Heterocyclic compounds as triggering receptor expressed on myeloid cells 2 agonists and methods of use

Abstract

The present disclosure provides compounds of Formula (I), 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

[0001] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0002] HETEROCYCLIC COMPOUNDS AS TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2 AGONISTS AND METHODS OF USE

[0003] FIELD

[0004] 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 Fonnula (I).

[0005] BACKGROUND

[0006] 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, protcotoxic 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 amultitude of physiological processes. With the ability to rapidly proliferate in response to stimuli, microglia characteristically exhibit myeloid cell functions such as phagocytosis, cytokinc / chcmokinc 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).

[0007] Tire 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 isPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0008] dynamically regulated and acts to recognize molecular patern 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 DAP 10 and DAP 12 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 Bret, 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).

[0009] 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 fortheir 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).

[0010] 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”) (Goldc et al. Alzhcimcrs Res Thcr 2013, Dardiotis et al. Ncurobiol Aging 2017). This progressive neurodegenerative disease typically manifests in the 3rddecade of life and is pathologicallyPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0011] 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.

[0012] 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. Elum 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-fimction in the CNS include elevated the plaque burden and lower levels of secreted microglial factors SPP 1 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).

[0013] 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 atenuated presence of dystrophic neurites when TREM2 was overexpressed. Id. Therefore, tire pharmacological activation of TREM2 is a target of interest for treating or preventing neurological, neurodegenerative and other diseases. Despite many attempts to alter disease progressionPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0014] 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.

[0015] SUMMARY

[0016] First, provided herein is a compound of Formula (I):

[0017]

[0018] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

[0019] Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula:

[0020] X1is CR10orN;

[0021] X2is C(R12)2, O, C(=O), S(O)2, or NR11;

[0022] X3and X4are each independently CR9or N;

[0023]

[0024] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0025] Xsis 0, N, S, or C(R12)2;

[0026] R1is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R13;

[0027] R2a, R2b, R3a, R3b, R4a, and R4bare each independently hydrogen, C alkyl, C2-6 alkenyl, C2-6 alkynyl, CM heteroalkyl, CM haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14; or

[0028] R2aand R2b, R3aand R3b, or R4aand R4btaken together with the atom they are attached to form an oxo group (e.g. C=O);

[0029] R5ais hydrogen, CM alkyl, C2-6 alkenyl, C2-6 alkynyl, CM heteroalkyl, C haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14:

[0030] R5bis cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R15;

[0031] R6and R6'are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, C1-6haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;

[0032] R7and R7'are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, C1-6haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;

[0033] R9is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;

[0034] R10and R11are each independently in each instance hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;

[0035] each R12is independently hydrogen, CM alkyl, or halogen;

[0036] each R13is independently C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0037] alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;

[0038] R14, R15, and R16are each independently hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, C1-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R17; or

[0039] two R14, two R15, or two R16, together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R17; or

[0040] two R14, two R15, or two R16independently fomr an oxo;

[0041] each RAis independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, or -N(RB)(RC), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;

[0042] each RBand Rcis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, Ci-e heteroalkyl, C1-6 haloalkyl, cycloalkyl, heterocyclyl, or -C(O)-alkyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17; or

[0043] RBand Rc, together with the nitrogen atom to which they are attached, form -N=C(RD)(RE) or a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R17;

[0044] each RDand REis independently hydrogen, C1-6alkyl, C2-6alkenyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;

[0045] each R17is C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, halogen, or cyano; or two R17form an oxo; and

[0046] n is 0, 1, 2, or 3.

[0047] Second, 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.

[0048] Third, 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.

[0049] Fourth, 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 described hereinabove, for use in treating or preventing Parkinson’s disease, rheumatoid arthritis,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0050] Alzheimer’s disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0051] 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 tire 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.

[0052] DETAILED DESCRIPTION

[0053] Provided herein is a compound of Formula (I):

[0054]

[0055] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

[0056] Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula:

[0057] R1

[0058] or O

[0059]

[0060] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0061] X

[0062]

[0063] 1is CR’° orN;

[0064] X2is C(R12)2, O, C(=O), S(O)2, or NR11;

[0065] X3and X4are each independently CR9or N;

[0066] X5is 0, N, S, or C(R12)2;

[0067] R1is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R13;

[0068] R2a, R2b, R3a, R3b, R4a, and R4bare each independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14; or

[0069] R2aand R2b, R3aand R3b, or R4aand R4btaken together with the atom they are attached to form an oxo group (e.g. C=O);

[0070] R5ais hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14;

[0071] R5bis cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R15;

[0072] R6and R6'are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, C1-6haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;

[0073] R7and R7'are each independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, C1-6haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;

[0074] R9is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0075] alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;

[0076] R10and R11are each independently in each instance hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;

[0077] each R12is independently hydrogen, C1-6alkyl, or halogen;

[0078] each R13is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-e haloalky l, cycloalky l, heterocyclyl, halogen, cyano, -O(RA), -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;

[0079] R14, R15, and R16are each independently hydrogen (e.g., deuterium), C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R17; or

[0080] two R14, two R15, or two R16, together with tire atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R17; or

[0081] two R14, two R15, or two R16independently form an oxo;

[0082] each RAis independently hydrogen (e.g., deuterium), C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, or -N(RB)(RC), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;

[0083] each RBand RCis independently hydrogen, C1-6alkyl, C2-6alkenyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, or -C(O)-alkyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17; or

[0084] RBand RC, together with the nitrogen atom to which they are attached, form -N=C(RD)(RE) or a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R17;

[0085] each RDand REis independently hydrogen, C1-6alkyl, C2-6alkenyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;

[0086] each R17is C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, halogen, or cyano; or two R17form an oxo; and

[0087] n is 0, 1, 2, or 3.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0088] As defined generally above, Ring

[0089]

[0090] B is

[0091] R4aR4bR4aR4b

[0092] In some embodiments. Ring B is selected from

[0093]

[0094] R5bO

[0095] . In some embodiments, Ring B is selected from

[0096]

[0097] As generally described herein, X1is CR10orN. In some embodiments, X1is CR10. In an embodiment, X1is CH. In an embodiment, X1is CCH3. In an embodiment, X1is COH. In an embodiment, X1is CF. In some embodiments. X1is N. In an embodiment, X1is selected from those depicted in Table A.

[0098] As generally described herein, X2is C(R12)2, 0, C(=O), S(O)2, or NR11. In some embodiments, X2is C(R12)2. In some embodiments, X2is CH2. In some embodiments, X2is O. In some embodiments, X2is C(=O). In some embodiments, X2is S(O)2. In some embodiments, X2is NR11. In an embodiment, X2is CH2, CF2, or 0. In an embodiment, X2is NR” or O. In an embodiment, X2is N(CHs). NH, or 0. In an embodiment, X2is selected from those selected in Table A.

[0099] In some embodiments, X1is CH and X2is 0. In some embodiments, X1is CH and X2is CH. In some embodiments, X1is N and X2is O.

[0100] As generally described herein, X3and X4are each independently CR9or N. In some embodiments, X3is CR9orN. In some embodiments, X3is CR9. In some embodiments, X3is N. In some embodiments, X4is CR9orN. In some embodiments, X4is CR9. In some embodiments, X4is N. hi some embodiments, one of X3and X4is independently N. In some embodiments, X3and X4are both independently N.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0101] As generally described herein, X5is 0, N, S, or C(R12)2. In some embodiments, X3is 0. In some embodiments, X3is N. In some embodiments, X5is S. In some embodiments, X3is C(R12)2.

[0102] As generally described herein, R1is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R13. In an embodiment, R1is aryl, cycloalkyl or heterocyclyl, optionally substituted with one or more R13. In an embodiment, R1is aryl or cycloalkyl, optionally substituted with one or more R13. In an embodiment, R1is cycloalkyl, optionally substituted with one or more R13. In an embodiment, R1is heterocyclyl, optionally substituted with one or more R13. In an embodiment, R1is ary l, optionally substituted with one or more R13. In an embodiment, R1is heteroaryl, optionally substituted w ith one or more R13. In an embodiment, R1is cycloalkyl, ary l, or heteroaryl, each of which is optionally substituted with one or more R13.

[0103] [f^(R13)o-5fjl^(R13)o^

[0104]

[0105] some embodiments, R1is. In some embodiments, R1is ■n~''. In some / K / (R13)O-7 embodiments, R1is

[0106]

[0107]

[0108] . In some embodiments, R1is. In some embodiments, R1is

[0109]

[0110] In some embodiments, R1is selected from those depicted in Table A below.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0111] As generally described herein, R2a, R2b, R3a, R3b, R4a, and R4bare each independently hydrogen, Ci-6 alkyl, C 2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-e haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14; or R2aand R2b, R3aand R3b, or R4aand R4btaken together with the atom they are attached to fonn an oxo group (e.g. C=O).

[0112] In an embodiment, R2aand R2bare each independently selected from hydrogen, C1-6 alkyl. C2-6 alkenyl, C2-6 alkynyl. Ci.6 heteroalkyl, Ci.e haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14. In an embodiment, R2aand R2bare each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl or alkenyl is optionally substituted with one or more R14. In an embodiment, R2aand R2bare each independently selected from hydrogen or Ci-6 alkyl, wherein each alkyl is optionally substituted with one or more R14. In an embodiment, R2aand R2bare each independently hydrogen. In an embodiment, R2aand R2btaken together with the atom they are attached to form an oxo group (e.g. C=O).

[0113] In an embodiment, R3aand R3bare each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci -6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14. In an embodiment, R3aand R3bare each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl or alkenyl is optionally substituted w ith one or more R14. In an embodiment, R3aand R3bare each independently selected from hydrogen or Ci-e alkyl, wherein each alkyl is optionally substituted with one or more R14. In an embodiment, R3aand R3bare each independently hydrogen. In an embodiment, R3aand R3btaken together with the atom they are attached to fonn an oxo group (e.g. C=O).

[0114] In an embodiment, R4aand R4bare each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl. Ci.6 heteroalkyl, C1.6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14. In an embodiment, R4aand R4bare each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl or alkenyl is optionally substituted with one or more R14. In an embodiment, R4aand R4bare each independently selected from hydrogen or Ci-6 alkyl, wherein each alkyl is optionally substituted with one or more R14. In an embodiment, R4aand R4bare each independently hydrogen. In an embodiment, R4aand R4btaken together with the atom they are attached to form an oxo group (e.g. C=O).

[0115] As generally described herein, R5ais hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano. -O(RA), or -N(RB)(RC), wherein eachPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0116] alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14. In an embodiment, R3ais hydrogen, Ci-6 alkyl, C2-6 alkenyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl or alkenyl is optionally substituted with one or more R14. In an embodiment, R5ais hydrogen or C1-6 alkyl, wherein each alkyl is optionally substituted with one or more R14. In an embodiment, R5ais hydrogen.

[0117] As generally described herein, R5bis cycloalkyl, heterocyclyl. aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R13. In an embodiment, R5bis cycloalkyl, optionally substituted with one or more R13. In an embodiment, R5bis heterocyclyl, optionally substituted with one or more R13. In an embodiment, R5bis aryl, optionally substituted with one or more R15. In some embodiments, R5bis heteroaryl, optionally substituted with one or more R15.

[0118] In an embodiment, R5bis monocyclic or bicyclic cycloalkyl, optionally substituted with one or more R15. In an embodiment, R5bis 3-8 membered cycloalkyl, optionally substituted with one or more R15. In an embodiment, R5bis monocyclic cycloalkyl, optionally substituted with one or more R15. In an embodiment, R5bis bicyclic cycloalkyl, optionally substituted with one or more R15. In an embodiment, R5bis 5-8 membered cycloalkyl, optionally substituted with one or more R15.

[0119] In an embodiment, R5bis monocyclic or bicyclic aryl, optionally substituted with one or more R15. In an embodiment, R5bis 6-10 membered aryl, optionally substituted with one or more R15.

[0120] In an embodiment, R5bis monocyclic or bicyclic heterocyclyl, optionally substituted with one or more R13. In an embodiment, R5bis 3-12 membered heterocyclyl (e.g., 3-8 membered, 7-12 membered heterocyclyl), optionally substituted with one or more R15.

[0121] In an embodiment, R5bis a monocyclic or bicyclic heteroaryl, optionally substituted with one or more R13. In an embodiment, R5bis a 5- to 10-membered heteroaryl, optionally substituted with one or more R13. In an embodiment, R5bis an 8- to 10-membered heteroaryl, optionally substituted with one or more R13. In some embodiments, R5bis a 5- or 6-membered heteroaryl, optionally substituted with one or more R13. In an embodiment, R5bis a 5-membered heteroaryl, optionally substituted with one or more R15. In an embodiment, R5bis a 6-membered heteroaryl, optionally substituted with one or more R15. In an embodiment, R5bis a nitrogen-containing heteroaryl, optionally substituted with one or more R15.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0122] In some embodiments, R5bis selected from

[0123]

[0124] embodiments,

[0125]

[0126] R’bis In some embodiments,

[0127]

[0128] R5bis

[0129]

[0130] embodiments,

[0131]

[0132] R5bis In some embodiments,

[0133]

[0134] R5bis

[0135] In some embodiments, R5bis

[0136]

[0137] As generally described herein, R6and R6'are each independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, Ci-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, ary l, and heteroaryl is optionally substituted with one or more R16. In some embodiments, R6and R6'are each independently hydrogen, C1-6PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0138] alkyl, C2-6 alkenyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R16. In some embodiments, R6and R6'are each independently hydrogen, Ci-6 alkyl, C1-6 haloalkyl, halogen, or cyano. In some embodiments, R6is H, -CF3, or -CH3.

[0139] As generally described herein, R7and R7'are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, C1-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, ary l, and heteroaryl is optionally substituted with one or more R16. In some embodiments, R7and R7'are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R16. In some embodiments, R7and R7'are each independently hydrogen, Ci-6 alkyl, C1-6 haloalkyl, halogen, or cyano. In some embodiments, R7is hydrogen or Ci-e alkyl. In some embodiments, R7is Ci-6 alkyl. In some embodiments, R7is -CH3.

[0140] In some embodiments, R6and R7are each independently hydrogen, halogen, haloalkyl, Ci-6 alkyl, or -CN.

[0141] As generally described herein, R9is hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16. In some embodiments, R9is hydrogen, Ci-6 alkyl, C2-6 alkenyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R16. In some embodiments, R9is hydrogen or Ci-6 alkyl, wherein each alkyl is optionally substituted with one or more R16.

[0142] As generally described herein, R10and R11are each independently in each instance hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, ary l, and heteroaryl is optionally substituted with one or more R16.

[0143] In some embodiments, R10is hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R19. In some embodiments, R10is hydrogen, halogen, or Ci-e alkyl, wherein alkyl is optionally substituted with one or more R16. In some embodiments, R10is hydrogen. In some embodiments, R10is halogen. In some embodiments, R10is F. In some embodiments,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0144] R10is -OH. In some embodiments, R10is Ci-e alkyl, optionally substituted with one or more R16. In some embodiments, R10is -CH3.

[0145] In some embodiments, R11is hydrogen, Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e heteroalkyl, Ci-e haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more R16. In some embodiments, R11is hydrogen or C1-6 alkyl, wherein alkyl is optionally substituted with one or more R16. In some embodiments, R11is hydrogen. In some embodiments, R11is Ci-6 alkyl, optionally substituted with one or more R16. In some embodiments, R11is -CH3.

[0146] As generally described herein, each R12is independently hydrogen, Cue alkyl, or halogen. In some embodiments, R12is hydrogen. In some embodiments, R12is Cue alkyl. In some embodiments, R12is -CH3. In some embodiments, R12is halogen. In some embodiments. R12is -F.

[0147] As generally described herein, each R13is independently Ci-6 alkyl, C2-6 alkenyl. C2-6 alkynyl, Ci-6 heteroalkyl, Cue haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17. In an embodiment, R13is Ci-6 alkyl, C2-6 alkenyl, Ci-e heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17. In an embodiment, R13is Ci-6 alkyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, halogen, or -O(RA), wherein each alkyl, heteroalkyl, or haloalkyl is optionally substituted with one or more R17. In an embodiment, R13is Ci-6 alkyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, or halogen, wherein each alkyl, heteroalkyl, or haloalkyl is optionally substituted with one or more R17. In an embodiment, R13is Ci-6 haloalkyl or halogen, wherein each haloalkyl is optionally substituted with one or more R17. In an embodiment, R13is Ci-6 haloalkyl, optionally substituted with one or more R17. In an embodiment. R13is -CF3. In an embodiment, R13is -CHF2. In an embodiment, R13is -CH2F. In an embodiment, R13is halogen. In an embodiment, R13is -F. In an embodiment, R13is -Cl. In an embodiment, R13is -Br.

[0148] As generally described herein, R14, R1’, and R16are each independently hydrogen (e.g., deuterium), Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-s haloalkyl, cycloalkyl, heterocyclyl, ary l, heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R17; or two R14, two R15, or two R16, together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, ary 1, or heteroaryl, wherein each cycloalky l, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R17; or two R14, two R15, or two R16independently form an oxo.

[0149] In an embodiment, R14is hydrogen (e.g., deuterium), Ci-6 alkyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl, heteroalkyl, and haloalkyl is optionally substitutedPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0150] with one or more R17. In an embodiment, R14is hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, or halogen, wherein each alkyl and haloalkyl is optionally substituted with one or more R17. In an embodiment, R14is hydrogen or Ci-e alkyl, wherein each alkyl is optionally substituted with one or more R17. In an embodiment, R14is hydrogen. In an embodiment, two R14taken together with the atom to which they are attached independently form an oxo (e.g., C=O).

[0151] In an embodiment, R1’ is hydrogen (e.g., deuterium), Ci-6 alkyl, C2-6 alkenyl, C1-6 heteroalkyl, C1-6 haloalkyl, cycloalkyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R17. In an embodiment, R15is hydrogen, Ci-6 alkyl, C1-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, or halogen, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R17. In an embodiment, R15is hydrogen. In an embodiment, R15is deuterium. In an embodiment, R15is C1-6 alkyl, optionally substituted with one or more R17. In an embodiment, R15is -CH3. In an embodiment, R15is C1-6 heteroalkyl, optionally substituted with one or more R17. In an embodiment, R15is C1-6 haloalkyl, optionally substituted with one or more R17. In an embodiment, R15is cycloalkyl, optionally substituted with one or more R17. In an embodiment, R15is halogen. In an embodiment, two R15taken together with the atom to which they are attached independently form an oxo (e g., C=O).

[0152] In an embodiment, R16is hydrogen (e.g., deuterium), C1-6 alkyl. C1-6 heteroalkyl, Ci-6 haloalkyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R17. In an embodiment, R1'’ is hydrogen or Cue alkyl. In an embodiment, R16is hydrogen. In an embodiment, R16is deuterium. In an embodiment, R16is Ci-e alkyl. In an embodiment, R15is -CH3. In an embodiment, two R16taken together with the atom to which they are attached independently form an oxo (e.g., C=O).

[0153] As generally described herein, each RAis independently hydrogen (e.g., deuterium), Ci-6 alkyl, Ci-e heteroalkyl, C 1.6 haloalkyl, cycloalkyl, heterocyclyl, or -N(RB)(RC), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17.

[0154] As generally described herein, each RBand RCis independently hydrogen, Ci-e alkyl, C2-6 alkenyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, or -C(O)-alkyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17; or RBand RC, together with the nitrogen atom to which they are attached, form -N=C(RD)(RE) or a heterocyclyl. wherein the heterocyclyl is optionally substituted with one or more R17.

[0155] As generally described herein, each RDand REis independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, Ci-e heteroalkyl, Ci-e haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0156] As generally described herein, each R17is Ci-6 alkyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, halogen, or cyano; or two R17taken together with the atom they are attached form an oxo.

[0157] As generally described herein, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0.

[0158] In some embodiments, the compound of Formula (I) is a compound of Formula (I-a):

[0159] R1

[0160]

[0161] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, X3, X4, X5, R1, R6, R7, and subvariables thereof are defined as for Formula (I).

[0162] In some embodiments, the compound of Formula (I) is a compound of Formula (I-b):

[0163] R1

[0164]

[0165] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, R6, R7, and subvariables thereof are defined as for Formula (I).

[0166] In some embodiments, the compound of Formula (I) is a compound of Formula (I-c):

[0167]

[0168] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of R1, R2a, R2b, R3a, R3b, R4a, R4b, R5b, R6, R7, and subvariables thereof are defined as for Formula (I).

[0169] In some embodiments, the compound of Fonnula (I) is a compound of Formula (I-d):

[0170] R1

[0171] (I-d),

[0172]

[0173] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0174] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of R1, R2a, R2b, R3a, R3b, R4a, R4b, R’a, R5b, R6, R7, and subvariables thereof are defined as for Fonnula (I).

[0175] In some embodiments, the compound of Formula (I) is a compound of Formula (I-e):

[0176] R6

[0177] R7

[0178]

[0179] (I-e),

[0180] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, X1, X2, R1, R3a, R3b, R5a, R6, R7, R15, and subvariables thereof are defined as for Formula (I).

[0181] In some embodiments, the compound of Formula (I) is a compound of Formula (I-f):

[0182] R6

[0183] R7

[0184]

[0185] (I-f),

[0186] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, X1, X2, R1, R3a, R3b, R5a, R6, R7, R15, and subvariables thereof are defined as for Formula (I).

[0187] In some embodiments, the compound of Formula (I) is a compound of Formula (I-g):

[0188] R6

[0189] R7

[0190]

[0191] (I-g).

[0192] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of R1, R3a, R3b, R’a, R6, R7, R15, and subvariables thereof are defined as for Formula (I).

[0193] In some embodiments, the compound of Formula (I) is a compound of Formula (I-h):PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0194] R6

[0195] R7

[0196]

[0197] (I-h),

[0198] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of R1, R3a, R3b, R’a, R6, R7, R15, and subvariables thereof are defined as for Formula (I).

[0199] In some embodiments, the compound of Formula (I) is a compound of Formula (I-i):

[0200] R1

[0201] R6

[0202] R7

[0203]

[0204] (I-i),

[0205] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X2, X4, X5, R1, R2a, R2b, R3a, R3b. R4a, R4b, R5a, R’b. R6, R7, and subvariables thereof are defined as for Formula (I).

[0206] Further provided herein is a pharmaceutical composition comprising one or more of the compounds of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer disclosed herein and a pharmaceutically acceptable excipient.

[0207] In some embodiments, the compound is a compound of any of the previous embodiments, or a pharmaceutical composition of the previous embodiments, for use in treating or preventing a condition associated with a loss of function of human TREM2.

[0208] Further provided herein is 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 the previous embodiments, or a pharmaceutical composition of the previous embodiments.

[0209] Exemplary compounds of the disclosure are set forth in Table A, below. In some embodiments, the compound is a compound set forth in Table A, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0210] Table A. Exemplary CompoundsPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0211]

[0212]

[0213] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0214]

[0215]

[0216] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0217]

[0218]

[0219] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0220]

[0221]

[0222] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0223]

[0224]

[0225] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0226]

[0227]

[0228] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0229]

[0230]

[0231] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0232]

[0233]

[0234] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0235]

[0236]

[0237] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0238]

[0239]

[0240] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0241]

[0242]

[0243] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0244]

[0245]

[0246] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0247]

[0248]

[0249] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0250]

[0251]

[0252] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0253]

[0254]

[0255] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0256]

[0257]

[0258] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0259]

[0260]

[0261] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0262]

[0263]

[0264] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0265]

[0266]

[0267] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0268]

[0269]

[0270] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0271]

[0272]

[0273] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0274]

[0275]

[0276] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0277]

[0278]

[0279] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0280]

[0281]

[0282] 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.

[0283] FORMULATION AND ROUTE OF ADMINISTRATION

[0284] 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.

[0285] 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.

[0286] 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,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0287] 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.

[0288] In one aspect, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a tautomer thereof, or a pharmacally acceptable salt of said compound or said tautomer and a pharmaceutically acceptable excipient.

[0289] In another aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer or a pharmaceutical composition comprising said compound, or a tautomer thereof, or a pharmacally acceptable salt of said compound or said tautomer, for use as a medicament.

[0290] Pharmaceutically acceptable compositions

[0291] 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.

[0292] 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, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable fomis 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.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0293] 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.

[0294] 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 com 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.

[0295] 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.

[0296] 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 tire eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0297] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0298] 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,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0299] sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] METHODS OF USE

[0306] 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.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0307] 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.

[0308] 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 1g 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 (Erkl / 2) activation, suggesting that TREM2 activation may act as a negative regulator of TLR driven RA pathogenesis. Huang and Pope 2009.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0309] 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.

[0310] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating or preventing a condition associated with a loss of function of human TREM2.

[0311] In another aspect, the present disclosure features a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer or a pharmaceutical composition thereof for use in treating a disease, disorder, or condition. Exemplary diseases, disorders, or conditions include proliferative diseases, cardiovascular diseases, metabolic diseases, inflammatory diseases, autoimmune disorders, neurodegenerative disorders, infectious diseases, and tissues injuries.

[0312] In some embodiments, the proliferative disease is a benign condition, e.g., a benign neoplasm. In some embodiments, the proliferative disease is a cancer. The cancer may be a cancer of any cell or tissue in the body, for example, a cancer of the brain, eye, thyroid, breast, lung, stomach, kidney, pancreas, bladder, colon, rectum, uterus, ovaries, prostate, skin, fibrous tissues, lymphatic system, bone marrow, blood, or immune system. The cancer may comprise a tumor or solid cancer (e.g., a carcinoma) or a nonmass cancer. Exemplary cancers include glioblastoma, retinoblastoma, skin cancer, ocular cancer, gastrointestinal cancer, breast cancer, lung cancer, ductal carcinoma, lung adenocarcinoma, lymphoma, endometrial cancer, liver cancer, pancreatic cancer, renal cell cancer, ovarian cancer, fibrosarcoma, leukemia, myeloma, and polycythemia vera.

[0313] In some embodiments, the disease, disorder, or condition is cardiovascular. Exemplary cardiovascular diseases, disorders, and conditions include stroke, coronary heart disease, cardiomyopathy, arrhythmia (e.g. atrial fibrillation), aortic aneurysms, and venous thrombosis.

[0314] In some embodiments, the disease, disorder, or condition is metabolic disease. Exemplary metabolic diseases include diabetes (e.g., Type 1 diabetes or Type 2 diabetes), metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic steatohepatitis (NASH), and Gaucher’s disease.

[0315] In some embodiments, the disease, disorder, or condition is an inflammatory disease. Exemplary inflammatory diseases include arthritis, acute and chronic colitis, ulcerative colitis, inflammatory bowel disease, Behcet’s disease, and granulomatous disorders.

[0316] In some embodiments, the disease, disorder, or condition is an autoimmune disease. Exemplary autoimmune diseases include diabetes (e.g., Type 1 diabetes), lupus, sarcoidosis, and multiple sclerosis.

[0317] In some embodiments, the disease, disorder, or condition is a neurological disease. In some embodiments, the neurological disease is a neurodegenerative disease. Exemplary neurodegenerative diseases include dementia, Alzheimer's disease, Creutzfeldt-Jakob disease, Parkinson’s disease,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0318] dementia with Lewy bodies, amyotrophic lateral sclerosis (ALS), Huntington’s disease, taupathy disease, Nasu-Hakola disease, dry age-related macular degeneration (dry AMD), multiple system atrophy (MSA), Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglionic degeneration, glaucoma, retinitis pigmentosa, and retinal degeneration, In other embodiments, the neurological condition is acute trauma, chronic trauma, acute disseminated encephalomyelitis, cognitive deficit and memory loss, essential tremor, central nervous system (CNS) lupus, normal pressure hydrocephalus, and seizures.

[0319] In some embodiments, the disease, disorder, or condition is an infectious disease. An infectious disease may be local or systemic. Exemplary infectious diseases include eye infections, malaria, respiratory tract infections, sepsis, herpes (e.g., CNS herpes), parasitic infections, Trypanosome infection, Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningitidis infection, type I HIV. and Haemophilus influenza.

[0320] In some embodiments, the disease, disorder, or condition is a tissue injury. Any tissues of the body may be injuried. Exemplary injuries include ocular (e.g. hyphoma), spinal cord injury, traumatic brain injury, hepatocellular, and wound repair in diabetes.

[0321] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer for treating or preventing a disease, disorder or condition. In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating or preventing Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0322] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing a condition associated with a loss of function of human TREM2.

[0323] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmacally acceptable salt of said compound or said tautomer, or a pharmacal 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.

[0324] In another aspect, the disclosure provides a method of treating or preventing a condition associated with a loss of function of human TREM2 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of the present disclosure,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0325] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.

[0326] In another aspect, the disclosure provides a method of treating or preventing Parkinson’s disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of the present disclosure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.

[0327] CSF1R

[0328] 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-phosphory lation 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).

[0329] The present disclosure relates to the 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 dsiclosure relates to the 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.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0330] To date, no prior study has shown that TREM2 agonism can rescue the loss of microglia in cells where mutations in the CSF 1R kinase domain reduce CSF1R activity, rather than the presence of a CSF1R inhibitor or a deficiency in CSF1R ligand. Furthermore, no prior study has taught or suggested that reversal of the loss of microglia due to a CSF1R mutation through TREM2 agonism can be used to treat a disease or disorder caused by and / or associated with a CSF1R mutation.

[0331] 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 mater abnonnalities 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.

[0332] 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 disclosure relates to the surprising discovery that activation of the TREM2 pathway can rescue the loss of microglia in CSF1R + / - ALSP patients, preventing microglia apoptosis, thereby treating the ALSP condition.

[0333] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating or preventing a condition associated with dysfunction of Colony stimulating factor 1 receptor (CSF1R, also known as macrophage colony-stimulating factor receptor / M-CSFR, or cluster of differentiation 115 / CD115).

[0334] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). pigmentary orthochromatic leukodystrophy (POLD), pediatric-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS).

[0335] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing a condition associated with dysfunction of CSF1R.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0336] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmentary orthochromatic leukodystrophy (POLD), pediatric-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS).

[0337] In another aspect, the disclosure 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 csflr gene. In some embodiments, the disease or disorder is caused by a missense mutation in the csflr gene. In some embodiments, the disease or disorder is caused by a mutation in the catalytic kinase domain of CSF1R. In some embodiments, the disease or disorder is caused by a mutation in an immunoglobulin domain of CSF1R. In some embodiments, the disease or disorder is caused by a mutation in the ectodomain of CSF1R. 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. CSF 1R 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 CSF 1R function. In some embodiments, the loss-of-function mutation results in a partial loss of CSF1R function, or a decrease in CSF1R activity.

