Tricyclic agonists of TREM2

Abstract

Provided are compounds of the Formula (I), or their pharmaceutically acceptable salts, wherein R3, Y1, RA, RZ, CY, and subscripts r, s, and p are as herein described (I). The compounds and their pharmaceutically acceptable salts can activate TREM2 and are expected to have utility as therapeutic agents, for example, for treating neurological disorders. The disclosure also provides pharmaceutical compositions which comprise the compounds disclosed herein or pharmaceutically acceptable salts thereof. The disclosure also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of neurological disorders and for preparing pharmaceuticals for this purpose.

Description

TRICYCLIC AGONISTS OF TREM2CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 777,095 filed March 25, 2025, and U.S. Provisional Patent Application Serial No.:63 / 942,485, filed on December 16, 2025, the entire contents of both which are incorporated by reference herein.FIELD

[0002] The present disclosure provides certain tricyclic compounds that are TREM2 agonists. The compounds are useful for treatment and prevention of a neurodegenerative disorder associated with a loss of function of human TREM2. The disclosed TREM2 agonists can be useful for the treatment of Alzheimer’s Disease and associated neurological conditions.BACKGROUND

[0003] Alzheimer’s disease (AD) is a neurodegenerative disease that is the most common cause of dementia in the United States. Worldwide, over 50 million people are living with dementia, and this prevalence is expected to triple by 2050. Of the top 10 causes of death in the United States, AD is the only major cause of morbidity and mortality without suitable treatments for prevention, slowing, or cure (2017 Alzheimer’s Association Report). Current therapies for AD such as acetylcholinesterase inhibitors (e.g., donepezil) and N-methyl-D-aspartate receptor antagonists (e.g., memantine) show modest and transient benefits to cognition and behavior parameters in AD patients, but do not slow or halt the progression of the disease (Cummings (2004) N Engl J Med, 351 : 56-67).

[0004] Triggering Receptor Expressed on Myeloid cells-2 (TREM2), an immunoglobulin-like transmembrane receptor, appears to play a key role in AD pathology. Heterozygous mutations in the TREM2 gene have been found to increase the risk of AD by up to 3-fold (Guerreiro et al. (2013), N Engl J Med, 368: 117-127; Jonsson et al. (2013) N Engl J Med, 368: 107-116), and increase the rate at which brain volume shrinks (Rajagopalan et al. (2013) N Engl J Med, 369: 1565-1567). Even individuals without AD who carry a heterozygous TREM2 mutation show impaired cognition compared to individuals with two normal TREM2 alleles. In the context of AD pathology, TREM2 expression impacts amyloid pathology, modulates neuritic dystrophy, tau hyperphosphorylation and aggregation, and affects synaptic and neuronal loss (Jay et al. (2017) Mol Neurodegener, 12(1 ): 56). In addition, it has been shown that TREM2 plays a key role inlimiting the development of peri-plaque tau pathologies (Leyns et al. (2019) Nat Neurosci 22: 1217-1222). Recent mouse genetic model studies also strongly support a key role for TREM2 in AD, with loss or deficiency of TREM2 being associated with increased pathology (Cheng-Hathaway et al. (2018) Mol Neurodegener, 13(1):29; Wang et al. (2015) Cell, 160: 1061-1071; Wang et al. (2016) J Exp Med, 213:667-675; Yuan et al. (2016) Neuron, 90:724-739).

[0005] As reflected in its name, TREM2 is expressed primarily on myeloid lineage cells, including microglia (Colonna & WangNat Rev Neurosci, 17:201-207). Microglia are resident macrophages of the central nervous system (CNS) that, when activated appropriately, are thought to serve an important protective role in Alzheimer’s disease through their housekeeping functions such as facilitating clearance of cellular debris through phagocytosis, as well as secretion of growth factors. In the CNS, TREM2 is exclusively expressed on microglia. It has been shown that TREM2 expression regulates microglial chemotaxis and phagocytosis, and enhances microglial cell survival, proliferation, and differentiation. In addition, it is well known that TREM2 is required to sustain microglial trophic function in the aging brain, and studies showed that an overlap exists between aged microglia phenotype and microglial molecular signatures found in animal models of AD, which include TREM2 pathways (Krasemann et al.Immunity, 47(3):566-581).

[0006] Certain reports have suggested that the role of TREM2 in experimental amyloid-based AD models is that the protein has an important role in plaque entrainment by microglia, where it appears to be overexpressed and drive transit of these innate immune cells to a disease-associated microglial (DAM) state. This transition is marked by microglial priming that is evident by a set of overexpressed genes and an improved phagocytic capacity. George, Neural Regeneration Research, 18(12): 2680-81 (2023).

[0007] These findings suggest that activation of TREM2 may ameliorate AD symptoms and result in improvements in cognitive function through activation of the innate immune system, and as such agonists of TREM2 may be useful in the treatment of Alzheimer’s disease and other dementias and related neurodegenerative disorders. There is a need in the art for novel agonists of TREM2 and methods of treating neurodegenerative disorders with such agonists.SUMMARY

[0008] The present disclosure provides certain tricyclic compounds which exhibit agonism of the TREM2 receptor. The present disclosure further provides for uses of these compounds in the treatment or prevention of a neurodegenerative disorder, in a subject in need thereof. The presentdisclosure provides compounds that may be adapted for pharmaceutical compositions that may be administered to a subject suffering from a neurodegenerative disorder.

[0009] The compounds of the present disclosure exhibit excellent potency in activating the TREM2 receptor, such as the human TREM2 receptor. In some embodiments, the compounds of the present disclosure exhibit superior potency as agonists of TREM2, as evidenced by the data reported herein. The compounds of the present disclosure may be useful in the treatment or prevention of neurodegenerative disorders (or one or more symptoms associated with such disorders) in which TREM2 is involved, including Alzheimer’s disease and other indications, diseases and disorders as described herein. The present disclosure also provides pharmaceutical compositions comprising a compound of the present disclosure and methods for the use of such compounds and compositions for the treatments described herein.

[0010] The summary of the technology described above is non-limiting and other features and advantages of the technology will be apparent from the following detailed description, and from the claims.DETAILED DESCRIPTIONCompounds of the Present Disclosure

[0011] In one embodiment, the present disclosure provides a compound of Formula (I)R3or a pharmaceutically acceptable salt thereof, wherein:R3 is(a) phenyl;(b) cyclohexyl;(c) a 5 - to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; orwherein R3 is unsubstituted or substituted by 1 to 3 R3a substituents independently selected from halo, C1-C3 alkyl, C1-C3 fluoroalkyl, and C1-C3 fluoroalkoxy;Y1 is C(H) orN;each RA is independently fluoro or Ci-3 alkyl;CY is(a) a 5 - to 6-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;(b) a 3- to 6-membered saturated heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S; or(c) a C3-C6 cycloalkyl;wherein CY is unsubstituted or substituted by 1 to 2 RY substituents independently selected from the group consisting of halo, Ci-3 alkyl, cyano, Ci-3 alkoxy, C3-6 cycloalkyl, and C3.6 fluorocycloalkyleach RZ is independently selected from the group consisting of Cl -3 alkyl, Cl -3 fluoroalkyl, and halo;subscript p is 0, 1, or 2;subscript r is 0, 1, or 2; andsubscript s is 1 or 2.

[0012] In another embodiment, the present disclosure provides a compound of Formula (I’)R3or a pharmaceutically acceptable salt thereof, wherein:R3 is(a) phenyl;(b) a C3-C7 monocycloalkyl, a C5-C9 spirocycloalkyl, or a C5-C9 bicycloalkyl;(c) a 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;(d) a 3- to 7- membered monocyclic, C5-C9 bicycloalkyl, or a 6- to 9-membered spirobicyclic heterocycloalkyl, wherein the heterocycloalkyl contains containing 1 to 2 heteroatoms independently selected from N, O, and S;(e) C1-C3 alkyl,26176wherein R3 is unsubstituted or substituted by 1 to 3 R3a substituents independently selected from halo, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, cyano and C1-C3 fluoroalkoxy;Y1 is C(H) orN;each RA is independently fluoro or C1.3 alkyl;CY is(a) a 5- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;(b) a 3- to 9-membered monocyclic, bicyclic, and bridged, or a 3- to 10-membered spirobicyclic saturated heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 2 heteroatoms independently selected from N, O, and S;(c) a C3-C6 cycloalkyl;(d) a C5-C9 bridged bicycloalkyl;(e) (CH2)scyano,(f) C1-C3 alkyl,wherein CY is unsubstituted or substituted by 1 to 2 RY substituents independently selected from the group consisting of halo, C1.3 alkyl, cyano, C1.3 alkoxy, C1-C3 fluoroalkyl, C3.6 cycloalkyl, C3.6 fluorocycloalkyl and C3.6 difluorocycloalkyl each RZ is independently selected from the group consisting of C1.3 alkyl, C1.3 fluoroalkyl, and halo;subscript p is 0, 1, or 2;subscript r is 0, 1, or 2; andsubscript s is 1 or 2.

[0013] In some embodiments of the compound of Formula (I) or Formula (F), R3 is unsubstituted or substituted phenyl.

[0014] In specific embodiments of the compound of Formula (I) or Formula (F), R3 is selected from the group consisting of:F F. F Cl F F F Cl F NCl ''T' F I F F X F. F W F F. F F^ w o a k I I I JVW I I ICl Cl F F \Z F JO ' y ' -w o o NF > F F Cl F Cl OO OwclFuxr Ix / x, I FF.F F F Cl ClCHF2I

[0015] In specific embodiments of the compound of Formula (I) or Formula (F), R3 is optionally substituted C1.3 alkyl.

[0016] In specific embodiments of the compound of Formula (I) or Formula (F), R3 is optionally substituted phenyl. An aspect of this embodiment is realized when R3 is substituted with 1 to 3 or 2 to 3 halo substituents. Another aspect of this embodiment is realized when R3is selected from:

[0017] In specific embodiments of the compound of Formula (I) or Formula (F), R3is optionally substituted 3- to 7- membered monocyclic, C5-C9 bicycloalkyl, or a 6- to 9-memberedspirobicyclic heterocycloalkyl. An aspect of this embodiment is realized when R3is selected V \ / / \from:andkZVv-

[0018] In certain embodiments of the compound of Formula (I) or Formula (F), Y1 is C(H). In other embodiments, Y1 is N.

[0019] In certain embodiments of the compound of Formula (I) or Formula (F), each RZ is independently selected from the group consisting of methyl, fluoromethyl, and F.

[0020] In specific embodiments of the compound of Formula (I) or Formula (F), each RZ is methyl.

[0021] In some embodiments of the compound of Formula (I) or Formula (F), subscript r is 0.

[0022] In certain embodiments of the compound of Formula (I) or Formula (F), subscript s is 1.

[0023] In certain embodiments of the compound of Formula (I) or Formula (F), subscript p is 0.

[0024] In certain embodiments of the compound of Formula (I) or Formula (F), subscript p is 1.

[0025] In some embodiments of the compound of Formula (I) or Formula (F), CY is a substituted or unsubstituted 5- to 6-membered heteroaryl ring containing 1 to 2 N heteroatoms. In specific embodiments, CY is substituted or unsubstituted pyrazolyl or pyridinyl.

[0026] In other embodiments of the compound of Formula (I) or Formula (F), CY is substituted or unsubstituted tetrahydrofuryl.

[0027] In other embodiments of the compound of Formula (I) or Formula (F), CY is substituted or unsubstituted thiazolyl or isothiazolyl.

[0028] In other embodiments of the compound of Formula (I) or Formula (F), CY is optionally susbstituted Ci-3 alkyl.

[0029] In still other embodiments of the compound of Formula (I) or Formula (F), CY is substituted or unsubstituted cyclopropyl.

[0030] In specific embodiments of the compound of Formula (I) or Formula (F), the groupris selected from the group consisting of:2617626176

[0031] In particular embodiments of the compound of Formula (I) or Formula (F):R3 is selected from the group consisting of:F Fthe group is selected from the group consisting of:26176Fsubscript s is 1; andsubscript p is 0.

[0032] In particular embodiments of the compound of Formula (I) or Formula (F):R3 is selected from the group consisting of:F Cl F FF F F C CF F\A / 0 ‘0 !W \A / !W< «AA !A? % / V !W ^ I A JW ! b F F26176subscript s is 1; andsubscript p is 1.

[0033] In specific embodiments of the compound of Formula (I) or Formula (F), the compound is selected from the group consisting of Example Nos. 1-1 through 5-13.26176DEFINITIONS

[0034] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0035] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0036] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0037] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0038] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0039] As used throughout this disclosure, “compound(s) of the present disclosure”, “compound(s) of the disclosure”, “compound(s) of Formula (I) or Formula (I’)”, “compound(s) disclosed herein”, “compound(s) described herein”, “compound(s) of the disclosure”, etc., are used interchangeably and are to be understood to include the disclosed compounds of Formula (I) or Formula (I’). The compounds of Formula (I) or Formula (F) can form salts which are also within the scope of the present disclosure. Reference to a compound of the present disclosure (or compound of Formula (I) or Formula (I’) herein is understood to include reference to salts thereof, unless otherwise indicated.

[0040] “Acyl” refers to a moiety derived by the removal of one or more hydroxyl groups from an oxoacid. An acyl group contains a central carbon atom, a double-bonded oxygen atom to the central carbon atom, and a single-bonded alkyl group to the central carbon atom.

[0041] “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched. Non-limiting examples include ethenyl, propenyl, and butenyl.

[0042] “Alkyl”, as well as other groups having the prefix “alk”, such as alkoxy, and the like, means carbon chains which may be linear or branched, or combinations thereof, containing the26176indicated number of carbon atoms. For instance, a Ci-Cg alkyl means an alkyl group having one (i.e., methyl) up to 6 carbon atoms (i.e., hexyl). In particular embodiments, linear alkyl groups have 1-6 carbon atoms and branched alkyl groups have 3-7 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

[0043] “Alkylamino” means an alkyl group linked to an amine, wherein the nitrogen atom is substituted by one or more alkyl substituents. The bond to the parent group is through the nitrogen atom of the amino component.

[0044] “Alkoxy” and “alkyl-O-” are used interchangeably and refer to an alkyl group linked to oxygen. “Haloalkoxy” means an alkoxy that is mono-or multiple-halo-substituted. The bond to the parent group is through the oxygen atom of the group.

[0045] “Cyano” means a N=C- group. The bond to the parent group is through the carbon atom.

[0046] “Cyanoalkyl” means a cyano group linked to an alkyl. The bond to the parent group is through the carbon atom of the alkyl component.

[0047] “Cycloalkyl” means a partially or fully saturated cyclic hydrocarbon radical. In particular embodiments, the cycloalkyl group has 3-12 carbon atoms, forming 1-3 carbocyclic rings, wherein cyclic systems having 2-3 rings can be fused. Bridged cycloalkyls are also included. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. “Fluorocycloalkyl” means a saturated cyclic hydrocarbon radical that is mono- or multiple-fluoro-substituted, e.g., doubly fluoro- substituted cyclopentyl.

[0048] “Spirocycloalkyl” means a saturated spirocyclic hydrocarbon radical having at least two rings sharing only a single atom. “Alkylcycloalkyl” means an alkyl group linked to a cycloalkyl, where the bond to the parent group is through the carbon atom of the cycloalkyl component.

[0049] “Dialkylamino” means an alkylamino as previously defined, wherein the nitrogen atom of the amine is substituted by two alkyl substituents, which substitutions can be the same or different, e.g., -N(CHs)2 or -N(CH3)(CH2CH3). The bond to the parent group is through the nitrogen atom of the amino component.

[0050] “Fluoroalkyl” includes mono-substituted as well as multiple fluoro-substituted alkyl groups, up to perfluoro substituted alkyl. For example, fluoromethyl, 1,1 -difluoroethyl, trifluoromethyl or 1,1,1,2,2-pentafluorobutyl are included. The bond to the parent group is through one of the carbon atoms of the alkyl component. “Fluoroalkoxy” includes monosubstituted as well as multiple fluoro-substituted “alkoxy” groups as previously defined.26176

[0051] “Halogen” or “halo”, unless otherwise indicated, includes fluorine (fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In one embodiment, halo is fluoro (-F) or chloro (-Cl).

[0052] “Heteroaryl” refers to aromatic monocyclic, bicyclic, tricyclic, or tetracyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S, or N atoms. Examples of heteroaryl groups include pyrazolyl, oxadi azol onyl, pyridinyl, pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.

[0053] “Heterocycloalkyl,” “Heterocyclyl” or “heterocycloalkyl ring” means a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, tricyclic or tetracyclic ring system comprising about 3 to about 17 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphorus or sulfur, alone or in combination. The heterocyclyl or heterocyclic ring can be saturated or unsaturated. There are no adjacent oxygen and / or sulfur atoms present in the ring system. In some embodiments, heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa, phospha or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, phosphorus or sulfur atom respectively is present as a ring atom. Non-limiting examples of suitable monocyclic heterocyclyls include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, phosphorinane, pyrrolinyl, dihydropyranyl, and the like. The rings may be “fused,” i.e., share two adjacent atoms, or “spirocyclic,” i.e., share only a single atom, or “bridged,” i.e., share three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom. For example, “spirocyclic heterocyclyl” means a heterocycloalkyl having at least two rings sharing only a single atom.

[0054] “Hydroxy” means a HO- group in which the bond to the parent moiety is through the oxygen atom.

[0055] “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. The bond to the parent moiety is through one of the carbon atoms of the alkyl component. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxy ethyl.

[0056] “ Oxo” means an oxygen atom double bonded to the parent moiety.

[0057] When any variable (e.g., R.A) occurs more than one time in any constituent or in Formula (I) or Formula (I’ ) or other generic formulas herein, its definition on each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or26176variables are permissible only if such combinations result in stable compounds. In choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, e.g., RA are to be chosen in conformity with well-known principles of chemical structure connectivity and stability. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring, or a saturated heteroaryl ring) provided such ring substitution is chemically allowed and results in a stable compound. A “stable” compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0058] The term “substituted” shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0059] Unless expressly depicted or described otherwise, variables depicted in a structural formula with a “floating” bond, such as Rx, are permitted on any available carbon atom in the ring to which the variable is attached. When a moiety is noted as being “optionally substituted” in Formula (I) or Formula (F) or any embodiment thereof, it means that Formula (I) or Formula (F) or the embodiment thereof encompasses compounds that contain the noted substituent (or substituents) on the moiety and also compounds that do not contain the noted substituent (or substituents) on the moiety.

[0060] The wavy line, as used herein, indicates a point of attachment to the compound, and when applicable, can be in either E or Z form. The cross line =— ■=, as used herein, indicates both the cis form and the trans form (and both the E form and the Z form) as well as mixtures of these forms in all ratios.

[0061] The compounds of Formula (I) or Formula (I’) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereoisomeric mixtures and individual diastereoisomers. Centers of asymmetry that are present in the compounds of Formula (I) or Formula (I’) can all independently of one another have S configuration or R configuration. The compounds of Formula (I) or Formula (I’) include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example, mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the disclosure in enantiomerically pure form, both as levorotatory and asdextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism, the disclosure includes both the cis form and the trans form (and both the E form and the Z form) as well as mixtures of these forms in all ratios. The present disclosure is meant to comprehend all such stereoisomeric forms of the compounds of Formula (I) or Formula (F). Where a structural formula or chemical name specifies a particular configuration at a stereocenter, the enantiomer or stereoisomer of the compound resulting from that specified stereocenter is intended. Where a structural formula of the compounds of Formula (I) or Formula (I’) indicates a straight line at a chiral center, the structural formula includes both the S and R stereoisomers associated with the chiral center and mixtures thereof.

[0062] The compounds of Formula (I) or Formula (I’) may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example, methanol or ethyl acetate or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Vibrational circular dichroism (VCD) may also be used to determine the absolute stereochemistry. Alternatively, any stereoisomer or isomers of the compounds of Formula (I) or Formula (I’) may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration.

[0063] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0064] The compounds of Formula (I) or Formula (I’) which contain olefinic double bonds, unless specified otherwise, are meant to include both E and Z geometric isomers.

[0065] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example,a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the compounds of Formula (I) or Formula (F).

[0066] Some of the compounds of Formula (I) or Formula (F) described herein may exist as atropisomers when the rotational energy barrier around a single bond is sufficiently high to prevent free rotation at a given temperature, thus allowing isolation of individual conformers with distinct properties. The individual atropisomers as well as mixtures thereof are encompassed with compounds of Formula (I) or Formula (F) of the present disclosure. When resolved, individual atropisomers can be designated by established conventions such as those specified by the International Union of Pure Applied Chemistry (TUPAC) 2013 Recommendations.

[0067] In the compounds of Formula (I) or Formula (I’), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of Formula (I) or Formula (F) and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples.Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0068] The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When a compound of Formula (I) or Formula (F) is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts.Preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts prepared from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines derived from both naturally occurring and synthetic sources.Pharmaceutically acceptable organic non-toxic bases from which salts can be formed include, for example, arginine, betaine, caffeine, choline, N,N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

[0069] When a compound of Formula (I) or Formula (F) is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. If a compound of Formula (I) or Formula (F) simultaneously contains acidic and basic groups in the molecule, the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula (I) or Formula (I’) by customary methods which are known to the person skilled in the art, for example, by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present disclosure also includes all salts of the compounds of Formula (I) or Formula (I’) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0070] Furthermore, the compounds of Formula (I) or Formula (I’) may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula (I) or Formula (I’), including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of Formula (I) or Formula (F) may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to ethyl acetate. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un-solvated and anhydrous forms.

[0071] Any pharmaceutically acceptable pro-drug modification of a compound of Formula (I) or Formula (I’) which results in conversion in vivo to a compound within the scope of this disclosure is also within the scope of this disclosure.26176

[0072] The terms “therapeutically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for treatment” or “an effective dose” are intended to mean that amount of a compound of Formula (I) or Formula (F) that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. In a preferred embodiment, the term “therapeutically effective amount” means an amount of a compound of Formula (I) or Formula (F) that alleviates at least one clinical symptom in a human patient. The terms “prophylactically effective (or efficacious) amount” and similar descriptions such as “an amount efficacious for prevention” are intended to mean that amount of a compound of Formula (I) or Formula (F) that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.TREM2 Agonism and Neurodegenerative Conditions

[0073] Impairment in TREM2 receptor function has been linked to several human 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. 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. J Exp Med. 2015; 212(3):287-9) In particular, the R47H variant has been identified in genome-wide studies as being associated with increased risk for late-onset AD with an overall adjusted odds ratio (for populations of all ages) of 2.3, second only to the strong genetic association of ApoE to AD. The R47H mutation resides on the extracellular IgV-set domain of the TREM2 protein and has been shown to impact lipid binding and uptake of apoptotic cells and amyloid-P (Wang et al. 2015; Yeh et al. Neuron 2016; 91 (2): 328-40), 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 CNS. Ulrich and Holtzman ACS Chem Neurosci. 2016; 7(4):420-7.

[0074] In addition, knockdown of TREM2 has been shown to aggravate a-synucl ein-induced inflammatory responses in vitro and exacerbate dopaminergic neuron loss in response to adeno-26176associated viral (AAV) vectors encoding synuclein in vivo (a model of Parkinson's disease), suggesting that impaired microglial TREM2 signaling exacerbates neurodegeneration by modulating microglial activation states. Guo et al. FASEB J. 2019; 33(11): 12164-12174. A variety of animal models also suggest that Toll-Like Receptor (TLR) signaling is important in the pathogenesis of Rheumatoid Arthritis (RA) via persistent expression of pro-inflammatory cytokines by macrophages. Signaling through TREM2 / DAP12 inhibits TLR responses by reducing MAPK (Erkl / 2) activation, suggesting that TREM2 activation may act as a negative regulator of TLR driven RA pathogenesis. Signaling through DAP10 and DAP12 also elicits recruitment of PI3K and SYK, which drive multiple downstream events resulting in Ca2+mobilization and activation of MAPK-mediated cascades as well as other pathways.

[0075] In view of the data indicating that deficiency in TREM2 activity affects macrophage and microglia function, the TREM2 agonist compounds disclosed herein are of particular use in treating, preventing, and / or reducing the severity of disorders such as those described below, and in neurodegenerative disorders more generally.

[0076] TREM2 consists of a single-pass transmembrane domain, an extracellular stalk region, and extracellular immunoglobulin variable-like (IgV) domain responsible for ligand interaction (Kleinberger et al. Sci Transl Med. 2014; 6 (243)). As TREM2 does not possess intracellular signal transduction-mediating domains, biochemical analysis has illustrated that interaction with adaptor proteins DAP10 and DAP12 mediate downstream signal transduction following ligand recognition (Peng et al. Sci Signal. 2010; 3(122):ra38; Jay et al. Mol Neurodegener, 2017).TREM2 / DAP12 complexes in particular act as a signaling unit that can be characterized as proactivation on microglial phenotypes in addition to peripheral macrophages and osteoclasts (Otero et al. J Immunol. 2012; 188(6):2612-21; Kobayashi et al. JNeurosci. 2016; 36(43): 11138-11150; Jaitin et al., Cell 2019; 178(3):686-698.el4). 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; 429(11): 1607-1629; Shirotani et al., Sci Rep. 2019; 9(l):7508). 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; 129(3):429-47, Wu et al., Mol Brain, 2017; 10(l):20).

[0077] In rodent models where TREM2 expression levels are elevated, brain amyloid pathology in the 5XF AD transgenic mice displayed reduced plaque volume and altered morphology (Lee et al. Neuron, 2018; 97(5): 1032-1048. e5). The changes in immunohistological markers relating to26176brain amyloid pathology were also accompanied by an attenuated presence of dystrophic neurites when TREM2 was overexpressed. As such, pharmacological agonism of TREM2 has gained interest in treating or preventing neurodegenerative disorders and conditions.

[0078] Genetic variation 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;49(9): 1373-1384). Genetic variation of other genes selectively expressed by microglia in the CNS, for example, CD33, PLCg2 and MS4A4A / 6A have reached genome-wide significance for their association with LOAD risk (Hollingworth et al. Nat Genet 2011, Sims et al. Nat Genet 2017, Deming et al. Set Transl Med 2019; 11(505): 2291). 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; 14(1): 1). 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. Set Transl Med 2019; 11 (507):6221). Additional studies have revealed that CSF sTREM2 levels are elevated in the earlier course of AD and attenuated in the dementia stage (Liu et al., Neurosci Lett. 2018; 686:10-16), and are elevated following brain amyloidosis, CSF phosphorylation, and total tau protein increases (Halaas et al., Cereb Cortex. 2020; 30(4):2295-2306).

