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] PAT25187-WO Attorney Docket No.: 34124 / 50019 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 isPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0008] dynamically regulated and acts to recognize molecular pattern that direct phenotypic responses to homeostatic changes in the central nervous system (“CNS”). Id. One of the receptors selectively expressed by brain microglia is TREM2, composed of a single-pass transmembrane domain, an extracellular stalk region, and extracellular immunoglobulin variable (“IgV”)-like domain responsible for ligand interaction (Kleinberger et al. Sci Transl Med, 2014). As TREM2 does not possess intracellular signal transduction-mediating domains, biochemical analysis has illustrated that interaction with adaptor proteins 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 Brett, J Mol Biol, 2017; Shirotani et al., Sci Rep, 2019). In mice lacking functional TREM2 expression or expressing a mutated form of the receptor, a core observation is blunted microglial responses to insults such as oligodendrocyte demyelination, stroke -induced tissue damage in the brain, and proteotoxic inclusions in vivo (Cantoni et al., Acta Neuropathol, 2015, Wu et al., Mol Brain, 2017).

[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 pathologicallyPAT25187-WO Attorney Docket No.: 34124 / 50019 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 attenuated 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 progressionPAT25187-WO Attorney Docket No.: 34124 / 50019 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] R1

[0018] R9I

[0019]

[0020] (I),

[0021] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

[0022] Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula:

[0023]

[0024] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0025]

[0026] X1is CR14orN;

[0027] X2is C(R15)(R16), O, C(=O), S(O)2, or NR17;

[0028] X3is CR18, C(R18a)(R18b), orN;

[0029] X4is CR19, C(R19a)(R19b), orN;

[0030] R1is Ci-ealkyl, C(=O)RA, cycloalkyl, heterocyclyl, aryl, or heteroaryl. each of which is optionally substituted with one or more R13;

[0031] R2a, R2b, R3a, R3b, R4a, and R4bare each independently hydrogen, Ci.e alkyl, C2-6 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 R12; or

[0032] R2aand R2b, R3aand R3b, or R4aand R4btaken together with the atom they are attached to form an oxo group (e.g. C=O);

[0033] R5ais hydrogen, Ci-ealkyl, C2-e alkenyl, C2-6 alkynyl, Ci-e 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 R12;

[0034] R5bis cycloalkyl, heterocyclyl, aryl, or heteroary l, optionally substituted with one or more R11;PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0035] R6, R6, R7, and R7are each independently selected from hydrogen, Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-ehaloalkyl, Ci- e haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), and -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R20;

[0036] R8and R9are each independently selected from hydrogen and Ci-ealkyk or

[0037] R8and R9are taken together with the atom they are attached to form an oxo group (e.g., C=O); R10is hydrogen, -O(RA), or C1-6 alkyl; or

[0038] R9and R10together with the atoms they are attached form a double bond;

[0039] each R11is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-ehaloalkyl, C1-6 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 each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, ary l, and heteroaryl is optionally substituted with one or more R21; or

[0040] two R11taken together with the atom to which they are attached form an oxo group;

[0041] each R12is hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e heteroalkyl, Ci-e haloalkyl, Ci-e 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 each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R21: or

[0042] two R12taken together with the atom to which they are attached form an oxo group;

[0043] each R13is independently hydrogen (e.g., deuterium), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e heteroalkyl, C 1-6 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 R22;

[0044] R14, R15, and Rlbare each independently hydrogen (e.g., deuterium), halo, or C1.3 alkyl;

[0045] R17is H or C1.6 alkyl;

[0046] R18, R18a, R18b, R19, R19a, and R19bare each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e heteroalkyl, Ci-e 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 R23;

[0047] each R20, R21, R22, and R23is independently selected from independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e heteroalkyl, Ci-ehaloalkyl, Ci-e haloalkoxy, cycloalkyl, heterocyclyl, ary l, heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), and -N(RB)(RC);PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0048] each RAis independently hydrogen (e.g, deuterium), Ci-e alkyl, Cue heteroalkyl, C haloalkyl. cycloalkyl, heterocyclyl, or -N(RB)(RC), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R24;

[0049] each RBand Rcis independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, Ci.6 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 R24; or

[0050] 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 R24;

[0051] each RDand REis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, Ci-e heteroalkyl, Cue haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R24;

[0052] each R24is Ci-6 alkyl, C 1.6 heteroalkyl. C1-6 haloalkyl, cycloalkyl, halogen, or cyano: or two R24taken together with the atom to which they are attached form an oxo group; and n is 0, 1, 2, or 3.

[0053] 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 pharmacally acceptable excipient.

[0054] 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.

[0055] Fourth, provided herein is a compound of Formula (I), or a tautomer thereof, or a pharmacally 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, Alzheimer’s disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0056] Reference will now be made in detail to embodiments of the present disclosure. While certain embodiments of the present disclosure w ill be described, it will be understood that it is not intended to limit the embodiments of the present disclosure to those described embodiments. To the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims.

[0057] DETAILED DESCRIPTION

[0058] Provided herein is a compound of Formula (I):PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0059] R9I

[0060]

[0061] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein:

[0062] Ring A together with the 6-membered ring system to which it is fused forms a bicyclic ring system of formula:

[0063]

[0064] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0065] X

[0066]

[0067] 1is CR14orN;

[0068] X2is C(R15)(R16), O, C(=O), S(O)2, or NR17;

[0069] X3is CR18, C(R18a)(R18b), orN;

[0070] X4is CR19, C(R19a)(R19b), orN;

[0071] R1is Ci-ealkyl, C(=O)RA, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with one or more R13;

[0072] R2a, R2b, R3a, R3b, R4a, and R4bare each independently hydrogen, Cue alkyl, C2-6 alkeny l, C2-6 alkynyl, Cue heteroalkyl, Ci-ehaloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RD)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R12; or

[0073] R2aand R2b, R3aand R3b, or R4aand R4btaken together with the atom they are attached to form an oxo group (e.g. C=O);

[0074] R5ais hydrogen, C1-6 alkyl, C2-6 alkenyl, C’2-6 alkynyl, C1-6 heteroalkyl, Ci-ehaloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RD)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R12;

[0075] R5bis cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R11; R6, R6, R7, and R7are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2.,, alkynyl, C1-6 heteroalkyl, Ci -6 haloalkyl, C.., haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R20;

[0076] R8and R9are each independently selected from hydrogen and C1-3alkyl; or

[0077] R8and R9are taken together with the atom they are attached to form an oxo group (e.g., C=O); R10is hydrogen or C1-6 alkyl; or

[0078] R9and R10together with the atoms they are attached form a double bond;

[0079] each R11is hydrogen, Ci-ealkyl, C2-6 alkenyl, C2-6 alkynyl. Ci-6 heteroalkyl, Ci-ehaloalkyl, C1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0080] C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, ary l, and heteroaryl is optionally' substituted with one or more R21; or

[0081] two R11taken together with the atom to which they are attached form an oxo group;

[0082] each R12is hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci- 6 haloalkyl, C1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC). or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, ary l, and heteroaryl is optionally substituted with one or more R21; or

[0083] two R12taken together with the atom to which they are attached form an oxo group;

[0084] each R13is independently hydrogen (e.g., deuterium), Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e heteroalkyl, C1-6 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 R22:

[0085] R14, R15, and R16are each independently hydrogen (e.g., deuterium), halo, or C1.3 alkyl;

[0086] R17is hydrogen or C1-3alkyl;

[0087] R18, R18a, R18b, R19, R19a, and R19bare each independently hydrogen, Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 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 R23:

[0088] each R20, R21, R22, and R23is independently selected from independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-e haloalkyl, C1-6 haloalkoxy, cycloalkyl, heterocyclyl, ar l, or heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC);

[0089] each RAis independently hydrogen (e.g., deuterium), C1-6 alkyl, Ci- 6 heteroalkyl, Ci-e haloalkyl, cycloalkyl, heterocyclyl, or -N(RB)(RC), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R24;

[0090] each RBand Rcis independently hydrogen, C1-6 alkyl, C2-6 alkenyl, Ci-e heteroalkyl, C 1.6 haloalkyl, cycloalkyl, heterocyclyl, or -C(O)-alkyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R24; or

[0091] 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 R24;

[0092] each RDand REis independently hydrogen, Ci-e alkyl, C2-6 alkenyl. Ci 6 heteroalkyl, Cue haloalkyl, cycloalkyl, or heterocyclyl, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R24;

[0093] each R24is C1-6 alkyl, C 1.6 heteroalkyl, C1-6 haloalkyl, cycloalkyl, halogen, or cyano; orPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0094] two R24taken together with the atom to which they are attached form an oxo group; and n is 0, 1, 2, or 3.

[0095] In an embodiment. Ring B is selected from

[0096]

[0097] In an embodiment, Ring B is R5b

[0098] selected from

[0099]

[0100] As generally described herein, X1is CR14or N. In some embodiments, X1is CR14. In an embodiment, X1is CH. In some embodiments, X1is N.

[0101] As generally described herein, X2is C(R15)(R16), O, C(=O), S(O)2, or NR17. In some embodiments, X2is C(R15)(R16). 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 NR17. In some embodiments, X2is NH. In an embodiment, X1is CH and X2is O.

[0102] As generally described herein, X3is CR18, C(R18a)(R18b), or N. In some embodiments, X3is CR18. In some embodiments, X3is CH. In some embodiments, X3is C(R18a)(R18b). In some embodiments, X3is CH2. In some embodiments, X3is N.

[0103] As generally described herein, X4is CR19. C(R19a)(R19b), or N. In some embodiments, X4is CR19. In some embodiments, X4is CH. In some embodiments, X4is C(R19a)(R19b). In some embodiments, X4is CH2. In some embodiments, X4is N.

[0104] In an embodiment, one of X3and X4is independently N. In an embodiment, X3and X4are each independently N.

[0105] As generally described herein, R1is C1-6alkyl, C(=O)RA, 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 aryl, optionally substituted with one or more R13. In an embodiment, R1is heteroaryl, optionally substituted with one or more R13. In an embodiment, R1is 6- to 10-membered aryl, optionally substituted with one or more R13. In an embodiment, R1is 6-membered aryl, optionally substituted with one or more R13. In an embodiment, R1is phenyl, optionally substituted with one or more R13. In an embodiment, R1is methyl. In an embodiment, R1is C(O)-cycloalkyl, such as C(O)-cyclopropyl, optionally susbstitued with one or more R13.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0106] In some embodiments, R1is a 4-membered, 5 -membered, or 6-membered cycloalkyl, each of which is optionally substituted with one or more R13. In some embodiments, R1is selected from cyclopropyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with one or more R13.

[0107] In an embodiment, R1is selected from

[0108]

[0109] . In some embodiments, R1

[0110]

[0111] . In some embodiments, R1is

[0112] CF3CF3

[0113] CF3

[0114] In an embodiment, R1is selected from

[0115]

[0116] QI*. In some embodiments, R13

[0117] CF3

[0118]

[0119] . In some embodiments, R1is In some embodiments,

[0120]

[0121] R1is

[0122] As generally described herein, R2a, R2b, R3a. R3b, R4a, and R4bare each independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C1-6 heteroalkyl, Cue 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 R12; or R2aand R2b, R3aand R3b, or R4aand R4btaken together with the atom they are attached to form an oxo group (e.g. C=O).

[0123] In an embodiment, R2aand R2bare each independently selected from hydrogen, Cue 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 R12. In an embodiment, R2aand R2bare each independently selected from hydrogen, Ci-e alkyl, C2-6 alkenyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl or alkenyl is optionally substituted with one or more R12. In an embodiment, R2aand R2bare each independently selected from hydrogen or Ci-6 alkyl, wherein each alkyl is optionally substituted with one or more R12. 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).

[0124] In an embodiment, R3aand R3bare each independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-e heteroalkyl, Ci-e haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl isPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0125] optionally substituted with one or more R12. In an embodiment, R3aand R3bare each independently selected from hydrogen, Ci-e alkyl, C2-6 alkenyl, halogen, -O(RA), or -N(RB)(RC), wherein each alkyl or alkenyl is optionally substituted with one or more R12. In an embodiment, R3aand R3bare each independently selected from hydrogen or C1-6 alkyl, wherein each alkyl is optionally substituted with one or more R12. In an embodiment, R3aand R3bare each independently hydrogen. In an embodiment, R3aand R3btaken together with the atom they are attached to form an oxo group (e.g. C=O).

[0126] In an embodiment, R4aand R4bare each independently selected from hydrogen, C1.6 alkyl, C2-6 alkenyl, C2-6alkynyl. Ci.6 heteroalkyl, Ci-ehaloalkyl, 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 R12. In an embodiment, R4aand R4bare 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 R12. In an embodiment. R4aand R4bare each independently selected from hydrogen or C1.6 alkyl, wherein each alkyl is optionally substituted with one or more R12. 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).

[0127] As generally described herein, R5ais hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-ehaloalkyl, 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 R12. In an embodiment, R3ais 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 R12. In an embodiment, R5ais hydrogen or C1-6alkyl, wherein each alkyl is optionally substituted with one or more R12. In an embodiment, R5ais hydrogen.

[0128] As generally described herein, R5bis cycloalkyl, heterocyclyl. aryl, or heteroaryl, optionally substituted with one or more R11. In an embodiment, R5bis cycloalkyl, optionally substituted with one or more R11In an embodiment, R5bis heterocyclyl, optionally substituted with one or more R11In an embodiment, R5bis aryl, optionally substituted with one or more R11. In some embodiments, R5bis heteroaryl, optionally substituted with one or more R11. In an embodiment, R5bis a 5 - to 10-membered heteroaryl, optionally substituted with one or more R11. In some embodiments, R5bis a 5- or 6-membered heteroaryl, optionally substituted with one or more R11. In an embodiment, R5bis a 5 -membered heteroaryl, optionally substituted with one or more R11. In an embodiment, R3bis a 6-membered heteroaryl, optionally substituted with one or more R11. In an embodiment, R5bis a nitrogen-containing heteroaryl, optionally substituted with one or more R11.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0129] In an embodiment, R5bis selected from

[0130]

[0131] R11

[0132] I

[0133] embodiment,

[0134]

[0135] R5bis. In an embodiment.

[0136]

[0137] R5bis

[0138] In an embodiment, R5bis selected from

[0139]

[0140] . In an embodiment, R’bis

[0141]

[0142] As generally described herein, R6. R6, R7and R7are each independently selected from hydrogen. Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci.6 heteroalkyl, Ci-ehaloalkyl, C1-6 haloalkoxy, cycloalkyl, heterocyclyl, ary l, or heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R20.

[0143] In some embodiments, R6and R6are each independently hydrogen. C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-ehaloalkyl, C 1.6 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 R20. In some embodiments, R6and R6are each independently hydrogen, Cue alkyl, C2-6 alkenyl, Ci-6heteroalkyl, Ci-6haloalkyl, 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 R20. In some embodiments, R6and R6are each independently hydrogen, Cue alkyl, Ci.6 haloalkyl. halogen, or cyano. In some embodiments, Rbis H, -CF3, or -CH3. In an embodiment, R6is H, -CH3, or -CN.

[0144] In some embodiments, R7is hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, Ci-e haloalkyl, cycloalkyl, heterocyclyl, ary l, heteroaryl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionallyPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0145] substituted with one or more R20. In some embodiments, R7is hydrogen, Cue alkyl, C2-6 alkenyl, Ci-e heteroalkyl, Ci-ehaloalkyl, 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 R20. In some embodiments, R7is hydrogen, C1-6 alkyl, Ci-e haloalkyl, halogen, or cyano. In some embodiments, R7is hydrogen or C1-6 alkyl. In some embodiments, R7is C1-6 alkyl. In some embodiments, R7is -CH3.

[0146] In some embodiments, R6and R7are each independently hydrogen, halogen, haloalkyl, C1.6 alkyl, or -CN. In an embodiment, R6and R7are each independently H, halogen, Ci-e alkyl, or -CN.

[0147] As generally described herein, R8and R9are each independently selected from hydrogen and Cisalkyl; or R8and R9are taken together with the atom they are attached to form an oxo group (e.g., C=O). In an embodiment, R8is hydrogen. In an embodiment. R8is Ci-salkyl. In an embodiment, R9is hydrogen. In an embodiment, R9is Ci-salkyl. In an embodiment, R8and R9are taken together with the atom they are attached to form an oxo group (e.g., C=O).

[0148] As generally described herein, R10is hydrogen or C1-6 alkyl; or R9and R10together with the atoms they are attached form a double bond. In some embodiments, R10is hydrogen. In some embodiments, R10is Ci.6 alkyl.

[0149] As generally described herein, R11is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, C1-6 haloalkyl, C i-e haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano. -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R21, or two R11taken together with the atom to which they are attached form an oxo group.

[0150] In an embodiment, R11is hydrogen (e g., deuterium), C1-6 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 R21. In an embodiment, R11is hydrogen (e.g., deuterium), Ci-ealkyl, Ci-e heteroalkyl, C1.6 haloalkyl, cycloalkyl, or halogen, wherein each alkyl, alkenyl, heteroalkyl, haloalkyl, or cycloalkyl is optionally substituted with one or more R21. In an embodiment, R11is hydrogen, and in a specific embodiment, deuterium. In an embodiment, R11is C1-6 alkyl, optionally substituted with one or more R21. In an embodiment, R11is -CH3. In an embodiment, R11is Ci-6 heteroalkyl, optionally substituted with one or more R21. In an embodiment, R11is Ci- 6 haloalkyl, optionally substituted with one or more R21. In an embodiment, R11is cycloalkyl, optionally substituted with one or more R21. In an embodiment, R11is halogen. In an embodiment, two R11taken together with the atom to which they are attached form an oxo group.

[0151] As generally described herein, each R12is hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Ci-ehaloalkyl, Ci-e haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano. -PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0152] O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R21; or two R12taken together with the atom to which they are attached form an oxo group.

[0153] As generally described herein, each R13is independently hydrogen (e.g., deuterium), Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 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 R22. In some embodiments, R13is hydrogen, and in a specific embodiment, deuterium. In some embodiments, R13is Ci- 6 alkyl. In some embodiments, R13is C 1-6 heteroalkyl. In some embodiments, R13is cycloalkyl. In some embodiments, R13is C1-6 haloalkyl. In some embodiments, R13is halogen. In some embodiments, R13is cyano. In some embodiments, R13is -C(O)N(RB)(RC).

[0154] As generally described herein, R14, R15, and R16are each independently hydrogen, halo, or C1.3 alkyl. In some embodiments, R14is hydrogen, halo, or C1.3 alkyl. In some embodiments, R14is hydrogen. In some embodiments, R14is halo. In some embodiments, R14is C1-3 alkyl. In some embodiments, R15is hydrogen, halo, or C1-3 alkyl. In some embodiments, R15is hydrogen. In some embodiments, R15is halo. In some embodiments, R15is C1-3 alkyl. In some embodiments, Rlbis hydrogen, halo, or C1-3 alkyl. In some embodiments, R16is hydrogen. In some embodiments. R16is halo. In some embodiments, R16is C1-3 alkyl.

[0155] As generally described herein, R17is hydrogen or C1.3 alkyl. In some embodiments, R17is hydrogen. In some embodiments, R17is C1-3 alkyl. In some embodiments, R17is CH3.

[0156] As generally described herein, R18, R18a, R18b, R19, R19a, and R19bare each independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci- 6 heteroalkyl, C1-6 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 R23.

[0157] In some embodiments, R18is hydrogen, C1-6 alkyl, C2-6 alkenyl, Ci-e heteroalkyl, C1-6haloalkyl. halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R23. In some embodiments, R18is hydrogen or Ci-e alkyl, wherein each alkyl is optionally substituted with one or more R23.

[0158] In some embodiments, R18aand R18bare independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, Cue heteroalkyl, Cue haloalkyl, halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R23. In some embodiments, R18aand R18bare independently selected from hydrogen or Ci-e alkyl, wherein each alkyl is optionally substituted with one or more R23.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0159] In some embodiments, R19is hydrogen, C1-6alkyl, C2-6 alkenyl, Cue heteroalkyl, C1-6haloalkyl. halogen, cyano, -O(RA), or -N(RB)(RC), wherein each alkyl, alkenyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R23. In some embodiments, R19is hydrogen or C1-6alkyl, wherein each alkyl is optionally substituted with one or more R23.

[0160] In some embodiments, R19aand R19bare independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6heteroalkyl, C1-6 haloalkyl, halogen, cyano. -O(RA). or -N(RB)(RC), wherein each alkyl, alkenyl, heteroalkyl, and haloalkyl is optionally substituted with one or more R23. In some embodiments, R19aand R19bare independently selected from hydrogen or C1-6alkyl, wherein each alkyl is optionally substituted with one or more R23.

[0161] As generally described herein, each R20, R21, R22, and R23is independently selected from independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl. C2-6alkynyl, C1-6 heteroalkyl. C1-6 haloalkyl, C 1.6 haloalkoxy, cycloalkyl, heterocyclyl. aryl, or heteroaryl, halogen, cyano, -O(RA). -C(O)RA. -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC).

[0162] As generally described herein, each RAis independently hydrogen (e.g., deuterium), Ci-e alkyl, Ci-6 heteroalkyl, C1-6haloalkyl, cycloalkyl, heterocyclyl, or -N(RB)(RC), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R24.

[0163] As generally described herein, each RBand Rcis independently hydrogen, Ci-6 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 R24; 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 R24.

[0164] As generally described herein, each RDand REis independently hydrogen, Ci-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 R24.

[0165] As generally described herein, each R24is Cue alkyl, Cue heteroalkyl, C1.6 haloalkyl, cycloalkyl, halogen, or cyano; or two R24taken together with the atom they are attached form an oxo.

[0166] 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.

[0167] In an embodiment, the compound of Formula (I) is a compound of Formula (I-a):PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0168]

[0169] or or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, R6, R7, R8, R9, and subvariables thereof are defined as for Formula (I).

[0170] In an embodiment, the compound of Formula (I) is a compound of Formula (I-b):

[0171]

[0172] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, R6, R7, R8, R9, and subvariables thereof are defined as for Formula (I).

[0173] In an embodiment, the compound of Formula (I) is a compound of Formula (I-c):

[0174] R6

[0175] R7

[0176]

[0177] (I-c),

[0178] 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).

[0179] In an embodiment, the compound of Formula (I) is a compound of Formula (I-d):

[0180] R1

[0181]

[0182] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0183] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, R6, R7, R8, R9, and subvariables thereof are defined as for Formula (I).

[0184] In an embodiment, the compound of Formula (I) is a compound of Formula (I-e):

[0185]

[0186] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, R6, R7, R8, R9, and subvariables thereof are defined as for Formula (I).