[0338] In another aspect, the disclosure provides a method of treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmentary orthochromatic leukodystrophyPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0339] (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 abnonnalities neurodegeneration and dysosteosclerosis (BANDDOS).

[0340] In yet another aspect, the disclosure provides a method of treating or preventing Nasu-Hakola disease, Alzheimer’s disease, frontotemporal dementia, multiple sclerosis. Guillain-Barre syndrome, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, traumatic brain injury, spinal cord injury, systemic lupus erythematosus, rheumatoid arthritis, prion disease, stroke, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysosteoplasia, Pyle disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, or metachromatic leukodystrophy wherein any of the aforementioned diseases or disorders are present in a patient exhibiting CSF1R dysfunction, or having a mutation in a 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.

[0341] ABCD1

[0342] The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein (ALDP). ABCD1 (ALDP) maps to Xq28. ABCD1 is a member of the ATP -binding cassete (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 faty 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., Armais 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). ItPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0343] 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.

[0344] The present disclosure relates to the 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. Tire present disclosure relates to the 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.

[0345] To date, no prior study has shown that TREM2 agonism can rescue the loss of microglia in cells where mutations in the ABCD1 and a VLCFA increase is present. No prior study has taught or suggested that reversal of the loss of microglia due to an ABCD 1 mutation through TREM2 agonism can be used to treat a disease or disorder caused by and / or associated with an ABCD1 mutation.

[0346] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer or a pharmaceutical composition thereof for use in treating or preventing a condition associated with dysfunction of ATP -binding cassete transporter 1 (ABCD1).

[0347] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmacally 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 mater disease (VWM), Alexander disease, fragile X-associatcd tremor ataxia syndromePAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0348] (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[0349] In one aspect, the disclosure provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing a condition associated with dysfunction of ABCD 1.

[0350] In one aspect, the invention provides a compound of Formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer or a pharmaceutical composition thereof for use in the preparation of a medicament for treating or preventing 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 mater 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).

[0351] In yet another aspect, the disclosure provides a method of treating or preventing a disease or disorder associated with dysfunction of ABCD1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, 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 tire 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 ABCD 1. 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 faty acids and / or faty acyl-CoAs and production of adrenoleukodystrophy protein (ALDP). In some embodiments, the disease or disorder is caused by a loss-of-fiinction 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 orPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0352] disorder is caused by a homozygous mutation in ABCD 1. In some embodiments, the disease or disorder is a neurodegenerative disorder. In some embodiments, the disease or disorder is a neurodegenerative disorder caused by and / or associated with an 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.

[0353] In yet another aspect, the disclosure provides a method of treating or preventing X-linked adrenoleukodystrophy (x-ALD), Globoid cell leukodystrophy (also known as Krabbe disease), Metachromatic leukodystrophy (MLD), Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Vanishing white mater 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 ABCD 1. 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-fimction mutation in ABCD 1.

[0354] In yet another aspect, the disclosure provides a method of treating or preventing Nasu-Hakola disease, Alzheimer’s disease, frontotemporal dementia, multiple sclerosis. Guillain-Barre syndrome, amyotrophic lateral sclerosis (ALS), or Parkinson’s disease, wherein any of the aforementioned diseases or disorders are present in a patient exhibiting ABCD 1 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.

[0355] Autism Spectrum Disorders

[0356] 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 dendriticPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0357] 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. Tire present disclosure relates to the discovery that activation of TREM2. using a compound of the present disclosure, can rescue microglia in subjects suffering from an ASD. This discovery has not been previously taught or suggested in the available art.

[0358] 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 pharmacal composition thereof for use in treating autism or autism spectrum disorders.

[0359] 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.

[0360] 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.

[0361] 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 tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer 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.

[0362] Combination Therapies

[0363] Depending upon tire 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.”

[0364] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0365] 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 tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer 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 coadministering one additional therapeutic agent. In some embodiments, the method includes coadministering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[0366] 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.

[0367] 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.

[0368] 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.

[0369] One or more other therapeutic agent may be administered separately from a compound or composition of tire 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.

[0370] In one embodiment, the present disclosure provides a composition comprising a provided compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer and one or more additional therapeutic agents. The therapeutic agent may be administered together with a provided compound or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer or may be administered prior to or following administration of a provided compound or a tautomerPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0371] thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. Suitable therapeutic agents are described in further detail below. In certain embodiments, a provided compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a provided compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0372] DEFINITIONS

[0373] The following definitions are provided to assist in understanding the scope of this disclosure. Unless otherw ise 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.

[0374] 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.

[0375] 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, 101stEd. 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”, 8thEd., Ed.: Smith, M. B., John Wiley & Sons, New York: 2019, the entire contents of which are hereby incorporated by reference.

[0376] Stereoisomers

[0377] 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 (z. 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 atropoisomericallyPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0378] 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.

[0379] 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, (lR)-l-methyl-2-(trifluoromethyl)cyclohexane is meant to encompass (lR,2R)-l-methyl-2-(trifluoromethyl)cyclohexane and (lR.2S)-l-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.

[0380] 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.

[0381] 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); andPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0382] Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972).

[0383] Tautomers

[0384] 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. For example, the following is illustrative of tautomers of the compounds of Formula (I), wherein Ring A, together with the 6-membered ring system

[0385] to which it is fused, forms a bicyclic ring system o

[0386]

[0387] f and wherein R8ais H:

[0388]

[0389] Additionally, a second tautomer is possible for compounds of Formula (I) wherein R3is H:

[0390]

[0391] Accordingly, the scope of the instant disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein.

[0392] Isotopically-Labelled Compounds

[0393] 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 as2H and3H, carbon, such asnC,13C and14C, chlorine, such as36C1, fluorine, such as1 SF, iodine, such as,23I and125I, nitrogen, such as13N and15N, oxygen, such as15O,17O and18O, phosphorus, such as32P, and sulphur, such as35S. It is specifically contemplated that when recitation of a particular atom is made, all isotopesPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0394] of that atom are embraced. For example, recitation of '‘hydrogen” or “H” encompasses any of 'H,2H (deuterium), and3H (tritium), unless otherw ise noted. 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 as11C,18F,15O and13N, can be useful in Positron Emission Tomography (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.

[0395] Solvates

[0396] 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.

[0397] 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.”

[0398] 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.

[0399] Miscellaneous Definitions

[0400] This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0401] The term “alkyl”, 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, that has a single point of attachment to the rest of the molecule. Unless otherwise specified, alkyl groups contain 1 to 6 alkyl carbon atoms. In some embodiments, alkyl groups contain 1 to 5 alkyl carbon atoms. In other embodiments, alkyl groups contain 1 to 4 alkyl carbon atoms. In still other embodiments, alkyl groups contain 1 to 3 alkyl carbon atoms, and in yet other embodiments, alkyl groups contain 1 to 2 alkyl carbon atoms.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0402] The term “cycloalkyl” or '‘carbocyclic” as used herein, means a hydrocarbon ring, substituted or unsubstituted that is completely saturated or that contains one or more units of unsaturation but which is not aromatic, that has a single point of atachment to the rest of the molecule. In some embodiments “cycloalkyl,” refers to a monocyclic or bicyclic, bridged bicyclic, or spirocyclic ring, C3-12 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable cycloalkyl groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0403] 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 alkyl groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

[0404]

[0405] Exemplary bridged bicyclics include:PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0406] H

[0407]

[0408] 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.

[0409] Tire term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0410] The term “Cue haloalkyl” refers to a C1-6 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0411] 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 quatemized form of any basic nitrogen; or an oxygen, sulfur, nitrogen, phosphorus, or silicon atom in a heterocyclic ring.

[0412] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. As used herein, the term “bivalent Cns (or Cue) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0413] Tire 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 methylenePAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0414] hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted alkyl group.

[0415] Tire term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenyl ene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted alkyl group.

[0416] 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.

[0417] 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. Hie 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 cycloalkyl 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 (=0) or thioxo (=S) substituent. The temi “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl. wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0418] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. Tire 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.

[0419] The terms “Ci-salkyl,” “Ci-salkyl,” and “Ci-salkyl” 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 Ci-salkyl, Ci-jalky, or Ci-ealkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl.

[0420] 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 branchedPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0421] moieties. Representative examples of C2-4alkenyl include, but are not limited to, 1 -propenyl, 2-propenyl, 2-m ethyl -2 -propenyl, and butenyl.

[0422] Tire term “Cs-ecycloalkyl” as used herein refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbon atoms. Representative examples of Cs-scycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0423] The terms “diCi.3alkylamino” as used herein refer to -NR*R**. wherein R* and R** independently represent a Cualkyl as defined herein. Representative examples of diCi.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.

[0424] Tire term “Ci.3alkoxy” and “Ci-galkoxy” as used herein refer to -OR#, wherein R#represents a Cisalkyl and Ci-galkyl group, respectively, as defined herein. Representative examples of Ci-3alkoxy or Ci-galkoxy include, but are not limited to. methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.

[0425] The term ‘‘halogen” as used herein refers to -F, -CI, -Br, or -I.

[0426] The term “halo” as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein. Hie halogen is independently selected at each occurrence. For example, the term “Ci. ghaloalkyl” refers to a Ci-galkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen. Representative examples of C1-6haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFC1, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3). Further, the term “Ci.ghaloalkoxy” for example refers to a C.galkoxy as defined herein, wherein one or more hydrogen atoms are substituted with a halogen. Representative examples of C1-6haloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCHFC1, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, -OCF(CHF2)2. and -OCH(CH2F)(CF3).

[0427] 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 0 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.

[0428] The term “Cs-gheterocycloalkyl” 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, 0, and S. If the CT hctcrocycloalkyl group is a C hetcrocycloalkyl. one or two carbon atoms arc substituted with ahctcroatom independently selected from N, O, and S.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0429] Representative examples of C3-6heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0430] Tire term “Cs-sspiroalkyl” 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.

[0431] The term “Cs-stricycloalkyl” 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

[0432] are not limited to, tricyclo[1.1.1.01,3]pentanyl,

[0433]

[0434] 1, tricyclo[2.1.1.01,4]hexanyl, tricyclo[3.1.1.01,5]hexanyl, and tricyclo[3.2.1.01,8]octanyl.

[0435] 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. Tire 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.

[0436] Tire 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 π 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 quatemized 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 tenns “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cyclo alkyl, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl. carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, andPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0437] pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic or bicyclic. A heteroaryl ring may include one or more oxo (=0) 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.

[0438] 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 tire purposes disclosed herein.

[0439] The term “pharmaceutically acceptable” as used herein refers to generally recognized for use in subjects, particularly in humans.

[0440] The term “pharmaceutically acceptable salt” as used herein refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine. N-methylglucamine, dicyclohexylamine, and the like. Additional examples of such salts can be found in Berge etal., J. Pharm. Sci. 66(1): 1-19 (1977). See also Stahl et al.. Pharmaceutical Salts: Properties, Selection, and Use, 2ndRevised Edition (2011).

[0441] 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,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0442] vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.

[0443] Tire term “subject” as used herein refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment the subject is a human.

[0444] 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.

[0445] GENERAL SYNTHETIC PROCEDURES

[0446] 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. 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.

[0447] 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.

[0448] 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.

[0449] EXAMPLES

[0450] This section provides specific examples of compounds of Formula (I) and methods of making the same.

[0451] List of Abbreviations

[0452] AcOH Acetic acid

[0453] aq or aq. Aqueous

[0454]

[0455] B2pin2Bis(pinacolato)diboronPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0456] Mesylate[(di( 1 -adamantyl)-n-butylphosphine)-2-(2'-amino- 1,1'- CataCXium A Pd G3

[0457] biphenyl)]palladium(II)

[0458] DCM Dichloromcthanc

[0459] DMAP 4-dimethylaminopyridine

[0460] DMF N, N -dimethylformamide

[0461] DMSO dimethyl sulfoxide

[0462] Dppf, DPPF or dppf 1, 1 '-bis(diphenylphosphino)ferrocene

[0463] eq or eq. or equiv. Equivalent

[0464] ESI orES electrospray ionization

[0465] Et Ethyl

[0466] EtOAc or EA ethyl acetate

[0467] EtOH Ethanol

[0468] G gram(s)

[0469] h or hr hour(s)

[0470] HPLC high pressure liquid chromatography

[0471] IBX 2-Iodoxybenzoic acid

[0472] iPr Isopropyl

[0473] iPr2NEt, DIEA, or

[0474] N-ethyl diisopropylamine (Hunig's base)

[0475] DIPEA LC MS, LCMS, LC-MS

[0476] liquid chromatography mass spectroscopy

[0477] or LC / MS

[0478] m / z mass divided by charge

[0479] Me Methyl

[0480] CH3CN or MeCN or

[0481] Acetonitrile

[0482] ACN

[0483] MeOH Methanol

[0484] Mg Milligrams

[0485] Min Minutes

[0486] mL Milliliters

[0487] MS mass spectra

[0488] n-BuLi n-butyllithium

[0489] NMR nuclear magnetic resonance

[0490] Bis(di-tert-butyl(4-dimethylaminophenyl)- Pd(amphos)C12

[0491] phosphine)dichloropalladium(II)

[0492] PE Petroleum ether

[0493] (l,3-Bis(2,6-diisopropylphenyl)imidazolidene) ( 3 -chloropyridyl) PEPPSI-SIPr

[0494] palladium(II) dichloride

[0495] Ph Phenyl

[0496] RT or rt or r.t. room temperature

[0497] (2-Dicyclohexylphosphino-2',6'-diisopropoxy-l.l'-biphenyl)[2- RuPhos Pd G3

[0498] (2'-amino-l, r-biphenyl)]palladium(II) methanesulfonate sat. Saturated

[0499]

[0500] SFC supercritical fluid chromatographyPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0501] TEA or EtsN Triethylamine

[0502] THF Tetrahydrofuran

[0503] TosMIC toluenesulfonylmethyl isocyanide

[0504] [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'- Xantphos Pd G3

[0505]

[0506] amino- 1, 1 '-biphenyl)]palladium(II) methane sulfonate

[0507] General Analytical and Purification Methods

[0508] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific compounds provided herein.

[0509] Column Chromatography:

[0510] Unless otherw ise indicated, crude product-containing residues w ere 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.

[0511] Preparative HPLC Method:

[0512] prep-HPLC purification was performed using one of the following HPLC conditions:

[0513] 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, 150 x 30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100 x 30 mm).

[0514] 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 fomric acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separations.

[0515] Condition 1: Column: Phenomenex luna C18 150 x 25mm x lOum; Mobile Phase A: water (0.1% FA); Mobile Phase B: MeCN; Flow Rate: 25 mL / min; Gradient 1: 48% B to 78% B in 9 min;

[0516] Chiral HPLC Method:

[0517] Chiral HPLC purification was performed using one of the following Chiral HPLC conditions: Condition 1: Column: Lux i-Amy-1 4.6 x 150 mm; Mobile Phase A: 10 mM ammonium formate (aq); Mobile Phase B: IPA; Gradient 1: 5% B to 60% B;

[0518] Analytical HPLC Method:

[0519] Where so indicated, the compounds described herein were analyzed using an Agilent 1100 series instrument with DAD detector (190 nm to 300 nm).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0520] Flash Chromatography Method:

[0521] 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 rnL / min, UV detection (254 and 220 nm).

[0522] Preparative Chiral Supercritical Fluid Chromatography (SFC) Method:

[0523] Where so indicated, the compounds described herein were purified via chiral SFC using one of the two following chiral SFC columns: (a) Chiralpak IG 2 x 25 cm, 5 pm or (b) Chiralpak AD-H 2 x 15 cm, 5pm.

[0524] Some CP Analytical-SFC experiments were nm on SFC Method Station (Thar, Waters) with the following conditions: Column temperature: 40 °C, Mobile phase: CO2 / Methanol (0.2% Methanol Ammonia) = Flow: 4.0 ml / min, Back Pressure: 120 Bar. Detection wavelength: 214 nm.

[0525] Some CP Analytical-SFC experiments were run on SFC-80 (Thar, Waters) with the following conditions: Column temperature: 35 °C, Mobile phase (example): CO2 / Methanol (0.2% Methanol Ammonia) = Flow rate: 80 g / min, Back pressure: 100 bar, Detection wavelength: 214 nm.

[0526] Preparative CP Method: Acidic reversed phase MPLC: Instrument type: Reveleris™ prep MPLC; Column: Phenomenex LUNA C18(3) (150 x 25 mm, lOp); Flow: 40 rnL / min; Column temp: room temperature: Eluent A: 0.1% (v / v) Fonnic acid in water. Eluent B: 0.1% (v / v) Fonnic acid in acetonitrile; using the indicated gradient and wavelength.

[0527] Proton NMR Spectra:

[0528] Unless otherwise indicated, all ’H 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 = 0.00 ppm) using the internal solvent peak as reference. All NMR were collected at about 25 °C.

[0529] LC / MS, Mass Spectra

[0530] The mass spectra were recorded with a Waters Micromass ZQ detector at 130 °C. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive ion mode and was set to scan between m / z 150-800 with a scan time of 0.3 s. Products and intermediates were analyzed by UPLC / MS on a Gemini-NX (5 M, 2.0 x 30 mm) using a low pH buffer gradient of 10% to 95% of ACN in H2O (0.1% HCOOH) over 5 min at 1.0 mL / min for a 3.5 min run.

[0531] Mass Spectra (MS)

[0532] 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 w as obtained by clcctrospray detection method (commonly referred to as an ESI MS) utilizing a Waters Acquity UPLC / MS system or a Gemini-NX UPLC / MS system. CompoundsPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0533] having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic patern, as appreciated by those skilled in the art.

[0534] Compound Names

[0535] Tire compounds disclosed and described herein have been named using the IUPAC naming function of ChemDraw Professional 17.0.

[0536] Specific Examples

[0537] 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.

[0538] Example 1: Synthesis of Compound 1

[0539] Synthesis of Al

[0540] F

[0541] HO'B'OH Pd(dppf)CI2DCM, K2CO3, dioxane, water, O 60°C, 2 h

[0542]

[0543] A mixture of methyl 2,6-dichloro-5-methoxy-pyrimidine-4-carboxylate (1.0 eq, 1.00 g, 4.22 mmol) and 2-(2,4-difluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.0 eq, 1.01 g, 4.22 mmol) in 1,4-Dioxane (40 mL) and Water (4 mb) was added K2CO3 (2.0 eq, 1.17 g, 8.44 mmol) and Pd(dppf)C12. DCM (0.10 eq, 345 mg, 0.422 mmol). The mixture was degassed with N2 (x3), and the reaction was stirred at 60°C for 2 h. The resulting mixture was combined with another batch. The final mixture was concentrated under reduced pressure and purified by silica gel column chromatography (25% EtOAc in PE) to afford methyl 2-chloro-6-(2,4-difluorophenyl)-5-methoxy-pyrimidine-4-carboxylate (Al, 1.10 g, 3.31 mmol, 79% yield) as a solid. LCMS: (M+H)+= 315.1. 'H NMR (400 MHz, CDC13) 8 = 7.61 (dt, J = 6.4, 8.3 Hz, 1H), 7.10 - 6.93 (m, 2H), 4.03 (s, 3H), 3.70 (s, 3H).

[0544] Synthesis ofA2PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0545]

[0546] To a solution of methyl 2-chloro-6-(2,4-difluorophenyl)-5-methoxy-pyrimidine-4-carboxylate (Al, 1.0 eq, 950 mg, 3.02 mmol) in THF (12 mL) and Water (4 mL) was added LiOH H2O (2.0 eq, 253 mg, 6.04 mmol), and the reaction was stirred at 20°C for 1 h. The mixture was added IN HC1 (aq) to pH = 1-2 and extracted with EtOAc (3 x 50 mL). The organic phase was dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure to afford 2-chloro-6-(2,4-difluorophenyl)-5-methoxy-pyrimidine-4-carboxylic acid (A2, 900 mg, 2.99 mmol, 99% yield) as a crude solid. 'H NMR (400 MHz, CDCL) 8 = 7.66 - 7.55 (m, 1H), 7.11 - 6.90 (m, 2H), 6.72 - 5.86 (m, 2H), 3.89 - 3.78 (m, 3H).

[0547] Synthesis of A3

[0548]

[0549] A2° A3 °

[0550] To a solution of 2-chloro-6-(2,4-difluorophenyl)-5-methoxy-pyrimidine-4-carboxylic acid (A2, 1.0 eq, 0.83 mL. 2.83 mmol) and N, O-dimethylhydroxylamine hydrochloride (1.3 eq, 358 mg, 3.68 mmol) in DMF (17 mL) was added HATU (2.0 eq, 2.15 g, 5.65 mmol) and N. N-diisopropylethylamine (5.0 eq, 2.5 mL, 14.1 mmol), and the reaction was stirred at 20°C for 1 h. The reaction mixture was combined with another batch. The final mixture was added to water (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-chloro-6-(2,4-difluorophenyl)-N,5-dimethoxy-N-methyl-pyrimidine-4-carboxamide (A3, 800 mg, 2.33 mmol, 82% yield) as a solid. LCMS:

[0551] (M+H)+= 343.9. 'H NMR (400 MHz. CDCL) 5 = 7.69 - 7.56 (m. 1H), 7.09 - 6.88 (m, 2H). 3.70 (d. J = 15.4 Hz, 6H), 3.39 (s, 3H).

[0552] Synthesis of A4PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0553]

[0554] A mixture of 2-chloro-6-(2,4-difluorophenyl)-N,5-dimethoxy-N-methyl-pyrimidine-4-carboxamide (A3, 1.0 eq, 300 mg, 0.87 mmol) and (2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.2 eq, 217 mg, 1.05 mmol) in 1.4-Dioxane (15 mL) was added K3PO4 (2.0 eq. 371 mg, 1.75 mmol), and the reaction was stirred at 100°C for 12 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-6-(2,4-difluorophenyl)-N,5-dimethoxy-N-methyl-pyrimidine-4-carboxamide (A4, 400 mg, 0.78 mmol, 89% yield) as an oil. LCMS: (M+H)+= 515.3. 'H NMR (400 MHz, CDCh) 5 = 7.67 - 7.54 (m, 1H). 7.50 (s. 2H), 7.08 - 6.86 (m, 2H). 4.79 - 4.50 (m, 3H), 3.82 - 3.72 (m, 1H). 3.69 (s. 3H), 3.55 (td. J = 3.6. 7.3 Hz. 1H), 3.46 (s, 3H), 3.39 (s, 3H). 2.93 (dd, J = 10.9, 13.2 Hz, 1H), 2.75 - 2.63 (m, 1H), 1.28 (d, J = 4.1 Hz, 3H), 1.14 - 1.07 (m, 2H), 1.04 - 0.94 (m, 2H). Synthesis ofA5

[0555]

[0556] A mixture of 2-[(2S,6R)-2-( l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-6-(2,4-difluorophenyl)-N,5-dimethoxy-N-methyl-pyrimidine-4-carboxamide (A4, 1.0 eq, 300 mg, 0.58 mmol) in DCM (30 mL) was cooled to 0°C. The mixture was added BBr3(5.0 eq, 0.28 mL, 2.92 mmol) at 0°C, and the reaction was stirred at 0°C for 1 h. The mixture was added NaHCO3(aq) at 0°C to pH = 7-8. The mixture was extracted with EtOAc (3 x 50 mL), concentrated under reduced pressure, and purified by silica gel column chromatography (50% EtOAc in PE) to afford 2-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-6-(2,4-difluorophenyl)-5-hydroxy-N-methoxy-N-methyl-pyrimidine-4-carboxamide (A5, 250 mg, 0.50 mmol, 86% yield) as an oil. (M+H)+= 501.2. 'H NMR (400 MHz,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0557] CDC1,) 5 = 11.27 - 10.41 (m, 1H), 7.64 - 7.55 (m, 1H), 7.53 - 7.46 (m, 2H), 7.04 - 6.85 (m, 2H), 4.63 -4.34 (m, 3H), 3.95 - 3.85 (m, 3H), 3.85 - 3.71 (m, 2H), 3.56 (t, J = 3.8, 7.3 Hz, 1H), 2.91 (dd, J = 10.9, 12.9 Hz, 1H), 2.68 (dd, J = 10.7, 12.9 Hz, 1H), 1.29 (d, J = 6.3 Hz, 3H), 1.14 - 1.08 (m, 2H), 1.04 - 0.97 (m, 2H).

[0558] Synthesis of A6

[0559]

[0560] A mixture of 2-[(2S,6R)-2-( l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-6-(2,4-difluorophenyl)-54iydroxy-N-methoxy-N-methyl-pyrimidine-4-carboxamide (A5, 1.0 eq, 100 mg, 0.20 mmol) in THF (3 mL) was cooled to 0°C. To the mixture was added EtMgBr (12.0 eq, 0.80 mL, 2.40 mmol) slowly at 0°C, and the reaction was stirred at 20°C for 0.5 h. The mixture was added sat. NH4CI (aq) to pH = 5-6 at 0°C. Hie mixture was warmed to 20°C and extracted with EtOAc (3 x 20 mL). The combined organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (50% EtOAc in PE) to afford l-[2-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-6-(2,4-difluorophenyl)-5-hydroxy-pyrimidin-4-yl]propan-l-one (A6, 40 mg, 0.082 mmol, 41% yield) as a solid. LCMS: (M+H)+ = 470.2. ‘H NMR (400 MHz, CDCE) 5 = 10.93 - 10.80 (m, 1H), 7.64 - 7.55 (m, 1H), 7.53 (s, 2H). 7.07 - 6.87 (m, 2H), 4.64 - 4.56 (m, 2H), 4.50 (br d, J = 12.6 Hz, 1H), 3.81 (ddd, J = 2.6, 6.3, 10.4 Hz, 1H). 3.57 (td, J = 3.6, 7.3 Hz, 1H), 3.26 (q, J = 7.3 Hz, 2H), 2.92 (dd. J = 11.3, 13.4 Hz. 1H), 2.69 (dd, J = 10.6. 13.0 Hz. 1H), 1.31 (d, J = 6.3 Hz, 3H). 1.22 (t. J = 7.3 Hz, 3H), 1.16 - 1.09 (m, 2H), 1.05 - 0.96 (m, 2H).

[0561] Synthesis of Compound 1

[0562]

[0563] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0564] A mixture of l-[2-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-6-(2,4-difluorophenyl)-5-hydroxy-pyrimidin-4-yl]propan-l-one (A6, 1.0 eq, 45 mg, 0.096 mmol) in Toluene (4.5 mL) was added DMF-DMA (2.0 eq, 23 mg, 0.192 mmol), and the reaction was stirred at 90°C for 1 h. Tire resulting mixture was concentrated under reduced pressure and purified by reversed phase-HPLC (0-30% MeCN in water(0.05% FA)) and lyophilized to afford 2-[(2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-4-(2,4-difluorophenyl)-7-methyl-pyrano[3.2-d]pyrimidin-8-one (Compound 1, 36 mg, 0.076 mmol, 79% yield) as a solid. LCMS: (M+H)+= 480. 'H NMR (400 MHz, CDCk) 5 = 7.71 (d, J = 1.0 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.53 (s, 2H), 7.06 (dt, J = 2.1, 8.2 Hz, 1H), 7.01 - 6.92 (m, 1H), 4.98 - 4.73 (m, 2H), 4.57 (dd, J = 2.6, 10.9 Hz, 1H), 3.80 (ddd, J = 2.5, 6.3, 10.5 Hz, 1H), 3.57 (t, J = 3.8, 7.3 Hz, 1H), 3.02 (dd, J = 11.1, 13.2 Hz, 1H), 2.79 (dd, J = 10.8, 13.3 Hz, 1H), 2.05 (s, 3H), 1.36 - 1.29 (m, 3H). 1.15 - 1.07 (m, 2H), 1.04 - 0.96 (m, 2H). SFC: 100% ee.

[0565] Example 2: Synthesis of Compound 8

[0566] Synthesis of A7

[0567] TMPMgCl-LiCI, -40 °C, 1 h

[0568]

[0569] N-methoxy-N-methyl-propanamide (2.0 eq, 2.3 g. 19.6 mmol) was added to a solution of 5-benzyloxy-2,4-dichloro-pyrimidine (1.0 eq, 2.5 g, 9.8 mmol) in THF (50 mL) and the reaction mixture was cooled to -40 °C. TMPMgCl. LiCl (1.06 M in THF, 1.95 eq, 18 mL, 19.1 mmol) was added dropwise and the reaction was stirred at -40 °C for 1 h. The reaction mixture was wanned to room temperature, quenched with sat. solution NH4Cl (aq.) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, and filtered. Tire filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (2% EtOAc in Hexanes) to afford l-(5-benzyloxy-2,6-dichloro-pyrimidin-4-yl)propan-l-one (A7, 2.35 g. 7.6 mmol, 77% yield) as a solid. ESIMS (m / z)+: 311. L 313.1 (obs).

[0570] Synthesis of A8PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0571]

[0572] A80

[0573] A flask equipped with a Teflon-coated magnetic stirring bar was charged with l-(5-benzyloxy-2,6-dichloro-pyrimidin-4-yl)propan-l-one (A7, 1.0 eq, 2.3 g, 7.4 mmol), [2-fluoro-4-(trifluoromethyl)-phenyl]boronic acid (1.04 eq, 1.6 g, 7.7 mmol), K2CO3 (1.96 eq, 2.0 g, 14.5 mmol) and Pd(dppf)C12 DCM (0.1 eq, 600 mg. 0.74 mmol). The flask was degassed with argon (x3) and 1,4-dioxane (25 mL) and water (2.5 mL) were added under argon. The reaction mixture was then placed in a pre-heated bath at 60 °C and stirred for 1 h. The reaction was cooled down to room temperature, filtered over a Celite pad, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5% EtOAc in Hexanes) to afford l-[5-benzyloxy-2-chloro-6-[2-fluoro-4-(trifluoromethyl)phenyl]-pyrimidin-4-yl]propan-l-one (A8, 2.19 g, 5.0 mmol, 67% yield) as a liquid. ESI-MS (m / z)+: 439.3 (obs).1H NMR (CHCW. 400 MHz): 3H7.54 (t, J= 7.3 Hz, 1H), 7.46 (d, J= 8.2 Hz, 1H), 7.38 (d, J= 9.4 Hz, 1H), 7.28-7.24 (m. 2H), 7.21-7.17 (m, 2H), 6.95-6.93 (m, 2H). 4.81 (s. 2H), 3.07 (q, J= 7.2 Hz, 2H), 1.22 (t, J= 7.2 Hz, 3H).19F NMR (CHCL-ri, 376 MHz): 5F -63.0 (s, 3F), -108.9 (dd, J= 9.4, 6.7 Hz, IF).