[0079] Accordingly, provided herein are methods of administering any of the disclosed compounds, or a pharmaceutically acceptable salt thereof, for treatment or prevention of LOAD. Further provided herein are methods for treatment or prevention of a condition associated with a loss of function of human TREM2, human DAP12 or human DAP10. Further provided herein are methods for reducing the amount of sTREM2 in the CSF of a subject.

[0080] In addition to human genetic evidence supporting a role of TREM2 in LOAD, homozygous loss-of-function mutations in TREM2 are causal for an early onset dementia syndrome known as Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (“PLOSL”) or Nasu-Hakola disease (“NHD”) (Golde et al. Alzheimer s Res Tuer 2013; 5(3):24, Dardiotis et al. Neurobiol Aging 2017 ; 53:194.el3-194.e22). This progressive neurodegenerative disease typically manifests in the third decade of life and is pathologically characterized by loss of myelin in the brain concomitant with gliosis, unresolved neuroinflammation, and cerebral atrophy. Typical neuropsychiatric presentations are often26176preceded by osseous abnormalities, such as bone cysts and loss of peripheral bone density (Bianchin et al. Cell Mol Neurobiol 2004; 24(l):l-24; Madry et al. Clin Orthop Relat Res 2007,454:262-9; Bianchin et al. Nat Rev Neural 2010, 6(9):2). 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; 198(4):669-75, Otero et al. J Immunol 2012). The link between TREM2 function and PLOSL / NHD and other adult-onset leukoencephalopathies has illustrated the importance of the receptor in sustaining key aspects of myeloid cell function in the human body.

[0081] Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously recognized as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD), is an autosomal-dominant central nervous system disease that manifests in the form of variable behavioral, cognitive and motor function changes in patients suffering from the disease. ALSP is characterized by patchy cerebral white matter abnormalities visible by magnetic resonance imaging. However, the clinical symptoms and MRI changes are not specific to ALSP and are common for other neurological conditions, including Nasu-Hakola disease (NHD) and AD, making diagnosis and treatment of ALSP very difficult. 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 CSF-1R, suggesting a reduced level of signaling on the macrophage colony-stimulating factor (M-CSF) / CSF-1R axis. CSF-1R is a 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.

[0082] Accordingly, provided herein are methods of administering any of the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, for treatment or prevention of PLOSL. Further provided herein are methods of administering any of the compounds of the disclosure for treatment or prevention of NHD. Further provided herein are methods of administering any of the compounds of the disclosure for treatment or prevention of adult-onset leukoencephalopathy, with or without axonal spheroids and pigmented glia. Further provided herein are methods of administering any of the compounds of the disclosure for treatment or prevention of ALSP.

[0083] Further provided herein are methods of administering any of the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, for treatment or prevention of argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear26176palsy, inherited frontotemporal dementia, Parkinson’s disease linked to chromosome 17, HIV-induced dementia or neuroinflammation.

[0084] In addition to the CNS, TREM2 is expressed in myeloid lineage cells of the liver. In some embodiments, the compounds of the disclosure, or a pharmaceutically acceptable salt thereof, may be useful to treat or prevent a liver disease associated with impaired TREM2 function. In some embodiments, these compounds are useful to treat or prevent alcoholic liver disease (ALD) or non-alcoholic steatohepatitis (NASH).

[0085] In various embodiments of any of the disclosed methods, the subject suffers from the disorder or condition being treated. In various embodiments, the subject is human.

[0086] In other embodiments, the subject is a non-human mammal. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a laboratory animal. In some embodiments, the subject is a rodent. In some embodiments, the subject is a non-human primate.Formulations

[0087] When administered to a subject, any of the compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, may be administered as a component of a composition that comprises a pharmaceutically acceptable carrier. The present disclosure provides pharmaceutical compositions comprising an effective amount of at least one of the compounds of the present disclosure and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, adapted for oral administration in the form of tablets or capsules, any of the compounds of the present disclosure may be combined with any pharmaceutically acceptable inert carrier. Solid form preparations include powders, tablets, dispersible granules, capsules, sachets and suppositories. Tablets, powders, sachets and capsules may be suitable for oral administration. Powders and tablets may be comprised of between about 0.5 and about 95 percent of any of the compounds of the disclosure.

[0088] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch,26176or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.

[0089] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0090] Moreover, when desired or needed, suitable binders, glidants, lubricants, disintegrating agents and coloring agents may also be incorporated in the composition, particularly in formulations for oral administration. The compositions may be formulated for extended or controlled release. In other embodiments, the compositions are formulated for immediate or modified release.

[0091] In particular embodiments, the disclosed compositions may be formulated in extended dosing, or sustained release, forms to provide a rate-controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., TREM2 activation. Suitable dosage forms for sustained release include long-acting injectable and implant dosage forms. Other suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

[0092] Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques known in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.These preparations may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like.

[0093] In some embodiments, any of the disclosed pharmaceutical compositions comprise pharmaceutically acceptable carriers that are suitable or adapted for administration to the subject by injection. In some embodiments, these carriers are adapted for long-acting injection. In some embodiments, these carriers are liquid form preparations that include solutions, suspensions, emulsions, or nano-emulsions for intramuscular or subcutaneous administration. In some embodiments, any of the disclosed pharmaceutical compositions are adapted for long-acting injectable formulations.

[0094] Any of the disclosed compositions may comprise pharmaceutically acceptable carriers that are suitable or adapted for administration parenterally, including subcutaneous, intravenous, intramuscular, intraperitoneal or intrastemal injection, or other infusion techniques (one or more injections or infusions may be administered at each dosing interval as needed to deliver the appropriate amount of active agent), in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional pharmaceutically acceptable carriers, adjuvants and vehicles for the treatment of a subject suffering from a neurodegenerative disorder. The compositions may also be administered parenterally via an implantable drug delivery composition or device adapted to provide an effective amount of the compound over an extended period of time. In some embodiments, the composition is administered parenterally once per month, once per every three months, once per every six months, or once per every twelve months.

[0095] In some embodiments, the disclosed compositions are adapted for intramuscular administration. In some embodiments, the disclosed compositions are adapted for subcutaneous administration. In some embodiments, the disclosed compositions are adapted for intravenous administration. In some embodiments, the disclosed compositions are adapted for intraperitoneal administration. In some embodiments, the disclosed compositions are adapted for intracerebroventricular (ICV), intrathecal, or intraci sternal administration. In some embodiments, the disclosed compositions may be adapted for inhalation spray, intranasal, vaginal, rectal, sublingual, buccal or topical routes of administration.

[0096] Parenteral compositions can be prepared according to techniques known in the art. These compositions may employ sterile water as a carrier and optionally other ingredients. A continuous dosing regimen may be used for subjects suffering from a neurodegenerative disease, such as Alzheimer’s Disease. Any of the disclosed pharmaceutical preparations for parenteral injection may comprise solutions, suspensions or emulsions that may include water, a suspending agent, a viscosity modifier, a tonicity modifier, and / or a pH modifier.

[0097] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions, emulsions and nano-emulsions. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Implantable compositions can be prepared according to methods known in the art wherein the carrier comprises the active chemical ingredient with polymers and suitable excipients, or utilizing an implantable device for drug delivery. Further description of methods suitable for use in preparing pharmaceutical compositions for use in the present disclosure and of ingredients suitable for use in said compositions is provided in Remington - The Science and Practice of Pharmacy, 22nd Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences, 2012, ISBN 9780 85711-062-6 and prior editions.

[0098] Formulations of compounds of the present disclosure that result in drug supersaturation and / or rapid dissolution may be utilized to facilitate oral drug absorption. Formulation approaches to cause drug supersaturation and / or rapid dissolution include, but are not limited to, nanoparticulate systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation approaches and techniques for preparing them are known in the art. For example, solid dispersions can be prepared using excipients and processes as described in reviews (e.g., A.T.M. Serajuddin, J Pharm Sci, 88:10, pp. 1058-1066 (1999)). Nanoparticulate systems based on both attrition and direct synthesis have also been described in reviews such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).

[0099] The compounds of the present disclosure may be administered in a dosage range of, e.g., 1 to 20 mg / kg, or 1 to 10 mg / kg, or about 5 mg / kg of mammal (e.g., human) body weight per day, or at other time intervals as appropriate, in a single dose or in divided doses. The compounds of the present disclosure may be administered in a dosage range of 0.001 to 2000 mg per day in a single dose or in divided doses. Examples of dosage ranges are 0.01 to 1500 mg per day, or 0.1 to 1000 mg per day, administered orally or via other routes of administration in a single dose or in divided doses.

[0100] For oral (e.g., tablets or capsules) or other routes of administration, the dosage units may contain 100 mg to 1500 mg of the active ingredient, for example but not limited to 0.1 mg to about 1500 mg of the active ingredient, for example but not limited to 0.1, 0.25, 0.5, 1, 2, 2.5, 5,10, 15, 20, 25, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 1000, 1250, or 1500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. Furthermore, the compound may be formulated in oral formulations for immediate or modified release such as extended or controlled release. When the compound of the present disclosure is administered as a salt, reference to an amount of the compound in milligrams or grams is based on the free form (i.e., the non-salt form) of the compound.

[0101] Daily administration can be via any suitable route of administration but is preferably via oral administration and can be a single dose or more than one dose at staggered times (divided daily doses) within each 24-hour period. Each dose may be administered using one or multiple dosage units as appropriate. In some embodiments, the compounds of the present disclosure and the disclosed compositions are administered once daily. In some embodiments, the compounds of the present disclosure and the disclosed compositions are administered twice daily.

[0102] The specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, the effect of other drugs the subject is taking, the severity of the particular condition, and the host undergoing therapy. In some cases, depending on the potency of the compound or the individual response, it may be necessary to deviate upwards or downwards from the given dose. The amount and frequency of administration will be regulated according to the judgment of the attending clinician considering such factors.

[0103] The compounds of the present disclosure are also useful in the preparation and execution of screening assays for agonists of TREM2. Furthermore, the compounds of this invention may be useful in establishing or determining the binding site of other TREM2 agonists.

[0104] Additional embodiments of the present disclosure include the following:(a) a pharmaceutical composition comprising an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and(b) a pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0105] Additional embodiments of the present disclosure include each of the pharmaceutical compositions, methods and uses set forth in the preceding paragraphs, wherein the compound of the present disclosure or its salt employed therein is substantially pure. With respect to a26176pharmaceutical composition comprising a compound of the present disclosure or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term “substantially pure” is in reference to a compound of the present disclosure or its salt per se.Combination Therapies

[0106] In some aspects, the present methods for treating or preventing a neurodegenerative disorder can further comprise the administration of one or more additional therapeutic agents that are not any of the compounds of the present disclosure.

[0107] Examples of additional therapeutic agents that the compounds of the present disclosure may also be combined with include, without limitation, treatments for Alzheimer’s disease, Parkinson's disease, rheumatoid arthritis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, demyelination disorder, Huntington’s disease, amyotrophic lateral sclerosis (ALS), tauopathy disease, adult-onset leukoencephalopathy, argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, HIV-induced dementia, or neuroinfl animation.

[0108] Accordingly, in one embodiment, the present invention provides methods for treating a neurodegenerative disorder in a subject, the method comprising administering to the subject: (i) at least one compound of the present disclosure (which may include two or more different compounds), or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than any of the compounds of the present disclosure, wherein the amounts administered are together effective to treat or prevent a neurodegenerative disorder.

[0109] In some embodiments, the additional therapeutic agent is a tau targeting therapy. In some embodiments, the additional therapeutic agent is an amyloid-P targeting therapy.Administration of a tau targeting therapy or an amyloid-P targeting therapy has been shown to improve cognitive function, reverse (partially) the neurodegenerative effects of Alzheimer’s Disease, and / or treat or prevent Alzheimer’s Disease. Accordingly, provided herein are methods of administering any of the compounds of the present disclosure wherein the methods further comprise a step of administering a tau targeting therapy or an amyloid-P targeting therapy to the subject. Such methods may be used to promote the treatment or prevention of a neurodegenerative disorder in a subject. Such methods may be used to promote the treatment or prevention of AD in a subject.

[0110] When administering a combination therapy of the invention to a subject, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising26176therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, a compound of the present disclosure and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like). In some embodiments, any of the compounds of the present disclosure or a pharmaceutically acceptable salt thereof, is administered orally, and the additional therapeutic agent is further administered orally. When administered orally, the compound of the present disclosure and the other agent(s) may be administered simultaneously (i.e., in separate compositions one right after the other) or sequentially.[oni] In some embodiments, a disclosed compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a compound of the present disclosure or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0112] In one embodiment, at least one compound of the present disclosure is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

[0113] In another embodiment, at least one compound of the present disclosure and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy. In another embodiment, at least one compound of the present disclosure and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy.

[0114] In some embodiments, the additional therapeutic agent(s) is present in a pharmaceutical composition. In one embodiment, this composition is suitable for subcutaneous administration. In another embodiment, this composition is suitable for intramuscular administration. In another embodiment, this composition is suitable for oral administration. In still another embodiment, this composition is suitable for intravenous administration.

[0115] The at least one compound of the present disclosure and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of26176lower dosages of one or more agents and / or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.

[0116] The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a neurodegenerative disorder may be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age, sex and general health of the subject; and the type and severity of the neurodegenerative disease or neurological symptoms thereof. When administered in combination, the compound of the present disclosure and the other agent(s) may be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another component is administered every six hours, or when the pharmaceutical compositions are different, e.g., one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous.ABBREVIATIONS

[0117] The abbreviations used herein, including in the General Synthetic Schemes and Examples, have the following tabulated meanings. Abbreviations not tabulated below have their meaning as commonly used in the synthetic organic chemical and biological arts.4CzIPN l,2,3,5-Tetrakis(carbazol-9-yl)-4,6-dicyanobenzene, 2,4,5,6-Tetrakis(9H- carbazol-9-yl) isophthalonitrileACN acetonitrileAcOH acetic acidAmF Ammonium formateaq aqueousB2(EPin)24,4,4',4',5,5,5',5'-octaethyl-2,2'-bi(l,3,2-dioxaborolane)BINAP-Pd-G4 (Methanesulfonatato-KO)[2'-(methylamino-KN)-2-biphenylyl-KC2]palladium - 1,1 '-binaphthalene-2,2'-diylbis(diphenylphosphine)Boc tert-butoxycarbamateBoc2O di-tert-butyl dicarbonateBTMG 2- / c' / 7-biit\ l- 1 , 1 ,3, 3 -tetramethylguanidine°C degrees Celsiuscalc’d CalculatedCDCh deuterated chloroformCD3OD deuterated methanolCs2CO3cesium carbonateCuTC Copper (I) thiophene-2 -carboxylatecone concentratedDCM DichloromethaneDCE dichloroethaneDIPEA Diisopropylethylamine26176DMA DimethylacetamideDMF DimethylformamideDMSO DimethylsulfoxideEDCI l-Ethyl-3-(3-dimethylaminopropyl)carbodiimideeq or equiv equivalentsESI electron spray ionizationEtOAc ethyl acetateEtOH EthanolEt3SiH triethylsilaneh hoursHBr Hydrobromic acidHC1 Hydrochloric acid1HNMR proton nuclear magnetic resonance (data)HPLC high performance liquid chromatographyIC50 inhibitory concentration at 50% maximum responseInt. IntermediateiPrOH Isopropyl alcoholiPrMgCl Isopropylmagnesium chlorideLCMS liquid chromatography mass spectrometryMeCN acetonitrileMeOH methanolMHz Megahertzmin minutesMS mass spectrum (data)Nal Sodium iodideNaOAc sodium acetateNa2SO4 Sodium sulfateNaSMe Sodium thiomethoxideNBS N-bromosuccinimideNiCl2«DME Nickel (II) chloride ethylene glycol dimethyl ether complex NCS N-ChlorosuccinimideNMR nuclear magnetic resonance (data)KOAc potassium acetateK3PO4 potassium phosphatePd2(dba)3tris(dibenzylideneacetone)dipalladium(0)PdCl2Palladium (II) chloridePdCl2(dppf) [1,1' -bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4Tetrakis (triphenylphosphine palladium (0)POC13Phosphoryl chlorideRT room temperaturesat saturatedSFC supercritical fluid chromatographySPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl TBAI Tetrabutylammonium iodideTEA triethylamineTFA trifluoroacetic acidTfOH Trifluoromethanesulfonic acidTHF tetrahydrofuranTLC thin layer chromatography%wt weight percentageZn Zinc26176GENERAL SYNTHETIC SCHEMES

[0118] The following reaction schemes illustrate methods which may be employed for the synthesis of the compounds of structural Formula (I) or Formula (I’ ) described in this present disclosure. These reaction schemes are provided to illustrate the invention and are not to be construed as limiting the invention in any manner. All substituents are as defined above unless indicated otherwise. Several strategies based upon synthetic transformations known in the literature of organic synthesis may be employed for the preparation of the compounds of structural Formula (I) or Formula (I’ ).Scheme 1-1

[0119] A general synthetic approach to some of the chemical matter is outlined in Scheme 1-1. In the first step of Scheme 1-1, the oxazolo group (or 1,3-oxazine group) is installed using a condensation reaction. In step two, R3can be installed via a Suzuki reaction. The amine derivative is formed through a C-N coupling.Scheme 1-2

[0120] A general synthetic approach to certain derivatives wherein Y1 is C(H) is outlined in Scheme 1-2. In the first step of Scheme 1-2, the tetrahydropyran group is installed through a sp2-sp3C-C coupling.26176Scheme 1-3R3R3

[0121] Another general synthetic approach to certain derivatives wherein Y1 is C(H) is outlined in Scheme 1-3. In the first step of Scheme 1-3, the dihydropyran group is installed through a sp2-sp2C-C coupling. In step two, a double bond is reduced.Scheme 2-1SMe SMe C-C coupling dehydrationSMe R3R3C-C coupling HO"6"OH

[0122] Another general synthetic approach to certain derivatives wherein Y1 is C(H) is outlined in Scheme 2-1. In the first step of Scheme 2-1, the oxazolo group (or 1,3-oxazine group) is installed through a condensation reaction with an amide, then a C-C coupling reaction installs the tetrahydropyran moiety. Finally, a C-C bond formation installs R3.26176Scheme 3-1C-C coupling dehydrationC-C coupling

[0123] Another general synthetic approach to certain derivatives wherein Y1 is C(H) is outlined in Scheme 3-1. In the first step of Scheme 3-1, the oxazolo group (or 1,3-oxazine group) is installed through a condensation reaction with an amide, then a C-C coupling reaction installs the tetrahydropyran moiety. Finally, a C-C bond formation installs R3.EXAMPLES

[0124] The following examples are meant to be illustrative and should not be construed as further limiting. The compounds of the present disclosure can be prepared according to the procedures of the following Examples, using appropriate materials. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of protecting groups, as well as of the conditions and processes of the following preparative procedures, can be used to prepare these compounds. It is also understood that whenever a particular chemical reagent is not commercially available, such a chemical reagent can be readily prepared following one of numerous methods described in the literature.

[0125] Reactions were monitored by liquid chromatography / mass spectrometry (LCMS) and visualized with UV light (215 or 254 nm). Proton nuclear magnetic resonance spectra were recorded on a 400, 500 or 600 MHz NMR spectrometer at ambient temperature. All chemical shifts (8) are reported in parts per million (ppm). Proton resonances are referenced to residual protium in the NMR solvent. Data are represented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (J) in Hertz (Hz), integration.26176SYNTHESIS OF COMMON INTERMEDIATESIntermediate 1-1. Preparation of (.S)-2-(l-methyl-l / / -pyrazol-4-yl)morpholine from SFC separationSFC

[0126] Int. 1-1 (5)-2-(l-methyl-lH-pyrazol-4-yl)morpholine was obtained from commercially available racemic 2-(l -methyl- lH-pyrazol-4-yl)morpholine and separated as Peak 1 by chiral SFC (tR = 3.5 min), while Peak 2 (tR = 4.5 min) was (A)-2-(l -methyl- lH-pyrazol-4-yl)morpholine. The SFC separation conditions: Column & Dimensions: IG, 21x250 mm, 5 pm. UV Wavelength: 215 nm; Flow Rate: 80 ml / min; Modifier: 20% MeOH w / 0.1% NH4OH;Outlet Pressure: 100 bar; Diluent: MeOH.Intermediate 1-2. Preparation of 7-chloro-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one1-2 Step 1. 5,7-dichloro-lH-oxazolor3,4-a1pyridol3,4-d1pyrimidin-9(3H)-one

[0127] To a solution of 3-amino-2,6-dichloroisonicotinic acid (500 mg, 2.415 mmol) in toluene (16 mL) was added POCI3 (0.675 mL, 7.25 mmol) at 0 °C. The mixture was stirred at 15 °C for 0.5 h. Then oxazolidin-4-one (421 mg, 4.83 mmol) was added. The resulting mixture was allowed to warm to 110 °C and stirred at 110 °C for 20 h under N2. The mixture was concentrated, treated with H2O (30 mL) and extracted with EtOAc (10 mL * 3). The combined organic fractions were washed with brine (20 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (eluent of 50% ethyl acetate / pet. ether gradient @ 20 mL / min) to give 5,7-dichloro-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0128] MS (ESI) m / z: calc’d for C9H6CI2N3O2 : 258.0 / 260.0, found [M+H]+: 258.0 / 260.0; 'H NMR (CDCI3, 400 MHz): 88.07 (s, 1H), 5.80 (s, 2H), 5.16 (s, 2H).26176Step 2. 7-chloro-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a1pyrido[3,4-d1pyrimidin-9(3H)- one

[0129] To a solution of 5,7-dichloro-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (110 mg, 0.298 mmol) in dioxane / ThO (V / V=5 / l) (3 mL) were added (2,4-difluorophenyl)boronic acid (42.4 mg, 0.269 mmol), Na2CO3 (95 mg, 0.895 mmol) and PdC12(dppf) (21.83 mg, 0.030 mmol) and the resulting mixture was stirred at 60 °C for 2 h under N2. The mixture was poured into water (10 mL) and extracted with EtOAc (8 mL * 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude product which was purified by prep-TLC (SiC>2, Pet. ether / EtOAc=l / l) to give 7-chloro-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0130] MS (ESI) m / z: calc’d for CI5H9C1F2N3O2+[M+H]+: 336.0 / 338.0, found [M+H]+:336.1 / 338.1; 'H NMR (CDCI3, 400 MHz): 88.13-8.21 (m, IH), 7.53-7.64 (m, IH), 6.99-7.08 (m,A1H), 6.94 (td, J= 9.4, 2.3 Hz, IH), 5.7 y° z=9 (s, 2H), 5.03 (s, 2H).

[0131] The intermediate compounds presented in Table 1 were prepared in accordance with the / # \ Asynthetic routes in Intermed / \A1111 —iaZte 1-2, using procedures analogous to those described above. OTable 1Intermediate Structure Name7-chloro-5-(2,3,4-trifluorophenyl)- 1-3 lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF,F7 -chi oro-5 -(2,4, 5 -trifluorophenyl)- F' j1-4 lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one0Cl7-chloro-5-(4-chloro-2-fluorophenyl)- F^y1-16 lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one026176Intermediate Structure Name7-chloro-5-(6- (trifluoromethyl)pyri din-3 -yl)- 1 H- 1-17oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF F7-chloro-5-(4,4-difluorocyclohex-l- 1-18 en-l-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin-9(3H)-one0F ft / 0 z / / W / \ LL r, m —(R or S)-7-chloro-5-(2,4- / / / \Odifluorophenyl)-3 -methyl - 1 H- 1-20Fz<— f Meoxazolo[3,4-a]pyrido[3,4- 0d]pyrimidin-9(3H)-one0F(S or R)-7-chloro-5-(2,4- difluorophenyl)-3 -methyl - 1 H- 1-21FMeoxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one0Intermediate 1-5. Preparation of l-cyclopropyl-4-(4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan- 2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole1-5 Step 1. 6-(l-methyl-lH-pyrazol-4-yl)-3.6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate

[0132] To a solution of l-methyl-lH-pyrazole-4-carbaldehyde (5 g, 45.4 mmol) in DCM (100 mL) under N2 in three-necked flask were added but-3-yn-l-ol (4.77 g, 68.1 mmol) and dropwise26176trifluoromethanesulfonic acid (12.71 mL, 159 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h, then quenched with sat. aq. NaHCO3(200 mL) and extracted with DCM (100 mL * 3). The combined organic fractions were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-40% ethyl acetate / pet. ether gradient) to give 6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate.

[0133] MS (ESI) m / z: calc’d for CIOHIIF3N204S+[M+H]+313.1, found [M+H]+312.8.Step 2. l-cyclopropyl-4-(4-(4,4,5,5-tetraethyl-L3,2-dioxaborolan-2-yl)-5,6-dihydro-2H- pyran-2-yl)-lH-pyrazole

[0134] To a solution of 6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (4.8 g, 14.19 mmo ~ LU LULU Vl) in 1,4-dioxane (40 mL) were added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (1.038 g, 1.419 mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octaethyl-2,2'-bi(l,3,2-dioxaborolane) (6.75 g, 18.45 mmol) and potassium acetate (5.57 g, 56.8 mmol). The mixture was then purged with N2three times and stirred for 1 h at 80 °C. Upon \ / °completion, the mixture was filtered and the filtrate was concentrated. The crude product was purified by flash silica gexZl ° chromatography (Eluent of 0-40% EtOAc / Pet. ether gradient, dry load) to afford 1-5 l-cyclopropyl-4-(4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-py ran-2-y 1 )- 1 H-py razol e .

[0135] MS (ESI) m / z: calc'd for C2iH34BN2O3+[M+H]+373.1, found [M+H]+373.2.

[0136] The intermediate compound presented in Table 2 was prepared in accordance with the synthetic routes in Intermediate 1-5, using procedures analogous to those described above.Table 2Intermediate Structure NameEti Et4,4,5,5-tetraethyl-2-(6- / h ? VEt1-6 (tetrahy drofuran-3 -y 1 ) -3 , 6-dihy dro- VyyB.oAEt2H-pyran-4-yl)- 1 ,3 ,2-dioxaborolane2-(6-(2,2-dimethyltetrahydrofuran-3- 1-22 yl)-3,6-dihydro-2H-pyran-4-yl)- 4, 4, 5 , 5 -tetraethyl - 1 , 3 ,2 -di oxab orol ane26176Intermediate 1-7: (R or .S)-4-(4-bromotet rahydro-2 / / -py ran-2-yl)-l -cyclopropyl- 1 / / -pyrazole'Z / —. / \ ( \ _ 1-7

[0137] Three reactions on the same scale were run in parallel. To a 40 mL vial containing 1-cyclopropylpyrazole-4-carbaldehyd °e \ (1.00 g, 7.3 mmol) and but-3-en-l-ol (583 mg, 0.70 mL, 8.08 mmol) was added DCM (12 mL). The reaction was cooled to 0 °C, followed by the addition CDof HBr in acetic acid (3.9 mL, 33% wt, 22.0 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The three reaction mixtures were combined and diluted with DCM (20 mL) and carefully quenched with sat. NaHCCh (aq.) until the solution became slightly basic. Then the mixture was extracted with 2x50 mL DCM. The organic extracts were combined and concentrated. The crude residue was purified by normal phase flash column chromatography (10-40% EtOAc / hexanes) to give the desired product 4-(4-bromotetrahydro-27 / -pyran-2-yl)- l-cyclopropyl-U / -pyrazole. The product was submitted for SFC purification using the following conditions to yield the isomers as Peak 1 at 3.76 min, Peak 2 at 4.36 min and Peak 3 (mixture of two isomers) at 5.03 min. Peak 3 mixture was further separated through a second SFC purification.