[0187] In an embodiment, the compound of Formula (I) is a compound of Formula (I-f):

[0188]

[0189] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X2, X3, X4, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

[0190] In an embodiment, the compound of Formula (I) is a compound of Formula (I-g):

[0191] (I-g),

[0192]

[0193] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0194] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X3, R1, R2a, R2b, R3a, R3b, R5a, R5b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

[0195] In an embodiment, the compound of Formula (I) is a compound of Formula (141):

[0196] R1

[0197]

[0198] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X3, R1, R5b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

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

[0200]

[0201] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

[0202] In an embodiment, the compound of Formula (I) is a compound of Formula (I-j):

[0203]

[0204] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0205] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X4, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R’b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

[0206] In an embodiment, the compound of Formula (I) is a compound of Formula (I-k):

[0207]

[0208] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0213] Table A. Exemplary Compounds

[0214]

[0215]

[0216] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0217]

[0218]

[0219] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0220]

[0221]

[0222] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0223]

[0224]

[0225] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0226]

[0227]

[0228] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0229]

[0230]

[0231] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0232]

[0233]

[0234] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0235]

[0236]

[0237] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0238]

[0239]

[0240] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0241]

[0242]

[0243] AT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0244] o ^, F

[0245] z— \ °r 1 0^1'—A

[0246] OCI'—

[0247] \ Zii — Tc / XX Xx CF3

[0248] " H - ^ ZX4O-n —-ZF1,2°J-|

[0249] UA XX

[0250] » ■

[0251] F1^F 107 1 1

[0252] 193OVN rlW " A <

[0253] 1

[0254] XX ^F3

[0255] FJ ^. F194° z" zNzf’ A < ILV / Ax 1 CF3

[0256] °'3A Xx

[0257] 1951 1

[0258] / F °VN / N N

[0259] XA. X

[0260]

[0261] XX

[0262]

[0263] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0264]

[0265]

[0266] 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.

[0267] FORMULATION AND ROUTE OF ADMINISTRATION

[0268] 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, aPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0269] pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.

[0270] 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, intrastemally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0271] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill. bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. The pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.

[0272] 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.

[0273] 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.

[0274] Pharmaceutically acceptable compositions

[0275] 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.

[0276] 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"PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0277] 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 forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0278] 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.

[0279] 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.

[0280] Alternatively, pharmaceutically acceptable compositions of this disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing tire 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.

[0281] 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,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0282] including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0283] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema fonnulation. Topically-transdermal patches may also be used.

[0284] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] The amount of compounds of tire 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.

[0289] 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,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0290] 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.

[0291] METHODS OF USE

[0292] 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.

[0293] 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.

[0294] 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 tire last few years, TREM2 has been linked to several diseases. For instance, mutations in both TREM2 and DAP 12 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, tire 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-PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0295] 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 tire pathogenesis of Rheumatoid Arthritis (RA) via persistent expression of pro -inflammatory cytokines by macrophages. Signaling through TREM2 / DAP12 inhibits TLR responses by reducing MAPK (Erk 1 / 2) activation, suggesting that TREM2 activation may act as a negative regulator of TLR driven RA pathogenesis. Huang and Pope 2009.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] 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 non-mass 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.

[0300] 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.

[0301] 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0302] 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.

[0303] 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.

[0304] 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, 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.

[0305] 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.

[0306] In some embodiments, the disease, disorder, or condition is a tissue injury. Any tissues of the body may be injured. Exemplary injuries include ocular (e.g. hyphema), spinal cord injury, traumatic brain injury, hepatocellular, and wound repair in diabetes.

[0307] 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 treating or preventing a disease, disorder or condition. In one aspect, the disclosure provides a compound of Fonnula (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.

[0308] 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0309] 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 Parkinson’s disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0310] 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, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof.

[0311] 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.

[0312] CSF1R

[0313] CSF1R is a cell-surface receptor primarily for the cytokine colony stimulating factor 1 (CSF-1), also known until recently as macrophage colony-stimulating factor (M-CSF), which regulates the survival, proliferation, differentiation and function of mononuclear phagocytic cells, including microglia of the central nervous system. CSF1R is composed of a highly glycosylated extracellular ligand-binding domain, a trans-membrane domain and an intracellular tyrosine -kinase domain. Binding of CSF-1 to CSF1R results in the formation of receptor homodimers and subsequent auto-phosphorylation of several tyrosine residues in the cytoplasmic domain, notably Tyr. In the brain, CSF 1R 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).

[0314] Tire 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,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0315] 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 CSF 1R mutation. This discovery has not been previously taught or suggested in the available art.

[0316] To date, no prior study has shown that TREM2 agonism can rescue the loss of microglia in cells where mutations in the CSF1R kinase domain reduce CSF1R activity, rather than the presence of a CSF1R inhibitor or a deficiency in CSF1R ligand. Furthermore, no prior study has taught or suggested that reversal of the loss of microglia due to a CSF1R mutation through TREM2 agonism can be used to treat a disease or disorder caused by and / or associated with a CSF1R mutation.

[0317] 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 tire disease. ALSP is characterized by patchy cerebral white matter abnormalities visible by magnetic resonance imaging. However, the clinical symptoms and MRI changes are not specific to ALSP and are common for other neurological conditions, including Nasu-Hakola disease (NHD) and AD, making diagnosis and treatment of ALSP very difficult.

[0318] 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). Tn 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.

[0319] 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 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).

[0320] 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 compositionPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0321] 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).

[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 dysfunction of CSF1R.

[0323] 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).

[0324] In another aspect, the disclosure provides a method of treating or preventing a disease or disorder associated with dysfunction of CSF 1R in a subject in need thereof, tire 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 CSF 1R mutation. In some embodiments, the disease or disorder is caused by a homozygous CSF 1R 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 tire ectodomain of CSF1R. In some embodiments, the disease or disorder is a disease or disorder resulting from a change (e.g. increase, decrease or cessation) in the activity of CSF1R. In some embodiments, the disease or disorder is a disease or disorder resulting from a decrease or cessation in the activity of CSF1R. CSF1R related activities that arc changed in the disease or disorder include, but arc not limited to: decrease or loss of microglia function; increased microglia apoptosis; decrease in Src signaling; decreasePAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0325] in Syk signaling; decreased microglial proliferation; decreased microglial response to cellular debris; decreased phagocytosis; and decreased release of cytokines in response to stimuli. In some embodiments, the disease or disorder is caused by a loss-of-function mutation in CSF1R. In some embodiments, the loss-of-function mutation results in a complete cessation of CSF1R function. In some embodiments, the loss-of-function mutation results in a partial loss of CSF1R function, or a decrease in CSF1R activity.

[0326] 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 leukodystrophy (POLD), pediatric-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof. In some embodiments, the method treats or prevents ALSP, which is an encompassing and superseding name for both HDLS and POLD. In some embodiments, the disease or disorder is a homozygous mutation in CSF1R. In some embodiments, the method treats or prevents pediatric-onset leukoencephalopathy. In some embodiments, the method treats or prevents congenital absence of microglia. In some embodiments, the method treats or prevents brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS).

[0327] 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 m etach romatic 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.

[0328] ABCD1

[0329] The ABCD1 gene provides instructions for producing the adrenoleukodystrophy protein (ALDP). ABCD1 (ALDP) maps to Xq28. ABCD1 is a member of the ATP -binding cassette (ABC) transporter superfamily. The superfamily contains membrane proteins that translocate a wide variety of substratesPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0330] 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 lon -chain fatty acids (VLCFAs) into peroxisomes, where they are broken down. As ABCD1 is highly expressed in microglia, it is possible that microglial dysfunction and their close interaction with other cell types actively participates in neurodegenerative processes (Gong et al., Annals ofNeurology. 2017: 82(5):813-827.). It has been shown that severe microglia loss and damage is an early feature in patients with cerebral form of x-linked ALD (cALD) carrying ABCD1 mutations (Bergner et al., Glia. 2019; 67: 1196-1209). It has also been shown that ABCD1 -deficiency leads to an impaired plasticity of myeloid lineage cells that is reflected in incomplete establishment of anti-inflammatory responses, thus possibly contributing to the devastating rapidly progressive demyelination in cerebral adrenoleukodystrophy (Weinhor et al., BRAIN 2018: 141; 2329-2342). These findings emphasize microglia / monocytes / macrophages as crucial therapeutic targets for preventing or stopping myelin destruction in patients with X-linked adrenoleukodystrophy.

[0331] Tire 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. The 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.

[0332] 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 ABCD1 mutation through TREM2 agonism can be used to treat a disease or disorder caused by and / or associated with an ABCD1 mutation.

[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 compositionPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0334] thereof for use in treating or preventing a condition associated with dysfunction of ATP -binding cassette transporter 1 (ABCD1).

[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 treating or preventing X-linked adrenoleukodystrophy (x-ALD). Globoid cell leukodystrophy (also known as Krabbe disease), Metachromatic leukodystrophy (MLD), Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Vanishing white matter disease (VWM), Alexander disease, fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[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 a condition associated with dysfunction of ABCD 1.

[0337] 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 matter disease (VWM), Alexander disease, fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[0338] 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 the ABCD1 gene is a mutation that causes a decrease in ABCD1 activity or a cessation of ABCD1 activity. In some embodiments, the disease or disorder is caused by a heterozygous ABCD1 mutation. In some embodiments, the disease or disorder is caused by a homozygous ABCD1 mutation. In some embodiments, the disease or disorder is caused by a splice mutation in the ABCD1 gene. In some embodiments, the disease or disorder is caused by a missense mutation in the ABCD1 gene. In some embodiments, the disease or disorder is a disease or disorderPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0339] 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 fatty acids and / or fatty acyl-CoAs and production of adrenoleukodystrophy protein (ALDP). In some embodiments, the disease or disorder is caused by a loss-of-function mutation in ABCD1. In some embodiments, the loss-of-function mutation results in a complete cessation of ABCD1 function. In some embodiments, the loss-of-function mutation results in a partial loss of ABCD1 function, or a decrease in ABCD1 activity. In some embodiments, the disease or disorder is caused by a homozygous mutation in 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, tire 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.

[0340] 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 matter disease (VWM), Alexander disease, fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof. In some embodiments, any of tire 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-function mutation in ABCD 1.

[0341] 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 arc 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 therapeuticallyPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0342] 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.

[0343] Autism Spectrum Disorders

[0344] It has been found that TREM2 deficient mice exhibit symptoms reminiscent of autism spectrum disorders (ASDs) (Filipello et al., Immunity, 2018, 48, 979-991). It has also been found that microglia depletion of the autophagy Aatg7 gene results in defective synaptic pruning and results in increased dendritic spine density, and abnormal social interaction and repetitive behaviors indicative of ASDs (Kim, et al., Molecular Psychiatry, 2017, 22, 1576-1584.). Further studies have shown that increased dendritic spin density detected in post-mortem ASD brains, likely caused by defective synaptic pruning, results in circuit hypoconnectivity and behavioral defects and are a potential origin of a number of neurodevelopmental diseases (Tang, et al., Neuron, 2014, 83, 1131-1143). Without intending to be limited to any particular theory, these findings suggest that TREM2 activation can reverse microglia depletion, and therefore correct the defective synaptic pruning that is central to neurodevelopmental diseases such as ASDs. The present 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.

[0345] In another aspect, the present invention provides a compound of the present disclosure, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition thereof for use in treating autism or autism spectrum disorders.

[0346] 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 pharmacal composition thereof for use in the preparation of a medicament for treating autism or autism spectrum disorders.

[0347] 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.

[0348] 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0349] Combination Therapies

[0350] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.”

[0351] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0352] 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 tw o additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] One or more other therapeutic agent may be administered separately from a compound or composition of the present disclosure, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the present disclosure may be administered simultaneously, sequentially or within a period of time from one another, for example within 1. 2, 3, 4, 5,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0357] 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.

[0358] 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 tautomer 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 of said compound, stereoisomer, or tautomer may be administered up to 5 minutes. 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a provided compound, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer of said compound, stereoisomer, or tautomer may be administered up to 5 minutes. 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours. 3 hours, 4 hours, 5. hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0359] DEFINITIONS

[0360] Tire following definitions are provided to assist in understanding the scope of this disclosure. Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification or claims are to be understood as being modified in all instances by the term "about ’ Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the standard deviation found in their respective testing measurements.

[0361] 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 tire compound.

[0362] 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 arc described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 2005, and “March's Advanced Organic Chemistry: Reactions Mechanisms and Structure”, 8thPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0363] Ed., Ed.: Smith, M. B., John Wiley & Sons, New York: 2019, the entire contents of which are hereby incorporated by reference.

[0364] Stereoisomers

[0365] Tire 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 atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.

[0366] 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.

[0367] 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 tire 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0368] 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 tire 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..

[0369] Tetrahedron 33:2725; Eliel, Stereochemistry' of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972).

[0370] Tautomers

[0371] 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 fomi, 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

[0372]

[0373] Additionally, a second tautomer is possible for compounds of Formula (I) wherein R3is H:

[0374]

[0375] Accordingly, the scope of tire instant disclosure is to be understood to encompass all tautomeric forms of the compounds disclosed herein.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0376] Isotopically-Labelled Compounds

[0377] 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 asHC,13C and14C, chlorine, such as36C1, fluorine, such as18F, iodine, such as123I and123I, nitrogen, such as13N and13N, 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 isotopes of that atom are embraced. For example, recitation of “hydrogen’’ or “H” encompasses any of ’H,2H (deuterium), and3H (tritium), unless otherwise 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 asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy. Isotopically-labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying General Synthetic Schemes and Examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

[0378] Solvates

[0379] 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.

[0380] Tire term “solvate” as used herein refers to a molecular complex comprising a compound or a pharmacally acceptable salt thereof as described herein and a stoichiometric or non-stoichiometric amount of one or more pharmacally acceptable solvent molecules. If the solvent is water, the solvate is referred to as a “hydrate.”

[0381] 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0382] Miscellaneous Definitions

[0383] This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0384] Tire 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 alkylcarbon atoms, and in yet other embodiments, alkyl groups contain 1 to 2 alkyl carbon atoms.

[0385] 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 attachment 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.

[0386] 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 ort / 70-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 hctcroatoms 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 isPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0387] 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:

[0388]

[0389] Exemplary bridged bicyclics include:

[0390] H

[0391]

[0392] 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.

[0393] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0394] The temr “C1-6 haloalkyl” refers to a Ci-e straight or branched alkyl group that is substituted with one or more halogen atoms.

[0395] Tire 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0396] The term ‘unsaturated,” as used herein, means that a moiety has one or more units of unsaturation. As used herein, the term “bivalent Ci-s (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0397] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(Cthln-, wherein n is a positive integer, preferably from 1 to 6. from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted alkyl group.

[0398] Tire term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted alkyl group.

[0399] 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.

[0400] 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 ar l, heteroaryl, or cycloalkyl rings, such as indolinyl, 377-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 term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0401] 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0402] The terms “Ci-salkyl,” “Ci.salkyl,” and “Ci-ealkyl” 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 Cualkyl, Chalky, 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.

[0403] The term “C2-4alkenyl” as used herein refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight and branched moieties. Representative examples of C2-4alkenyl include, but are not limited to, 1 -propenyl, 2-propenyl, 2-m ethyl -2 -propenyl, and butenyl.

[0404] Tire term ■’Ci-., cycloalky I" 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.

[0405] The terms “diCi ialkylamino ' as used herein refer to -NR*R**_ wherein R* and R** independently represent a Cualkyl as defined herein. Representative examples of diCi.?alkylamino include, but are not limited to, -NiCH.fi. -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH2CH2CH3)2, and -N(CH(CH3)2)2.

[0406] The term “Ci.3alkoxy'’ and “Ci-ealkoxy” as used herein refer to -OR#, wherein R#represents a Cisalkyl and Ci-ealkyl group, respectively, as defined herein. Representative examples of Ci-3alkoxy or Ci-ealkoxy include, but are not limited to. methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.

[0407] The term ‘‘halogen” as used herein refers to -F, -CI, -Br, or -I.

[0408] 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. ehaloalkyl” refers to a Ci-ealkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen. Representative examples of Ci-ehaloalkyl 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- ehaloalkoxy” for example refers to a Ci-ealkoxy as defined herein, wherein one or more hydrogen atoms are substituted with a halogen. Representative examples of Ci- ehaloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCHFC1, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, -OCF(CHF2)2. and -OCH(CH2F)(CF3).

[0409] 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 he ternary I include, but arc not limited to, fury l. imidazolyl,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0410] pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyL Representative examples of a 6-membered heteroaryl include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl.

[0411] Tire term “Cs-eheterocycloalkyl” 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 C / Jietcrocycloalkyl group is a Chctcrocycloalkyl. one or two carbon atoms are substituted with a heteroatom independently selected from N, O, and S.

[0412] Representative examples of Cs-eheterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0413] 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 Cs-sspiroalkyl 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.

[0414] 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 Cs-stricycloalkyl include, but

[0415] are not limited to, tricyclofl. l.l. O’ ^pentanyl,

[0416]

[0417] ', tricyclo[2.1.1.0’’4]hexanyl, tricyclo[3.1.1.01,5]hexanyl, and tricyclo[3.2.1.0’-5]octanyl.

[0418] The term aryl" used alone or as part of a larger moiety as in "‘aralkyl.” “aralkoxy,” or “aryloxyalkyl.” refers to monocyclic or bicyclic ring systems having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0419] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6. 10, or 14 TI 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, py ridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0420] naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cyclo alkyl, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl. quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be monocyclic or bicyclic. A heteroaryl ring may include one or more oxo (=0) orthioxo (=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.

[0421] 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 tire group, and w hen 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' fortheir production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of tire purposes disclosed herein.

[0422] The term “pharmaceutically acceptable” as used herein refers to generally recognized for use in subjects, particularly in humans.

[0423] 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 fomied 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,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0424] 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).

[0425] Tire tenn “pharmacally acceptable excipient’’ as used herein refers to a broad range of ingredients that may be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.

[0426] 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.

[0427] 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.

[0428] GENERAL SYNTHETIC PROCEDURES

[0429] The compounds provided herein can be synthesized according to tire 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.

[0430] 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.

[0431] 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 arc set forth in the Examples below.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0432] EXAMPLES

[0433] This section provides specific examples of compounds of Fonnula (I) and methods of making the same.

[0434] List of Abbreviations

[0435] AcOH Acetic acid

[0436] aq or aq. Aqueous

[0437] B2pin2Bis(pinacolato)diboron

[0438] DCM Dichloromethane

[0439] DMAP 4-dimethylaminopyridine

[0440] DMF N, N-dimethylfonnamide

[0441] DMSO dimethyl sulfoxide

[0442] Dppf. DPPF or dppf 1.1 '-bis(diphenylphosphino)ferrocene

[0443] eq or eq. or equiv. Equivalent

[0444] ESI orES electrospray ionization

[0445] Et Ethyl

[0446] EtOAc or EA ethyl acetate

[0447] EtOH Ethanol

[0448] g gram(s)

[0449] h or hr hour(s)

[0450] HPLC high pressure liquid chromatography

[0451] iPr Isopropyl

[0452] iPr2NEt, DIEA, or

[0453] N-ethyl diisopropylamine (Hunig's base)

[0454] DIPEA LC MS, LCMS, LC-MS

[0455] liquid chromatography mass spectroscopy

[0456] or LC / MS

[0457] m / z mass divided by charge

[0458] Me Methyl

[0459] CH3CN Acetonitrile

[0460] MeOH Methanol

[0461] mg Milligrams

[0462] min Minutes

[0463] mL Milliliters

[0464] MS mass spectra

[0465] n-BuLi n-butyllithium

[0466] NMR nuclear magnetic resonance

[0467] Bis(di-tert-butyl(4-dimethylaminophenyl)- Pd(amphos)Cl2

[0468] phosphine)dichloropalladium(II)

[0469] PE Petroleum ether

[0470] (1,3-Bis(2,6-diisopropylphenyl)imidazolidene) ( 3 -chloropyridyl) PEPPSl-SIPr

[0471] palladium(II) dichloride

[0472] Ph Phenyl

[0473]

[0474] RT or rt or r.t. room temperaturePAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0475] (2-Dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2- RuPhos Pd G3

[0476] (2'-amino-l, l'-biphenyl)]palladium(II) methanesulfonate sat. Saturated

[0477] SFC supercritical fluid chromatography

[0478] TEA or EtsN Triethylamine

[0479] THF Tetrahydrofuran

[0480] TosMIC toluenesulfonylmethyl isocyanide

[0481] [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'- Xantphos Pd G3

[0482]

[0483] amino- 1, 1 '-biphenyl)]palladium(II) methane sulfonate

[0484] General Analytical and Purification Methods

[0485] Provided in this section are descriptions of the general analytical and purification methods used to prepare the specific compounds provided herein.

[0486] Column Chromatography:

[0487] Unless otherwise indicated, crude product-containing residues were purified by passing the crude material or concentrate through either a Biotage brand silica gel column pre-packed with flash silica (SiO2) or reverse phase flash silica (C18) and eluting the product off the column with a solvent gradient as indicated. For example, a description of silica gel (0-40% EtOAc / hexane) means the product was obtained by elution from the column packed with silica using a solvent gradient of 0% to 40% EtOAc in hexanes.

[0488] Preparative HPLC Method:

[0489] prep-HPLC purification was performed using one of the following HPLC conditions:

[0490] Where so indicated, the compounds described herein were purified via reverse phase HPLC using Waters Fractionlynx semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenominex Gemini column (5 micron, C18, 150x30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100x30 mm).

[0491] A typical run through the instrument included: eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separations.

[0492] Condition 1: Column: Phenomenex luna C18 150 x 25mm x 10um; 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;

[0493] Condition 2: Column: Phenomenex luna C18 150 x 25mm x 10um; Mobile Phase A: water (0.225% FA); Mobile Phase B: MeCN;

[0494] Chiral HPLC Method:

[0495] Chiral HPLC purification was performed using one of the following Chiral HPLC conditions:PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0496] 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;

[0497] Analytical HPLC Method:

[0498] Where so indicated, the compounds described herein were analyzed using an Agilent 1100 series instrument with DAD detector (190 nm to 300 nm).

[0499] Flash Chromatography Method:

[0500] Where so indicated, flash chromatography was performed on Teledyne Isco instruments using pre-packaged disposable SiO2 stationary phase columns with eluent flow rate range of 15 to 200 mL / min, UV detection (254 and 220 nm).

[0501] Preparative Chiral Supercritical Fluid Chromatography (SFC) Method:

[0502] 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 μm or (b) Chiralpak AD-H 2 x 15 cm, 5 μm.

[0503] 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.

[0504] 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.

[0505] Preparative CP Method: Acidic reversed phase MPLC: Instrument type: Reveleris™ prep MPLC; Column: Phenomenex LUNA C18(3) (150x25 mm, 10μ); Flow: 40 mL / min; Column temp: room temperature: Eluent A: 0.1% (v / v) Formic acid in water, Eluent B: 0.1% (v / v) Formic acid in acetonitrile; using the indicated gradient and wavelength.

[0506] Proton NMR Spectra:

[0507] Unless otherw ise indicated, all 1H NMR spectra were collected on a Bruker NMR Instrument at 300, 400 or 500 MHz or a Varian NMR Instrument at 400 MHz. Where so characterized, all observed protons are reported as parts-per-million (ppm) downfield from tetramethylsilane (TMS = 0.00 ppm) using the internal solvent peak as reference. All NMR were collected at about 25 °C.