[0574] Synthesis of A9

[0575]

[0576] TFA (26.2 eq, 5.0 mL, 65.3 mmol) was added to a solution of l-[5-benzyloxy-2-chloro-6-[2-fluoro-4-(trifluoromethyl)phenyl]pyrimidin-4-yl]propan-l-one (A8, 1.0 eq, 1.1 g, 2.5 mmol) in DCM (5 mL) and the reaction was stirred at 25 °C under argon for 16 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with heptanes (x3) to afford l-[2-chloro-6-[2-fluoro-4-(trifluoromethyl)phenyl]-5-hydroxy-pyrimidin-4-yl]propan-l-one (A9, 790 mg, 2.3 mmol, 91% yield) as a solid. ESI-MS (m / z)-: 347.0 (obs).

[0577] Synthesis of A10PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0578]

[0579] A round-botomed flask was charged with l-[2-chloro-6-[2-fluoro-4-(trifluoromethyl)-phenyl]-5-hydroxy-pyrimidin-4-yl]propan-l-one (A9, 1.0 eq, 686 mg, 1.97 mmol) and toluene (10 mL). N, N-dimethylformamide dimethyl acetal (1.05 eq, 275 pL, 2.1 mmol) was added and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (5-55% EtOAc in Hexanes) to afford 2-chloro-4-[2-fluoro-4-(trifluoromcthyl)phcnyl |-7-mcthyl-pyrano| 3.2-<7|pyrimidin-8-onc (A10, 480 mg, 1.3 mmol, 68% yield) as a solid. ESI-MS (m / z)+: 359.3 (obs). 'H NMR (DMSO-6, 400 MHz): & 8.38 (d, J= 1.1 Hz, 1H), 8.02 (d, J= 9.1 Hz, 1H), 7.98 (t, J= 7.4 Hz, 1H), 7.86 (d, J= 8.0 Hz, 1H), 1.94 (d, J= 0.9 Hz, 3H).,9F NMR (DMSO-t / 6, 376 MHz): 8F-61.4 (s, 3F), -109.8 (dd, J= 9.9, 7.0 Hz, IF).

[0580] Synthesis of Compound 8

[0581]

[0582] A microwave vial equipped with a Teflon-coated magnetic stirring bar was charged with (2.8'.6 / ?)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl -morpholine (1.7 eq, 30 mg, 0.15 mmol), 2-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pyrano[3,2-<7]pyrimidin-8-one (A10, 1.0 eq, 30 mg, 0.08 mmol) and DMSO (1 mL). DIPEA (3.0 eq, 44 pL, 0.25 mmol) was added, the vial was capped, and the reaction was stirred at 70 °C for 3 h. Tire reaction mixture was cooled down to RT, quenched with water and extracted with EtOAc (x3). The combined organic phases were washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (20-70% EtOAc: EtOH (3:1) in Hexanes), and by reverse phase column chromatography (20-80% CH3CN in formic acid 0.1% (aq.)) to afford 2-|(2. S'.6 / ?)-2-(l-cyclopropylpyrazol-4-yl)-6-mcthyl-PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0583] morpholin-4-yl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-pyrano[3,2-<7]pyrimidin-8-one (Compound 8, 6.6 mg, 0.013 mmol, 15% yield) as a solid. ESI-MS (m / z)+: 530.4 (obs). 'H NMR (CHCW, 400 MHz): SH7.77 (t, J= 7.2 Hz, 1H), 7.70 (d, J= 1.1 Hz, 1H), 7.60 (d, J= 7.8 Hz, 1H), 7.54-7.49 (m, 3H), 4.90-4.77 (m, 2H), 4.57 (dd, J= 10.7, 2.3 Hz, 1H), 3.83-3.78 (m, 1H), 3.58 (td, J= 7.1, 3.6 Hz, 1H), 3.03 (dd, J= 12.9, 11.3 Hz, 1H), 2.8O (dd, J= 12.9, 10.9 Hz. 1H), 2.06 (s, 3H), 1.32 (d, J= 6.2 Hz, 3H), 1.12-0.99 (m, 4H).19F NMR (CHCW, 376 MHz): 5F-62.9 (s. 3F), -109.3 (dd, J= 9.4, 6.9 Hz, IF).

[0584] Example 3: Synthesis of Compound 15

[0585] Synthesis of All

[0586]

[0587] A round-botomed flask was charged with l-[2-chloro-6-[2-fluoro-4-(trifluoromethyl)-phenyl]-5-hydroxy-pyrimidin-4-yl]propan-l-one (A9, 1.0 eq, 380 mg, 1.1 mmol) dissolved in toluene (10 mL). To the flask was added N, N-dimethylacetamide dimethyl acetal (1.1 eq, 190 pL. 1.17 mmol), and the reaction was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (2-40% EtOAc in hexanes) to afford 2-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrano[3,2-d]pyrimidin-8-one (All. 57 mg, 0.15 mmol, 14% yield) as a solid. 1H NMR (CHCl3-r / . 400 MHz): 5H 7.88 (t, J= 7.2 Hz, 1H), 7.65 (d, J= 7.8 Hz, 1H), 7.55 (d, J= 9.8 Hz, 1H), 2.42 (s, 3H), 2.13 (s, 3H).19F NMR (CHCW, 376 MHz): 5F-63.0 (s, 3F), - 107.9 (dd, J= 9.7, 6.8 Hz, IF). ESI-MS (m / z)+: 373.2 (obs).

[0588] Synthesis of Compound 15

[0589]

[0590] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0591] A microwave vial equipped with a Teflon-coated stirring bar was charged with (2.8'.6 / ?)-2-( I-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.3 eq, 21 mg, 0.1 mmol), 2-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrano[3,2-d]pyrimidin-8-one (All, 1.0 eq, 29 mg, 0.07 mmol) in THF (1 mL). DIPEA (3.0 eq, 40 pL, 0.23 mmol) was added to the vial which was capped and stirred at 70 °C for 3 h. The reaction mixture was cooled down to RT and treated with water, then extracted with EtOAc (x3). The combined organic phases were washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (10-80% EtOAc: EtOH (3:1) in Hexanes) to afford 2-|(2, S.6 / ?)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl] -4-[2-fluoro-4-(trifluoromethyl)phenyl] -6,7 -dimethyl -pyrano [3,2-d]pyrimidin-8-one (Compound 15, 24 mg, 0.04 mmol, 58% yield) as a solid. ESI-MS (m / z)+: 544.4 (obs). 1H NMR (CHCl3-t / . 400 MHz): 5H7.79 (t, J= 7.3 Hz, 1H), 7.61 (d. J= 8.2 Hz, 1H), 7.55 (d, J = 4.5 Hz, 2H). 7.51 (d, J= 9.4 Hz. 1H), 4.84 (dd, J= 37.2, 14.8 Hz. 2H), 4.58 (dd, J= 11.0.2.3 Hz. 1H), 3.82-3.78 (m, 1H), 3.60-3.57 (m, 1H), 3.02 (dd, J= 13.0, 11.0 Hz, 1H), 2.79 (dd, J= 13.4, 10.6 Hz, 1H), 2.35 (s, 3H), 2.08 (s, 3H), 1.32 (d, J= 6.2 Hz, 3H), 1.14-1.11 (m, 2H), 1.05-1.02 (m, 2H).19F NMR (CHCW, 376 MHz): SF-62.9 (s, 3F), -109.0 (dd, J= 9.8, 7.0 Hz, IF).

[0592] An analogous method was followed to obtain the following compounds.

[0593] Compound Starting Material Characterization

[0594] CF31-cyclopropyl-5- 2-[(2S',6R)-2-(l -cyclopropyl -6- |(2. S'.6 / ?)-6-mcthyl- oxo-3-pyridyl)-6-methyl- morpholin-2-yl]pyridin- morpholin-4-yl] -4-[2-fluoro-4- Y X

[0595] 2-one; (trifluoromethyl)phenyl] -6,7- C%, N N'M'Z

[0596] 2-chloro-4-[2-fluoro-4- dimethyl -pyrano [3,2 -d] pyrimidin- X I XX X

[0597] (trifluoromethyl)- 8-one (Compound 22). ESI-MS o phenyl]-6,7- (m / z)+: 571.4. 'll NMR (CHCE- dimethylpyrano [3,2- <7, 400 MHz): 5H7.79 (t, J= 7.3 Compound 22 d]pyrimidin-8-one Hz, 1H), 7.61 (d. J= 8.0 Hz, 1H),

[0598] 7.52 (t, J= 4.7 Hz, 1H), 7.42 (d, J = 8.7 Hz, 2H), 6.60 (d, J= 9.6 Hz, 1H), 4.85-4.78 (m. 2H), 4.35 (dd, J= 10.9, 2.4 Hz, 1H), 3.82- 3.78 (m, 1H), 3.35-3.30 (m, 1H), 2.90 (dd, J= 13.0, 11.2 Hz, 1H), 2.78 (dd, J= 13.3, 10.7 Hz, 1H), 2.35 (s, 3H), 2.08 (s, 3H), 1.33 (d, J= 6.2 Hz. 3H), 1.15 (dd, J = 13.6, 6.5 Hz, 2H), 0.90 (dd, J = 10.6, 6.3 Hz, 2H).19F NMR (CHCW, 376 MHz): δF-62.9 (s.

[0599]

[0600] 3F), -109.0-109.0 (m, IF).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0601] F l-cyclopropyl-5- 2-((2S,6R)-2-(l-cyclopropyl-6- ((2S,6R)-6-methyl- oxo- 1,6-dihydropyridin-3 -y 1) -6 - Y X morpholin-2-yl)pyridin- methylmorpholino)-4-(2,4- 2(lH)-one; 2-chloro-4- difluorophenyl)-6,7-dimethyl-8H- XI JJX X (2,4-difluorophenyl)-6.7- pyrano[3,2-d]pyrimidin-8-one o dimethyl-8H-pyrano[3,2- (Compound 78). ESI-MS d]-pyrimidin-8-one (m / z)+: 521.3. *H NMR (400 MHz, CHCh-t / ): 87.65 (dd, J = Compound 78

[0602] 14.6, 8.2 Hz, 1H), 7.41-7.38 (m, 2H), 7.06 (td, J = 8.2, 2.3 Hz, 1H), 7.00-6.95 (m, 1H), 6.56 (d, J - 9.4 Hz, 1H), 4.80 (t, J = 14.1 Hz, 2H), 4.33 (dd, J = 10.9, 2.4 Hz, 1H), 3.78 (ddd, J = 10.4, 6.3.

[0603] 2.5 Hz, 1H), 3.33-3.28 (m, 1H), 2.88 (dd, J = 13.0, 11.0 Hz, 1H), 2.76 (dd, J = 13.3, 10.7 Hz, 1H), 2.34 (s, 3H), 2.06 (s, 3H), 1.31 (d, J = 6.2 Hz, 3H), 1.13 (q, J = 6.8 Hz, 2H), 0.88 (dd, J = 10.6, 6.5 Hz, 2H).19F NMR (376 MHz, CHCh-d): 5 -105.3-105.4 (m, IF), -106.6 (dd, J = 18.4, 9.6 Hz, IF).

[0604] F^F (2S,6R)-2-(l- 2-((2S,6R)-2-(l-cyclopropyl-lH- cyclopropyl- IH-pyrazol- pyrazol-4-yl)-6- 4-yl)-6-methyl- methylmorpholino)-4-(4- Y XF morpholine: 2-chloro-4- (difluoromethyl)-2-fluorophenyl)- (4-(difluoromethyl)-2- 6,7-dimethyl-8H-pyrano[3.2-N\JL A A 1 fluorophenyl)-6,7- d]pyrimidin-8-one (Compound dimethyl-8H-pyrano [3,2- 85). ESI-MS (m / z)+: 526.4. ‘H 0

[0605] d] -pyrimidin-8 -one NMR (DMSO-J,. 400 MHz): 5H7.87 (t, J= 7.5 Hz, 1H), 7.81 (s, Compound 85

[0606] 1H), 7.65 (d, J= 10.5 Hz, 1H), 7.60 (d, J= 8.0 Hz, 1H), 7.43 (s, 1H), 7.13 (d, J= 110.7 Hz, 1H), 4.58 (t, J = 11.7 Hz, 2H), 4.48 (dd, J= 10.9. 2.4 Hz. 1H), 3.72- 3.63 (m, 2H), 2.99 (dd, J= 13.0, 11.0 Hz, 1H), 2.69 (dd, J= 13.2, 10.6 Hz, 1H), 2.28 (s, 3H), 1.91 (s, 3H), 1.17 (d, J= 6.2 Hz, 3H), 1.01-0.97 (m, 2H), 0.94-0.87 (m,

[0607]

[0608] 2H).19F NMR (DMSO- d6. 376PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0609] MHz): 5F -111.1 (d, J= 55.3 Hz, 2F), -111.4 (dd, 7= 10.1.7.3 Hz. IF).

[0610] (2S,6R)-2-(l- 2-((2S,6R)-2-(l-cyclopropyl-lH- cyclopropyl-lH-pyrazol- pyrazol-4-yl)-6- 4-yl)-6-methyl- methylmorpholino)-6,7-dimethyl- morpholine; 2-chloro- 4-(6-(trifluoromethyl)pyridin-3- 6,7-dimethyl-4-(6- yl)-8H-pyrano [3.2-d]pyrimidin-8-N(trifluoromethyl) - one (Compound 92). ESI-MS \JL T A Ji pyridin-3-yl)-8H- (m / z)+: 527.4. 'HNMR (DMSO- O^J 0 pyrano[3,2-d] -pyrimidin- d6, 400 MHz): 5H9.43 (s. 1H),

[0611] 8 -one 8.75 (d, 7= 8.5 Hz, 1H), 8.10 (d, Compound 92.7= 8.2 Hz, 1H), 7.83 (s, 1H),

[0612] 7.45 (s. 1H), 4.65 (t, J= 11.0 Hz, 2H), 4.49 (dd, J= 11.0, 2.3 Hz, 1H), 3.72-3.64 (m, 2H), 3.00 (dd, J= 13.2, 11.1 Hz, 1H). 2.70 (dd, J= 13.0, 10.7 Hz, 1H), 2.40 (s, 3H), 1.94 (s, 3H), 1.19 (d, 7= 6.2 Hz, 3H), 1.02-0.97 (m, 2H), 0.95- 0.88 (m, 2H).19FNMR (DMSO- d6, 376 MHz): 5F-66.6 (s, 3F). F^F 1-(2,2-difluoroethyl)-5- 2-[(2S,6R)-2-[l-(2.2- [(2S,6R)-6-mcthyl- difluorocthyl)-6-oxo-3 -pyridyl] - morpholin-2-yl]pyridin- 6-m ethy 1 -m orph ol in -4 -y 1 ] -4 - [ 2 -F" I1 C Yl" F 2-one; 2-chloro-4-[2- fluoro-4- fluoro-4- (trifhioromethyl)phenyl] -6,7- XI (trifluoromethyl)- dimethyl-pyrano[3,2-d]pyrimidin- N I NX I phenyl] -6,7-dimethyl- 8-one (Compound 99). ESI-MS 0 pyrano[3,2-d] -pyrimidin- (m / z)+: 595.3. 'HNMR(CHC13- 8 -one 7, 400 MHz): 5H7.79 (t, J= 1A Compound 99

[0613] Hz, 1H), 7.62 (d. J= 8.0 Hz, 1H), 7.53-7.47 (m, 2H), 7.37 (d, J= 2.1 Hz, 1H), 6.61 (d,7= 9.4 Hz, 1H), 6.14 (t, 7= 56.1, 4.5 Hz, 1H), 4.84 (dd, 7= 26.9, 12.9 Hz, 2H), 4.39-4.17 (m, 3H), 3.81 (ddd.7= 10.6, 6.2, 2.5 Hz, 1H), 2.83 (ddd, J= 37.0, 13.3, 10.7 Hz, 2H), 2.36 (s, 3H), 2.09 (s, 3H), 1.33 (d, 7= 6.2 Hz, 3H).19F NMR (CHCh-ri, 376 MHz): & - 62.9 (s, 3F), -109.0-109.0 (m,

[0614]

[0615] IF), -122.4-122.6 (m, 2F).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0616] F^F (2S,6R)-2-[l- 4-[2-fluoro-4- (methoxymethyl)- (trifluoromethyl)phenyl] -2- pyrazol-4-yl]-6-methyl- [(2S,6R)-2-[l- morpholine: 2-chloro-4- (methoxymethyl)pyrazol-4-yl]-6- X"F[2-fluoro-4- methyl-morpholin-4-yl]-6,7-N\JL J II (trifluoromethyl) - dimethyl-pyrano [3,2-d]pyrimidin- phenyl] -6, 7-dimethyl- 8-one (Compound 106). ESI-MS 0

[0617] pyrano[3,2-d] -pyrimidin- (m / z)+: 548.3. 'HNMR(CHC13- Compound 106 8 -one d, 400 MHz): 8H7.82-7.78 (m,

[0618] 1H), 7.65-7.60 (m, 3H), 7.51 (d, J = 10.3 Hz, 1H), 5.37 (s, 2H), 4.93-4.78 (m, 2H), 4.66-4.61 (m, 1H), 3.84-3.80 (m, 1H), 3.34 (s, 3H), 3.04 (dd, J = 13.5, 11.2 Hz, 1H), 2.81 (dd, J= 13.3, 10.7 Hz, 1H), 2.35 (s, 3H), 2.08 (s, 3H), 1.33 (d, J= 6.2 Hz, 3H).19F NMR (CHCl3-<7, 376 MHz): 5F- 62.9 (s, 3F), -109.0 (dd, J = 9.2, 7.1 Hz. IF).

[0619] F-v-'F l-cyclopropyl-5- 2-((2S,6R)-2-( 1 -cyclopropyl-6- ((2S,6R)-6- oxo- 1,6-dihydropyridin-3 -yl)-6- methylmorpholin-2- methylmorpholino)-4-(4- Y CA yl)pyridin-2(lH)-one; 2- (difluoromethyl)-2-fluorophenyl)- chloro-4-(4- 6,7-dimethyl-8H-pyrano[3,2- X I A A 1

[0620] X / \ / XN'ZXNIIS(difluoromethyl)-2- d]pyrimidin-8-one (Compound O^J o fluorophenyl)-6,7- 113). ESI-MS (m / z)+: 553.3. ’H dimethyl-8H-pyrano [3,2- NMR (DMSOX. 400 MHz): 5H Compound 113 d] -pyrimidin-8 -one 7.87 (t, J= 7.4 Hz, 1H), 7.66-7.59

[0621] (m, 2H), 7.56 (s, 1H), 7.46 (dd, J = 9.4, 2.3 Hz, 1H), 7.13 (t, J = 55.5 Hz, 1H), 6.35 (d, J= 9.4 Hz, 1H), 4.53 (q, J= 12.6 Hz, 2H), 4.38 (dd, J= 10.9, 2.4 Hz, 1H), 3.72-3.68 (m, 1H), 3.26 (dd, J = 7.7, 3.5 Hz, 1H), 2.95 (dd, J = 12.8, 11.2 Hz, 1H), 2.71 (dd, J= 12.9, 10.9 Hz, 1H). 2.28 (s, 3H), 1.92 (s, 3H), 1.19 (d, J = 5.9 Hz, 3H), 0.95-0.92 (m, 2H), 0.95-0.80 (m. 4H), 0.86-0.80 (m, 2H).19F NMR (DMSO- d6, 376 MHz): 5F- 111.1 (d, J= 55.5 Hz, 2F), -111.5

[0622]

[0623] (dd, J= 10.1.7.4 Hz. IF).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0624] l-cyclopropyl-5- 2-((2S,6R)-2-(l-cyclopropyl-6- ((2S,6R)-6-methyl- oxo- 1,6-dihydropyridin-3 -y 1) -6 -YU morpholin-2-yl)pyridin- methyhnorpholino)-6,7-dimethyl- 2(lH)-one; 2-chloro-6,7- 4-(6-(trifluoromethyl)pyridin-3- A°r dimethyl-4-(6- yl)-8H-pyrano [3.2-d]pyrimidin-8- (trifluoromethyl) - one (Compound 120). ESI-MS pyridin-3-yl)-8H- (m / z)+: 554.3. *HNMR(DMS0- 0 pyrano[3,2-d] -pyrimidin- d6, 400 MHz): 5H9.43 (s. 1H),

[0625] 8 -one 8.77 (dd, J = 8.3, 1.5 Hz, 1H), Compound 120 8.11 (d,.7= 8.2 Hz, 1H), 7.58 (d,

[0626] J = 2.1 Hz, 1H), 7.48 (dd, J = 9.4, 2.5 Hz, 1H), 6.36 (d, J= 9.4 Hz, 1H), 4.61 (dd, J = 25.5, 12.2 Hz, 2H), 4.38 (dd, J= 10.7, 2.5 Hz, 1H), 3.70 (ddd, J= 10.6, 6.2, 2.6 Hz, 1H), 3.26 (dd, J= 7.4, 4.2 Hz, 1H), 2.96 (dd, J= 12.9, 11.1 Hz, 1H), 2.72 (dd, J= 12.9, 10.9 Hz, 1H), 2.40 (s, 3H), 1.94 (s, 3H), 1.21 (d, J= 6.2 Hz, 3H), 0.97-0.93 (m, 2H), 0.87-0.78 (m, 2H).19F NMR (DMSO-t / e, 376 MHz): 5F -66.6 (s, 3F).

[0627] (2S,6R)-2-(l- ethyl 2-((25,67?)-2-(l- cyclopropylpyrazol-4- cyclopropyl-l / / -pyrazol-4-yl)-6- yl)-6-methyl- methylmorpholino)-4-(2-fluoro-4- 0 morpholine; ethyl 2- (trifluoromethyl)phenyl)-7- -N~n N / ^ / °Y' x> Et chloro-4-(2-fluoro-4- methyl-8-oxo-8H-pyrano[3,2-N\A A JI JL (trifluoromethyl) - d]pyrimidine-6-carboxylate 0 phenyl)-7-methyl-8-oxo- (Compound 127). ESI-MS 8H-pyrano|3.2- (m / z)+: 602.3. H-NMR (CHC13- Compound 127 d]pyrimidine-6- d, 400 MHz): 5H7.83 (t, J = 7.3 carboxylate Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H),

[0628] 7.52 (s, 2H), 7.49 (d, J = 9.8 Hz, 1H), 4.89-4.80 (m, 2H), 4.57 (dd, J = 10.7, 2.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.82-3.77 (m, 1H), 3.58-3.53 (m, 1H), 3.07-3.01 (m, 1H), 2.81 (dd, J = 12.9, 10.9 Hz, 1H), 2.39 (s, 3H), 1.34-1.30 (m, 6H), 1.12-1.06 (m, 2H), 1.05-0.97 (m, 2H).19F NMR (CHCh-d, 376 MHz): 5F -63.0 (S, 3F), -108.3

[0629]

[0630] (dd, J = 9.5, 6.8 Hz, IF).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0631] 5-((2S,6R)-6- 4-[2-fluoro-4- methylmorpholin-2- (trifluoromethyl)phenyl] -6.7- yl)pyridin-2(lH)-one; 2- dimethyl-2-[(2R,6S)-2-methyl-6- tjL chloro-4-[2-fluoro-4- (6-oxo- 1 H-pyridin-3 - (trifluoromethyl) - yl)morpholin-4-yl]pyrano[3,2- °YA if phenyl]-6,7- d]pyrimidin-8-one (Compound dimethylpyrano [3,2-d] - 134). ESI-MS (m / z)+: 531.3. 'H O^J 0 pyrimidin-8-one NMR (CHCW, 400 MHz): 5H7.79 (t, J= 7.3 Hz, 1H), 7.62 (d, J Compound 134 = 8.2 Hz, 1H), 7.57-7.51 (m, 2H),

[0632] 7.44 (d, J= 2.3 Hz, 1H), 6.60 (d, J= 9.4 Hz, 1H), 4.85 (d, 13.5 Hz, 2H), 4.39 (dd, J= 10.7, 2.5 Hz, 1H), 3.81 (ddd, J= 10.6, 6.1, 2.6 Hz, 1H), 2.87 (dd, J= 13.2, 11.1 Hz, 1H), 2.78 (dd, J= 13.2, 10.9 Hz, 1H), 2.35 (s, 3H), 2.08 (s, 3H), 1.32 (d, J = 6.2 Hz, 3H).

[0633] 19F NMR (CHCh-A 376 MHz): 8F -62.9 (s, 3F), -109.0-109.1 (m, IF).

[0634] FAF (2S,6R)-2-(l- 2-[(2S,6R)-2-(l- cyclopropyl- IH-pyrazol- cyclopropylpyrazol-4-yl)-6- 4-yl)-6- methyl-morpholin-4-yl]-4-[2- methylmorpholine; 2- fluoro-4- chloro-4-(2-fluoro-4- (trifluoromethyl)pheny 1] -7 -NNxAjIiNTV J r II (trifluoromethyl) - methyl-8-oxo-pyrano[3,2- phenyl)-7-methyl-8-oxo- d]pyrimidine-6-carbonitrile O.^J 0 8H-pyrano[3,2- (Compound 141). ESI-MS d]pyrimidine-6- (m / z)+: 555.2. 'HNMR(CHC13- Compound 141

[0635] carbonitrile <7, 400 MHz): & 7.77 (t, J= 7.1

[0636] Hz, 1H), 7.63 (d, J= 8.2 Hz, 1H), 7.57-7.53 (m, 3H), 4.89-4.75 (m, 2H), 4.57 (dd, J= 10.7, 2.3 Hz, 1H), 3.79 (t, J= 9.4 Hz, 1H). 3.59-3.54 (m, 1H), 3.06 (dd, J= 12.9, 11.8 Hz, 1H), 2.83 (dd, J = 12.8, 11.4 Hz, 1H). 2.33 (s, 3H), 1.32 (d, J= 6.2 Hz, 3H), 1.13- 0.98 (m, 4H).19F NMR (CHCW, 376 MHz): 5F-63.0 (s, 3F), -

[0637]

[0638] 109.3 (dd, J= 9.1, 6.7 Hz, IF).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0639] FAF (2S,6R)-2-(l- 2-((2S,6R)-2-(l-cyclopropyl-lH- cyclopropyl- IH-pyrazol- pyrazol-4-yl)-6- 4-yl)-6- methylmorpholino)-4-(2-fluoro-4- methylmorpholine; 2- (trifluoromethyl)phenyl)-7- jX chloro-4-(2-fluoro-4- methyl-6-(trifluoromethyl)-8H-NXJL J II (trifluoromethyl) - pyrano[3,2-d]pyrimidin-8-one N y ^- phenyl)-7-methyl-6- (Compound 148). ESI-MS O (trifluoromethyl)-8H- (m / z)+: 598.4. 'H NMR (400 pyrano [3,2 -d] -pyrimidin- MHz, DMSO-ZA): 58.08 - 7.96 Compound 148

[0640] (m, 2H), 7.85 (d, J= 9.2 Hz, 2H), 8-one

[0641] 7.47 (s, 1H), 4.62 (d, J= 12.2 Hz, 2H), 4.53 (dd, J= 11.0, 2.6 Hz, 1H), 3.81 - 3.64 (m, 2H), 3.09 (dd, J= 13.2. 10.9 Hz, 1H), 2.78 (dd, J= 13.2, 10.7 Hz, 1H), 2.11 (q, J = 2.2 Hz, 3H), 1.21 (d, J = 6.4 Hz. 3H), 1.02 (d, J= 3.7 Hz, 2H), 0.95 (dd, J= 7.4, 4.8 Hz, 2H).19F NMR (376 MHz, DMSO-t / s): 5 -61.34. -64.43 (q, J= 2.2 Hz), -110.27 - -110.45 (m).

[0642] l-cyclopropyl-5- 2-((2S,6R)-2-( 1 -cyclopropyl-6- F^F

[0643] ((2S,6R)-6- oxo- 1,6-dihydropyridin-3 -yl)-6- methylmorpholin-2- methylmorpholino)-4-(2-fluoro-4- (trifluoromethyl)pheny 1) -7- Y IFX yl)pyridin-2(lH)-one; 2- O^, N NA / OVX chloro-4-(2-fluoro-4- methyl-6-(trifluoromethyl)-8H- (trifluoromethyl)- pyrano[3,2-d]pyrimidin-8-one XI fl i phenyl)-7-methyl-6- (Compound 155). ESI-MS O

[0644] (trifluoromethyl)-8H- (m / z)+: 625.2. 'H NMR (400 pyrano[3,2-d]-pyrimidin- MHz, DMSO-A): 58.08 - 7.98 Compound 155

[0645] (m. 2H), 7.85 (d, J= 8.1 Hz, 1H), 8-one

[0646] 7.61 (s, 1H), 7.50 (dd, J= 9.4, 2.5 Hz, 1H), 6.39 (d, J= 9.3 Hz, 1H), 4.58 (dd, J= 25.8, 13.1 Hz, 2H), 4.42 (dd, J= 11.0, 2.7 Hz, 1H), 3.74 (ddd, J= 9.2, 6.4, 2.5 Hz, 1H), 3.29 (dd, J = 7.4, 4.2 Hz, 1H), 3.05 (dd, J= 13.1, 11.0 Hz, 1H), 2.80 (dd, J= 13.2, 10.7 Hz, 1H), 2.11 (q, J= 2.2 Hz, 3H), 1.23 (d, J = 6.1 Hz, 3H), 0.98 (dd, J= 7.1, 2.5 Hz, 2H), 0.92 - 0.75 (m, 2H).19FNMR (376

[0647]

[0648] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0649] MHz, DMSO-ds): 6 -61.35, - 64.44 (q, J= 2.2 Hz), -110.29 - - 110.45 (m).

[0650] CF31 -methyl -5-((2S,6R)-6- 4-(2-fluoro-4- methylmorpholin-2- (trifluoromethyl)phenyl)-6.7- JO yl)pyridin-2(177)-one; 2- dimethyl-2-((2R,6S)-2 -methyl -6- 1F1 chloro-4-[2-fluoro-4- ( 1 -m ethyl -6 -oxo - 1, 6 - (trifluoromethyl)phenyl] - dihydropyridin-3 -yl)morpholino)- XI N I NX X 6,7-dimethyl- 8H-pyrano [3,2-d] pyrimidin-8 -one °^J ° pyrano[3,2-d]pyrimidin- (Compound 162). ESI-MS

[0651] 8-one (m / z+): 545.3. 'H NMR (DMSO- Compound 162 d6, 400 MHz) 87.79 (t, J= 13 Hz, 1H), 7.61 (d,.7= 8.0 Hz, 1H), 7.53-7.51 (m, 1H), 7.42 (d. J = 9.4 Hz, 2H), 6.59 (d, J= 9.6 Hz, 1H), 4.87-4.78 (m, 2H), 4.37 (dd, J= 10.7, 2.5 Hz, 1H), 3.84-3.76 (m, 1H), 3.56 (s, 3H), 2.88 (dd, J = 13.3, 11.0 Hz, 1H), 2.78 (dd, J = 13.5, 10.7 Hz, 1H). 2.35 (s, 3H), 2.08 (s, 3H), 1.57 (s, 4H), 1.33 (d,.7= 6.2 Hz, 3H).

