the organics washed with sat. brine solution (10 mL). The organics were then separated and dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude residue that was then purified by prep-TLC (66% EtOAc/PE) to give (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, 70 mg, 0.13 mmol, 77% yield) as a solid. LCMS: [M+H]+ = 539.1.
Figure imgf000132_0002
[0338] 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. LCMS showed raw material was consumed and the major peak showed desired MS. The reaction solution was added water (10 mL) and then extracted with EtOAc (3x5 mL), the organics washed with sat. brine solution (5 mL). The organics were then separated and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was then purified by prep-HPLC (Condition A) and freeze-drying to give (2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-4-[7-[2-fluoro-4-(trifluoromethyl)-phenyl]-2-isopropoxy-thiazolo[4,5- d]pyrimidin-5-yl]-6-methyl-morpholine (Compound 118, 5.2 mg, 0.009 mmol, 8% yield) as a solid. LCMS: [M+H]+ = 563.3.1H NMR (400 MHz, CDCl3) δ: 0.97 - 1.04 (m, 2H), 1.08 - 1.16 (m, 2H), 1.31 (d, J = 6.25 Hz, 3H), 1.48 (d, J = 6.13 Hz, 6H), 2.76 (dd, J = 13.20, 10.69 Hz, 1H), 3.00 (dd, J = 13.13, 11.01 Hz, 1H), 3.57 (tt, J = 7.29, 3.72 Hz, 1H), 3.75 - 3.88 (m, 1H), 4.59 (dd, J = 10.88, 2.63 Hz, 1H), 4.78 (br d, J = 13.26 Hz, 1H), 4.89 (br d, J = 13.01 Hz, 1H), 5.56 - 5.69 (m, 1H), 7.46 - 7.60 (m, 4H), 7.88 (t, J = 7.57 Hz, 1H) ppm. Example 12: Synthesis of Compounds 119-122
Figure imgf000133_0001
[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. Cooled down, then iodine (0.02 eq, 22 mg, 0.08 mmol) in THF (1mL) was introduced and the reaction was stirred at 55 °C for another 20 min, 5-(4-bromotetrahydropyran-2-yl)-1- methyl-pyridin-2-one (1 eq, 1200 mg, 4.4 mmol) in THF (9 mL) was then added to the warm suspension of activated zinc. And the reaction solution was stirred at 55 °C for 12 h. LCMS (quenched with EtOH) showed reactant was consumed and major De-Br mass was detected. The reaction mixture (containing Int- A23) was used directly for next step with syringe. LCMS: [M-Zn-Br+H]+ = 194.3.
Figure imgf000133_0002
[0340] 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 N2 (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. LCMS showed reactant was consumed and ~46% of desired mass. The reaction solution was poured into H2O (12 mL), extracted with EtOAc (3x15 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude which was then purified with flash column chromatography (9% MeOH/EtOAc) and evaporated under reduced pressure to give 400 mg purple product, which was then purified with Prep-HPLC (Condition D, Gradient 1) and lyophilized to give 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, 0.3 mmol, 17% yield) as a solid and 1-methyl-5-[rac-(2R,4R)-4-[7-(2,4- difluorophenyl)-2-(dimethylamino)-thiazolo[4,5-d]pyrimidin-5-yl]tetrahydropyran-2-yl]pyridin-2-one (Int-A24b, 110 mg, 0.23 mmol, 12% yield) as a solid. Int-A24a, LCMS: [M+H]+ = 484.3. Int-A24b, LCMS: [M+H]+ = 484.3.
Figure imgf000134_0001
[0341] 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). The crude P1 was separated by SFC (Condition E, Gradient 1) and lyophilized to give 5-[(2R,4S)-4-[7-(2,4- difluorophenyl)-2-(dimethylamino)thiazolo[4,5-d]pyrimidin-5-yl]tetrahydropyran-2-yl]-1-methyl-pyridin- 2-one (Compound 119, 54 mg, 0.11 mmol, 90% yield) as a solid. Compound 119: LCMS: [M+H]+ = 484.2. 1H NMR (400 MHz, CDCl3) δ: 7.79 (dt, J = 6.6, 8.4 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.06 (dt, J = 2.4, 8.3 Hz, 1H), 6.98 (ddd, J = 2.5, 8.7, 10.7 Hz, 1H), 6.56 (d, J = 9.1 Hz, 1H), 4.32 - 4.23 (m, 2H), 3.75 (dt, J = 3.1, 11.5 Hz, 1H), 3.55 (s, 3H), 3.33 (ddd, J = 3.9, 7.8, 15.4 Hz, 6H), 2.31 - 2.23 (m, 1H), 2.21 - 1.98 (m, 4H) ppm. The crude P2 was separated by SFC (Condition E, Gradient 1) and lyophilized to give 5-[(2S,4R)-4-[7-(2,4- difluorophenyl)-2-(dimethylamino)thiazolo[4,5-d]pyrimidin-5-yl]tetrahydropyran-2-yl]-1-methyl-pyridin- 2-one (Compound 120, 46 mg, 0.09 mmol, 75% yield) as a solid. LCMS: [M+H]+ = 484.2.1H NMR (400 MHz, CDCl3) δ: 7.79 (dt, J = 6.5, 8.4 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.06 (dt, J = 2.1, 8.1 Hz, 1H), 6.98 (ddd, J = 2.4, 8.6, 10.7 Hz, 1H), 6.56 (d, J = 9.1 Hz, 1H), 4.28 (dt, J = 2.3, 10.7 Hz, 2H), 3.75 (dt, J = 3.0, 11.6 Hz, 1H), 3.55 (s, 3H), 3.42 - 3.24 (m, 6H), 2.30 - 2.22 (m, 1H), 2.21 - 1.98 (m, 4H) ppm. 1-methyl-5-[rac-(2R,4R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5-d]pyrimidin-5- yl]tetrahydropyran-2-yl]pyridin-2-one (Int-A24b, 110 mg) was seperated by SFC (Condition E, Gradient 1) and lyophilized to give 5-[(2S,4S)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5-d]pyrimidin- 5-yl]tetrahydropyran-2-yl]-1-methyl-pyridin-2-one (Compound 121, 46 mg, 0.09 mmol, 45% yield) as a solid, and 5-[(2R,4R)-4-[7-(2,4-difluorophenyl)-2-(dimethylamino)thiazolo[4,5-d]pyrimidin-5- yl]tetrahydropyran-2-yl]-1-methyl-pyridin-2-one (Compound 122, 42 mg, 0.07 mmol, 37% yield) as a solid. Compound 121: LCMS: [M+H]+ = 484.2. 