[0138] First SFC condition: Column & Dimensions: IG, 21x250 mm, Modifier: 20% MeOH w / 0.1%NH4OH.

[0139] Second SFC condition with peak 3: Column & Dimensions: IB-N, 21x250 mm, Modifier: 15% MeOH w / 0.1% NH4OH.

[0140] The Peak 3 mixture sample from above was separated via a second SFC run to yield one of the isomers as Peak 3-1 at 2.7 min and Peak 3-2 (1-7) at 3.3 min. MS (ESI) m / z: calc'd for CnHi6BrN2O [M+H]+: 271, 273, found: 271, 273.

[0141] Intermediate compounds presented in Table 3 were prepared in accordance with the synthetic routes in Intermediate 1-7, using procedures analogous to those described above.Table 3Intermediate Structure Name4-(4-bromotetrahydro-2H-pyran-2- 1-8yl)-2-methylpyridine26176Intermediate Structure Name5-(4-bromotetrahydro-2H-pyran-2- 1-9yl)-2-methylthi azole5-(4-bromotetrahydro-2H-pyran-2- 1-10yl)-3-methylisothi azole A OMe4-(4-bromotetrahydro-2H-pyran-2- 1-11Nll ° \yl)-2-methoxypyridine OT CDo-X- 4-bromo-2-(2,2- 1-12 AxY / x. / Br dimethyltetrahy drofuran-3 - yl)tetrahydro-2H-pyran FFA4-(4-bromotetrahydro-2H-pyran-2- 1-13yl)-l-(difluoromethyl)-lH-pyrazole4-bromooctahydro-2H,2'H-2,4'- 1-23°^A bipyranAF4-bromo-2-(2,2- 1-24 ,Br difluorocyclobutyl)tetrahydro-2H-OJ pyran / LFV> 4-bromo-2-(3-fluorotetrahydrofuran- 1-25 CA\ ,Br3 -yl)tetrahy dro-2H-py ran °\AMeO. _4-bromo-2-(3- 1-26 A=A / \ Rr methoxybicyclof 1.1.1 ]pentan- 1 - °\A yl)tetrahydro-2H-pyran V 4-bromo-2-(2,2- 1-27 ,Br difluorocyclopropyl)tetrahydro-2H- °\A pyran4-(4-bromotetrahydro-2H-pyran-2- 1-28 VA^ / \ .Bryl)-2-oxabicyclo[2.1.1 ]hexane°\A26176Intermediate Structure NameNC. _3-(4-bromotetrahydro-2H-pyran-2- 1-29 Rr yl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrile2-(bicyclo[ 1.1.1 ]pentan- 1 -yl)-4- 1-30bromotetrahydro-2H-pyran / ^N 5-(4-bromotetrahydro-2H-pyran-2- 1-31yl)-2-ethylthi azole O^Jtn 5-(4-bromotetrahydro-2H-pyran-2- 1-32yl)-2-cyclopropylthi azole / °H4-(4-bromotetrahydro-2H-pyran-2- 1-33Nllyl)-6-methylpyrimidine ,Br3-(4-bromotetrahydro-2H-pyran-2- 1-34yl)propanenitrile4-((2R,6R)-4-bromo-6- 1-35 1 II methyltetrahydro-2H-pyran-2-yl)-2- o^ J methylpyridineMe5-(4-bromotetrahydro-2H-pyran-2- 1-36vVrBryl)-3-methylisothi azole O-,4-bromo-2-(tetrahy drofuran-3 - 1-37 .BrCk^J yl)tetrahydro-2H-pyranF\ "\ 4-bromo-2-(3- 1-38 Wx ^^Br fluorobicyclof 1.1.1 ]pentan- 1 - O^J yl)tetrahydro-2H-pyran u 5-(4-bromotetrahydro-2H-pyran-2- 1-39NvA^-yBryl)-2-methyloxazole26176Intermediate Structure NameF4-(4-bromotetrahydro-2H-pyran-2- 1-40 yl)- 1 -(2,2-difluorocyclopropyl)- 1H- pyrazole^ ZO5-(4-bromotetrahydro-2H-pyran-2- 1-41N\^k / \ Rryl)-2-cyclopropyloxazolecn “14-(4-bromotetrahydro-2H-pyran-2- 1-42yl)- 1 -cyclobutyl- IH-pyrazole4-bromo-2',2'-dimethyloctahydro- 1-432H,2'H-2,4'-bipyranO^JR / FV 4-(4-bromotetrahydro-2H-pyran-2- 1-44yl)-l-(l,l -difluoroethyl)- 1 H-pyrazole4-(4-bromotetrahydro-2H-pyran-2- 1-45VyY' yl)- 1 -isopropyl- IH-pyrazole O^J3-(4-bromotetrahydro-2H-pyran-2- 1-46yl)dihydrofuran-2(3H)-oneIntermediate 1-14. 7-bromo-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one26176step 1 step 21-14Step 1.

[0142] To a dark brown solution of 5-amino-2-bromo-4-pyridinecarboxylic acid (10.0 g, 46.079 mmol) in DMF (92.2 mL) was added N-chlorosuccinimide (6.15 g, 46.1 mmol). The reaction mixture was stirred at 60 °C for 16 hours to complete the reaction. After cooling to room temperature, the resulting mixture was poured into H2O (600 mL) to form a solid. The solid was collected, washed with H2O several times, and dried to afford 3-amino-6-bromo-2-chloroisonicotinic acid.

[0143] MS (ESI) m / z: calc’d for C6H3BrClN2O2 [M-H]" = 249.1 and 251.1, found [M-H]" = 249.1 and 251.1.Step 2.

[0144] A mixture of 3-amino-6-bromo-2-chloroisonicotinic acid (3.70 g, 14.7 mmol), potassium carbonate (4.07 g, 29.4 mmol), and sodium methanethiolate (4.12 g, 58.9 mmol) in DMA (36.8 mL) was stirred at 100 °C for 0.25 hour. The resulting mixture was poured into H2O (200 mL) and acidified with IM HC1 aq. (80 mL). The precipitate formed was collected via vacuum filtration, washed with water, and dried under vacuum to afford 3-amino-6-bromo-2-(methylthio)isonicotinic acid.

[0145] MS (ESI) m / z: calc’d for C7H7BrN2O2S+[M+H]+: 262.9, 264.9, found [M+H]+: 263.0, 264.9.Step 3.

[0146] A mixture of 3-amino-6-bromo-2-(methylthio)isonicotinic acid (3.00 g, 11.4 mmol) in toluene (15.2 mL) was cooled to 0 °C. To the mixture was added phosphorus oxychloride (5.24 g, 3.15 mL, 34.2 mmol), and the mixture was allowed to stir at 0 °C for 0.5 hours. Oxazolidine-4-one (3.50 g, 71% Wt, 28.5 mmol) was then added, and the mixture was stirred at 110 °C for 126176hour. Water was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic phase was dried overNa2SC>4, filtered and the filtrate was concentrated. The crude product was triturated in EtOAc and then filtered by vacuum filtration. The precipitate was washed with water, filtered, and dried by vacuum filtration to obtain 1-147-bromo-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0147] MS (ESI) m / z: calc'd for CioH8BrN302S+[M+H]+314.0, 316.0 found [M+H]+314.1, 315.9.

[0148] The intermediate compound presented in Table 4 was prepared in accordance with the synthetic routes in Intermediate 1-14, using procedures analogous to those described above.Table 4Intermediate Structure NameSMe8-bromo-6-(methylthio)-3,4-dihydro- 1H,1OH- 1-15pyrido[3',4':4,5]pyrimido[l,2- c] [ 1 ,3 ] oxazin- 10-one0SMeMe(S or R)-7-bromo-3-methyl-5- 1-47 (methy Ithi 0)- 1 H-oxazol 0 [3 , 4- a]pyrido[3,4-d]pyrimidin-9(3H)-one 0SMeMe(R or S)-7-bromo-3-methyl-5- 1-48 (methy Ithi 0)- 1 H-oxazol 0 [3 , 4- . -5m a]pyrido[3,4-d]pyrimidin-9(3H)-oneOIntermediate G-l: 2,2-difluorocyclobutane-l-carbaldehydeDMP, CH2CI2G-1

[0149] To a solution of (2,2-difluorocyclobutyl)methanol (1.00 g, 8.19 mmol) in CH2CI2 (10.0 mL) was added 3-oxo-ll5-benzo[ ][l,2]iodaoxole-l,l,l(3J7)-triyl triacetate (Dess-Martin periodinane, 4.17 g, 9.83 mmol) at 0 °C under N2. The reaction was brought to 25 °C and stirred for 2h. The reaction mixture was neutralized with NaHCCh (aq. sat.) and Na2S2O3 (aq. sat.). The organic layer was extracted with CH2CI2 (20 mL x 3), washed with brine, dried over anhydrous sodium sulfate, then partially concentrated under reduced pressure to afford 2,2-difluorocyclobutane-l-carbaldehyde as a CH2CI2 solution. The product was carried over to the next step as is.26176Intermediate G-2: 3-fluorotetrahydrofuran-3-carbaldehydeIBX, DCEG-2

[0150] To a mixture of (3-fluorotetrahydrofuran-3-yl)methanol (826 mg, 6.88 mmol) in DCE (12 mL) was added one portion of IBX (5.78 g, 20.6 mmol). The reaction mixture was stirred at 80 °C for 17.5 hours. The resulting mixture was filtered through a pad of Celite to deliver a solution of 3-fluorotetrahydrofuran-3-carbaldehyde, which was directly used for the next reaction without further purification and concentration.^NMR^OO MHz, CDC13) 69.90 (d, J = 4.9 H, 1H), 4.10 - 3.98 (m, 4H), 2.40 - 2.23 (m, 2H).

[0151] Compounds presented in Table 7 were prepared in accordance with the synthetic routes in Intermediate G-l and G-2, using procedures analogous to those described above.Table 7Intermediate Structure IUPAC Name3 -formylbicyclo[ 1.1.1 ]pentane- 1 - G-3carbonitrileOMeO^3 -methoxybicyclo[ 1.1.1 ]pentane- 1 - G-4n carbaldehyde02,2-difluorocyclopropane-l- G-5K carbaldehyde0bicyclofl .1. l]pentane-l - G-6carbaldehyde02-oxabicyclo[2.1.1 ]hexane-4- G-7carbaldehyde03 -fluorobicyclofl .1.1 ]pentane- 1 - G-8carbaldehyde0F\ / FV ( 1 -( 1 , 1 -difluoroethyl)- 1 H-pyrazol-4- G-9yl)methanol026176Intermediate H-l : l-(2.,2-difluorocvclopropyl)-lH-pyrazole-4-carbaldehvdePOCI31DMFH-1

[0152] POCI3 (16.0 g, 9.70 mL, 104 mmol) was added dropwise to DMF (41.6 mL) at 25 °C and was stirred for 30 min. l-(2,2-difluorocyclopropyl)-lH-pyrazole (3.00 g, 20.8 mmol) in DMF (27.8 mL) was added to the resulting mixture and was stirred for 16 hours at 110 °C. Upon completion, the reaction mixture was poured over ice and quenched with NaHCCh until the pH reached 7-8. The solution was extracted with EtOAc (x3) and washed with brine, dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (SiC>2, 2-40% EtOAc / Hexanes) to give the desired l-(2,2-difluorocyclopropyl)-lH-pyrazole-4-carbaldehyde.'H NMR (400 MHz, CDCI3) 89.88 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 4.21 - 4.12 (m, 1H), 2.31 - 2.12 (m, 2H).Intermediate J-l: 2-cyclopropyl-5-(4-iodotetrahvdro-2H-pyran-2-yl)thiazoleNal, acetone1-34

[0153] A microwave vial was charged with 3-(4-bromotetrahydro-2H-pyran-2-yl)propanenitrile (85 mg, 0.32 mmol), sodium iodide (0.24 g, 1.6 mmol) in acetone (1 mL). The vial was sealed and irradiated in a microwave reactor for 20 min at 120 °C. Upon completion, the suspension was concentrated, the residue was resuspended in CH2Q2, filtered, and concentrated to yield crude 3-(4-iodotetrahydro-2H-pyran-2-yl)propanenitrile, which was used without additional purification. MS (ESI) m / z: calc’d for C8HI2INO [M+H]+: 266.0; found: 266.0.

[0154] Examples shown in Table 8 below were prepared according to procedures analogous to those outlined for Intermediate J-l above, using the appropriate starting materials.Table 8Intermediate Structure IUPAC Name4-(4-iodotetrahydro-2H-pyran-2-yl)-2- methylpyridine26176Intermediate Structure IUPAC Name4-iodo-2-(tetrahydrofuran-3- J-3yl)tetrahydro-2H-pyranl-cyclobutyl-4-(4-iodotetrahydro-2H- J-4 N'XJ1 1 pyran-2-yl)-lH-pyrazole O^J01 4-iodo-2',2'-dimethyloctahydro- J-52H,2'H-2,4'-bipyran O^JR / 1 -(1 , 1 -difluoroethyl)-4-(4-F N~-iJ-6 N\ Jl , iodotetrahydro-2H-pyran-2-yl)-lH- pyrazoleFF— (1 -(difluoromethyl)-4-(4- J-7N~~lN\J1 I iodotetrahydro-2H-pyran-2-yl)-lH- pyrazoleO^J1 -cy cl opropy 1 -4 -(4-i odotetrahydro-2H- J-8pyran-2-yl)-lH-pyrazole °\X3-(4-iodotetrahydro-2H-pyran-2- J-9yl)bicyclo[ 1.1.1 ]pentane- 1 -carbonitrile°\X26176Intermediate K-l, (A)-5-methyloxazolidin-4-onestep 1 step 2BnNH2, DBU, pTSA, PhMe, Triazole Paraformaldehydestep 3_ K-1 _Step 1.

[0155] To a stirred solution of phenylmethanamine (10.0 g, 10.2 mL, 93.3 mmol) was added l,8-Diazabicyclo[5.4.0]undec-7-ene (2.84 g, 2.79 mL, 0.2 equiv, 18.7 mmol), (+)-methyl D-lactate (9.71 g, 8.90 mL, 93.3 mmol), and 1H-1,2,4-Triazole (1.29 g, 18.7 mmol). The resulting mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted in EtOAc, and the organic phase was washed with brine, dried over MgSCh, filtered, and concentrated under reduced pressure. The material was used without additional purification.MS (ESI) m / z: calc’d for C10H14NO2 [M+H]+: 180.1 found [M+H]+: 180.3.Step 2.

[0156] To a solution of (A)-N-benzyl-2-hydroxypropanamide (16.7 g, 93.2 mmol) in toluene (200 mL) was added paraformaldehyde (11.2 g, 373 mmol) and pTSA (2.66 g, 14.0 mmol). The resulting mixture was stirred at reflux for 16 hours under a Dean-Stark apparatus. The reaction mixture was cooled to room temperature, and the solvents were removed under reduced pressure. The residue was purified by flash chromatography (Si O2, 50% EtOAc / Heptane) to afford (A)-3-benzyl-5-methyloxazolidin-4-one.MS (ESI) m / z: calc’d for C11H14NO2 [M+H]+: 192.1 found [M+H]+: 192.2.Step 3.

[0157] In a round-bottom flask, 4,4’-di-tert-butylbiphenyl (6.97 g, 26.1 mmol) was subjected to vacuum and flame-dried until it melted. The flask was backfilled with Ar and allowed to cool to room temperature. At 0 °C, THF (70 mL) was added, followed by finely chopped pieces of lithium wire (1.81 g, 261 mmol), and stirred for 5 hours at 0 °C. This procedure involves26176preparing a 0.4 M solution of LiDBB, which is assumed to be quantitative. In a second roundbottom flask purged with Ar, (R)-3-benzyl-5-methyloxazolidin-4-one (1.00 g, 5.23 mmol) was dissolved in anhydrous THF (35 mL) and cooled to -78 °C before the LiDBB solution (22 mL of a 0.4 M solution) was slowly added. The clear mixture slowly turned brown and finally reached the same color as the LiDBB solution. After 30 minutes, the mixture was quenched at -78 °C with slow addition of NH4CI (aq. sat.) until the slurry started to thicken. Then, the reaction was allowed to warm up to room temperature and was concentrated under reduced pressure.Purification by normal phase flash chromatography, dry-loaded onto an 80 g SiCL column, eluted from 0 to 10% MeOH / CILCh to afford (A)-5-methyloxazolidin-4-one.'H NMR (500 MHz, CDCI3) 87.08 (t, J = 14.9 Hz, 1H), 5.06 (ddd, J = 11.9, 2.8, 1.6 Hz, 2H), 4.28 (qt, J = 10.6, 3.5 Hz, 1H), 1.42 (d, J = 6.7 Hz, 3H).

[0158] Compounds presented in Table 9 were prepared in accordance with the synthetic routes in Intermediate K-l, using procedures analogous to those described above.Table 9Intermediate Structure IUPAC Name9\ MeK-2 (5)-5-methyloxazolidin-4-oneHNv>°Intermediate M-l, 7-bromo-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin- 9(3H)-oneO OM-1

[0159] To a suspension of 5-amino-2-bromoisonicotinic acid (5.98 g, 27.6 mmol) and oxazolidin-4-one (2.00 g, 23.0 mmol) in 2-MeTHF (91.9 mL) was added phosphorus oxychloride (10.6 g, 6.35 mL, 68.9 mmol) at 0 °C. The mixture was stirred at 60 °C for 18 hours. The reaction was quenched with NaHCCh (aq. sat.). The mixture was diluted with CH2Q2 (50 mL), and the suspension was filtered to afford 7-bromo-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one. MS (ESI) m / z: calc'd for C9H7BrN3O2 [M+H]+: 268.0, 270.0, found [M+H]+: 268.0, 269.9.

[0160] Compounds presented in Table 10 were prepared in accordance with the synthetic routes in Intermediate M-l, using procedures analogous to those described above.26176Table 10Intermediate Structure IUPAC Name(R)-7-bromo-3 -methyl- 1 H- M-2 oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneIntermediate L-1, CD 7-chloro-5-(2,4-difluorophenyl)-3,3-dimethyl-lH-oxazolor3,4- a1pyridol3,4-d1pyrimidin-9(3H)-one^ ^"*01-2 L-1

[0161] To a solution of 7-chloro-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (500.0 mg, 1.49 mmol) in THF (4.9 mL) was added dropwise lithium bis(trimethylsilyl)amide solution (274.2 mg, 1.638 mL, 1 molar, 1.64 mmol) at -78 °C under N2 atmosphere. The resulting mixture was stirred at -78 °C for 1 hour. Methyl iodide (317.1 mg, 144.5 pL, 1.5 equiv, 2.23 mmol) was added dropwise at -78 °C, and the resulting mixture was stirred at 25 °C for 16 hours. The crude was diluted with EtOAc, then washed with NH4CI (sat. aq.) followed by brine. The combined organic layers were dried over Na2SC>4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (eluent of 0-90 % MeCN / TEO) followed by flash chromatography (Si O2, 0-90 % EtOAc / CEECh) to give 7-chloro-5-(2,4-difluorophenyl)-3,3-dimethyl-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one MS (ESI) m / z: calc’d for C17H13CIF2N3O2 [M+H]+: 364.8 found [M+H]+: 364.3.Intermediate N-l. 7-chloro-5-(4,4-difluoropiperidin-l-yl)-lH-oxazolor3,4-a1pyridol3,4- d]pyrimidin-9(3H)-one26176

[0162] 5,7-Dichloro-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (150 mg, 1 equiv, 581 pmol), 4,4-difluoropiperidine (70.4 mg, 581 pmol), and DMA (2.91 mL) were added to a 20 mL vial. DIPEA (301 mg, 405 pL, 2.33 mmol) was added in one portion and heated to 70 °C for 16 hours. The material was purified by flash chromatography (SiCh, eluent of 20-70% EtOAc / Hexanes). The fractions were collected and concentrated to afford 7-chloro-5-(4,4-difluoropiperidin-l-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one. MS (ESI) m / z: calc'd for CuHuC^N^ [M+H]+343.1 found [M+H]+343.0.Intermediate P-1: E3-dioxoisoindolin-2-yl 3,3-difluorocvclohexane-l-carboxylateP-1

[0163] To a solution of 3,3-difluorocyclohexanecarboxylic acid (180.8 mg, 1.10 mmol) in CH2CI2 (5.51 mL) was added EDCI (253.4 mg, 1.32 mmol), N-hydroxyphthalimide (188.7 mg, 1.16 mmol), and 4-dimethylaminopyridine (13.5 mg, 110 pmol) at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours. The crude was diluted with CH2CI2, then washed with IM HC1 (10 mL) followed by brine (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Crude material was used without further purification.

[0164] 'H-NMR (400 MHz, CDCI3) 87.92 - 7.87 (m, 2H), 7.83 - 7.77 (m, 2H), 3.11 - 2.99 (m, 1H), 2.60 - 2.48 (m, 1H), 2.32 - 2.21 (m, 1H), 2.21 - 2.12 (m, 1H), 2.12 - 2.00 (m, 1H), 2.02 -1.93 (m, 1H), 1.82 - 1.48 (m, 3H).

[0165] Examples shown in Table 11 below were prepared according to procedures analogous to those outlined for Intermediate P-1 above, using the appropriate starting materials.Table 11Intermediate Structure IUPAC NameOK0 l,3-dioxoisoindolin-2-ylP-2spiro[2.4]heptane-5-carboxylate 0Ox0i \ / / l,3-dioxoisoindolin-2-yl 3- P-3 (trifluoromethyl)cyclobutane- 1 - / Vk°'N'< carboxylateF3CT °26176Intermediate Structure IUPAC NameCL / ~\o YVA l,3-dioxoisoindolin-2-yl 3- P-4 (trifluoromethyl)bicyclo[ 1.1.1 ]pentane- A oA 1 -carboxylate F3C'XZ^0Ox AA0T A / / l,3-dioxoisoindolin-2-yl 4- P-5oxaspiro [2.5 ] octane-6 -carb oxy 1 ate0A »AYY0Ox AAo AY l,3-dioxoisoindolin-2-yl 4- P-6oxaspiro[2.4]heptane-6-carboxylate oJ0Ox AA l,3-dioxoisoindolin-2-yl 3- o YP-7 \r°YYA^zN-A (trifluoromethyl)cyclopentane- 1 - F3CA A-Y0A carboxylateb o AA oY c>l,3-dioxoisoindolin-2-yl P-8spiro[2.5]octane-6-carboxylateOx AAo YYY l,3-dioxoisoindolin-2-yl P-9bicyclo[2.2.1]heptane-l -carboxylate A>YYNYYJ oP-10 Ox AA0T \ / / l,3-dioxoisoindolin-2-yl 3,3- difluorocyclopentane- 1 -carboxylate S / A°'NA FAJ oP-11 Ox AAl,3-dioxoisoindolin-2-yl 6,6- o YYYdimethyltetrahy dro-2H-pyran-3 - carboxylateYY °P-12 Ox AA° YA / / 1 , 3 -dioxoi soindolin-2-yl i sobutyrate A°-A1 oP-13 Ox AAl,3-dioxoisoindolin-2-yl 3- o Y AA(difluoromethyl)bicyclo[ 1.1.1 ]pentane- A / ^A 1 -carboxylate F2HCA"7 026176Intermediate Structure IUPAC NameP-14 AAo AA l,3-dioxoisoindolin-2-yl spiro[2.2]pentane-l-carboxylate Av 0' ’ oP-151 ,3 -dioxoisoindolin-2-yl cyclohex-3 - o ene-1 -carboxylateP-16L ■ l,3-dioxoisoindolin-2-yl qO / y z- cyclopentanecarboxylate P-17 OK A ° A j- Ao l,3-dioxoisoindolin-2-yl bicyclo[4.2.0]octa-l(6),2,4-triene-7- C 170Az u carb oxy lateP-18 K b Az o °b b °A O O l,3- ^^^ o o== dioxoisoindolin-2-yl 4,4,4- =trifluoro-2-methylbutanoate P-19l,3-dioxoisoindolin-2-yl 1- fluorocyclohexane-l -carboxylate Ai oP-20 OK AA0l A / / l,3-dioxoisoindolin-2-yl 3- methylbicyclof 1.1.1 ]pentane- 1 - z1A-' °-NA 0 carboxylateP-21 OK AA0T A / / l,3-dioxoisoindolin-2-yl 3- z cyclv A I A opropyl-2-methylpropanoate oP-220OK AArX / / l,3-dioxoisoindolin-2-yl 5- OA OY oxaspiro[3.5]nonane-7-carboxylate JJ °P-23l,3-dioxoisoindolin-2-yl l-ethyl-2- oxabicyclo[2.2.2]octane-4-carboxylateP-24 OK AAo YA / l,3-dioxoisoindolin-2-yl 3- fluorocyclohexane-l -carboxylate YJ o26176Intermediate Structure IUPAC NameP-25 0,. AAo YA / l,3-dioxoisoindolin-2-yl 4- A AA fluorocyclohexane-1 -carboxylate A JF0P-26 O - -0Y / / l,3-dioxoisoindolin-2-yl A / / AA0bi cy cl o [2.2.1 ] hept-2 -ene- 1 -carb oxy 1 ateP-27o O Yx A AAY l,3-dioxoisoindolin-2-yl 6,6- A0-NA difluorospiro[2.3]hexane-4-carboxylate oF [>P-28 FFA O O Y\ / UA. l,3-dioxoisoindolin-2-yl 6,6- A 4 )AA difluorobicyclo[3.2.0]heptane- 1 -0carboxylateP-29 Ox / ~\o YA_ / l,3-dioxoisoindolin-2-yl 2-ethyl-3,3-F-TM A A 0 difluorocyclobutane- 1 -carboxylate F \P-300O Yx A / ^ / X / l,3-dioxoisoindolin-2-yl bicyclo[2.1. l]hexane-l -carboxylate ©AP-31 Ox AAH M-A l,3-dioxoisoindolin-2-yl 4- A AA)Y fluorobicyclo[2.2. l]heptane-2- o carb oxy lateFP-32o O Yx V AAA l,3-dioxoisoindolin-2-yl 1- Fx A / / 0Y AA / o / fluorospiro[2.3]hexane-5-carboxylate oP-33 Ox AA l,3-dioxoisoindolin-2-yl 4- o YAY (fluoromethyl)bicyclo[2.1. l]hexane-2- v A \JJ A carb oxy late0P-34 Ox AAo YAY l,3-dioxoisoindolin-2-yl \ AAAA spiro[2.4]heptane-4-carboxylate o26176Intermediate Structure IUPAC NameP-35 O. / X0 py l,3-dioxoisoindolin-2-yl 3- methylcyclobutane-1 -carboxylate0P-36 O. AA0 yA / l,3-dioxoisoindolin-2-yl 2- fluorocyclohexane-1 -carboxylate L A 0Intermediate N-l: 4,4,5,5-tetramethyl-2-(4-oxaspiro[2.51oct-6-en-6-yl)-L3,2-dioxaborolanestep 1 step 2 step 3 O Ph2Se2. O OH OTBS OMe ...a^moniun,.P.er5uifate.. MftO. - - . OMe NaBH4, MeOH - I . TBSCI, Imidazole . . > I . 7.. ». MeO.. ,-' . xv OMe . > MeO OMe Y MeOH I Y \ 11 DMF I Y O OMe O OMe O OMe O step 4 step 5 step 6 step 7OTBSEtMgBr, Ti(O;Pr)4PTSA. MeOH BSTFA, DCM IBX, EtOAc THF OMe EtjSiH. BFj-EbO OH step 8 step 9 LHMDS, PhNTf2B2Pin2, Pd(dppf)CI2THF KOAc, PhMe I OTfN-1Step 1: methyl 5, 5 -dimethoxy -4-oxopentanoate

[0166] To a stirred solution of methyl 4-oxopentanoate (70 g, 0.54 mol) in methanol (700 mL) were added 1,2-diphenyldiselane (0.17 kg, 0.54 mol) and ammonium persulfate (0.25 kg, 1.1 mol) at 25 °C. The reaction mixture was stirred at 65 °C for 6 h. The reaction mixture was diluted with water (2000 mL) and extracted with DCM (3 x 800 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure.Silica gel flash column chromatography (eluting with 18% EtOAc in hexane) yielded the desired product.