[0652] 19F NMR (376 MHz. DMSO-A.) 8 -62.9 (d, J= 8.6 Hz, 3F), -109.0 (t,.7= 8.2 Hz. IF).

[0653] F. F l-(2-chloro-6-(4,4- 2-((25,6R)-2-( 1 -cyclopropyl -6- difluorocyclohexyl)-5- oxo- 1,6-dihydropyridin-3 -yl)-6- hydroxypyrimidin-4- methylmorpholino)-4-(4,4- Y 9 yl)propan-l-one; 1- difluorocyclohexyl)-7-methyl-8- cyclopropyl-5-((2. S'.6 / ?)- oxo-877-pyrano [3,2-d] pyrim idine- 6-methylmorpholin-2- 6-carbonitrile (Compound 179). ti A r

[0654] yl)pyridin-2( 17 / )-onc ESI-MS (m / z)+: 538.2. 'H NMR o (DMSO-J... 400 MHz) 57.59 (d,

[0655] .7 = 2.3 Hz, 1H), 7.48 (dd, J= 9.4, Compound 179 2.5 Hz. 1H), 6.39 (d, J= 9.4 Hz,

[0656] 1H), 4.55 (d, J= 11.9 Hz, 1H), 4.48 (d, J= 13.0 Hz, 1H), 4.37 (dd, J= 10.7.2.5 Hz. 1H), 3.69 (ddd, J= 10.5, 6.3, 2.5 Hz, 1H), 3.45-3.40 (m, 1H), 3.31-3.28 (m, 1H), 2.97 (dd, J = 12.6. 11.4 Hz, 1H), 2.72 (dd,.7= 13.2, 10.6 Hz, 1H), 2.14 (s, 3H), 2.12-2.04 (m,

[0657]

[0658] 3H), 1.99-1.96 (m, 2H), 1.84-1.78PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0659] (m, 2H), 1.22 (d, J= 6.2 Hz, 3H), 1.00-0.96 (m, 2H), 0.90-0.85 (m.

[0660] 1H), 0.82-0.79 (m, 1H).19F NMR (DMSO- < 376 MHz) 5 -89.6 (d, J= 233.3 Hz, IF), -99.3 (d, J =

[0661]

[0662] 236.0 Hz, IF).

[0663] Example 4: Synthesis of Compound 33

[0664] N

[0665] N. I ZnBr

[0666] Pd(OAc)2, CPhos, THF, 20 °C, 1 h

[0667]

[0668] To a flame-dried round-botomed flask equipped with a Teflon-coated magnetic stirring bar was added 2-chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrano[3,2-d]pyrimidin-8-one (Al l, 1.0 eq, 0.10 g, 0.27 mmol) and CPhos (0.2 eq, 23 mg, 0.05 mmol). The flask was purged with Ar and charged with anhydrous THF (2 mL). Tire resulting solution was degassed with Ar and charged with Pd(OAc)2 (0.1 eq, 6.0 mg, 0.027 mmol) and bromo-|(2 / ?)-2-( l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]zinc (1.12 eq. 2.4 mL, 0.3 mmol) at 0 °C. and the reaction was stirred at RT for 1 h. The reaction mixture was diluted with EtOAc and quenched with sat. NaHCOs (aq). Anhydrous Na2SO4was added, and the resulting mixture was filtered over a short bed of celite and SiC washing with copious amounts of EtOAc. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-70% EtOAc: EtOH (3:1) in Hexanes), followed by reverse phase column chromatography (Cl 8) (20-80% MeCN in 0.1% fonnic acid (aq)) to afford 4-[2-fluoro-4-(trifluoromcthyl)phenyl|-6.7-dimcthyl-2-|rac-(2 / ?)-2-( l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]pyrano[3.2-d]pyrimidin-8-one (Compound 33. 25 mg, 0.047 mmol, 18% yield) as a solid. ESI-MS (m / z)+: 529.3 (obs). 'H NMR (CHCE-t / . 400 MHz): 5H 7.86 (t, J= 7.3 Hz, 1H), 7.65 (d, J= 7.8 Hz, 1H), 7.54 (d, J= 9.8 Hz, 1H), 7.48 (s, 2H), 4.53-4.50 (m, 1H), 4.25-4.21 (m, 1H), 3.77 (td, J= 11.9, 2.6 Hz, 1H), 3.63-3.53 (m, 2H), 2.41 (s, 3H), 2.31 (d, J= 13.5 Hz, 1H), 2.16-2.03 (m, 6H), 1.11-1.07 (m, 2H), 1.01-0.97 (m, 2H).19F NMR (CHCW, 376 MHz): 5F-62.9 (s, 3F), -108.6 (dd, J= 9.7, 6.8 Hz, IF).

[0669] An analogous method was followed to obtain the following compounds.

[0670] Compound

[0671]

[0672] Starting Material Characterization

[0673]

[0674] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0675] bromo-[(27?)-2-(l- 2-[(2S,67?)-2-(l-cyclopropyl-6-oxo-3-pyridyl)- cyclopropyl- 6-methyl-morpholin-4-yl]-4-[2-fhioro-4- pyrazol-4-yl)- (trifluoromethyl)-phenyl]-6,7-dimethyl- tetrahydropyran-4- pyrano[3,2-d]pyrimidin-8-one (Compound yl]zinc; 50). ESI-MS (m / z)+: 501.4. 1H NMR (CHCl3- 2-chloro-6,7- d, 400 MHz): 8H7.46 (d, J= 3.8 Hz, 2H), 4.49 dimethyl-4-[3- (d, J = 11.4 Hz, 1H), 4.21 (dd, J= 11.5, 4.4 Hz, (trifluoromethyl)- 1H), 3.93 - 3.67 (m, 1H), 3.67 - 3.51 (m, 1H). 1 -bicyclofl.1.1]- 3.51 - 3.39 (m, 1H), 2.54 (s, 6H), 2.49 (s, 2H), pentanyl]pyrano- 2.29 - 2.13 (m, 2H), 2.11 (s, 3H), 2.09 - 1.91 [3,2-d]pyrimidin-8- (m, 2H), 1.09 (dq, J= 8.1, 4.1 Hz, 2H), 1.03 - one 0.86 (m, 2H).19F NMR (CHCh-d, 376 MHz):

[0676]

[0677] 5F -73.00 (s, 3F).

[0678] Example 5: Synthesis of Compound 36

[0679] Synthesis of Al 2

[0680] AgNO3, (NH4)2S2O8,

[0681] MeCN, H2O, 80°C, 3 h

[0682]

[0683] A12

[0684] To a round-botomed flask equipped with a Teflon -coated magnetic stirring bar was added 5-benzyloxy-2-chloro-pyrimidine (1.0 eq, 1.0 g. 4.5 mmol), 3-(trifluoromethyl)-bicyclo[l.l.l]pentane-l-carboxylic acid (1.3 eq, 1.06 g, 5.9 mmol) and AgNO₃ (1.3 eq, 995 mg, 5.9 mmol). MeCN (20 mL) and water (10 mL) were added, and the reaction mixture was vigorously stirred at 80 °C for 5 min.

[0685] Ammonium persulfate (3.3 eq, 3.4 g, 15.0 mmol) was added, and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to RT and concentrated under reduced pressure to give a crude. Tire crude was diluted with EtOAc (50 mL) and washed with saturated NaHCCL (aq.) (20 mL) and brine (20 mL). The resulting suspension was filtered over a short pad of celite, washing with EtOAc. The layers were separated, and the organic layer was washed with brine. The organic layer was collected, dried over Na2SO_i, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (1-15% EtOAc in Hexanes) to afford 5-benzyloxy-2-chloro-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimidine (A12, 1.5 g, 2.1 mmol, 46% yield) obtained as a 1:1 mixture with remaining 5 -benzyloxy-2 -chloro-pyrimidine as a solid, and used as is for next step. ESIMS (m / z)+: 355.1 (obs).

[0686] Synthesis of A l 3PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0687] O

[0688]

[0689] A12 A13

[0690] To a solution of 5-benzyloxy-2-chloro-4-t3-(trifluoromethyl)-l-bicyclotl.l.l]pentanylJ-pyrimidine (A 12, 1.0 eq, 1.95 g, 5.5 mmol) in THF (20 mL) was added N-m ethoxy-N-m ethyl -propanamide (2.0 eq, 1.3 g, 11.1 mmol), and cooled to -40 °C. TMPMgCl. LiCl (1.9 eq, 10 mL, 10.6 mmol) was added to the solution, and the resulting mixture was stirred for 0.5 h at -40 °C. Saturated NH4CI (aq.) (30 mL) and EtOAc was added at 0 °C and the aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (1-15% EtOAc in Hexanes) to afford 1 -[5-benzyloxy-2-chloro-6-[3-(trifluoromethyl)-l -bicyclofl.1.1 ]pentanyl]pyrimidin-4-yl]propan-l -one (A13, 775 mg, 1.9 mmol, 34% yield) as a solid. ESI-MS (m / z)+: 411.4 (obs). 'H NMR (CHCL-i / .

[0691] 400 MHz): δH7.42-7.36 (m, 5H), 4.97 (s, 2H), 3.03 (q, J= 7.2 Hz, 2H), 2.35 (s, 6H), 1.18 (t, J= 7.2 Hz, 3H).19F NMR (CHCW, 376 MHz): δF-73.0 (s, 3F).

[0692] Synthesis of Al 4

[0693]

[0694] A13 A14

[0695] To a solution of l-[5-benzyloxy-2-chloro-6-[3-(trifluoromethyl)-l-bicyclo[l. Ll]pentanyl]-pyrimidin-4-yl]propan-l-one (A13, 1.0 eq, 0.73 g. 1.77 mmol) in DCM (5 mL) was added Trifluoroacetic acid (26.2 eq, 3.5 mL. 46.2 mmol), and the reaction was stirred at 45 °C for 16 h under argon. The resulting mixture was concentrated under reduced pressure, co -evaporating with heptanes, and purified by silica gel column chromatography (1% EtOAc in Hexanes) to afford l-[2-chloro-5-hydroxy-6-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-pyrimidin-4-yl]propan-l-one (A14, 378 mg, 1.2 mmol, 67% yield) as a solid. ESI-MS (m / z)-: 319.0 (obs).

[0696]

[0697] NMR (CHCW, 400 MHz): δH11.40 (s, 1H), 3.27 (q, J = 12 Hz, 2H). 2.48 (s. 6H), 1.22 (t, J= 12 Hz, 3H).19F NMR (CHCW, 376 MHz): δF-73.1 (s, 3F). Synthesis of Al 5PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0698] Toluene, 20 °C, 2 h

[0699]

[0700] A15

[0701] To a mixture of 1 -[2 -chloro-5-hydroxy-6-[3-(tri fluoromethyl)-] -bicyclofl.1.1 ]pentanyl]-pyrimidin-4-yl]propan-l-one (A14, 1.0 eq, 192 mg, 0.6 mmol) in Toluene (3mL) was added N, N-dimcthylacctamidc dimethyl acetal (1.2 cq, 0.11 mL, 0.72 mmol), and the reaction was stirred at 20 °C for 2 h. The reaction water and EtOAc were added. Hie organic phase was washed with water (x5). Hie combined aqueous phases were extracted with EtOAc (x3). The combined organic phases were washed with brine, dried over anhydrous NaiSOi. and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5-60% EtOAc in Hexanes) to afford 2-chloro-6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-pyrano[3,2-d]pyrimidin-8-one (A15, 36 mg, 0.1 mmol, 17% yield) as a solid. ESI-MS (m / z)+: 345.0 (obs).19F NMR (CHCW, 376 MHz): δF-73.0 (s, 3F). 'H NMR (CHCW, 400 MHz): δH2.57 (s. 6H), 2.51 (s, 3H), 2.12 (s, 3H).

[0702] Synthesis of Compound 36

[0703]

[0704] To a microwave vial equipped with a Teflon -coated stirring bar was added (2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl-morpholine (1.3 eq, 14 mg, 0.068 mmol), 2-chloro-6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[3,2-d]pyrimidin-8-one (A15, 1.0 eq, 18 mg, 0.05 mmol) and THF (1 mL). DIPEA (3.0 eq, 27 pL, 0.158 mmol) was added and the reaction mixture was stirred at 70 °C for 3 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (10-80% EtOAc: EtOH (3: 1) in Hexanes) to afford 2-|(2. S’.6 / ?)-2-( I -cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[3,2-d]pyrimidin-8-one (Compound 36, 20 mg, 0.039 mmol, 74% yield) as a solid. ESI-MS (m / z)+: 516.4 (obs). 'H NMR (CHCW, 400 MHz): δH7.53 (s, 2H), 4.85-4.72 (m, 2H),PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0705] 4.54 (dd, J= 11.0, 2.5 Hz, 1H), 3.79-3.74 (m, 1H), 3.60-3.54 (m, 1H), 2.97 (dd, J= 13.3, 11.0 Hz, 1H), 2.73 (dd, J= 13.3, 10.7 Hz, 1H), 2.48 (s, 6H), 2.43 (s, 3H), 2.06 (s, 3H), 1.31 (d, J= 6.2 Hz, 3H), 1.14- 1.10 (m, 2H), 1.03-0.98 (m, 2H).19F NMR (CHCl3-ri, 376 MHz): δF-73.0 (s, 3F).

[0706] An analogous method was followed to obtain the following compounds.

[0707] Compound Starting Material Characterization

[0708] CF31-cyclopropyl-5- 2-[((2S,6R)-2-(l-cyclopropyl-6-oxo-3- [(2S,67?)-6-methyl- pyridyl)-6-methyl -morpholin -4-yl] -6,7- Y 4 morpholin-2- dimethyl-4-[3-(trifluoromethyl)-l- yl]pyridin-2-onc; bicyclo [1.1.1 ]pcntanyl] -pyrano [3,2- Yi A Y 2-chloro-6,7- d]pyrimidin-8-one (Compound 43). ESI0 dimethyl-4-[3- MS (m / z)+: 543.4. 'H NMR (CHCT-ri. 400 (trifluoromcthyl) - MHz): δH7.41-7.39 (m, 2H), 6.58 (d, J = Compound 43 1 -bicyclo [ 1.1.1] - 10.1 Hz, 1H), 4.80-4.73 (m, 2H), 4.32 (dd, J pentanyl]pyrano- = 11.0, 2.5 Hz, 1H). 3.79-3.74 (m, 1H), 3.35- [3,2-d]pyrimidin-8- 3.30 (m, 1H), 2.84 (dd, J = 13.2, 10.9 Hz, one 1H), 2.72 (dd, J = 13.4, 10.9 Hz, 1H), 2.49

[0709] (s, 6H), 2.44 (s, 3H), 2.07 (s, 3H). 1.32 (d, J = 6.2 Hz, 3H), 1.17-1.12 (m, 2H), 0.92-0.88 (m, 2H).19F NMR (CHCh-ri. 376 MHz): δF-

[0710]

[0711] 73.0 (s, 3F).

[0712] Example 6: Synthesis of Compound 57

[0713] Synthesis of Al 6

[0714] Cu(OAc)2H2O, 2,2'-bipyridine, Na2CO3, 70 °C, 16 h

[0715]

[0716] A16

[0717] To a solution of [rac-(67?)-6-(6-oxo-lH-pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (1.0 eq, 1.75 g, 5.4 mmol) in DCE (30 mL) was added cyclopropylboronic acid (2.2 eq, 1.0 g, 11.8 mmol), 2,2'-bipyridine (1.1 eq, 924 mg, 5.9 mmol), copper (II) acetate monohydrate (1.1 eq, 1.2 g, 5.9 mmol) and Na₂CO₃ (2.2 eq, 1.3 g, 11.8 mmol). Tire reaction mixture was bubbled with air then heated at 70 °C for 16 h open to air. Water and DCM were added to the reaction mixture. Hie aqueous phase was extracted with DCM, and the combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-40% MeOH in DCM) to afford |rac-(6 / ?)-6-( l-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (A16, 870 mg, 2.1 mmol, 39% yield) as an oil. ESI-MS (m / z)+: 366.3 (obs).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0718] Synthesis of Al 7

[0719] Pd(dppf)CI2, B2pin2, KOAc, 1,4-dioxane, 90 °C, 1 h

[0720]

[0721] A microwave vial equipped with a Teflon coated stirring bar was charged with |rac-(6 / ?)-6-( I -cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethane sulfonate (A16, 1.0 eq, 870 mg, 2.1 mmol), KOAc (4.0 eq, 832 mg, 8.5 mmol), bis(pinacolato)diboron (1.5 eq, 808 mg, 3.2 mmol) in 1,4-dioxane (13 mL). The reaction mixture was purged with argon before adding Pd(dppf)C12. DCM (0.1 eq, 173 mg, 0.21 mmol). The vial was degassed with Ar again then placed in a pre-heated metal beads bath at 90 °C and stirred for 1 h. The resulting mixture was cooled to room temperature, filtered over Celite pad, and rinsed with EtOAc. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (1-30% MeOH in DCM) to afford rac-(A)-l-cyclopropyl-5-(4-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)pyridin-2(lH)-one (A17, 390 mg, 1.1 mmol. 54% yield) as a liquid. ESI-MS (m / z)+: 344.3 (obs).

[0722] Synthesis of Al 8

[0723]

[0724] A solution of l-[5-benzyloxy-2-chloro-6-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-pyrimidin-4-yl]propan-l-one (A13, 1.0 eq, 380 mg, 0.79 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added K2CO3 (2.5 eq, 272 mg, 1.97 mmol), rac-( / ?)-l-cyclopropyl-5-(4-(4.4.5.5-tetramcthyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)pyridin-2(lH)-one (A17, 1.0 eq, 390 mg, 0.80 mmol) and Pd(dppf)C12. DCM (0.1 eq, 64 mg, 0.08 mmol). The reaction mixture was purged (x3) with argon then stirred at 80 °C for 1 h. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (1-40% EtOAc in Hexanes) to afford 5-[4-[5-benzyloxy-4-propanoyl-6-[3-(trifluoromethyl)-l-bicyclo[l.1. l]pentanyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyran-6-yl]-l-cyclopropylpyridin-2-one (A18, 270 mg, 0.46 mmol, 58% yield) as a solid. ESI-MS (m / z)+: 592.3 (obs). 'H NMR (CHCW. 400 MHz): SH7.44-7.33 (m, 7H), 7.09 (s, 1H), 6.57 (d, J = 10.1 Hz, 1H), 5.12PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0725] (s, 1H), 4.96 (s, 2H), 4.19-4.15 (m, 1H), 3.89-3.82 (m, 1H), 3.33-3.30 (m, 1H), 3.07 (q, J= 7.2 Hz, 2H), 2.77 (d, J= 9.8 Hz, 2H), 2.34 (s, 6H), 1.21-1.12 (m, 6H), 0.89-0.86 (m, 4H).

[0726] Synthesis of Al 9

[0727]

[0728] A round-botomed flask equipped with a Teflon coated stirring bar charged with 5-[4-[5-benzyloxy-4-propanoyl-6-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrimidin-2-yl]-3,6-dihydro-2H-pyran-6-yl]-l-cyclopropyl-pyridin-2-one (A18, 1.0 eq, 270 mg, 0.46 mmol) and [Rh(dppb)(COD)]BF4 (0.6 eq, 200 mg, 0.28 mmol) in THF (3mL) was purged with hydrogen and stirred under hydrogen atmosphere at 50 °C for 3 h. The reaction mixture was filtered over a pad of Celite with a small layer of silica gel and rinsed with EtOAc. Tire filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5-55% 3:1 EtOAc: EtOH in Hexanes) to afford l-cyclopropyl-5-[rac-(2A.45')-4-[5-benzyloxy-4-propanoyl-6-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrimidin-2-yl]tetrahydropyran-2-yl]pyridin-2-one (A19, 157 mg, 0.26 mmol, 58% yield) as a solid. ESI-MS (m / z)+: 594.4 (obs).

[0729] Synthesis ofA20

[0730]

[0731] To a solution of l-cyclopropyl-5-[rac-(2A,4S)-4-[5-benzyloxy-4-propanoyl-6-[3-(trifluoromethyl)- 1 -bicyclo[ 1.1.1 ]pentanyl]pyrimidin-2-yl]tetrahydropyran-2-yl]pyridin-2-one (A 19, 1.0 eq, 157 mg, 0.26 mmol) in DCM (2 mL) was added TFA (24.6 eq, 0.50 mL, 6.50 mmol), and the reaction was stirred at 45 °C for 16 h under argon. Tire resulting mixture was concentrated under reduced pressure with heptanes and purified by silica gel column chromatography (10-80% EtOAc: EtOH (3:1) in Hexanes) to afford l-cyclopropyl-5-[rac-(2A,45)-4-[5-hydroxy-4-propanoyl-6-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-pyrimidin-2-yl]tetrahydropyran-2-yl]pyridin-2-one (A20, 113 mg, 0.22 mmol,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0732] 85% yield) as a solid. ESI-MS (m / z)-: 504.3 (obs). 'H NMR (CHCW, 400 MHz): δH 11.37 (s, 1H), 7.41-7.29 (m, 3H), 7.03 (s, 1H), 6.59 (d, J= 9.4 Hz, 1H), 5.13 (d, J= 2.5 Hz, 1H), 4.17-4.12 (m, 1H), 3.93-3.83 (m, 3H), 3.30 (q, J= 7.2 Hz, 2H), 2.78-2.73 (m, 2H), 2.45 (s, 6H), 1.79 (td, J= 14.9, 7.5 Hz, 3H), 1.26-1.18 (m, 4H), 1.00-0.95 (m, 3H).19F NMR (CHCW, 376 MHz): δF-73.1 (s, 3F).

[0733] Synthesis of Compound 57

[0734]

[0735] To a mixture of l-cyclopropyl-5-[rac-(2 / ?,4 )-4-[5-hydroxy-4-propanoyl-6-[3-(trifluoromethyl)- l-bicyclo[l.l.l]pentanyl]pyrimidin-2-yl]tetrahydropyran-2-yl]pyridin-2-one (A20, 1.0 eq, 113 mg, 0.22 mmol) in Toluene (2 mL) was added N, N-dimethylacetamide dimethyl acetal (2.0 eq, 66 pL. 0.45 mmol), and the reaction was stirred at 80°C for 5 h. Hie resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (10-50% 3: 1 EtOAc: EtOH in Hexanes), followed by reverse phase column chromatography (C18) (10-80% ACN in water (0.1% FA)) to afford 6,7-dimethyl-2-[rac-(27?,4iS)-2-(l-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[3,2-d]pyrimidin-8-one (Compound 57, 16 mg, 0.03 mmol, 13% yield) as a solid. ESI-MS (m / z)+: 528.3.0 (obs). 'H NMR (DMSO-iC. 400 MHz): δH7.66 (d, J= 2.3 Hz, 1H), 7.33 (dd, J= 9.4, 2.5 Hz, 1H), 7.08 (s, 1H), 6.34 (d, J= 9.4 Hz, 1H), 5.16 (d, J= 2.3 Hz, 1H). 4.05-4.00 (m, 1H), 3.80-3.74 (m, 3H), 2.66 (s, 2H), 2.51 (s, 6H), 2.48 (s, 3H), 1.94 (s, 3H). 1.60 (td, J= 14.7, 7.4 Hz, 2H), 0.82 (t, J= 7.3 Hz, 3H).19F NMR (DMSO-e, 376 MHz): δF-73.1 (s, 3F).

[0736] Example 7: Synthesis of Compound 64

[0737] Synthesis of A21

[0738]

[0739] To a suspension of l-(2-chloro-5-hydroxy-6-(3-(trifluoromethyl)bicyclo [1.1.1 ]pentan-l-yl)pyrimidin-4-yl)propan-l-one (A14, 1.0 eq, 50 mg, 0.16 mmol) and TFAA (2.0 eq, 44 pL, 0.31 mmol)PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0740] was added pyridine (1.0 eq, 13 pL, 0.16 mmol) and the reaction was stirred at 80 °C for 1 h. The reaction was cooled down to room temperature, diluted with 10% HC1 (aq) (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine, dried over anhydrous MgSCL, and filtered. Hie filtrate was concentrated under reduced pressure to afford (Z)-4-(2-chloro-5-hydroxy-6-(3-(trifluoromethyl)bicyclo[ 1.1.1 Jpentan- 1 -yl)pyrimidin-4-yl)- 1,1,1 -trifluoro-4-hydroxy-3 -methylbut-3 -en-2-one (A21. 60 mg, 0.15 mmol, 95% yield) which was used in the next reaction without further purification.

[0741] 'H NMR (400 MHz, CHCk- ): δ 2.58 (s, 6H), 2.29 (d, J= 2.2 Hz, 3H). ESI-MS (m / z+): 415.1 [M+l]+. Synthesis of Compound 64

[0742]

[0743] A reaction vial was charged with (Z)-4-(2-chloro-5-hydroxy-6-(3-(trifluoromethyl)-bicycl o| 1.1.1 ]pentan- 1 -yl)pyrimidin-4-yl)- 1,1,1 -trifluoro-4-hydroxy-3-methylbut-3 -en-2-one (2) ( 1.0 eq, 19 mg, 0.048 mmol), (2S,6R)-2-(l-cyclopropylpyrazol-4-yl)-6-methyl -morpholine (1.2 eq, 12 mg, 0.057 mmol) and K2CO3 (3.0 eq, 20 mg, 0.143 mmol). THF (0.5 mL) was added and the reaction mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure and purified by reverse phase column chromatography (5-95% MeCN in water (0.1% of HCOOH)) to afford (7-methyl-2-[rac-(2S,6R)-2-(l-cyclopropyl-pyrazol-4-yl)-6-methyl-morpholin-4-yl]-6-(trifluoromethyl)-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[3,2-d]pyrimidin-8-one (Compound 64, 5.5 mg, 9.66 pmol, 20% yield) as a solid. 'H NMR (400 MHz, DMSO ) 87.82 (s, 1H), 7.44 (d, J= 0.8 Hz, 1H), 4.58 (t, J= 11.0 Hz, 2H), 4.45 (dd, J= 10.9, 2.6 Hz, 1H), 3.67 (tt, J= 7.5, 3.9 Hz, 2H), 3.29 (s, 6H), 2.98 (dd, J= 13.3, 10.9 Hz. 1H), 2.68 (dd, J= 13.3, 10.6 Hz, 1H), 2.05 (d, J= 2.2 Hz, 3H). 1.17 (d, J = 6.2 Hz, 3H). 1.03 - 0.86 (m, 4H).19F NMR (376 MHz, DMSO-6) 5 -64.28 (d, J= 2.3 Hz). -71.45. ESI-MS (m / z+): 570.3 [M+l]+.

[0744] An analogous method was followed to obtain the following compounds.

[0745]

[0746] Compound Starting Material CharacterizationPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0747] CF31 -cyclopropyl -5 - 2-((2. S.6 / ?)-2-( 1 -cyclopropyl-6-oxo-y| |(2. S',6 / ?)-6-mcthyl- l,6-dihydropyridin-3-yl)-6-methyl- morpholin-2-yl]pyridin- morpholino)-7-methyl-6- XI 11 1 2 -one; (Z)-4-(2-chloro-5- (trifluoromethyl)-4-(3- hydroxy-6-(3- (trifluoromethyl)bicyclo [1.1.1]- 0 (trifluoromethyl)- pentan- 1 -yl)-8H-pyrano[3,2- bicyclo [1.1.1 ] -pentan- 1- <7]pyrimidin-8-one (Compound 71). Compound 71 yl)pyrimidin-4-yl)- 1,1,1- ESI-MS (m / z+): 597.4. 'H NMR (400 trifluoro-4-hydroxy-3 - MHz, DMSO-D6) δ 7.57 (d, J= 2.5 methylbut-3-en-2-one Hz, 1H), 7.46 (dd, J= 9.4, 2.5 Hz,

[0748] 1H), 6.36 (d, J= 9.3 Hz, 1H), 4.53 (dd, J = 26.6, 13.0 Hz, 2H), 4.35 (dd, J= 11.0, 2.7 Hz, 1H), 3.66 (ddd, J = 9.6, 6.2. 2.6 Hz, 1H), 3.29 (s, 6H), 2.95 (dd, J= 13.1, 11.0 Hz, 1H), 2.69 (dd, J= 13.2, 10.7 Hz, 1H), 2.56 - 2.49 (m. 1H), 2.06 (d, J= 2.3 Hz, 3H), 1.19 (d, J = 6.1 Hz, 3H), 0.96 (dd, J = 7.0, 2.6 Hz, 2H), 0.89 - 0.73 (m, 2H).

[0749] 19F NMR (376 MHz, DMSO-D6) 8 - 64.28 (q, J= 2.1 Hz, 3F), -71.45 (s,

[0750]

[0751] 3F).

[0752] Example 8: Synthesis of Compound 163

[0753] Synthesis of A23

[0754] Br2, NaOAc Br

[0755] MeOH: H2O, 0°C to r.t., 1h

[0756]

[0757] A22

[0758] To a solution of 3-hydroxypyridine-2-carbonitrile (A22, 1.0 eq, 9 g, 74.9 mmol), NaOAc (2.0 eq, 12.3 g, 150 mmol) in MeOH (45 mL) and water (135 mL) was added bromine (3.0 eq, 12 mL, 225 mmol) dropwise, and the mixture was stirred at 20°C for 12 h. The mixture was cooled to 5-10°C and 20% aqueous solution of Na2SOs (60 mL) was added. The resulting mixture was stirred for 30 min and filtered. The filter cake was washed with water and dried to give 4,6-dibromo-3-hydroxy-pyridine-2-carbonitrile (A23, 19 g, 68.4 mmol, 91% yield) as a solid. ESI (M+H+2)+= 278.9. ¹H NMR (400 MHz, MeOH-d) δ = 8.06 (s, 1 H).

[0759] Synthesis ofA24PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0760]

[0761] To a solution of 4, 6-dibromo-3-hydroxy-pyridine-2 -carbonitrile (A23, 1.0 eq, 19 g, 68.4 mmol) in THF (300 mL) was added ethylmagnesium bromide (2.0 eq, 46 mL, 137 mmol) at 0°C over 30 min under N2 and at 0 - 5°C. The mixture was then stirred at 20°C for 12 h. The reaction mixture was added to 6 M solution of HC1 (200 mL) and stirred for 30 min before being quenched with NaHCCL, adjusting the pH =7~8. Tire aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-15% 1:10 EtOAc / Petroleum ether to afford l-(4,6-dibromo-3-hydroxy-2-pyridyl)propan-l-one (A24, 15 g. 48.5 mmol. 71% yield) as a solid. 'H NMR (400 MHz, CHCh-ri) 5 12.53 (s, 1 H) 7.83 (s, 1 H) 3.28 (q, J=1.25 Hz, 2 H) 1.23 (t, J=7.27 Hz, 3 H).