1H NMR (400 MHz, CDCl3) δ: 7.81 (dt, J = 6.4, 8.5 Hz, 1H), 7.40 (dd, J = 2.4, 9.3 Hz, 1H), 7.37 (s, 1H), 7.08 (dt, J = 2.3, 8.2 Hz, 1H), 7.01 (ddd, J = 2.4, 8.6, 10.7 Hz, 1H), 6.58 (d, J = 9.4 Hz, 1H), 4.63 (dd, J = 2.3, 9.9 Hz, 1H), 3.97 - 3.86 (m, 2H), 3.63 - 3.57 (m, 1H), 3.55 (s, 3H), 3.36 (br d, J = 12.3 Hz, 6H), 2.72 (br d, J = 13.5 Hz, 1H), 2.52 (br dd, J = 1.8, 13.7 Hz, 1H), 2.19 - 2.11 (m, 1H), 2.11 - 2.01 (m, 1H) ppm. Compound 122: LCMS: [M+H]+ = 484.2. 1H NMR (400 MHz, CDCl3) δ: 7.81 (dt, J = 6.4, 8.5 Hz, 1H), 7.41 (dd, J = 2.4, 9.3 Hz, 1H), 7.37 (s, 1H), 7.08 (dt, J = 2.1, 8.1 Hz, 1H), 7.01 (ddd, J = 2.4, 8.6, 10.7 Hz, 1H), 6.58 (d, J = 9.4 Hz, 1H), 4.63 (dd, J = 2.3, 10.0 Hz, 1H), 3.97 - 3.87 (m, 2H), 3.59 (br s, 1H), 3.56 (s, 3H), 3.36 (br d, J = 12.4 Hz, 6H), 2.72 (br d, J = 13.4 Hz, 1H), 2.52 (br dd, J = 1.8, 13.7 Hz, 1H), 2.20 - 2.11 (m, 1H), 2.10 - 2.01 (m, 1H) ppm. Example 13: Synthesis of Compound 123
Figure imgf000135_0001
[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). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (50% EtOAc/PE) to afford the product (10 mg) as a solid. The residue was purified by prep-HPLC (Condition C, Gradient 1) and lyophilized to afford 7-(2,4- difluorophenyl)-N,N-dimethyl-5-[(2R,6S)-2-methyl-6-(2-methyl-4-pyridyl)morpholin-4-yl]thiazolo[4,5- d]pyrimidin-2-amine (Compound 123, 1.3 mg, 0.003 mmol, 7% yield) as a solid. LCMS: [M+H]+ = 483.2.1H NMR (400 MHz, CDCl3) δ: 8.49 (br d, J = 5.1 Hz, 1H), 7.76 (dt, J = 6.7, 8.3 Hz, 1H), 7.30 (s, 1H), 7.23 (br d, J = 4.5 Hz, 1H), 7.06 - 6.91 (m, 2H), 4.96 (br d, J = 13.6 Hz, 1H), 4.84 (br d, J = 13.0 Hz, 1H), 4.60 (dd, J = 2.3, 10.6 Hz, 1H), 3.90 - 3.81 (m, 1H), 3.28 (br s, 6H), 2.77 (ddd, J = 10.8, 13.2, 18.3 Hz, 2H), 2.60 (s, 3H), 1.36 (d, J = 6.1 Hz, 3H) ppm. Example 14: Synthesis of Compounds 124-125
Figure imgf000136_0001
[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). The reaction vial was purged and plunged to a pre-heated bath at 100 °C for 3 h. The LC-MS showed complete consumption of the starting material. To the mixture was added saturated solution of NaHCO3 (20 mL), and the organic phase was extracted with EtOAc (20 mL), The organic phase was washed with water (10 mL), brine (10 mL) and dried over Na2SO4 concentrated and purified by flash chromatography (0-100% EtOAc/Hexanes, then 0-20% MeOH/DCM), followed by Prep-HPLC purification (Gemini® 5 um NX-C18110 Å, 100 x 30 mm) using aqueous 10 mM ammonium bicarbonate and ACN (35-55%) to get 6-(2,4-difluorophenyl)-7-methyl-2- [(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-8-[(2R)-2-methylpyrrolidin-1-yl]purine as a solid (Compound 124, 20 mg, 0.038 mmol, 36% yield). Compound 124: ESI-MS (m/z+): 520.4.1H NMR (CHCl3-d, 400 MHz): δH 7.71 (1H, d, J = 7.9 Hz), 7.46 (2H, s), 7.07 (1H, s), 6.90-6.95 (1H, m), 4.43-4.48 (2H, m), 4.15-4.19 (1H, m), 3.80 (1H, dd, J = 9.4, 6.8 Hz), 3.71 (1H, t, J = 11.7 Hz), 3.58 (1H, s), 3.50-3.54 (1H, m), 3.27-3.29 (3H, m), 2.13-2.25 (4H, m), 2.00 (3H, t, J = 16.6 Hz), 1.65 (2H, br s), 1.32 (3H, d, J = 6.1 Hz), 1.04-1.07 (2H, m), 0.93-0.97 (2H, m). The following compound was made following the above procedure:
Figure imgf000137_0002
Example 15: Synthesis of Compound 126
Figure imgf000137_0001
[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 NH4Cl (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 MgSO4 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). The selected fractions were pooled and concentrated under reduced pressure to yield the desired 2,6- dichloro-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (Int-A26, 2.2 g, 7 mmol, 64% yield) as a syrup. 1H NMR (CHCl3-d, 400 MHz): δH 8.23 (1H, s), 5.61 (2H, s), 3.61 (3H, t, J = 8.3 Hz), 0.90-0.94 (2H, m), - 0.04 (9H, s).
