Modulators of TREM2 activity

Abstract

Provided herein are agonists of TREM2, pharmaceutical compositions comprising the TREM2 agonist compounds, and methods for using the TREM2 agonist compounds for the treatment of diseases or disorders.

Description

WSGR Docket No. 55754-728.601MODULATORS OF TREM2 ACTIVITYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of US Provisional Application No. 63 / 763,078, filed February 25, 2025, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is a type I transmembrane glycoprotein that is involved in various cellular functions, such as regulating immune responses, phagocytosis, and maintaining tissue homeostasis in the brain. Aberrant TREM2 signaling has been implicated in various pathological conditions, such as neurodegenerative diseases, dysregulated inflammatory response, and altered immune response.BRIEF SUMMARY OF THE INVENTION

[0003] Provided herein are agonists of TREM2, pharmaceutical compositions comprising said agonist compounds, and methods for using said agonist compounds for the treatment of a disease or disorder.

[0004] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof,wherein,Ring A is a 6-membered aryl or heteroaryl ring system;RingB is a 5- or 6-membered heteroaryl ring system;X is H or -CH2-O-P(O)(OR1)2;R1is selected from H, or optionally substituted C1-C6 alkyl;G is described by Formula (a):WSGR Docket No. 55754-728.601wherein,Q is O, N-R12, C(R13)2, or SO2;T is C(R30)(R31) or O;V is C(R23)(R24), N-R14, or O;U is N, C-H or C-F;R10is selected from optionally substitutedCl-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted carbocyclyl;R11is selected from H, D, halogen, or optionally substituted Cl -C6 alkyl; or R10and R11join to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;R12and R14are each independently selected from H, optionally substituted Cl -C6 alkyl, -CO(optionally substituted C1-C6 alkyl), or -SO2(optionally substituted C1-C6 alkyl);each R13is independently selected from H, halo, or optionally substituted Cl -C6 alkyl; R15is selected from H or optionally substituted C1-C6 alkyl;R23and R24are independently selected from H, halo, optionally substituted Cl -C6 alkyl, or optionally substituted C1-C6 alkoxy; orR23and R24are both optionally substitutedCl-C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R23and R24form an oxo or an =N-OR15; or R12and R23are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R11and R23are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R23and R30are both optionally substituted C1-C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R30and R32are both optionally substituted C1-C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring;R30and R31are independently selected from H, D, or optionally substituted Cl -C6 alkyl; or R30and R31are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring;R32and R33are independently selected from H, D, or optionally substituted Cl -C6 alkyl; or R32and R33are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; andRa, Rb, Rc, and Rdare each independently selected from H, D, F, Cl, Br, -CN, CH3, CF3, or -OCF3.WSGR Docket No. 55754-728.601

[0005] One embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the Ring A-RingB bicyclic system is selected from the group consisting of:wherein,WSGR Docket No. 55754-728.601R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.

[0006] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or pharmaceutically acceptable salt, solvate, or N-oxide thereof, and at least one pharmaceutically acceptable excipient.

[0007] One embodiment provides a method of treating a disease or disorder in a patient in need thereof comprising administering to the patient a compound of Formula (I), or pharmaceutically acceptable salt, solvate, or N-oxide thereof.INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTION

[0009] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and sub -combinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.WSGR Docket No. 55754-728.601Definitions

[0010] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0011] " Amino" refers to the -NH2 radical.

[0012] "Cyano" refers to the -CN radical.

[0013] "Nitro" refers to the -NO2 radical.

[0014] " Oxa" refers to the -O- radical.

[0015] " Oxo" refers to the =0 radical.

[0016] " Thioxo" refers to the =S radical.

[0017] " Imino" refers to the =N-H radical.

[0018] " Oximo" refers to the =N-0H radical.

[0019] "Hydrazino" refers to the =N-NH2radical.

[0020] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cg alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., Ci-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (w-propyl), 1 -methylethyl (Ao-propyl), 1 -butyl (w-butyl), 1 -methylpropyl (secbutyl), 2-methylpropyl (Ao-butyl), 1,1 -dimethylethyl (ferAbutyl), 1 -pentyl (w-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted withWSGR Docket No. 55754-728.601halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). In certain embodiments, an optionally substituted alkyl is a haloalkyl. In other embodiments, an optionally substituted alkyl is a fluoroalkyl. In other embodiments, an optionally substituted alkyl is a -CF3group.