[0508] LC / MS, Mass Spectra

[0509] 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 w as 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 μM, 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.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0510] Mass Spectra (MS)

[0511] 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 electrospray detection method (commonly referred to as an ESI MS) utilizing a Waters Acquity UPLC / MS system or a Gemini-NX UPLC / MS system. Compounds having an isotopic atom, such as bromine and the like, are generally reported according to the detected isotopic pattern, as appreciated by those skilled in the art.

[0512] Compound Names

[0513] Tire compounds disclosed and described herein have been named using the IUPAC naming function of ChemDraw Professional 17.0.

[0514] Specific Examples

[0515] 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 othenvise noted, or known in the art and may be synthesized by employing known procedures using ordinary skill.

[0516] Example 1: Synthesis of Compound 101

[0517] Synthesis of Al

[0518] CDI, MeNO2, DBU, THF, RT, 18 h

[0519]

[0520] To a stirring solution of (2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-carboxylic acid (1.0 equiv, 2.01 g, 8.5 mmol), CDI (1.10 equiv, 1.52 g, 9.36 mmol) and MeNO2 (3.0 equiv, 1.37 mL, 25.5 mmol) in anhydrous THF (40 mL) at RT, was added DBU (4.50 equiv, 5.72 mL, 38.3 mmol). The resulting mixture was stirred at this temperature for 18 h. The reaction mixture was concentrated under reduced pressure and diluted with EtOAc (150 mL). The resulting solution was washed with 1.0 M HCl (aq) (x2). The combined aqueous layers were extracted with EtOAc (x2). The combined organic layers w ere washed with brine, dried over anhydrous Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel flash-column chromatography (1-5% MeOH in DCM) to afford 1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-nitroethan-1-one (A1, 1.83 g, 6.55 mmol, 77% yield) as a solid. ESI-MS (m / z+): 280.3 (obs). 1H-NMR (400 MHz, CDCl3) δ7.44-7.41 (m, 2H), 5.37 (s, 2H), 4.39-4.34 (m, 1H), 4.18-4.14 (m, 1H), 3.63-3.52PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0521] (m, 2H), 2.86 (tt, J = 11.8, 4.1 Hz, 1H), 2.09-2.04 (m, 1H), 1.84-1.71 (m, 3H), 1.10-1.03 (m, 2H), 1.03- 0.96 (m, 2H).

[0522] Synthesis of A3

[0523] NaBH4, DCM, MeOH, -15 °C, 1 h

[0524]

[0525] To a stirring solution of 1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-nitroethan-1-one (A1, 1.0 equiv, 1.80 g, 6.41 mmol) in anhydrous DCM (15 mL) and MeOH (10 mL), cooled to -15 °C, was added NaBH4 (0.7 equiv, 173 mg, 4.48 mmol) in one portion, and the reaction mixture was stirred at this temperature for 1 h. The reaction was quenched with a pre-cooled, 5% KHSO4 (0.15 mL) (aq) solution and the resulting mixture was stirred at -15 °C for 10 min. The reaction mixture was diluted with DCM and H2O / brine (1:1, v:v). The layers were separated, and the aqueous layer was extracted with DCM (x2). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford 1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-nitroethan-1-ol (A2, 1.64 g, 5.82 mmol, 91% yield) as a foam. ESI (m / z)+: 282.2 (obs).

[0526] 1H-NMR (400 MHz, CDCl3) δ7.43 (s, 2H), 4.53-4.43 (m, 2H), 4.32 (d, J = 11.2 Hz, 1H), 4.15-4.09 (m, 2H). 3.58-3.53 (m, 2H), 3.18 (s, 1H), 2.12-1.71 (m, 2H), 1.59-1.46 (m, 2H), 1.06-0.98 (m. 4H).

[0527] Synthesis of A3

[0528] H2, Pd / C, EtOH, RT, 20 h 2 NH2

[0529]

[0530] A3

[0531] To a stirring solution of 1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-nitroethan-1-ol (A2, 1.0 equiv, 1.64 g, 5.82 mmol) in de-gassed EtOH (55 mL) was added 10% Pd on carbon (0.1 equiv. 619 mg, 0.58 mmol), and the reaction was stirred at room temperature under an atmosphere of H2 for 20 h. The reaction mixture was degassed with Ar and filtered over a short pad of celite, washing with EtOH. The filtrate was concentrated under reduced pressure and purified by silica gel flash-column chromatography (2-10% MeOH in DCM, supplemented with 1% NH4OH) to afford 2-amino-1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)ethan-1-ol (A3, 1.10 g, 4.38 mmol, 75% yield) as a syrup. ESI-MS (m / z)+: 252.4 (obs).PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0532] Synthesis of A4

[0533]

[0534] To a glass vial, equipped with a Teflon-coated magnetic stirring bar was added 2-amino-1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)ethan-1-ol (A3, 1.0 equiv, 126 mg, 0.50 mmol), K3PO4 (2.0 equiv, 212 mg, 1.0 mmol), ethylene glycol (2.0 equiv, 0.06 mL, 1.0 mmol), 1-iodo-4-(trifluoromethyl)benzene (1.0 equiv, 136 mg, 0.50 mmol), Cui (0.05 equiv, 4.8 mg, 0.03 mmol) and z-PrOH (0.6 mL). The vial was sealed and stirred at 80 °C for 18 h. Tire reaction mixture was cooled to RT and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel flash-column chromatography (0-8% MeOH in DCM) to afford 1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-((4-(trifluoromethyl)phenyl)amino)ethan-1-ol (A4, 141 mg, 0.36 mmol, 71% yield) as a foam. ESI (m / z)+: 396.3 (obs). 1H-NMR (400 MHz, DMSO-D6) δ7.61 (s, 1H), 7.32-7.29 (m, 3H), 6.67 (d, J = 8.5 Hz, 2H), 6.22 (d, J = 3.2 Hz, 1H), 4.75 (d, J = 5.3 Hz, 1H), 4.19 (d, J = 9.6 Hz, 1H), 3.92 (td, J = 11.2. 3.7 Hz, 1H), 3.63-3.57 (m, 1H). 3.43-3.37 (m. 2H), 3.16 (t, J = 6.4 Hz, 1H). 2.98-2.92 (m. 1H), 1.91-1.63 (m.

[0535] 2H), 1.46-1.26 (m, 2H), 0.94 (d, J = 3.4 Hz, 2H), 0.91-0.86 (m, 2H).

[0536] Synthesis of Compound 101

[0537] XantPhos Pd G3, CS2CO3, Dioxane,

[0538] 110 °C, 24 h

[0539]

[0540] To a flame-dried microwave vial, equipped with a Teflon-coated magnetic stirring bar was added 1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-((4-(trifluoromethyl)phenyl)amino)ethan-1-ol (A4, 1.0 equiv, 40 mg, 0.10 mmol), 2,3-dichloro-5,6-dimethyl-pyrazine (1.0 equiv, 18 mg, 0.10 mmol), XantPhos Pd G3 complex (0.10 equiv, 9.5 mg, 0.01 mmol),PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0541] CS2CO3 (2.20 equiv, 72 mg, 0.22 mmol) and anhydrous 1,4-Dioxane (1.0 mL). The vial was sealed, purged / degassed under Ar and stirred at 110 °C for 24 h. The reaction mixture was cooled to RT, diluted with EtOAc and washed with H2O and brine. The organic layer was dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (5-40% Acetone in Hexanes) to afford 2-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethyl-4-(4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazine (Compound 101, 18 mg, 0.03 mmol, 33% yield) as a solid. ESI-MS (m / z)+: 500.3 (obs).

[0542] 1H-NMR (400 MHz, DMSO-D6) δ7.66-7.62 (m, 5H), 7.30 (d, J = 7.3 Hz, 1H), 4.28-4.15 (m, 2H), 3.97-3.91 (m, 2H), 3.80-3.73 (m, 1H), 3.61 (tt, J = 11.4, 3.8 Hz, 1H), 3.45 (dd, J = 22.0, 10.5 Hz, 1H), 2.23 (d, J = 2.5 Hz, 3H), 2.19 (s, 3H), 2.08-2.02 (m, 2H), 1.83-1.83 (m, 1H), 1.55-1.41 (m, 2H), 0.98-0.90 (m, 2H). 0.89-0.84 (m, 2H). 19F-NMR (376 MHz, DMSO-D6) δ -60.1 (s, 3F). -60.1 (s, 3F).

[0543] An analogous method was followed to obtain the following compounds.

[0544] Compound Starting Materials Characterization

[0545] CF3l-((2R,45)-2-(l- 2-((2A.45)-2-(l -cyclopropyl- IH- cyclopropyl-177- pyrazol-4-yl)tetrahydro-277-pyran- pyrazol-4-yl)- 4-yl)-4-(2-fluoro-4- tetrahydro-2 / 7- (trifluoromethyl)phenyl)-6,7- pyran-4-yl)-2-((2- dimethyl-3,4-dihydro-277- fluoro-4- pyrazino [2, 3 -b] [ 1,4] oxazine (trifluoromethyl)- (Compound 108).

[0546] Compound 108 phenyl)amino)- ESI-MS (m / z)+: 518.4. ’H-NMR

[0547] ethan-l-ol; 2,3- (400 MHz, CDCh) 87.47-7.39 (m, dichloro-5,6- 5H), 4.36-4.33 (m, 1H), 4.24-4.11 dimethylpyrazine (m, 2H), 3.79-3.75 (m, 2H), 3.62- 3.51 (m, 2H), 2.39 (d, J = 13.0 Hz,

[0548] 1H), 2.34 (d. J = 1.6 Hz, 3H), 2.24

[0549] (s, 3H), 2.16-2.04 (m, 1H), 1.86 (d,

[0550] J = 11.9 Hz, 1H), 1.65-1.56 (m,

[0551] 4H), 1.09-0.96 (m, 4H).19F-NMR

[0552] (376 MHz, CDCh) 8 -62.3 (d, J =

[0553] 1.4 Hz, 3F), -1 15.0 (dd, J = 17.1,

[0554] 7.3 Hz. IF).

[0555] CF3l-((2R,45)-2-(l- (R)-2-((2R,45)-2-( 1 -cyclopropyl - cyclopropyl-177- l / 7-pyrazol-4-yl)tetrahydro-277- pyrazol-4- pyran-4-yl)-4-(2-fluoro-4- yl)tetrahydro-277- (trifluoromethyl)-phenyl)-6,7- pyran-4-y 1) -2 -((2 - dimethyl-3,4-dihydro-277- N\JL y I II J

[0556] fluoro-4- pyrazino [2,3 -b] [ 1,4] oxazine (trifluoromethy 1) - (Compound 110).

[0557] Compound 110 phenyl)amino)-

[0558]

[0559] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0560] ethan-l-ol; 2,3- ESI-MS (m / z)+: 518.4. 'H-NMR dichloro-5,6- (400 MHz, CDCl3) δ7.47-7.39 (m, 5H), 4.34 (d, J = 9.6 Hz, 1H), 4.20

[0561] (dd, J = 12.7, 5.6 Hz, 1H), 4.12 (d,

[0562] J = 11.2 Hz, 1H), 3.76 (d, J = 5.3

[0563] Hz, 2H), 3.62-3.50 (m, 2H), 2.39

[0564] (d, J = 13.5 Hz, 1H), 2.34 (d, J =

[0565] 6.6 Hz. 3H), 2.24 (s, 3H), 2.13 (t, J

[0566] = 8.0 Hz, 1H), 1.62-1.53 (m, 3H),

[0567] 1.09-1.03 (m, 2H), 1.02-0.94 (m,

[0568] 2H).9F-NMR (376 MHz, CDCI3)

[0569] 5 -62.2 (s, 3F), -115.0-115.1 (m,

[0570] IF).

[0571] CF3l-((27?,45)-2-(l- (S)-2-((2R,4S)-2-( 1 -cyclopropyl- cyclopropyl-177- 17 / -pyrazol-4-yl)tetrahydro-277- pyrazol-4- pyran-4-yl)-4-(2-fluoro-4- yl)tetrahydro-277- (trifluoromethyl)-phenyl) -6,7- pyran-4-yl) -2 -((2- dimethyl-3,4-dihydro-277- N\JL - JL JL JL fluoro-4- pyrazino [2, 3 -b] - [ 1,4]oxazine (trifluoromethyl)- (Compound 111).

[0572] Compound 111 phenyl)amino)- ESI-MS (m / z)+: 518.4. 'H-NMR

[0573] ethan-l-ol; 2,3- (400 MHz, CDCl3) δ7.47-7.38 (m, 5H), 4.33 (d, J = 11.0 Hz, 1H), dimethylpyrazine 4.24-4.19 (m, 1H), 4.15 (dd, J =

[0574] 11.5, 4.0 Hz, 1H), 3.79-3.72 (m,

[0575] 2H), 3.62-3.56 (m, 1H), 3.55-3.49

[0576] (m, 1H), 2.34 (s, 3H), 2.24 (s, 3H),

[0577] 2.18-2.09 (m, 1H), 2.06 (d, J =

[0578] 13.5 Hz, 1H), 1.86 (d, J = 12.1 Hz,

[0579] 1H), 1.67-1.56 (m, 2H), 1.08-1.02

[0580] (m, 2H), 1.01-0.94 (m, 2H).19F- NMR (376 MHz, CDCh) 5 -62.3

[0581] (s, 3F), -115.0 (dd, J = 10.7, 6.2

[0582] Hz, IF).

[0583] CF36.7-dimethyl-2- 6,7-dimethyl-2-((2R,4S)-2-( 1 - ((27?,4S)-2-(6-oxo- methyl-6-oxo- 1,6-dihydropyridin- 1,6-dihydropyridin- 3-yl)tctrahydro-2 / / -pyran-4-yl)-4- 3 -yl)tetrahydro-277- (3 -(trifluoromethyl) - 'OC^XC pyran-4-yl)-4-(3- bicyclof 1.1. l]pentan- 1 -yl)-277- (trifluoromethyl)- pyrazino [2, 3 -b] [ 1,4] oxazin-3 (477) - bicyclo[1.1.1]-one (Compound 115).

[0584] Compound 115 pentan-l-yl)-277- ESI-MS (m / z)+: 505.1. 'H-NMR pyrazino-[2,3- (400 MHz, CDCl3) δ7.33-7.28 (m,

[0585]

[0586] b][l,4]oxazin- 2H), 6.54 (t, J = 8.2 Hz, 1H). 4.53PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0587] 3 (427) -one; Methyl (d, J = 3.0 Hz, 1H), 4.18-4.08 (m,

[0588] iodide 2H), 3.60-3.50 (m, 4H), 2.72 (s,

[0589] 6H), 2.49-2.41 (m, 7H), 1.90-1.78

[0590] (m, 2H), 1.67-1.57 (m, 2H).19F- 19F-NMR (376 MHz, CDCl3) δ -70.9

[0591]

[0592] (s, 3F).

[0593] Example 2: Synthesis of Compound 157

[0594] Synthesis of A5

[0595] Cui, DMF,

[0596] 70°C, 2 h

[0597]

[0598] To a mixture of 3-chloro-5-methyl-pyrazin-2-amine (1.0 eq, 200 mg, 1.39 mmol) and CuI (3.0 eq, 796 mg, 4.18 mmol) in DMF (4 mL) was added tert-butylnitrite (3.0 eq, 431 mg, 4.18 mmol) slowly under N2, then the mixture was stirred at 70°C for 2 h. The reaction was quenched by aq. Na2SO3 (30 mL), extracted with EtOAc (3 x 20 mL). The combined organic layers was dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by Prcp-TLC (9% EtOAc in PE, desired product: Rf = 0.6) to afford 3-chloro-2-iodo-5-methyl-pyrazine (A5, 90 mg, 0.35 mmol, 25% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.51 (s, 3H), 8.16 (s, 1H).

[0599] Synthesis of Compound 157

[0600]

[0601] Compound 157

[0602] To a mixture of l-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[2-fluoro-4-(trifluoromethyl)anilino]ethanol (1.0 eq, 30 mg, 0.073 mmol), 3 -chloro-2-iodo-5 -methyl -pyrazine (1.0 eq, 18 mg, 0.073 mmol) in 1,4-Dioxane (1 mL) were added CS2CO3 (3.0 eq, 71 mg, 0.22 mmol) and Xanthos Pd G3 (0.15 eq, 10 mg, 0.011 mmol) under N2. The reaction was stirred under microwave at 110°C for 12PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0603] h under N2. The reaction was filtered and the filtrate was concentrated under reduced pressure and purified by Prep-HPLC (Condition 1, Gradient 1), followed by Prep-TLC (67% EtOAc in PE, desired product: Rf = 0.25) to afford 2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-[2-fluoro-4-(trifluoromethyl)-phenyl]-7-methyl-2,3-dihydropyrazino[2,3-b][l,4]oxazine (Compound 157, 9.8 mg, 0.018 mmol, 24% yield) as a solid. [M+H]+= 504.2. 1H NMR (400 MHz, CDCl3) δ = 7.53 - 7.38 (m, 6H). 4.36 (br d, J = 11.5 Hz. 1H), 4.26 - 4.10 (m, 2H). 3.85 - 3.73 (m, 2H), 3.66 - 3.48 (m, 2H), 2.40 (br d, J = 13.4 Hz, 1H), 2.25 (s, 3H), 2.21 - 2.12 (m, 1H), 2.11 - 2.03 (m, 1H), 1.87 (br d, J = 12.5 Hz, 1H), 1.70 - 1.62 (m, 1H), 1.12 - 1.04 (m, 2H), 0.98 (br d, J = 7.4 Hz, 2H).

[0604] Example 3: Synthesis of Compound 122

[0605] Synthesis of A7

[0606] pyridine, Bu3P,

[0607] DIAD, THF,

[0608] 25°C, 12 h

[0609]

[0610] To a solution of 3-bromo-5,6-dimethyl-pyridin-2-ol (1.5 eq, 29 mg, 0.145 mmol) in THF (0.5 mL) were added pyridine (1.0 eq, 7.6 mg, 0.097 mmol) and DIAD (6.0 eq, 117 mg, 0.58 mmol) at 25°C under N2, the mixture was stirred at 25°C for 5 min under N2. A solution of nBu3P (6.0 eq, 0.096 mL, 0.58 mmol) in THF (0.5 mL) was added, followed by a solution of 1-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[2-fluoro-4-(trifluoromethyl)-anilino]ethanol (1.0 eq, 40 mg, 0.097 mmol) in THF ( 1 mL) at 25°C. The mixture was stirred at 25°C for 12 h under N2. Water (30 mL) was added to quench the reaction, the mixture was extracted with DCM (50 mL). Tire organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by Pre-TLC (50% EtOAc in DCM, Rf = 0.6) to afford N-[2-[(3-bromo-5,6-dimethyl-2-pyridyl)oxy]-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]ethyl]-2-fluoro-4-(trifluoromethyl)aniline (A7, 48 mg, 0.08 mmol, 83% yield) as a solid. [M+H]+= 597.1, 599.1. 1H NMR (400 MHz, CDCl3) δ = 7.57 (s, 1H), 7.49 - 7.41 (m, 2H), 7.25 (br s, 1H), 7.16 (br d, J = 11.7 Hz, 1H), 6.76 (br t, J = 7.7 Hz, 1H), 6.39 - 6.26 (m, 1H), 5.30 - 5.23 (m, 1H), 4.39 (br d, J = 11.1 Hz, 1H), 4.22 - 4.13 (m, 1H), 3.68 - 3.60 (m, 1H), 3.54 (td, J = 3.5, 7.1 Hz, 1H), 2.37 (s, 3H), 2.20 (s, 4H), 1.90 (brd, J = 12.7 Hz, 1H), 1.77 - 1.55 (m, 4H), 1.09 (br s, 2H), 0.99 (br d, J = 6.4 Hz, 2H)

[0611] Synthesis of Compound 122PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0612] RuPhos Pd G3, CS2CO3, Dioxane, 110 “C, 2 h

[0613]

[0614] A7 Compound 122 To a solution ofN-[2-[(3-bromo-5,6-dimethyl-2-pyridyl)oxy]-2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]ethyl]-2-fluoro-4-(trifluorometliyl)aniliiie (1.0 eq, 40 mg, 0.067 mmol) in 1,4-Dioxane (2.6 mL) were added CS2CO3 (3.0 eq, 65 mg. 0.201 mmol) and Ruphos Pd G3 (0.4 eq, 22 mg, 0.027 mmol), then the mixture was stirred at 110°C for 2 h under N2. The reaction mixture was purified by reversed phase column (Phenomenex luna C18 150*25mm* lOum, water (FA)-ACN) and lyophilized to afford a crude product, which was purified by prep-TLC (67% EtOAc in DCM, Rf = 0.25) to afford 3-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-l-[2-fluoro-4-(trifluoromethyl)phenyl]-6,7-dimethyl-2,3-dihydropyrido[2,3-b][l,4]oxazine (Compound 122, 7.87 mg, 0.014 mmol, 21% yield) as a solid. [M+H]+= 517.1.

[0615]

[0616] 1H NMR (400 MHz, CDCl3) δ = 7.49 - 7.39 (m, 4H). 7.37 - 7.30 (m. 1H), 6.76 (s, 1H). 4.39 - 4.30 (m. 1H), 4.19 - 4.09 (m, 2H). 3.66 - 3.51 (m, 4H), 2.37 (d, J = 2.4 Hz, 3H), 2.13 (s, 3H), 2.10 - 2.04 (m, 1H), 1.67 - 1.54 (m, 4H), 1.11 - 1.06 (m, 2H), 1.02 - 0.96 (m, 2H), 0.87 - 0.81 (m, 1H); 19F NMR (400 MHz, CDCl3) δ = -62.269, -117.795.

[0617] Example 4: Synthesis of Compound 164

[0618]

[0619] Compound 164

[0620] A mixture of l-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[2-fluoro-4-(trifluoromethyl)anilino]ethanol (1.0 eq. 40 mg, 0.097 mmol). 4,5-dibromo-2-methyl-pyridazin-3-one (1.0 eq, 26 mg, 0.097 mmol), CS2CO3 (3.0 eq, 94 mg, 0.29 mmol) and XantPhos Pd G3 (0.10 eq, 9.2 mg,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0621] 0.0097 mmol) in 1,4-Dioxane (2 mL) was degassed and purged with N2 for 3 times, then the mixture was stirred at 110°C for 12 h under N2 atmosphere. The reaction mixture was filtered and the filtrate was purified by prep-HPLC (Condition 2) and lyophilized to afford a crude. Hie crude product was purified by prep-TLC (9% MeOH in DCM, Rf = 0.6) and lyophilized to afford 2-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-4-[2-fluoro-4-(trifluoromethyl)phenyl]-7-methyl-2,3-dihydro-pyridazino[4.5-b][l,4]oxazin-8-one (Compound 164, 3.7 mg, 0.007 mmol. 7% yield) as a gum.

[0622] [M+H]+= 520.3. ¹H NMR (400 MHz, CDCl₃) 8 ppm 0.95 - 1.02 (m, 2H), 1.06 - 1.11 (m, 2H), 1.48 - 1.58 (m, 2H), 1.84 (br s, 1H), 2.00 - 2.25 (m, 1H), 2.35 (br s, 1H), 3.52 - 3.72 (m, 4H), 3.77 (d, J=1.88 Hz, 3H), 4.01 (brt, J=7.32 Hz, 1H), 4.09 - 4.23 (m, 1H), 4.34 (brt, J=9.69 Hz, 1H), 7.29 - 7.36 (m, 2H), 7.38 - 7.46 (m, 2H), 7.46 - 7.54 (m, 2H).