Figure imgf000138_0001
[0345] 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). The selected fractions were pooled and concentrated under reduced pressure to yield the desired 2-chloro-6-(2-fluoro-4-(trifluoromethyl)phenyl)-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (Int-A27, 1.9 g, 3.8 mmol, 67% yield) as a crystalline solid.1H NMR (CHCl3-d, 400 MHz): δH 8.28 (1H, s), 8.12 (1H, t, J = 7.5 Hz), 7.61 (1H, d, J = 8.3 Hz), 7.55 (1H, d, J = 10.0 Hz), 5.68 (2H, s), 3.68 (2H, t, J = 8.2 Hz), 0.97 (2H, t, J = 8.2 Hz), 0.00 (9H, s). LC-MS: [M+H]+ 447.2.
Figure imgf000138_0002
[0346] 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). The selected fractions were pooled and concentrated under reduced pressure to yield the desired (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-methyl-morpholine (Int-A28, 1.01 g, 1.63 mmol, 81% yield) as a foam.1H NMR (CHCl3-d, 400 MHz): δH 8.10 (1H, t, J = 7.5 Hz), 7.93 (1H, s), 7.48-7.57 (4H, m), 5.53 (2H, s), 4.86 (1H, d, J = 13.2 Hz), 4.76 (1H, d, J = 13.2 Hz), 4.60 (1H, dd, J = 10.9, 2.7 Hz), 3.78-3.86 (1H, m), 3.65 (2H, t, J = 8.3 Hz), 3.57 (1H, tt, J = 7.8, 3.2 Hz), 3.00 (1H, dd, J = 13.2, 10.9 Hz), 2.76 (1H, dd, J = 13.2, 10.6 Hz), 1.33 (3H, d, J = 6.2 Hz), 1.10-1.13 (2H, m), 1.00-1.04 (2H, m), 0.95 (2H, t, J = 8.3 Hz), -0.03 (9H, s). LC-MS: [M+H]+ 618.4.
Figure imgf000139_0001
[0347] 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. Anhydrous THF (12.5 mL) was added and the resulting solution was cooled to -78°C with stirring. TMPMgCl·LiCl (1M in THF/toluene) (1.3 eq, 1.60 mL, 1.63 mmol) was added dropwise over 3 min and the reaction mixture was stirred at -78°C for 1 h. A solution of NBS (3 eq, 670 mg, 3.8 mmol) in THF (8 mL) was added dropwise into the reaction mixture at -78 °C. The reaction mixture was allowed to warm to room temperature and then heated to 50 °C for 16 h with stirring. The reaction mixture was cooled to room temperature and quenched with aqueous saturated NH4Cl (1 mL) and concentrated under reduced pressure. The resulting residue was dissolved in EtOAc (100 mL) and 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 (10-35% EtOAc/Hexanes). The selected fractions were pooled and concentrated under reduced pressure to yield the desired (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-methyl-morpholine (Int-A29, 330 mg, 0.47 mmol, 38% yield) as a foam. 1H NMR (CHCl3-d, 400 MHz): δH 8.07 (1H, t, J = 7.4 Hz), 7.47-7.56 (4H, m), 5.54 (2H, s), 4.83 (1H, d, J = 13.3 Hz), 4.73 (1H, d, J = 13.2 Hz), 4.58 (1H, dd, J = 10.9, 2.7 Hz), 3.77-3.85 (1H, m), 3.67-3.71 (2H, m), 3.57 (1H, tt, J = 7.2, 3.8 Hz), 2.99 (1H, dd, J = 13.2, 10.9 Hz), 2.75 (1H, dd, J = 13.2, 10.7 Hz), 1.32 (3H, d, J = 6.2 Hz), 1.10-1.14 (2H, m), 1.00-1.04 (2H, m), 0.97 (2H, dd, J = 9.1, 7.5 Hz), -0.03 (9H, s). ESI-MS (m/z+): 698.2 [M+H]+.
Figure imgf000140_0001
[0348] 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). The selected fractions were pooled and concentrated under reduced pressure to yield the desired 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, 246 mg, 0.35 mmol, 75% yield) as a foam.1H NMR (CHCl3-d, 400 MHz): δH 8.16 (1H, t, J = 7.5 Hz), 7.51-7.53 (3H, m), 7.45 (1H, d, J = 10.2 Hz), 5.39 (2H, s), 4.74 (1H, d, J = 13.2 Hz), 4.58- 4.65 (2H, m), 3.80-3.84 (3H, m), 3.57 (1H, tt, J = 7.2, 3.9 Hz), 3.15 (6H, s), 2.93 (1H, dd, J = 13.1, 10.9 Hz), 2.69 (1H, dd, J = 13.1, 10.6 Hz), 1.31 (3H, d, J = 6.2 Hz), 1.10-1.14 (2H, m), 0.96-1.03 (4H, m), - 0.03 (9H, s). LC-MS: [M + H]+ 661.3.