[0167] 'HNMR (400 MHz, CDCh): 6 (ppm) 4.53 (s, 1H), 3.68 (s, 3H), 3.42 (s, 6H), 2.89 (t, J= 6.6 Hz, 2H), 2.64-2.55 (m, 2H).Step 2: methyl 4-hydroxy-5,5-dimethoxypentanoate

[0168] To a stirred solution of methyl 5, 5-dimethoxy -4-oxopentanoate (25 g, 0.13 mol) in methanol (350 mL) was added sodium borohydride (5.2 g, 0.14 mol) at 0 °C. The reaction26176mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with ice-cold water (500 mL) and extracted with DCM (3 x 500 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to yield the desired product.

[0169] 'HNMR (400 MHz, CDC13): 6 (ppm) 4.14 (d, J= 6.0 Hz, 1H), 3.70 (s, 3H), 3.66-3.60 (m, 1H), 3.51-3.41 (m, 6H), 2.65-2.40 (m, 2H), 2.33-2.12 (m, 1H), 2.03-1.92 (m, 1H), 1.79-1.69 (m, 1H).Step 3: methyl 4-((tert-butyldimethylsilyl)oxy)-5,5-dimethoxypentanoate

[0170] To a stirred solution of methyl 4-hydroxy-5,5-dimethoxypentanoate (22 g, 0.11 mol) in DMF (200 mL) were added imidazole (16 g, 0.23 mol) and TBDMS-C1 (21 g, 0.14 mol) at 25 °C. The resulting reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 15% EtOAc in hexane) yielded the desired product.

[0171] 'H NMR (400 MHz, CDCI3): 8 (ppm) 4.08 (d, J= 5.6 Hz, 1H), 3.75-3.64 (m, 4H), 3.41 (s, 3H), 3.40 (s, 3H), 2.50-2.34 (m, 2H), 1.99-1.88 (m, 1H), 1.85-1.72 (m, 1H), 0.89 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H).Step 4: l-(3-((tert-butyldimethylsilyl)oxy)-4,4-dimethoxybutyl)cyclopropan-l-ol

[0172] To a stirred solution of methyl 4-((terLbutyldimethylsilyl)oxy)-5,5-dimethoxypentanoate (5 g, 0.02 mol) in THF (50 mL) was added titanium tetraisopropoxide (1 mL, 4 mmol) and 3M ethylmagnesium bromide solution (0.02 L, 0.05 mol) dropwise at 25 °C. The reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with water (200 mL) and ethyl acetate (200 mL). The reaction mixture was filtered through a celite pad and the filter cake was washed with ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (200 mL). Combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 30% EtOAc in hexane) yielded the desired product.

[0173] 'H NMR (400 MHz, CDCI3): 6 (ppm) 5.30 (s, 1H), 4.25 (d, J= 6.3 Hz, 1H), 3.77-3.72 (m, 1H), 3.45 (s, 3H), 3.42 (s, 3H), 1.89-1.74 (m, 3H), 1.52-1.42 (m, 1H), 0.90 (s, 9H), 0.81-0.65 (m, 2H), 0.46-0.40 (m, 2H), 0.10 (s, 3H), 0.09 (s, 3H).Step 5: 5-methoxy-4-oxaspiro[2.51octan-6-ol

[0174] To a stirred solution of l-(3-((terCbutyldimethylsilyl)oxy)-4,4-dimethoxybutyl)cyclopropan-l-ol (3.25 g, 10.67 mmol) in methanol (30 mL) was added p-TsOH26176(2.030 g, 10.67 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 8 h. The reaction mixture was quenched with saturated aq. sodium bicarbonate solution (150 mL) and extracted with DCM (2 x 150 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 30% EtOAc in hexane) yielded the desired product.

[0175] 1HNMR (400 MHz, CDC13): 6 (ppm) 4.17 (d, = 7.1 Hz, 1H), 3.54-3.46 (m, 1H), 3.46-3.40 (m, 4H), 2.16-2.04 (m, 2H), 2.00-1.62 (m, 2H), 0.80-0.32 (m, 4H).Step 6: 4-oxaspiror2.5]octan-6-ol

[0176] To a stirred solution of 5-methoxy-4-oxaspiro[2.5]octan-6-ol (1.7 g, 11 mmol) in DCM (30 mL) was added BSTFA (2.3 mL, 8.6 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. Then triethylsilane (6.9 mL, 43 mmol) and boron trifluoride etherate (3.4 mL, 27 mmol) were added dropwise to the reaction mixture at -10 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 4 h. The reaction mixture was diluted with water (150 mL), neutralized with saturated aq. ammonium bicarbonate solution and extracted with 10% methanol in DCM (3 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Silica gel flash column chromatography (eluting with 40% EtOAc in hexane) yielded the desired product.

[0177] GCMS (ESI) calcd. for (C7H12O2) [M]+128.08, found, 128.10, Rt= 5.612 min.Step 7. Synthesis of 4-oxaspiro[2.51octan-6-one

[0178] To a stirred solution of 4-oxaspiro[2.5]octan-6-ol (8.00 g, 60.5 mmol) in 1,2-di chloroethane (200 mL) was added IBX (33.9 g, 2 Eq, 121 mmol) at RT. The mixture was heated to 80 °C for 16 hours. The reaction mixture was filtered on a celite bed and washed with DCM. Filtrate was concentrated under reduced pressure. Purification by normal phase flash chromatography, dry -loaded onto a 120 g SiC>2 column, eluted from 0 to 15% EtOAc / Hexanes to afford 4-oxaspiro[2.5]octan-6-one.

[0179] GCMS (ESI) calcd. for (C7H10O2) [M]+126.16, found, 126.05.Step 8: Synthesis of 4-oxaspiro[2.51oct-6-en-6-yl trifluoromethanesulfonate

[0180] To a stirred solution of 4-oxaspiro[2.5]octan-6-one (600 mg, 4.76 mmol) in THF (25 mL) was added IM lithium bis(trimethylsilyl)amide solution (7.13 mL, 7.13 mmol) at -45 °C and stirred at -45 °C for 1 h. Then a solution of phenyl triflimide (1.70 g, 4.76 mmol) in THF (3 mL) was added to the reaction mixture at -45 °C. The reaction mixture was stirred at 26 °C for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Neutral alumina column chromatography (eluting with 2%26176EtOAc in hexane) yielded the desired product. GCMS (ESI) cal cd. for (C8H9F3O4S) [M]+258, found, 258.Step 9: Synthesis of 4,4,5, 5-tetramethyl-2-(4-oxaspiro[2.5]oct-6-en-6-yl)-L 3,2- dioxaborolane

[0181] To a stirred solution of 4-oxaspiro[2.5]oct-6-en-6-yl trifluoromethanesulfonate (220 mg, 852 pmol) and I Pin? (325 mg, 1.28 mmol) in toluene (10 mL) were added potassium acetate (251 mg, 2.56 mmol) and [l,r-Zh (diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (34.8 mg, 42.6 pmol) at 26 °C in a glove box. The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was filtered through a celite pad, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to yield the desired product that was used in next step without purification. GCMS (ESI) calc’d. for (C13H21BO3) [M]+236, found, 236.Intermediate F-l: l,3-dioxoisoindolin-2-yl (4-oxaspirol2.51octan-6-yl) oxalateDMAP. Et3NTHFF-1

[0182] To a solution of 4-oxaspiro[2.5]octan-6-ol (100 mg, 780 pmol) in THF (2.6 mL) was added l,3-dioxoisoindolin-2-yl 2-chloro-2-oxoacetate (396 mg, 1.56 mmol), DMAP (9.53 mg, 78.0 pmol), and triethylamine (217 pL, 1.56 mmol). The resulting mixture was stirred at 25 °C for 1 hour. Solvents were removed under reduced pressure. The crude residue was dissolved in CH2CI2 and then poured into heptanes. The resulting heterogeneous mixture was filtered through celite and washed with heptanes. The filtrate was concentrated under reduced pressure to yield l,3-dioxoisoindolin-2-yl (4-oxaspiro[2.5]octan-6-yl) oxalate.

[0183] 'H NMR (400 MHz, CDCI3) 57.96 - 7.90 (m, 2H), 7.87 - 7.81 (m, 2H), 5.20 - 5.12 (m, 1H), 3.85 (qd, J= 12.1, 4.2 Hz, 2H), 2.16 (dt, J= 12.2, 4.0 Hz, 1H), 2.12 - 1.95 (m, 2H), 1.58 - 1.50 (m, 1H), 0.96 - 0.90 (m, 2H), 0.59 - 0.38 (m, 2H).26176SYNTHESIS OF EXAMPLE COMPOUNDS EXAMPLE 1-1Preparation of 1-1 (S)-5-(2,4-difluorophenyl)-7-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)- IH-oxazolo [3,4-a]pyrido [3,4-d] pyrimidin-9(3H)-one1-2 1-11-1

[0184] To a solution of 1-27-chloro-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (30 mg, 0.089 mmol) in dioxane (1 mL) were added 1-1 (S)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (22.41 mg, 0.134 mmol), CS2CO3 (87 mg, 0.268 mmol), rac-BINAP Pd G4 (8.99 mg, 8.94 pmol) and the resulting mixture was stirred at 100 °C for 1 h under N2. LCMS showed the desired compound was found and the reaction was completed. The mixture was poured into water (10 mL) and extracted with EtOAc (5 mL * 3). The combined organic fractions were washed with brine (6 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure to give crude product which was purified by prep-HPLC (water (0.01%TFA)-MeCN) and then re-purified by prep-HPLC (Water (0.05% NH3H2O+IO mM NH4HCO3)-MeCN), then purified by prep-TLC (SiC>2, DCM / MeOH=10 / l) to give (S)-5-(2,4-difluorophenyl)-7-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0185] MS (ESI) m / z: calc’d for C23H2IF2N6O3+[M+H]+: 467.2, found [M+H]+: 467.1; 'H NMR (MeOD, 400 MHz): 8 ppm 7.67 (s, 1 H), 7.55 - 7.61 (m, 1 H), 7.54 (s, 1 H), 7.43 (s, 1 H), 6.99 - 7.10 (m, 2 H), 5.72 (s, 2 H), 4.92 (s, 2 H), 4.63 - 4.68 (m, 1 H), 4.37 - 4.43 (m, 1 H), 4.17 -4.24 (m, 1 H), 4.06 - 4.13 (m, 1 H), 3.88 (s, 3 H), 3.80 - 3.87 (m, 1 H), 3.12 - 3.19 (m, 1 H), 3.04 - 3.11 (m, 1 H).

[0186] The examples shown in Table 12 below were prepared using the appropriate starting materials according to procedures analogous to those outlined in Examples above.Table 12: EXAMPLE 1-2Exact Mass Example Structure Name[M+H]+(S)-5-(4,4-difluoropiperidin-l- yl)-7-(2-(2-methylpyridin-4- i-lH-oxazolo[3,4- 485 a]pyrido[3,4-d]pyrimidin- 9(3H)-oneEXAMPLES 2-1, 2-2, 2-3Preparation of 2-15-(2,4-difluorophenyl)-7-((trans)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one, 2-25-(2,4-difluorophenyl)-7-((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo [3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one, and 2-35-(2,4-difluorophenyl)-7-((2R,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-oneNiCI2-DME, TBAI, Zn, DME

[0187] To a solution of 1-27-chloro-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (200 mg, 0.596 mmol) in DMA (4 mL) were added nickel (II) chloride ethylene glycol dimethyl ether complex (26.2 mg, 0.119 mmol), zinc (117 mg, 1.787 mmol), tetrabutylammonium iodide (330 mg, 0.894 mmol), picolinimidamide hydrochloride (18.78 mg, 0.119 mmol), 4-(4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine (244 mg, 0.953 mmol) under N2 and the resulting mixture was stirred at 40 °C for 2 h under N2. LCMS showed the reaction was completed. The crude product was purified by HPLC (Water (0.05%NH3H20+10mM NH4HCO3)-ACN) to give 5-(2,4-difluorophenyl)-7-((cA)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one and rac-2-15-(2,4-difluorophenyl)-7-(( / raw )-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.EXAMPLE rac-2-1 5-(2,4-difluorophenyl)-7-(( / raws)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one was further purified by preparative HPLC (water (0.01%TFA)-MeCN).

[0188] MS (ESI) m / z: calc’d for C26H23F2N4O3+[M+H]+: 477.2 found [M+H]+: 477.1; 'H NMR (CD3OD, 400 MHz): 68.58-8.66 (m, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.83-7.88 (m, 1H), 7.65-7.74 (m, 1H), 7.05-7.17 (m, 2H), 5.77-5.81 (m, 2H), 5.21-5.29 (m, 1H), 5.03 (s, 2H), 3.96-4.03 (m, 2H), 3.55-3.65 (m, 1H), 2.78 (s, 3H), 2.72 (dt, J= 13.8, 3.8 Hz, 1H), 2.24-2.31 (m, 2H), 2.16 (ddd, J= 14.0, 9.5, 4.9 Hz, 1H).

[0189] The compound 5-(2,4-difluorophenyl)-7-((cv.s)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one was separated by SFC to give as 2-25-(2,4-difluorophenyl)-7-((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR=0.991 min) as the first eluting peak and 2-35-(2,4-difluorophenyl)-7-((2R,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR=1.320 min) as the second eluting peak.

[0190] Chiral SFC separation conditions: Column: Chiralpak AD-3 50x4.6 mm I.D., 3pm; Mobile phase: A: CO2B: Methanol (0.2% NH3) Isocratic: 40% of B in A; Flow rate: 4 mL / min; Column temp.: 35°C; ABPR: 1500 psi.EXAMPLE 2-2 Peak 1: MS (ESI) m / z: calc’d for C26H23F2N4O3+[M+H]+: 477.2 found [M+H]+: 477.1; 'H NMR (CD3OD, 400 MHZ): 88.30-8.37 (m, 1H), 8.05 (s, 1H), 7.52-7.61 (m, 1H), 7.36 (s, 1H), 7.25-7.31 (m, 1H), 7.01-7.14 (m, 2H), 5.76 (s, 2H), 4.99 (s, 2H), 4.60 (s, 1H), 4.27-4.35 (m, 1H), 3.84 (td, J= 11.0, 3.9 Hz, 1H), 3.37-3.45 (m, 1H), 2.52 (s, 3H), 2.29 (br d, J= 13.7 Hz, 1H), 1.99-2.11 (m, 2H), 1.78 (q, J= 12.1 Hz, 1H).EXAMPLE 2-3 Peak 2: MS (ESI) m / z: calc’d for C26H23F2N4O3+[M+H]+: 477.2 found [M+H]+: 477.2; 'H NMR (CD3OD, 400 MHZ): 68.31-8.36 (m, 1H), 8.05 (s, 1H), 7.52-7.61 (m, 1H), 7.36 (s, 1H), 7.28 (d, J= 4.8 Hz, 1H), 7.02-7.14 (m, 2H), 5.76 (s, 2H), 4.99 (s, 2H), 4.60-4.63 (m, 1H), 4.28-4.36 (m, 1H), 3.80-3.89 (m, 1H), 3.37-3.47 (m, 1H), 2.52 (s, 3H), 2.25-2.33 (m, 1H), 1.99-2.10 (m, 2H), 1.78 (q, J= 12.4 Hz, 1H).EXAMPLES 2-4, 2-5Preparation of 2-47-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo [3,4-a] pyrido [3,4-d] pyrimidin-9(3H)-one and2-57-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one1-2 1-5Step 1. 7-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-5-(2,4- difluorophenyl)-lH-oxazolor3,4-a1pyrido[3,4-d1pyrimidin-9(3H)-one.

[0191] A mixture of K3PO4 (190 mg, 0.894 mmol), Pd(dppf)C12 (32.7 mg, 0.045 mmol), 1-51-cyclopropyl-4-(4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (216 mg, 0.581 mmol) and 1-27-chloro-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (150 mg, 0.447 mmol) in dioxane (4 mL) and water (0.400 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 60 °C for 2 h. LCMS showed the reaction was completed and desired product was found. The reaction was diluted with water (10 mL), extracted with EtOAc (3 * 10 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure The residue was purified by flash silica gel chromatography (eluent of 50% ethyl acetate / pet. ether gradient) to give7-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0192] MS (ESI) m / z: calc’d for C26H22F2N5O3+[M+H]+: 490.1 found [M+H]+: 490.0.Step 2.

[0193] To a solution of 7-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (190 mg, 0.388 mmol) and Palladium(II) chloride (6.88 mg, 0.039 mmol) in THF (0.5 mL) was added TEA (0.162 mL, 1.164 mmol) and tri ethylsilane (0.186 mL, 1.164 mmol) under N2. The resulting mixture was stirred at 0-25 °C for 2 h. LCMS showed the starting material was consumed, and the desired26176compound was found. The reaction mixture was quenched with water (4 mL) and extracted with EtOAc (3 mL * 2). The combined organic phases were washed with brine (1 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC (water (0.1%TFA)-ACN) to give 7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0194] 7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (80 mg, 0.163 mmol) was separated by SFC to give 2-47-((2S,4R or 2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one((tR = 2.169 min) as the first eluting peak, and 2-57-(2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 3.179 min) as the second eluting peak.

[0195] Chiral SFC separation conditions: Column: Chiralpak AD-3 50^4.6 mm I.D., 3 pm Mobile phase: A: CO2 B: ethanol (0.2% MNH3) Isocratic: 40% B; Flow rate: 3.5mL / min;Column temp.: 35 °C; AB PR: 1500 psi.EXAMPLE 2-4 SFC Peak 1:

[0196] MS (ESI) m / z: calc'd for C26H24F2N5O3+[M+H]+492.1, found [M+H]+: 492.1; 'H NMR (CD3OD, 400 MHz): 88.03-8.07 (m, 1H), 7.68 (s, 1H), 7.54-7.62 (m, 1H), 7.48 (s, 1H), 7.02-7.14 (m, 2H), 5.76 (s, 2H), 4.99 (s, 2H), 4.56 (br d, J= 1.7 Hz, 1H), 4.18 (dt, J= 11.2, 3.0 Hz, 1H), 3.76-3.85 (m, 1H), 3.57-3.64 (m, 1H), 3.32-3.38 (m, 1H), 2.18-2.27 (m, 1H), 1.91-2.06 (m, 3H), 0.93-1.09 (m, 4H).EXAMPLE 2-5 SFC Peak 2:

[0197] MS (ESI) m / z: calc'd for C26H24F2N5O3+[M+H]+492.1, found [M+H]+: 492.1; 'H NMR (CD3OD, 400 MHz): 68.01-8.07 (m, 1H), 7.65-7.70 (m, 1H), 7.53-7.62 (m, 1H), 7.48 (s, 1H), 7.01-7.15 (m, 2H), 5.77 (s, 2H), 4.99 (s, 2H), 4.54-4.59 (m, 1H), 4.12-4.24 (m, 1H), 3.74-3.87 (m, 1H), 3.55-3.67 (m, 1H), 3.32-3.38 (m, 1H), 2.14-2.31 (m, 1H), 1.88-2.06 (m, 3H), 0.94-1.08 (m, 4H).EXAMPLES 2-6, 2-7Preparation of 2-67-((2R,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,6-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one and 2-77-26176((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,6-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-oneStep 1.

[0198] A mixture of nickel chloride, dimethoxyethane adduct (41.96 mg, 190.99 pmol), 4,4',4"-tri-tert-butyl-2,2':6',2"-terpyridine (76.70 mg, 76.39 pL, 190.99 pmol) in DMA (9 mL) was purged with N2 and stirred for 1 hour. In a parallel vial were added 7-bromo-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (300.00 mg, 954.93 pmol), 4-(4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine (489.19 mg, 1.9099 mmol) and zinc (187.3 mg, 2.8648 mmol), and the tube was purged with N2. The catalyst mixture was transferred to the reactants, and the combined mixture was stirred in an oil bath at 40 °C for 6 hours. The solution was diluted with EtOAc, filtered, and concentrated under reduced pressure. The crude was purified directly by flash column chromatography to obtain 7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0199] MS (ESI) m / z: calc’d for C2IH22N4O3S+[M+H]+: 411.5, found [M+H]+: 411.2.Step 2.

[0200] A mixture of 2,4,6-trifluoro bromobenzene (94.6 mg, 52.8 pL, 448 pmol) in THF (780 pL) in a flame-dried vial was purged with N2for 5 mins and sealed. The mixture was cooled to 0°C and isopropylmagnesium chloride 2.0 M in THF (87.6 mg, 426 pL, 2.0 molar, 852 pmol) was added dropwise via syringe. The reaction mixture was stirred at 0 °C for 1 hour. A solution of zinc chloride 1.9M in 2-MeTHF (122 mg, 472 pL, 1.9 molar, 896 pmol) was added dropwise via a syringe at 0 °C, and the reaction mixture was removed from the cooling bath and stirred at 25 °C for an additional 1 hour. A mixture of 7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (92.0 mg, 224 pmol), 2-26176di cy cl ohexylphosphino-2,6-dimethoxy- 1,1 -biphenyl (36.8 mg, 89.6 pmol) and palladium diacetate (10.1 mg, 44.8 pmol) in THF (200 pL) was then added, and the reaction mixture was allowed to stir at 25 °C under N2 for 5 hours. Water was added and the mixture was extracted with ethyl acetate (3 ^ 15 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash silica chromatography to obtain 7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,6-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one. 7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,6-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one was separated by SFC to give 2-67-((2R,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,6-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 9.35 min) as the first eluting peak, and 2-77-((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,6-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 11.17 min) as the second eluting peak.

[0201] Chiral SFC separation conditions: Column: Chiralpak IA 10x250 mm I.D., 5 pm Mobile phase: A: CO2 B: ACN: EtOH (1:1) + 10 mM AmF Isocratic: 25% B; Flow rate: 10 mL / min; Column temp.: 35 °C; ABPR: 1500 psi.EXAMPLE 2-6 SFC Peak 1 :

[0202] MS (ESI) m / z: calc'd for C26H2iF3N4O3+[M+H]+: 495.5, found [M+H]+: 495.5; 'H NMR (400 MHz, DMSO-d6) 88.37 (d, J = 5.1 Hz, 1H), 8.04 (s, 1H), 7.38 - 7.29 (m, 2H), 7.25 (s, 1H), 7.17 (d, J = 5.2 Hz, 1H), 5.70 (s, 2H), 5.00 (s, 2H), 4.57 - 4.53 (m, 1H), 4.27 - 4.18 (m, 1H), 3.77 - 3.68 (m, 1H), 3.49 - 3.38 (m, 1H), 2.44 (s, 3H), 2.26 - 2.17 (m, 1H), 1.99- 1.92 (m, 1H), 1.90 - 1.80 (m, 1H), 1.68 - 1.58 (m, 1H).EXAMPLE 2-7 SFC Peak 2:

[0203] MS (ESI) m / z: calc'd for C26H2iF3N4O3+[M+H]+: 495.5, found [M+H]+: 495.5; 'H NMR (400 MHz, DMSO-d6) 68.37 (d, J = 5.0 Hz, 1H), 8.04 (s, 1H), 7.36 - 7.30 (m, 2H), 7.25 (s, 1H), 7.09 - 7.15 (m, 2H), 5.70 (s, 2H), 5.00 (s, 2H), 4.58 -4.52 (m, 1H), 4.24 -4.18 (m, 1H), 3.78 - 3.68 (m, 1H), 3.48 - 3.38 (m, 1H), 2.44 (s, 3H), 2.25 - 2.19 (m, 1H), 1.98 - 1.93 (m, 1H), 1.92 - 1.80 (m, 1H), 1.68 - 1.57 (m).EXAMPLES 2-8, 2-9Preparation of 2-85-(4-chloro-2-fluorophenyl)-7-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-26176one and 2-95-(4-chloro-2-fluorophenyl)-7-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol- 4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo [3,4-a] pyrido [3,4-d] pyrimidin-9(3H)-oneStep 1.

[0204] A mixture of nickel chloride, dimethoxy ethane adduct (20.982 mg, 95.493 pmol) and 4,4'-di-tert-butyl-N-cyano-[2,2'-bipyridine]-6-carboximidamide (32.033 mg, 95.493 pmol) in DMA (15 mL) was purged with N2 and stirred for 1 h. In a parallel vial were added 7-bromo-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (300.00 mg, 954.93 pmol), 4-(4-bromotetrahydro-2H-pyran-2-yl)-l-cyclopropyl-lH-pyrazole (388.41 mg, 1.4324 mmol), zinc (249.7 mg, 3.8197 mmol) and TBAI (529.10 mg, 1.4324 mmol) in DMA (5 mL), and was purged with N2 and stirred for 15 mins. The catalyst mixture was transferred to the reactants and the combined mixture was stirred at 40 °C for 2 hours. Water was added and the mixture was extracted with EtOAc (3 x 20 mL). The organic phase was further washed with brine and dried over Na2SC>4. After filtration and concentration, the crude product was purified by flash silica gel chromatography to obtain 7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0205] Additional ligands, such as 4, 4', 4"- tri-tert-butyl-2,2':6',2"-terpyridine, were found to promote this reaction using various alkyl bromides.Step 2.