[0623] Example 5: Synthesis of Compound 171

[0624] Synthesis ofA8

[0625] NBS, THF, ^. N

[0626] 60°C, 2 h

[0627] O N O N H H

[0628]

[0629] A8

[0630] To a solution of 6-hydroxy-2-methyl-pyridine-3-carbonitrile (1.0 eq, 700 mg, 5.22 mmol) in THF (13 mL) was added NBS (1.05 eq, 975 mg, 5.48 mmol). The reaction was stirred at 60°C for 2 h. The reaction mixture (combined with another batch) was triturated in water (50 mL) and stirred for 5 min. The solid was filtered and collected to afford 5-bromo-2-methyl-6-oxo-lH-pyridine-3-carbonitrile (A8, 1.4 g, 6.5 mmol, 125% yield) as a solid. [M+H]+= 213.0.1H NMR (400 MHz, CDCh) 8 = 7.87 (s, 1H). 2.60 (s.

[0631] 3H).

[0632] Synthesis of A9

[0633]

[0634] To a solution of (2R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-one (1.0 eq, 20.0 g, 97.0 mmol), 4A molecular sieves (1.0 eq, 10.0 g) and TosMIC (1.1 eq, 20.8 g, 107 mmol) in Monoglyme (550 mL) was added a solution of t-BuOK (2.50 eq, 27.2 g, 242 mmol) in t-BuOH / 2,2-dimethoxyethane (1:1, 400 mL). Then the mixture was stirred at 30°C for 12 h. The reaction was diluted with 5% NaHCOs (400 mL) and extracted with EtOAc (3 x 200 mL). Tire combined organic layers were washed with brine (3 x 100 mL), dried over Na2SC>4, and filtered. The filtrate was concentrated under reduced pressure andPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0635] purified by silica gel column chromatography (0-100% EtOAc in PE) (100% EtOAc, the desired product Rf = 0.5) to afford (2R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-carbonitrile (A9, 14.2 g, 61.4 mmol, 63% yield) as an oil. [M+H]+= 218.1. 'H NMR (400 MHz, CDCfi) 8 = 7.50 - 7.38 (m, 4H), 4.72 (dd, J = 2.1, 11.2 Hz, 1H), 4.31 (dd, J = 2.0, 11.4 Hz, 1H), 4.12 - 3.89 (m, 4H), 3.62 - 3.50 (m, 3H), 3.21 (br s, 1H), 2.84 (tt, J = 4.2, 12.1 Hz, 1H), 2.24 (td, J = 1.8, 13.4 Hz, 1H), 2.11 (brdd, J = 2.1, 13.7 Hz.

[0636] 1H). 2.01 - 1.84 (m. 6H), 1.14 - 1.06 (m, 4H), 1.05 - 0.97 (m, 4H).

[0637] Synthesis of A 10

[0638]

[0639] A9 A10

[0640] To a solution of (2R)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-carbonitrile (A9, 1.0 eq, 12.0 g, 55.2 mmol) in Ethanol (120 mL) and water (60 mL) was added NaOH (9.0 eq. 19.9 g, 497 mmol) under N2 atmosphere, and the reaction was stirred at 90°C for 12 h. The reaction was diluted with water (100 mL) and washed with EtOAc (100 mL). Then the aqueous phase was adjust to pH<3 by 1 N HC1 and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford crude (2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-carboxylic acid (A10, 14.0 g, 59.3 mmol, 107% yield) as an oil. [M+H]+= 237.0. ‘H NMR (400 MHz, CDC13) 8 = 7.48 (s, 1H), 7.45 (s, 1H), 4.36 (dd, J = 1.7, 11.5 Hz, 1H), 4.15 (dd, J = 3.4, 11.6 Hz, 1H), 3.67 - 3.51 (m, 2H), 2.71 (tt, J = 3.7, 12.2 Hz, 1H), 2.25 - 2.15 (m, 1H), 1.99 - 1.89 (m, 1H), 1.88 - 1.73 (m, 2H), 1.12 - 1.05 (m, 2H), 1.04 - 0.92 (m, 2H).

[0641] Synthesis of All

[0642]

[0643] A10 A11

[0644] A solution of (2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tctrahydropyran-4-carboxylic acid (1.0 cq, 6.0 g, 25.4 mmol) and CDI (1.1 eq, 4.53 g, 27.9 mmol) in THF (90 mL) was stirred at 25°C for 1 h under N2. DBU (4.5 eq, 17 mL, 114 mmol) and MeNCL (3.0 eq, 4.1 mL. 76.2 mmol) were added and the mixture was stirred at 25 °C for 12 h under N2. The reaction mixture was concentrated under reducedPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0645] pressure and diluted with EtOAc (150 mL). The resulting solution was washed with 1 M HC1 (aq., 2 x 50 mL). The combined aqueous layers were extracted with EtOAc (2 x 50mL). The combined organic layers were washed with brine (3 x 30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by flash column (9% MeOH in DCM, UV, Rf = 0.5) to afford l-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran -4-yl] -2 -nitro-ethanone (Al 1, 4.40 g, 15.4 mmol, 61% yield) as an oil. [M+H]+= 280.0. 'H NMR (400 MHz. CDCL) 5 = 7.50 - 7.40 (m, 2H), 5.38 (s, 2H). 4.38 (dd, J = 1.9, 11.4 Hz, 1H), 4.25 - 4.14 (m, 1H), 3.69 - 3.51 (m, 2H), 2.96 - 2.82 (m, 1H), 2.14 - 2.03 (m, 1H), 1.89 - 1.74 (m, 3H), 1.14 - 1.06 (m, 2H), 1.06 - 0.96 (m, 2H).

[0646] Synthesis of Al 2

[0647]

[0648] To a solution of l-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2 -nitro-ethanone (1.0 eq, 3.40 g, 12.2 mmol) in Methanol (20 mL) and DCM (30 mL) was added sodium borohydride (0.70 eq, 322 mg, 8.52 mmol) under N2 at -15°C. Tire mixture was stirred at -15°C for 10 min under N2. The reaction was quenched with 5% KHSO4 (aq) (4 mL, pre-cooled in ice bath) and the mixture was stirred at -15°C for 10 min. The reaction mixture was diluted with DCM (100 mL), H2O (100 mL) and brine (80 mL). The layers were separated and the aqueous layer was extracted with DCM (80 mL * 2). The combined DCM layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford l-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-nitro-ethanol (A12, 3.50 g, 11.8 mmol, 97% yield) as a crude oil. [M+H]+= 282.0. ¹H NMR (400 MHz, CDCl₃) 5 = 7.48 -7.41 (m, 2H), 5.31 (s, 1H), 4.58 - 4.42 (m, 2H), 4.33 (brd, J = 11.3 Hz, 1H), 4.24 - 4.07 (m, 2H), 3.63 -3.50 (m. 2H), 2.12 (brd. J = 13.1 Hz, 1H), 1.94 - 1.72 (m, 2H), 1.62 - 1.46 (m, 2H), 1.14 - 1.06 (m, 2H), 1.03 - 0.93 (m, 2H).

[0649] Synthesis of Al 3

[0650] A12A13

[0651]

[0652] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0653] To a solution of l-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2 -nitro-ethanol (1.0 eq, 500 mg, 1.78 mmol) and 4,4-dipyridyl (0.08 eq, 22 mg, 0.142 mmol) in DMSO (3 mL) and Ethanol (4 mL) was added tetrahydroxydiboron (3.0 eq, 478 mg, 5.33 mmol) at 0°C, and the reaction was stirred at 0°C for 0.5 h. Tire resulting mixture was fdtered, concentrated with silica gel, and purified by silica gel column chromatography (0-100% MeOH in DCM with 1% NH4OH) (67% MeOH in DCM, Rt- = 0.2) to afford 2-amino-l-[(2R.4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]ethanol (A13, 400 mg, 1.43 mmol, 81% yield) as a solid. [M+H]+= 252.1. 'H NMR (400 MHz, CDCI3) 5 = 7.47 - 7.40 (m, 2H), 4.32 (br d, J = 11.4 Hz, 1H), 4.19 - 4.04 (m, 1H), 3.61 - 3.53 (m, 2H), 3.35 - 3.26 (m, 2H), 3.24 -3.13 (m, 1H), 3.03 - 2.86 (m, 1H), 2.65 - 2.53 (m, 1H), 2.17 - 2.09 (m, 1H), 1.85 - 1.75 (m, 2H), 1.53 -1.45 (m, 3H), 1.10 - 1.07 (m, 2H), 0.98 (br d, J = 6.1 Hz, 2H).

[0654] Synthesis of Al 4

[0655]

[0656] The reaction were operated 350 mg*2 batches. Each batch shown as below:

[0657] To a solution 2-amino-l-[(2R.4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]ethanol (1.0 eq, 350 mg, 1.39 mmol) and K3PO4 (2.0 eq, 591 mg, 2.79 mmol) in iPrOH (7 mL) were added ethylene glycol (2.0 eq, 173 mg, 2.79 mmol), Cui (0.05 eq, 13 mg, 0.07 mmol) and 2 -fluoro- l-iodo-4-(trifluoromethyl)benzene (2.0 eq, 808 mg, 2.79 mmol), then the mixture was stirred at 80°C for 4 h. The solution was diluted with water (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL) and dried over Na2SC>4. The solvent was fdtered, concentrated under reduced pressure, and purified by silica gel flash column chromatography (100% EtOAc, Rt- = 0.4) to afford l-[(2R_4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[2-fluoro-4-(trifluoromethyl)anilino]ethanol (A 14, 650 mg, 1.54 mmol, 111 % yield) as a solid. (The yield was -55% due to two batches run in parallel). [M+H]+= 414.2. 'H NMR (400 MHz, CDCI3) 5 = 7.45 (br s, 2H), 7.23 (brd, J = 12.1 Hz, 1H), 6.72 (brt, J = 8.4 Hz, 1H), 4.73 - 4.52 (m, 1H), 4.37 (br d, J = 9.8 Hz, 1H), 4.24 - 4.07 (m, 1H), 3.77 - 3.49 (m, 3H), 3.41 (br d, J = 9.0 Hz, 1H), 3.21 (brd, J = 7.3 Hz, 1H).2.15 (br d, J = 10.5 Hz, 1H), 1.97 - 1.78 (m, 2H), 1.62 - 1.52 (m, 4H), 1.09 (br s, 2H), 1.05 - 0.92 (m, 2H).PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0658] Synthesis of Al 5

[0659]

[0660] To a solution of 5 -bromo-2-methyl-6-oxo-lH-pyridine-3 -carbonitrile (A8, 1.5 eq, 39 mg, 0.18 mmol) in THF (0.5 mL) was added pyridine (1.0 eq, 9.6 mg, 0.12 mmol), followed by DIAD (6.0 eq, 147 mg, 0.73 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 5 min under N2. A solution of nBusP (6.0 eq. 0.12 mL, 0.73 mmol) in THF (0.5 mL) was added, followed by a solution of l-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[2-fluoro-4-(trifluoromethyl)anilino]ethanol (A14, 1.0 eq, 50 mg, 0.12 mmol) in THF ( 1 mL) at 25°C. The mixture was stirred at 25°C for 12 h under N2. The solution was diluted with water (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layers were washed with brine (15 mL * 3) and dried over Na2SC>4. Tire combined organic layers were concentrated under reduced pressure, purified by Prep-HPLC (water (FA)-ACN), and lyophilized to afford a crude product (30 mg). The crude product was purified by prep-TLC (50% EtOAc in DCM, the desired product Rf = 0.4) to afford 5-bromo-6-[(lR)-l-f(2R.4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[2-fluoro-4-(trifluoromethyl)-anilino]ethoxy]-2-methyl-pyridine-3-carbonitrile (A15, 20 mg, 0.024 mmol, 20% yield) as an oil. [M+H+2]+= 610.2. 'H NMR (400 MHz, CDC13) 5 = 7.97 - 7.94 (m, 1H), 7.46 - 7.41 (m, 2H), 7.27 - 7.24 (m, 1H), 7.17 (dd, J = 1.6, 11.6 Hz, 1H), 6.78 (t, J = 8.3 Hz, 1H), 5.51 - 5.37 (m, 1H), 5.03 - 4.92 (m, 1H), 4.43 - 4.36 (m, 1H), 4.21 - 4.14 (m, 1H), 3.68 -3.51 (m. 4H), 2.58 (s, 3H), 2.33 - 2.20 (m. 1H), 2.10 (br d, J = 13.4 Hz, 1H), 1.70 - 1.60 (m. 2H), 1.33 -1.27 (m. 1H), 1.14 - 1.05 (m, 2H). 1.02 - 0.95 (m, 2H).

[0661] Synthesis of Compound 171PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0662] Ruphos Pd G3, Cs2CO3, dioxane, 110°C, 2 h

[0663]

[0664] To a solution of 5-bromo-6-[l-[(2R,4S)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[2-fluoro-4-(trifluoromethyl)anilino]ethoxy]-2-methyl-pyridine-3-carbonitrile (A15, 1.0 eq, 15 mg, 0.025 mmol) in 1,4-Dioxane (1 mL) were added CS2CO3 (3.0 eq, 24 mg, 0.074 mmol) and Ruphos Pd G3 (0.40 eq, 8.2 mg, 0.01 mmol), then the mixture was stirred at 110°C for 2 h under N2. Hie resulting mixture was filtered and purified by Prep-HPLC (Condition 1, Gradient 1) and lyophilized to afford a crude. The crude was purified by prep-TLC (100% EtOAc, Rf = 0.4) and lyophilized to afford 3-[(2R,4S)-2-( 1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl] - 1 -[2-fluoro-4-(trifluoromethyl)phenyl] -6-methyl-2,3-dihydropyrido[2,3-b][l,4]oxazine-7-carbonitrile (Compound 171, 7.1 mg, 0.012 mmol, 47% yield) as a solid. [M+H]+= 528.1. ’H NMR (400 MHz, CDCh) 5 = 7.49 - 7.41 (m, 2H), 7.40 - 7.27 (m, 3H), 6.89 (d, J = 2.1 Hz, 1H), 4.35 - 4.17 (m, 2H), 4.14 - 4.02 (m. 1H), 3.64 - 3.41 (m, 4H). 2.60 - 2.47 (m, 3H), 2.35 -2.04 (m, 2H), 2.03 - 1.72 (m, 1H). 1.60 - 1.54 (m, 2H), 1.06 - 0.98 (m, 2H), 0.96 - 0.87 (m, 2H).

[0665] Example 6: Synthesis of Compound 177

[0666] Synthesis of Al 7

[0667] F3

[0668] 3Cdppa-NEt3 F3C

[0669] X t-BuOH, 80 °C, 24 h3X

[0670] COOH ^ NHBoc

[0671]

[0672] A16 A17

[0673] To 3-(trifluoromethyl)bicyclo[l.l.l]pentane-l-carboxylic acid (A16, 1 eq, 10 g, 55.5 mmol) was added tert-butanol (161.9 mL), [azido(phenoxy)phosphoryl]oxybenzene (1 eq, 12 mL, 55.5 mmol), and TEA (1.0 eq, 7.7 mL, 55.5 mmol). The mixture was stirred at 80 °C under Ar atmosphere for 24 h. Tire reaction mixture was cooled to r.t. and concentrated in vacuo. The crude was dissolved in EtOAc and washed with sat. NaHCOs (aq), water, and brine. The organic layer was dried over anhydrous Na2SO4. filtered, and concentrated in vacuo. The crude was purified by flash column chromatography (10-30% EtOac in Hexanes) to yield tert-butyl A-[3-(trifluoromethyl)-l -bicyclo[ 1.1. l]pentanyl]carbamatePAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0674] (A17, 11.30 g, 45.0 mmol, 81% yield) as a solid. 'H NMR (CDCl₃, 400 MHz) 555.11 (s, 1H), 2.19 (s, 6H), 1.42 (s, 9H).

[0675] Synthesis of Al 8

[0676] F3C Mel, NaH

[0677] DMF, 0 °C NHBoc NBoc

[0678]

[0679] A17

[0680] To tert-butyl jV-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]carbamate (A17. 1 eq, 5 g, 19.9 mmol) was added anhydrous DMF (31.2 mL). The flask was sealed, purged under Ar and cooled to 0 °C with stirring. Sodium hydride (2 eq, 955 mg, 39.8 mmol) was added, followed by methyl iodide (4 eq, 5.0 mL, 79.6 mmol). The reaction mixture was stirred at r.t. for 3 h. The reaction mixture was cooled to 0 °C and quenched with sat. Nl LCl (aq) (10 mL). Water (20 mL) was added and the organic phase was extracted with Et2O (30 mL), washed with brine (20 mL), dried overNa2SC>4 and concentrated in vacuo. to yield tert-butyl A'-mcthyl- / V-|3-(trifluoromcthyl)-l-bicyclo| l. l.l |pcntanyl|carbamatc (A18. 800 mg, 3.02 mmol, 95% yield) as a solid. ‘H NMR (CDCl₃, 400 MHz) 52.79 (s, 3H), 2.23 (d, J= 7.1 Hz, 6H), 1.45 (s, 9H).19F NMR (CDCl₃, 376 MHz) 5 -71.1 (s, 3F).

[0681] Synthesis of A20

[0682]

[0683] To (27?,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-carboxylic acid (A19, 1 eq, 5 g, 16.0 mmol) was added anhydrous DCM (63.8 mL). The flask was sealed and stirred at r.t. under Ar. N, N'-Carbonyldiimidazole (1.2 eq, 3.1 g, 19.1 mmol) was added batch -wise. The resulting mixture was stirred at r.t. for 1 h. A solution of N, (9-Dimethylhydroxylamine ( 1.4 eq, 2.18 g, 22.3 mmol) and N. N-diisopropylethylamine (3 eq, 8.3 mL, 47.9 mmol) in anhydrous DCM (31.9 mL) was added to the reaction mixture. After 3 h, the mixture was concentrated in vacuo, and re-dissolved in EtOAc (1 0 mL). The solution was washed with 0.5 M HC1 (aq), sat. NaHCOs (aq), and brine. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to yield (27.4. S')-2-(6-bcnzyloxy-3-pyridyl)-A'-methoxy-JV-methyl-tetraliydropyran-4-carboxamide (A20, 5.50 g, 15.4 mmol, 97% yield) as a syrup. ESIMS (m / z)+: 357.3. ’H NMR (CDCl₃, 400 MHz) 58.12 (d, J= 2.4 Hz. 1H), 7.65 (dd, J= 8.6, 2.5 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.40 - 7.34 (m, 2H), 7.33 - 7.28 (m, 1H), 6.80 (d, J= 8.5 Hz, 1H), 5.37 (s, 2H), 4.38 (dd, J= 8.2, 5.7 Hz, 1H), 4.21 (ddd, J= 11.6, 4.7, 1.6 Hz, 1H), 3.75 (d, J= 0.7 Hz, 3H), 3.68 (td, J =PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0684] 12.1, 2.2 Hz, 1H), 3.20 (s, 3H), 3.11 (d, J= 8.8 Hz, 1H), 1.96 (td, J= 12.8, 4.6 Hz, 1H), 1.91 - 1.83 (m.

[0685] 2H), 1.73 (dd, J= 12.6, 3.3 Hz, 1H).

[0686] Synthesis of A21

[0687] LiAlH4, THF, -45 °C, 1 h

[0688]

[0689] A20 A21

[0690] To THF (40 mL) was added lithium aluminum hydride (1.2 eq, 9.3 mL, 18.5 mmol) under Ar atmosphere. The flask was cooled to -45 °C and a solution of (2 / ?.4. S)-2-(6-bcnzy loxy-3 -pyridyl )- / V-methoxy -jV-methyl-tetrahydropyran-4-carboxamide (A20, 1 eq, 5.5 g, 15.4 mmol) dissolved in anhydrous THF (40 mL) was added dropwise to the mixture. After stirring for 1 h at - 45 °C, the solution was quenched with sat. Rochelles salt (aq). The reaction mixture was warmed to r.t., anhydrous Na2SC>4 was added, and the mixture was filtered over a pad of celite, washed with EtOAc and concentrated in vacuo to yield (27?,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-carbaldehyde (A21, 4.24 g, 14.3 mmol, 92% yield) as a solid. ESI-MS (m / z)+: 298.3. 'H NMR (CDCl₃, 400 MHz) 59.66 (d, J= 1.2 Hz, 1H), 8.13 (d, 7= 2.4 Hz, 1H), 7.62 (dd, J= 8.6, 2.5 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.41 - 7.34 (m, 2H). 7.34 - 7.28 (m. 1H), 6.81 (d, J= 8.5 Hz, 1H), 5.38 (s, 2H). 4.37 (dd, 7= 11.4, 2.3 Hz, 1H). 4.26 (ddd, 7= 11.6, 4.7, 1.6 Hz, 1H), 3.66 (td, 7= 12.0, 2.3 Hz, 1H), 2.75 - 2.65 (m, 1H), 2.13 - 2.05 (m, 1H), 1.93 (ddd,7= 13.4, 3.9, 1.9 Hz, 1H), 1.76 - 1.65 (m, 1H), 1.65 - 1.58 (m, 1H).

[0691] Synthesis of A22

[0692] s-BuLi, TMEDA THF, -78 °C, 1h

[0693]

[0694] To tert-butyl jV-methyl-jV-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]carbamate (A21, 1.5 eq, 1.34 g.