[0762] Synthesis ofA25

[0763] Br

[0764] BnBr, K2CO3 Acetone, 80°C, 12 h

[0765]

[0766] A mixture of l-(4,6-dibromo-3-hydroxy-2-pyridyl)propan-l-one (A24, 1.0 eq, 15 g, 48.5 mmol), K2CO3 (1.5 eq, 10 g, 72.8 mmol) and benzyl bromide (1.1 eq, 6.4 mL, 53.4 mmol) in acetone (12 mL) was stirred at 80°C for 16 h under an N2 atmosphere. The reaction was filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-6% 1:10 Ethyl acetate / Petroleum ether) to give l-(3-benzyloxy-4,6-dibromo-2-pyridyl)propan-l-one (A25, 11 g, 27.6 mmol, 57% yield) as an oil. ESI (m / z+): 400.0.1H NMR (400 MHz, CHCh-ri) 57.59 (s, 1 H) 7.50 (br d, J=7.25 Hz, 2 H) 7.35 - 7.44 (m, 3 H) 6.48 (q, J=7.13 Hz, 1 H) 4.98 (s, 2 H) 2.20 (s, 3 H) 1.80 (d, J=7.13 Hz, 3 H).

[0767] Synthesis of A26

[0768] NaOAc, AcoO, 120°C, 12 h

[0769] A26

[0770]

[0771] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0772] A mixture of l-(3-benzyloxy-4,6-dibromo-2-pyridyl)propan-l-one (A25, 1.0 eq, 9 g, 22.6 mmol) and sodium acetate (1.0 eq, 1.85 g, 22.6 mmol) in acetic anhydride (40 eq, 85 mL, 902 mmol) was stirred at 120°C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-10% 1:10 EtOAc / Petroleum ether) to give 1 -(3 -benzyloxy -4, 6-dibromo-2-pyridyl)-2-methyl-butane-l, 3-dione (A26, 7 g, 15.9 mmol, 70% yield) as an oil. ESI (m / z+): 442.0. 'H NMR (400 MHz, CHCh-t / ) 57.59 (s, 1 H) 7.47 - 7.53 (m, 2 H) 7.35 - 7.44 (m, 3 H) 4.98 (s, 2 H) 2.19 (s, 3 H) 1.80 (d, J=7.13 Hz, 3 H).

[0773] Synthesis of A27

[0774]

[0775] A26

[0776] A mixture of l-(3-benzyloxy-4,6-dibromo-2-pyridyl)-2-methyl-butane-l, 3-dione (A26, 1.0 eq, 500 mg, 1.13 mmol) and Eaton's reagent (8 eq, 2.2 g, 9.07 mmol) was stirred at 100°C for 1.5 h. The reaction mixture was poured into NaHCO3 solution and extracted with EtOAc (100 mL x 2). The organic layer was dried over Na2SO4and evaporated to give a residue which was purified by column chromatography (10-100% 1:1 EtOAc / Petroleum ether) to give 6,8-dibromo-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (A27, 180 mg, 0.541 mmol. 48 % yield) as a solid. ESI (m / z+): 333.8. ’H NMR (400 MHz, CHCl3-d) 37.97 (s, 1H), 2.51 (s, 3H). 2.12 (s. 3H).

[0777] Synthesis ofA28

[0778] A27O O

[0779]

[0780] A28

[0781] To a solution of 6,8-dibromo-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (A27, 1.0 eq, 800 mg, 2.4 mmol) in THF (30 mL) was added sodium methanethiolate (1.0 eq, 168 mg, 2.40 mmol) at -10 °C. The mixture was stirred at -10°C for 0.5 h and then at 25°C for 2 h under N2. The reaction mixture was poured into NaHCO3 solution (50 mL) and extracted with EtOAc (200 mL x 2). The organic layer was dried over Na2SO4 and evaporated to give a residue which was purified by column chromatography (10-100% 1: 1 EtOAc / Petroleium ether) to give 6-bromo-2,3-dimethyl-8-methylsulfanyl-pyrano[3,2-b]pyridin-4-one (A28, 350 mg, 1.17 mmol, 49% yield) as a solid. ESI (m / z+): 299.9. 'H NMR (400 MHz, CHCl3-d) 8 7.34 (s, 1H), 2.57 (s, 3H), 2.46 (s, 3H), 2.10 (s, 3H).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0782] Synthesis of A29

[0783]

[0784] A29 To a solution of (2S,67?)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholine (1.0 eq, 150 mg, 0.528 mmol) and 6-bromo-2,3-dimethyl-8-methylsulfanyl-pyrano[3.2-b]pyridin-4-one (A28, 1.0 eq. 158 mg, 0.528 mmol) in 1.4-dioxane (3 mL) were added Pd-PEPPSI-IHeptCl (0.12 eq. 62 mg, 0.0633 mmol) and Cs2CO3(3 eq, 514 mg, 1.58 mmol). The mixture was stirred at 90°C for 12 h under N2. The reaction mixture was poured into NaCl solution (50 mL) and extracted with EtOAc (80 mL x 2). The organic layer was dried over Na2SO4and evaporated to give a residue which was purified by column chromatography (10-100% 1:1 EtOAc / Petroleium ether) to give 6-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-8-methylsulfanyl-pyrano[3.2-b]pyridin-4-one (A29, 120 mg, 0.238 mmol, 45% yield) as a solid. ESI (m / z+):504.3. 'H NMR (400 MHz. CHCl3-d) 58.24 (d, J= 2.2 Hz, 1H), 7.73 (dd, J= 2.2, 8.6 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.42 - 7.31 (m, 3H), 6.84 (d, J= 8.6 Hz, 1H), 6.64 (s, 1H), 5.41 (s, 2H), 4.64 (dd, J = 2.6, 10.8 Hz, 1H), 4.41 (br d, J= 12.6 Hz, 1H), 4.26 (br d, J= 12.1 Hz, 1H), 3.91 (ddd, J= 2.4, 6.2, 10.3 Hz, 1H), 2.91 (dd, J= 11.0, 12.3 Hz, 1H), 2.80 - 2.71 (m, 1H), 2.54 (s, 3H), 2.44 (s, 3H), 2.07 (s, 3H), 1.40 - 1.34 (m, 3H).

[0785] Synthesis ofA30

[0786]

[0787] To a solution of 6-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-8-methylsulfanyl -pyrano [3, 2-b]pyridin-4-one (A29, 1.0 eq, 90 mg, 0.179 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (5.0 eq, 170 mg, 0.894 mmol) in DMF (4.5 mL) was added Ag2OPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0788] (8.0 eq, 330 mg, 1.43 mmol). Pd(dppf)C12. DCM (0.40 eq, 62 mg, 0.0715 mmol) was added at 25°C under N2 and the mixture was stirred at 100°C for 2 h under N2. EtOAc (150 mL) was added and the mixture was filtered. The filtrate was washed with brine (30 mL x 4). The organic layer was dried over Na2SO4and evaporated to give a residue which was purified by purified by column chromatography (10-100% 1:1 EtOAc / Petroleium ether)to give 6-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-8-[4-(trifluoromethyl)phenyl]pyrano[3,2-b]pyridin-4-one (A30, 70 mg, 0.116 mmol, 65% yield) as a solid. ESI (m / z+): 602.4. 'H NMR (400 MHz, CHCl3-d) 58.24 (d, J= 2.3 Hz, 1H), 7.81 - 7.76 (m, 2H), 7.75 - 7.69 (m, 3H), 7.49 - 7.44 (m, 2H), 7.38 (t, J= 7.3 Hz, 2H), 7.32 (s, 1H), 6.98 (s, 1H), 6.83 (d, J= 8.5 Hz, 1H), 5.40 (s, 2H), 4.65 (dd, J= 2.5, 10.8 Hz, 1H), 4.44 (br d, J= 12.0 Hz, 1H), 4.34 (br d, J= 12.0 Hz, 1H), 3.92 (ddd, J= 2.7, 6.3, 10.4 Hz, 1H), 2.94 (dd, J= 11.0, 12.6 Hz, 1H), 2.79 (dd, J= 10.8, 12.6 Hz, 1H), 2.35 (s, 3H), 2.09 (s, 3H), 1.37 (d, J = 6.3 Hz, 3H).

[0789] Synthesis ofA31

[0790]

[0791] To a solution of 6-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-8-[4-(trifluoromethyl)phenyl]pyrano[3,2-b]pyridin-4-one (A30, 1.0 eq, 60 mg, 0.0997 mmol) in DCE (2 mL) was added TFA (1 mL). The mixture was stirred at 50°C for 4 h. The reaction mixture was evaporated to give a residue which was dissolved in EtOAc (50 mL). NaHCO3 solution (20 mL) was then added and the solution was extracted with EtOAc (50 mL x 2) and DCM (50 mL x 2). The organic phase was concentrated under vacuum to give 2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-lH-pyridin-3-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)phenyl]pyrano[3,2-b]pyridin-4-one (A31, 35 mg, 0.0684 mmol, 69% yield) as a solid.. ESI (m / z+): 512.2. 'H NMR (400 MHz, CHCl3-d) 57.82 - 7.76 (m, 2H), 7.74 -7.69 (m, 2H), 7.38 (d, J= 4.5 Hz, 4H), 6.98 (s, 1H), 6.60 (d, J= 9.5 Hz, 1H), 4.54 - 4.41 (m, 2H), 4.28 (br d, J= 12.5 Hz, 1H), 3.93 - 3.82 (m, 1H), 2.90 - 2.74 (m, 2H), 2.35 (s, 3H), 2.09 (s, 3H), 1.34 (d, J = 6.1 Hz, 3H).

[0792] Synthesis of Compound 163PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0793] CH3I, K2CO3, DMF, 50°C, 1.5 h

[0794]

[0795] Compound 163 To a solution of 2,3-dimethyl-6-[(27?,6S)-2-methyl-6-(6-oxo-177-pyridin-3-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)phenyl]pyrano[3,2-b]pyridin-4-one (A31, 1.0 eq, 20 mg, 0.0391 mmol) in DMF (3 mL) was added K2CO3 (3.0 eq, 16 mg, 0.117 mmol) and Mel (5.0 eq, 28 mg, 0.196 mmol). The mixture was stirred at 50°C for 2 h. The reaction mixture was filtered and the filtrate was evaporated to give a residue which was purified by Prep-TLC (12: 1 DCM / MeOH ) and lyophilized to give 2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(1-methyl-6-oxo-3-pyridyl)morpholin-4-yl]-8-[4-(trifluoromethyl)phenyl]pyrano[3,2-b]pyridin-4-one (Compound 163, 10.14 mg, 0.0187 mmol, 48% yield) as a solid. ESI (m / z+): 526.3. 'H NMR (400 MHz, MeOH-d4) 57.94 - 7.88 (m, 2H), 7.87 - 7.82 (m, 2H), 7.80 (d, J= 2.1 Hz, 1H), 7.74 (dd, J= 2.5, 9.3 Hz, 1H), 7.37 (s, 1H), 6.59 (d, J = 9.3 Hz, 1H), 4.76 (br d. J= 13.0 Hz, 1H). 4.55 - 4.42 (m, 2H), 3.92 - 3.82 (m, 1H), 3.61 (s, 3H), 2.86 - 2.67 (m, 2H), 2.41 (s, 3H).2.10 (s, 3H). 1.34 (d. J= 6.3 Hz. 3H).

[0796] An analogous method was followed to obtain the following compounds.

[0797] Compound Starting Material Characterization CF38-[2-fluoro-4- 6-[(2S,6A)-2-[l-(2,2- (trifluoromethyl)phenyl] -2,3 - difluoroethyl)-6-oxo-3- dimethyl -6 - [ (2 R, 6S) -2 -methyl - pyridyl] -6-methyl-fI ifX J 6-(6-oxo-lH-pyri din-3 - morpholin-4-yl]-8-[2- yl)morpholin-4-yl]pyrano[3,2- fluoro-4- XI XX X b]pyridin-4-one; l,l-difluoro-2- (trifhioromethyl)phenyl] - iodo-ethane 2,3 -dimethyl -pyrano [3,2- b]pyridin-4-one OyJ O

[0798] (Compound 164). ESIMS (m / z+):594.3.

[0799] Compound 164

[0800] NMR (400 MHz, MeOH- d4) 57.84 - 7.77 (m, 3H), 7.74 - 7.67 (m, 2H), 7.42 (s, 1H), 6.69 - 6.59 (m, 1H), 6.41 - 6.06 (m, 1H),

[0801]

[0802] 4.77 (br s, 1H), 4.54 (dd,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0803] J = 2.2, 10.9 Hz, 1H), 4.50 - 4.40 (m, 3H), 3.90 (ddd, J=2.8, 6.3, 10.4 Hz, 1H), 2.89 - 2.73 (m, 2H), 2.38 (s, 3H), 2.11 (s, 3H), 1.36 (d, J= 6.3 Hz, 3H).

[0804] CF38-[2-fluoro-4- 6-[(2S,6R)-2-[6-(2,2- (trifluoromethyl)phenyl] -2,3 - difluoroethoxy)-3- dimethyl-6-[(2R,6S)-2-methyl- pyridyl] -6-methyl- A 6-(6-oxo-l / f-pyridin-3- morpholin-4-yl]-8-[2- 0 N yl)morpholin-4-yl]pyrano[3,2- fluoro-4- T 1 b]pyridin-4-one; 1, 1 -difluoro-2- (trifluoromethyl)phenyl] - N X NI I

[0805] iodo-ethane 2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (Compound 165). ESICompound 165 MS (m / z+): 594.2. 'H NMR (400 MHz, MeOH- d4) 88.30 (s, 1H), 7.90 (dd, J= 1.9, 8.6 Hz, 1H).

[0806] 7.84 - 7.77 (m, 1H), 7.74 - 7.66 (m, 2H), 7.41 (s, 1H), 6.91 (d, J= 8.3 Hz, 1H), 6.41 - 6.01 (m, 1H), 4.75 - 4.68 (m, 2H), 4.57 - 4.47 (m, 3H), 3.98 - 3.87 (m, 1H), 2.92 - 2.74 (m, 2H), 2.37 (s, 3H), 2.10 (s. 3H), 1.36 (d, J= 6.1 Hz, 3H).

[0807] CF36-[(25,67?)-2-( 1 -cyclopropyl-6- 6-[(2S,6R)-2-(l- oxo-3 -pyridyl)-6-methyl- cyclopropyl-6-oxo-3- morpholin-4-yl]-2,3-dimethyl- pyridyl)-6-methyl- 8 -m ethyl sul fany 1 -pyrano [3,2- morpholin-4-yl]-8-[2- O^ YNFI / h]pyridin-4-one; [2-fluoro-4- fluoro-4- (trifluoromethyl)phenyl]boronic (trifluoromethyl)phenyl] - L I I I I

[0808] O^J acid 2,3 -dimethyl -pyrano [3,2- 0 b]pyridin-4-one (Compound 172). ESI Compound 172 (m / z+): 570.3. 'H-NMR (400 MHz, CHCls-c / ) 8 7.56 (s, 2H), 7.49 (d, 1H, J= 9.8 Hz), 7.41 (dd, 2H,

[0809]

[0810] J= 7.2, 2.4 Hz), 6.96 (s,PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0811] 1H), 6.58-6.55 (m, 1H), 4.46-4.38 (m, 2H), 4.21 (d, 1H, J= 12.6 Hz), 3.85-3.81 (m, 1H), 3.32- 3.28 (m, 1H), 2.79 (ddd, 2H, J= 34.0, 12.4, 10.9 Hz), 2.29 (s, 3H), 2.05 (s, 3H), 1.31 (d, 3H. J = 6.2 Hz), 1.12 (dd, 2H, J = 12.9, 6.1 Hz), 0.90-0.86 (m. 2H).19F-NMR (376 MHz, CHCl3-d) 8 -62.8 (s, 3F), -110.3 - 110.4 (m, IF).

[0812] CF36-[(2S,6R)-2-(1- 6-[(2S,67?)-2-(l- cyclopropylpyrazol -4-yl)-6- cyclopropylpyrazol-4-yl)- methyl-morpholin-4-yl]-2,3- 6-methyl-morpholin-4- dimethyl-8-methylsulfanyl- yl]-8-[2-fluoro-4- pyrano[3,2-ft]pyridin-4-one; [2- (trifluoromethyl)phenyl] -n\ jl |T T jT fluoro-4- 2,3 -dimethyl -pyrano [3.2- (trifluoromethyl)phenyl]boronic / >|pyridin-4-one o acid (Compound 173). ESIMS (m / z+): 543.3. ’H- Compound 173 NMR (400 MHz, CHCl3-d) 67.57-7.51 (m, 4H), 6.94 (s. 1H), 4.63 (dd, 1H, J= 10.7, 2.5 Hz), 4.35 (d, 2H, J= 11.4 Hz), 3.85 (ddd, 1H, J= 10.6, 6.3, 2.5 Hz), 3.58-3.52 (m, 1H), 2.98 (dd, 1H,.7 = 12.8, 11.0 Hz), 2.75 (dd, 1H, J= 12.8, 10.5 Hz), 2.29 (s, 3H), 2.07 (s, 3H), 1.32 (d, 3H, J = 6.2 Hz), 1.12-1.08 (m, 2H), 0.98- 0.96 (m, 2H).19F-NMR (376 MHz, CHCl3-d) δ -62.9–-62.7 (3F), -110.4–

[0813]

[0814] 110.2 (IF).

[0815] Example 9: Synthesis of Compound 166PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0816]

[0817] To a solution of 2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-1H-pyridin-3-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)phenyl]pyrano[3,2-b]pyridin-4-one (A31, 1.0 eq, 50 mg, 0.0978 mmol) in DCE (4 mL) were added Na2CO3 (3.0 eq, 31 mg, 0.293 mmol), Cu(OAc)2 (1.5 eq, 27 mg, 0.147 mmol), cyclopropylboronic acid (2.0 eq, 17 mg, 0.196 mmol) and bipyridine (1 eq, 15 mg, 0.0978 mmol). The mixture was stirred at 70°C for 30 min under O2 (15 psi). The reaction mixture was filtered and the filtrate was evaporated to give a residue which was purified by Prep-HPLC (Phenomenex luna C18 150*25mm* lOum, water (formic acid)-ACN) and lyophilized to give 6-[(2S,6R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-8-[4-(trifluoromethyl)phenyl]pyrano[3,2-b]pyridin-4-one (Compound 166, 18.91 mg, 0.0310 mmol, 32% yield) as a solid. ESI (m / z+): 552.3. *H NMR (400 MHz, MeOH-d4) 57.92 - 7.82 (m, 4H), 7.76 - 7.67 (m, 2H), 7.37 (s, 1H), 6.57 (d, J= 9.9 Hz, 1H), 4.72 (br d, J= 12.8 Hz, 1H), 4.55 - 4.41 (m, 2H), 3.86 (ddd, J= 2.6, 6.3, 10.5 Hz, 1H), 3.39 - 3.35 (m, 1H), 2.85 - 2.68 (m, 2H), 2.40 (s, 3H). 2.09 (s, 3H), 1.33 (d, J= 6.2 Hz, 3H), 1.20 - 1.11 (m, 2H), 1.00 - 0.89 (m, 2H).

[0818] Example 10: Synthesis of Compound 167 and Compound 168

[0819]

[0820] Intermediate 32 was synthesized according to the procedure in Example 3. To a solution of 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-lH-pyridin-3-yl)morpholin-4-yl]pyrano[3,2-b]pyridin-4-one (A32, 1.0 eq, 60 mg, 0.113 mmol) in DMF (1.5 mL) were added K2CO3 (1.5 eq, 235 mg, 1.70 mmol) and 3-bromo-l,l-difluoro-cyclobutane (40 eq, 775 mg, 4.53 mmol), then the mixture was stirred at 80°C for 24 h. The reaction mixture was filtered and purified by Prep-HPLC (Phenomenex luna C18 150*25mm* lOum, water (formic acid)-ACN) and lyophilized to give 6-((2S,6R)-2-[l-(3,3-PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0821] difluorocyclobutyl)-6-oxo-3-pyridyl]-6-methyl-morpholin-4-yl]-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (Compound 167, 8.23 mg, 0.0124 mmol, 11% yield) as a solid and 6-[(2S,6R)-2-[l-(3-fluorocyclobut-2-en-l-yl)-6-oxo-3-pyridyl]-6-methyl-morpholin-4-yl]-8-[2-fluoro-4-(trifluorometliyl)phenyl]-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (Compound 168, 14.73 mg, 0.0228 mmol, 20 % yield) as a solid. Compound 167 Data: ESI (m / z+): 620.3. 'H NMR (400 MHz, MeOH-d4) 58.28 (d, J= 2.3 Hz. 1H), 7.89 (dd, J= 2.4, 8.6 Hz, 1H), 7.80 (d, J= 7.3 Hz, 1H). 7.75 - 7.66 (m, 2H), 7.42 (s, 1H), 6.87 (d, J= 8.5 Hz, 1H), 5.16 (br dd, J= 4.9, 7.4 Hz, 1H), 4.78 - 4.67 (m, 2H), 4.50 (br d, J= 12.8 Hz, 1H), 3.92 (ddd, J= 2.4, 6.3, 10.5 Hz, 1H), 3.21 - 3.10 (m, 2H), 2.92 - 2.66 (m, 4H), 2.38 (s, 3H), 2.11 (s, 3H), 1.37 (d, J= 6.1 Hz, 3H). Compound 168 Data: ESI (m / z+): 600.2. ‘HNMR (400 MHz, MeOH-cL) 57.98 (s, 1H), 7.86 - 7.67 (m, 5H), 7.43 (s, 1H), 6.86 - 6.70 (m, 1H), 6.63 (d, J = 9.5 Hz, 1H). 4.92 (br d, J= 2.9 Hz, 1H). 4.85 - 4.73 (m, 2H), 4.57 (br d. J= 10.6 Hz, 1H). 4.45 (br d, J= 12.9 Hz. 1H), 3.90 (brdd. J= 6.1. 7.5 Hz. 1H), 2.93 - 2.72 (m, 2H). 2.38 (s. 3H), 2.11 (s, 3H), 1.36 (d, J = 6.3 Hz, 3H).

[0822] Example 11: Synthesis of Compound 169

[0823] Synthesis of A34

[0824]

[0825] A solution of (2R)-2-(6-benzyloxy-3 -pyridyl) tetrahydropyran-4-one (A33, 1.0 eq, 1.0 g, 3.53 mmol) in THF (20 mL) was cooled to -70°C and LiHMDS was added (1.2 eq, 4.2 mL, 4.24 mmol) dropwise at -70°C under N2. The mixture was stirred at -70°C for 1 h under N. Then a solution of 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (1.2 eq, 1.51 g, 4.24 mmol) in THF (5 mL) was added to the mixture at -70°C under N2. The reaction mixture was warmed to 25°C and stirred for 1 h. Tire mixture was then stirred at 25°C for another 16 h. The reaction mixture was poured into water (60 mL) slowly and stirred at 0 °C for 10 min, then the mixture was extracted with EtOAc (30 mL x 3). The organic layer was dried over Na2SO4. The solution was filtered and the filtrate was concentrated to give a residue, which was purified by flash silica gel chromatography (0 - 20% 1:5 EtOAc / Petroleum ether) to give the mixture of [(6R)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate and [(2R)-2-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (A34, 800 mg, 1.232 mmol, 35% yield) as an oil. ESI (m / z+): 416.1. 'H NMRPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0826] (400 MHz, CHCh- ) 58.15 (dd, J= 2.4, 7.6 Hz, 1H), 7.66 - 7.56 (m, 1H), 7.49 - 7.44 (m, 2H), 7.43 -7.36 (m, 4H), 7.35 - 7.29 (m, 3H), 6.95 (br s, 1H), 6.84 (dd, J= 3.6, 8.8 Hz, 1H), 5.98 - 5.87 (m, 1H), 5.39 (s, 2H), 5.27 (q, J= 2.8 Hz, 1H), 4.63 (dd, J= 3.6, 10.0 Hz, 1H), 4.56 - 4.37 (m, 1H), 4.20 - 4.05 (m, 1H), 3.93 - 3.82 (m, 1H), 2.80 - 2.64 (m, 1H), 2.57 - 2.38 (m, 1H) (mixture).

[0827] Synthesis of A35

[0828] B2Pin2, Pd(dppf)CI2DCM, KOAc dioxane, 90°C, 2 h

[0829]

[0830] To a solution of [(6R)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate and [(2R)-2-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate (mixture) (A34, 1.0 eq, 700 mg, 1.69 mmol), B2(pin)2 (1 eq, 428 mg, 1.69 mmol), KOAc (3 eq, 496 mg, 5.06 mmol) in 1,4-dioxane (15 mL) was added Pd(dppf)C12 DCM (0.1 eq, 138 mg, 0.169 mmol) at 20°C and then the mixture was stirred at 90°C for 2 h under N2. The reaction mixture was concentrated to give a residue, which was purified by flash silica gel chromatography (0-20% 1:5 EtOAc / Petroleum ether) to give a mixture of 2-benzyloxy-5-[(6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine and (R)-2-(benzyloxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-yl)pyridine (A35, 460 mg, 0.795 mmol, 47% yield) as an oil. ESI (m / z+): 394.0. 'H NMR (400 MHz, CHCh-t / ) 58.15 (dd, J= 2.4, 4.8 Hz, 1H), 7.63 (ddd, J = 2.4, 8.8, 13.6 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.41 - 7.29 (m, 4H), 6.80 (d, J= 8.8 Hz, 1H), 6.63 - 6.49 (m, 1H), 5.38 (s, 2H), 4.44 - 4.40 (m, 1H), 4.02 - 3.95 (m, 1H), 3.79 - 3.70 (m, 1H), 2.47 - 2.34 (m, 1H), 2.25 - 2.16 (m, 1H), 1.28 (s, 12H) (mixture).

[0831] Synthesis of A36

[0832] Pd(dppf)CI2DCM, K2CO3dioxane, H2O, 100°C, 2 h

[0833]

[0834] A36

[0835] CF3

[0836] A mixture of 2-benzyloxy-5-[(6R)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine and (R)-2-(benzyloxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-yl)pyridine (mixture) (A35, 1.0 eq, 425 mg, 1.08 mmol), 6-bromo-2,3-dimethyl-8-PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0837] methylsulfanyl -pyrano [3, 2-b]pyridin-4-one (A28, 1.0 eq, 324 mg, 1.08 mmol), K2CO3 (2.0 eq, 298 mg, 2.16 mmol), Pd(dppf)C12-DCM (0.10 eq, 88 mg, 0.108 mmol) in 1,4-Dioxane (10 mL) and water (1 mL) was stirred at 100°C for 2 h under N2. The reaction mixture was concentrated to give a residue which was purified by flash silica gel chromatography (40-60% 1:1 EtOAc / Petroleum ether) to give the mixture of 6-[(6R)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-8-methylsulfanyl-pyrano[3,2-b]pyridin-4-one and (R)-6-(2-(6-(benzyloxy)pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-8-(methylthio)-4H-pyrano[3,2-b]pyridin-4-one (A36, 300 mg, 0.524 mmol, 49% yield) as an oil. ESI (m / z+): 487.2. 'H NMR (400 MHz, CHCl3-d) 58.22 (dd, J= 2.4, 12.0 Hz, 1H), 7.76 - 7.64 (m, 1H), 7.50 - 7.44 (m, 2H), 7.41 - 7.35 (m, 3H), 7.34 - 7.29 (m, 1H), 6.88 - 6.80 (m, 1H), 5.40 (d, J= 4.4 Hz, 2H), 5.36 - 5.32 (m, 1H), 4.68 - 4.63 (m, 1H), 4.60 (br s, 1H), 4.26 - 4.17 (m, 1H), 3.97 - 3.88 (m, 1H). 3.19 - 3.11 (m, 1H), 2.97 - 2.86 (m, 1H), 2.80 - 2.69 (m, 1H), 2.58 (d, J= 6.0 Hz, 3H), 2.48 (s, 3H), 2.10 (d, J = 2.4 Hz, 3H) (mixture).

[0838] Synthesis of A 37

[0839] CF3

[0840]

[0841] A mixture of 6-[(6R)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-8-methylsulfanyl-pyrano[3,2-b]pyridin-4-one and (R)-6-(2-(6-(benzyloxy)pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-8-(methylthio)-4H-pyrano[3,2-b]pyridin-4-one (mixture) (A36, 1.0 eq, 280 mg, 0.575 mmol), [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (5.0 eq, 598 mg, 2.88 mmol), Ag2O (8 eq, 1.1 g, 4.60 mmol), Pd(dppf)Cl2·DCM (0.4 eq, 199 mg, 0.230 mmol) in DMF (6 mL) was stirred at 100°C for 2 h under N2. The reaction mixture was diluted with EtOAc (30 mL) and filtered. The filtrate was poured into water (60 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (50 mL x 2) and dried over Na2SO4. The solution was concentrated to give a residue, which was purified by flash silica gel chromatography (30-50% 1:1 EtOAc / Petroleum ether) to give the mixture of 6-[(6R)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one and (R)-6-(2-(6-(benzyloxy)pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-4H-pyrano[3,2-b]pyridin-4-one (A37, 200 mg, 0.259 mmol, 45% yield) as a solid. ESI (m / z+): 603.2. 'H NMR (400 MHz, CHCl3-d) 58.22PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0842] (dd, J= 2.4, 15.6 Hz, 1H), 7.73 (dd, J= 2.4, 8.8 Hz, 1H), 7.70 (d, J= 4.8 Hz, 1H), 7.65 (dd, J= 2.4, 8.4 Hz, 1H), 7.63 - 7.57 (m, 2H), 7.54 (dd, J= 3.6, 9.6 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.38 (dt, J = 5.6, 6.8 Hz, 2H), 7.35 - 7.28 (m, 1H), 6.88 - 6.79 (m, 1H), 6.73 (d, J= 1.6 Hz, 1H), 5.40 (d, J= 8.4 Hz, 2H), 5.35 (br d, J= 2.4 Hz, 1H), 4.67 (dd, J= 3.2, 10.2 Hz, 1H), 4.61 (br d, J= 1.6 Hz, 1H), 4.24 (td, J= 4.4, 11.2 Hz, 1H). 3.99 - 3.90 (m, 1H), 3.19 (br d, J= 17.2 Hz, 1H). 2.94 (br s, 1H). 2.86 - 2.74 (m, 1H), 2.35 (s, 3H).