[0206] A mixture of 7-(2-(l -cyclopropyl- IH-pyrazol -4-yl)tetrahy dro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (100 mg, 235 pmol), (4-chloro-2-fluorophenyl)boronic acid (57.4 mg, 329 pmol), tetrakis(triphenylphosphine)palladium(0) (27.2 mg, 23.5 pmol) and copper(I) thiophene-2 -carboxylate (134 mg, 705 pmol) in THF (5 mL) was purged with N2 and stirred at 55 °C for 7 hours. The reaction was diluted with EtOAc and washed with sat. NH4CI, brine, dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel26176chromatography and a subsequent reverse-phase chromatography to obtain 5-(4-chloro-2-fluorophenyl)-7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one. 5-(4-chloro-2-fluorophenyl)-7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one was separated by chiral SFC to give 2-85-(4-chloro-2-fluorophenyl)-7-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 15.98 min) as the first eluting peak, and 2-95-(4-chloro-2-fluorophenyl)-7-((2S,4R or 2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR= 18.11 min) as second eluting peak

[0207] Chiral SFC separation conditions: Column: ChiralPak IB, 5 pm, 20 mm x 250 mm ID Mobile phase: A: CO2 B: ethanol: DCM = 1:1 Isocratic: 20% B; Flow rate: 15 mL / min; Column temp.: 22 °C; ABPR: 1500 psi.EXAMPLE 2-8 SFC Peak 1 :

[0208] MS (ESI) m / z: calc’d for C26H23C1FN5O3+[M+H]+: 508.1, found [M+H]+: 508.2; 'H NMR (400 MHz, DMSO-d6) 87.99 (s, 1H), 7.73 (s, 1H), 7.60 - 7.54 (m, 2H), 7.43 (dd, J= 8.3, 2.0 Hz, 1H), 7.38 (s, 1H), 5.72 (s, 2H), 5.00 (s, 2H), 4.46 (dd, J= 11.2, 1.7 Hz, 1H), 4.07 (dd, J = 10.8, 3.6 Hz, 1H), 3.71 - 3.60 (m, 2H), 3.37 - 3.29 (m, 1H), 2.19 - 2.14 (m, 1H), 1.95 - 1.77 (m, 3H), 1.02 - 0.96 (m, 2H), 0.95 - 0.87 (m, 2H).EXAMPLE 2-9 SFC Peak 2:

[0209] MS (ESI) m / z: calc’d for C26H23C1FN5O3+[M+H]+: 508.1, found [M+H]+: 508.2; 'H NMR (400 MHz, DMSO-d6) 67.99 (s, 1H), 7.73 (s, 1H), 7.60 - 7.55 (m, 2H), 7.43 (dd, J= 8.3, 2.0 Hz, 1H), 7.38 (s, 1H), 5.72 (s, 2H), 5.00 (s, 2H), 4.46 (dd, J= 11.1, 1.7 Hz, 1H), 4.07 (dd, J = 11.4, 2.8 Hz, 1H), 3.71 - 3.60 (m, 2H), 3.36 - 3.28 (m, 1H), 2.19 - 2.14 (m, 1H), 1.93 - 1.76 (m, 3H), 1.01 - 0.95 (m, 2H), 0.94 - 0.86 (m, 2H).

[0210] EXAMPLES 2-10, 2-11Preparation of 2-107-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,5-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one and 2-11 7-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,5-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one26176Step 1. 7-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-5-(2,4,5- trifluorophenyl)-lH-oxazolor3,4-a1pyridor3,4-d1pyrimidin-9(3H)-one.

[0211] A mixture of K3PO4 (56 mg, 0.27 mmol), Pd(dppf)Ch (9.7 mg, 13 pmol), 1-5 1-cyclopropyl-4-(4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (64 mg, 0.17 mmol) and 1-47-chloro-5-(2,4,5-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (47 mg, 0.13 mmol) in dioxane (1.2 mL) and water (0.12 mL) was degassed and backfilled with N2 (three times). The mixture was heated to 60 °C for 2 h. LCMS showed the reaction was completed, and the desired product was found. The reaction was diluted with water (10 mL), extracted with EtOAc (3 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The residue was purified by flash silica gel chromatography (eluent of 0 to 100% EtOAc / heptane gradient) to give 7-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-5-(2,4,5-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0212] MS (ESI) m / z: calc’d for C26H2iF3N5O3+[M+H]+: 510.2 found [M+H]+: 510.2.Step 2, 2-107-((2R,4S or 2S,4R)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahy dro-2H- pyran-4-yl)-5-(2,4,5-trifluorophenyl)-lH-oxazolor3,4-a1pyridor3,4-d1pyrimidin-9(3H)- one and 2-117-((2S,4R or 2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahy dro-2H- pyran-4-yl)-5-(2,4,5-trifluorophenyl)-lH-oxazolor3,4-a1pyridor3,4-d1pyrimidin-9(3H)- one

[0213] To a solution of 7-(2-( l-cyclopropyl- IT / -pyrazol-4-yl)tetrahydro-27 / -pyran-4-yl)-5-(2,4,5-trifluorophenyl)-U / -oxazolo[3,4-a]pyrido[3,4- ]pyrimidin-9(3J7)-one (42 mg, 71 pmol) in THF (3.3 mL) was added palladium chloride (11 mg, 63 mol), triethylamine (0.12 g, 1.2 mmol), and triethylsilane (0.14 g, 1.2 mmol) at 0 °C. The mixture was stirred at 25 °C under N2 for 60 h,26176then filtered through Celite and concentrated. Heptane was then added to triturate the product and the supernatant was removed. The residue was purified by Pre-HPLC (water (0.1%TFA)-ACN) to give 7-(2-(l-cyclopropyl-l / / -pyrazol-4-yl)tetrahydro-2Z / -pyran-4-yl)-5-(2,3,4-tri fluorophenyl)- l / / -oxazolo[3,4-a]pyrido[3, 4- ]pyrimidin-9(3J7)-one.

[0214] 7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,5-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one was separated by SFC to give 2-107-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,5-trifhiorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0215] (tR = 3.63 min) as the first eluting peak, and 2-117-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4,5-trifluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 5.42 min) as the second eluting peak.

[0216] Chiral SFC separation conditions: Column: Lux Cellulose-2250^10 mm, 5 pm Mobile phase: A: CO2 B: ACN / ethanol = 1:1 (0.1% MNH3) Isocratic: 60% B; Flow rate: 10 mL / min; Column temp.: 35 °C; AB PR: 2100 psi.EXAMPLE 2-10 SFC Peak 1:

[0217] MS (ESI) m / z: calc'd for C26H23F3N5O3+[M+H]+510.2, found [M+H]+: 510.4;1H NMR (400 MHz, CDCI3) 88.04 (s, 1H), 7.69 (s, 1H), 7.60 (s, 1H), 7.46 - 7.38 (m, 1H), 7.10 -7.01 (m, 1H), 5.79 (s, 2H), 5.03 (s, 2H), 4.57 (d, J= 9.8 Hz, 1H), 4.30 - 4.22 (m, 1H), 3.83 -3.71 (m, 2H), 3.44 - 3.29 (m, 1H), 2.31 (d, J= 12.9 Hz, 1H), 2.08 - 1.98 (m, 2H), 1.98 - 1.85 (m, 1H), 1.25 - 1.16 (m. 4H).EXAMPLE 2-11 SFC Peak 2:

[0218] MS (ESI) m / z: calc'd for C26H23F3N5O3+[M+H]+510.2, found [M+H]+: 510.5;1H NMR (400 MHz, CDCI3) 58.07 (s, 1H), 7.79 (s, 1H), 7.66 (s, 1H), 7.47 - 7.39 (m, 1H), 7.10 -7.03 (m, 1H), 5.80 (s, 2H), 5.03 (s, 2H), 4.59 (dd, J= 11.1, 1.8 Hz, 1H), 4.33 - 4.23 (m, 1H), 3.88 - 3.74 (m, 2H), 3.48 - 3.39 (m, 1H), 2.34 (d, J = 12.8 Hz, 1H), 2.14 - 1.97 (m, 2H), 1.97 -1.81 (m, 1H), 1.33 - 1.22 (m, 4H).EXAMPLES 2-107, 2-108

[0219] Preparation of 2-107 (R or S)-7-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-3-methyl-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one and 2-108 (S or R)-7-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-26176yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-3-methyl-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0220] To a first vial was added nickel chloride, dimethoxyethane adduct (21.73 mg, 98.88 pmol) and 4,4', 4"- tri-tert-butyl-2,2':6',2"-terpyridine (39.71 mg, 98.88 pmol). The reaction was purged with N2 for 5 min and DMA (4.944 mL) was added. The resulting mixture was stirred at 25 °C for 1 hour. In a second vial was added 1-207-chloro-5-(2,4-difluorophenyl)-3-methyl-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (172.9 mg, 494.4 pmol), 1-74-(4-bromotetrahydro-2H-pyran-2-yl)-l -cyclopropyl- IH-pyrazole (402.2 mg, 1.483 mmol) and zinc (96.97 mg, 1.483 mmol). The reaction was purged with N2 for 5 min, and the solution of the catalyst was added. The resulting mixture was stirred at 40 °C for 16 hours. The crude was diluted in EtOAc and filtered through Celite. The liquid was washed with NH4CI (sat. aq.) followed by brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash Cl 8 chromatography (Cl 8 column, 50 mL / min, eluent of 0-90 % MeCN / NH4HCO3) to give 7-(2-(l -cyclopropyl- 1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-3-methyl-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0221] 7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-3-methyl-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one was separated by SFC to give 2-107 (R or S)-7-((2R,4S or 2S,4R)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-3-methyl-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 18.19 min) as first eluting peak and 2-108 (S or R)-7-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-3-methyl-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 20.20 min) as the second eluting peak.

[0222] Chiral SFC separation conditions: Column: Lux Cellulose-2250^10 mm, 5 pm Mobile phase: A: CO2 B: ACN / ethanol = 1:1 (0.1% MNH3) Isocratic: 25% B; Flow rate: 10 mL / min; Column temp.: 35 °C; AB PR: 2100 psi.

[0223] Each peak was subjected to additional chiral SFC to remove impurities.

[0224] Second chiral SFC separation conditions: Column: ChiralPak AS-H 250x21.2 mm, 5 pm Mobile phase: A: CO2 B: MeOH (10 mM ammonium formate) Isocratic: 25% B; Flow rate: 50 mL / min; Column temp.: 35 °C; AB PR: 1500 psi.26176EXAMPLE 2-107 SFC Peak 1:

[0225] MS (ESI) m / z: calc'd for C27H26F2N5O3+[M+H]+506.5, found [M+H]+: 506.4; 'H NMR (400 MHz, DMSO-t / 6) 67.97 (s, 1H), 7.73 (s, 1H), 7.64 (dt, J= 8.3, 6.9 Hz, 1H), 7.42 - 7.33 (m, 2H), 7.23 (dd, J= 9.5, 7.1 Hz, 1H), 5.77 (d, J= 5.6 Hz, 1H), 5.58 (d, J= 4.7 Hz, 1H), 5.18 (q, J= 6.6 Hz, 1H), 4.47 (d, J= 9.5 Hz, 1H), 4.07 (d, J= 11.1 Hz, 1H), 3.71 - 3.60 (m, 2H), 3.33 - 3.25 (m, 1H), 2.16 (d, J= 13.5 Hz, 1H), 1.94 - 1.77 (m, 3H), 1.44 (d, J= 6.6 Hz, 3H), 1.02 - 0.95 (m, 2H), 0.95 - 0.81 (m, 2H).EXAMPLE 2-108 SFC Peak 2:

[0226] MS (ESI) m / z: calc'd for C27H26F2N5O3+[M+H]+506.5, found [M+H]+: 506.4; 'H NMR (400 MHz, DMSO-t / 6) 67.97 (s, 1H), 7.73 (s, 1H), 7.70 - 7.60 (m, 1H), 7.43 - 7.34 (m, 2H), 7.23 (dd, J= 9.6, 7.3 Hz, 1H), 5.77 (d, J= 5.6 Hz, 1H), 5.58 (d, J= 4.6 Hz, 1H), 5.18 (q, J =2o z=6.5 Hz, 1H), 4.47 (d, J= 10.3 Hz, 1H), 4.07 (dd, J= 10.9, 2.8 Hz, 1H), 3.74 - 3.57 (m, 2H), 3.32 - 3.20 (m, 1H), 2.15 (d,J= 13.0 Hz, 1H), 1.95 - 1.75 (m, 3H), 1.45 (d, J= 6.6 Hz, 3H), 1.03 - ) \ LL LL -0.95 (m, 2H), 0.95 - 0.84 (m, 2H).