[0695] 5.0 mmol) was added anhydrous THF (30.3 mL) and N. N, N', N'- tetramethylethylenediamine (1.5 eq, 0.76 mL, 5.0 mmol). The flask was sealed, purged under Ar, and cooled to -75 °C with stirring, sec-Butyllithium (1.5 eq, 3.9 mL, 5.0 mmol) was added dropwise. After 15 min, the solution of (2 / ?.4. S)-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-carbaldehyde (A22, 1 eq, 1.0 g, 3.36 mmol) in THF (15.1 mL) was added to the mixture and the obtained solution was stirred for 1 h at - 78 °C. The reaction mixturePAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0696] was quenched with sat. NH4CI (aq) and gradually warmed to r.t., diluted with EtOAc and washed with sat. NH4C1 (aq) and brine. The organic phase was collected and dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (0-10% MeOH in DCM) to yield tert-butyl A'-|2-hydro\y-2-|(2 / ?.4. S')-2-(6-bcnzyloxy-3-pyridyl)tctrahydropyran-4-yl ]ethyl ]-A-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]carbamate (A22, 1,7 g. 3.02 mmol, 90 % yield) as a solid. ESI-MS (m / z)+: 563.4. ‘H NMR (CHC13400 MHz) 58.12-8.10 (m, 1H), 7.60 (dd. J= 8.7, 2.3 Hz, 1H), 7.44 (d, J= 7.1 Hz, 2H), 7.36 (t, J= 7.2 Hz, 2H), 7.29 (t, J = 7.2 Hz, 1H), 6.80-6.77 (m, 1H), 5.36 (s, 2H), 4.29 (d, J= 10.1 Hz, 1H), 4.22-4.15 (m, 1H), 3.65-3.52 (m, 2H), 3.40-3.32 (m, 1H), 3.20 (t, J= 13.3 Hz, 1H), 2.23 (t, J= 12.3 Hz, 6H), 1.76 (d, J= 12.1 Hz, 2H), 1.59-1.54 (m, 4H), 1.48 (d, J- 6.6 Hz. 9H). Synthesis of A23

[0697]

[0698] A solution of TFA (4.0 eq, 0.54 mL, 7.11 mmol) in DCM (2mL) was slowly added to tert-butyl A'-|2-hydroxy-2-ft2 / ?.4. S)-2-(6-bcnzyloxy-3-pyridyl)tctrahydropyran-4-yl|cthyl|-A-|3-(trifluoromcthyl)-l-bicyclofl. l.l]pentanyl]carbamate (A22, 1.0 eq, 1.0 g, 1.8 mmol) while stirring. After 16 h, the crude was concentrated in vacuo, and purified by reverse phase chromatography (10-65% ACN in water containing 0.1% fomric acid) to yield l-|(2 / .4. S)-2-(6-bcnzyloxy-3-pyridyl)tctrahydropyran-4-yl|-2-||3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]amino]ethanol (A23. 570 mg, 1.23 mmol, 69% yield) as an oil. ESI-MS(m / z+): 463. 'H NMR (CHCh-A 400 MHz) 58.17 - 8.00 (m, 1H). 7.61 (dd, 7= 8.6, 2.4 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.39 - 7.32 (m, 2H), 7.32 - 7.27 (m, 1H), 6.84 - 6.76 (m, 1H), 5.36 (s, 2H), 4.29 (dd, 7 = 11.3, 2.1 Hz, 1H), 4.24 - 4.11 (m, 1H), 3.59 (td, J= 11.8, 2.2 Hz, 1H), 3.38 (t, 7= 7.6 Hz, 1H), 2.94 (q, J= 7.2 Hz, 2H), 2.79 (td, 7= 12.2, 2.9 Hz, 1H), 2.50 (ddd, 7= 12.5, 9.5, 3.7 Hz, 2H), 2.00 - 1.97 (m, 4H), 1.80 (s, 2H), 1.58 - 1.39 (m, 2H), 1.33 (d,7= 7.3 Hz, 2H).19F-NMR (CHCh-7. 376 MHz) 8 -71.4 (s, 3F).

[0699] Synthesis of A24PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0700] XantPhos Pd G3, CS2CO3, Dioxane, 100 °C, 16h

[0701]

[0702] To l-[(27?,4 )-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-yl]-2-[[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]amino]ethanol (A23, 1.0 eq, 540 mg, 1.2 mmol) was added 2,3-dibromo-5,6-dimethyl-pyrazine (2.0 eq, 622 mg, 2.3 mmol), CS2CO3 (3.0 eq, 1.16 g, 3.6 mol), XantPhos Pd G3 (0.05 eq, 55 mg, 0.06 mmol), and 1,4-Dioxanc (5.4 mL) and the mixture was degassed and heated with stirring at 100 °C for 16 h. Water (20 mL) was added and the organic phase was extracted with EtOAc (30 mL), washed with brine (20 mL), dried over Na2SC>4 and concentrated in vacuo. The residue was purified by flash chromatography ( 10-60% EtOAc in Hexanes) to yield l-|(2 / ?,4. S)-2-(6-bcnzyloxy-3-pyridyl)tetrahydropyran-4-yl]-2-[(3-bromo-5,6-dimethyl-pyrazin-2-yl)-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]amino]ethanol (A24, 270 mg, 0.42 mmol, 36% yield) as a solid. ESI-MS (m / z)+: 649.3. ‘HNMRfCDCl₃, 400 MHz) 58.10 (s, 1H), 7.59 (d, J= 13.0 Hz, 1H), 7.43 (d, J= 5.3 Hz, 2H), 7.37-7.33 (m, 2H), 7.31-7.27 (m, 1H), 6.77 (dd, J= 8.6, 4.7 Hz, 1H), 5.35 (d, J= 3.4 Hz, 2H). 5.18-5.12 (m, 1H).4.31 (d, J = 11.2 Hz, 1H), 4.17 (dd, J= 11.4. 4.1 Hz. 1H), 3.65-3.58 (m, 1H), 2.90-2.88 (m, 2H).

[0703] 2.41 (t, J= 4.0 Hz, 3H), 2.38-2.36 (m, 3H), 2.32-2.24 (m, 1H), 2.16 (s, 3H), 1.97 (s, 6H), 1.77-1.65 (m, 3H).19F-NMR (CDCl₃, 376 MHz) 5 -71.4 (s, 3F).

[0704] XantPhos Pd G3, CS2CO3 Dioxane, 100 °C, 16h

[0705]

[0706] A25 To l-((2,45')-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-ylJ-2-[(3-bromo-5,6-dimethyl-pyrazin-2-yl)-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]amino]ethanol (A24, I eq, 270 mg, 0.42 mmol) was added CS2CO3 (3.5 eq, 415 mg, 1.3 mmol), XantPhos Pd G3 (0.05 eq, 20 mg, 0.021 mmol) and 1,4-Dioxane (3mL) and the mixture was degassed and heated with stirring at 100 °C for 16h. Water (20 mL) was added and the organic phase was extracted with EtOAc (30 mL), washed withPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0707] brine (20 mL), dried over Na2SC>4, and concentrated in vacuo. The residue was purified by flash chromatography (10-60% EtOAc in Hexanes) to yield 2-|(2 / ?.4, S')-2-(6-bcnzyloxy-3-pyridyl)tetrahydropyran-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.1.l]pentanyl]-2,3-dihydropyrazino[2,3-Z)][l,4]oxazine (A25, 230 mg, 0.41 mmol, 97% yield) as a solid ESI-MS (m / z)+: 567.5. 'H NMR (CDCl₃-d. 400 MHz) 88.11 (t, J= 2.1 Hz, 1H), 7.61 (td, J= 9.0, 2.4 Hz, 1H), 7.49 -7.41 (m. 2H), 7.36 (ddt, J= 7.1. 5.7. 1.2 Hz. 2H), 7.32 - 7.26 (m, 1H), 6.78 (t. J= 8.9 Hz. 1H), 5.36 (d, J = 1.4 Hz, 2H), 4.36 - 4.28 (m, 1H), 4.21 (dd, J= 11.1, 4.0 Hz, 1H), 4.10 - 4.02 (m, 1H), 3.68 - 3.56 (m, 1H), 3.34 (ddd, J= 14.1, 11.8, 2.5 Hz, 1H), 3.19 (ddd, J= 11.9, 8.4, 6.7 Hz, 1H), 2.39 (d, J= 6.7 Hz, 6H), 2.34 - 2.27 (m, 6H), 2.15 - 1.98 (m, 2H), 1.83 - 1.66 (m, 1H), 1.65 - 1.59 (m, 1H), 1.53 - 1.45 (m, 1H).19F-NMR (CDCl₃, 376 MHz) 8 -71.1 (s, 3F).

[0708] Synthesis of A26

[0709]

[0710] 2-[(2A)-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3- / >][l,4]oxazine (A25, 1.0 eq, 75 mg, 0.13 mmol) was dissolved with MsOH (13 eq, 1.1 mL, 16.9 mmol) and the reaction mixture was stirred at r.t. for 2 h. Water (20 mL) was added and the organic phase w as extracted with EtOAc (30 mL), washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (0-20% MeOH in DCM) to yield 5-((27L45)-4-(6,7-dimethyl-4-(3-(trifluoromethyl)bicyclo[l.1.1 Ipcntan- 1 -yl)-3.4-dihydro-27 / -pyrazino|2.3- / i || 1.4|oxazin-2-yl)tctrahydro-277-pyran-2-yl)pyridin-2(177)-one (A26, 42 mg, 0.09 mmol, 67% yield) as a solid. ESI-MS (m / z)+: 477.4. 'H NMR (CDCl₃-d 400 MHz) 87.55 (d, J= 5.5 Hz, 1H), 7.40 (s, 1H), 6.61 (t, J= 4.3 Hz, 1H), 4.17 (d, J= 10.7 Hz, 2H), 4.08-4.02 (m, 1H), 3.73 (t, J= 6.5 Hz, 2H), 3.61-3.53 (m, 1H), 3.36-3.30 (m, 1H). 3.18 (t, J= 11.3 Hz, 1H). 2.40 (s. 6H), 2.31 (t, J= 1A Hz, 6H). 2.11-1.97 (m, 2H), 1.88-1.75 (m. 3H). 1.59 (d, J= 9.1 Hz. 1H), 1.41 (s, 3H).19F-NMR (CDCl₃. 376 MHz) 8 -71.1 (s. 3F).

[0711] Synthesis of Compound 177PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0712] CU(OAC)2, Na2CO3, 2,2'-bipyridine DCE, -78 °C, 30 min, O2

[0713]

[0714] To a solution of 5-[(2 / ?,4lS)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-Z)][l,4]oxazin-2-yl]tetrahydropyran-2-yl]-177-pyridin-2-one (A26, 1 eq, 120 mg, 0.25 mmol) in DCE (6.3 mL) were added Na₂CO₃ (3 eq, 80 mg, 0.76 mmol), Cu(OAc)2 (1.5 eq, 69 mg, 0.38 mmol), cyclopropylboronic acid (2 eq, 43 mg, 0.5 mmol), and 2,2’ -bipyridine (1 eq, 39 mg, 0.25 mmol). The mixture was stirred at 70°C for 30 min under O2 (15 psi). Hie reaction mixture was filtered through the celite, washed with EtOAc, and concentrated in vacuo. The obtained solid was purified by flash chromatography (50-100% EtOAc in Hexanes followed by 0-10% MeOH in DCM). The obtained product was further purified by reverse phase chromatography (using 30-70% ACN in water (0.1%FA) over 12CV) and lyophilized to yield racemic mixture l-cyclopropyl-5-|(2 / ?.4. S)-4-|6.7-dimethyl-4-|3-(trifluoromethyl)- 1 -b i cy cl 011.1.1 ]pentanyl] -2,3 -dihydropyrazino [2,3 -Z>] [ 1,4] oxazin-2 -yl]tetrahy dropyran-2-yl]pyridin-2-one (Compound 177, 80 mg, 0.15 mmol, 61% yield) as a solid. ESI-MS (m / z)+: 517.3. 'H NMR (CHCh-t / , 400 MHz) 57.31-7.27 (m, 2H), 6.54-6.51 (m, 1H), 4.20-4.16 (m, 1H). 4.10-4.01 (m. 2H), 3.61-3.52 (m, 1H), 3.37-3.26 (m, 2H), 3.18 (dd, J= 11.8, 8.6 Hz, 1H), 2.39 (d, J= 3.0 Hz, 6H), 2.31 (s, 3H), 2.29 (d, J= 3.0 Hz, 3H), 2.09-1.75 (m, 2H), 1.57 (s, 3H), 1.14-1.09 (m, 2H), 0.87-0.85 (m, 2H).

[0715] 19F-NMR (CDCl₃, 376 MHz) 5 -71.1 (s, 3F).

[0716] An analogous method was followed to obtain the following compounds.

[0717] Compound Starting Materials Characterization

[0718] 5-[(2R,4S)-4-[6,7- l-cyclopropyl-5-[(2R,4S)-4-[(2S)- dimethyl-4-[3- 6, 7 -dimethyl -4 - [ 3 - (trifluoromethyl) - 1 - (trifluoromethyl)- 1- bicyclo [1.1. l]pcntanyl]- bicyclo[l.1. l]pcntanyl]-2,3- 2,3- dihydropyrazino[2,3- dihydropyrazino[2,3 - b] [1,4] oxazin -2- 6][l,4]oxazin-2- yl]tctrahydropyran-2-yl]pyridin-2- yl]tetrahydropyran-2- one (Compound 178). ESI-MS Compound 178 yl]-l / / -pyridin-2-one; (m / z)+: 517.4. 'H NMR (DMSO- cyclopropylboronic d6, 400 MHz). 57.38-7.35 (m, acid. Obtained by SFC 2H), 6.31 (d, J= 9.1 Hz, 1H), 4.1O separation of (d, J= 10.5 Hz. 1H), 4.03-3.98 (m, Compound 177 using 2H), 3.47-3.38 (m, 2H), 3.27-3.18

[0719]

[0720] Cellulose-3 (4.6x250 (m, 2H), 2.37 (t, J= 9.7 Hz, 6H),PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0721] mm column) and 2.21 (s, 3H), 2.14 (s, 3H), 1.98- gradient of 10-50% 1.89 (m, 2H), 1.56 (d. J = 12.1 Hz, MeOH (0.1%NH3) in 1H), 1.44 (td, J = 12.4, 4.3 Hz, CO2. 1H), 1.34 (q, 7 = 12.1 Hz, 1H),

[0722] 0.96-0.91 (m. 2H), 0.79-0.75 (m, 2H).19F-NMR (DMSO-dd, 376 MHz) 5F -69.5 (s, 3F).

[0723] CF35-[(2R,4S)-4-[6,7- l-cyclopropyl-5-[(2A,45)-4-[(2 / ?)- dimethyl-4-[3- 6, 7 -dimethyl -4 - [ 3 - Y 4 (tri fluoromethyl)- 1 - (tri fluoromethyl)- 1 - °<x / Nx ZN'X / N\,Zbicyclo [1.1. l]pentanyl]- bicyclo[ 1.1. l]pentanyl]-2,3- 11 u 1 1 2,3- dihydropyrazino[2,3- dihydropyrazino[2,3- Z>][l,4]oxazin-2- / >][1.4]oxazin-2- yl]tetrahydropyran-2-yl]pyridin-2- yl]tetrahydropyran-2- one (Compound 179). ESI-MS Compound 179 yl]-17 / -pyridin-2-one; (m / z)+: 517.4. 'H NMR (DMSO- cyclopropylboronic d6, 400 MHz) 87.40-7.36 (m, 2H), acid. Obtained by SFC 6.32 (d, J= 9.1 Hz, 1H), 4.11 (d, J separation of = 10.5 Hz, 1H), 4.00 (d, J= 7.1 Compound 177 using Hz, 2H), 3.43 (t, J = 11.0 Hz, 2H), Cellulose-3 (4.6x250 3.27-3.22 (m, 1H), 3.17 (dd, J = mm column) and 12.2, 8.3 Hz, 1H), 2.36 (t J= 9.8 gradient of 10-50% Hz, 6H), 2.22 (s, 3H). 2.15 (s, 3H), MeOH (0.1%NH3) in 1.99-1.91 (m, 1H), 1.79 (d, J= CO2. 12.8 Hz, 1H), 1.71 (d, J= 12.6 Hz,

[0724] 1H), 1.45-1.32 (m, 2H), 0.97-0.92 (m, 2H), 0.81-0.74 (m, 2H).19F- NMR (DMSO-< 376 MHz) 8 -

[0725]

[0726] 69.5 (s, 3F).

[0727] Example 7: Synthesis of Compound 180

[0728] Mel, Cs2CO3, THF, 50 °C

[0729]

[0730] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0731] To a solution of 5-|(2 / ?.4. S)-4-|6.7-dimcthyl-4-|3-(trifluoromcthyl)-l-bicyclo| 1.1.1 |pcntanyl|-2.3-dihydropyrazino|2.3- )|| l.4|oxazin-2-yl|tctrahydropyran-2-yl|-IH-pyridin-2-one (A27, 1 eq, 75 mg, 0.16 mmol) in THF (1.5 mb) was added Cs2CO3(3 eq, 154 mg, 0.47 mmol) and Mel (3.4 eq, 33 pL, 0.54 mmol) in one portion, then the mixture was stirred at 50°C for 1 h. Tire reaction mixture was filtered, washed with EtOAc, concentrated in vacuo, and purified by flash chromatography (30-70% 3:1 EtOAc / EtOH in Hexanes) to yield l-mcthyl-5-|(2 / .4. S)-4-|6,7-dimcthyl-4-|3-(trifluoromcthyl)-l-bicyclo| 1.1.1 |pcntanyl|-2.3-dihydropyrazino|2.3-5|| 1.4|oxazin-2-yl|tctrahydropyran-2-yl|pyridin-2-onc (Compound 180, 40 mg, 0.081 mmol, 52% yield) as a solid. ESI-MS (m / z)+: 491.4. 'H NMR (CHCE-r / , 400 MHz) 57.34-7.29 (m, 2H), 6.55 (dd, J= 9.7, 5.6 Hz, 1H), 4.20-4.02 (m, 3H), 3.61-3.56 (m, 1H), 3.53 (s, 3H), 3.37-3.30 (m, 1H), 3.18 (dd, J= 11.7, 8.0 Hz, 1H), 2.40 (d, J= 3.0 Hz, 6H), 2.30 (d, J= 7.8 Hz, 6H). 2.13-1.77 (m, 2H), 1.57 (s, 3H).19F-NMR (CHCl₃, 376 MHz) δ -71.1 (s, 3F). An analogous method was followed to obtain the following compounds.

[0732] Compound Starting Materials Characterization

[0733] < CF35-[(2A.45)-4-[6,7- l-methyl-5-[(2R,45)-4-[(25)-6,7- dimethyl-4-[3- dimethyl-4-[3-(trifluoromethyl)- 1 - (trifluoromethyl)- 1 - bicyclo[l.1. l]pentanyl]-2,3- bicyclo [1.1.1] pentanyl] - dihydropyrazino [2,3- I l n i l 2,3- &][l,4]oxazin-2- dihydropyrazino [2,3- yl]tetrahydropyran-2-yl]pyridin-2- 6][l,4]oxazin-2- one (Compound 181). ESI-MS yl]tetrahydropyran-2 - (m / z)+: 591.3. 'H NMR (CHCh-A Compound 181

[0734] yl]-l / 7-pyridin-2-one; 400 MHz) 57.33 (dd, J= 9.1, 2.5 Methyl iodide. Hz, 1H), 7.30 (d, J= 2.3 Hz, 1H). Obtained by SFC 6.55 (d, J = 9.1 Hz, lH), 4.19 (d, J separation of = 14.2 Hz, 1H), 4.12 (d, J= 9.8 Compound 180 using Hz, 1H), 4.05 (t, J = 7.9 Hz. 1H), Ccllulosc-3 (4.6x250 3.62-3.56 (m, 1H), 3.53 (s, 3H), mm column) with a 3.37 (dd, J = 11.9, 2.5 Hz, 1H), gradient of 10-50% 3.19 (dd, J= 11.8, 8.3 Hz, 1H), MeOH ( 0.1%NH3) in 2.41 (s, 6H), 2.32 (s, 3H), 2.30 (s, CO23H), 2.10-2.00 (m, 1H), 1.62 (s,

[0735] 3H), 1.43 (dd. J = 24.7, 11.7 Hz, 1H).19F-NMR (CHCl3-<7, 376

[0736]

[0737] MHz) 5 -71.1 (s, 3F).PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0738] ^CF35-[(27?,45)-4-[6,7- l-methyl-5-[(2R,4S)-4-[(27?)-6,7- dimethyl-4-[3- dimethyl-4-[3-(trifhioromethyl)- 1 - (trifluoromethyl)- 1 - bicyclo [1.1.1 ]pentanyl] -2,3 - bicyclo[l.1. l]pentanyl]- dihydropyrazino [2,3- ZN\ / N'v / 2,3- 6][l,4]oxazin-2- l n i l dihy dropy razino [2, 3 - yl]tetrahydropyran-2-yl]pyridin-2- 6][l,4]oxazin-2- one (Compound 182). ESI-MS °\I

[0739] yl]tetrahydropyran-2- (m / z)+: 591.3. ’H NMR (CDCl₃, Compound 182 y 1] - 1 H-py ri di n -2 -one; 400 MHz) 87.31 (t, J = 4.9 Hz, Methyl iodide. 2H), 6.57 (t, J= 5.0 Hz, 1H), 4.21- Obtained by SFC 4.08 (m, 3H), 3.60-3.54 (m, 4H), separation of 3.32 (d, J = 11.7 Hz, 1H), 3.22- Compound 180 using 3.17 (m, 1H), 2.40 (s, 6H), 2.31 (d, Cellulose-3 (4.6x250 J= 7.5 Hz, 6H). 2.18-2.05 (m, mm column) with a 1H), 1.88 (dd, J= 70.1, 13.8 Hz, gradient of 10-50% 1H), 1.59 (s, 3H).19F-NMR MeOH ( 0.1%NH3) in (CHCls-t / . 376 MHz) 8 -71.1 (s, CO23F).

[0740] 5-[(2R,4S)-4-[4-(l- 5-[(2R,4S)-4-[4-(l- bicyclo [1.1.1] pentanyl) - bicyclo[l.1. l]pentanyl)-6.7- 6, 7-dimethyl -2, 3 - dimethyl -2, 3 -dihydropyrazino [2,3 - dihydropyrazino [2,3- b][l,4]oxazin-2- I X X I b][l,4]oxazin-2- yl]tetrahydropyran-2-yl] - 1 -methyl- °\I yl]tetrahydropyran-2- pyridin-2-one (Compound 183).

[0741] yl] - lH-pyridin-2-one; ESI-MS (m / z)+: 423.4. 'H NMR Compound 183 Methyl iodide. (400 MHz, CHCF-J) 87.38 - 7.29

[0742] (m, 2H), 6.57 (dd, J= 6.5, 9.7 Hz, 1H), 4.23 - 4.09 (m, 2H), 4.09 - 3.99 (m, 1H), 3.65 - 3.56 (m, 1H), 3.55 (d, J = 2.4 Hz, 3H), 3.39 (ddd, J = 2.0, 12.1, 16.5 Hz, 1H), 3.19 (dd,.7= 8.4, 12.0 Hz, 1H), 2.52 (d, J= 2.2 Hz, 1H), 2.32 (s, 3H), 2.29 (d, J = 2.1 Hz, 3H), 2.20 (d, J = 2.9 Hz, 6H), 2.14 - 2.04 (m, 1H), 2.03 - 1.95 (m, 1H), 1.88 -

[0743]

[0744] 1.75 (m, 1H), 1.56 - 1.39 (m, 2H).PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0745] ^3 5-[(2R,4S)-4-[6- l-methyl-5-[(2R,4S)-4-[6-methyl- methyl-7- 7-(trifluoromethyl)-4-[3- (trifluoromethyl)-4-[3- (trifluoromethyl) - 1 - (trifluoromethyl)- 1 - bicyclo [ 1.1. l]pentanyl]-2,3- CN, N.

[0746] XX jX I bicyclo [1.1.1] pentanyl] - dihydropyrazino [2,3- 2,3- b][l,4]oxazin-2- dihydropyrazino[2,3- yl]tetrahydropyran-2-yl]pyridin-2- b][l,4]oxazin-2- one (Compound 184). ESI-MS Compound 184 yl]tetrahydropyran-2- (m / z)+: 545.2. 'H NMR (400 yl] - lH-pyridin-2-one; MHz, DMSO-J6) 57.69 - 7.61 (m, Methyl iodide. 1H), 7.47 - 7.39 (m. 1H), 6.40 - 6.33 (m, 1H), 4.25 - 4.11 (m, 2H), 4.10 - 4.01 (m, 1H), 3.66 - 3.56 (m, 1H), 3.56 - 3.43 (m. 2H), 3.42 - 3.40 (m, 3H), 2.48 - 2.31 (m, 9H), 2.12 - 1.96 (m, 2H), 1.89 - 1.76 (m, 1H), 1.51 - 1.35 (m, 2H).