[0843] 2.12 (d, J= 2.4 Hz, 3H) (mixture).

[0844] Synthesis of A 38

[0845] Pd / C, TEA, MgO EtOAc, H, (15 psi), 25°C, 36 h

[0846]

[0847] A37 To a solution of 6-[(6R)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one and (R)-6-(2-(6-(benzyloxy)pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-4H-pyrano[3,2-b]pyridin-4-one (mixture) (A37, 1.0 eq, 150 mg, 0.249 mmol) in EtOAc (15 mL) were added MgO (10 eq, 100 mg, 2.49 mmol), TEA (1.2 eq, 30 mg, 0.299 mmol) and Pd / C (1 eq, 27 mg, 0.249 mmol) at 25°C, then the mixture was stirred at 25 °C for 16 h under H2(15 Psi). Tire reaction mixture was then stirred at 25°C for another 20 h under H2(15 Psi). The reaction mixture was then filtered and concentrated to give a residue, which was purified by prep-HPLC (Phenomenex Luna C18 150 * 25mm*10um, water (2.25% formic acid) - ACN; B%: 35% - 65%, 10min) and lyophilized to give 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R,4S)-2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]pyrano[3,2-b]pyridin-4-one (A38, 40 mg, 0.0777 mmol, 31% yield) as a solid. ESI (m / z+): 515.2. ¹H NMR (400 MHz, CHCl₃-d) δ 7.61 (d, J= 3.2 Hz, 2H), 7.57 - 7.49 (m, 2H), 7.46 (s, 1H), 7.37 (d, J= 2.0 Hz, 1H), 6.58 (d, J= 9.2 Hz, 1H), 4.37 - 4.22 (m, 2H), 3.80 - 3.72 (m, 1H), 3.54 - 3.43 (m, 1H), 2.35 (s, 3H), 2.23 (br d, J= 12.8 Hz, 1H), 2.12 (s, 3H), 2.07 - 1.96 (m, 2H), 1.85 - 1.78 (m, 1H).

[0848] Synthesis of Compound 169PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0849]

[0850] To a solution of 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R,4S)-2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]pyrano[3,2-b]pyridin-4-one (A38, 1.0 eq, 40 mg, 0.0777 mmol) in DCE (1.5 mL) were added Na₂CO₃ (3.0 eq, 25 mg, 0.233 mmol), cyclopropylboronic acid (2 eq, 13 mg.

[0851] 0.155 mmol), Cu(OAc)2 (1.5 eq. 21 mg. 0.117 mmol), and bipyridine (1.0 eq, 12 mg, 0.0777 mmol) at 20°C and then the mixture was stirred at 70°C for 30 min under O2 (15 Psi). The reaction mixture was filtered and concentrated to give a residue, which was purified by prep-HPLC (Waters Xbridge C18 150*25mm*5um, H2O (0.05% NH3H2O) - ACN; B%: 32% - 62%, 12 min) and lyophilized to give 6-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (Compound 169, 11 mg, 0.0190 mmol, 24% yield) as a solid.

[0852] ESI (m / z+): 515.3. ¹H NMR (400 MHz, CHCl₃-d) δ 7.60 (d, J= 2.8 Hz, 2H). 7.54 (d. J= 10.4 Hz, 1H), 7.46 (s, 1H), 7.36 - 7.31 (m, 2H), 6.56 - 6.51 (m, 1H), 4.33 - 4.24 (m, 2H), 3.80 - 3.72 (m, 1H), 3.53 -3.42 (m, 1H), 3.35 - 3.28 (m, 1H), 2.35 (s, 3H), 2.26 - 2.18 (m, 1H), 2.12 (s, 3H), 2.05 - 1.99 (m, 2H), 1.87 - 1.75 (m, 1H), 1.16 - 1.10 (m, 2H), 0.91 - 0.85 (m, 2H).

[0853] Example 12: Synthesis of Compound 170

[0854] Synthesis of A39

[0855]

[0856] Tetrakis(triphenylphosphine)palladium (0.1 eq, 687 mg, 0.595 mmol) was added to a solution of 6,8-dibromo-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (A27, 1 eq, 1.98 g, 5.95 mmol) and sodium formate (2.0 eq, 809 mg, 11.9 mmol) in DMF (32 mL). The reaction mixture was stirred for 12 h at 80°C under N2. DMF was removed under reduced pressure and the residue was purified by flash silica gel chromatography (0-56% 1:1 EtOAc / Petroleum ether) to afford 6-bromo-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (A39, 490 mg, 1.64 mmol, 28% yield) as a solid. ESI (m / z+): 254.0. ’H NMR (400 MHz, CHCh-r / ) 57.74 - 7.69 (m, 1H), 7.69 - 7.64 (m, 1H), 2.46 (s, 3H), 2.13 (s, 3H).

[0857] Synthesis of A40PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0858]

[0859] To a solution of 6-bromo-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (A39, 1.0 eq, 500 mg, 1.97 mmol), 3-(trifluoromethyl)bicyclo[l.l.l]pentane-l-carboxylic acid (3 eq, 1.1 g, 5.90 mmol) in ACN (10 mL) and water (10 mL) were added TFA (1.1 eq, 247 mg, 2.16 mmol) and AgNOs (1.3 eq, 432 mg, 2.56 mmol). The reaction mixture was vigorously stirred at 80°C for 5 min. Ammonium persulfate (3.3 eq, 1.5 g, 6.49 mmol) was added and the resulting mixture was stirred at 80°C for 12 h. The reaction mixture was quenched by addition of NaHCO₃ (20 mL) and 20% aq. Na₂SO₃ (20 mL) at 25°C. The mixture was extracted with EtOAc (50 mL x 3) and the combined organic layers were washed with sat. NaCl (50 mL x 1), dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue, whcih was purified by flash silica gel chromatography (0-32% 1:1 EtOAc / Petroleum ether) to afford 6-bromo-2,3-dimethyl-8-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[3,2-b]pyridin-4-one (A40, 120 mg, 0.257 mmol, 13% yield) as a solid. ESI (m / z+): 388.0. ‘H NMR (400 MHz, CHCL-t / ) 57.43 (s, 1H), 2.48 (s, 9H), 2.11 (s, 3H).

[0860] Synthesis of A41

[0861]

[0862] To a solution of 6-bromo-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrano[3,2-b]pyridin-4-one (A40, 1.0 eq, 120 mg, 0.309 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) were added 2-benzyloxy-5-[(67?)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydro-277-pyran-6-yl]pyridine (1.5 eq, 182 mg, 0.464 mmol), cataCXium A Pd-G3, (0.1 eq, 23 mg, 0.0309 mmol) and Cs2CO3(3 eq, 302 mg, 0.927 mmol). The mixture was stirred at 80°C for 2 h under N2. Tire reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-39% 2: 1 EtOAc / PetroleumPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0863] ether) to afford 6-[(67?)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-27f-pyran-4-yl]-2,3-dimethyl-8-[3- (trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[3,2-b]pyridin-4-one (A41, 90 mg, 0.152 mmol, 49% yield) as an oil. ESI (m / z+): 575.3. ¹H NMR (400 MHz, CHCl₃-d) δ 8.26 - 8.18 (m, 1H), 7.75 - 7.62 (m, 1H), 7.52 - 7.45 (m, 2H), 7.44 - 7.35 (m, 3H), 7.35 - 7.29 (m, 1H), 6.88 - 6.63 (m, 2H), 5.45 - 5.37 (m, 2H), 5.36 - 5.28 (m, 1H), 4.69 - 4.56 (m, 2H), 4.26 - 3.85 (m, 1H), 2.92 - 2.68 (m, 1H), 2.49 (d, J= 2.4 Hz, 7H), 2.11 (s, 3H), 1.30 - 1.22 (m, 2H).

[0864] Pd / C, TEA, MgO, EtOAc, H2(15 psi), 25 °C, 12 h

[0865]

[0866] To a solution of 6-[(6R)-6-(6-benzyloxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrano[3,2-b]pyridin-4-one (A41, 1.0 eq, 80 mg, 0.139 mmol) in EtOAc (10 mL) were added MgO (10 eq, 56 mg, 1.39 mmol), TEA (1.2 eq, 17 mg, 0.167 mmol) and Pd / C (1.0 eq, 80 mg. 0.139 mmol) at 25°C under N₂, then the mixture was stirred at 25°C for 3 h under H₂ (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Phenomenex Luna C18 150*25mm* lOum, water (2.25% formic acid)-ACN; B%: 35%-65%, gradient time: lOmin, Detector, UV 220 nm) and lyophilized to give 2,3-dimethyl-6-[(2R,4S)-2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrano[3,2-b]pyridin-4-one (A42, 20 mg, 0.0411 mmol, 30% yield) as a solid. ESI (m / z+): 487.2. 'H NMR (400 MHz, CHCl3-d) 57.56 - 7.49 (m, 1H), 7.38 (d, J = 16.4 Hz, 2H), 6.63 - 6.56 (m, 1H), 4.37 - 3.68 (m, 3H), 3.55 - 3.33 (m, 1H), 2.92 - 2.77 (m, 1H), 2.56 -2.41 (m, 9H), 2.20 - 2.08 (m, 4H), 2.01 - 1.90 (m, 2H), 1.76 (br d, J= 12.4 Hz, 1H).

[0867] Synthesis of Compound 170

[0868]

[0869] A42 Compound 170 To a solution of 2,3-dimethyl-6-[(2R,4S)-2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrano[3,2-b]pyridin-4-one (A42, 1.0 eq, 13 mg, 0.0267PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0870] mmol) in DCE (2 mL) were added Na-> CCf (3 eq, 8.5 mg, 0.0802 mmol), cyclopropylboronic acid (2 eq, 4.6 mg, 0.0534 mmol), Cu(OAc)2 (1.5 eq, 7.3 mg, 0.0401 mmol) and bipyridine (1 eq, 4.2 mg, 0.0267 mmol) at 25 °C and then the mixture was stirred at 70°C for 5 h under O2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Phenomenex luna C18 150*25mm* lOum, water (2.25% formic acid)-ACN; B%: 40%-70%, gradient time: 15min, Detector, UV 220 nm) and lyophilized to give 6-[(2.4< S)-2-(l -cyclopropyl -6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[3,2-b]pyridin-4-one (Compound 170, 1.67 mg, 0.00317 mmol, 12% yield) as a solid. ESI (m / z+):527.3. 'H NMR (400 MHz, CHCl3-< ) 87.36 - 7.30 (m, 2H), 7.17 (s, 1H), 6.57 -6.50 (m, 1H), 4.33 - 4.21 (m, 2H), 3.81 - 3.68 (m, 1H), 3.44 - 3.26 (m. 2H), 2.48 (s, 7H), 2.20 - 2.08 (m, 4H). 2.03 - 1.90 (m, 2H), 1.83 - 1.69 (m, 1H), 1.41 - 1.30 (m, 1H), 1.28 - 1.08 (m, 3H), 0.94 - 0.84 (m, 2H).

[0871] An analogous method was followed to obtain the following compounds.

[0872] Compound Starting Material Characterization

[0873] F 6-bromo-2,3-dimethyl- 6-[(27?,4S)-2-(l-cyclopropyl- pyrano [3,2-b]pyridin-4-one; 6-oxo-3-Y<y 3- pyridyl)tetrahydropyran-4- o^N fluorobicyclo[ 1.1. l]pentane- yl]-8-(3-fluoro-l- 1 -carboxylic acid bicyclof 1.1. l]pentanyl)-2,3- T l X I I

[0874] dimethyl-pyrano [3,2-0b]pyridin-4-one (Compound Compound 171 171). ESI-MS (m / z+); 477.3.

[0875] ¹H NMR (400 MHz, CHCl₃-d) δ 7.35 - 7.31 (m, 2H), 7.19 (s, 1H), 6.57 - 6.51 (m, 1H), 4.31 - 4.22 (m, 2H), 3.74 (dt, J= 3.6, 11.2 Hz, 1H), 3.43 - 3.27 (m, 2H), 2.58 (d, J= 2.4 Hz, 6H), 2.47 (s, 3H), 2.15 (br d, J= 13.2 Hz, 1H), 2.11 (s, 3H), 1.96 (br dd, J = 4.0, 9.6 Hz, 2H), 1.81 - 1.70 (m, 1H), 1.16 - 1.11 (m, 2H),

[0876]

[0877] 0.90 - 0.87 (m, 2H).

[0878] Example 13: Synthesis of Compound 174PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0879]

[0880] Compound 174 Intermediate A43 was synthesized using a method based on Example 8. Chloro-(2,4-difluorophenyl)zinc (2.0 eq, 1.3 m, 0.14 mmol) was added dropwise to a solution of 6-[(2S,6R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-8-methylsulfanyl-pyrano[3,2-b]pyridin-4-one (A43. 1.0 eq, 32 mg, 0.071 mmol), and PEPPSI-SIPr (0.2 eq, 9.6 mg. 0.014 mmol) in ACN (1 mL) at r.t. The reaction was stirred 5 h at 60 °C, then The quenched with NaHCCh and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄. filtered and concentrated in vacuo. The crude was purified by chromatography (0-3% MeOH in DCM) and reverse phase chromatography (15-85% ACN in water containing 0.1% formic acid) to afford 6-[(2S,67?)-2-(l-cyclopropyl-6-oxo-3-pyridyl)-6-methyl-morpholin-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethyl-pyrano[3,2- / >]pyridin-4-one (Compound 174, 10 mg, 0.019 mmol. 27% yield). ESI (m / z+): 520.5. ¹H-NMR (400 MHz, CHCl₃-d) δ 7.43-7.37 (m, 3H), 7.04-6.94 (m, 3H), 6.57 (dd, 1H, J= 7.9, 2.4 Hz), 4.46-4.38 (m, 2H), 4.21 (d, 1H, J= 12.3 Hz), 3.83 (ddd, 1H, J= 10.5, 6.2, 2.6 Hz), 3.32-3.29 (m, 1H), 2.78 (ddd, 2H, J= 34.2, 12.7, 10.6 Hz), 2.29 (s, 3H), 2.05 (s, 3H), 1.31 (d, 3H, J= 6.2 Hz), 1.15-1.10 (m, 2H), 0.90-0.86 (m, 2H). ¹⁹F-NMR (376 MHz, CHCl₃-d) δ -107.4 (s, 1F), -108.5 (s, 1F).

[0881] An analogous method was followed to obtain the following compounds.

[0882] Compound Starting Material Characterization CF36-[(2. S,,6A)-2-( 1 -cyclopropyl-6- 6-[(2S',6A)-2-(l- oxo-3-pyridyl)-6-methyl- cyclopropyl-6-oxo-3- morpholin-4-ylJ-2,3-dimethyl- pyridyl)-6-methyl-YU 8-methylsulfanyl-pyrano [3,2- morpholin-4-yl] -2,3 - O^N 6]pyridin-4-one; chloro-[6- dimethyl-8-[6- (trifluoromethyl ) -3 -pyridyljzinc (trifluoromethy l)-3 - L i I I I

[0883] N N pyridyl]pyrano[3,2- O / >|pyridin-4-one (Compound 175). ESI-MS Compound 175 (m / z+): 553.4. ¹H-NMR (400 MHz, CHCl₃-d) δ 8.95 (d, 1H, J= 1.4 Hz), 8.10

[0884]

[0885] (dd, 1H, J= 8.1, 1.7 Hz),PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0886] 7.84 (d, 1H, J= 8.2 Hz), 7.43-7.40 (m, 2H), 6.97 (s.

[0887] 1H), 6.61-6.56 (m, 1H), 4.49-4.39 (m, 2H), 4.22 (d, 1H, J= 12.3 Hz), 3.86-3.82 (m, 1H), 3.33-3.29 (m, 1H), 2.81 (ddd, 2H, J= 31.7, 12.6. 10.7 Hz). 2.34 (s. 3H), 2.06 (d, 3H, J= 11.2 Hz), 1.32 (dd, 3H, J= 6.1, 3.8 Hz), 1.13 (q, 2H, J = 6.6 Hz), 0.90-0.86 (m, 2H).

[0888] 19F-NMR (376 MHz, chloroform-J) 5 -67.8 (s, 3F).

[0889] R / F 6-[(2S,6R)-2-( 1 -cyclopropyl-6- 6-[(2S,6R)-2-(l- oxo-3-pyridyl)-6-methyl- cyclopropyl-6-oxo-3- morpholin-4-yl]-2,3-dimethyl- pyridyl)-6-methyl- Y 8-methylsulfanyl-pyrano [3,2- morpholin-4-yl]-8-[4- 6]pyridin-4-one; chloro-[4- (difluoromethyl)-2 -fluoroLX 1 / 1 1 (difluoromethyl)-2 -fluorophenyl] -2,3 -dimethyl - phenyl] zinc pyrano[3,2-b]pyridin-4-one 0 (Compound 176). ESI-MS (m / z+): 552.3. ¹H-NMR (400 MHz, CHCl₃-d) δ 7.53 Compound 176

[0890] (t, 1H, J= 7.4 Hz). 7.44- 7.38 (m, 4H), 6.96 (s, 1H), 6.60 (t, 1H, J= 10.3 Hz), 4.46-4.40 (m, 2H), 4.22 (d.

[0891] 1H, J= 11.9 Hz), 3.88-3.83 (m, 1H), 3.33-3.30 (m, 1H), 2.87-2.73 (m, 2H), 2.29 (s, 3H), 2.06 (s, 3H), 1.32 (d, 3H, J= 6.2 Hz), 1.18-1.11 (m, 2H), 0.91-0.87 (m, 2H).

[0892] ¹⁹F-NMR (376 MHz, chloroform-d) δ -111.1 (dd, 1F, J= 9.6, 7.1 Hz), -111.7

[0893]

[0894] (s, IF), -111.9 (s, IF).

[0895] Example 14: Synthesis of Compound 177

[0896] Synthesis of A45PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0897]

[0898] A45

[0899] To 5-(Benzyloxy)-2 -chloropyrimidine (A44, 1.0 eq, 1.50 g, 6.80 mmol) was added 4,4-Difluorocyclohexanecarboxylic acid (1.3 eq, 1.45 g, 8.84 mmol) and AgNO₃ (1.3 eq, 1.49 mL, 8.84 mmol). The solids were then suspended in ACN (30 mL) and water (15 mL). The mixture was stirred at 80 °C for 5 minutes and then (NH4)2S20s (3.3 eq, 5.12 g, 22.4 mmol) was added while the mixture was hot. The reaction was stirred for 1 h at 80 °C. The mixture was then cooled and poured into a separatory funnel and diluted with water (50 mL) and EtOAc (100 mL). The phases were separated and the aqueous were extracted two additional times with EtOAc (2x 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was further purified by silica gel chromatography using (0-15% gradient of EtOAc / hexanes) to afford 5-(benzyloxy)-2-chloro-4-(4,4-difluorocyclohexyl)pyrimidine (A45, 1.41 g, 4.16 mmol, 61 % yield) as a solid. ESI-MS (m / z)+: 339.1.

[0900] Synthesis of A46

[0901]

[0902] To 5-(benzyloxy)-2-chloro-4-(4,4-difluorocyclohexyl)pyrimidine (A45. 1.0 eq, 1.41 g, 4.16 mmol) was added THF (21 mL). N-Methoxy-N-methylpropionamide (2.0 eq, 975 mg, 8.32 mmol) was then added in one portion. The solution was cooled to -40 °C and then a 1.06 M solution of Knochel-Hauser base (7.85 mL, 8.32 mmol) in THF was added over 15 min. The reaction was stirred at -40°C for 15 min. The solution was warmed to -20°C and then 5 mL of a saturated solution of ammonium chloride was added. The heterogeneous mixture was vigorously stirred 2 min and then water (20 mL) was added. The mixture was extracted with EtOAc (3x 100 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was further purified by silica gel chromatography (0-10% gradient of EtOAc / hexanes)PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0903] to afford 1-(5-(benzyloxy)-2-chloro-6-(4,4-difluorocyclohexyl)pyrimidin-4-yl)propan-1-one (A46, 1.60 g, 4.04 mmol, 97 % yield) as a solid. ESI-MS (m / z)+: 395.3.

[0904] Synthesis of A47

[0905]

[0906] To l-(5-(benzyloxy)-2-chloro-6-(4,4-difluorocyclohexyl)pyrimidin-4-yl)propan-l-one (A46, 1.0 eq, 300 mg, 760 pmol) was added MsOH (500 pL). The solution was stirred for 1 h. The mixture was then poured into a separator}’ funnel and diluted with water (20 mL) and EtOAc (90 mL). The phases were separated, and the organic was washed with brine (20 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated, under reduced pressure. The crude mixture was used directly into the next step. ESI-MS (m / z)-: 303.0.

[0907] Synthesis of A48

[0908] F F F F

[0909] I QH Acetic anhydride, Eaton's reagent, 90°CtI N N ft cr I A ci^ AN A'y 1'^

[0910]

[0911] o oA47

[0912]

[0913] A48To 1-(5-(benzyloxy)-2-chloro-6-(4,4-difluorocyclohexyl)pyrimidin-4-yl)-2-methylbutane-1,3-dione (A47, 1.0 eq, 230 mg, 755 μmol) was added Eaton's reagent (2.33 mL), followed by acetic anhydride (3.2 eq, 234 μL, 2.45 mmol). The solids were dissolved and then mixture was heated to 90°C for 15 min. The solution was then poured into ice / water (50 mL) and stirred until the ice melted. The aqueous phase was then extracted with EtOAc (3x 30 mL). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was further purified by silica gel chromatography (10-60% 1:3 EtOH / EtOAc in hexanes) to afford 2-chloro-4-(4,4-difluorocyclohexyl)-6,7-dimethyl-8H-pyrano[3,2-d]pyrimidin-8-one (A48, 60.0 mg, 227 μmol, 30 % yield) as a solid. ESI-MS (m / z)+: 329.1.

[0914] Synthesis of Compound 177PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0915]

[0916] To 2-chloro-4-(4,4-difluorocyclohexyl)-6,7-dimethyl-8H-pyrano[3,2-d]pyrimidin-8-one (A48, 1.0 eq, 30.0 mg, 91.3 μmol) was added (2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholine (1.2 eq, 22.7 mg, 91.3 μmol) in THF (650 pL). To the mixture was then added DIPEA (3.0 eq, 47.7 pL, 274 pmol) and the mixture was heated to 60 °C for 4 h. Tire solution was then concentrated under reduced pressure and directly purified by chromatography (12g cartridge, 20-60% 3: 1 EtOAc / EtOH in hexanes) to afford 2-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-4-(4,4-difluorocyclohexyl)-6,7-dimethyl-8H-pyrano[3,2-d]pyrimidin-8-one (Compound 177, 15.1 mg, 15.5 μmol, 17 %) as a solid after lyophilisation. ESI-MS (m / z)+: 500.4. ’H-NMR (DMSO-r / e, 400 MHz) 5 7.81 (s, 1H), 7.43 (s, 1H), 4.56-4.51 (m, 2H), 4.45 (dd, J= 10.7, 2.5 Hz, 1H), 3.69-3.64 (m, 2H), 3.40 (t, J = 11.3 Hz, 1H), 2.93 (dd, J= 13.0, 11.2 Hz, 1H), 2.63 (dd, J= 12.9, 10.9 Hz, 1H), 2.40 (s, 3H), 2.10-2.04 (m, 3H), 1.99-1.92 (m, 3H), 1.90 (s, 3H), 1.83-1.76 (m, 2H), 1.16 (d, J = 6.2 Hz, 3H), 1.02-0.98 (m, 2H), 0.93-0.88 (m, 2H). ¹⁹F NMR (DMSO-d₆, 376 MHz) δ -89.5 (d, J= 232.2 Hz, 1F), -99.3 (d, J= 240.3 Hz, 1F).

[0917] An analogous method was followed to obtain the following compounds.

[0918] Compound Starting Material Characterization

[0919] FFl-cyclopropyl-5-((2S,67?)-6- 2-((2S,67?)-2-(l- methylmorpholin-2-yl)pyridin- cyclopropyl-6-oxo- 1,6- 2(l / / )-one; 2-chloro-4-(4,4- dihydropyridin-3-yl)-6- difluorocyclohexy l)-6, 7- methylmorpholino)-4-(4,4- Y vi m T e dimcthy I -87 / -py rano [3,2- difluorocy clohexyl) -6, 7- <7]pyrimidin-8-one dimethyl-8E7-pyrano[3,2- d]pyrimidin-8-one

[0920] 0 (Compound 178). ESI-MS (m / z)+:527.3. ’H NMR Compound 178 (CHCT-r / , 400 MHz) 57.56

[0921] (d, J = 2.3 Hz, 1H), 7.46

[0922]

[0923] (dd, J= 9.4, 2.5 Hz, 1H),PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0924] 6.36 (d, J= 9.4 Hz, 1H), 4.52 (d, J= 11.9 Hz, 1H), 4.45 (d, J= 13.0 Hz, 1H), 4.35 (dd, J = 10.9, 2.6 Hz, 1H), 3.67 (ddd, J= 10.5, 6.2, 2.5 Hz, 1H), 3.40 (t, J = 11.1 Hz, 1H), 3.28-3.25 (m, 1H), 2.89 (dd, J= 12.9, 11.1 Hz, 1H), 2.65 (dd, J= 12.9, 10.9 Hz, 1H), 2.40 (s, 3H), 2.10-2.05 (m, 3H), 2.00-1.93 (m, 3H), 1.90 (s, 3H), 1.83-1.77 (m, 2H), 1.19 (d, J = 6.2 Hz, 3H), 0.97-0.91 (m, 2H), 0.87- 0.82 (m, 1H), 0.81-0.77 (m, 1H).19F NMR (CDCl3, 376 MHz) δ -89.5 (d, J= 235.6 Hz, 1F), -99.3 (d, J =

[0925]

[0926] 253.1 Hz, 1F).

[0927] Example 15: Synthesis of Compound 180

[0928] Synthesis ofA49

[0929] A15

[0930]

[0931] To 2-chloro-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-8H-pyrano[3,2-d]pyrimidin-8-one (A15, 1.0 eq, 95.5 mg, 277 pmol) was added (2S,6R)-2-(6-(benzyloxy)pyridin-3-yl)-6-methylmorpholine (1.2 eq, 94.5 mg. 332 pmol), followed by THF (1.85 mL). The solids were dissolved and DIPEA (3 eq, 145 pL, 831 pmol) was slowly added. The solution was then heated to 50 °C for 18 h. The mixture was cooled down and diluted with a sat. solution of NH4Cl (20 mL) and EtOAc (30 mL). The phases were separated and the aqueous were extracted with EtOAc (2x 30 mL). The combined organics were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, andPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0932] concentrated under reduced pressure. The crude mixture was used directly in the next step. ESI-MS (m / z)+: 593.3.

[0933] Synthesis ofA50

[0934]

[0935] The crude mixture of 2-((2S,6R)-2-(6-(benzyloxy)pyridin-3-yl)-6-methylmorpholino)-6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-8H-pyrano[3,2-d]pyrimidin-8-one (A49, 1.0 eq, 152 mg, 256 pmol) was dissolved in MsOH (1.5 mL) and stirred for 3 h. The mixture was then poured diluted with water (20 mL) and EtOAc (100 mL). The phases were separated and the organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mixture was used directly into the next step. ESI-MS (m / z)+: 503.3. Synthesis of Compound 180

[0936]

[0937] To 6,7-dimethyl-2-((2R,6S)-2-methyl-6-(6-oxo-1,6-dihydropyridin-3-yl)morpholino)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-8H-pyrano[3,2-d]pyrimidin-8-one (A50, 1.0 eq. 139 mg, 277 pmol) was added Cs2CO3(3.5 eq, 319 mg, 968 pmol) and THF (2 mL). To the suspension was added iodomcthanc-t / 3 (3.4 eq, 60.4 μL, 941 pmol) and the suspension was heated to 50 °C for 4 h. The suspension was cooled down and the solids were filtered and washed with DCM (20 mL). The filtrate was concentrated under reduced pressure and further purified by silica gel chromatography (10-60% 1:3 EtOH / EtOAc in hexanes) to afford 6,7-dimethyl-2-((2R,6S)-2-methyl-6-(1-(methyl-d3)-6-oxo-1,6-dihydropyridin-3-yl)morpholino)-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-8H-pyrano[3,2-d]pyrimidin-8-one (Compound 180, 64.5 mg, 45 % yield over three steps), as a solid. ESI-MS (m / z)+:PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0938] 520.4. 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (d, J= 2.5 Hz, 1H), 7.50 (dd, J= 9.4, 2.7 Hz, 1H), 6.40 (d, J= 9.4 Hz, 1H), 4.58 (t, J= 9.9 Hz, 2H), 4.33 (dd, J= 10.9, 2.4 Hz, 1H), 3.71 (ddd, J = 10.5, 6.2, 2.5 Hz, 1H), 2.90 (dd, J= 13.2, 11.1 Hz, 1H), 2.67 (dd, J= 13.2, 10.6 Hz, 1H), 2.44 (s, 3H), 1.93 (s, 3H), 1.22 (d, J= 6.2 Hz, 3H).19F NMR (DMSO-d6, 376 MHz) δ -71.2 (s, 3F).

[0939] Example 16: Synthesis of Compound 181

[0940] Synthesis of A52

[0941] H

[0942] BnBr, Ag2CO3, Toluene, 100 °C, 1 h

[0943] A51

[0944]

[0945] A52

[0946] To 5-iodopyridin-2-ol (A51, 1.0 eq, 5.0 g, 22.6 mmol) was added benzyl bromide (1.1 eq, 3.0 mL, 24.9 mmol), Ag2CO3 (1.5 eq, 9.36 g, 33.9 mmol) and toluene (130.6 mL). The mixture was heated at 100 °C for 1 h. The solution was cooled down to rt, filtered, rinsed with EtOAc (300 mL), and concentrated. The crude material was purified by flash chromatography (0- 20% EtOAc in hexanes) to yield 2-benzyloxy-5 -iodo-pyridine (A52, 4.50 g,14.5 mmol, 64% yield) as a solid. ESI-MS (m / z+): 312.0. 1H NMR (CHCl3, 400 MHz) δ 8.30-8.42 (1H), 7.74-7.82 (1H), 7.43-7.50 (2H), 7.31-7.42 (3H), 6.53-6.70 (1H), 5.32-5.40 (2H).