[0021] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-1 -enyl (i.e., allyl), but-l-enyl, pent-l-enyl, penta-1, 4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0023] " Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, anWSGR Docket No. 55754-728.601alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0024] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, w-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., Ci-Cg alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., Ci-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cs alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -WSGR Docket No. 55754-728.601N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms (e.g., C2-C8alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., C5-C8alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, orWSGR Docket No. 55754-728.601trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or tri fluoromethyl).

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C2-C8alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (e.g., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., Cs-C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SIU, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)-N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or tri fluoromethyl).

[0027] "Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, z.e., it contains a cyclic, delocalized (4n+2) 71-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in theWSGR Docket No. 55754-728.601specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, andRcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0028] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0029] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0030] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0031] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.WSGR Docket No. 55754-728.601

[0032] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, spiro, or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond.Carbocyclyl is saturated (z.e., containing single C-C bonds only) or unsaturated (z.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as "cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (z.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, andRcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0033] "Carbocyclylalkyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.WSGR Docket No. 55754-728.601

[0034] "Carbocyclylalkynyl" refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0035] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0037] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2 -fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0038] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes fused, spiro, or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted withWSGR Docket No. 55754-728.601halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, andRcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0039] "A-heterocyclyl" or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An^'-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1 -morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, and imidazolidinyl.

[0040] " C-heterocyclyl" or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2 -morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0041] "Heterocyclylalkyl" refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen -containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0042] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heteroaryl" refers to a radical derived from a 3 - to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, orWSGR Docket No. 55754-728.601tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^-electron system in accordance with the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[Z»][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl,6.7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5.6.7.8.9.10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5.6.7.8.9.10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,5.8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1 -phenyl- UT-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from optionally substituted alkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted alkenyl, optionally substituted alkynyl, halo, optionally substituted fluoroalkyl, optionally substituted haloalkenyl, optionally substituted haloalky nyl, oxo, thioxo, cyano, nitro, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t isWSGR Docket No. 55754-728.6011 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the Ra, Rb, or Rcsubstituents is unsubstituted unless otherwise indicated.

[0044] "A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0045] " C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen -containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0047] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O-Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0048] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that areWSGR Docket No. 55754-728.601defined, in terms of absolute stereochemistry, as (R)- or (5 -. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers (e.g., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term “geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0049] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0050] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,nC,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0051] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example,WSGR Docket No. 55754-728.601compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0052] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes atone or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,nC,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br,125I are all contemplated. In some embodiments, isotopic substitution with18F is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0053] In certain embodiments, the compounds disclosed herein have some or all of theJH atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0054] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 1 lOpp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0055] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0056] Deuterium -transfer reagents suitable for use in nucleophilic substitution reactions, such as iodomethane-d3(CD3I), are readily available and may be employed to transfer a deuterium -substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.DWSGR Docket No. 55754-728.601

[0057] Deuterium -transfer reagents, such as lithium aluminum deuteride (LiAlD4), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4is illustrated, by way of example only, in the reaction schemes below.

[0058] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon -carbon linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0059] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeableJH hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material.

[0060] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the TNF-a inhibitory compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0061] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromaticWSGR Docket No. 55754-728.601acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. etal., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19(1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0062] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2 -dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., supra.

[0063] "Pharmaceutically acceptable solvate" refers to a composition of matter that is the solvent addition form. In some embodiments, solvates contain either stoichiometric or non -stoichiometric amounts of a solvent, and are formed during the process of making with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds describedWSGR Docket No. 55754-728.601herein are conveniently prepared or formed during the processes described herein. The compounds provided herein exist in either unsolvated or solvated forms.

[0064] "Prodrug" is meant to indicate a compound that may be converted under physiological conditions to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in the active compounds and the like.

[0065] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0066] As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and / or a prophylactic benefit. By “therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.WSGR Docket No. 55754-728.601Triggering Receptor Expressed on Myeloid cells 2 (TREM2) Protein and Function

[0067] Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor that plays a pivotal role in the immune system by modulating the activity of microglia, macrophages, dendritic cells, and osteoclasts. The ligands of TREM2 encompass a wide array of anionic molecules, free and bound to the plasma membrane, including bacterial products, DNA, lipoproteins, and phospholipids. TREM2 is involved in several crucial physiological processes. It enhances the phagocytic ability of immune cells, facilitating the engulfment and clearance of apoptotic cells, debris, and pathogens. It also promotes an anti-inflammatory environment by regulating the production of cytokines and chemokines. Additionally, TREM2 signaling supports the survival and proliferation of myeloid cells and maintains tissue homeostasis by modulating immune responses and promoting tissue repair (Kober and Brett, TREM2 -Ligand Interactions in Health and Disease. J. Mol. Biol. 2017; 429: 1607-1629).