Figure imgf000141_0001
[0349] 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. The crude residue was dissolved in EtOAc (100 mL) and washed with aqueous saturated NaHCO3 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 (75-100% EtOAc/Hexanes). The selected fractions were pooled and concentrated under reduced pressure to yield the desired 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)- 6-(2-fluoro-4-(trifluoromethyl)phenyl)-N,N-dimethyl-9H-purin-8-amine (Compound 126, 210 mg, 0.40 mmol, 95% yield) as a solid. Compound 126: 1H NMR (CHCl3-d, 400 MHz): δH 8.23 (1H, t, J = 7.8 Hz), 7.57 (1H, dd, J = 8.2, 1.6 Hz), 7.53 (1H, s), 7.51 (1H, s), 7.43 (1H, dd, J = 11.4, 1.6 Hz), 4.86 (1H, d, J = 13.2 Hz), 4.74 (1H, d, J = 13.1 Hz), 4.59 (1H, dd, J = 10.8, 2.7 Hz), 3.77-3.85 (1H, m), 3.55 (1H, tt, J = 7.2, 3.8 Hz), 3.23 (6H, s), 2.93 (1H, dd, J = 13.1, 10.9 Hz), 2.69 (1H, dd, J = 13.1, 10.6 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.08-1.12 (2H, m), 0.95-1.00 (2H, m).19F NMR (CHCl3-d, 376 MHz): δF -62.9 (3F, s), -112.7 (1F, s). LC-MS: [M + H]+ 531.3. Example 16: Synthesis of Compound 127
Figure imgf000141_0002
[0350] 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 α,α,α-trifluorotoluene (1 mL) and Water (0.4 mL), was added TFA (1 eq, 79 µL, 0.10 mmol) followed by slow addition of tert-butyl hydroperoxide (5 eq, 50 µL, 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). The diastereoisomers were separated by preparative HPLC to afford 2-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]- 8-(difluoromethyl)-6-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-purine (Compound 127, 20 mg, 0.03 mmol, 36% yield). Compound 127: 1H NMR (DMSO-d6, 400 MHz): δH 7.94-7.98 (2H, m), 7.82 (1H, dd, J = 8.1, 1.5 Hz), 7.68 (1H, s), 7.53 (1H, t, J = 51.6 Hz), 7.33 (1H, d, J = 0.8 Hz), 4.44 (1H, dd, J = 11.3, 2.0 Hz), 4.02-4.06 (1H, m), 3.58-3.67 (2H, m), 3.57 (3H, s), 2.15-2.20 (1H, m), 1.79-1.96 (3H, m), 0.92- 0.97 (2H, m), 0.83-0.90 (2H, m).19F NMR (DMSO-d6, 376 MHz): δF -61.3 (3F, s), -112.9 (1F, t, J = 9.5 Hz), -118.8 (dd, J = 8.1, 1.5 Hz). ESI-MS: m/z 537.2, [M+H]+. Example 17: Synthesis of Compounds 128-129
Figure imgf000142_0001
[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). DIPEA (2 eq, 120 uL, 0.69 mmol) was added followed by dichloromethylene(dimethyl)ammonium;chloride (1.2 eq, 67 mg, 0.4 mmol). The mixture was heated at 83 °C for 16 h. After cooling the solution at room temperature, water (20 ml) was added and the organic phase was extracted with EtOAc (20ml), washed with brine (20ml) and dried over Na2SO4 and concentrated. The crude product was purified by reverse phase chromatography (10-50% aq. 10 mM ammonium formate/MeCN) followed by prep-hplc purification (Condition E, Gradient 1) to get 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 as a solid (Compound 129, 21 mg, 0.042 mmol, 12% yield). ESI-MS (m/z+): 488.3.1H NMR (DMSO- d6, 400 MHz): δH 7.64 (1H, s), 7.31 (1H, s), 4.38 (1H, d, J = 11.2 Hz), 3.99 (1H, d, J = 11.2 Hz), 3.58-3.64 (2H, m), 3.28 (7H, d, J = 0.0 Hz), 2.40 (6H, s), 2.06 (1H, d, J = 13.1 Hz), 1.70-1.79 (3H, m), 0.92-0.97 (2H, m), 0.84-0.91 (2H, m).
Figure imgf000143_0001
[0352] 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. Iodomethane (3 eq, 15 μL, 0.25 mmol) was added in one portion and stirred at 50 °C for 16 h. The solution was cooled down and transferred into a separatory funnel and partitioned between the saturated solution of NaHCO3 (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 normal phase chromatography (30-70% acetone/hexane) followed by reverse phase purification (10-75% ACN in 10 mm aqueous AMF). The obtained product was then purified by prep-HPLC (Condition F, Gradient 1) to get 2-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-N,N-9-trimethyl-6-[3- (trifluoromethyl)-1-bicyclo[1.1.1] pentanyl]purin-8-amine as a solid (Compound 128, 20 mg, 0.04 mmol, 48% yield). ESI-MS (m/z+): 502.3.1H NMR (CHCl3-d, 400 MHz): δH 7.45 (2H, d, J = 2.6 Hz), 4.49 (1H, d, J = 11.3 Hz), 4.16-4.20 (1H, m), 3.74 (1H, t, J = 11.8 Hz), 3.66 (3H, s), 3.50-3.56 (1H, m), 3.18-3.26 (1H, m), 3.06 (5H, s), 2.49 (6H, s), 2.21 (1H, ddd, J = 13.4, 3.6, 2.0 Hz), 2.00-2.09 (2H, m), 1.93 (1H, ddd, J = 13.4, 3.9, 2.1 Hz), 1.04-1.08 (2H, m), 0.93-1.01 (2H, m). Example 18: Synthesis of Compound 130
Figure imgf000143_0002
[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). Fractions with the desired product were pooled together and concentrated to dryness to get 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, 61 mg, 0.13 mmol, 49% yield) as a solid. ESI-MS (m/z+): 464.3.1H NMR (CHCl3-d, 400 MHz): δH 7.49 (2H, d, J = 3.8 Hz), 5.15 (1H, s), 4.59 (1H, d, J = 13.4 Hz), 4.45-4.49 (3H, m), 3.70 (1H, ddd, J = 10.5, 6.4, 2.0 Hz), 3.54 (1H, tt, J = 7.2, 3.8 Hz), 2.76 (1H, dd, J = 13.1, 10.7 Hz), 2.55 (2H, s), 2.32 (5H, s), 1.98 (2H, s), 1.24 (3H, d, J = 6.2 Hz), 1.06-1.09 (2H, m), 0.98 (2H, t, J = 6.8 Hz).
Figure imgf000144_0001
[0354] 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. The mixture was concentrated to dryness before purification by normal phase chromatography (30-70% Acetone/Hexanes) followed by reverse phase purification (10 mM aqueous solution of formic acid in MeCN). The isolated product was then purified by prep-hplc purification (Condition E, Gradient 1) to get 2-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]- N,N,7-trimethyl-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]purin-8-amine (Compound 130, 37 mg, 0.07 mmol, 32% yield) as a solid. ESI-MS (m/z+): 517.3.1H NMR (CHCl3-d, 400 MHz): δH 7.50 (2H, d, J = 6.1 Hz), 4.79 (1H, d, J = 13.2 Hz), 4.67 (1H, d, J = 13.1 Hz), 4.53 (1H, dd, J = 10.8, 2.7 Hz), 3.73- 3.77 (1H, m), 3.53-3.59 (4H, m), 3.08 (6H, s), 2.84 (1H, dd, J = 13.2, 10.9 Hz), 2.61 (1H, dd, J = 13.2, 10.6 Hz), 2.41 (7H, s), 1.26 (3H, d, J = 6.2 Hz), 1.07-1.11 (2H, m), 0.95-1.00 (2H, m). 19F NMR: -73.0. Example 19: Synthesis of Compounds 131-132
Figure imgf000145_0001
[0355] 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). The reaction mixture was stirred at 80 °C. After completion, the reaction was cooled down to room temperature and diluted with EtOAc. The organic phase was then washed with water and brine, dried over MgSO4, and filtered. The volatiles were removed under reduced pressure and the crude material was purified by flash chromatography (0-30% DCM/EtOAc). The selected fractions were evaporated to afford a solid (Int-A35, 122 mg, 0.46 mmol, 40% yield).