[0947] Synthesis ofA53

[0948] NaOtBu, Pd(OAc)2, XPhos

[0949] THF, 50 °C, 16 h

[0950]

[0951] A52

[0952] To the solution of NaO / Bu (3 eq, 1.39 g, 14.5 mmol) in THF (32.1 mL) were added 1-Boc-4-piperidone (1.5 eq, 1.44 g, 7.23 mmol) and 2-benzyloxy-5-iodo-pyridine (A52, 1.0 eq, 1.5 g, 4.8 mmol). XPhos (0.1 eq, 230 mg, 0.482 mmol) and Pd(OAc)2 (0.05 eq, 54 mg, 0.24 mmol) were added and the resulting mixture was stirred at 50 °C for 16 h. The reaction was washed with water and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo, and purified by reverse phase chromatography (50-80% ACN in water (0.1% formic acid)) to yield tert-butyl 3 -(6-benzyloxy-3-pyridyl)-4-oxo-piperidine-l -carboxylate (A53, 0.91 g, 2.38 mmol, 49% yield) as an oil. ESI-MS (m / z) +: 383.4. 1H NMR (CHCl3, 400 MHz) δ 7.96 (d, J =PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0953] 2.5 Hz, 1H), 7.44 (d, J= 6.9 Hz, 2H), 7.41-7.29 (m, 4H), 6.80 (d, J= 8.5 Hz, 1H), 5.35 (s, 2H), 4.34-4.26 (m, 1H), 3.66 (dd, J= 10.5, 5.9 Hz, 1H), 3.43-3.34 (m, 2H), 2.65-2.51 (m, 2H), 2.16 (s, 2H), 1.49 (s, 9H). Synthesis of A54

[0954] DAST, DCM, -78 °C to r.t., 16 h

[0955]

[0956] A53 DAST (2 eq, 0.66 mL, 5.0 mmol) was added dropwise to a -78°C solution of tert-butyl 3-(6-benzyloxy-3-pyridyl)-4-oxo-piperidine-l -carboxylate (A53, 1 eq, 950 mg, 2.5 mmol) in DCM (16 mL). Tire resulting mixture was allowed to warm up to rt under stirring overnight. Sat. aqueous solution of NaHCOs was added at 0 °C. The mixture was extracted with EtOAC, washed with brine, dried over Na2SO4. concentrated, and purified by flash chromatography (10%-60% EtOAc in hexanes) to yield tertbutyl 3-(6-benzyloxy-3-pyridyl)-4,4-difluoro-piperidine-l-carboxylate (A54, 540 mg, 1.34 mmol, 54% yield) as an oil. ESI-MS (m / z)+: 405.3. 1H NMR (CHCl3, 400 MHz) δ 8.10 (s, 1H), 7.56 (d, J= 8.9 Hz, 1H), 7.47-7.45 (m, 2H), 7.40-7.36 (m, 2H), 7.34-7.30 (m, 1H), 6.80 (d, J= 8.5 Hz, 1H), 5.37 (s, 2H), 4.27-4.19 (m, 1H), 3.27-2.96 (m, 3H), 2.21-2.11 (m, 2H), 2.06-1.89 (m, 1H), 1.47 (s, 9H). 19F NMR (CDCl3, 376 MHz) δ -95.8 (d, J= 245.7 Hz, 1F), -114.2 (d, J= 237.1 Hz, 1F).

[0957] Synthesis of A55

[0958]

[0959] A54 A55

[0960] TFA (9 eq, 0.92 mL, 12.0 mmol) was added to a solution of tert-butyl 3-(6-benzyloxy-3-pyridyl)-4,4-difluoro-piperidine-l -carboxylate (A54, 1.0 eq, 540 mg, 1.34 mmol) in DCM (5 mL). The resulting mixture was stirred at 23 °C for 2 days. Tire product was evaporated until dryness to yield 2-benzyloxy-5-(4,4-difluoro-3-piperidyl)pyridine (A55, 400 mg, 1.31 mmol, 98% yield) as an oil.

[0961] Synthesis ofA56PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0962]

[0963] A11 A56

[0964] 2-Chloro-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrano[3,2-d]pyrimidin-8-one (All, 1.0 eq, 104 mg, 0.279 mmol), 5-(4,4-difluoro-3-piperidyl)-lH-pyridin-2-one (A55, 2.0 eq, 120 mg, 0.56 mmol), and DIPEA (2.0 eq, 1.0 mL, 0.56 mmol) were stirred in THF (1.9 mL) at 70 °C for 4 h. The compound was washed with water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered. and concentrated in vacuo. The crude was purified by flash chromatography (50%-100% acetone in hexanes) to yield 2-[4,4-difluoro-3-(6-oxo-1H-pyridin-3-yl)-1-piperidyl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrano[3,2-d]pyrimidin-8-one (A56, 125 mg, 0.22 mmol, 81% yield) as a solid. ESI-MS (m / z)+: 551.2. 1H NMR (CHCl3-d, 400 MHz) δ 7.76 (t, J= 7.2 Hz, 1H), 7.60 (d, J= 8.9 Hz, 1H), 7.51 (d, J= 9.8 Hz, 1H), 7.45 (d, J= 9.8 Hz, 1H), 7.31 (s, 1H), 6.56 (d, J= 9.4 Hz, 1H), 5.06-4.96 (m, 2H), 3.73 (t, J= 6.5 Hz, 2H), 3.41-3.32 (m, 2H), 2.97-2.88 (m, 1H), 2.35 (s, 3H), 2.07 (s, 3H), 1.86-1.82 (m, 2H). 19F NMR (CDCl3, 376 MHz) δ -62.89 (s, 3F), -96.19 (d, J= 240.9 Hz, 2F), -109.07 (s, 1F).

[0965] Synthesis of Compound 181

[0966] F F

[0967]

[0968] A56

[0969] Compound 181 To a solution of 2-[4,4-difluoro-3-(6-oxo-1H-pyridin-3-yl)-1-piperidyl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrano[3,2-d]pyrimidin-8-one (A56, 1.0 eq, 50 mg, 91 pmol) in DCE (2 mL) were added Na2CO3 (3.0 eq, 29 mg, 0.27 mmol), Cu(OAc)2 (1.5 eq, 25 mg, 0.14 mmol), cyclopropylboronic acid (2.0 eq, 16 mg, 0.18 mmol), and bipyridine (1 eq, 14 mg, 0.091 mmol) and the mixture was stirred at 70 °C for 30 min under O2 (15 psi). The reaction mixture was filtered, washed withPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0970] EtOAc, and concentrated. The obtained solid was purified by flash chromatography (50-100% EtOAc in DCM followed by 0-10% MeOH in DCM). The product was further purified by reverse phase chromatography (30-70% ACN in water (0.1% formic acid)). Fractions with the desired product were pulled together, concentrated, dissolved in ACN / H2O (3 mL), frozen, and lyophilized to yield 2-[3-( 1-cyclopropyl-6-oxo-3-pyridyl)-4,4-difluoro-l-piperidyl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-pyrano[3,2-d]pyrimidin-8-one (Compound 181, 17 mg, 0.029 mmol, 32% yield) as a solid. ESI-MS (m / z)+: 591.3. 1H NMR (CHCl3, 400 MHz) δ 7.77 (t, J= 7.3 Hz, 1H), 7.60 (d, J= 8.1 Hz, 1H), 7.56 - 7.45 (m, 1H), 7.30 (dd, J= 9.7, 2.6 Hz, 1H), 7.26 (s, 1H), 6.53 (d, J= 9.4 Hz, 1H), 5.02 (d, J= 15.7 Hz, 2H), 3.49 - 3.34 (m, 2H), 3.30 (t, J= 1.1, 4.1 Hz, 1H), 3.05 - 2.77 (m, 1H), 2.35 (s, 3H), 2.25 (ddd, J= 10.7, 7.5, 3.1 Hz, 1H), 2.07 (s, 4H), 1.15 - 1.07 (m, 2H), 0.87 (dq, J= 5.2, 2.4 Hz, 2H). 19F NMR (CDCl3, 376 MHz) δ -62.89 (s, 3F), -96.21 (d, J= 240.4 Hz, 1F), -109.07 (s, 1F), -114.5- -112.8 (d, J= 241.7 Hz, 1F).

[0971] Example 17: Synthesis of Compound 182

[0972]

[0973] To a solution of 1-cyclopropyl-5-[(2S,6R)-6-methylmorpholin-2-yl]pyridin-2-one (1.0 eq, 18 mg, 0.077 mmol) and the mixture of 6-bromo-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrano[3,2-b]pyridin-4-one (A40) (1.0 eq, 30 mg, 0.077 mmol) in 1,4-dioxane (1 mL) was added Pd-PEPPSI-IHeptCl (0.12 eq, 9.0 mg, 9.3 pmol) and Cs2CO3(3.0 eq, 75 mg, 0.23 mmol). The reaction mixture was sparged with argon three times then stirred at 100 °C for 4 h. The reaction mixture was cooled and filtered, rinsing with EtOAc. Tire resulting solution was concentrated under reduced pressure then purified, firstly, by normal phase flash chromatography (10-90% 3:1 EtOAc / EtOH in Heptanes), secondly, by SFC purification (ChiralPak IH, 4.6x250mm, 5pm column) using 15% of MeOH+0.1%NH3 as co-solvent, to yield 6-[(2S,6R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrano[3,2-b]pyridin-4-one (Compound 182, 3.0 mg, 5.5 pmol, 7% yield). ESI-MS (m / z)+: 542.5. 1H NMR (CHCl3-PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0974] d, 400 MHz) δ 7.43-7.40 (m, 2H), 6.68 (s, 1H), 6.57 (d, J= 9.8 Hz, 1H), 4.43-4.36 (m, 2H), 4.17 (d, J= 12.6 Hz, 1H), 3.86-3.81 (m, 1H), 3.35-3.29 (m, 1H), 2.80 (td, J= 11.9, 2.4 Hz, 1H), 2.72 (dd, J= 12.5, 10.6 Hz, 1H), 2.45 (s, 6H), 2.44 (s, 3H), 2.07 (s, 3H), 1.34 (d, J= 6.2 Hz, 3H), 1.15 (q, J= 7.0 Hz, 2H), 0.92-0.87 (m, 2H). 19F NMR (CDCl3, 376 MHz) δ -73.0 (s, 3F).

[0975] Example 18: Synthesis of Compound 183

[0976] Synthesis ofA57

[0977]

[0978] A54 A57

[0979] A solution of tert-butyl 3-(6-(benzyloxy)pyridin-3-yl)-4,4-difluoropiperidine-1-carboxylate (A54, 1.0 eq, 380 mg, 0.94 mmol) in EtOH (9.0 mL) was degassed and purged with argon before adding 10% Pd / C (20 wt%, 80 mg). The resulting mixture was purged with hydrogen and stirred for 2 h at rt, after which the reaction was purged with argon and filtered through a celite pad. The pad was washed with a mixture of DCM and MeOH and the crude product was purified by chromatography (0-3% MeOH in DCM) to afford tert-butyl 4,4-difluoro-3-(6-oxo-l,6-dihydropyridin-3-yl)piperidine-l-carboxylate (A57, 123 mg, 0.39 mmol, 42% yield). ESI-MS (m / z)+: 315.3.

[0980] Synthesis of A58

[0981]

[0982] To a solution of tert-butyl 4,4-difluoro-3-(6-oxo-1H-pyridin-3-yl)piperidine-1-carboxylate (A57, 1.0 eq, 120 mg, 0.38 mmol) in DCE (2.0 mL) were added Na2CO3 (3.0 eq, 121 mg, 1.15 mmol), Cu(OAc)2 (1.5 eq, 104 mg, 0.57 mmol), cyclopropylboronic acid (2.0 eq, 66 mg, 0.76 mmol), and bipyridine (1 eq, 60 mg, 0.38 mmol). The mixture was stirred at 70 °C for 6 h. The reaction mixture was filtered over celite and purified by flash chromatography (0-60% EtOAc in Hexanes) to afford tert-butyl 3-(l-cyclopropyl-6-oxo-3-pyridyl)-4,4-difluoro-piperidine-l-carboxylate (A58, 70 mg, 0.20 mmol, 52% yield) as a solid. ESI-MS (m / z)+: 355.2.

[0983] Synthesis of A59PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0984]

[0985] A58 A59

[0986] tert-Butyl 3-(1-cyclopropyl-6-oxo-3-pyridyl)-4,4-difluoro-piperidine-1-carboxylate (A58, 1.0 eq, 74 mg, 0.21 mmol) was stirred in a mixture of TFA (1.0 eq, 1.0 mL, 0.21 mmol) and DCM (1 mL) at rt for 30 min. The reaction was concentrated to afford crude 1-cyclopropyl-5-(4,4-difluoro-3-piperidyl)pyridin-2-one;2,2,2-trifluoroacetic acid (A59, 77 mg, 0.21 mmol, 99% yield), which was used without further purification.

[0987] Synthesis ofA60

[0988]

[0989] To a solution of 1 -cyclopropyl-5-[4,4-difluoro-3-piperidyl]pyridin-2-one (A59, 1.1 eq, 88 mg, 0.24 mmol) and 6-bromo-2,3-dimethyl-8-methylsulfanyl-pyrano[3,2-b]pyridin-4-one (A28, 1.0 eq, 65 mg, 0.22 mmol) in 1,4-dioxane (3.0 mL) was added Pd-PEPPSI-IHeptCl (0.12 eq, 25 mg, 0.026 mmol) and Cs2CO3(4 eq, 282 mg, 0.87 mmol). Hie mixture was stirred at 110 °C for 3 h. The reaction mixture was cooled down to rt and diluted with DCM and MeOH then filtered over a pad of Celite. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography (2-8% MeOH in DCM) to afford 6-[3-(1-cyclopropyl-6-oxo-3-pyridyl)-4,4-difluoro-1-piperidyl]-2,3-dimethyl-8-methylsulfanyl-pyrano[3,2-b]pyridin-4-one (A60, 23 mg, 0.049 mmol, 22% yield) as an oil. ESI-MS (m / z)+: 474.4.

[0990] Synthesis of Compound 183PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0991]

[0992] Compound 183 Chloro-[2-fluoro-4-(trifluoromethyl)phenyl]zinc (2.0 eq, 0.81 mL, 0.097 mmol) was added dropwise to a solution of 6-[3-(1-cyclopropyl-6-oxo-3-pyridyl)-4,4-difluoro-1-piperidyl]-2,3-dimethyl-8-methylsulfanyl-pyrano[3,2-b]pyridin-4-one (A60, 1.0 eq, 23 mg, 0.049 mmol) and PEPPSI-SIPr (0.20 eq, 6.6 mg, 0.0097 mmol) in ACN (1.0 mL) at 80 °C. After 1 h, an additional portion of chloro-[2-fluoro-4-(trifluoromethyl)phenyl]zinc (2.0 eq, 0.81 mL, 0.097 mmol) was added and the mixture was stirred for 2 h. The reaction was quenched with NaHCO3 and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography (0-3% MeOH in DCM) and reverse phase chromatography (15-85% ACN in water containing 0.1% formic acid) to afford 6-[3-(l-cyclopropyl-6-oxo-3-pyridyl)-4,4-difluoro-l-piperidyl]-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[3,2-b]pyridin-4-one (Compound 183, 8.7 mg, 0.015 mmol, 30% yield). ESI-MS (m / z)+: 590.3. 1H-NMR (400 MHz, chloroform-d) δ 7.56 (d, 2H, J= 3.2 Hz), 7.50 (d, 1H, J= 9.6 Hz), 7.35-7.31 (m, 2H), 7.03 (s, 1H), 6.54 (d, 1H, J= 9.4 Hz), 4.62 (d, 1H, J= 13.0 Hz), 4.45 (d, 1H, J= 11.9 Hz), 3.40-3.28 (m, 3H), 3.03-2.92 (m, 1H), 2.30-2.23 (m, 4H), 2.06-1.98 (m, 4H), 1.14-1.09 (m, 2H), 0.92-0.87 (m, 2H). 19F-NMR (376 MHz, chloroform-d) δ -62.7-62.8 (m, 3F), -96.0 (m, 1F), -110.4-110.5 (m, 1F), -112.9-113.6 (m, 1F).

[0993] Example 19: Synthesis of Compound 184

[0994] Synthesis ofA62

[0995]

[0996] A61 A62

[0997] A solution of TsCl (1.0 eq, 5.5 g, 28.7 mmol) in DCM (30 mL) was added to a solution of 6-bromopyridin-3-ol (A61, 1.0 eq, 5.0 g, 28.7 mmol) and TEA (1.5 eq, 6.0 mL, 43.1 mmol) in DCM (60 mL) at 23 °C under N2 and the reaction mixture was stirred 30 min at rt. The reaction was cooled to 0°C and quenched with sat. NaHCO3 (aq) (50 mL). The phases were separated and further extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine, dried over MgSO4, andPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[0998] concentrated under reduced pressure. Crystallization from EtOAc / hexanes afforded 6-bromopyridin-3-yl 4-methylbenzenesulfonate (A62, 9.1 g, 27.7 mmol, 97% yield) as a solid. ESI-MS (m / z)+: 328.1.

[0999] Synthesis of A63

[1000]

[1001] To 6-bromopyridin-3-yl 4-methylbenzenesulfonate (A62, 1.0 eq, 5.0 g, 15.2 mmol) was added THF (60 mL). The solution was cooled to -78 °C and LDA (1M in hexanes, 1.5 eq, 23 mL, 23.0 mmol) was added dropwise. The resulting slurry was stirred at -78 °C for 2 h, after which N-methoxy-N-methyl-propanamide (1.75 eq, 3123 mg, 26.7 mmol) was added dropwise. The mixture was stirred at -78 °C for 1.5 h. The reaction was poured into an ice-cold saturated sat. NaHCO3 (aq) (50 mL), diluted with water (25 mL), and extracted with EtOAc (3x100 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (2-40% EtOAc in hexanes) to afford 6-bromo-4-propionylpyridin-3-yl 4-methylbenzenesulfonate (A63, 5.9 g, 15.4 mmol, 100% yield) as a solid. ESI-MS (m / z)+: 386.1. 1H NMR (400 MHz, CHCl3) δ 7.99 (s, 1H), 7.71 - 7.63 (m, 2H), 7.58 (s, 1H), 7.37 (d, J= 8.0 Hz, 2H), 2.89 (q, J= 12 Hz, 2H), 2.48 (s, 3H), 1.19 - 1.08 (m, 3H).

[1002] Synthesis of A64

[1003] O O

[1004]

[1005] A63A64

[1006] A solution of 6-bromo-4-propionylpyridin-3-yl 4-methylbenzenesulfonate (A63, 1.0 eq, 3.9 g, 10.1 mmol) in THF (25 mL) at 0 °C was treated with LiOH·H2O (2 eq, 853 mg, 20.3 mmol) in water (6 mL) and the resulting mixture was stirred at rt for 16 h. The solution was concentrated, acidified with sat. NH4CI (aq) (100 mL), and extracted with EtOAc (3x100 mL). The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-60% EtOAc in hexanes) to afford l-(2-bromo-5-hydroxypyridin-4-yl)propan-l-one (A64, 1.0 g, 4.61 mmol, 45% yield)) as a solid. ESI-MS (m / z)+: 330.1. 1H NMR (400 MHz, CHCl3-d) δ 11.46 (s, 1H), 8.29 (s, 1H), 7.72 (s, 1H), 3.05 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).

[1007] Synthesis of A 65PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1008] AC2O, MSOH, 90 °C, 16 h

[1009] * Br

[1010] O

[1011]

[1012] A64 A65

[1013] A mixture of l-(2-bromo-5-hydroxypyridin-4-yl)propan-l-one (A64, 1 eq, 615 mg, 2.7 mmol) and AC2O (3.0 eq, 0.76 mL, 8.0 mmol) was stirred in MsOH (10.0 eq. 1.7 mL, 26.7 mmol) at 90 °C for 16 h. The reaction mixture was quenched with water / ice then the aqueous was extracted with EtOAc (3x50 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Tire crude material was purified by flash chromatography (2-8% MeOH in DCM) to afford 6-bromo-2.3-dimcthyl-4 / / -pyrano|2.3-c|pyridin-4-one (A65, 310 mg, 1.22 mmol. 45% yield) ) as a solid. ESI-MS (m / z)+: 254.1. 'H NMR (400 MHz. CHC’ ) 58.68 (d, J = 0.7 Hz, 1H), 8.14 (d, J = 0.7 Hz, 1H), 2.46 (d. J = 0.8 Hz, 3H), 2.06 (d, J = 0.8 Hz, 3H).

[1014] Synthesis of A66

[1015]

[1016] A reaction vial under argon was charged with Ir[dF(CF3)ppy)]2(dtbbpy)PF6(0.5 mol%, 6.2 mg, 5.5 pmol). (NH4)2S2O8(3.0 eq, 754 mg, 3.3 mmol), 6-bromo-2,3-dimethyl-4 / 7-pyrano[2,3-c]pyridin-4-one (A65, 1.0 eq, 280 mg, 1.1 mmol), and 3-(trifluoromethyl)bicyclo[l.l.l]pentane-l-carboxylic acid (10.0 eq, 2.0 g, 11.0 mmol). DMSO (11 mL) was added and the reaction vial was irradiated using two 456 nm Kessil lamps (100% intensity, 5 cm away from the vial) with stirring for 3 h then for 13 h at 75% intensity. The reaction mixture was quenched with sat. NH4CI (aq) and diluted with EtOAc (50 mL). The resulting solution was washed with sat. NH4CI (aq), sat. NaHCO3(aq), and brine. The organic layer was collected, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (0-60% EtOAc in hexanes) to afford 6-bromo-2,3-dimethyl-8-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-477-pyrano[2,3-c]pyridin-4-one (A66, 89 mg, 0.3 mmol, 21% yield) ). ESI-MS (m / z)+: 388.2. 'H NMR (400 MHz, CHCI3- ) 58.05 (s, 1H), 2.51 (s, 6H), 2.49 (d, J = 0.8 Hz, 3H), 2.29 (s, 6H), 2.06 (d, J = 0.9 Hz, 3H).

[1017] Synthesis of Compound 184PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1018]

[1019] Compound 184

[1020] To a solution of l-cyclopropyl-5-((2S,67?)-6-methylmorpholin-2-yl)pyridin-2(127)-one (A66, 1.3 eq, 63 mg, 0.27 mmol) and 6-bromo-2,3-dimethyl-8-(3-(trifluoromethyl)bicyclo[l.l.l]pentan-l-yl)-477-pyrano[2,3-c]pyridin-4-one (A66, 1.0 eq, 80 mg, 0.21 mmol) in 1,4-dioxane (2.0 mL) was added Pd-PEPPSI-IHeptCl (0.12 eq, 24 mg, 0.03 mmol) and Cs2CO3(3 eq, 201 mg, 0.62 mmol) at 25°C under N2. The mixture was stirred at 110 °C for 3 h. The reaction mixture was cooled down to rt and diluted with DCM and MeOH and filtered over a pad of Celite. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography (2-8% MeOH in DCM) to afford the crude product. The material was further purified by reverse phase flash chromatography (Biotage® column 6 g, using a gradient from 5% ACN in water (0.1% of HCOOH) to 95% ACN in water (0.1% of HCOOH)). The selected fractions were lyophilized to yield 6-((2S,6R)-2-(l-cyclopropyl-6-oxo-l,6-dihydropyridin-3-yl)-6-methylmorpholino)-2,3-dimethyl-8-(3-(trifluoromethyl)bicyclo[ 1.1.1 ]pentan-l-yl)-4H-pyrano[2,3-c]pyridin-4-one (Compound 184, 6.0 mg, 0.01 mmol, 5% yield) as a solid. ESI-MS (m / z)+:

[1021]

[1022] 542.3.

[1023] 1H NMR (400 MHz, DMSO-6) 57.55 (d, J= 2.4 Hz, 1H), 7.46 (dd, J= 9.3, 2.5 Hz, 1H), 7.02 (s, 1H), 6.35 (d, J= 9.4 Hz, 1H), 4.39 (d, J= 9.6 Hz, 1H), 4.16 (d, J= 12.4 Hz, 2H), 3.71 (t, J= 7.7 Hz, 1H), 3.26 (t, J = 3.8 Hz, 1H), 2.75 - 2.50 (m, 2H), 2.44 (s, 6H), 2.43 (s, 3H), 1.91 (s, 3H), 1.20 (d, J= 6.1 Hz, 3H), 0.96 (dd, J= 7.7, 3.9 Hz, 2H), 0.83 (dt, J= 11.9, 4.2 Hz, 2H).19F NMR (376 MHz, DMSO-6) 8 -71.16 (s, IF).

[1024] An analogous method was followed to obtain the following compounds.

[1025]

[1026] Compound Starting Material CharacterizationPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1027] 6-bromo-2,3-dimethyl-8-[3- 6-[(2S,6R)-2-(l- (trifluoromethyl)- 1 - cyclopropylpyrazol-4-yl)-6- bicyclo[ 1.1. l]pentanyl]pyrano[2, methyl-morpholin-4-yl]-2,3- 3-c]pyridin-4-one: (2S,6R)-2-(l- dimethyl-8-[3-(trifluoromethyl)- cyclopropylpyrazol-4-yl)-6- 1- methyl -morpholine bicyclo [ 1.1.1 ]pentanyl]pyrano [2,

[1028] 3-c]pyridin-4-one (Compound 191). ESI-MS (m / z): 515.2. 'H NMR (400 MHz, CHCl3-d) 5 7.54 (s, 2H), 7.09 (s, 1H), 4.65 (dd, J = 2.3. 10.8 Hz, 1H), 4.30 (br d, J= 12.0 Hz, 1H), 4.14 (br d, J= 12.5 Hz, 1H), 3.92 - 3.79 (m, 1H), 3.66 - 3.55 (m. 1H), 2.84 (t, J= 11.7 Hz, 1H), 2.70 - 2.55 (m, 1H), 2.47 (s, 6H), 2.45 (s. 3H), 2.06 (s, 3H), 1.33 (d, J = 6.3 Hz, 3H), 1.18 - 1.11 (m, 2H),

[1029]

[1030] 1.05 - 1.00 (m, 2H).

[1031] Example 20: Synthesis of Compound 185

[1032] Synthesis of A 68

[1033] I tBuOK, MOMBr, I

[1034] DMF, 0-25°C, 2 h

[1035]

[1036] A67 A68

[1037] To a solution of 6-chloro-2-iodo-pyridin-3-ol (A67, 1.0 eq, 10 g, 39.1 mmol) in DMF (100 mL) was added tBuOK (1.28 eq, 50 mL, 50.0 mmol) at 0°C under N2. The mixture was stirred at 0°C for 0.5 h. Bromo(methoxy)methane (1.5 eq, 5.3 mL, 58.7 mmol) was then added to the mixture at 0°C and the resulting mixture was stirred at 0°C for 0.5 h. Tire reaction was then stirred for 1 h at 25°C. The reaction was quenched by water (200 mL) and diluted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2) and dried over sodium sulfate. The combined organic layers were concentrated under reduced pressure to provide 6-chloro-2-iodo-3-(methoxymethoxy)pyridine (A68, 11 g, 36.4 mmol, 93% yield) as an oil. ESI-MS (m / z)+: 300.1. ‘H NMR (400 MHz, CHCl3-d) 57.29 (d, J = 3.8 Hz, 1H), 7.23 - 7.18 (m, 1H), 5.27 (s, 2H), 3.53 (s, 3H).

[1038] Synthesis of A69PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1039] K3PO4, Pd(dppf)CI2-DCM, 1,4-dioxane, H2O, 90 °C, 1 h

[1040]

[1041] To a solution of 6-chloro-2-iodo-3-(methoxymethoxy)pyridine (A68, 1.0 eq, 10.00 g, 33.4 mmol) and [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (0.98 eq, 6.80 g, 32.7 mmol) in 1,4-dioxane (170 mL) and water (17 mL) were added K3PO4 (1.74 eq, 8.03 g, 58.1 mmol) and Pd(dppf)C12 DCM (0.0937 eq, 2.55 g. 3.13 mmol). The mixture was stirred at 90°C for 1 h under N2. The reaction was quenched by 200 mL water and extracted with EtOAc (150 mL x 3). The combined organic layers was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-30% 1:3 EtOAc / Petroleum ether) to give 6-chloro-2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(methoxymethoxy)pyridine (A69, 7.2 g, 20.8 mmol, 62% yield) as an oil. ESI-MS (m / z)+: 336.0. ‘H NMR (400 MHz, CHCL-cZ) 57.68 (t, J= 7.4 Hz, 1H), 7.62 (d, J= 8.8 Hz, 1H). 7.53 (d, J= 8.0 Hz. 1H), 7.41 (d, J= 9.6 Hz, 1H), 7.35 (d, J= 8.8 Hz, 1H). 5.18 (s. 2H), 3.45 (s, 3H).

[1042] Synthesis of A70

[1043]

[1044] A70 was synthesized via flow chemistry. utilizing three solutions. Solution 1, comprising 6-chloro-2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(methoxymethoxy)pyridine (A69, 1.0 eq, 5000 mg, 14.9 mmol) in 250 mL of THF and solution 2, comprising LDA (1.5 eq, 11 mL, 22.3 mmol) were pumped to flow reactor 1. Solution 3, comprising propanal (1.1 eq, 952 mg, 16.4 mmol) in 250 mL of THF was pumped to flow reactor 2. The mixture was collected with a bottle and quenched by NH4CI (20 mL) at 25 °C. The solution was extracted with EtOAc (60 mL x 3) and water (60 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (PE: EA = 3:1) to give l-[6-chloro-2-[2-fluoro-4-PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1045] (trifluoromethyl)phenyl]-3-(methoxymethoxy)-4-pyridyl]propan-l-ol (A69, 1.3 g, 2.44 mmol, 16% yield) as an oil. A70: ESI-MS (m / z)+: 394.1. »H NMR (400 MHz, CHCL-t / ) 57.71 (t, J= 7.4 Hz, 1H), 7.55 (d, J= 1.9 Hz, 1H), 7.52 (s, 1H), 7.44 (d, 9.5 Hz, 1H), 4.98 (br d, J= 5.4 Hz, 1H), 4.71 - 4.56 (m, 2H), 3.30 (s, 3H), 1.91 - 1.81 (m, 2H), 1.08 - 1.03 (m, 3H).