[0068] TREM2 is part of the immunoglobulin superfamily and is characterized by an extracellular domain that includes a single V-type immunoglobulin domain, a short ectodomain, a transmembrane region, and a short cytosolic tail that lacks any signal transduction or trafficking motifs. TREM2 undergoes ectodomain shedding, leading to release of soluble fragments, known as soluble TREM2 (sTREM2). Since TREM2 lacks an intracellular signaling domain, it relies on association with DNAX-activating protein of 12 kDa (DAP12) and DAP10 to transduce signals. Upon TREM2 -ligand interaction, these co-receptors are phosphorylated and recruit intracellular signal transduction machinery. DAP12, also known as TYRO protein tyrosine kinase -binding protein (TYROBP), is an adaptor protein that contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic tail and mediates activation of spleen tyrosine kinase Syk, whereas DAP10 promotes signal propagation by recruiting phosphatidylinositol 3 -kinase (PI3K). TREM2 can bind DAP12 orDAPIO and possibly form TREM2-DAP12-DAP10 heterodimers. The TREM2-DAP12 complex is essential for initiating intracellular signaling cascades following ligand binding to TREM2 (Peng et al. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci. Signal. 2010; 3: ra38). For example, in mouse macrophages, DAP12 is required for Ca2+ mobilization. DAP10 is critical for activation of serine / threonine protein kinase (AKT1) and extracellular signal -regulated kinase (ERK).

[0069] ITAM is a conserved sequence found in the cytoplasmic domains of various immune receptors, including DAP12. ITAMs are critical for transmitting activation signals from the cell surface to intracellular signaling pathways. Upon ligand binding, TREM2 forms a complex with DAP12, leading to the phosphorylation of ITAM and the recruitment of spleen tyrosine kinase (Syk), and inducing a conformational change in the TREM2-DAP12 complex (Zhong et al.WSGR Docket No. 55754-728.601“Unraveling the Molecular Dance: Insights into TREM2 / DAP12 Complex Formation in Alzheimer's Disease through Molecular Dynamics Simulations.” ACS omega vol. 9,26 (2024) 28715-28725). The phosphorylated ITAM then serves as a docking site for spleen tyrosine kinase (Syk), which contains tandem SH2 domains that bind to the phosphorylated tyrosines. Activated Syk phosphorylates and activates various downstream signaling molecules and pathways, including phosphoinositide 3 -kinase (PI3K), extracellular signal -regulated kinases (ERK), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-KB). These pathways promote cell survival, proliferation, differentiation, and regulate the transcription of genes involved in inflammation and immune responses (Deczkowska et al. “The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway.” Cell vol. 181,6 (2020): 1207-1217).

[0070] Through these pathways, TREM2 attenuates inflammatory responses by modulating the production of pro-inflammatory cytokines such as interleukin- ip (IL-ip), tumor necrosis factoralpha (TNF-a), and chemokines such as CCL2. TREM2 also enhances the phagocytic capacity of macrophages, facilitating the clearance of apoptotic cells and cellular debris. This function is crucial for resolving inflammation and preventing chronic inflammatory conditions. Experimental models have demonstrated that TREM2 deficiency leads to exaggerated inflammatory responses and impaired resolution, underscoring the role of TREM2 in acute inflammation.

[0071] One of the first observations pointing to the importance of TREM2 for human health was made in the context of Nasu-Hakola disease (NHD), where genetic studies identified loss-of-function mutations in TREM2 and DAP12. NHD, also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a fatal disease characterized by progressive pre-senile dementia (Klunemann et al. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology. 2005; 64: 1502-1507). TREM2 is highly expressed on microglia, the resident immune cells of the central nervous system (CNS) and plays a role in regulating their activation and function.