Figure imgf000145_0002
[0356] 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. The organic phase was then washed with water and brine, dried over MgSO4, and filtered. The volatiles were removed under reduced pressure and the crude material was purified by flash chromatography (40-100% DCM/EtOAc). The selected fractions were evaporated to afford (2S,6R)-2-(1- cyclopropyl-1H-pyrazol-4-yl)-4-(7-(2,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-6- methylmorpholine (Compound 131, 41 mg, 0.46 mmol, 99% yield) as a solid. Compound 131: 1H NMR (CHCl3-d, 400 MHz): δH 8.13 (1H, s), 7.79 (1H, td, J = 8.3, 6.2 Hz), 7.51 (1H, s), 7.50 (1H, s), 6.97-7.08 (2H, m), 6.54 (1H, s), 4.57 (1H, dd, J = 10.6, 2.4 Hz), 4.50 (2H, bs), 3.79 (1H, ddd, J = 10.7, 6.1, 2.6 Hz), 3.55 (1H, tt, J = 7.2, 3.8 Hz), 3.06 (1H, t, J = 12.0 Hz), 2.83 (1H, t, J = 11.9 Hz), 1.30 (3H, d, J = 6.2 Hz), 1.05-1.11 (2H, m), 0.95-1.02 (2H, m).19F NMR (CHCl3-d, 376 MHz): δF -104.0, -104.0, -104.0, -104.0, - 104.0, -107.0, -107.0, -107.1, -107.1. ESI-MS (m/z+): 438.3 [M+1]+.
Figure imgf000146_0001
[0357] 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 mixture was stirred at -78 °C for 1 h, then iodomethane (1.2 eq, 0.04 mL, 0.041 mmol) was introduced. This was stirred at -78 °C for 10 min, then warmed slowly to room temperature. The reaction was quenched with water and diluted with EtOAc. The organic phase was washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by reverse phase preparative-HPLC to afford (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(7-(2,4-difluoro-3- methylphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)-6-methylmorpholine (Compound 132, 8 mg, 0.02 mmol, 52% yield). Compound 132: 1H NMR (CHCl3-d, 400 MHz): δH 8.14 (1H, s), 7.56 (1H, td, J = 8.2, 6.2 Hz), 7.52 (1H, s), 7.51 (1H, s), 7.02 (1H, td, J = 8.6, 1.4 Hz), 6.52 (1H, s), 4.58 (1H, dd, J = 10.9, 2.6 Hz), 4.50 (2H, bs), 3.81 (1H, ddd, J = 10.7, 6.2, 2.6 Hz), 3.56 (1H, tt, J = 7.2, 3.8 Hz), 3.04-3.10 (1H, m), 2.81-2.87 (1H, m), 2.27 (3H, t, J = 1.9 Hz), 1.32 (3H, d, J = 6.2 Hz), 1.06-1.13 (2H, m), 0.97-1.02 (2H, m).19F NMR (CHCl3-d, 376 MHz): δF -108.5, -111.7. ESI-MS (m/z+): 452.4 [M+1]+. Example 20: Synthesis of Compound 133
Figure imgf000146_0002
[0358] Step 1: To a solution of 7-chloro-2-methyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidine (1 eq, 500 mg, 2.34 mmol) in 1,4-dioxane (20 mL) was added [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (1.5 eq, 730 mg, 3.51 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). The selected fractions were evaporated to afford 3-chloro-1-(2- fluoro-4-(trifluoromethyl)phenyl)-6-methylpyrrolo[1,2-c]pyrimidine (Int-A36, 165 mg, 0.50 mmol, 21% yield) as a solid.
Figure imgf000147_0001
[0359] 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 Na2CO3 (2M in water, 3 eq, 0.45 mL, 0.91 mmol). The reaction was then stirred at 90 °C overnight. The reaction was quenched with sat. NH4Cl solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by flash chromatography (35-100% DCM/EtOAc, then 5-15% DCM/MeOH) to afford (R)-7-(6-(1-cyclopropyl- 1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-2- methylimidazo[1,2-c]pyrimidine (Int-A37, 120 mg, 0.25 mmol, 82% yield).
Figure imgf000147_0002
[0360] 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. The residue was purified by reverse phase prep-HPLC chromatography (10-95% MeCN/water(0.1% FA)). The selected fractions were lyophilized to afford 7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-2-methylimidazo[1,2-c]pyrimidine (Compound 133, 15 mg, 0.03 mmol, 20% yield).1H NMR (CHCl3-d, 400 MHz): δH 7.84-7.88 (1H, m), 7.66-7.68 (1H, m), 7.59 (1H, d, J = 9.7 Hz), 7.48 (2H, s), 7.32 (1H, s), 7.11 (1H, d, J = 3.6 Hz), 4.51-4.54 (1H, m), 4.22-4.27 (1H, m), 3.74-3.81 (1H, m), 3.54-3.59 (1H, m), 3.08-3.15 (1H, m), 2.45 (3H, s), 2.26-2.31 (1H, m), 1.88-2.03 (3H, m), 1.57-1.58 (3H, m), 1.09-1.13 (2H, m), 0.97-1.02 (2H, m).19F NMR (CHCl3-d, 376 MHz): δF - 63.1, -108.0. ESI-MS (m/z+): 486.2 [M+1]+. Example 21: Synthesis of Compound 134
Figure imgf000148_0001
[0361] 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 Cs2CO3 (3 eq, 1830 mg, 5.6 mmol) and XantPhos Pd G3 (0.1 eq, 161 mg, 0.19 mmol). The reaction mixture was then 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 (35-100% DCM/EtOAc). The selected fractions were evaporated to afford 3-chloro-1-(2- fluoro-4-(trifluoromethyl)phenyl)-6-methylpyrrolo[1,2-c]pyrimidine (Int-A38, 380 mg, 1.0 mmol, 53% yield) as a solid.