[0227] The examples / sOhown in Table 5 below were prepared using the appropriate starting materials according to procedures analogous to those outlined in Examples above.Table 5: Examples 2-10 to 2-134Exact Mass Example Structure Name[M+H]+7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-12 5105-(2,3,4-trifluorophenyl)-lH- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2S,4R or 2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 510 2-13FI 5-(2,3,4-trifluorophenyl)-lH- * if Y'V oxazolo[3,4-a]pyrido[3,4-NJk- . zx .-UyVd]pyrimidin-9(3H)-one026176F5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(2- methylthiazol-5-yl)tetrahydro- 2-14 483Ao 2H-pyran-4-yl)- 1 H- _ ( / 4 I II I o oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneA ( o— o,J o( '1 -n .• - 5 -(2,4-difluorophenyl)-7 - C^ / v ((2S,4R or 2R,4S)-2-(2- methylthiazol-5-yl)tetrahydro- 2-15 / O Z= 4832H-pyran-4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4- u d]pyrimidin-9(3H)-oneFo y z= a5 -(2,4-difluorophenyl)-7 - ((2S,4R or 2R,4S)-2-((R or S)- tetrahy drofuran-3 - 2-16 2 u. < — 4560-! yl)tetrahydro-2H-pyran-4-yl)- / 1 H 1Y » lH-oxazolo[3,4-a]pyrido[3,4- / ° d]pyrimidin-9(3H)-one0F4 5 -(2,4-difluorophenyl)-7 - ((2S,4R or 2R,4S)-2-((S or R)- tetrahy drofuran-3 - 2-17 456 yl)tetrahydro-2H-pyran-4-yl)- / J H *■ lH-oxazolo[3,4-a]pyrido[3,4- fe e- AC d]pyrimidin-9(3H)-one05 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((R or S)- tetrahy drofuran-3 - 2-18 456 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((S or R)- tetrahy drofuran-3 - 2-19 F^^y 456 yl)tetrahydro-2H-pyran-4-yl)- A YA lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneHo^jj0261766-(2,4-difluorophenyl)-8- ((2R,4S or 2S,4R)-2-(2- methylpyridin-4-yl)tetrahydro- 2-20 z Z— 2H-pyran-4-yl)-3,4-dihydro- 490 / / f\ V \ <o _- 1H,1OH- >D C pyrido[3',4':4,5]pyrimido[l,2- Z O CH- c] [ 1 ,3 ] oxazin- 10-one\ / ' "H -q F- \\ \Z Z-=A 6-(2,4-difluorophenyl)-8- ((2S,4R or 2R,4S)-2-(2- C c y "H "n- — — — \ \7 / / ? methylpyridin-4-yl)tetrahydro- 2-21 I / O z O= Z\= 2H-pyran-4-yl)-3,4-dihydro- 490NiiN^¥NV^ 1H,1OH- n pyrido[3',4':4,5]pyrimido[l,2- 07o— c] [ 1 ,3 ] oxazin- 10-oneO^J 0Cl5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(3- F'X^Y methylisothiazol-5- 2-22 499 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- o o y n» d]pyrimidin-9(3H)-one O^J 0Cl5 -(4-chloro-2-fluorophenyl)-7 - ((2S,4R or 2R,4S)-2-(3- F^'Y methylisothiazol-5- 2-23 499 yl)tetrahydro-2H-pyran-4-yl)- Vx N ArNv%% OA. < y Ax >| t0lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one°\X05 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(2- methoxypyridin-4- 2-24 493 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - ((2S,4R or 2R,4S)-2-(2- OMe F^ y^ methoxypyridin-4- 2-25 493 yl)tetrahydro-2H-pyran-4-yl)-N^iiNirNv^n lH-oxazolo[3,4-a]pyrido[3,4- U'...n.-<UYC° d]pyrimidin-9(3H)-one026176Cl5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(2- methylpyridin-4-yl)tetrahydro- 2-26 4932H-pyran-4-yl)- 1 H- A oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneO^J 0Cl5 -(4-chloro-2-fluorophenyl)-7 - ((2S,4R or 2R,4S)-2-(2- methylpyridin-4-yl)tetrahydro- 2-27 4932H-pyran-4-yl)- 1 H-NHNoxazolo[3,4-a]pyrido[3,4- U-..n.KXK-N-V° d]pyrimidin-9(3H)-one O^J 0Fo a z x 5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(3- F'x^ M M)ry methylisothiazol-5- 2-28 \ \z483I LL.\ .n - yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- o o yo i n» d]pyrimidin-9(3H)-one r 4 —. O^J 0Y^ ° F5 -(2,4-difluorophenyl)-7 - ((2S,4R or 2R,4S)-2-(3- F^'Y methylisothiazol-5- 2-29 483 yl)tetrahydro-2H-pyran-4-yl)- Vx N ArNv% lH-oxazolo[3,4-a]pyrido[3,4- % OA. < y Ax >| t0d]pyrimidin-9(3H)-one°\X05 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((R or S)- tetrahy drofuran-3 - 2-30 472 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneCl5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((S or R)- tetrahy drofuran-3 - 2-31 472 ex yl)tetrahydro-2H-pyran-4-yl)- / \ H i lH-oxazolo[3,4-a]pyrido[3,4- x ;»d]pyrimidin-9(3H)-one0Cl5 -(4-chloro-2-fluorophenyl)-7 - ((2S,4R or 2R,4S)-2-((R or S)- tetrahy drofuran-3 - 2-32 m 472 yl)tetrahydro-2H-pyran-4-yl)- Z Z^ oo Z-^ / 4 f 1 H I- \ 4 Z —" lH-oxazolo[3,4-a]pyrido[3,4- 4 46 ' oZ-— d]pyrimidin-9(3H)-one0O\' -n —' - X z\ 4Z-=. 5 -(4-chloro-2-fluorophenyl)-7 - C — \ v ((2S,4R or 2R,4S)-2-((S or R)- y - - \ \ / \ / tetrahy drofuran-3 - 2-33 / 47 / OZ= z 2 o z= yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- V d]pyrimidin-9(3H)-one64o z \= 7-((2R,4S or 2S,4R)-2-(l- (difluoromethyl)- IH-pyrazol- 4-yl)tetrahydro-2H-pyran-4- 2-34 \ \z501\ I LL.\n - yl)-5-(2,4-difluorophenyl)-lH- oxazolo[3,4-a]pyrido[3,4- 2 O T'~ d]pyrimidin-9(3H)-one / l Y —^ / O F5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((R or S)- F 4^ 2, 2-dimethyltetrahy drofuran-3 - 2-35 484°4 X VA yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- CP44JLZ0d]pyrimidin-9(3H)-one 44 J5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((S or R)- 2, 2-dimethyltetrahy drofuran-3 - 2-36 484 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - ((2S,4R or 2R,4S)-2-((S or R)- 2, 2-dimethyltetrahy drofuran-3 - 2-37 484 oZ— yl)tetrahydro-2H-pyran-4-yl)- / 1 n i- lH-oxazolo[3,4-a]pyrido[3,4- 4 4d]pyrimidin-9(3H)-oneoF 8-((2R,4S or 2S.4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-38 6-(2,4-difluorophenyl)-3,4- 506 dihydro-lH,10H- pyrido[3',4':4,5]pyrimido[l,2- c]fl,3]oxazin-10-one6-(4-chloro-2,5- ClJ. F difluorophenyl)-8-((2R,4S or 2S,4R)-2-(l -cyclopropyl- 1H- pyrazol-4-yl)tetrahydro-2H- 2-39 <!FT^ 526 pyran-4-yl)-3 ,4-dihy dro- 1H,1OH- pyrido[3',4':4,5]pyrimido[l,2- c]fl,3]oxazin-10-one6-(4-chloro-2,5- Cldifluorophenyl)-8-((2R,4S or JL / F2S,4R)-2-(l -cyclopropyl- 1H- pyrazol-4-yl)tetrahydro-2H- 2-40 <!FT^ 526 pyran-4-yl)-3 ,4-dihydro- v..0...NijO 1H,1OH- pyrido[3',4':4,5]pyrimido[l,2- c]fl,3]oxazin-10-oneCl5 -(4-chloro-2-fluorophenyl)-7 - A ((2S,4R or 2R,4S)-2-((R or S)- F^^ 2,2-dimethyltetrahydrofuran-3 - 2-41 500 oA- yl)tetrahydro-2H-pyran-4-yl)- / T H H | ¥ Y °lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneCl5 -(4-chloro-2-fluorophenyl)-7 - A ((2S,4R or 2R,4S)-2-((R or S)- F^Y 2,2-dimethyltetrahydrofuran-3 - 2-42 500 oY- - - yl)tetrahydro-2H-pyran-4-yl)- / T H H | ¥ YY\YzvzxYn-- / lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneCl5 -(4-chloro-2-fluorophenyl)-7 - A ((2S,4R or 2R,4S)-2-((R or S)- F"Y^ 2,2-dimethyltetrahydrofuran-3 - 2-43 500 yl)tetrahydro-2H-pyran-4-yl)- / T H H | ¥ ToXXxI^xI / AAY'nlH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2S,4R or 2R,4S)-2-((R orFx Jk S)-2,2- F I^TJ dimethyltetrahy drofuran-3 - 2-44 yl)tetrahydro-2H-pyran-4-yl)- 502 / O- TMH H X II T V T v Y. 5-(2,3,4-trifluorophenyl)-lH- VAi / TYT-N-yoxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-oneF 7-((2S,4R or 2R,4S)-2-((R orFx J\ S)-2,2- Y j dimethyltetrahy drofuran-3 - 2-45 yl)tetrahydro-2H-pyran-4-yl)- 502 / TH H || T T h 5-(2,3,4-trifluorophenyl)-lH- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF (R or S)-5-(2,4- difluorophenyl)-3 -methyl -7 - a ((2S,4R or 2R,4S)-2-(2- 2-46 methylpyridin-4-yl)tetrahydro- 4912H-pyran-4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF (R or S)-5-(2,4- difluorophenyl)-3 -methyl -7 - a ((2S,4R or 2R,4S)-2-(2- 2-47 methylpyridin-4-yl)tetrahydro- 4912H-pyran-4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2S,4R or 2R,4S)-2-((R orFx J\ S)-2,2- YT•\j#^F dimethyltetrahy drofuran-3 - 2-48 yl)tetrahydro-2H-pyran-4-yl)- 502O^L- NYY'N<5I- < / T HH| || ; h 5 -(2,4, 5 -tri fluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2S,4R or 2R,4S)-2-((R or F^ J. S)-2,2- YTX<?^F dimethyltetrahy drofuran-3 - 2-49 o^L- yl)tetrahydro-2H-pyran-4-yl)- 502 / TH H | if T o 5 -(2,4, 5 -tri fluorophenyl)- 1 H- TTXX'TTXTY-N-yoxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2S,4R or 2R,4S)-2-((R orS)-2,2- YTXjS^-F dimethyltetrahy drofuran-3 - 2-50 o^L.N<Y'N<;r-\ yl)tetrahydro-2H-pyran-4-yl)- 502 / T H H | |f ; h 5 -(2,4, 5 -tri fluorophenyl)- 1 H- VT / vATvNx / oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2R,4S or 2S,4R)-2-((S orF4FR)-2,2- difluorocyclopropyl)tetrahydro2-51 QF F-2H-pyran-4-yl)-5-(6- 495T NX i |f T% (trifluoromethyl)pyri din-3 -yl)- Tyx XT / N'7lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one26176F 6-(2,4-difluorophenyl)-8- ((2R,4S or 2S,4R)-2-((R or S)- F-Ju 2, 2-di methyl tetrahydrofuran-3 - 2-52 yl)tetrahydro-2H-pyran-4-yl)- 498 oJ-N3,4-dihydro-lH,10H- pyrido[3',4':4,5]pyrimido[l,2- c]fl,3]oxazin-10-oneF 6-(2,4-difluorophenyl)-8- A ((2R,4S or 2S,4R)-2-((R or S)- 2,2-dimethyltetrahydrofuran-3 - 2-53 yl)tetrahydro-2H-pyran-4-yl)- 4983,4-dihydro-lH,10H- pyrido[3',4':4,5]pyrimido[l,2- c] [ 1 ,3 ] oxazin- 10-oneF 6-(2,4-difluorophenyl)-8- ((2R,4S or 2S,4R)-2-((S or R)- n tetrahy drofuran-3 - 2-54 yl)tetrahydro-2H-pyran-4-yl)- 470 / %NifNY^ 3,4-dihydro-lH,10H- pyrido[3',4':4,5]pyrimido[l,2- c]fl,3]oxazin-10-one8-((2R,4S or 2S,4R)-2-((R orF4FS)-2,2- dimethyltetrahy drofuran-3 - QNyl)tetrahydro-2H-pyran-4-yl)- 2-55 5316-(6-(trifluoromethyl)pyridin- 3 -y 1 )- 3 ,4-dihy dro- 1 H, 10H- pyrido[3',4':4,5]pyrimido[l,2- c]fl,3]oxazin-10-oneF5 -(2,4-difluorophenyl)-7 - ((2S,4R or 2R,4S)-2-(3- F^ Aj^ fluorobicyclof 1.1.1 ]pentan- 1 - 2-56N470 ANxr^ yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - ((2S,4R or 2R,4S)-2-(3- F^ AY^ fluorobicyclof 1.1.1 ]pentan- 1 - 2-57 470F^NANxr-\ yl)tetrahydro-2H-pyran-4-yl)- M^JLXpO3lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneFF^ JL 7-((2R,4S or 2S,4R)-2-(2- methyloxazol-5-yl)tetrahydro- F^ DX^ 2H-pyran-4-yl)-5 -(2,3,4- 2-58 485 trifluorophenyl)- 1 H- rX? ? ifN<r%oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one26176FJ. F 7-((2R,4S or 2S,4R)-2-(2- I Y methyloxazol-5-yl)tetrahydro- 2H-pyran-4-yl)-5 -(2,4,5- 2-59 485 trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(2- jf l methyloxazol-5-yl)tetrahydro- F'^Xj^'F 2H-pyran-4-yl)-5 -(2,4,6- 2-60 485>0 "V'YA, trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneFF7-((2R,4S or 2S,4R)-2-(2- x^xmethyloxazol-5-yl)tetrahydro- F^ Dxs^ 2H-pyran-4-yl)-5 -(2,3,4- 2-61 485>0 "V'YA, trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneFJ\^F7-((2R,4S or 2S,4R)-2-(2- methyloxazol-5-yl)tetrahydro- F^ £XjYS^ 2H-pyran-4-yl)-5 -(2,4,5- 2-62 485 trifluorophenyl)- 1 H- hyyOjC- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(2- methyloxazol-5-yl)tetrahydro- F^ jAXjS^F 2H-pyran-4-yl)-5 -(2,4,6- 2-63 485>0 "V'YA, trifluorophenyl)- 1 H- vCyULb oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneFFxY. 7-((2R,4S or2S,4R)-2-(3- m ethoxybicyclofl .1. l]pentan- F-^ iXj^ J 1 -yl)tetrahydro-2H-pyran-4- 2-64 500A "ArNv% yl)-5-(2,3,4-trifluorophenyl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or2S,4R)-2-(3- J[ Y m ethoxybicyclofl .1. l]pentan- F^xS^ 1 -yl)tetrahydro-2H-pyran-4- 2-65 500A "Ar“v% y 1 )- 5 -(2,4, 5 -trifluorophenyl)- XX^x xOkx "-■ / lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one26176F7-((2R,4S or 2S,4R)-2-(3- m ethoxybicyclofl .1. l]pentan- 1 -yl)tetrahydro-2H-pyran-4- 2-66 482“ArNv% yl)-5-(3,4-difluorophenyl)-lH- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(3- JM m ethoxybicyclofl .1. l]pentan- 1 -yl)tetrahydro-2H-pyran-4- 2-67 »ArV% 482 yl)-5-(2,4-difluorophenyl)-lH- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2S,4R or 2R,4S)-2-(l-((SFor R)-2,2- difluorocy clopropyl)- 1 H- pyrazol-4-yl)tetrahydro-2H- 2-68 528 pyran-4-yl)-5-(2,4- difluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2S,4R or 2R,4S)-2-(l-((SFor R)-2,2- difluorocy clopropyl)- 1 H- pyrazol-4-yl)tetrahydro-2H- 2-69 528^J^yO5pyran-4-yl)-5-(2,4- difluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(2- Jk ^Fcy cl opropy 1 oxazol - 5 - yl)tetrahydro-2H-pyran-4-yl)- 2-70 5115 -(2,4, 5 -trifluorophenyl)- 1 H- xAz^vL^ oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(2- cy cl opropy 1 oxazol - 5 - yl)tetrahydro-2H-pyran-4-yl)- 2-71 5115 -(2,4, 5 -trifluorophenyl)- 1 H- xAvvAJL^ oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or2S,4R)-2-(3- A m ethoxybicyclofl .1. l]pentan- 1 -yl)tetrahydro-2H-pyran-4- 2-72 500»ArV% yl)-5-(2,4,6-trifluorophenyl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one26176FF\J\.Y j 7-((2R,4S or 2S,4R)-2-(2- 1 N cy cl opropy Ithi azol - 5 - yl)tetrahydro-2H-pyran-4-yl)- 2-73 ^^JUOX05275 -(2,4, 5 -trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneFF\J\11 7-((2R,4S or 2S,4R)-2-(2- cy cl opropy Ithi azol - 5 - XY yl)tetrahydro-2H-pyran-4-yl)- 2-74 / xYA / 1-^ 5275 -(2,4, 5 -trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- S'Y d]pyrimidin-9(3H)-oneF (R)-7-((2S,4R or 2R,4S)-2-(l- J. F cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-75 YNXNY 5 -(3 ,4-difluorophenyl)-3 - 506 methyl-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-oneF 3-((2R,4S or 2S,4R)-4-(5-(2,4- difluorophenyl)-9-oxo-3 , 9- F'^ JO-X dihydro-lH-oxazolo[3,4- 2-76 a]pyrido[3,4-d]pyrimidin-7- 477V, NJVVVV<| ’AJCX> yl)tetrahydro-2H-pyran-2- yl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrileF 3-((2R,4S or 2S,4R)-4-(5-(2,4- difluorophenyl)-9-oxo-3 , 9- JO dihydro-lH-oxazolo[3,4- 2-77N^< NX-V-X a]pyrido[3,4-d]pyrimidin-7- 477 vki^iXJQO5yl)tetrahydro-2H-pyran-2- yl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrile5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(6- methylpyrimidin-4- 2-78 478 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one261765 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(2- methylpyridin-4-yl)tetrahydro- 2-79 4932H-pyran-4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one(y- 5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(2- methylpyridin-4-yl)tetrahydro- 2-80 4932H-pyran-4-yl)- 1 H- HIX oxazolo[3,4-a]pyrido[3,4- ( o= d]pyrimidin-9(3H)-oneCl$ 5 -(4-chloro-2-fluorophenyl)-7 - JM ((2S,4R or 2R,4S)-2-((R or S)- F^T^ 2,2-dimethyltetrahydrofuran-3 - 2-81 500O^L- NX / % — yl)tetrahydro-2H-pyran-4-yl)- / T H H | ¥ 7 YX lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(2- JM cy cl opropy Ithi azol - 5 - F / y^ yl)tetrahydro-2H-pyran-4-yl)- 2-82 5095 -(2,4-difluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2S,4R or 2R,4S)-2-((R orF4FS)-2,2- dimethyltetrahy drofuran-3 - QNyl)tetrahydro-2H-pyran-4-yl)- 2-83 5170-1- N^V% - 5-(6-(trifluoromethyl)pyridin- / TH H | ¥ ; bxA^iATzNx / 3-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-one7-((2S,4R or 2R,4S)-2-((R orF4FS)-2,2- dimethyltetrahy drofuran-3 - QNyl)tetrahydro-2H-pyran-4-yl)- 2-84 517O-d- N^V% — 5-(6-(trifluoromethyl)pyridin- / TH H | |f T b 3-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-one7-((2S,4R or 2R,4S)-2-((R orF4FS)-2,2- dimethyltetrahy drofuran-3 - QNyl)tetrahydro-2H-pyran-4-yl)- 2-85 5175-(6-(trifluoromethyl)pyridin- / oY T-H H | ¥ T Y 3-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin-9(3H)-one261767-((2S,4R or 2R,4S)-2-((R orF4FS)-2,2- dimethyltetrahy drofuran-3 - QNyl)tetrahydro-2H-pyran-4-yl)- 2-86 517 oX 5-(6-(trifluoromethyl)pyridin- < TH H | ¥ Y b 3-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-oneF5 -(2,4-difluorophenyl)-7 - O-F ((2R,4S or 2S,4R)-octahydro- 2-87 2H,2'H-[2,4'-bipyran]-4-yl)- 470 lH-oxazolo[3,4-a]pyrido[3,4- k OoOOd]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-octahydro- 2-88 OL 2H,2'H-[2,4'-bipyran]-4-yl)- 470°'x\,lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2R,4S or 2S,4R)-2-((R orS)-2,2- difluorocyclopropyl)tetrahydro2-89 -2H-pyran-4-yl)-5-(2,4- 462 difluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- V O r°d]pyrimidin-9(3H)-oneCl 5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((R or S)- 2,2- 2-90 difluorocyclobutyl)tetrahydro- 4922H-pyran-4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneCl 5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((R or S)- 2,2- 2-91 difluorocyclobutyl)tetrahydro- 4922H-pyran-4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2S,4R or 2R,4S)-2- JO (bicyclof 1.1.1 ]pentan- 1 - F-^Xj^ yl)tetrahydro-2H-pyran-4-yl)- 2-92 452Xo 5 -(2,4-difluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- <0 ','lJxisgxd]pyrimidin-9(3H)-one26176Cl7-((2R,4S or 2S,4R)-2-(2- oxabicyclo[2.1. l]hexan-4- Clyl)tetrahydro-2H-pyran-4-yl)- 2-93 4845-(4-chloro-2-fluorophenyl)- A ClH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneCl7-((2R,4S or 2S,4R)-2-(2- oxabicyclo[2.1. l]hexan-4- Clyl)tetrahydro-2H-pyran-4-yl)- 2-94 4845-(4-chloro-2-fluorophenyl)- CAlH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2R,4S or 2S,4R)-2-((R orS)-2,2- difluorocyclobutyl)tetrahydro- 2-95 2H-pyran-4-yl)-5 -(2,4- 476 difluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(2- A oxabicyclo[2.1. l]hexan-4- yl)tetrahydro-2H-pyran-4-yl)- 2-96 468O N<C% - < 5 -(2,4-difluorophenyl)- 1 H- wH Hi T i ° oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(2- ethy Ithi azol -5 -y l)tetrahy dro- 2-97 4972H-pyran-4-yl)- 1 H- h rrv .oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(2- ethy Ithi azol -5 -y l)tetrahy dro- 2-98 4972H-pyran-4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4- C*1"'^) ''^ s A° d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - jl j ((2S,4R or 2R,4S)-2-((R or S)- 3 -fluorotetrahy drofuran-3 - 2-99 474°-1NXY% - v / Hyl)tetrahydro-2H-pyran-4-yl)- H I T T blH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one26176F5 -(2,4-difluorophenyl)-7 - JM ((2S,4R or 2R,4S)-2-((S or R)- 3 -fluorotetrahy drofuran-3 - 2-100 474O - - yl)tetrahydro-2H-pyran-4-yl)- <HH | |f f YlH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 5 -(2,4-difluorophenyl)-7 - ((2R,4S,6R or 2S,4R,6R orA2R,4S,6S or 2S,4R,6S)-2- 2-101 methyl-6-(2-methylpyridin-4- 491A pYNY%yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 5 -(2,4-difluorophenyl)-7 - ((2R,4S,6R or 2S,4R,6R or 2R,4S,6S or 2S,4R,6S)-2- 2-102 iFX»Nmethyl-6-(2-methylpyridin-4- 491 iiNif V'Vyl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(2- F-x Jx,jQ methylpyridin-4-yl)tetrahydro- 2H-pyran-4-yl)-5 -(2,3,4- 2-103 495 trifluorophenyl)- 1 H- A pYNV\oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF X J. 7-((2R,4S or 2S,4R)-2-(2- methylpyridin-4-yl)tetrahydro- JU 2H-pyran-4-yl)-5 -(2,3,4- 2-104 495 trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(2- Jx / Fmethylpyridin-4-yl)tetrahydro-FXJ 2H-pyran-4-yl)-5 -(2,4,5- 2-105 NA NX / V^ 495 trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF Fv7-((2R,4S or2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- <7 yl)tetrahydro-2H-pyran-4-yl)- 2-106 499V NMYX 5-(4,4-difluoropiperidin-l-yl)- ^OyxAXJO3lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one26176F5 -(2,4-difluorophenyl)-3 , 3 - dimethyl-7-((2S,4R or 2R,4S)- 2-(2-methylpyridin-4- 2-109 505 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - ((2R,4S or 2S,4R)-2-(l- f ji sopropy 1 - 1 H-py razol -4- 2-110 494 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF5 -(2,4-difluorophenyl)-7 - [ j ((2R,4S or 2S,4R)-2-(l- Y^Fi sopropy 1 - 1 H-py razol -4- 2-111 494 yl)tetrahydro-2H-pyran-4-yl)- \ % N'-'VVvlH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF F7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-112 4985-(4,4-difluorocyclohexyl)-lH- 51NV"r%oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF F7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-113 5 V1,Q,.. "YYynV 4985-(4,4-difluorocyclohexyl)-lH- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF F 6-(4,4-difluorocyclohexyl)-8- ((2R,4S or 2S,4R)-2-((R or S)- 2,2-dimethyltetrahydrofuran-3 - 2-114 yl)tetrahydro-2H-pyran-4-yl)- 504NiyNVA 3,4-dihydro-lH,10H- pyrido[3',4':4,5]pyrimido[l,2- c]fl,3]oxazin-10-oneF F 6-(4,4-difluorocyclohexyl)-8- ((2R,4S or 2S,4R)-2-((R or S)- 2,2-dimethyltetrahydrofuran-3 - 2-115 yl)tetrahydro-2H-pyran-4-yl)- 504°-ANjyNYA3,4-dihydro-lH,10H- AA^\AI>AS / N^.Opyrido[3',4':4,5]pyrimido[l,2- c] [ 1 ,3 ] oxazin- 10-one26176F F 8-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-116 6-(4,4-difluorocyclohexyl)-3,4- 512\ Xv, dihydro-lH,10H- pyrido[3',4':4,5]pyrimido[l,2- c]fl,3]oxazin-10-oneF F5-(4,4-difluorocyclohexyl)-7- ((2R,4S or 2S,4R)-2-((S or R)- tetrahy drofuran-3 - 2-117 462 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- <1FxixFyl)tetrahydro-2H-pyran-4-yl)- 2-118 5105 -(2, 4, 6-tri fluorophenyl)- 1H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2R,4S or 2S,4R)-2-((R orS)-2,2- FZJVM^: dimethyltetrahy drofuran-3 - 2-119 yl)tetrahydro-2H-pyran-4-yl)- 5025 -(2, 4, 6-tri fluorophenyl)- 1 H- ctf fucooxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2R,4S or 2S,4R)-2-((R orS)-2,2- F'-^ AXj^LF dimethyltetrahy drofuran-3 - 2-120 / TH H yl)tetrahydro-2H-pyran-4-yl)- 502OTL - x| ¥ J Y 5 -(2, 4, 6-tri fluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2R,4S or 2S,4R)-2-((R orS)-2,2- AlF / ZV^: dimethyltetrahy drofuran-3 - 2-121 yl)tetrahydro-2H-pyran-4-yl)- 502 oJT^H H X |Nv\,¥ TY 5 -(2, 4, 6-tri fluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF (R)-7-((2R,4S or2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-122FX^F, 3-methyl-5-(2,4,6- 524 trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one26176(R)-3-methyl-7-((2R,4S or 2S,4R)-2-(2-methylpyridin-4- yl)tetrahydro-2H-pyran-4-yl)- 2-123 5095 -(2,4, 5 -trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneFl^ F (R)-3-methyl-7-((2R,4S orrj 2S,4R)-2-(2-methylpyridin-4- yl)tetrahydro-2H-pyran-4-yl)- 2-124 509A 5 -(2,4, 5 -trifluorophenyl)- 1 H- R\ / \ / pRYRN*A~7 oxazolo[3,4-a]pyrido[3,4- ( Q= d]pyrimidin-9(3H)-oneF 3-((2R,4S or 2S,4R)-4-(9-oxo- l^ F 5-(2,4,5-trifluorophenyl)-3,9- f JF'R^ dihydro-lH-oxazolo[3,4- 2-125 a]pyrido[3,4-d]pyrimidin-7- 495«Ru ^ RR yl)tetrahydro-2H-pyran-2- RO Z Lk=Ryl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrile3-((2R,4S or 2S,4R)-4-(9-oxo- 5-(2,4,5-trifluorophenyl)-3,9- dihydro-lH-oxazolo[3,4- 2-126 a]pyrido[3,4-d]pyrimidin-7- 495 yl)tetrahydro-2H-pyran-2- zyl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrileF (R)-7-((2R,4S or2S,4R)-2-(l- I F (difluoromethyl)-lH-pyrazol- 4-yl)tetrahydro-2H-pyran-4- 2-127Fv R , yl)-3-methyl-5-(2,4,5- 534 trifluorophenyl)- 1 H- R Roxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF (R)-7-((2R,4S or2S,4R)-2-(l- XA-F(difluoromethyl)-lH-pyrazol- 4-yl)tetrahydro-2H-pyran-4- 2-128FV R , yl)-3-methyl-5-(2,4,5- 534 trifluorophenyl)- 1 H- R R oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF(R)-3-methyl-7-((2R,4S or 2S,4R)-2-(2-methylpyridin-4- I J1 F'R^F yl)tetrahydro-2H-pyran-4-yl)- 2-129 5095-(2,4,6-trifluorophenyl)-lH- A iRA / ^RR RI AROoxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one26176F (R)-7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-130 3-methyl-5-(2,3,4- 524 \ A U trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF (R)-7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)- 2-131 <!FI > 3-methyl-5-(2,3,4- 524 trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF(R)-3-methyl-7-((2R,4S or2S,4R)-2-(2-methylpyridin-4- yl)tetrahydro-2H-pyran-4-yl)- 2-132 5095-(2,3,4-trifluorophenyl)-lH- A ArMooxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2R,4S or 2S,4R)-2-(6- methylpyrimidin-4- yl)tetrahydro-2H-pyran-4-yl)- 2-133 4965 -(2,4, 5 -trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF(R)-5-(2,4-difluorophenyl)-3- methyl-7-((2R,4S or 2S,4R)-2- (6-methylpyrimidin-4- 2-134 1 F492 NANlAV n yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- A A Ad]pyrimidin-9(3H)-oneA0EXAMPLES 3-1, 3-2Preparation of 3-17-((2R,4S or 2S,4R)-2-(l-(l,l-difluoroethyl)-lH-pyrazol-4-yl)tetrahydro- 2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo [3,4-a] pyrido [3,4-d] pyrimidin-9(3H)-one26176and 3-27-((2S,4R or 2R,4S)-2-(l-(l,l-difluoroethyl)-lH-pyrazol-4-yl)tetrahydro-2H-pyran- 4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-oneStep 1.

[0228] To a flame-dried vial was added 7-bromo-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (100 mg, 318 pmol), l-(l,l-difluoroethyl)-4-(4-iodotetrahydro-2H-pyran-2-yl)-lH-pyrazole (272 mg, 80 w / w %, 637 pmol), zinc (62.4 mg, 955 pmol), [Ni(tBuTerpy)(H2O)3]Ch (33.8 mg, 63.7 pmol) and DMA (3.18 mL). The reaction vessel was purged with N2 for 5 min, and the resulting mixture was stirred at 45 °C for 1 hour. Upon completion, the reaction was cooled to room temperature, diluted with EtOAc, filtered over Celite, and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography to afford 7-(2-(l-(l,l-difluoroethyl)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.MS (ESI) m / z: calc’d for C20H22F2N5O3S [M+H]+: 450.5 found [M+H]+: 450.4.Step 2.

[0229] A mixture of (2,4-difluorophenyl)boronic acid (0.11 g, 0.70 mmol), copper(I) thiophene-2-carboxylate (0.10 g, 0.53 mmol), tetrakis(triphenylphosphine)palladium(0) (41 mg, 35 pmol) and 7-(2-(l-(l,l-difluoroethyl)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (89 mg, 89 w / w%, 0.18 mmol) were diluted in THF (1.8 mL). The mixture was sparged with nitrogen for 5 min and stirred at 55 °C for 18 hours. Upon completion, the reaction mixture was cooled, diluted with EtOAc, and filtered over Celite. The organic layer was then washed with NH4CI (aq. sat.), and dried over Na2SC>4. The volatiles were removed under reduced pressure, and the crude was purified by reverse phase chromatography to afford 7-(2-(l-(l,l-difluoroethyl)-lH-pyrazol-4-26176yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one. Enantiomers were separated by chiral SFC to give 3-17-((2R,4S or 2S,4R)-2-(l-(l,l-difluoroethyl)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 4.38 min) as the first eluting peak, and 3-2 7-((2S,4R or 2R,4S)-2-(l-(l,l-difluoroethyl)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 6.93 min) as second eluting peak.

[0230] Chiral SFC separation conditions: Column: Phenomenex Lux Amylose-1, 5 pm, 21.5 mm x 250 mm ID Mobile phase: A: CO2 B: EtOH: ACN = 2:1 + 0.1% NH4OH Isocratic: 35% B; Flow rate: 50 mL / min; Column temp.: 22 °C; ABPR: 1750 psi.EXAMPLE 3-1 SFC Peak 1:

[0231] MS (ESI) m / z: calc’d for C25H22F4N5O3 [M+H]+: 516.4, found [M+H]+: 516.3; 'H NMR (400 MHz, DMSO-d6) 88.15 (s, 1H), 7.96 (s, 1H), 7.71 (s, 1H), 7.62 - 7.53 (m, 1H), 7.33 (td, J = 9.8, 2.4 Hz, 1H), 7.19 (td, J = 8.5, 2.2 Hz, 1H), 5.68 (s, 2H), 4.97 (s, 2H), 4.53 (d, J = 9.4 Hz, 1H), 4.12 - 4.05 (m, 1H), 3.72- 3.64 (m, 1H), 3.37-3.31 (m, 1H), 2.27-2.17 (m, 4H), 1.95 - 1.77 (m, 3H).EXAMPLE 3-2 SFC Peak 2:

[0232] MS (ESI) m / z: calc’d for C25H22F4N5O3 [M+H]+: 516.4, found [M+H]+: 516.3; 'H NMR (400 MHz, DMSO-d6) 68.15 (s, 1H), 7.96 (s, 1H), 7.71 (s, 1H), 7.60 - 7.53 (m, 1H), 7.33 (td, J = 9.9, 2.5 Hz, 1H), 7.22 - 7.14 (m, 1H), 5.68 (s, 2H), 4.97 (s, 2H), 4.53 (d, J = 10.2 Hz, 1H), 4.08 (dd, J = 11.5, 3.3 Hz, 1H), 3.67 (td, J = 11.9, 2.3 Hz, 1H), 3.35-3.31 (m, 1H), 2.27 - 2.18 (m, 4H), 1.94 - 1.77 (m, 3H).EXAMPLE 3-3, 3-4Preparation of 3-35-(4,4-difluorocyclohexyl)-7-((2R,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one and 3-4 5-(4,4-difluorocyclohexyl)-7-((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo [3,4-a] pyrido [3,4-d] pyrimidin-9(3H)-one26176Step 1.

[0233] To the first vial was added nickel chloride dimethoxyethane adduct (29.88 mg, 136.0 pmol) and 4, 4', 4"- tri-tert-butyl-2,2':6',2"-terpyridine (54.61 mg, 136.0 pmol). The reaction was purged with N2 for 5 min, and DMA (6.8 mL) was added. The resulting mixture was stirred at 25 °C for 1 hour. In a second vial was added 7-chloro-5-(4,4-difluorocyclohex-l-en-l-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (231.0 mg, 680.0 pmol), 4-(4-iodotetrahydro-2H-pyran-2-yl)-2 -methylpyridine (618.4 mg, 2.040 mmol), and zinc (133.4 mg, 2.04 mmol). The reaction was purged with N2 for 5 min, and the catalyst solution was added. The resulting mixture was stirred at 40 °C for 16 hours. The crude was diluted with EtOAc, then washed with NH4CI (aq. sat.) followed by brine. The combined organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiC>2, eluent of 0-100 % EtOAc / Heptane) to give 5-(4,4-difluorocyclohex-l-en-l-yl)-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0234] MS (ESI) m / z: calc’d for C26H27F2N4O3 [M+H]+: 481.5, found [M+H]+: 481.5Step 2.

[0235] To a solution of 5-(4,4-difluorocyclohex-l-en-l-yl)-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (127.6 mg, 265.5 pmol) in THF (1.328 mL) was added triethylsilane (463.2 mg, 636 pL, 3.98 mmol), palladium chloride (37.67 mg, 212.4 pmol) and triethylamine (403.1 mg, 555 pL, 3.98 mmol). The resulting mixture was stirred at 25 °C for 48 hours. The crude was diluted in EtOAc. After filtration and concentration, the crude product was purified by flash chromatography to obtain 5-(4,4-difluorocyclohexyl)-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one, which was separated by chiral SFC to give 3-35-(4,4-26176difluorocyclohexyl)-7-((2R,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one as first eluting peak (tR = 7.57 min) and 3-45-(4,4-difluorocyclohexyl)-7-((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one as second eluting peak (tR = 10.13 min).

[0236] Chiral SFC separation conditions: Column: ChiralPak AS-H, 5 pm, 20 mm x 250 mm ID Mobile phase: A: CO2 B: MeOH + 10 mM HCO2NH4 Isocratic: 25% B; Flow rate: 50 mL / min; Column temp.: 40 °C; AB PR: 1500 psi.EXAMPLE 3-3 SFC Peak 1:

[0237] MS (ESI) m / z: calc’d for C26H29F2N4O3 [M+H]+: 483.5, found [M+H]+: 483.4; 'H NMR (400 MHz, DMSO-d6) 88.39 (s, 1H), 7.75 (s, 1H), 7.27 (s, 1H), 7.18 (d, J = 4.7 Hz, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 4.55 (d, J = 9.7 Hz, 1H), 4.22 (dd, J = 10.8, 3.5 Hz, 1H), 3.94 - 3.84 (m, 1H), 3.74 (td, J = 11.5, 2.9 Hz, 1H), 3.30 - 3.16 (m, 1H), 2.56 - 2.39 (m, 3H), 2.26 - 1.77 (m, 11H), 1.61 (dd, J = 24.1, 12.0 Hz, 1H).EXAMPLE 3-4 SFC Peak 2:

[0238] MS (ESI) m / z: calc’d for C26H29F2N4O3 [M+H]+: 483.5, found [M+H]+: 483.4; 'H NMR (400 MHz, DMSO-d6) 68.39 (s, 1H), 7.75 (s, 1H), 7.27 (s, 1H), 7.18 (d, J = 4.3 Hz, 1H), 5.71 (s, 2H), 5.09 (s, 2H), 4.55 (d, J = 9.5 Hz, 1H), 4.22 (dd, J = 10.7, 3.6 Hz, 1H), 3.97 - 3.81 (m, 1H), 3.74 (td, J= 11.5, 2.9 Hz, 1H), 3.32 - 3.22 (m, 1H), 2.45 (s, 3H), 2.24 - 1.80 (m, 11H), 1.61 (dd, J = 24.1, 12.0 Hz, 1H).