[0072] In the CNS, TREM2-DAP12 signaling influences microglial activation, promoting their phagocytic activity and enhancing the clearance of amyloid -beta plaques, tau tangles, and other neurotoxic substances. In human cerebrospinal fluid (CSF), studies have shown that sTREM2 levels are elevated in CSF of patients with various neurological conditions, such as Multiple sclerosis, Alzheimer's disease, Parkinson’s disease (PD), and frontotemporal dementia (FTD) associated with progranulin (GRN) mutations (Woollacott et al. Cerebrospinal fluid soluble TREM2 levels in frontotemporal dementia differ by genetic and pathological subgroup. Alzheimers Res. Ther. 2018; 10: 79). TREM2 also modulates microglial responses to damaged neurons and synapses, promoting a supportive environment for neuronal health. For example, microglial TREM2 is crucial for induction of the transcriptomic and functional program of disease -associatedWSGR Docket No. 55754-728.601microglia (DAMs), a subtype of microglia that occurs in the brain in various animal models of neurodegeneration. Additionally, overexpression of human TREM2 in microglia in a mouse model of Alzheimer's disease attenuated the pathological phenotype, including plaque load and cognitive impairment. Moreover, the most prevalent TREM2 variant associated with Alzheimer's disease is R47H, a mutation that confers loss of ligand binding ability and has been linked to an increased risk of other neurodegenerative disorders (Zhong et al. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). Mol. Neurodegener.2018; 13: 15).

[0073] TREM2 activation can antagonize responsiveness to pro -inflammatory stimuli at the signaling level. For example, several hallmark anti-inflammatory genes are expressed in a TREM2-dependent manner in microglia and macrophages in mice; among these genes are Galectin-1 and -3 (Lgalsl andLgals3), interleukin 1 receptor antagonist (IL- IRA), progranulin (Gm), and others, all known modulators of the inflammatory response (Jaitin et al. Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2 -Dependent Manner. Cell. 2019; 178: 686-698. el4). TREM2 activation in cardiac macrophages can foster an anti-inflammatory phenotype, characterized by increased production of anti-inflammatory cytokines such as interleukin- 10 (IL-10) and transforming growth factor-beta (TGF-P). This anti-inflammatory environment is crucial for the resolution of injury and the prevention of adverse cardiac remodeling. For example, cardiac disease, including myocardial infarction and heart failure, involves significant inflammatory responses that contribute to tissue damage and impaired cardiac function. Following myocardial infarction, TREM2-DAP12 signaling enhances the clearance of necrotic cells and debris, reducing inflammation and promoting tissue repair. Studies have shown that TREM2 deficiency leads to exacerbated cardiac inflammation, increased fibrosis, and impaired healing (Gong et al. TREM2 macrophage promotes cardiac repair in myocardial infarction by reprogramming metabolism via SLC25A53. Cell Death Differ 31, 239-253 (2024)).

[0074] TREM2 signaling in macrophages has recently been linked to metabolic disease. Metabolic homeostasis is intricately linked to immune regulation, with TREM2 playing a significant role in this interplay. TREM2 is expressed on adipose tissue macrophages, which are crucial for maintaining metabolic balance. In healthy metabolic states, TREM2 signaling promotes the antiinflammatory phenotype of adipose tissue macrophages, supporting insulin sensitivity and metabolic function (Deczkowska et al. “The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway.” Cell vol. 181,6 (2020): 1207-1217).

[0075] TREM2-DAP12 signaling in adipose tissue macrophages promotes the expression of antiinflammatory cytokines and enhances their ability to clear dead adipocytes, reducing adipose tissue inflammation. This process involves the activation of PI3K-Akt and ERK pathways, which areWSGR Docket No. 55754-728.601important for cell survival and anti-inflammatory responses. Deficiency or dysfunction of TREM2 exacerbates adipose tissue inflammation, characterized by increased infiltration of pro-inflammatory macrophages, and insulin resistance. For example, studies have shown that TREM2 deficiency in adipose tissue macrophages results in increased inflammation, characterized by elevated levels of pro-inflammatory cytokines such as IL-6 and TNF-a, and insulin resistance, contributing to the pathophysiology of metabolic syndrome. Additionally, enhancing TREM2 signaling can reduce adipose tissue inflammation and improve insulin sensitivity, maintaining the balance of macrophage activation states, and promoting an anti-inflammatory environment that mitigates obesity-associated metabolic complications. For example, studies have demonstrated that TREM2 is required for induction of monocyte -derived lipid-associated macrophages (LAMs), which reside in obese adipose tissue, and that LAMs are critical locally for visceral adipose tissue (VAT) tissue remodeling in obesity and systemically for limiting obesity -related metabolic derailment (Jaitin et al. Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner. Cell. 2019; 178: 686-698. el4).Prior Art Agonists