Figure imgf000149_0001
[0362] 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 PEPPSI™-SIPr (0.2 eq, 73 mg, 0.064 mmol). The mixture was stirred at 25 °C for 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 under reduced pressure. The crude material was purified by flash chromatography (0-10% DCM/MeOH) and then by reverse phase prep-HPLC chromatography (10-95% MeCN/water(0.1% FA)). The selected fractions were lyophilized to afford (2S,6R)-4-(5-(4-chloro-2-fluorophenyl)-2-methylimidazo[1,2-c]pyrimidin-7-yl)-2-(1-cyclopropyl-1H- pyrazol-4-yl)-6-methylmorpholine (Compound 134, 12 mg, 0.026 mmol, 8% yield). 1H NMR (CHCl3-d, 400 MHz): δH 7.59 (1H, t, J = 7.8 Hz), 7.50 (2H, d, J = 2.3 Hz), 7.28-7.34 (2H, m), 6.88 (1H, d, J = 3.6 Hz), 6.46 (1H, s), 4.63 (1H, dd, J = 10.8, 2.7 Hz), 4.16-4.20 (1H, m), 3.98 (1H, ddd, J = 12.5, 2.7, 1.4 Hz), 3.83-3.88 (1H, m), 3.52-3.58 (1H, m), 2.83 (1H, dd, J = 12.6, 10.9 Hz), 2.58-2.64 (1H, m), 2.34 (3H, d, J = 1.0 Hz), 1.27-1.30 (3H, m), 1.05-1.12 (2H, m), 0.95-1.00 (2H, m). ESI-MS (m/z+): 467.3 [M+1]+. Example 22: Compounds 218-226
Figure imgf000149_0002
Figure imgf000150_0001
Figure imgf000151_0001
Example 23: Synthesis of Compound 227
Figure imgf000152_0001
[0363] 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. Then the reaction mixture was stirred at 45 °C for 16 hours. LCMS (5- 95AB/1.5min): RT = 0.568 min, ESI-MS (m/z+): 331.0 [M+H]+showed 25% desired mass was detected. The reaction mixture was diluted with water 10 mL and extracted with EA (30 mL * 2). The combined organic layers were dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue.The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 6-chloro-2-methyl-4-[4-(trifluoromethyl)cyclohexen-1-yl]-3H-pyrrolo[3,4- c]pyridin-1-one (Int-A39, 500 mg, 0.907 mmol, 26.25% yield) as yellow solid. LCMS (5- 95AB/1.5min): RT = 0.568 min.1H NMR (400 MHz, CHCl3-d) δ ppm 1.70 (qd, J = 12.04, 5.32 Hz, 1 H) 2.15 - 2.26 (m, 1 H) 2.32 - 2.63 (m, 4 H) 2.82 - 2.99 (m, 1 H) 3.23 (s, 3 H) 4.53 (s, 2 H) 6.32 (br d, J = 2.32 Hz, 1 H) 7.61 (s, 1 H). ESI-MS (m/z+): 331.0 [M+H]+.
Figure imgf000152_0002
[0364] 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. LCMS (5-95AB/1.5min): RT = 0.587 min, ESI-MS (m/z+): 502.2 [M+H]+, ESI+ showed starting material was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE:EA = 1:1 to EA:MeOH = 10:1) to give the crude product. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 20:1, Rf = 0.5) ro give 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, 120 mg, 0.218 mmol, 16.00% yield) as yellow solid. LCMS (5-95AB/1.5min): RT = 0.587 min. 1H NMR (400 MHz, CHCl3-d) δ ppm 0.97 - 1.06 (m, 2 H) 1.09 - 1.19 (m, 2 H) 1.33 (d, J = 6.23 Hz, 3 H) 1.64 - 1.74 (m, 1 H) 2.12 - 2.22 (m, 1 H) 2.35 - 2.55 (m, 4 H) 2.65 - 2.71 (m, 1 H) 2.82 - 2.94 (m, 2 H) 3.21 (s, 3 H) 3.52 - 3.62 (m, 1 H) 3.86 (ddd, J = 10.45, 6.23, 2.51 Hz, 1 H) 4.16 - 4.23 (m, 1 H) 4.36 (dt, J = 12.65, 2.23 Hz, 1 H) 4.46 (s, 2 H) 4.63 (dd, J = 10.82, 2.51 Hz, 1 H) 6.24 (br d, J = 2.32 Hz, 1 H) 6.95 (s, 1 H) 7.54 (s, 2 H). ESI-MS (m/z+): 502.2 [M+H]+.