[0239] The examples shown in Table 13 below were prepared using the appropriate starting materials according to procedures analogous to those outlined in Examples above.Table 13: Examples 3-5 to 3-22Exact Mass Example Structure IUPAC Name[M+H]+ F F 6-(4,4-difluorocyclohexyl)-8- ((2R,4S or 2S,4R)-2-(2- methylpyridin-4-yl)tetrahydro- 3-5 2H-pyran-4-yl)-3,4-dihydro- 497 NA 1H,1OH- pyrido[3',4':4,5]pyrimido[l,2- o... J 6c] [ 1 ,3 ] oxazin- 10-one26176Cl5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((S or R)- tetrahydrofuran-3-yl)tetrahydro- 3-6 472. 4 . 2H-pyran-4-yl)-lH-oxazolo[3,4- OyiCyO a]pyrido[3,4-d]pyrimidin- 9(3H)-oneCl5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((S or R)- tetrahydrofuran-3-yl)tetrahydro- 3-7 . 4 . 4722H-pyran-4-yl)-lH-oxazolo[3,4- OyiCyO a]pyrido[3,4-d]pyrimidin- 9(3H)-oneCl5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((S or R)- tetrahydrofuran-3-yl)tetrahydro- 3-8 ex 4722H-pyran-4-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-oneCl5 -(4-chloro-2-fluorophenyl)-7 - ((2R,4S or 2S,4R)-2-((S or R)- tetrahydrofuran-3-yl)tetrahydro- 3-9 472 ex 2H-pyran-4-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-oneF7-((2R,4S or 2S,4R)-2-(l- cy cl obuty 1 - 1 H-py razol -4 - yl)tetrahydro-2H-pyran-4-yl)-5- 3-10 506(2,4-difluorophenyl)- 1 H- ^□YVA° oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 5 -(2,4-difluorophenyl)-7 - ((2R,4S,4'S or 2R,4S,4'R orJO 2S,4R,4'S or 2S,4R,4'R)-2',2'- 3-11 dimethyloctahydro-2H,2'H- 498N^ITN<VAC) [2,4'-bipyran] -4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneCl 5 -(2-fluoro-4-chlorophenyl)-7 - ((2R,4S,4'S or 2R,4S,4'R or CXF2S,4R,4'S or 2S,4R,4'R)-2',2'- 3-12 dimethyloctahydro-2H,2'H- 51 eX NXY^ 4[2,4'-bipyran] -4-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one26176F7-((2S,4R or 2R,4S)-2-(l- F^ JS(difluoromethyl)- lH-pyrazol-4- X i^j^F yl)tetrahydro-2H-pyran-4-yl)-5- 3-13 520F N (2,4,5-trifluorophenyl)-lH- ^O..Q,."UyO)oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2S,4R or 2R,4S)-2-(l- (difluoromethyl)-lH-pyrazol-4- yl)tetrahydro-2H-pyran-4-yl)-5- 3-14 520(2,3,4-trifluorophenyl)-lH- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF7-((2S,4R or 2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 3-15 492(3 ,4-difluorophenyl)- 1 H- Vo Z oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF (R)-7-((2S,4R or 2R,4S)-2-(l- Jx^-F cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-3- 3-16 \ : -w methyl-5-(2,4,5- 524 trifluorophenyl)- 1 H- z / oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF (R)-7-((2S,4R or 2R,4S)-2-(l- / S ,Fcy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-3- 3-17 methyl-5-(2,4,5- 524V ' S ri trifluorophenyl)- 1 H- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF(R or S)-3-{4-[5-(3,4- difluorophenyl)-9-oxo-3 , 9- 3-18 dihydro-lH-[l,3]oxazolo[3,4- 439 a]pyrido[3,4-d]pyrimidin-7- yl]oxan-2-yl}propanenitrile3-((2S,4R or 2R,4S)-4-((R)-5- (2,4-difluorophenyl)-3-methyl- 9-oxo-3 , 9-dihy dro- 1 H- oxazolo[3,4-a]pyrido[3,4- 3-19 491 d]pyrimidin-7-yl)tetrahydro-2H- pyran-2- yl)bicyclo[ 1.1.1 ]pentane- 1 -carbonitrile261763-((2R,4S or 2S,4R)-4-((R)-5- F(2,4-difluorophenyl)-3-methyl- 9-oxo-3 , 9-dihy dro- 1 H- F'^ Y^ oxazolo[3,4-a]pyrido[3,4- 3-20 491d]pyrimidin-7-yl)tetrahydro-2H-N- ° pyran-2- o^J 0 yl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrileCl3-((2S,4S or 2R,4R)-4-(5-(4- chloro-2-fluorophenyl)-9-oxo- F^^y 3,9-dihydro-lH-oxazolo[3,4- 3-21 455a]pyrido[3,4-d]pyrimidin-7- yl)tetrahydro-2H-pyran-2- 0. .,.- 0 yl)propanenitrileci3-((2R,4R or 2S,4S)-4-(5-(4- chloro-2-fluorophenyl)-9-oxo- F^y 3,9-dihydro-lH-oxazolo[3,4- 3-22 455a]pyrido[3,4-d]pyrimidin-7-NK txNx> yl)tetrahydro-2H-pyran-2- O Y”''O yl)propanenitrileEXAMPLES 4-1, 4-2Preparation of 4-17-((cis)-2-((S or R)-4-oxaspiro[2.4]heptan-7-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one and 4-27-((cis)-2-((R or S)-4-oxaspiro[2.4]heptan-7-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo [3,4-a]pyrido [3,4-d] pyrimidin-9(3H)-oneStep 1.

[0240] To a flask was added nickel chloride dimethoxyethane adduct (222.5 mg, 1.013 mmol) and 4,4',4"-tri-tert-butyl-2,2':6',2"-terpyridine (406.8 mg, 1.013 mmol). The reaction vessel was purged with N2 for 15 min. Dry DMA (50.6 mL) was added. The resulting mixture was stirred for 1 hour at 25 °C. In a second flask was added 7-chloro-5-(2,4-difluorophenyl)-lH-26176oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (1700 mg, 5.06 mmol), 3-(4-bromotetrahydro-2H-pyran-2-yl)dihydrofuran-2(3H)-one (3.154 g, 12.66 mmol), tetrabutylammonium bromide (3.26 g, 10.13 mmol) and zinc (993.3 mg, 15.19 mmol). The reaction was purged with N2 for 15 min, and the solution of the catalyst was added. The resulting mixture was stirred at 40 °C for 2 hours. Upon completion, the reaction was cooled to RT, diluted with EtOAc, and filtered over Celite. DMA was removed with a flow of air overnight. The crude product was purified by flash chromatography (SiO2, eluent of 5-60 % EtOAc / Heptane). Fractions were concentrated affording 5-(2,4-difluorophenyl)-7-(2-(2-oxotetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0241] MS (ESI) m / z: calc’d for C24H22F2N3O5+[M+H]+: 470.2, found [M+H]+: 470.4.Step 2.

[0242] 5-(2,4-difluorophenyl)-7-(2-(2-oxotetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (250 mg, 533 pmol) and titanium tetraisopropoxide (1.51 g, 1.58 mL, 5.33 mmol) were dissolved in anhydrous 1,4-dioxane (7.00 mL) at 0 °C. Ethyl magnesium bromide (639 mg, 4.79 mL, 1 molar, 4.79 mmol) was added. The reaction was stirred for 4 hours at RT. An aqueous solution of 10% H2SO4 was added, and the reaction was poured into an extraction funnel. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, NaHCCh (aq. sat.), and brine. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, eluent of 2-100% EtOAc / Heptane). Fractions were concentrated affording 5-(2,4-difluorophenyl)-7-(2-(3-hydroxy-l-(l-hydroxycyclopropyl)propyl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0243] MS (ESI) m / z: calc’d for C26H28F2N3O5+[M+H]+: 500.2, found [M+H]+: 500.5.Step 3.

[0244] In a nitrogen-filled glovebox, di-tert-butyl diazene- 1,2-dicarboxylate (11.6 mg, 50.4 pmol) was dissolved in 336 pL DMA, and the resulting solution was treated with tributyl phosphine (10.2 mg, 12.5 pL, 50.4 pmol) and allowed to stir for 5 min at 25 °C. Separately, 5-(2,4-difluorophenyl)-7-(2-(3-hydroxy-l-(l-hydroxycyclopropyl)propyl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (21.0 mg, 42.0 pmol) was dissolved in 504 pL DMA, and the resulting solution was added to the stirring solution of tributyl phosphine and di-tert-butyl diazene- 1,2-dicarboxylate. The vial was sealed and allowed to stir at 80 °C for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (2 mL x 3). The combined organic fractions were dried with Na2SC>4, and the solvent was removed under26176reduced pressure. The crude material was purified by prep-HPLC (eluent of 30-60% MeCN / fhO + 10 mM HCO2NH4) to afford 4-17-((cis)-2-((S or R)-4-oxaspiro[2.4]heptan-7-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one and 4-27-((cis)-2-((R or S)-4-oxaspiro[2.4]heptan-7-yl)tetrahydro-2H-pyran-4-yl)-5-(2,4-difluorophenyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.EXAMPLE 4-1 HPLC Peak 1 :

[0245] MS (ESI) m / z: calc’d for C26H26F2N3O? [M+H]+: 482.2, found [M+H]+: 482.1 'HNMR (400 MHz, CD3CN) 67.94 (s, 1H), 7.64 - 7.53 (m, 1H), 7.17 - 7.03 (m, 2H), 5.69 (s, 2H), 4.91 (s, 2H), 4.09 - 4.02 (m, 1H), 3.84 - 3.75 (m, 1H), 3.69 - 3.63 (m, 1H), 3.59 - 3.51 (m, 1H), 3.38 - 3.30 (m, 1H), 3.22- 3.12 (m, 1H), 2.11 -2.05 (m, 4H), 1.89 - 1.82 (m, 2H), 1.74 -1.61 (m, 1H), 0.90 - 0.81 (m, 1H), 0.80 - 0.72 (m, 1H), 0.63 - 0.54 (m, 1H), 0.38 - 0.30 (m, 1H).EXAMPLE 4-2 HPLC Peak 2:

[0246] MS (ESI) m / z: calc’d for C26H26F2N3O? [M+H]+: 482.2, found [M+H]+: 482.1.

[0247] 1HNMR(400MHz, CD3CN) 67.95 (s, 1H), 7.62 - 7.54 (m, 1H), 7.16 - 7.03 (m, 2H), 5.69 (s, 2H), 4.91 (s, 2H), 4.01 - 3.95 (m, 1H), 3.80 - 3.73 (m, 1H), 3.71 - 3.63 (m, 1H), 3.55 -3.46 (m, 1H), 3.40 -3.33 (m, 1H), 3.23 - 3.13 (m, 1H), 2.36 - 2.23 (m, 1H), 2.12 - 2.00 (m, 2H), 1.88 - 1.74 (m, 3H), 1.63 - 1.49 (m, 1H), 0.91 - 0.82 (m, 1H), 0.69 - 0.61 (m, 1H), 0.59 - 0.51 (m, 2H).EXAMPLES 5-1, 5-2, 5-3, 5-4Preparation of 5-17-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((S or R)-3,3-difluorocyclohexyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one, 5-27-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran- 4-yl)-5-((R or S)-3,3-difluorocyclohexyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one, 5-37-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)- 5-((S or R)-3,3-difluorocyclohexyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one, 5-4261767-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((R or S)-3,3-difluorocyclohexyl)-lH-oxazolo [3,4-a] pyrido [3,4-d] pyrimidin-9(3H)-one.Step 1.

[0248] To a solution of 7-bromo-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (500.0 mg, 1.86 mmol) in DMA (18.65 mL) was added 4-(4-bromotetrahydro-2H-pyran-2-yl)-l-cyclopropyl-lH-pyrazole (1.01 g, 3.73 mmol), Zinc (243.9 mg, 3.73 mmol) and Ni(zBuTerpy)C12 (198.2 mg, 373.0 pmol). The resulting mixture was stirred at 40 °C for 16 hours. The crude material was diluted with EtOAc (30 mL), then washed with NH4CI (aq. sat., 30 mL) and brine (30 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiC>2, eluent of 0-100% EtOAc / Heptane) followed by reverse-phase chromatography (Cl 8 SiC>2, eluent of 0-50% MeCN / FLO + 10 mM HCO2NH4) to give 7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.MS (ESI) m / z: calc’d for C20H22N5O3 [M+H]+: 380.4, found [M+H]+: 380.3.Step 2.

[0249] To a solution of 7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (40.0 mg, 105 pmol) in DMSO (527 pL) was added l,3-dioxoisoindolin-2-yl 3,3-difluorocyclohexane-l-carboxylate (48.9 mg, 158 pmol), trifluoroacetic acid (24.0 mg, 16.1 pL, 211 pmol), and 4CzIPN (832 pg, 1.05 pmol). The resulting mixture was bubbled with N2 for 60 sec and irradiated at 450 nM (5 cm from the lamp with no fan) for 16 hours. The crude was directly purified by reverse-phase flash chromatography (C18 SiO2, eluent of 0-100% MeCN / H2O + 10 mM HCO2NH4) to give 7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(3,3-difluorocyclohexyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.26176

[0250] Isomers were separated by chiral SFC to give 5-17-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((S or R)-3,3-difluorocyclohexyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one as first eluting peak (tR = 2.94 min), 5-27-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((R or S)-3,3-difluorocyclohexyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one as second eluting peak (tR = 3.68 min), 5-37-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((S or R)-3,3-difluorocyclohexyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one as third eluting peak (tR = 4.22 min), 5-47-((2R,4S or 2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((R or S)-3,3-difluorocyclohexyl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one as fourth eluting peak (tR = 6.04 min),

[0251] Chiral SFC separation conditions: Column: Phenomenex I Amylosel, 5 pm, 21.2 mm x 250 mm; Mobile phase: A: CO2 B: IPA + 10 mM HCO2NH4 Isocratic: 55% B; Flow rate: 60 mL / min; Column temp.: 40 °C; ABPR: 1725 psi.EXAMPLE 5-1 SFC Peak 1:

[0252] MS (ESI) m / z: calc’d for C26H3oF2N503+[M+H]+: 498.6, found [M+H]+: 498.4 'HNMR (500 MHz, DMSO-d6) 87.76 (s, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 5.71 (s, 2H), 5.11 (s, 2H), 4.50 - 4.43 (m, 1H), 4.11 - 4.00 (m, 2H), 3.74 - 3.62 (m, 2H), 3.28 - 3.16 (m, 1H), 2.39 -2.23 (m, 1H), 2.19 -2.03 (m, 3H), 1.96 - 1.73 (m, 6H), 1.71 - 1.45 (m, 2H), 1.04 -0.95 (m, 2H), 0.95 - 0.87 (m, 2H).EXAMPLE 5-2 SFC Peak 2:

[0253] MS (ESI) m / z: calc’d for C26H3oF2N503+[M+H]+: 498.6, found [M+H]+: 498.4 'HNMR (500 MHz, DMSO-d6) 67.76 (s, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 5.71 (s, 2H), 5.11 (s, 2H), 4.49 - 4.44 (m, 1H), 4.11 - 4.01 (m, 2H), 3.71 - 3.63 (m, 2H), 3.27 - 3.09 (m, 1H), 2.39 -2.21 (m, 1H), 2.13 (d, J = 10.9 Hz, 3H), 2.03 - 1.72 (m, 6H), 1.72 - 1.46 (m, 2H), 1.03 - 0.94 (m, 2H), 0.94 -0.86 (m, 2H).EXAMPLE 5-3 SFC Peak 3:

[0254] MS (ESI) m / z: calc’d for C26H3oF2N503+[M+H]+: 498.6, found [M+H]+: 498.4 'HNMR (500 MHz, DMSO-d6) 67.76 (s, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 5.71 (s, 2H), 5.11 (s, 2H), 4.47 (dd, J = 11.2, 1.8 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.73 - 3.61 (m, 2H), 3.28 - 3.17 (m, 1H), 2.39 - 2.23 (m, 1H), 2.21 - 2.04 (m, 3H), 1.98 - 1.75 (m, 6H), 1.71 - 1.48 (m, 2H), 1.06 -0.95 (m, 2H), 0.95 - 0.86 (m, 2H).26176EXAMPLE 5-4 SFC Peak 4:

[0255] MS (ESI) m / z: calc’d for C26H3oF2N503+[M+H]+: 498.6, found [M+H]+: 498.4 'H NMR (500 MHz, DMSO-d6) 67.76 (s, 1H), 7.72 (s, 1H), 7.38 (s, 1H), 5.71 (s, 2H), 5.11 (s, 2H), 4.47 (dd, J = 11.2, 1.7 Hz, 1H), 4.11 -4.01 (m, 2H), 3.70 - 3.62 (m, 2H), 3.27 - 3.18 (m, 1H), 2.38 - 2.23 (m, 1H), 2.18 - 2.06 (m, 3H), 1.99 - 1.74 (m, 6H), 1.70 - 1.48 (m, 2H), 1.03 -0.95 (m, 2H), 0.95 - 0.87 (m, 2H).

[0256] The examples shown in Table 14 below were prepared using the appropriate starting materials according to procedures analogous to those outlined in Examples above.Table 14: Examples 5-5 to 5-69Exact Mass Example Structure IUPAC Name[M+H]+ 7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- x yl)tetrahydro-2H-pyran-4-yl)-5- 5-5 « 474 ((S or R)-spiro[2.4]heptan-5-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-6 X / Uu Xc«o 474 ((S or R)-spiro[2.4]heptan-5-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- X yl)tetrahydro-2H-pyran-4-yl)-5- 5-7 474 ((S or R)-spiro[2.4]heptan-5-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2R,4S or 2S,4R)-2-(l- FX cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-8 (3- X 514NITNW (trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)- lH-oxazolo[3 ,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-oneX 7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-9 X (3- 514 (trifluoromethyl)bicyclo[ 1.1.1 ]pentan- 1 -yl)- lH-oxazolo[3 ,4- a]pyrido[3,4-d]pyrimidin-9(3H)-one26176(R)-3-methyl-7-((2R,4S or r '° 2S,4R)-2-(2-methylpyridin-4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-10 1 X N J ((R or S)-4-oxaspiro[2.5]octan- 489? H ? if VS 6-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- G~ 9(3H)-one7-((2R,4S or 2S,4R)-2-(l- 4Fcy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-11 1 VO (] x« ((cis or trans)-3- 502(trifluoromethyl)cyclobutyl)- V^X O z=\V lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2R,4S or 2S,4R)-2-(l-F4Fcy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-12 \ \ / / X.X.- ,ZOX "Xv' ((cis or trans)-3- 502 z (trifluoromethyl)cyclobutyl)- v>°lH-oxazolo[3,4-a]pyrido[3,4- _ | LL \ Ovl d]pyrimidin-9(3H)-one(R)-3-methyl-7-((2R,4S orXo- 2S,4R)-2-(2-methylpyridin-4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-13 V7V v zz^~ X% ■((R or S)-4-oxaspiro[2.5]octan- 489 6-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-one(R)-7-((2R,4S or2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-14 ((R or S)-3,3- 512 difluorocyclohexyl)-3-methyl- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one(R)-7-((2R,4S or2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-15 ((S orR)-3,3- 512 difluorocyclohexyl)-3-methyl- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one F (R)-7-((2S,4R or 2R,4S)-2-(l-F| X cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-16 1.%N?IXVX ((R or S)-3,3- 512 difluorocyclohexyl)-3-methyl- lH-oxazolo[3,4-a]pyrido[3,4- °-X 0d]pyrimidin-9(3H)-one261767-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-17 ((1S or 1R,3R or 3S)-3- 516(trifluoromethyl)cyclopentyl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF\F7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-18 ((IR or 1S,3R or 3S)-3- 516(trifluoromethyl)cyclopentyl)- lH-oxazolo[3,4-a]pyrido[3,4- od]pyrimidin-9(3H)-one7-((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-19 ((IS or 1R,3S or 3R)-3- 516 go1oLL 1 Z IL Z XO LL 1 Z >O== . A . A(trifluoromethyl)cyclopentyl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one\ \ 7-((2R,4S or 2S,4R)-2-(l- Ao \ / - ° cy cl opropy 1 - 1 H-py razol -4- d z yl)tetrahydro-2H-pyran-4-yl)-5- 5-20 7 \ Zz 2((IR or 1S,3S or 3R)-3- 516I (trifluoromethyl)cyclopentyl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one7-((2R,4S or 2S,4R)-2-(l- FXF cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-21 (3- 514(trifluoromethyl)bicyclo[ 1.1.1 ]p entan- 1 -yl)- lH-oxazolo[3 ,4- 0 a]pyrido[3,4-d]pyrimidin- 9(3H)-one7-((2S,4R or 2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-5- 5-22 (3- 514(trifluoromethyl)bicyclo[ 1.1.1 ]p entan- 1 -yl)- lH-oxazolo[3 ,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-one7-((2S,4R or 2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)oxan-4-yl]-5- 5-23 \ x- ., 488(spiro[2.5]octan-6-yl)-lH- [l,3]oxazolo[3,4-a]pyrido[3,4- o. ^J od]pyrimidin-9(3H)-one261765-(bicyclo[2.2.1]heptan-l-yl)-7- ((2R,4S or 2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- 5-24 474 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- O^J O d]pyrimidin-9(3H)-oneo~ 3-((2R,4S or 2S,4R)-4-((R)-3- Z O- methyl-9-oxo-5-((S or R)-4- / \ / oxaspiro[2.5]octan-6-yl)-3,9- dihydro-lH-oxazolo[3,4- 5-25 489 a]pyrido[3,4-d]pyrimidin-7- \oA“ / yl)tetrahydro-2H-pyran-2- yl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrile3-((2S,4R or 2R,4S)-4-((R)-3- V methyl-9-oxo-5-((S or R)-4- ^0oxaspiro[2.5]octan-6-yl)-3,9- A - dihydro-lH-oxazolo[3,4- 5-26 489 -^Moa]pyrido[3,4-d]pyrimidin-7- yl)tetrahydro-2H-pyran-2- O.. J o yl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrile3-((2R,4S or2S,4R)-4-((R)-3- methyl-9-oxo-5-((R or S)-4- oxaspiro[2.5]octan-6-yl)-3,9- z 6 dihydro-lH-oxazolo[3,4- 5-27 489 a]pyrido[3,4-d]pyrimidin-7- ■ e n"1'. yl)tetrahydro-2H-pyran-2- O^J O yl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrile3-((2S,4R or 2R,4S)-4-((R)-3- methyl-9-oxo-5-((R or S)-4- oxaspiro[2.5]octan-6-yl)-3,9- dihydro-lH-oxazolo[3,4- 5-28 489 a]pyrido[3,4-d]pyrimidin-7- yl)tetrahydro-2H-pyran-2- yl)bicyclo[ 1.1.1 ]pentane- 1 - carbonitrile5-((R or S)-6,6- dimethyltetrahy dro-2H-pyran-3 - yl)-7-((2R,4S)-2-(2- 5-29 methylpyridin-4-yl)tetrahydro- 4772H-pyran-4-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin-9(3H)-one261765-((S or R)-6,6- $ dimethyltetrahy dro-2H-pyran-3 - yl)-7-((2R,4S)-2-(2- 5-30 methylpyridin-4-yl)tetrahydro- 4772H-pyran-4-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- \z , 0-A 09(3H)-onepzF 5-((S orR)-3,3- ° \ difluorocyclohexyl)-7-((2R,4Sor 2S,4R)-2-(6- 5-31 AA methylpyrimidin-4- 484NICXA^ X |TN<:r^'r>yl)tetrahydro-2H-pyran-4-yl)- A ■" / < O z cz^lH-oxazolo[3,4-a]pyrido[3,4- oA d M n \ / '0 d]pyrimidin-9(3H)-one" ''oF 5-((R or S)-3,3- difluorocyclohexyl)-7-((2R,4Sor 2S,4R)-2-(6- 5-32 , FNA NA-VV methylpyrimidin-4- 484 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- oA °d]pyrimidin-9(3H)-one7-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-((S orR)-3,3- 5-33 484 difluorocyclopentyl)-lH- oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oneF 7-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- . - pyran-4-yl)-5-((R or S)-3,3- 5-34 484 difluorocyclopentyl)-lH- ANFA-ANAAAAYA%0oxazolo[3,4-a]pyrido[3,4- oA ° d]pyrimidin-9(3H)-one(R)-7-((2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- “Xyl)tetrahydro-2H-pyran-4-yl)-3- 5-35 methyl-5-((R or S)-4- 490NAJ^XNXArANvA4° oxaspiro[2.4]heptan-6-yl)- 1 H- oA^ 0 oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one(R)-7-((2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-3- 5-36 methyl-5-((S or R)-4- 490 oxaspiro[2.4]heptan-6-yl)- 1 H- oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one261767-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- 7. pyran-4-yl)-5-((R or S)- 5-37 446 spiro[2.2]pentan-l-yl)-lH- T T if oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-oney r~ 7-((2R,4S or 2S,4R)-2-(2- O O--methylpyridin-4-yl)tetrahydro- ° ° ° \ \ \ 2H-pyran-4-yl)-5 -(3 - 5-38 (trifluoromethyl)bicyclo[ 1.1.1 ]p 499NA \ IZ -nF- _A{ y <-- entan- 1 -yl)- lH-oxazolo[3 ,4- a]pyrido[3,4-d]pyrimidin- O.^>< ° 0° ?f=\ 9(3H)-onev 7-((2S,4R or 2R,4S)-2-(2- methylpyridin-4-yl)tetrahydro- 2H-pyran-4-yl)-5 -(3 - 5-39 (trifluoromethyl)bicyclo[ 1.1.1 ]p 499 entan- 1 -yl)- lH-oxazolo[3 ,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-one5-(3- (difluoromethyl)bicyclo[ 1.1.1 ]p entan-l-yl)-7-((2R,4S or5-40 2S,4R)-2-(2-methylpyridin-4- 481 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one5-(3- (difluoromethyl)bicyclo[ 1.1.1 ]p entan-l-yl)-7-((2S,4R or5-41 2R,4S)-2-(2-methylpyridin-4- 481 yl)tetrahydro-2H-pyran-4-yl)- lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one(R)-7-((2R,4S or2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- 10yl)tetrahydro-2H-pyran-4-yl)-3- 5-42 methyl-5-((R or S)-4- 504N^Y'YO oxaspiro[2.5 ]octan-6-yl)- 1 H- 0 oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one(R)-7-((2R,4S or2S,4R)-2-(l- cy cl opropy 1 - 1 H-py razol -4- 10yl)tetrahydro-2H-pyran-4-yl)-3- 5-43 Y / methyl-5-((S or R)-4- 504N•YN^TYNTYYYNYn oxaspiro[2.5 ]octan-6-yl)- 1 H- if -AO..^J 0 oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one26176(R)-7-((2S,4R or 2R,4S)-2-(l- I0cy cl opropy 1 - 1 H-py razol -4- yl)tetrahydro-2H-pyran-4-yl)-3- 5-44 <i I ! methyl-5-((R or S)-4- 504 oxaspiro[2.5 ]octan-6-yl)- 1 H- T T oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one(R)-7-((2S,4R or 2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- 10yl)tetrahydro-2H-pyran-4-yl)-3- 5-45 : methyl-5-((S or R)-4- 501, XM04 oxaspiro[2.5 ]octan-6-yl)- 1 H- X o o z \ / "H / oxazolo[3,4-a]pyrido[3,4- 0 Z(w— - d]pyrimidin-9(3H)-oneV7-((2R,4S)-2-(l-cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- 5-46 o o pyran-4-yl)-5 -i sopropyl- 1 H- 422\ / oxazolo[3,4-a]pyrido[3,4- z y°=VH d]pyrimidin-9(3H)-one5-(cyclohex-3-en-l-yl)-7- H u ”Hl c ((2R,4S)-2-(l-cyclopropyl-lH- pyrazol-4-yl)tetrahydro-2H- 5-47 460 pyran-4-yl)-lH-oxazolo[3,4- "bk^jX^X;0a]pyrido[3,4-d]pyrimidin- ' / z r. ' XO^J 0xz9(3H)-one (mixture of isomers)5-cyclopentyl-7-((2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- 5-48 yl)tetrahydro-2H-pyran-4-yl)- 448 lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one5-(bicyclo[4.2.0]octa-l(6),2,4- trien-7-yl)-7-((2R,4S)-2-(l- cy cl opropy 1 - 1 H-py razol -4- 5-49N'JXXX^X° yl)tetrahydro-2H-pyran-4-yl)- 482 lH-oxazolo[3,4-a]pyrido[3,4- O^J 0 d]pyrimidin-9(3H)-one (mixtureof isomers)7-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(4,4,4- 5-50 trifluorobutan-2-yl)- 1H- 490 oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one(mixtureof isomers)7-((2R,4S)-2-(l-cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(l- 5-51 \ ^V-o480 fluorocyclohexyl)- 1H- oxazolo[3,4-a]pyrido[3,4-NA °-^X> oC° d]pyrimidin-9(3H)-one261767-((2R,4S)-2-(l-cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(3- 5-52 methylbicyclof 1.1.1 ]pentan- 1 - 460 yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- A'A z z z. ," / / > Zz z / / . f \ / i 9(3H)-one7-((2R,4S)-2-(l-cyclopropyl- ( ° o— \ lH-pyrazol-4-yl)tetrahydro-2H- Qpyran-4-yl)-5-(l- 5-53 V frv> cyclopropylpropan-2-yl)-lH- 462 oxazolo[3,4-a]pyrido[3,4- / ° o z\==d]pyrimidin-9(3H)-one (mixture Y of isomers)y / c7-((2R,4S)-2-(l-cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(5- 5-54 oxaspiro[3.5 ]nonan-7-yl)- 1 H- 504 oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one (mixtureof isomers)7-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- K0pyran-4-yl)-5-(l -ethyl-2- 5-55 oxabicyclo[2.2.2]octan-4-yl)- 518“XN'T^O lH-oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one (mixture °^J oof isomers)F 7-((2R,4S)-2-(l-cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(3- 5-56 7 , fluorocyclohexyl)- 1H- 480 oxazolo[3,4-a]pyrido[3,4- O^J 0 d]pyrimidin-9(3H)-one (mixtureof isomers)F 7-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(4- 5-57;0 fluorocyclohexyl)- 1H- 480NJL^UUL.L / ° oxazolo[3,4-a]pyrido[3,4- 0,^J d]pyrimidin-9(3H)-one (mixture0of isomers)5-(bicyclo[2.2.1]hept-2-en-l- yl)-7-((2R,4S)-2-(l- <q Y cy cl opropy 1 - 1 H-py razol -4- 5-58 yl)tetrahydro-2H-pyran-4-yl)- 472NJYV^V- / lH-oxazolo[3,4-a]pyrido[3,4- o^J o d]pyrimidin-9(3H)-one (mixtureof isomers)26176F F 7-((2R,4S)-2-(l-cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- <( Y3pyran-4-yl)-5-(6,6- 5-59 difluorospiro[2.3 ]hexan-4-yl)- 496 lH-oxazolo[3,4-a]pyrido[3,4- AC > O^J 0 d]pyrimidin-9(3H)-one (mixture M Z z z z z. / / / Z Z z z / / / / / of isomers)7-((2R,4S)-2-(l-cyclopropyl- ° ° ° \ \ \ lH-pyrazol-4-yl)tetrahydro-2H- \ / m _ pyran-4-yl)-5-(6,6- z5-60 A#H’V~ / #V7yi \z <_ difluorobicyclo[3.2.0]heptan-l- 510\ / " yl)-lH-oxazolo[3,4- #Z ■”< ° O o Z z o z °z==\\== , a]pyrido[3,4-d]pyrimidin- 9(3H)-one (mixture of isomers) A %7-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(2-ethyl-3,3- 5-61 difluorocyclobutyl)- 1H- 498 oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one (mixtureof isomers)5-(bicyclo[2.1.1]hexan-l-yl)-7- ((2R,4S)-2-(l-cyclopropyl-lH- pyrazol-4-yl)tetrahydro-2H- 5-62 460 pyran-4-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- 9(3H)-one7-((2R,4S)-2-(l -cyclopropyl- ,- . ,„FlH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(4- 5-63 fluorobicyclo[2.2. l]heptan-2- 492 yl)-lH-oxazolo[3,4- 0 1... , J 1 011 a]pyrido[3,4-d]pyrimidin- 9(3H)-one (mixture of isomers)7-((2R,4S)-2-(l-cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(l- 5-64 fluorospiro[2.3 ]hexan-5 -yl)- 1 H- 478 oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one (mixtureof isomers)7-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(4- 5-65 (fluoromethyl)bicyclo[2.1. l]hex 492 an-2-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin-9(3H)-one (mixture of isomers)261767-((2R,4S)-2-(l -cyclopropyl- 4 A lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5 -(spiro [2.4]heptan- 5-66 4744-yl)-lH-oxazolo[3,4- 0 a]pyrido[3,4-d]pyrimidin- A A 9(3H)-one (mixture of isomers) z7-((2R,4S)-2-(l-cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- ( o—pyran-4-yl)-5-(3- 5-67 Q Y methylcyclobutyl)- 1H- 448YY (J oxazolo[3,4-a]pyrido[3,4- O^J < O o d]pyrimidin-9(3H)-one (mixturez= of isomers)A 5-(bicyclo[3.1 ,0]hexan-3-yl)-7- V((2R,4S)-2-(l-cyclopropyl-lH- pyrazol-4-yl)tetrahydro-2H- 5-68 Y 460pyran-4-yl)-lH-oxazolo[3,4- a]pyrido[3,4-d]pyrimidin- O^J o 9(3H)-one (mixture of isomers)7-((2R,4S)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H- pyran-4-yl)-5-(2- 5-69 fluorocyclohexyl)- 1H- 480oxazolo[3,4-a]pyrido[3,4- d]pyrimidin-9(3H)-one (mixtureof isomers)EXAMPLES 6-1, 6-2Preparation of 6-17-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((R or S)-4-oxaspiro [2.5] octan-6-yl)-lH-oxazolo [3,4-a]pyrido [3,4-d]pyrimidin-9(3H)-one, 6-27-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((S or R)-4-oxaspiro[2.5]octan-6-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.- Ill -26176Step 1.