[0747] 5-[(2R,4«S)-4-[6,7- 5-[(2R,4S)-4-[(2S)-6,7-dimethyl- dimethyl-4-[3- 4-[3-(trifluoromethyl)- 1 - (trifluoromethyl)- 1 - bicyclo [1.1. l]pentanyl]-2.3- bicyclo [ 1.1. l]pentanyl]- dihydropyrazino [2,3 - 2,3- b][l,4]oxazin-2- CK X / N\zNv /

[0748] 11H1 I I dihy dropy razino [2, 3 - yl]tetrahydropyran-2-yl] - 1 -methyl- W pnA- 6][l,4]oxazin-2- pyridin-2-one (Compound 185).

[0749] yl]tetrahydropyran-2- ESI-MS (m / z)+: 491.3. 'H NMR yl] - 1 W-py ridin-2-one; (400 MHz, CHCE-tO 57.38 - 7.27 Compound 185 Methyl iodide. (m, 2H), 6.55 (d, J= 92 Hz, 1H),

[0750] Obtained by SFC 4.24 - 4.15 (m, 1H), 4.12 (br d, J= separation of 10.4 Hz, 1H), 4.05 (dt, J= 2.4, 8.0 Compound 180 using Hz, 1H), 3.64 - 3.55 (m, 1H), 3.53 DAICEL CHIRALPAK (s, 3H), 3.36 (s, 1H), 3.24 - 3.14 AS (250mm*30mm, (m, 1H), 2.41 (s, 6H), 2.31 (d. J = lOurn); mobile phase: 10.4 Hz, 7H), 2.10 - 2.01 (m, 1H), [A: CO2; B: EtOH 1.61 (brd, J= 32 Hz, 2H), 1.43 (0.1%NH3H2O)]; B%: (q, J= 12.0 Hz, 1H).

[0751] 25.00%-25.00%,

[0752] 4.40min; flow rate:

[0753]

[0754] 150.00 mL / minPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0755] 5-[(27?,45)-4-[6,7- 5-[(2R,4S)-4-[(2R)-6,7-dimethyl- dimethyl-4-[3- 4-[3-(trifluoromethyl)- 1 - (trifluoromethyl)- 1 - bicyclo [1.1.1 ]pentanyl] -2,3 - bicyclo[l.1. l]pentanyl]- dihydropyrazino [2,3- 2,3- b][l,4]oxazin-2- dihy dropy razino [2, 3 - yl]tetrahydropyran-2-yl] - 1 -methyl - Z?][l,4]oxazin-2- pyridin-2-one (Compound 186). yl]tetrahydropyran-2- ESI-MS (m / z)+: 491.3. 'H NMR y 1] - 1 H-py ri di n -2 -one; (400 MHz, CHCT-J) 57.32 (dd, J Compound 186 Methyl iodide. = 2.4, 4.8 Hz, 2H), 6.57 (d, J = Obtained by SFC 10.0 Hz, 1H), 4.24 - 4.05 (m, 3H), separation of 3.62 - 3.55 (m, 1H), 3.54 (s, 3H), Compound 180 using 3.35 - 3.30 (m, 1H), 3.24 - 3.17 DAICEL CHIRALPAK (m, 1H), 2.41 (s, 6H), 2.31 (d. J = AS (250mm*30mm, 7.6 Hz, 6H), 2.10 (dt, J= 2.8, 6.4 lOum); mobile phase: Hz, 1H), 2.02 - 1.92 (m, 1H), 1.80 [A: CO2; B: EtOH (br d, J= 12.4 Hz, 1H), 1.68 - 1.59 (0.1%NH3H3O)]; B%: (m, 1H), 1.55 - 1.46 (m, 1H).

[0756] 25.00%-25.00%,

[0757] 4.40min; flow rate:

[0758]

[0759] 150.00 mL / min

[0760] Example 8: Synthesis of Compound 187

[0761] Synthesis of A29

[0762] HCI CDI, DIEA, DCM, 25°C, 12 h

[0763]

[0764] A29 /

[0765] To a solution of 3 -methoxycarbonylbicyclo [1.1.1 ]pentane-l -carboxylic acid (A28, 1 eq, 10 g, 58.8 mmol) in DCM (150 mL) was added CDI (1.3 eq, 12.38 g, 76.4 mmol) and the mixture was stirred at 25°C for 1 h. A solution ofN, O-dimethylhydroxylamine hydrochloride (1.5 eq, 8.60 g, 88.2 mmol) and DIEA (2 eq, 20 mL, 118 mmol) in DCM (100 mL) was added and the reaction mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was was diluted with EtOAc (200 mL) and washed with aq. HC1 (0.5 M, 100 mL x 2) and sat. NaHCOs (100 mL x 2). The organic layer was dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-70% 1:1 EtOAc / Petroleum ether) to give methyl 3-[methoxy(methyl)carbamoyl]bicyclo[l.l.l]pentane-l-carboxylate (A29. 11 g.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0766] 51.6 mmol, 88% yield) as a solid. ESI-MS (m / z)+: 214.1.XH-NMR (400 MHz, CHCL-c / ) 83.67 (d, 7=5.62 Hz, 6 H) 3.17 (s, 3 H) 2.36 (s, 6 H).

[0767] Synthesis of A30

[0768] MeMgBr, THF, -78°C, 2 h

[0769]

[0770] A29 / A30

[0771] To a solution of methyl 3-[methoxy(methyl)carbamoyl]bicyclo[l.1. l]pentane-l -carboxylate (A29, 1.0 eq, 8.00 g, 37.5 mmol) in THF (180 mL) was added MeMgBr (3 eq, 38 mL, 113 mmol) dropwise at -78°C under N2 and stirred for 2 h. The reaction mixture was quenched with sat. aq. NH4CI (200 mL) and then extracted with EtOAc (200 mL x 3). Hie combined organic layers were dried over Na2SC>4. filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-30% EtOAc / Petroleum ether) to give methyl 3-acetylbicyclo[l.l.l]pentane- 1 -carboxylate (A30, 5 g, 29.7 mmol, 79 % yield) as a solid. ‘H NMR (400 MHz, CDCl₃-d) δ 3.70 (s, 3 H) 2.29 (s, 6 H) 2.14 (s, 3 H).

[0772] Synthesis of A31

[0773] DAST, DCM, -78-25°C, 16 h

[0774]

[0775] A30 A31

[0776] To a solution of methyl 3-acetylbicyclo[l.l.l]pentane-l-carboxylate (A30, 1 eq, 5 g, 29.7 mmol) in DCM (100 mL) was added DAST (3 eq, 12 mL, 89.2 mmol) dropwise at -78°C. The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was quenched with slow addition of sat. NaHCO? (100 mL) upon stirring at 0°C and then extracted with EtOAc (150 mL x 3). The combined organic layers were dried over Na₂SO₄. filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-20% EtOAc / Petroleum ether) to give methyl 3-(l,l-difluoroethyl)bicyclo[l.l.l]pentane-l-carboxylate (A31, 4.5 g, 23.7 mmol, 80% yield) as a liquid. 'H NMR (400 MHz, CDCl₃-d) δ 3.70 (s, 3 H), 2.13 (s, 6 H), 1.47 - 1.60 (m, 3 H).

[0777] Synthesis of A32

[0778] LiOH, MeOH / H2O / THF, 2 h

[0779]

[0780] A31 A32

[0781] To a solution of methyl 3 -( 1, 1 -difluoroethyl)bicy clo[ 1.1.1] pentane -1 -carboxy late (A31. 1.0 eq, 2.5 g, 13.1 mmol) in MeOH (9 mL), water (9 mL), and THF (27 mL) was added LiOH (2 eq, 631 mg, 26.3 mmol). The mixture was stirred at 25°C for 2 h. The pH was adjusted to 2 with 1 M HC1 and diluted with water (100 mL) and extracted with EtOAc (70 mL x 3). The combined organic layers were driedPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0782] over Na2SC>4, filtered, and concentrated under reduced pressure to give 3-(l,l-difluoroethyl)bicyclo[LLl]pentane-l-carboxylic acid (A32) as a solid.

[0783] ’HNMR (400 MHz, CDCl₃-d) δ 2.16 (s, 6 H) 1.56 (t, 7=18.15 Hz, 3 H).

[0784] Synthesis of A33

[0785] Dry t-BuOH, Et3N, DPPA, 90°C, 12 h

[0786]

[0787] A32 A solution of 3-(l,l-difluoroethyl)bicyclo[l.l.l]pentane-l-carboxylic acid (A32, 1 eq, 3.5 g, 19.9 mmol) in tert-butanol (60 mL) was added DPPA (1.5 eq, 6.4 mL, 29.8 mmol) and EtgN (2 eq, 5.5 mL, 39.7 mmol) under N2. After stirring for 3 h at 25°C, the mixture was stirred for 12 h at 90°C. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-17% EtOAc / Petroleum ether) to give tert-butyl N-[3-(l,l-difluoroethyl)-l-bicyclo[l.l.l]pentanyl]carbamate (A33, 3.8 g, 15.4 mmol, 77% yield) as asolid. ‘H NMR (400 MHz, CDCl₃-d) δ 5.02 (br s. 1H), 2.08 (br s. 6H), 1.56 (dt, J= 1.8, 18.0 Hz. 3H), 1.45 (s, 9H). Synthesis of A34

[0788]

[0789] To a solution of tert-butyl N-[3-(l,l-difluoroethyl)-l-bicyclo[l.l.l]pentanyl]carbamate (A33. 1. eq, 1 g, 3.44 mmol) in DMF (10 mL) was added NaH (2 eq. 275 mg, 6.87 mmol) at 0°C under N2, and the mixture was stirred for 1 h at 25°C. Mel (2 eq, 0.43 mL, 6.87 mmol) was added and the mixture was stirred for 1 h at 25°C. The reaction mixture was poured slowly into sat. aq. NH4CI (10 mL) and then extracted with EtoAc (10 mL x 3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-12% 1:10 EtOAc / Petroleum ether) to give tert-butyl N-[3-(l,l-difluoroethyl)-l-bicyclo[l.l.l]pentanyl]-N-methyl-carbamate (A34, 800 mg. 3.06 mmol, 89% yield) as an oil. 'H NMR (400 MHz, CDCl₃-d) δ 2.81 (s, 3H), 2.11 (s, 6H), 1.58 (t, 7 = 18.0 Hz, 3H), 1.47 (s, 9H).

[0790] Synthesis of Compound 187PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0791] Example 6 Method

[0792]

[0793] Compound 187

[0794] Compound 187 was synthesized from A34 according to the procedure described in Example 6 (Compound 187, 8.4 mg, 0.0156 mmol, 12% yield in final step). ESI-MS (m / z)+: 487.3 ’H NMR (400 MHz, CHCl₃-d) δ 7.37 - 7.28 (m, 2H). 6.57 (dd, J= 5.7, 9.7 Hz. 1H), 4.24 - 4.01 (m, 3H), 3.65 - 3.50 (m, 4H). 3.37 (ddd, 7= 2.4, 12.0, 17.1 Hz. 1H), 3.20 (dd, J= 8.4, 11.9 Hz, 1H), 2.33 (s, 3H), 2.30 (d, 7= 2.2 Hz, 3H), 2.28 (d, 7= 3.1 Hz, 6H), 2.17 - 2.04 (m, 1H), 2.01 - 1.78 (m, 1H), 1.68 (d, 7= 2.8 Hz, 1H), 1.63 (d, 7= 2.8 Hz, 2H), 1.59 (br d, 7= 2.9 Hz, 1H), 1.53 (brd, 7= 12.2 Hz, 1H), 1.43 (br d,7= 12.7 Hz, 1H).

[0795]

[0796] To a solution of 5-[(2R)-4-[6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-b][l,4]oxazin-2-yl]tetrahydropyran-2-yl]-lH-pyridin-2-one (A27, 1.0 eq, 50 mg, 0.105 mmol) in DMF (1 mL) were added K2CO3 (2 eq, 29 mg, 0.210 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.5 eq. 34 mg, 0.157 mmol), then the mixture was stirred at 20°C for 2 h. Then to the mixture was added K2CO3 (2 eq, 29 mg, 0.210 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (1.5 eq, 34 mg, 0.157 mmol), and the mixture was stirred at 20°C for 2 h. The mixture was filtered and purified by prep-HPLC (Unisil 3-100 C18 Ultra 150*50mm*3 urn, water (2.25% fomiic acid)-ACN; B%: 60%-90%, gradient time: 15min, Detector, UV 220 nm) and lyophilized to give l-(2,2-difluoroethyl)-5-[(2R,4S)-4-[6,7-dimethyl-4-[3-(trifluoromediyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-b][1.4]oxazin-2-yl]tetrahydropyran-2-yl]pyridin-2-one (Compound 188, 7.3 mg. 0.0122 mmol, 12% yield) as a solid and 2-[(2R,4S)-2-[6-(2,2-difluoroethoxy)-3-pyridyl]tetrahydropyran-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-b][ 1,4] oxazine (Compound 189, 12 mg, 0.0208 mmol, 20% yield) as a solid. Data for Compound 188: ESI-MS (m / z)+: 541.3. 'H NMR (400 MHz, DMSO-d₆) δ 7.63 (dd, 7= 2.4, 7.6 Hz, 1H), 7.50 (td, 7 =PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0797] 3.2, 9.6 Hz, 1H), 6.48 - 6.14 (m, 2H), 4.37 (dt, J= 4.0, 14.8 Hz, 2H), 4.20 - 4.01 (m, 3H), 3.58 - 3.41 (m, 2H), 3.27 - 3.19 (m, 1H), 2.41 (s, 6H), 2.26 (s, 3H), 2.19 (d, J = 3.2 Hz, 3H), 2.10 - 1.91 (m, 2H), 1.87 -1.76 (m, 1H), 1.61 - 1.35 (m, 2H). Data for Compound 189: ESI-MS (m / z)+: 541.3. 'H NMR (400 MHz, DMSO-6) δ 8.15 (dd, J = 2.4, 7.2 Hz, 1H), 7.79 - 7.70 (m, 1H), 6.90 (dd, J= 5.4, 8.6 Hz, 1H), 6.55 -6.22 (m, 1H), 4.63 - 4.49 (m, 2H), 4.39 (br d, J = 10.8 Hz. 1H), 4.17 - 4.01 (m, 2H), 3.62 - 3.41 (m, 2H), 3.27 - 3.18 (m, 1H). 2.41 (d. J = 4.4 Hz. 6H), 2.26 (s, 3H), 2.19 (d, J= 6.0 Hz, 3H), 2.13 - 1.96 (m, 2H), 1.91 - 1.82 (m, 1H), 1.65 - 1.38 (m, 2H).

[0798] Example 10: Synthesis of Compound 190

[0799] Synthesis of A35

[0800] O o HATU, DIEA, DCM N

[0801] O I

[0802]

[0803] A10 A35

[0804] To a solution of (2 / ?.4. S')-2-( l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-carboxylic acid (A10, 1 eq, 6.2 g, 26.2 mmol) in DCM (93 mL) was added HATU (1.5 eq. 15 g, 39.4 mmol) under N2, and the mixture was stirred at 25°C for 1 h. A solution of N. O-dimethylhydroxylamine hydrochloride (1.2 eq. 3 g, 31.5 mmol) and DIEA (2 eq, 9.1 mL, 52.5 mmol) in DCM (62 mL) was added and the reaction mixture was stirred at 25°C for 12 h. The solution was extracted with EtOAc (150 mL x 3) and water (150 mL). The combined organic layers were dried over Na2SC>4, fdtered, and concentrated under reduced pressure to give a residue, which was purified by reversed-phase column chromatography (water (formic acid / H2O)-ACN; B%: 10-30%) to give (27?,4S)-2-(l-cyclopropylpyrazol-4-yl)-N-methoxy-N-methyl-tetrahydropyran-4-carboxamide (A35. 3.2 g, 11.5 mmol, 44% yield) as an oil. ESI-MS (m / z)+: 280.2.1H NMR (400 MHz, CHCh) 5 = 7.45 (s, 2H), 4.39 (dd, J= 3.0, 10.6 Hz, 1H), 4.15 - 4.10 (m, 1H), 3.73 (s, 3H), 3.64 (dt, J = 2.2, 12.1 Hz, 1H), 3.58 - 3.48 (m, 1H), 3.21 - 3.19 (m, 3H), 3.05 (brt, J= 11.9 Hz, 1H), 1.95 - 1.83 (m, 3H), 1.71 - 1.63 (m, 1H), 1.10 - 1.04 (m, 2H), 1.02 - 0.94 (m, 2H).

[0805] Synthesis of A36PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0806] LiAlH4, THF, -40°C

[0807]

[0808] A solution of LiAlH4(1.2 eq, 2.1 mL, 5.16 mmol) in the anhydrous THF (20 mL) was stirred at -40°C under N2. A solution of (2 / ?.4. S')-2-( l-cyclopropylpyrazol-4-yl)-N-methoxy-N-methyl-tetrahydropyran-4-carboxamide (A35, 1 eq, 1.2 g, 4.30 mmol) in anhydrous THF (20 mL) was added dropwise to the mixture at -40°C and the resulting mixture was stirred for 1 h at -40°C under N2. Na2SO4·10H2O (600 mg) was then added, and the solution was stirred for 0.5 h at 0°C and fdtered, then washed with EtOAc (30 mL). The filtrate was concentrated under vacuum to give a residue, which was purified by flash column (2:1 EtOAc / Petroleum ether) to give (2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-carbaldehyde (A36, 700 mg, 3.18 mmol, 74% yield) as an oil. ESI-MS (m / z)+: 221.2. 'H NMR (400 MHz, CHCh) δ 7.50 - 7.41 (m, 2H), 4.38 (dd, J = 2.0, 11.4 Hz, 1H), 4.27 - 4.09 (m, 1H), 3.70 - 3.47 (m, 2H), 2.71 - 2.55 (m, 1H), 2.21 - 1.82 (m, 2H), 1.79 - 1.45 (m, 2H), 1.14 - 0.92 (m,

[0809]

[0810] Synthesis ofA37

[0811] F3C

[0812] S-BuLi, TMEDA, THF, -70°C

[0813]

[0814] To a solution of tert-butyl N-methyl-N-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]carbamate (A36, 1.5 eq, 903 mg, 3.40 mmol), N, N, N', N'-tetramethylethylenediamine (1.5 eq, 0.51 mL, 3.40 mmol) in THF (8 mL) was added sec-butyllithium (1.5 eq, 2.6 mL, 3.40 mmol) dropwise at -78°C under N2. After 0.5 h, a solution of (27?,45)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-carbaldehyde (AX, 1 eq, 500 mg, 2.27 mmol) in THF (4 mL) was added at -78°C. The mixture was stirred at -78°C for 1 h under N2. The solution was extracted with EtOAc (30 mL x 3) and water (30 mL). The combined organic layers were washed with brine (90 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by reversed-phase column chromatography (water (formic acid, H2O)-MeCN; B%: 30-60%) and extracted with EtOAc (500 mL x 3). The combined organic layers were concentrated under reduced pressure to give crude tert-butyl N-[2-[(2R,4S)-2-(1-cyclopropylpyrazol-4-PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0815] yl)tetrahydropyran-4-yl]-2 -hydroxy -ethyl]-N-[3-(tri fluoromethyl)-! -bicyclo[Ll.l]pentanyl]carbamate (A37) as an oil. ESI-MS (m / z)+: 486.1. 'H NMR (400 MHz, CHCh) δ 7.47 - 7.40 (m, 2H), 4.32 (br d, J = 11.1 Hz, 1H), 3.83 - 3.15 (m, 5H), 2.35 - 2.15 (m, 9H), 1.91 - 1.66 (m, 3H), 1.49 (s, 9H), 1.15 - 0.94 (m, 4H).

[0816] Synthesis of A38

[0817] TFA / DCM=3 / 1, 25°C

[0818]

[0819] To a solution of tert-butyl N-[2-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-hydroxy-ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A37, 1.0 eq, 570 mg, 1.17 mmol) in DCM (15 mL) was added TFA (1 eq, 5.0 mL, 1.17 mmol) and then the mixture was stirred at 25°C for 1 h. The solution was added into water (15 mL) and adjusted to pH = 7 by aq. NaHCO3. The mixture was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SC>4. filtered and concentrated under reduced pressure to give a residue, which was purified by reversed-phase column chromatography (water (FA. H2O)-MeCN; B%: 30-60%) and adjusted to pH = 7 by aq. NaHCO3 (15 mL). The mixture was extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give 1-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]ethanol (A38. 350 mg, 0.908 mmol, 77% yield) as an oil. ESI-MS (m / z)+: 386.1. 'H NMR (400 MHz, CHCL) δ 7.46 - 7.40 (m, 2H), 4.36 - 4.26 (m, 1H), 4.18 - 4.03 (m, 1H), 3.72 -3.31 (m, 3H), 2.91 - 2.72 (m, 2H), 2.52 (dd, J= 10.1, 11.4 Hz, 1H), 2.14 - 1.78 (m, 10H), 1.54 - 1.37 (m, 2H), 1.14 - 0.89 (m, 4H).

[0820] Synthesis of Compound 190PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0821]

[0822] To a mixture of l-[(27?,45)-2-(l-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-[[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]amino]ethanol (A38, 1.0 eq, 50 mg, 0.130 mmol) and 2,3-dibromo-5,6-dimethyl -pyrazine (2 eq, 69 mg, 0.259 mmol) in 1,4-dioxane (5 mL) were added CS2CO3 (4 eq, 169 mg, 0.519 mmol) and XantPhos Pd G3 (0.2 eq, 25 mg, 0.0259 mmol). The reaction was degassed and purged with N2 and the mixture was stirred at 100°C for 12 h. Tire solution was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Phenomenex luna C18 150 *

[0823] 25mm * lOum, water (Formic acid)-ACN) and lyophilized to afford 2-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dihydropyrazino[2,3-b][1,4]oxazine (Compound 190, 2.4 mg, 0.00434 mmol, 3% yield) as a solid. ESIMS (m / z): 490.2. ’H NMR (400 MHz, CHC13) δ 7.49 - 7.43 (m, 2H), 4.96 - 4.84 (m, 1H), 4.35 (br d, J=

[0824] 11.9 Hz. 1H), 4.21 - 4.03 (m, 2H), 3.67 - 3.52 (m, 2H), 3.37 (ddd, J= 2.4, 8.7, 11.5 Hz, 1H), 3.21 (dd, J = 8.4, 11.7 Hz, 1H), 2.46 - 2.30 (m, 13H), 2.16 - 1.96 (m, 2H), 1.91 - 1.79 (m. 1H), 1.13 - 1.07 (m, 2H).

[0825] 1.01 (br d, J= 7.5 Hz. 2H).