Figure imgf000153_0001
[0365] 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. The mixture was stirred under H2 (15 psi) at 20°C for 16 hours. LCMS (5-95AB/1.5min): RT = 0.590 min, ESI- MS (m/z+): 504.2 [M+H]+ showed 42% of desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, DCM:MeOH = 20:1, Rf = 0.5) to give the crude product. The crude product was purified by reversed-phase HPLC (0.1% FA condition) and lyophilized to give 6-[(2S,6R)-2-(1- cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2-methyl-4-[4-(trifluoromethyl)cyclohexyl]- 3H-pyrrolo[3,4-c]pyridin-1-one (Compound 227, 39 mg, 0.0733 mmol, 36.78% yield, mixture of diastereomers as drawn) as white solid. ( LCMS (5-95AB/1.5min): RT = 0.588 min. 1H NMR (400 MHz, CHCl3-d) δ ppm 0.93 - 1.05 (m, 2 H) 1.06 - 1.18 (m, 2 H) 1.26 - 1.36 (m, 3 H) 1.41 - 1.53 (m, 1 H) 1.76 (br s, 3 H) 1.90 - 2.07 (m, 2 H) 2.07 - 2.27 (m, 3 H) 2.56 - 2.76 (m, 1 H) 2.91 (br t, J = 12.44 Hz, 1 H) 2.95 - 3.10 (m, 1 H) 3.20 (s, 3 H) 3.59 (dq, J = 7.29, 3.62 Hz, 1 H) 3.80 - 3.92 (m, 1 H) 4.14 - 4.25 (m, 1 H) 4.28 - 4.38 (m, 3 H) 4.65 (br d, J = 10.38 Hz, 1 H) 6.89 - 6.97 (m, 1 H) 7.49 - 7.57 (m, 2 H). ESI-MS (m/z+): 504.2 [M+H]+. Example 24: Synthesis of Compound 228
Figure imgf000154_0001
[0366] 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. The reaction mixture was added NBS (0.3 eq, 684 mg, 3.84 mmol), then stirred at 80 °C for 4 h. LCMS (5-95AB/1.5min): RT = 0.604 min, ESI-MS (m/z+): 313.8 [M+H]+ showed 72% of desired product. The reaction mixture was partitioned between ethyl acetate (100 mL*2) and Na2SO3 (aq, 100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE:EA = 10:1, Rf = 0.5) and concentrated to give ethyl 3-(bromomethyl)-2,6-dichloroisonicotinate (Int-A41, 3900 mg, 12.5 mmol, 97.23% yield) as colorless oil. LCMS RT = 0.603 min.1H NMR (400 MHz, CDCl3) δ = 7.75 - 7.67 (m, 1H), 4.98 (s, 2H), 4.47 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). ESI-MS (m/z+): 313.83 [M+1]+.
Figure imgf000155_0001
[0367] 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 oC for 2 h. LCMS (5-95AB/1.5min): RT = 0.398 min, 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. The crude product was triturated with EA (60 mL) at 25 °C for 30 min. The organic layer was filtered and concentrated under reduced pressure to give 4,6-dichloro-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Int- A42, 1900 mg, 9.36 mmol, 75.10% yield) as pink solid. LCMS RT = 0.410 min.1H NMR (400 MHz, DMSO-d) δ = 7.79 (s, 1H), 7.07 (br d, J = 1.1 Hz, 1H), 4.48 - 4.40 (m, 2H). ESI-MS (m/z+): 203.0 [M+1]+.
Figure imgf000155_0002
[0368] 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. Then the reaction mixture was stirred at 60 °C for 2 h. LCMS (5-95AB/1.5min): RT = 0.531 min, ESI-MS (m/z+): 331.0 [M+H]+ showed 18% of desired product and LCMS (5-95AB/1.5min): RT = 0.555 min, ESI-MS (m/z+): 331.0 [M+H]+ showed 29% of desired product. The reaction mixture was partitioned between ethyl acetate (50 mL * 2) and water (80 mL).The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel chromatography (PE/EA = 0~60%, PE/EA = 1/1, the desired product Rf = 0.4) to give 700 mg the mixture. The mixture of was purified by reversed-phase HPLC(0.1% FA condition) to give 6-chloro-4-(2-fluoro-4- (trifluoromethyl)phenyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Int-A43, 440 mg, 1.33 mmol, 27.01% yield) as white solid. LCMS (5-95AB/1.5min): RT = 0.527 min.1H NMR (400 MHz, CHCl3-d) δ = 7.89 - 7.81 (m, 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 10.4 Hz, 1H), 6.97 - 6.83 (m, 1H), 4.54 (s, 2H). -ESI-MS (m/z+): 331.0 [M+1]+.
Figure imgf000156_0001
[0369] 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. LCMS (5-95AB/1.5min): RT = 0.591 min, ESI-MS (m/z+): 411.0 [M+H]+ showed 47% of desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to give 6-chloro-4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(1-methyl-1H-pyrazol-3-yl)-2,3-dihydro- 1H-pyrrolo[3,4-c]pyridin-1-one (Int-A44, 190 mg, 0.463 mmol, 38.24% yield) as white solid. LCMS (5-95AB/1.5min): RT = 0.590 min.1H NMR (400 MHz, CDCl3) δ = 7.90 - 7.81 (m, 2H), 7.61 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 10.3 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 4.98 (s, 2H), 3.87 (s, 3H). ESI-MS (m/z+): 411.0 [M+1]+.
Figure imgf000157_0001
[0370] 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. LCMS (5-95AB/1.5min): RT = 0.622 min, ESI-MS (m/z+): 582.2 [M+H]+ showed 62% of desired product. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel chromatography (PE/EA = 0~100%, PE/EA = 1/1, the desired product Rf = 0.6) and lyophilized to give 6-((2S,6R)-2-(1- cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(2-fluoro-4-(trifluoromethyl)phenyl)-2-(1- methyl-1H-pyrazol-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (Compound 228, 49 mg, 0.0818 mmol, 48.02% yield) as yellow solid.LCMS (5-95AB/1.5min): RT = 0.623 min.1H NMR (400 MHz, CHCl3-d) δ = 7.77 (t, J = 7.5 Hz, 1H), 7.59 - 7.44 (m, 4H), 7.34 (d, J = 2.3 Hz, 1H), 7.19 (s, 1H), 7.00 (d, J = 2.4 Hz, 1H), 4.89 (s, 2H), 4.66 (dd, J = 2.5, 10.8 Hz, 1H), 4.45 - 4.21 (m, 2H), 3.93 - 3.87 (m, 1H), 3.86 (s, 3H), 3.64 - 3.52 (m, 1H), 3.05 - 2.69 (m, 2H), 1.34 (d, J = 6.3 Hz, 3H), 1.16 - 1.09 (m, 2H), 1.05 - 0.98 (m, 2H). ESI-MS (m/z+): 582.2 [M+1]+. 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. To perform the assay, HEK-hTREM2 cells were plated at 14,000 cells per well in a 384 well plate, in 25 μL of complete growth media and incubated at 37 °C, 5% CO2 for 20-24 hours. [0372] 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 μL 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 μL of lysis buffer was added. Plates were shaken for 20 minutes at 350 RPM at room temperature. After complete lysis, AlphaLisa reagents were added to the lysate, and fluourescence intensity was measured using a Perkin Elmer Envision plate reader. Intensities were used to generate a standard curve, and % activation was calculated. Curve fitting was performed using Prism v9 software, log(agonist) vs response – variable slope (four parameters), and EC50s were calculated from the curve fit. [0373] The results presented in Tables D and D-2 have been generated with the in vitro assay described above. This assay may be used to test any of the compounds described herein to assess and characterize a compound’s ability to act as an agonist of TREM2. [0374] Compounds designated as “A” demonstrated an EC50 of ≤ 0.05 μM. Compounds designated as “B” demonstrated an EC50 > 0.05 μM and ≤ 0.5 μM. Compounds designated as “C” demonstrated an EC50 > 0.5 μM and ≤ 3.0 μM. Compounds designated as “D” demonstrated an EC50 > 3.0 μM and ≤ 100 μM. Compounds designated as “
Figure imgf000158_0001
-” had not been tested as of the filing of the present application, but can be tested using the methods described herein.