[0257] To a flask were added 7-bromo-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (1000 mg, 3.183 mmol), 4-((2R)-4-bromotetrahydro-2H-pyran-2-yl)-l-cyclopropyl-lH-pyrazole (1.726 g, 6.366 mmol), Ni(zBuTerpy)C12 (338.2 mg, 636.6 pmol), and zinc (624.3 mg, 9.55 mmol). DMA (50 mL) was added to the reaction mixtures. The flask was then placed in a pre-heated heating block at 55 °C and stirred for 16 hours under inert atmosphere. Upon completion, the reaction was cooled to RT, diluted with EtOAc, and filtered over Celite. DMA was removed with a flow of air overnight. The crude product was purified by flash chromatography (neutral AI2O3, eluent of 45-50 % EtOAc / Hexanes). Fractions were concentrated affording 7-((2R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0258] MS (ESI) m / z: calc’d for C2iH24N5O3S+[M+H]+: 425.2, found [M+H]+: 425.3.Step 2.

[0259] To a stirred solution of 7-((2R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (257 mg, 70% Wt, 761 pmol) in DMF (3 mL) was added silver oxide (147 mg, 635 pmol) at 25 °C. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (41.5 mg, 50.8 pmol) was added. The reaction mixture was heated to 75 °C for 16 hours under inert atmosphere. The reaction mixture was cooled to room temperature and filtered with a celite pad, washed with 2 ^ 10 mL of EtOAc. and diluted with water (50 ml). The Organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. Crude material was purified by flash chromatography (neutral AI2O3, eluent of 45-50 % EtOAc / Hexanes). Fractions were concentrated affording 7-((2R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0260] MS (ESI) m / z: calc’d for C27H3oN504+[M+H]+: 487.2, found [M+H]+: 487.3.Step 3.

[0261] 7-((2R)-2-(l -cyclopropyl- lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (70 mg, 70% Wt, 0.10 mmol) was dissolved in 2,2,2-trifluoroethanol (2 mL) in a reaction vial equipped with a stir bar. Pearlman's catalyst (75 mg, 5% Wt, 35 pmol) was added, and the vial was sealed and purged with hydrogen. The reaction mixture was stirred under a hydrogen atmosphere at 25 °C. After 24 h, a second portion of Pearlman’s catalyst (75 mg, 0.35 equiv) was added, and stirring under hydrogen was continued. After an additional 48 hours, the reaction mixture was filtered through a pad of Celite The filtrate was concentrated under reduced pressure. Crude material was purified by flash26176chromatography (neutral AI2O3, eluent of 55-60 % EtOAc / Hexanes). Fractions were concentrated, affording 7-((2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-(4-oxaspiro[2.5]octan-6-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one.

[0262] Isomers were separated by chiral SFC to give 6-17-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((R or S)-4-oxaspiro[2.5]octan-6-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 3.63 min), 6-27-((2S,4R or 2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5-((S or R)-4-oxaspiro[2.5]octan-6-yl)-lH-oxazolo[3,4-a]pyrido[3,4-d]pyrimidin-9(3H)-one (tR = 5.87 min)Chiral SFC separation conditions: Column: Chiralcel OJ-H, 5 pm, 30 mm x 250 mm; Mobile phase: A: CO2 B: IPA / MeOH = 9:1 (0.5% NH3) Isocratic: 35% B; Flow rate: 120 mL / min;Column temp.: 30 °C; ABPR: 1725 psi.EXAMPLE 6-1 SFC Peak 1:MS (ESI) m / z: calc’d for C27H32N5OZ [M+H]+: 490.2, found [M+H]+: 490.3 1HNMR (400 MHz, DMSO-d6): 8 (ppm) 7.74 (s, 1H), 7.73 (s, 1H), 7.38 (s, 1H), 5.71 (s, 2H), 5.12 (s, 2H), 4.48 (d, J = 10.8 Hz, 1H), 4.13-3.99 (m, 2H), 3.85 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 3.74-3.61 (m, 3H), 3.29-3.20 (m, 1H), 2.25-2.07 (m, 3H), 2.01-1.71 (m, 4H), 1.30-1.20 (m, 1H), 1.04-0.97 (m, 2H), 0.97-0.88 (m, 2H), 0.81-0.72 (m, 1H), 0.66-0.50 (m, 2H), 0.50-0.40 (m, 1H).EXAMPLE 6-2 SFC Peak 2:MS (ESI) m / z: calc’d for C27H32N5OZ [M+H]+: 490.2, found [M+H]+: 490.3 1HNMR (400 MHz, DMSO-d6): 6 (ppm) 7.74 (s, 1H), 7.73 (s, 1H), 7.38 (s, 1H), 5.71 (s, 2H), 5.12 (s, 2H), 4.48 (d, J = 9.6 Hz, 1H), 4.13-4.00 (m, 2H), 3.85 (dd, J = 10.4 Hz, 2.4 Hz, 1H), 3.75-3.60 (m, 3H), 3.30-3.20 (m, 1H), 2.25-2.09 (m, 3H), 2.05-1.72 (m, 4H), 1.35-1.19 (m, 1H), 1.04-0.97 (m, 2H), 0.97-0.89 (m, 2H), 0.80-0.73 (m, 1H), 0.66-0.50 (m, 2H), 0.50-0.40 (m, 1H).ASSAY DATAMethod A: In vitro measurement of TREM2 activity using cell-based pSyk (phosphorylation of Spleen Tyrosine Kinase) assay

[0263] 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 TREM2, and activation of the TREM2 / DAP12 complex, increases phosphorylation of SYK. The resultant levels of Syk phosphorylation are measured using a commercial AlphaLISA reagent kit. To26176perform the assay, HEK-hTREM2 cells were plated at 14,000 to 20,000 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.

[0264] Prior to the assay, test compounds were titrated by acoustic dispensing into 384-well plates and then diluted to the appropriate test concentrations in serum-free media. The cell plates were removed from the incubator and allowed to equilibrate to room temperature for 30 minutes. Growth media was removed from cell plates by inversion and flicking, followed by tapping out excess media on blotting paper, and 25 pL of test articles in serum-free media was added to cells. Cells were incubated for 45 minutes at room temperature. After 45 minutes, the serum-free media was removed by the same flicking and tapping procedure above, and 10 pL of lysis buffer were added. Plates were shaken for 20 minutes at 350 RPM at room temperature. After complete lysis, AlphaLISA reagents were added to the lysate using the manufacturer's recommended bead ratios and incubation times, and fluorescence intensity was measured using a BMG LabTech PHERAstar FSX plate reader. Intensities were used to generate Max and Min controls, and % activation was calculated. Curve fitting was performed using IDBS ABASE software with XE runner, which generates a four parameter fit with variable slope using the log(agonist) vs response, and EC50s were calculated from the curve fit.Method B: In vitro measurement of TREM2 activity using cell-based pSyk (phosphorylation of Spleen Tyrosine Kinase) assay (+ 5% FBS)

[0265] Measurement of TREM2 agonist potency was done using a HEK cell line expressing human TREM2 and DAP12 (HEK293T-hTREM2 cells). Binding of small molecules to, and activation of, TREM2 increases the phosphorylation of Syk. The resultant levels of Syk phosphorylation are measured using a commercial AlphaLISA reagent kit. To perform the assay, HEK-hTREM2 cells were plated at 14,000 cells per well in a 384 well plate, in 25 pL of complete growth media and incubated at 37 °C, 5% CO2 for 20-24 hours.

[0266] Prior to the assay, the cell plates were removed from the incubator and allowed to equilibrate to room temperature for 30 minutes. Test compounds were diluted in intermediate 384 well plates in media containing 5% FBS. Growth media was removed from cell plates by inversion and flicking, followed by tapping out excess media on blotting paper, and 25 pL of test articles in media containing 5% FBS were added to cells. Cells were incubated for 45 minutes at room temperature. After 45 minutes, the media containing 5% FBS was removed by the same flicking and tapping procedure above, and 10 pL of lysis buffer were added. Plates were shaken for 20 minutes at 350 RPM at room temperature. After complete lysis, AlphaLISA reagents were added to the lysate using the manufacturer's recommended bead ratios and incubation times, and fluorescence intensity was measured using a BMG LabTech PHERAstar FSX plate reader.26176Intensities were used to generate Max and Min controls, and % activation was calculated using a TREM2 antibody as the Max and DMSO as the Min. Curve fitting was performed using curvefitting software, which generates a four-parameter fit with variable slope using the log(agonist) vs response, and EC50s were calculated from the curve fit.

[0267] 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. Potency results from the pSYK assays of the disclosed compounds are provided in Table 6, below:Table 6Method B (+ 5% FBS) Example No. Method A HEK293 PotencyHEK293 Potency (EC50, (EC50, nM)nM)1-1 25 nM 52-1 284 nM ND2-2 816 nM ND2-3 9 nM 4 nM2-4 859 nM ND2-5 22 nM 6 nM2-6 6 nM 3 nM2-7 1555 nM ND2-8 11 nM 2 nM2-9 331 nM ND2-10 12 nM 4 nM2-11 818 nM ND2-12 15 nM 3 nM2-13 513 nM 301 nM2-14 773 nM ND2-15 20 nM ND2-16 105 nM 62 nM2-17 47 nM 29 nM2-18 2990 nM ND2-19 2307 nM ND2-20 1552 nM ND2-21 7 nM 3 nM26176Method B (+ 5% FBS) Example No. Method A HEK293 PotencyHEK293 Potency (EC50, (EC50, nM)nM)2-22 12 nM 2 nM2-23 307 nM ND2-24 31 nM 37 nM2-25 2726 nM ND2-26 185 nM 56 nM2-27 5 nM 2 nM2-28 10 nM 4 nM2-29 312 nM ND2-30 398 nM ND2-31 429 nM ND2-32 10 nM 11 nM2-33 24 nM 8 nM2-34 70 nM ND2-35 329 nM ND2-36 927 nM ND2-37 26 nM 9 nM2-38 22 nM 4 nM2-39 11 nM 2 nM2-40 254 nM ND2-41 9 nM 2 nM2-42 73 nM ND2-43 330 nM ND2-44 8 nM 2 nM2-45 246 nM ND2-46 22 nM 5 nM2-47 8 nM 2 nM2-48 332 nM ND2-49 10 nM 5 nM2-50 274 nM ND2-51 119 nM ND2-52 825 nM ND2-53 59 nM 8 nM2-54 123 nM ND2-55 66 nM ND2-56 699 nM ND26176Method B (+ 5% FBS) Example No. Method A HEK293 PotencyHEK293 Potency (EC50, (EC50, nM)nM)2-57 63 nM ND2-58 33 nM 11 nM2-59 62 nM ND2-60 65 nM 31 nM2-61 249 nM ND2-62 294 nM ND2-63 531 nM ND2-64 44 nM 12 nM2-65 54 nM 11 nM2-66 60 nM 9 nM2-67 48 nM 24 nM2-68 45 nM 11 nM2-69 33 nM ND2-70 39 nM 7 nM2-71 114 nM ND2-72 64 nM 18 nM2-73 43 nM 6 nM2-74 252 nM ND2-75 30 nM 3 nM2-76 32 nM 24 nM2-77 714 nM ND2-78 23 nM 8 nM2-79 182 nM 29 nM2-80 164 nM ND2-81 53 nM ND2-82 30 nM 6 nM2-83 299 nM ND2-84 529 nM ND2-85 190 nM ND2-86 12 nM 3 nM2-87 622 nM ND2-88 36 nM ND2-89 62 nM ND2-90 21 nM ND2-91 316 nM ND2-92 140 nM ND2-93 34 nM ND2-94 437 nM ND2-95 128 nM 81 nM2-96 64 nM ND2-97 766 nM ND26176Method B (+ 5% FBS) Example No. Method A HEK293 PotencyHEK293 Potency (EC50, (EC50, nM)nM)2-98 28 nM ND2-99 105 nM 108 nM2-100 21 nM 39 nM2-101 637 nM ND2-102 10 nM 2 nM2-103 778 nM ND2-104 11 nM 2 nM2-105 12 nM 3 nM2-106 563 nM ND2-107 27 nM 4 nM2-108 85 nM ND2-109 173 nM ND2-110 60 nM ND2-111 709 nM ND2-112 746 nM ND2-113 29 nM 3 nM2-114 887 nM ND2-115 53 nM 5 nM2-116 25 nM 4 nM2-117 76 nM ND2-118 41 nM 5 nM2-119 683 nM ND2-120 28 nM 8 nM2-121 731 nM ND2-122 25 nM 2 nM2-123 829 nM ND2-124 16 nM 2 nM2-125 893 nM ND2-126 33 nM 7 nM2-127 902 nM ND2-128 18 nM 4 nM2-129 17 nM 2 nM2-130 990 nM ND2-131 19 nM 2 nM2-132 23 nM 2 nM2-133 16 nM 7 nM2-134 ND 4 nM3-1 22 nM 9 nM3-2 835 nM ND3-3 865 nM ND3-428 nM 3 nM26176Method B (+ 5% FBS) Example No. Method A HEK293 PotencyHEK293 Potency (EC50, (EC50, nM)nM)3-5 57 nM 4 nM3-6 20 nM 8 nM3-7 12 nM 11 nM3-8 429 nM ND3-9 399 nM ND3-10 83 nM ND3-11 99 nM 26 nM3-12 56 nM 10 nM3-13 22 nM 10 nM3-14 16 nM 5 nM3-15 18 nM 6 nM3-16 980 nM ND3-17 33 nM 3 nM3-18 85 nM 48 nM3-19 ND 248 nM3-20 ND 5 nM3-21 ND 326 nM3-22 ND 13 nM4-1 576 nM ND4-2 52 nM 18 nM5-1 11520 nM ND5-2 2513 nM ND5-3 148 nM ND5-4 33 nM 3 nM5-5 397 nM 86 nM5-6 28 nM 3 nM5-7 27 nM 3 nM5-8 671 nM 135 nM5-9 26 nM 4 nM5-10 23 nM 3 nM5-11 310 nM ND5-12 82 nM 3 nM5-13 26 nM 3 nM5-14 ND 44 nM5-15 ND 202 nM5-16 ND 4 nM5-17 ND 17 nM5-18 ND 16 nM5-19 ND 9 nM26176Method B (+ 5% FBS) Example No. Method A HEK293 PotencyHEK293 Potency (EC50, (EC50, nM)nM)5-20 ND 6 nM5-21 ND 4 nM5-22 ND 52 nM5-23 ND 5 nM5-24 ND 32 nM5-25 ND 28 nM5-26 ND 3 nM5-27 ND 123 nM5-28 ND 4 nM5-29 ND 11 nM5-30 ND 14 nM5-31 ND 92 nM5-32 ND 7 nM5-33 ND 13 nM5-34 ND 7 nM5-35 ND 32 nM5-36 ND 11 nM5-37 ND 109 nM5-38 ND 60 nM5-39 ND 5 nM5-40 ND 159 nM5-41 ND 3 nM5-42 ND 88 nM5-43 ND 4 nM5-44 ND 372 nM5-45 ND 6 nM5-46 ND 139 nM5-47 ND 5 nM5-48 ND 18 nM5-49 ND 161 nM5-50 ND 27 nM5-51 ND 12 nM5-52 ND 11 nM5-53 ND 38 nM5-54 ND 205 nM5-55 ND 63 nM5-56 ND 12 nM5-57 ND 3 nM5-58 ND 21 nM26176Method B (+ 5% FBS) Example No. Method A HEK293 PotencyHEK293 Potency (EC50, (EC50, nM)nM)5-59 ND 216 nM5-60 ND 561 nM5-61 ND 101 nM5-62 ND 107 nM5-63 ND 256 nM5-64 ND 39 nM5-65 ND 57 nM5-66 ND 264 nM5-67 ND 72 nM5-68 ND 23 nM5-69 ND 7 nM6-1 ND 5.3 nM6-2 ND 11.9 nMND = Not determined

[0268] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Such modifications are intended to fall within the scope of the appended claims.

[0269] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the following claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I’)R3or a pharmaceutically acceptable salt thereof, wherein:R3 is(a) phenyl;(b) a C3-C7 monocycloalkyl, a C5-C9 spirocycloalkyl, or a C5-C9 bicycloalkyl;(c) a 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S;(d) a 3- to 7- membered monocyclic, C5-C9 bicycloalkyl, or a 6- to 9-membered spirobicyclic heterocycloalkyl, wherein the heterocycloalkyl contains containing 1 to 2 heteroatoms independently selected from N, O, and S;(e) C1-C3 alkyl,wherein R3 is unsubstituted or substituted by 1 to 3 R3a substituents independently selected from halo, C1-C3 alkyl, C1-C3 fluoroalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, cyano and C1-C3 fluoroalkoxy;Y1 is C(H) orN;each RA is independently fluoro or Ci-3 alkyl;CY is(a) a 5- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S;(b) a 3- to 9-membered monocyclic, bicyclic, and bridged, or a 3- to 10-membered spirobicyclic saturated heterocycloalkyl, wherein the heterocycloalkyl contains 1 to 2 heteroatoms independently selected from N, O, and S;(c) a C3-C6 cycloalkyl;(d) a C5-C9 bridged bicycloalkyl;(e) (CH2)scyano,(f) C1-C3 alkyl,wherein CY is unsubstituted or substituted by 1 to 2 RY substituents independently selected from the group consisting of halo, C1.3 alkyl, cyano, C1.3 alkoxy, C1-C3 fluoroalkyl, C3-6 cycloalkyl, C3-6 fluorocycloalkyl and C3-6 difluorocycloalkyl each RZ is independently selected from the group consisting of Cl -3 alkyl, Cl -3 fluoroalkyl, and halo;subscript p is 0, 1, or 2;subscript r is 0, 1, or 2; and subscript s is 1 or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is unsubstituted or substituted phenyl.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of:Cl Cl F F \ZI I . I I I I N, F F F Cl H ClI I I I I I I FF^ F ,_F F F F Cl Cl F■ c. . ■ v . • • >.r FCl F.F F0 0 p f £ £ £ 6 $v<> P §261764. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y1 is C(H).

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y1 is N.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein subscript r is 0.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein subscript s is 1.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein CY is a substituted or unsubstituted 5- to 6-membered heteroaryl ring containing 1 to 2 N heteroatoms.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein CY is substituted or unsubstituted pyrazolyl or pyridinyl.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein CY is substituted or unsubstituted tetrahydrofuryl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein CY is substituted or unsubstituted cyclopropyl.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein thegroupis selected from the group consisting of:2617613. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein subscript p is 0.

14. The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Example Nos. 1-1 through 1-3, 2-1 through 2-2-134, 3-1 through 3-22, 4-1 through 4-2, 5-1 through 5-69 and 6-1 to 6-2.

15. A pharmaceutical composition comprising an effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-14, and a pharmaceutically acceptable carrier.

16. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is a tablet or capsule.

17. A method for the activation of TREM2 receptor in a subject which comprises administering to the subject an effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-14, or pharmaceutical composition of any one of claims 15-16.

18. A method for the treatment or prevention of a condition associated with a loss of function of human TREM2 in a subject, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-14, or pharmaceutical composition of any one of claims 15-16.

19. A method for the treatment or prevention of a neurodegenerative disorder in a subject, comprising administering to the subject an effective amount of the compound or a pharmaceutically acceptable salt of any one of claims 1-14, or pharmaceutical composition of any one of claims 15-16.

20. The method of claim 19, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, demyelination disorder, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis (ALS), tauopathy disease, Nasu-Hakola disease, and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

21. The method of claim 19 or 20, wherein the neurodegenerative disorder is Alzheimer’s Disease.

22. The method of any one of claims 18-21, wherein the subject is human.

23. The method of any one of claims 18-22, wherein the compound of any one of claims 1-14 or the pharmaceutical composition of any one of claims 15-16 is administered by oral, injectable, intramuscular, subcutaneous, intravenous, or intraperitoneal administration.

24. The method of any one of claims 19-23, further comprising the step of administering a tau targeting therapy or an amyloid-P targeting therapy.

25. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the treatment or prevention of a neurodegenerative disorder in a subject.

26. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, for use in therapy.

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