[0826] Example 11: Synthesis of Compound 191

[0827] Synthesis of A40

[0828]

[0829] To a solution of 1-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)-2-nitroethan-1-one (A39. 1.0 eq, 600 mg. 1.68 mmol) in a mixture of MeOH (12 mL) and AcOH (6 mL) was added, at rt under argon, zinc powder (5.0 eq, 562 mg, 8.42 mmol) in portions. The reaction mixture was stirred for 45 minutes at rt and then filtered. The resulting filtrate was concentrated under reduced pressure to yield

[0830] 2-amino-1-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)ethan-1-one (A40, 800 mg,

[0831] 1.68 mmol, quant.) as a solid. The crude product was used directly for the next step without further purification. ESI-MS (m / z)+: 326.2; 327.2 (obs).PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0832] Synthesis of A41

[0833] NaBH4, DCM / MeOH (1 / 1) O’Cto rt, 1h

[0834]

[0835] To a solution of (S)-2-amino-1-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)ethan-1-ol (A40. 1.0 eq, 800 mg crude, 1.68 mmol) in a mixture of anhydrous DCM (8 mL) and MeOH (8mL) was added, at 0 °C under argon, NaBH4 (3.0 eq, 195 mg, 5.06 mmol) in portions. The reaction mixture was stirred at 0 °C for 10 min, then at rt for 1 h. Water (3 ml) was added to the reaction mixture at 0 °C and the mixture was then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0-40% MeOH (0.1% NH4OH) in DCM) to yield (S)-2-amino-1-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)ethan-1-ol (A41. 380 mg, 1.16 mmol, 69% yield) as a solid. ESI-MS (m / z)+: 328.2; 329.3 (obs).

[0836] Synthesis of A42

[0837] O

[0838] EDCI, HOAt, NMM

[0839]

[0840] DMF, rt, 45 min To a solution of (S)-2-amino-1-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)ethan-1-ol (A41, 1.0 eq, 100 mg, 0.305 mmol) and cyclopropanecarboxylic acid (1.2 eq, 31.5 mg, 0.365 mmol) in anhydrous DMF (2 mL) were added, at rt. l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq, 92 mg, 0.457 mmol), HOAt (1.5 eq, 457 μL, 0.457 mmol, IM in DMA), and 4-methylmorpholine (3.0 eq, 100 μL, 0.914 mmol). The reaction mixture was stirred at rt for 45 minutes. After completion, the reaction mixture was diluted with EtOAc (10 mL) and was then hydrolyzed by addition of water (10 mL). The mixture was extracted with EtOAc (3x10 mL). Tire combined organic layers were washed with brine (20 mL), dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (0-7% MeOH in DCM) to yield N-((S)-2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)-2-hydroxyethyl)cyclopropanecarboxamide (A42, 87 mg, 0.219 mmol, 72% yield) as a colorless oil. ESI-MS (m / z): 396.2; 397.3 (obs).

[0841] Synthesis of A43PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0842] XantPhos Pd G3, Cs2CO3Dioxane, 100°C, 16h

[0843]

[0844] To a solution of N-((S)-2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)-2-hydroxyethyl)cyclopropanecarboxamide (A42, 1.0 eq, 87 mg, 0.219 mmol) and 2,3-dibromo-5,6-dimethylpyrazine (2.0 eq, 117 mg, 0.439 mmol) in anhydrous 1,4-dioxane (2 mL) was added XantPhos Pd G3 (0.05 eq, 11 mg, 11.0 μmol) followed by the addition of CS2CO3 (3.0 eq, 214 mg, 0.658 mmol). The reaction mixture was sparged with argon then stirred at 100 °C for 16 h. The reaction mixture was cooled down and filtered through celite. rinsing with EtOAc. The resulting solution was concentrated under reduced pressure then purified by flash column chromatography ( 0-60% EtOAc in Hexanes) to yield N-((R)-2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)-2-hydroxyethyl)-N-(3-bromo-5,6-dimethylpyrazin-2-yl)cyclopropanecarboxamide (A43, 100 mg, 0.171 mmol, 78% yield) as a solid. ESI-MS (m / z)+: 580.2; 581.3 (obs).

[0845] XantPhos Pd G3, Cs2CO3Dioxane, 100°C, 10h

[0846]

[0847] To a solution of N-((R)-2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)-2-hydroxyethyl)-N-(3-bromo-5,6-dimethylpyrazin-2-yl)cyclopropanecarboxamide (A43, 1.0 eq, 100 mg, 0.172 mmol) in anhydrous 1,4-dioxane (1.6 mL) was added XantPhos Pd G3 (0.05 eq, 8.6 mg, 8.62 μmol) followed by the addition of CS2CO3 (3.0 eq, 168 mg, 0.516 mmol). The reaction mixture was sparged with argon then stirred at 100 °C for 10 h. The reaction mixture was cooled down and filtered through celite, rinsing with EtOAc. The resulting solution was concentrated under reduced pressure then purified by flash column chromatography (0-60% EtOAc in Hexanes) to yield (( / ^)-2-((2 / ,4, S’)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-277-pyran-4-yl)-6,7-dimethyl-2,3-dihydro-4H-pyrazino[2,3-b][l,4]oxazin-4-yl)(cyclopropyl) methanone (A44, 47 mg, 93.89 mmol, 55% yield) as an off white solid.

[0848] ESI-MS (m / z)+: 500.2; 501.4 (obs).

[0849] Synthesis of A45PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0850] MsOH, rt, 3h

[0851]

[0852] ((R)-2-((2R,4S)-2-(6-(benzyloxy)pyridin-3-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethyl-2,3-dihydro-4H-pyrazino[2,3-b][1,4]oxazin-4-yl)(cyclopropyl)methanone (A44, 1.0 eq, 47 mg, 93.89 mmol) was mixed with MsOH (55.0 eq, 338 μL, 5.16 mmol) at rt and the reaction mixture was stirred for 4 h. A cold, saturated aqueous solution of NaHCOs was added and the resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (10 mL), dried (MgSO4) and concentrated under reduced pressure to yield 5-((2R,4S)-4-((R)-4-(cyclopropanecarbonyl)-6,7-dimethyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-2-yl)tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one (A45, 40 mg, 93.9 mmol, quant.) as an oil. The crude product was used directly for the next step without further purification. ESI-MS (m / z)+: 410.2; 411.4 (obs).

[0853] Synthesis of Compound 191

[0854] Mel, CS2CO3 THF, 50 °C, 2h

[0855]

[0856] Compound 191 To a solution of 5-((2R,4S)-4-((R)-4-(cyclopropanecarbonyl)-6,7-dimethyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-2-yl)tetrahydro-2H-pyran-2-yl)pyridin-2(1H)-one (A45, 1.0 eq, 38 mg, 92.6 mmol) in anhydrous THF (2 mL) were added iodomethane (3.4 eq, 20 μL, 0.315 mmol) and CS2CO3 (3.0 eq, 92.3 mg, 0.278 mmol) at rt. Hie reaction mixture was heated at 50 °C and stirred for 2 h. The reaction mixture was cooled down and filtered through celite, rinsing with EtOAc. The resulting solution was concentrated under reduced pressure then purified by flash column chromatography (0-80% EtOAc in Hexanes) to yield 5-((2R,4S)-4-((R)-4-(cyclopropanecarbonyl)-6,7-dimethyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-2-yl)tetrahydro-2H-pyran-2-yl)-1-methylpyridin-2(1H)-one (Compound 191, 13 mg, 30.62 mmol, 33% yield) as a solid. ESI-MS (m / z)+: 424.2; 425.3 (obs). 1H NMR (DMSO-d6, 400 MHz) 57.65-7.60 (m, 1H), 7.43-7.37 (m, 1H), 6.39-6.33 (m, 1H), 4.40-4.28 (m, 1H), 4.21-4.02 (m, 3H), 3.58-3.39 (m, 5H), 3.33 (s, 2H), 2.97-2.89 (m, 1H), 2.39-2.33 (m, 6H), 2.04-1.99 (m, 1H), 1.85-1.72 (m, 1H). 1.58-1.32 (m, 2H), 0.97-0.80 (m, 3H).PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0857] Example 12: Synthesis of Compound 192

[0858] Synthesis of A47

[0859] CD3I, CS2CO3 THF, 50 °C, 20 min

[0860]

[0861] To a solution of tert-butyl N-[2-[(2R,4S)-2-(6-hydroxy-3-pyridyl)tetrahydropyran-4-yl]-2-oxo-ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A46, 1.0 eq, 800 mg, 1.70 mmol) in THF (11.3 mL) were added CS2CO3 (3.0 eq, 1.7 g, 5.10 mmol) and Iodomethane-d3 (3.4 eq, 0.36 mL, 5.78 mmol). The mixture was stirred at 50 °C for 20 min. The reaction mixture was filtered through Celite using EtOAc and concentrated in vacuo. The residue was purified by flash chromatography (0% - 20% MeOH in DCM) to yield tert-butyl N-[2-oxo-2-[(2R,4S)-2-[6-oxo-1-(trideuteriomethyl)-3-pyridyl]tetrahydropyran-4-yl]ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A47, 665 mg, 1.36 mmol, 80% yield) as a solid. ESI-MS (m / z)+: 488.3. 'H NMR (CDCl₃, 400 MHz) δ 7.30 - 7.26 (m, 2H), 6.63 - 6.49 (m, 1H). 4.30 - 3.92 (m.

[0862] 5H). 3.57 (td, J= 11.8, 2.5 Hz, 1H). 2.75 (td, J= 9.9, 5.5 Hz, 1H). 2.18 (d, J= 12.3 Hz. 7H), 1.94 (d, J = 13.6 Hz, 1H), 1.79 (s, 2H), 1.76 - 1.51 (m, 3H), 1.42 - 1.31 (m, 2H), 1.18 (d, J= 6.1 Hz, 4H).19F NMR (CDCl₃, 376 MHz) 5 -71.07 (s, 3F).

[0863] Synthesis of A48

[0864] NaBD4, MeOH, rt, 20 min

[0865]

[0866] NaBD4 (1.0 eq, 19 mg, 0.45 mmol) was slowly added to a stirred solution of tert-butyl N-[2-oxo-2-[(2R,4S)-2-[6-oxo-1-(trideuteriomethyl)-3-pyridyl]tetrahydropyran-4-yl]ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A47, 1.0 eq, 220 mg, 0.45 mmol) in MeOH (10 mL). The mixture was stirred for 20 min., then water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0867] to yield tert-butyl N-[2-deuterio-2-hydroxy-2-[(2R,4S)-2-[6-oxo-1-(trideuteriomethyl)-3-pyridyl]tetrahydropyran-4-yl]ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A48, 204 mg, 0.42 mmol, 92% yield) as an oil. ESI-MS (m / z)+: 491.5. 'H NMR (CDCl₃, 400 MHz) δ 7.36 - 7.30 (m, 1H), 7.29 (d, J= 15 Hz, 1H), 6.55 (d, J= 9.2 Hz, 1H), 4.12 (td, J= 12.5, 7.5 Hz, 3H), 3.60 -3.51 (m, 1H), 3.36 (d, J= 15.0 Hz, 1H), 3.24 - 3.15 (m, 1H), 2.25 (d, J= 4.3 Hz, 6H). 2.04 (s, 2H), 1.82 -1.68 (m. 2H), 1.62 (s, 7H), 1.58 - 1.52 (m, 1H), 1.36 (dd, J= 19.0, 12.2 Hz. 1H), 1.26 (t, J= 7.1 Hz, 1H).

[0868] 19F NMR (CHCk-, 376 MHz) 5 -71.08 (s, 3F).

[0869] Synthesis of A49

[0870] TFA / DCM (3 / 10), rt, 1h

[0871]

[0872] A solution of TFA (58.8 eq, 1.8 mL, 24.0 mmol) in DCM (7mL) was slowly added into tert-butyl N-[2-deuterio-2-hydroxy-2-[(2R,4S)-2-[6-oxo-1-(trideuteriomethyl)-3-pyridyl]tetrahydropyran-4-yl]ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A48, 1.0 eq, 200 mg, 0.41 mmol). The resulting mixture was stirred for 5 h. The solution was concentrated in vacuo, to yield 5-[(2R,4S)-4-[1-deuterio-1-hydroxy-2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]ethyl]tetrahydropyran-2-yl]-1-(trideuteriomethyl)pyridin-2-one (A49, 152 mg, 0.389 mmol, 95% yield) as an oil. ESI-MS (m / z)+: 391.3.

[0873] XantPhos Pd G3, Cs2CO3Dioxane, 100 °C, 16h

[0874]

[0875] To 5 -[(27?,45)-4-[ 1 -deuterio- 1 -hydroxy-2-[ [3 -(trifluoromethyl)- 1 -bicyclo[l.1. l]pentanyl]amino]ethyl]tetrahydropyran-2-yl]-l-(trideuteriomethyl)pyridin-2-one (A49, 1.0 eq, 153 mg, 0.39 mmol) was added 2,3-dibromo-5,6-dimethyl-pyrazine (2.0 eq, 208 mg, 0.78 mmol), CS2CO3 (3.0 eq, 389 mg, 1.19 mmol), XantPhos Pd G3 (0.12 eq, 46 mg, 0.047 mmol) and 1,4-PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0876] dioxane (3.3 mL). The mixture was degassed and heated with stirring at 100 °C for 16 h. Water and EtOAc were added to the reaction mixture and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo. The residue was purified by flash chromatography (10-60% EtOAc in Hexanes) to afford 5-[(2R,4S)-4-[2-deuterio-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-pyrazino[2,3-b][1,4]oxazin-2-yl]tetrahydropyran-2-yl]-1-(trideuteriomethyl)pyridin-2-one (A50, 25 mg, 0.043 mmol.

[0877] 11% yield) as a solid. ESI-MS (m / z)+: 577.1.

[0878] Synthesis of Compound 192

[0879] XantPhos Pd G3, Cs2CO3Dioxane, 100 °C, 1h

[0880]

[0881] To a mixture of 1-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2-((4-(trifluoromethyl)phenyl)amino)ethan-1-ol (A50, 25 mg, 0.043 mmol, 1 eq), were added CS2CO3 (3.0 eq, 389 mg, 1.19 mmol), XantPhos Pd G3 (0.12 eq, 46 mg, 0.047 mmol) and 1,4-dioxane (3.3 mL). The solution obtained was degassed and heated with stirring at 100 °C for 2 h. Water was added, and the organic phase was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (10-60% EtOAc in hexanes) and lyophilized to yield 5-[(2R,4S)-4-[2-deuterio-6,7-dimethyl-4-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-pyrazino[2,3-b][1,4]oxazin-2-yl]tetrahydropyran-2-yl]-1-(trideuteriomethyl)pyridin-2-one (Compound 192, 3.0 mg. 6.1 pmol, 14% yield) as a solid. ESI-MS (m / z)+: 595.3. 'H NMR (CDCl₃, 400 MHz) δ 7.30 (q, J = 4.6 Hz, 2H), 6.55 (dd, J= 9.6, 5.6 Hz, 1H), 4.18 (d, J= 11.4 Hz, 1H), 4.11 (d,.7= 11.0 Hz, 1H), 3.56 (t,.7= 11.8 Hz, 1H), 3.33 (dd, J= 17.7, 11.8 Hz, 1H), 3.18 (d, J= 11.8 Hz, 1H), 2.60 (s, 1H), 2.40 (d, J= 3.0 Hz, 6H), 2.35 -2.28 (m, 6H), 2.07 (d, J= 11.9 Hz, 1H), 1.95 (d, J= 13.6 Hz, 1H), 1.78 (d, J= 12.9 Hz, 1H), 1.51 - 1.35 (m, 2H).19F NMR (CDCl₃, 376 MHz) 8 -71.14 (s, 3F).

[0882] An analogous method was followed to obtain the following compounds.

[0883] Compound

[0884]

[0885] Starting Materials Characterization

[0886]

[0887]

[0888] PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0889] 5-[(27?,45)-4-[l-deuterio-l-hydroxy-2- 5-[(27?,4S)-4-[2- [[3 -(trifluoromethyl) - 1 - deuterio-6.7 -dimethyl - bicyclofl.1. l]pentanyl]amino]ethyl]tetra 4- [3 -(trifluoromethyl) - hydropyran-2-yl] - 1 -methyl -pyridin-2- 1- one; 2,3-dibromo-5,6-dimethyl-pyrazine bicyclof 1.1. l]pentanyl]

[0890] -377-pyrazino[2,3- / >][!, 4]oxazin-2- yl]tetrahydropyran-2- yl] - 1 -methyl-pyridin-2- one (Compound 199). ESI-MS (m / z)+: 592.5.

[0891] ¹H NMR (CHCl₃-d, 400 MHz) 57.31 (ddt, J= 8.0, 5.5, 2.6 Hz, 2H), 6.55 (dd, 7 = 9.8, 5.4 Hz, 1H), 4.21 - 4.07 (m, 2H), 3.61 - 3.54 (m, 1H), 3.52 (d, J = 2.3 Hz, 3H), 3.33 (dd, J= 17.7, 11.8 Hz, 1H), 3.18 (d, J= 11.8 Hz, 1H), 2.40 (d, 7= 3.0 Hz, 6H), 2.33 - 2.25 (m, 7H), 2.05 (s, 1H), 1.87 (dd, 7= 67.2, 13.2 Hz, 1H), 1.61 (s, 1H), 1.53 - 1.36 (m, 1H).19F NMR (CDCl₃, 376

[0892]

[0893] MHz) 5 -71.14 (s, 3F).

[0894] Example 13: Synthesis of Compound 193

[0895] Mel, K2CO3, DMF, 50 °C, 3 h

[0896]

[0897] Intermediate A51 was synthesized via the method in Example 6. To a solution of 5-[(2R,4S)-4-[4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2,3-dihydropyrazino[2,3-b][l,4]oxazin-2-yl]tetrahydropyran-2-yl]-PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0898] 1H-pyridin-2-one (A51, 1.0 eq, 100 mg, 0.217 mmol) and K2CO3 (2.0 eq, 141 mg, 0.434 mmol) in DMF (2 mL) was added Mel (2.0 eq, 62 mg, 0.434 mmol). The mixture was stirred at 50°C for 2 h. The reaction mixture was purified by prep-HPLC (Phenomenex Luna C18 150*25mm* lOurn; H₂O (0.225% FA)-ACN; B%: 35%-65%, lOmin) and lyophilized to give 5-[(2R,4S)-4-[4-(4,4-difluorocyclohexyl)-6,7-dimethyl-2,3-dihydropyrazino[2,3-b][l,4]oxazin-2-yl]tetrahydropyran-2-yl]-l-methyl-pyridin-2-one (Compound 193, 11.5 mg. 0.0221 mmol, 10% yield) as a solid. ESI-MS (m / z)+: 475.3. ¹H NMR (DMSO-d6, 400 MHz) 57.64 (dd, 1H, 7=2.4, 8.0 Hz), 7.42 (td, 1H, 7=3.2, 9.2 Hz), 6.36 (dd, 1H, 7=4.8, 9.6 Hz), 4.5-4.6 (m, 1H), 4.11 (br d, 1H, 7=12.0 Hz), 3.9-4.1 (m, 2H), 3.4-3.5 (m, 2H), 3.41 (d, 3H, 7=2.0 Hz), 3.1-3.2 (m, 1H), 2.24 (s, 3H), 2.17 (d, 3H, 7=4.0 Hz), 1.9-2.1 (m, 5H), 1.6-1.9 (m, 6H), 1.3-1.5 (m, 2H).

[0899] Example 14: Synthesis of Compound 194

[0900] Synthesis ofA53

[0901] NBS, DCM, 0 to 30°C

[0902]

[0903] A52 A53

[0904] To a solution of 5-methylpyrazin-2-amine (A52, 1.0 eq, 1000 mg, 9.16 mmol) in DCM (15 mL) was added NBS (1.0 eq, 1631 mg, 9.16 mmol), and the mixture was stirred at 20°C for 2 h. Tire reaction mixture was diluted with sat. Na2SOs (30 mL) and extracted with DCM (20 mL x 2). The combined organic layers were washed with brine (20 mL x 2). dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (20-40% 1:3 EtOAc / Petroleum ether) to give 3-bromo-5-methyl-pyrazin-2 -amine (A53, 1400 mg, 7.22 mmol, 79% yield) as an oil. ESI-MS (m / z)+: 188.0. ¹H NMR (400 MHz, CHCl₃-d) 57.81 (s, 1H), 4.87 (br s, 2H), 2.39 (s, 3H).

[0905] Synthesis of A54

[0906] 3-Methylbutyl nitrite, CuI, I2,

[0907] ]| 2 MeCN, 70°C, 2 h BC 'N^^ " Br

[0908]

[0909] A53

[0910]

[0911] A54

[0912] To a mixture of 3-bromo-5-methyl-pyrazin-2-amine (A53, 1.0 eq, 1.30 g, 6.91 mmol) in MeCN (13 mL) were added Cui (1.5 eq, 1.97 g, 10.4 mmol), I₂ (2.0 eq, 3.51 g, 13.8 mmol) and 3-methylbutyl nitrite (1.5 eq, 1.4 mL, 10.4 mmol) at 0°C. Then the mixture was stirred at 70°C for 2 h. The mixture was queched by sat. Na₂SO₃ (50 mL), and then extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-30% 1:3PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0913] EtOAc / Petroleum ether) to give 3 -bromo-2-iodo-5 -methyl -pyrazine (A54, 1.20 g, 3.89 mmol, 56% yield) as a solid. ESI-MS (m / z)+: 298.9. ¹H NMR (400 MHz, CHCl₃-d) 58.17 (s, 1H), 2.49 (s, 3H).

[0914] Synthesis of A55

[0915]

[0916] To a solution of 1-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-yl]-2-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]amino]ethanol (A49, 1.0 eq, 300 mg, 0.649 mmol) in 1,4-Dioxane (9 mL) were added 3-bromo-2-iodo-5-methyl-pyrazine (2.0 eq, 388 mg, 1.30 mmol), XantPhos Pd Gs (0.05 eq, 31 mg, 0.0324 mmol) and CS2CO3 (3.0 eq, 632 mg, 1.95 mmol). The mixture was stirred at 100°C for 12 h under N2. Tire reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Phenomenex luna Cl 8 150*25mm* lOum, water(2.25% formic acid)-ACN; B%: 0%-79%, gradient time: lOmin. Detector. UV 220 nm) and lyophilized to give 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-yl]-7-methyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-b][l,4]oxazine (A55, 20 mg, 0.0300 mmol, 5% yield) as a solid. ESI-MS (m / z)+: 553.3.

[0917] Synthesis of A56

[0918] MsOH / HFIP, 25°C, 12 h

[0919]

[0920] To a solution of 2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-yl]-7-methyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-b][l,4]oxazine (A55, 1.0 eq, 20 mg, 0.0362 mmol) in HFIP (1.0 eq, 0.40 mL, 0.0362 mmol) was added MsOH (22.7 eq, 0.053 mL, 0.821 mmol), and the mixture was stirred at 25°C for 12 h. The reaction mixture was adjusted to pH 7 with sat.PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0921] NaHCOs. Then the mixture was extracted with DCM (3 mL x 2). The combined organic layers were washed with brine (1 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-[(2R,4S)-4-[7-methyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-b][l,4]oxazin-2-yl]tetrahydropyran-2-yl]-lH-pyridin-2-one (A56, 20 mg, 0.0355 mmol, 97.98% yield) as a solid. ESI-MS (m / z)+: 463.3.