Table D. hTREM2 EC50 Data (HEK293 Cells) Cmpd hTREM2 No. EC50 μM 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
Figure imgf000159_0001
117 B Table D-2. hTREM2 EC50 Data (HEK293 Cells) Cmpd hTREM2 No. EC50 μM 200 D 201 C 202 C 203 D 204 B 205 C 206 C 207 D 208 D 209 D 210 D 211 D 212 B 213 D
Figure imgf000159_0002
214 D All references, for example, a scientific publication or patent application publication, cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims (7)

  1. What is claimed is: 1. A compound of Formula I
    Figure imgf000161_0001
    I or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein R1 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 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, 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 is optionally substituted; X1 is CR13, CH or N; X2 is CR14, CH or N; Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
    Figure imgf000162_0001
    Y is C or N, as required by the bicyclic ring system formed by Ring A; X3 is CHR3, or NR4; X4 is CHR3, NR4, O or S; each Z1 is independently CR2 or N; Z2 is CR3 or N; Z11 is CHR3, C(R3)2, or NR4; Z12 is CHR2, C(R2)2, NR4, or C(=N-R4); R2, R2a, R2b, and R3 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -NR-C(O)-R, -C(=O)OR, -C(=O)NR2, -SO2R, - SO2NR2, C1-6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or one of R2, R2a, R2b, and R3 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 is optionally substituted; R4 is hydrogen, an optionally substituted C1-6 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 R3 and R4 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 is optionally substituted;
    Figure imgf000163_0001
    L is a bond or an optionally substituted straight chain or branched C1-6 alkylene; X5 is CH, N or CR5; X6 is CH, N or CR6; provided that when one of X5 or X6 is N, the other is not N; R5 and R6 are each independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, halogen, C1-6haloalkyl, C1- 6haloalkoxy, or 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 is optionally substituted; or R5 and R6 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 is optionally substituted; X7 is N, CH, or CR7; X8 is O, NR8, C(R8)2, CHR8, SO2, or C=O; X9 is O, NR9, C(R9)2, CHR9, SO2, or C=O; X10 is O, NR10, C(R10)2, CHR10, SO2, or C=O; X11 is O, NR11, C(R11)2, CHR11, SO2, or C=O; X12 is a direct bond, O, NR12, C(R12)2, CHR12, -CH2CH2-, -OCH2-, SO2, or C=O; R7 is an optionally substituted aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, - C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; each of R8, R9, R10, R11, and R12 is independently selected from hydrogen, an optionally substituted C1-6 aliphatic group, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1- 6haloalkyl, C1-6haloalkoxy, or 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 is optionally substituted; or any two of R7, R8, R9, R10, R11, and R12 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 is optionally substituted; R13 and R14 are each independently hydrogen, an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, -C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1- 6haloalkoxy; R16 is an optionally substituted C1-6 aliphatic group, halogen, -OR, -CN, -NR2, -C(=O)R, - C(=O)OR, -C(=O)NR2, -SO2R, -SO2NR2, C1-6haloalkyl, or C1-6haloalkoxy; m is 0, 1 or 2; each R is independently hydrogen, an optionally substituted C1-6 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 two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated, or heteroaryl ring (having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur). 2. The compound of claim 1, wherein R1 is optionally substituted C3-6cycloalkyl, optionally substituted spiro[3.3]heptanyl, optionally substituted spiro[5.
  2. 2]octanyl, optionally substituted
    Figure imgf000165_0001
    , 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).
  3. 3. The compound of claim 1, wherein R1 is:
    Figure imgf000166_0001
  4. 4. The compound of claim 1, wherein R1 is :
    Figure imgf000167_0001
    Figure imgf000168_0001
    .
  5. 5. The compound of any one of claims 1-4, wherein Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula
    Figure imgf000168_0002
    .
  6. 6. The compound of any one of claims 1-5, wherein Ring
    Figure imgf000168_0003
    .
  7. 7. The compound of any one of claims 1-6, wherein Ring
    Figure imgf000169_0001
    Figure imgf000169_0002
    8. The compound of any one of claims 1-5, wherein Ring B is selected from:
    Figure imgf000169_0003
    Figure imgf000170_0001
    Figure imgf000171_0001
    10. The compound of any one of claims 1-5 and 8-9, wherein R9 is selected from: , , , , , , , ,
    Figure imgf000172_0001
    Figure imgf000173_0001
    11. The compound of any one of claims 1-9 and 8-9, wherein R9 is
    Figure imgf000173_0002
    , , or
    Figure imgf000173_0003
    . 12. The compound of any one of claims 1-11, wherein the compound is a compound of Formula IIa1, IIa2, IIb1, IIb2, IIc1, IIc2, IIIa, IIIb, IIIc, IVa, IVb, IVc, Va, Vb, Vc, VIa, VIb, VIc, VIIa, VIIb, VIIc, VIIIa, VIIIb, or VIIIc. 13. A compound of Table A or Table A3, or a pharmaceutically acceptable salt thereof. 14. A pharmaceutical composition comprising the compound according to any one of claims 1-13, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient. 15. A method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1-13, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. 16. 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 according to any one of claims 1-13, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.
PCT/US2024/028689 2023-05-10 2024-05-09 Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use WO2024233848A1 (en)

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