[1046] Synthesis of A71

[1047] IBX, MeCN, 60 C, 1 h

[1048]

[1049] A solution of l-[6-chloro-2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(methoxymethoxy)-4-pyridyl]propan-l-ol (A70, 1.0 eq, 1000 mg, 2.54 mmol) and IBX (3.0 eq, 2.13 g, 7.62 mmol) in ACN (20 mL) was stirred at 60°C for 1 h. Tire mixture was filtered and washed with ACN (10 mL). The filtrate was concentrated in vacuo to give 1-[6-chloro-2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(methoxymethoxy)-4-pyridyl]propan-1-one (A71, 1.1 g, 1.68 mmol, 66% yield) as an oil. ESI-MS (m / z)+: 392.0. 'H NMR (400 MHz, CHCL-t / ) 57.75 - 7.69 (m, 1H), 7.56 (br d, J= 8.1 Hz, 1H), 7.45 (d,.7= 9.4 Hz, 1H), 7.40 (s, 1H), 4.73 (s, 2H), 3.06 (s, 3H), 2.99 (q, J= 7.2 Hz, 2H), 1.25 - 1.21 (m, 3H). Synthesis of A72

[1050] CF3CF3

[1051] JO

[1052] F^' ^Y HCI / EtOAc, 60°C, 1 h

[1053] N-k-0-0- N-VOH J I J J

[1054] 0A72°

[1055]

[1056] A71

[1057] A solution of l-[6-chloro-2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-(methoxymethoxy)-4-pyridyl]propan-l-one (A71, 1.0 eq, 1000 mg, 2.55 mmol) in HC1 (solution in EtOAc, 1 M, 15 mL) was stirred at 60°C under N2 for 1 h. The mixture was concentrated under vacuum to give a residue, which was purified by flash silica gel chromatography (0-40% 1:3 EtOAc / Petroleum ether) to give l-[6-chloro-2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-hydroxy-4-pyridyl]propan-l-one (A72, 700 mg, 1.97 mmol, 77% yield) as yellow solid. ESI-MS (m / z): 348.0. ’H NMR (400 MHz, CHCh-t / ) 5 12.00 (s. 1H), 7.73 -7.65 (m, 2H), 7.56 - 7.51 (m, 1H), 7.45 (d,.7= 9.6 Hz, 1H), 3.14 (q,.7= 7.1 Hz, 2H), 1.34 - 1.26 (m, 3H).PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1058] Synthesis of A73

[1059] AC2O, eaton's reagent, 90°C, 1 h

[1060]

[1061] A mixture of l-[6-chloro-2-[2-fluoro-4-(trifluoromethyl)phenyl]-3-hydroxy-4-pyridyl]propan-l-one (A72, 1.0 eq, 600 mg, 1.73 mmol) and acetic anhydride (3 eq, 0.49 mL, 5.18 mmol) in Eaton's reagent (10 eq, 2.7 mL, 17.3 mmol) was stirred at 90°C for 1 h. Tire reaction was quenched by 40 mL water, extracted with EtOAc (25 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (1:3 0-100% EtOAc / Petroleum ether) to give 6-chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (A73, 220 mg, 0.580 mmol, 34% yield) as a solid. ESI-MS (m / z)+: 372.0. 'H NMR (400 MHz, CHCL- ) δ 8.11 (s, 1H), 7.81 (t, J = 7.4 Hz, 1H), 7.62 (d. J - 8.0 Hz. 1H), 7.51 (d, J = 9.8 Hz, 1H), 2.40 (s, 3H), 2.09 (s, 3H).

[1062] Synthesis of A74

[1063] Cs2CO3, Pd-PEPPSI-IHeptCl, dioxane, 90°C, 3 h

[1064]

[1065] To a solution of (2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholine (A73, 1 eq. 161 mg, 0.565 mmol) and 6-chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (AX, 1.0 eq, 210 mg, 0.565 mmol) in 1,4-dioxane (1 mL) were added Pd-PEPPSI-IHeptCl (0.12 eq, 66 mg, 0.0678 mmol) and Cs2CO3(3 eq, 551 mg, 1.69 mmol) at 25°C under N2. The mixture was stirred at 90°C for 3 h. Tire solution was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography (PE: EA = 3: 1) to give 6-PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1066] [(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (A74, 210 mg, 0.241 mmol, 43% yield) as a solid. ESI-MS (m / z)+: 620.4. 'H NMR (400 MHz, CHCL-t / ) 58.24 (d, J= 2.4 Hz, 1H), 7.76 (t, J= 7.4 Hz, 1H), 7.71 (dd, J= 2.4, 8.6 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.50 - 7.45 (m, 3H), 7.42 - 7.36 (m, 2H), 7.34 - 7.31 (m, 2H). 6.84 (d, J= 8.4 Hz, 1H), 5.40 (s, 2H), 4.66 (dd, J= 2.6, 10.8 Hz, 1H), 4.38 (br d. J= 12.8 Hz, 1H). 4.22 - 4.16 (m. 1H), 4.00 - 3.87 (m, 1H), 2.88 - 2.68 (m, 2H), 2.36 (s, 3H), 2.07 (s. 3H), 1.37 (d, J = 6.3 Hz, 3H).

[1067] Synthesis of A75

[1068]

[1069] To a solution of 6-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (A74, 1.0 eq, 200 mg, 0.323 mmol) in DCE (1 mL) was added TFA (1.0 eq, 0.50 mL, 0.323 mmol), and the mixture was stirred at 50°C for 2 h. The reaction mixture was poured into aq. NaHCOs (20 mL) and extracted with EtOAc (10 mL x 3). Hie combined extracts were washed with brine (15 mL). dried over sodium sulfate, filtered, and concentrated under vacuum to give 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-1H-pyridin-3-yl)morpholin-4-yl]pyrano[2,3-c]pyridin-4-one (A75, 170 mg, 0.183 mmol, 57% yield) as a solid. ESI-MS (m / z)+: 530.2. 'H NMR (400 MHz, CHCh-r / ) 57.76 (t, J = 7.4 Hz, 1H), 7.58 - 7.56 (m, 1H), 7.47 (s, 1H), 7.39 (s, 2H), 7.33 - 7.31 (m, 1H), 6.62 (d, J= 9.4 Hz, 1H), 4.72 (s, 1H), 4.54 - 4.34 (m, 2H). 4.14 (br d, J= 12.6 Hz, 1H), 3.96 - 3.86 (m, 1H). 2.71 (ddd, J= 10.9, 12.5. 17.5 Hz, 2H), 2.36 (s. 3H), 2.08 (s, 3H), 1.35 (d, J= 6.1 Hz, 3H).

[1070] Synthesis of Compound 185PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1071]

[1072] Compound 185

[1073] To a solution of 8-[2-fhioro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-lH-pyridin-3-yl)morpholin-4-yl]pyrano[2,3-c]pyridin-4-one (A75, 1.0 eq, 80 mg, 0.151 mmol) in DCE (3 mL) were added Na2CO3(3.0 eq, 48 mg, 0.453 mmol), Cu(OAc)2 (1.5 eq, 41 mg, 0.227 mmol), cyclopropylboronic acid (2.0 eq, 26 mg, 0.302 mmol) and bipyridine (1.00 eq, 24 mg, 0.151 mmol). The mixture was stirred at 70°C for 30 min under 02(15 psi). The solution was filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Waters xbridge 150 x 25mm lOum; H2O (10 mM NH4HCO3-ACN) and lyophilized to give 6-[(2S,6R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)-6-methyl-morpholin-4-yl]-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (Compound 185, 35 mg, 0.0612 mmol, 40% yield) as a solid. ESI-MS (m / z)+: 570.2. 'H NMR (400 MHz, CHCl3-d) 57.76 (t, J= 7.6 Hz, 1H), 7.58 (d, J= 8.7 Hz, 1H), 7.49 (d, J= 9.5 Hz, 1H), 7.43 - 7.37 (m, 2H), 7.31 (s, 1H), 6.59 (d, J= 10.0 Hz, 1H), 4.43 (dd, J= 2.4, 10.9 Hz, 1H), 4.35 - 4.26 (m, 1H). 4.18 (br d, J= 12.5 Hz, 1H), 3.96 - 3.81 (m, 1H). 3.40 - 3.26 (m. 1H), 2.83 - 2.65 (m, 2H), 2.36 (s, 3H), 2.08 (s, 3H), 1.35 (d, J= 6.2 Hz, 3H), 1.20 - 1.10 (m, 2H), 0.94 - 0.84 (m, 2H).

[1074] Example 21: Synthesis of Compound 186

[1075] Synthesis of A76

[1076]

[1077] A76

[1078] To a solution of 6-bromo-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (A65, 1.0 eq, 500 mg, 1.97 mmol) in ACN (5 mL) and water (5 mL) were added bicyclo[l. Ll]pentane-l-carboxylic acid (3.0 eq, 662 mg, 5.90 mmol), TFA (1.1 eq. 0.17 mL, 2.16 mmol) and AgNOs (1.3 eq, 432 mg, 2.56 mmol) and the mixture was stirred at 80°C for 5 min. Ammonium persulfate (3.30 eq, 1482 mg, 6.49 mmol) was addedPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1079] and the solution was stirred at 80°C for 2 h. The reaction mixture was poured into saturated Na-’S-’Oi aqueous solution (50 mL) and then extracted with DCM (30 mL x 3). Tire combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (0-100% EtOAc / Petroleum ether) to afford 8-(l-bicyclo[l.l.l]pentanyl)-6-bromo-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (A76, 80 mg, 0.150 mmol, 8% yield) as an oil. ESI-MS (m / z)+: 320.1. 'H NMR (400 MHz, DMSO-t / 6) 57.85 (s, 1H). 2.64 (s. 1H), 2.54 (s, 3H), 2.31 (s, 8H).

[1080] Synthesis of A77

[1081] Cs2CO3, Pd-PEPPSI IHeptCI, dioxane, 90°C, 2 h

[1082]

[1083] To a solution of 8-(l-bicyclo[l.l.l]pentanyl)-6-bromo-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (A76, 1.0 eq, 80 mg, 0.250 mmol) and (2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholine (1.0 eq, 71 mg, 0.250 mmol) in 1,4-dioxane (2 mL) were added Pd-PEPPSI IHeptCI (0.2 eq, 49 mg, 0.0500 mmol) and Cs2CO3(3.0 eq, 244 mg, 0.750 mmol) at 25°C under N2. The solution was stirred at 90°C for 2 h under N2. The reaction mixture was cooled to rt. DCM (20 mL) and water (20 mL) were added and the layers were separated. The aqueous phase was extracted with DCM (20 mL x 2) and the combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by column chromatography on silica gel (0-100% EtOAc / Petroleum ether) to afford 6-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-8-(l-bicyclo[l.l.l]pentanyl)-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (A77, 70 mg, 0.124 mmol, 50% yield) as a solid. ESI-MS (m / z)+: 524.1. 'H NMR (400 MHz, CDCL) 58.25 (d, J= 2.4 Hz, 1H), 7.72 (dd, J= 2.4, 8.6 Hz, 1H), 7.48 (d, J= 7.3 Hz, 2H). 7.42 - 7.35 (m, 2H), 7.35 - 7.31 (m. 1H), 7.04 (s, 1H), 6.85 (d, J= 8.6 Hz, 1H), 6.62 (d, J= 2.3 Hz, 1H), 6.18 - 6.11 (m, 1H), 5.41 (s, 2H), 4.67 (dd, J= 2.4, 10.6 Hz, 1H), 4.38 (br d, J= 12.8 Hz, 1H), 4.17 - 4.08 (m, 1H), 3.93 (dt, J= 3.4, 6.4 Hz, 1H), 3.17 (dd, J= 2.2, 13.3 Hz, 1H), 2.81 - 2.62 (m, 3H), 2.44 (s, 3H), 2.07 (s, 3H), 1.63 (s, 3H), 1.36 (d, J = 6.3 Hz, 3H). Synthesis of A78PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1084] TFA, DCE, 50°C, 3 h

[1085]

[1086] To a solution of 6-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-8-(l-bicyclo[l.l.l]pentanyl)-2,3-dimethyl-pyrano[2,3-c]pyridin-4-one (A77, 1.0 eq, 60 mg, 0.115 mmol) in DCE (5 mL) was added TFA (1.0 eq, 2.0 mL, 0.115 mmol). The solution was stirred at 50°C for 3 h. DCM (20 mL) and water (20 mL) were added and the layers were separated. The aqueous phase was extracted with DCM (30 mL x 2) and the combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give a residue, which was purified by Prep-TLC (PE: EtOAc = 0:1, DP: Rf = 0.35) to afford 8-(l-bicyclo[l.l.l]pentanyl)-2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-lH-pyridin-3-yl)morpholin-4-yl]pyrano[2,3-c]pyridin-4-one (A78. 55 mg, 0.108 mmol, 94% yield) as a solid. ESI-MS (m / z)+: 434.2. 'H NMR (400 MHz, CHCh) 87.62 (br d, J = 9.5 Hz. 1H), 7.53 (s, 1H), 7.38 (d,.7= 4.8 Hz, 1H), 7.04 (s, 1H), 6.69 (br d,.7= 9.4 Hz, 1H), 6.62 (d,.7= 2.8 Hz, 1H), 6.16 (br s, 1H), 4.50 (br d, J = 10.8 Hz, 1H), 4.44 - 4.34 (m, 1H), 4.09 (br dd, J= 3.9, 11.2 Hz, 1H), 3.97 - 3.83 (m, 1H), 3.16 (d, J= 13.8 Hz, 1H), 2.68 - 2.57 (m, 2H), 2.45 (s, 3H), 2.07 (s, 3H), 1.64 (s, 3H), 1.34 (br d,.7= 6.3 Hz, 3H).

[1087] Synthesis of Compound 186

[1088] K2CO3, Mel, DMF, _ 70°Cr2 h _

[1089]

[1090] Compound 186 To a solution of 8-(l-bicyclo[l.l.l]pentanyl)-2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-lH-pyridin-3-yl)morpholin-4-yl]pyrano[2,3-c]pyridin-4-one (A78, 1.0 eq, 50 mg, 0.115 mmol) in DMF (1 mL) were added K2CO3 (3.0 eq, 48 mg, 0.346 mmol) and Mel (5 eq, 82 mg, 0.577 mmol). The solution was stirred at 70°C for 2 h. The reaction mixture was cooled to rt DCM (10 mL) and water (10 mL) were added and layers were separated. The aqueous phase was extracted with DCM (10 mL x 2). Combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under vacuum toPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1091] give a residue. The residue was purified by prep-HPLC (Column, [Phenomenex luna C18250x50mmxl0 um]; mobile phase: [ACN] and [H2O] (conditions: [water (0.225% NH4HCO3) - ACN], B%: 35%-40%; Detector, UV 254 nm. RT: [22 min]) to afford 8-(l-bicyclo[l.l.l]pentanyl)-2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(l-methyl-6-oxo-3-pyridyl)morpholin-4-yl]pyrano[2,3-c]pyridin-4-one (Compound 186, 13 mg, 0.0294 mmol, 26% yield) as a solid. ESI-MS (m / z)+: 448.2. 'H NMR (400 MHz. DMSO-tfc) 57.77 (d, J = 2.1 Hz, 1H). 7.57 - 7.49 (m. 1H), 6.98 (s, 1H). 6.65 (dd. J = 1.8. 2.6 Hz. 1H), 6.40 (d, J= 9.4 Hz, 1H), 6.17 (d, J= 2.5 Hz, 1H), 4.45 - 4.39 (m, 1H), 4.20 (brt, J= 11.3 Hz, 2H), 3.85 - 3.73 (m, 1H), 3.44 (s, 3H), 3.12 (dd, J = 4.1, 13.6 Hz, 1H), 2.74 - 2.63 (m, 2H), 2.54 (br d, J= 5.0 Hz, 1H), 2.44 (s, 3H), 1.95 (s, 3H), 1.57 (s, 3H), 1.25 (d, J = 6.3 Hz, 3H).

[1092] An analogous method was followed to obtain the following compounds.

[1093] Compound Starting Material Characterization

[1094] F 6-bromo-2,3-dimethyl- 8-(3-fluoro-l- pyrano[2,3-c]pyridin-4-one; 3- b i cycl 0 [ 1.1. l]pentanyl)- fluorobicyclo[ 1.1. l]pentane-l- 2,3-dimethyl-6-[(2R,6S)-2- carboxylic acid mcthyl-6-( 1 -methyl -6-oxo- XI XI I 3 -pyridyl)morpholin-4- yl]pyrano[2.3-c]pyridin-4- onc (Compound 187). ESI0

[1095] MS (m / z)+: 446.2. 'H NMR (400 MHz, CHCl3) 5 Compound 187 7.43 - 7.39 (m, 2H), 7.08 (s, 1H), 6.65 - 6.60 (m, 1H). 4.44 (dd, J= 2.6, 10.6 Hz, 1H), 4.29 (br d, J = 12.6 Hz, 1H), 4.13 (brd, J = 12.5 Hz. 1H), 3.91 - 3.82 (m, 1H), 3.59 (s, 3H), 2.73 - 2.60 (m, 2H), 2.58 (d, J = 2.5 Hz, 6H). 2.45 (s. 3H), 2.06 (s, 3H), 1.35 (d, J =

[1096]

[1097] 6.3 Hz, 3H).

[1098] Example 22: Synthesis of Compound 188

[1099] Synthesis ofA80PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1100]

[1101] Compound A79 was synthesized via the method described in Example 19. To a solution of 6-[(2S,6R)-2-(6-benzyloxy-3-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-8-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[2,3-c]pyridin-4-one (A79, 1.0 eq, 70 mg. 0.118 mmol) in DCE (3 mL) was added TFA (1 eq, 1.5 mL. 0.118 mmol), then the mixture was stirred at 50°C for 4 h. NaHCO3was added until pH ~ 8 and the solution was extracted with EtOAc (20 mL x 3). The combined extracts were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to give crude 2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-1H-pyridin-3-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl] pyrano[2,3-c]pyridin-4-one (A80) as an oil. ESI-MS (m / z)+: 502.1. 'H NMR (400 MHz, CHCl3-d) 57.60 - 7.56 (m. 1H), 7.49 (brd, J= 1.2 Hz, 1H), 7.37 (d. J= 5.2 Hz. 1H), 6.68 (d, J= 9.2 Hz, 1H), 4.41 (s, 2H), 4.11 - 4.07 (m, 1H), 3.92 - 3.85 (m, 1H), 3.74 (s, 2H), 2.49 - 2.43 (m, 10H), 2.07 (s, 3H), 1.34 (d, J= 6.2 Hz, 3H).

[1102] Synthesis of Compound 188

[1103]

[1104] Compound 188 To a solution of 2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(6-oxo-lH-pyridin-3-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[2,3-c]pyridin-4-one (A80, 1.0 eq, 70 mg, 0.140 mmol) in DMF (2 mL) was added K2CO3 (3.0 eq, 58 mg, 0.419 mmol) and Mel (5 eq, 99 mg, 0.698 mmol), then the mixture was stirred at 50°C for 12 h. Tire reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by pre-HPLC (Column: Phenomenex Luna C18 150*25mm* lOum, Condition: H2O (0.225% formic acid) - ACN ) andPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1105] lyophilized to give 2,3-dimethyl-6-[(2R,6S)-2-methyl-6-(l-methyl-6-oxo-3-pyridyl)morpholin-4-yl]-8-[3-(trifluoromethyl)- 1 -bicyclo [1.1.1] pentanyl] pyrano[2,3-c]pyridin-4-one (Compound 188, 24 mg, 0.0459 mmol, 33% yield) as a solid. ESI-MS (m / z)+: 516.2. 'HNMR (400 MHz, DMSO-d6) 57.77 (d, J= 2.0 Hz, 1H), 7.52 (dd, J= 2.4, 9.6 Hz, 1H), 7.06 (s, 1H), 6.40 (d, J= 9.2 Hz, 1H), 4.46 - 4.36 (m, 1H), 4.23 (brt, J = 14.0 Hz, 2H), 3.84 - 3.71 (m. 1H), 3.44 (s, 3H), 2.70 (br t, J= 11.6 Hz. 1H), 2.55 (br s. 1H), 2.49 - 2.40 (m, 9H). 1.95 (s. 3H), 1.24 (d, J= 6.0 Hz, 3H).

[1106] Example 23: Synthesis of Compound 189

[1107] Synthesis of Compound 189

[1108] K2CO3, Mel, DMF, 70°C, 4 h

[1109]

[1110] A81 Compound 189 Compound A81 was synthesized via the method described in Example 19. To a solution of 2,3-dimethyl-6-[(2R,4S)-2-(6-oxo-lH-pyridin-3-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-l-bicyclo[1.1.1]pentanyl]pyrano[2,3-c]pyridin-4-one (A81, 1.0 eq, 13 mg. 0.0267 mmol) and K2CO3 (3 eq, 11 mg, 0.0802 mmol) in DMF (1 mL) was added Mel (5 eq, 19 mg, 0.134 mmol), and the mixture was stirred at 70°C for 4 h. The mixture was diluted with MeOH (1 mL) and then filtered. The filtrate was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [A: H2O (0.225% FA); B: ACN]; B%: 47.00% - 77.00%, 10. OOmin; flow rate: 25.00 mL / min) and lyophilized to give 2,3-dimethyl-6-[(2R,4S)-2-(l-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]pyrano[2,3-c]pyridin-4-one (Compound 189, 6.13 mg. 0.0110 mmol, 41% yield) as a solid. ESI-MS (m / z)+: 501.2. 'H NMR (400 MHz, DMSO-d6) 5 = 7.68 (s, 2H), 7.47 (dd, J = 2.6, 9.3 Hz, 1H), 6.35 (d, J = 9.3 Hz, 1H), 4.30 (br d, J= 10.0 Hz, 1H), 4.12 (brdd, J= 3.3, 11.2 Hz, 1H), 3.67 (dt, = 2.3, 11.7 Hz, 1H), 3.41 (s, 3H), 3.21 - 3.16 (m, 1H), 2.51 (br d, J = 1.5 Hz, 9H), 2.05 (br d, J = 12.6 Hz, 1H), 1.99 - 1.96 (m, 3H), 1.91 - 1.84 (m, 1H), 1.75 (s, 1H), 1.74 - 1.65 (m, 1H).

[1111] An analogous method was followed to obtain the following compounds.

[1112] Compound

[1113]

[1114] Starting Material Characterization

[1115]

[1116]

[1117] PAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1118] Cl 6-bromo-2, 3 -dimethyl - 8-(3-chloro-l- pyrano[2,3-c]pyridin-4-one; bicyclof 1.1.1 Jpentanyl)- 3- 2,3-dimethyl-6-[(2R,4S)- 1 1 chlorobicyclo[ 1.1.1 ]pentane- 2-(l-methyl-6-oxo-3- 1 -carboxylic acid pyridyl)tetrahydropyran- 4-yl]pyrano[2,3- °^J 0 c]pyridin-4-one Compound 190 (Compound 190). E SIMS (m / z)+: 467.2. 'H NMR (DMSO4, 400 MHz) 8 = 7.6-7.7 (m, 2H), 7.46 (dd, 1H, >2.4, 9.2 Hz), 6.35 (d, 1H, >9.2 Hz), 4.30 (br d, 1H, >10.4 Hz), 4.11 (dd, 1H, >3.2, 11.6 Hz), 3.67 (dt, 1H, >2.4, 11.6 Hz), 3.41 (s, 3H), 3.2-3.2 (m, 1H), 2.7-2.7 (m, 6H), 2.5-2.5 (m, 3H), 2.04 (br d, 1H,>12.8 Hz), 2.0-2.0 (m, 3H), 1.8-1.9 (m, 1H), 1.7-1.8 (m, 1H), 1.6-1.7 (m,

[1119]

[1120] 1H).

[1121] Example 24: In vitro Assay Data

[1122] In vitro Measurement of Triggering Receptor Expressed on Myeloid Cells 2 activity using cellular phosphorylation of Spleen Tyrosine Kinase (“Syk”) Assays

[1123] 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 pL of complete growth media and incubated at 37 °C, 5% CO2 for 20-24 hours.

[1124] 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 pL of test articles in assay buffer was added to cells. Cells were incubated for 45 minutes at roomPAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1125] temperature. After 45 minutes, assay buffer was removed and 10 pL 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 fluorescence 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.

[1126] The results presented in Table B 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.

[1127] Compounds designated as “A” demonstrated an EC50 of < 10.0 nM. Compounds designated as B' demonstrated an EC50 > 10.0 nM and < 30.0 nM. Compounds designated as C demonstrated an EC50 > 30.0 nM and < 300.0 nM. Compounds designated as “D” demonstrated an EC50< 300 nM.

[1128] Table B. hTREM2 ECso Data (HEK293 Cells)

[1129] Compound hTREM2 EC50 164 A

[1130] No. (nM) 165 C

[1131] 1 A 166 A 8 B 167 C 15 A 168 B

[1132] 169 C

[1133] 22 A

[1134] 170 C

[1135] 33 B 171 D

[1136] 36 A 172 A 43 A 173 B

[1137] 50 C 174 B

[1138] 57 C 175 C 64 A 176 B

[1139] 71 A 177 D

[1140] 78 A 178 B

[1141] 85 A 179 A

[1142] 180 A

[1143] 92 A

[1144] 181 A

[1145] 99 A

[1146] 182 B

[1147] 106 B 183 B

[1148] 113 A 184 A

[1149] 120 A 185 A

[1150] 127 C 186 C

[1151] 134 A 187 D

[1152] 141 A 188 A

[1153] 148 A 189 A

[1154] 155 A 190 C

[1155] 162 A 191 A

[1156]

[1157] 163 A

[1158]

[1159] 192 APAT25188-WO Attorney Docket No.: 34124 / 50020 PC

[1160]

[1161] 193 A

[1162]

[1163] 194 A

[1164] 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

PAT25188-WO Attorney Docket No.: 34124 / 50020 PC CLAIMS1. A compound of Formula (I):or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula:X2is C(R12)(R12), 0, C(=O), S(O)2, or NR11;X3and X4are each independently CR9or N;X5is 0, N, S, or C(R12)2;R1is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R13;R2a, R2b, R3a, R3b, R4a, and R4bare each independently hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-ehaloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC),PAT25188-WO Attorney Docket No.: 34124 / 50020 PC wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14; orR2aand R2b. R3aand R3b, or R4aand R4btaken together with the atom they are attached to form an oxo group (e.g. C=O);R5ais hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci- 6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R14;R5bis cycloalkyl, heterocyclyl, ary l, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R13;R6and R6'are each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-6 haloalkyl, Ci.6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;R7and R7'are each independently hydrogen, Ci-6 alkyl, C2-6 alkenyl. C2-6 alkynyl, Cn 6 heteroalkyl, Ci-6 haloalkyl. Ci-6 haloalkoxy, cycloalkyl, heterocyclyl. aryl, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl. heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;R9is hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e heteroalkyl, Ci-e haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;R10and R11are each independently in each instance hydrogen, C1.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci -6 haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R16;each R12and R12is independently hydrogen, Ci-6 alkyl, or halogen;each R13is independently Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;R14, R15, and R16are each independently hydrogen, deuterium, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, and, and heteroaryl is optionally substituted with one or more R17; orPAT25188-WO Attorney Docket No.: 34124 / 50020 PC two R14, two R15, or two R16, together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R17: ortwo R14, two R15, or two R16independently form an oxo:each RAis independently hydrogen, Ci-e alkyl, Ci-e heteroalkyl, Ci-ehaloalkyl, cycloalkyl, heterocyclyl, or -N(RB)(RC), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;each RBand Rcis independently hydrogen, Ci- 6 alkyl, C2-6 alkenyl, Ci.6 heteroalkyl, Ci-ehaloalkyl, cycloalkyl, heterocyclyl, or -C(O)-alkyl. wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17; orRBand Rc, together with the nitrogen atom to which they are attached, form -N=C(RD)(RE) or a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R17;each RDand REis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, Ci -6 heteroalkyl, Ci -6 haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R17;each R17is independently C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, cycloalkyl, halogen, or cyano; ortwo R17form an oxo; and11 is 0, 1, 2, or 3.

2. The compound of any one of the preceding claims, wherein R1is aryl, heteroaryl, or cycloalkyl, optionally substituted with one or more R13.The compound of any one of the preceding claims, wherein R1is selected from % / www 0]* s / WVPAT25188-WO Attorney Docket No.: 34124 / 50020 PC CF34. The compound of any one of the preceding claims, wherein R1is selected from5. The compound of any one of the preceding claims, wherein Ring B is selected fromR4aR4b6. The compound of any one of the preceding claims, wherein Ring B is selected fromOPAT25188-WO Attorney Docket No.: 34124 / 50020 PC7. The compound of any one of the preceding claims, wherein R?bis selected from9. The compound of any one of the preceding claims, wherein X1is CH and X2is 0.

10. Tire compound of any one of the preceding claims, wherein X1is CH and X2is CH.

11. The compound of any one of the preceding claims, wherein X1is N and X2is O.

12. The compound of any one of the preceding claims, wherein one of X3and X4is independently N.

13. Tire compound of any one of the preceding claims, wherein X3and X4are each independently N.

14. The compound of any one of the preceding claims, wherein R6and R7are each independently H, halogen, haloalkyl, Ci-6 alkyl, -C(O)ORA, or -CN.

15. Tire compound of any one of the preceding claims, wherein R6is H, -CF3, or -CH3.

16. The compound of any one of the preceding claims, wherein R7is -CH3.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC17. The compound of any one of the preceding claims, wherein X5is 0.

18. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-a):R1or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, X3, X4, X5, R1, R6, R7, and subvariables thereof are defined as for Formula (I).

19. Tire compound of any one of the preceding claims, wherein tire compound of Fonnula (I) is a compound of Formula (I-b):R1or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, Rb, R7, and subvariables thereof are defined as for Fonnula (I).

20. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-c):(I-c),or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of R1, R2a, R2b, R3a, R3b, R4a, R4b, R5b, R6, R7, and subvariables thereof are defined as for Formula (I).

21. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-d):PAT25188-WO Attorney Docket No.: 34124 / 50020 PCR1(I d),or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, and subvariables thereof are defined as for Formula (I).

22. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-e):or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X2, R1, R3a, R3b, R’a, R6, R7, R15, and subvariables thereof are defined as for Formula (I).

23. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-f):(I-f),or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X2, R1, R3a, R3b, R5a, R6, R7, R15, and subvariables thereof are defined as for Formula (I).

24. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-g):PAT25188-WO Attorney Docket No.: 34124 / 50020 PCor a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of R1, R3a, R3b, R5a, R6, R7, R15, and subvariables thereof are defined as for Formula (I).

25. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-h):(I-h),or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of R1, R3a, R3b, R5a, R6, R7, R15, and subvariables thereof are defined as for Formula (I).

26. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-i):or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X2, X4, X5, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, and subvariables thereof are defined as for Formula (I).

27. The compound of any one of claims 1-26. wherein the compound is a compound provided in Table A.PAT25188-WO Attorney Docket No.: 34124 / 50020 PC 28. A pharmaceutical composition comprising the compound according to any one of claims 1-27, and a pharmacally acceptable excipient.

29. A compound according to any one of claims 1-27 or a pharmaceutical composition of claim 28, for use in treating or preventing a condition associated with a loss of function of human TREM2.

30. 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 1-27, or a pharmaceutical composition of claim 28.

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