[0922] Synthesis of Compound 194

[0923]

[0924] Compound 194 To a solution of 5-[(2R,4S)-4-[7-methyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-b][1,4]oxazin-2-yl]tetrahydropyran-2-yl]-1H-pyridin-2-one (A56, 1.0 eq, 10 mg, 0.0216 mmol) and K2CO3 (3.0 eq, 9.0 mg, 0.0649 mmol) in DMF (0.5 mL) was added Mel (5.0 eq, 15 mg, 0.108 mmol), and the mixture was stirred at 25°C for 16 h. Tire 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%: 48%-78%, gradient time: lOmin, Detector, UV 220 nm) and further purified again by prep-HPLC (Phenomenex luna Cl 8 150*25mm* lOum, water(2.25% formic acid)-ACN; B%: 23%-43%, gradient time: lOmin, Detector, UV 220 nm) and lyophilized to give l-methyl-5-[(2R,4S)-4-[7-methyl-4-[3-(trifluoromethyl)-l-bicyclofl.1. l]pentanyl]-2,3-dihydropyrazino[2,3-b] [l,4]oxazin-2-yl]tetrahydropyran-2-yl]pyridin-2-one (Compound 194, 2.1 mg, 0.00408 mmol, 19% yield) as a solid. ESI-MS (m / z)+: 477.3. ¹H NMR (400 MHz, CHCl₃-d) 57.37 - 7.28 (m, 3H). 6.58 (dd, J= 6.4, 9.6 Hz, 1H), 4.26 - 3.99 (m, 3H), 3.65 - 3.48 (m, 4H). 3.46 - 3.33 (m, 1H), 3.31 - 3.19 (m, 1H), 2.43 (dd, J = 3.2, 9.6 Hz, 6H), 2.37 - 2.17 (m. 4H), 2.17 -2.03 (m, 1H), 2.02 - 1.77 (m, 1H), 1.53 - 1.38 (m, 2H).

[0925] Example 15: Synthesis of Compound 195

[0926] Synthesis of A58PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0927] lr[dF(CF3)ppy]2(4,4’-dCF3bpy)PF6, CuCN, bathophenanthroline, Togni’s reagent I, BTMG, water,

[0928]

[0929] EtOAc, 40 W blue LED, 25°C, 6 h To a vial were added photocatalyst Ir[dF(CF3)ppy]2(4,4’-dCF3bpy)PFs (0.010 eq, 6 mg), CuCN (0.20 eq, 10 mg), bathophenanthroline (1.0 eq, 50 mg), 2-(tert-butoxycarbonylamino)spiro[3.3]heptane-6-carboxylic acid (A57, 1.0 eq, 200 mg, 3.92 mmol), and 3, 3 -dimethyl- 1 -(trifluoromethyl)- 1X3, 2-benziodoxole (1.0 eq, 258.6 mg, 3.92 mmol). EtOAc was added (2 mL, 40 mL / mmol of substrate), followed by addition of BTMG (1.0 eq, 43 mg) and water (20 mL). Tire vial was capped, purged with nitrogen, sonicated and wrapped with parafilm. The reaction was stirred and irradiated using 40 W blue LED lamps (6 cm away, with cooling fan to keep tire reaction at room temperature) for 16 h. The solution was extracted with EtOAc (500 mL x 3). 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 10 / 1) to give crude tert-butyl N-[6-(trifluoromethyl)spiro[3.3]heptan-2-yl]carbamate (A58, 3400 mg, 12.2 mmol, 86% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) 54.64 (br s, 1H), 3.99 (br d, J= 7.1 Hz, 1H), 2.53 - 2.43 (m, 1H), 2.42 - 2.31 (m, 1H), 2.27 - 2.08 (m, 5H), 1.90 - 1.80 (m, 2H). 1.43 (s. 9H).

[0930] Synthesis of Compound 195

[0931]

[0932] Compound 195

[0933] The methods used in Examples 6 and 13 were used to complete the synthesis of 5-[(2R,4S)-4-[6,7-dimethyl-4-[6-(trifluoromethyl)spiro[3.3]heptan-2-yl]-2,3-dihydropyrazino[2,3-b][l,4]oxazin-2-yl]tetrahydropyran-2-yl]-l -methyl -pyridin-2 -one (Compound 195, 10 mg, 0.0174 mmol, 22% yield from final step) as a solid. ESI-MS (m / z)+: 519.4. ¹H NMR (400 MHz, CHCl₃-d) 87.33 (br d, J= 7.0 Hz, 2H), 6.59 (dd, J= 5.9, 9.5 Hz, 1H), 4.90 - 4.62 (m, 1H), 4.29 - 3.96 (m, 3H), 3.55 (d, J= 2.0 Hz, 4H), 3.40 (brPAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0934] t, J= 13.4 Hz, 1H), 3.18 - 3.05 (m, 1H), 2.95 - 2.80 (m, 1H), 2.56 - 2.39 (m, 2H), 2.37 - 2.27 (m, 8H), 2.21 - 1.98 (m, 6H), 1.63 - 1.40 (m, 3H).

[0935] Example 16: Synthesis of Compound 196

[0936] Synthesis of A60

[0937] NBS, MeCN, 0-25°C, 12 h

[0938]

[0939] A60

[0940] To the mixture of 6-(trifluoromethyl)pyrazin-2 -amine (A59, 1.0 eq, 8.80 g, 54.0 mmol) in MeCN (160 mL) was added NBS (1.0 eq, 9604 mg, 54.0 mmol) at 0°C, then the reaction mixture was stirred at 25°C for 12 h. The reaction mixture was quenched by addition of Na2SO3(200 mL) at 0°C, diluted with water (100 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with sat. NaCl (100 mL x 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-12% 1:2 EtOAc / Petroleum ether) to afford 5-bromo-6-(trifluoromethyl)pyrazin-2 -amine (A60, 9.68 g, 40.0 mmol, 74 % yield) as a solid. ESIMS (m / z)+: 244.0. 'H NMR (400 MHz, CDCl₃-d) 57.94 (s, 1H), 5.02 - 4.73 (m, 2H).

[0941] Synthesis of A62

[0942] WXPS1004, K2CO3, dioxane / H2O, 80°C, 12 h

[0943]

[0944] A61 A62

[0945] To a solution of 5-bromo-6-(trifluoromethyl)pyrazin-2-amine (A61, 1.0 eq, 10.78 g, 44.5 mmol) in L4-dioxane (200 mL) and water (50 mL) were added 2,4,6-trimethyl-l,3,5,2,4,6-trioxatriborinane (2.0 eq, 11.18 g, 89.1 mmol), WXPS1004 (0.020 eq, 4.18 g, 0.891 mmol) and K2CO3(2.0 eq, 12.29 g, 89.1 mmol). The mixture was stirred at 80°C for 12 hours under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (0-25% 1:2 EtOAc / Petroleum ether) to afford 5-methyl-6-(trifluoromethyl)pyrazin-2-amine (A62. 5.20 g. 25.2 mmol. 57% yield) as a solid. ESI-MS (m / z)+: 178.1. ¹H NMR (400 MHz, CHCl₃-d) 58.07 (s, 1H), 4.72 (br s, 2H), 2.58 (q, J= 2.0 Hz, 3H).

[0946] Synthesis of Compound 196PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0947]

[0948] Compound 196

[0949] The method of Example 14 was then used to synthesize l-methyl-5-[(2R,4S)-4-[7-methyl-6-(trifluoromethyl)-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-2,3-dihydropyrazino[2,3-b][l,4]oxazin-2-yl]tetrahydropyran-2-yl]pyridin-2-one (Compound 196. 20 mg, 0.0289 mmol, 51% yield) as a solid. ESI-MS (m / z)+: 545.3. ¹H NMR (400 MHz, DMSO-d6) 57.62 (s, 1H), 7.48 - 7.38 (m. 1H), 6.37 (dd, 7= 5.2, 9.2 Hz, 1H). 4.28 (br d, J= 8.4 Hz, 1H).4.21 - 4.11 (m, 1H), 4.10 - 4.00 (m, 1H), 3.6O -3.49 (m, 2H), 3.41 (d, J= 2.0 Hz, 3H), 3.39 - 3.37 (m, 1H), 2.44 - 2.34 (m, 9H), 2.12 - 1.94 (m, 2H), 1.89 - 1.75 (m, 1H), 1.51 - 1.34 (m, 2H). Example 17: Synthesis of Compound 200

[0950] Synthesis of A63

[0951]

[0952] A mixture of tert-butyl N-[2-[(2R,4S)-2-(6-benzyloxy-3-pyridyl)tetrahydropyran-4-yl]-2-oxo-ethyl]-N'-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A22, 1.0 eq, 495 mg, 0.88 mmol) and 10% Pd / C (1.0 eq, 100 mg) in EtOAc (17 mL) was degassed and flushed with hydrogen. The reaction was stirred under hydrogen atmosphere at rt for 45 min. The reaction was purged with argon and filtered through a celite pad to yield tert-butyl N'-[1-[(2R,4S)-2-(6-hydroxy-3-pyridyl)tetrahydropyran-4-yl]-2-oxo-ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A63, 413 mg, 0.88 mmol, 99% yield). The crude was used without further purification for next step. ESI-MS (m / z)+: 471.4 (obs). Synthesis of A64PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0953]

[0954] A mixture of tert-butyl N-[2-[(2R,4S)-2-(6-hydroxy-3-pyridyl)tetrahydropyran-4-yl]-2-oxo-ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A63, 1.0 eq, 413 mg, 0.88 mmol), methyl iodide (3.0 eq, 0.16 mL, 2.6 mmol) and CS2CO3 (2.0 eq, 572 mg, 1.7 mmol) was stirred in acetone (9.0 mL) at 50 °C for 30 min. The reaction was quenched with sat. NaHCCL (aq.) and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude was purified by normal phase chromatography (40-100% EtOAc in hexanes) to afford tert-butyl N'-[2-[(2R,4S)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2-oxo-ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A64, 313 mg, 0.65 mmol, 74% yield). ESI-MS (m / z)+: 485.4 (obs).

[0955] Synthesis of A65

[0956] TBD (10 mol%) CDCI3, r.t.

[0957]

[0958] A solution of tert-butyl N'-[2-[(2R,4S)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2-oxo-ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A64, 1.0 eq, 174 mg, 0.36 mmol) and 3,4,6,7,8,9-hexahydro-277-pyrimido[l,2-a]pyrimidine (0.1 eq, 5.0 mg, 0.036

[0959] mmol) in deuterated chloroform (3.6 mL) was stirred for 1 h. Tire reaction was concentrated in vacuo to yield tert-butyl N'-[1,1-dideuterio-2-[(2R,4S)-4-deuterio-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2-oxo-ethyl]-N-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]carbamate (A65, 175 mg, 0.36 mmol, 99% yield) was used without further purification. ESI-MS (m / z)+: 488.3 (obs).

[0960] Synthesis of Compound 200PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0961] Method of Example 12

[0962]

[0963] The method of example 12 was used, with NaBH4 instead of NaBD4, to synthesize 5-[(27?,4S)-4-deuterio-4-[3,3-dideuterio-6,7-dimethyl-4-[3-(trifluoromethyl)-l-bicyclo[l.l.l]pentanyl]-277-pyrazino[2,3-b][l,4]oxazin-2-yl]tetrahydropyran-2-yl]-l-methyl-pyridin-2-one (Compound 200, 37 mg, 0.075 mmol, 26% yield) as a 1: 1 mixture between diastereoisomers. ESI-MS (m / z)+: 494.5 (obs). 'H NMR (CDCl₃, 400 MHz): 8H7.33-7.29 (m, 2H), 6.54 (dd, 1H, J = 9.7, 5.4 Hz), 4.17 (dd, 1H, J = 11.7, 3.2 Hz). 4.10 (d. 1H, J = 11.4 Hz). 4.04 (d, 1H, J = 17.8 Hz), 3.59-3.54 (m, 1H). 3.52 (d, 3H, J = 2.1 Hz), 2.39 (d, 6H, J = 3.0 Hz), 2.31 (s, 3H), 2.29 (s, 3H), 1.86 (dd, 1H, J = 67.2, 13.0 Hz), 1.59 (dd, 1H, J = 8.1, 3.5 Hz), 1.54-1.38 (m, 1H).19F NMR (CDCl₃, 376 MHz) 5 -71.1 (s, 3F).

[0964] Example 18: Synthesis of Compound 201

[0965] 1.) Mel (3.0 equiv)

[0966] Cs2CO3(3.0 equiv)

[0967] 70 °C, THF, 2h

[0968] 2.) Mel, NaH (2.0 equiv) THF, rt, 6h

[0969]

[0970] Intermediate A66 was synthesized via the method in Example 11. To a solution of 5-[(2R,4S)-4-(6,7-dimethyl-3,4-dihydro-2H-pyrazino[2,3-b][1,4]oxazin-2-yl)tetrahydropyran-2-yl]-1H-pyridin-2-one (A66, 1.0 eq, 5.5 mg, 0.016 mmol) in THF (0.63 mL) were added CS2CO3 (3.0 eq, 16 mg, 0.048 mmol) and methyl iodide (1.0 eq, 1 μL, 0.016 mmol) in one portion, then the mixture was stirred at 50°C for 1 h. The mixture was fdtered through Celite and concentrated. The obtained crude was dissolved in THF (0.6 mL) and sodium hydride (1.1 eq, 0.71 mg, 0.018 mmol) was added at 0 °C. After 5 minutes, the mixture was warmed at rt for 6h. The reaction mixture was filtered with EtOAc through Celite then evaporated under reduced pressure before purification by reverse phase flash chromatography (10%-75% ACN in water containing 0.1% formic acid) to yield 1-methyl-5-[(2R,4S)-4-(4,6,7-trimethyl-2,3-dihydropyrazino[2,3-b][1,4]oxazin-2-yl)tetrahydropyran-2-yl]pyridin-2-one (Compound 201, 2.2 mg, 60 pmol, 37% yield) as a solid. ESI-MS (m / z)+: 471.3 (obs). ¹H NMR (400 MHz, DMSO-d6) 57.65 (d. J = 7.9 Hz, 1H), 7.43 (d, J= 9.4 Hz, 1H), 6.54 (s, 2H), 6.37 (d, J= 8.9 Hz, 1H), 4.16 - 4.01 (m, 2H), 3.48 (d,PAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0971] J= 13.8 Hz, 2H), 3.41 (s, 3H), 3.23 (d, J= 12.4 Hz, 1H), 2.98 (d, 7= 4.3 Hz, 3H), 2.23 (s, 3H), 2.17 (d, J = 4.4 Hz, 3H), 2.01 (s, 1H), 1.40 (s, 2H).

[0972] Example 19: In vitro Assay Data

[0973] In vitro Measurement of Triggering Receptor Expressed on Myeloid Cells 2 activity using cellular phosphorylation of Spleen Tyrosine Kinase (“Syk”) Assays

[0974] 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, HEK4 / TREM2 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.

[0975] 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 room 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 fluourescence intensity’ was measured using a Perkin Elmer Envision plate reader. Intensities were used to generate a standard curve, and % activation was calculated. Curve fitting was performed using Prism v9 software, log(agonist) vs response - variable slope (four parameters), and EC50s were calculated from the curve fit.

[0976] Tire 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.

[0977] Compounds designated as “A” demonstrated an EC50 of < 100 nM. Compounds designated as ‘" B” demonstrated an EC50 > 100 nM and < 500 nM. Compounds designated as ‘" C” demonstrated an EC50 > 500 nM.

[0978] Table B. hTREM2 EC50Data (HEK293 Cells)

[0979] hTREM2 ECso

[0980] Compound No.

[0981] (nM)

[0982] 101 A

[0983] 108 A

[0984] 110 A

[0985] 111 B

[0986] 115 B

[0987] 122 B

[0988] 177 A

[0989]

[0990] 178 APAT25187-WO Attorney Docket No.: 34124 / 50019 PC

[0991] 179 A

[0992] 180 A

[0993] 181 A

[0994] 182 B

[0995] 183 C

[0996] 184 B

[0997] 185 A

[0998] 186 B

[0999] 187 A

[1000] 188 A

[1001] 189 B

[1002] 190 A

[1003] 191 C

[1004] 192 A

[1005] 193 A

[1006] 194 A

[1007] 195 C

[1008] 196 A

[1009] 197 A

[1010] 198 A

[1011] 199 A

[1012] 200 A

[1013]

[1014] 201 C

[1015] 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.

[1016] Ill

Claims

PAT25187-WO Attorney Docket No.: 34124 / 50019 PC CLAIMS1. A compound of Formula (I):R9Ior 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:PAT25187-WO Attorney Docket No.: 34124 / 50019 PCX2is C(R15)(R16), O, C(=O), S(O)2, or NR17:X3is CR18, C(R18a)(R18b), orN;X4is CR19, C(R19a)(R19b), orN;R1is Ci-6alkyl, C(=O)RA, 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, Cue alkyl, C2-6 alkenyl, C2-6 alkynyl, Cue 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 R12; 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, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, Cn 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 R12;R5bis cycloalkyl, heterocyclyl, aryl, or hctcroaryl, optionally substituted with one or more R11; R6, R6, R7and R7are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 heteroalkyl, C1-6 haloalkyl, C 1.6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), and -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R2C;R8and R9are each independently selected from hydrogen and Cualkyl; orR8and R9are taken together with the atom they are attached to form an oxo group (e.g.. C=O);PAT25187-WO Attorney Docket No.: 34124 / 50019 PC R10is hydrogen. -O(RA), or Ci-6 alkyl; orR9and R10together with the atoms they are attached form a double bond;each R11is hydrogen, Ci-ealkyl. C2-6 alkenyl, C2-6alkynyl, C1-6 heteroalkyl, Ci-ehaloalkyl, C1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, ar l, and heteroaryl is optionally substituted with one or more R21; ortwo R11taken together with the atom they are attached to form an oxo group (e.g., C=O); each R12is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl. Cue heteroalkyl, Ci-ehaloalkyl, C1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, ary l, and heteroaryl is optionally substituted with one or more R21; ortwo R12taken together with the atom they arc attached to form an oxo group (c.g., C=O); each R13is independently hydrogen. Ci.g alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci-6 heteroalkyl, C1-6 haloalkyl, cycloalkyl, heterocyclyl, halogen, cyano, -O(RA). -C(O)N(RB)(RC). or -N(RD)(RC), wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more R22;R14, R15, and R16are each independently hydrogen, halo, or C1-3 alkyl;R17is hydrogen or C1-3 alkyl;Ris,RI sa,RmRi9Ri9a,Risbare each independently hydrogen, Cue alkyl, C2-6 alkenyl, C2-6 alkynyl. Cue heteroalkyl, Ci-ehaloalkyl, 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 R23;each R20, R21, R22, and R23is independently selected from independently selected from hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cn 6 heteroalkyl, C1-6 haloalkyl, C1-6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl, halogen, cyano, -O(RA), -C(O)RA, -C(O)ORA, -C(O)N(RB)(RC), or -N(RB)(RC);each RAis independently hydrogen, Ci-e alkyl, Cue heteroalkyl, C1.6 haloalkyl, cycloalkyl, heterocyclyl, or -N(RB)(RC), wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is optionally substituted w ith one or more R24;each RBand Rcis independently hydrogen, Ci-6 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 R24; orRBand Rc, together with the nitrogen atom to w hich they are attached, form -N=C(RU)(RE) or a heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more R24;PAT25187-WO Attorney Docket No.: 34124 / 50019 PC each RDand REis independently hydrogen, Ci-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 R24;each R24is C1.6 alkyl, C1.6 heteroalkyl, Ci.e haloalkyl, cycloalkyl, halogen, or cyano; or two R24taken together with the atom to which they are attached form an oxo group; and n is 0, 1, 2, or 3.

2. The compound of claim 1, wherein R1is ary l, cycloalkyl or heterocyclyl, optionally substituted with one or more R13.

3. Tire compound of any one of the preceding claims, wherein R1is aryl or cycloalkyl, optionally substituted with one or more R13.

4. Tire compound of any one of the preceding claims, wherein R15. The compound of any one of the preceding claims, wherein R1isR4aR4b6. The compound of any one of the preceding claims, wherein RingB is7. The compound of any one of the preceding claims, wherein Ring B isPAT25187-WO Attorney Docket No.: 34124 / 50019 PC R118. The compound of any one of the preceding claims, whereinR5bisOMThe compound of any one of the preceding claims, whereinR?bis10. Tire compound of any one of the preceding claims, wherein X1is CH and X2is 0.

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

12. The compound of any one of the preceding claims, wherein X3and X4are each N.

13. Tire compound of any one of the preceding claims, wherein R8and R9are taken together with the atom they are attached to form an oxo group (e.g., C=O).

14. The compound of any one of the preceding claims, wherein R6and R7are each independently hydrogen, halogen, Ci-6 alkyl, or -CN.

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

16. The compound of any one of the preceding claims, wherein R7is -CH,.

17. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-a):PAT25187-WO Attorney Docket No.: 34124 / 50019 PCR9I\. N R6R8R7or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, R6, R7, R8, R9, and subvariables thereof are defined as for Formula (I).

18. Tire compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-b):R8NBor a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, R6, R7, R8, R9, and subvariables thereof are defined as for Formula (I).

19. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-c):N NNBor 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).

20. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-d):PAT25187-WO Attorney Docket No.: 34124 / 50019 PCR1or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of Ring B, R1, R6, R7, R8, R9, and subvariables thereof are defined as for Formula (I).

21. The compound of any one of the preceding claims, wherein tire 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 Ring B, R1, R6, R7, R8, R9, 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-f):or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X2, X3, X4, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, Rs, R9, R10and subvariables thereof are defined as for Formula (I).PAT25187-WO Attorney Docket No.: 34124 / 50019 PC 23. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-g):R9I\ RR8,5bO N R RW O R2aR2b(I-g), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X3, R1, R2a, R2b, R3a, R3b, R5a, R5b, Rb, R7, R8, R9. R10and 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-h):R8O NR10or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X3, R1, R5b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

25. Tire compound of any one of the preceding claims, wherein the compound of Fonnula (I) is a compound of Formula (I-i):PAT25187-WO Attorney Docket No.: 34124 / 50019 PC(I-i), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, R8, R9, R10and 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-j):or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X4, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

27. The compound of any one of the preceding claims, wherein the compound of Formula (I) is a compound of Formula (I-k):PAT25187-WO Attorney Docket No.: 34124 / 50019 PCR7(I-k), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein each of X1, X3, R1, R2a, R2b, R3a, R3b, R4a, R4b, R5a, R5b, R6, R7, R8, R9, R10and subvariables thereof are defined as for Formula (I).

28. The compound of any one of claims 1-27, wherein the compound is a compound provided in Table A.

29. A pharmaceutical composition comprising the compound according to any one of claims 1-28, and a pharmaceutically acceptable excipient.

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

31. 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 1-28, or a pharmaceutical composition of claim 29.

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