[0076] Neurodegenerative disorders, including Alzheimer's disease, are associated with microgliosis. Microglia have long been considered to have detrimental roles in Alzheimer's disease. One of the major risk genes for Alzheimer's disease is TREM2. Risk variants of TREM2 are loss-of-function mutations affecting chemotaxis, phagocytosis, lipid and energy metabolism, and survival and proliferation. There are numerous possible interventions to modulate the TREM2 pathway as a therapeutic target. The most prominent one is to directly target the receptor’s active domain with a specific monoclonal antibody or small molecule that would block or activate downstream signaling (Schlepckow et al. Stimulation of TREM2 with agonistic antibodies-an emerging therapeutic option for Alzheimer's disease. Lancet Neurol., 22 (2023), pp. 1048-1060). Agonistic anti-TREM2 antibodies have been developed to boost these protective functions in patients with intact TREM2 alleles (N. Orti-Casan et al., Front Neuro sci. 2019; 13: 49). Agonistic anti-TREM2 antibodies that have been developed include: AL002, a humanized monoclonal antibody for treating mild cognitive impairment and mild dementia caused by Alzheimer's disease; ATV:TREM2, a human-specific TREM2 -activating antibody for treating Alzheimer's disease which is engineered to cross the blood-brain barrier using the transferrin receptor; and PY314, a TREM2 monoclonal antibody for treating solid tumors (Tong et al. “Targeting dysregulated lipid metabolism for the treatment of Alzheimer's disease and Parkinson's disease: Current advancements and future prospects.” Neurobiology of disease vol. 196 (2024): 106505).

[0077] TREM2 therapeutic antibodies are being investigated as a potential treatment for Alzheimer's disease. An estimated 6.9 million Americans are living with Alzheimer's disease.WSGR Docket No. 55754-728.601Alzheimer's disease is a progressive and irreversible neurological disorder that primarily affects the brain, leading to a decline in cognitive function, memory loss, and changes in behavior and personality. It is the most common cause of dementia, accounting for around 60-70% of all cases.

[0078] Recent reports also indicate that TREM2 agonists can be used alone or in combination for treatment of cancer, such as gynecological cancer, breast cancer, and colorectal cancer (Patnaik et al. A phase la dose-escalation study of PY314, a TREM2 (Triggering Receptor Expressed on Macrophages 2) targeting monoclonal antibody. J Clin Oncol. 2022;40(16_suppl):2648).Combination therapies can include treatment with pembrolizumab. Accumulating evidence suggests a role of TREM2 in tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). For example, a recent study found that TREM2 was significantly upregulated on peripheral blood monocytes and on TAMs in lung cancer patients (Yao et al. TREM-2 serves as a negative immune regulator through Syk pathway in an IL-10 dependent manner in lung cancer. Oncotarget. 2016; 7: 29620-29634).

[0079] Small molecules can bind to TREM2, thereby activating TREM2 signaling pathways. The activation of TREM2 can potentially enhance the phagocytic and anti-inflammatory functions of microglia, which may have therapeutic benefits in conditions characterized by impaired TREM2 function. VG-3927 is a small molecule TREM2 agonist being investigated as a potential treatment for Alzheimer's disease. TREM2 small molecule agonists may also have the potential to treat common neurodegenerative diseases associated with microglial dysfunction, acute inflammation, cardiac disease, metabolic disorders, and obesity. TREM2 signaling has been associated with metabolic disorders such as obesity, insulin resistance, and fatty liver disease. TREM2 has been implicated in the regulation of adipose tissue inflammation and metabolism. By activating TREM2, agonists could potentially promote the clearance of dysfunctional adipocytes, regulate adipose tissue inflammation, modulate the immune response in cardiac tissues, and improve metabolic parameters associated with obesity.

[0080] Additionally, TREM2 is constantly shed by ADAMs (a disintegrin and metalloproteinase), thus inhibiting or accelerating this process is another potential point of intervention. However, because ADAMI 0 / 17 have a wide range of substrates, inhibiting a specific protease activity is in most cases associated with unwanted side effects.Novel TREM2 Agonist Compounds

[0081] In one aspect, provided herein are TREM2 agonist compounds.

[0082] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof,WSGR Docket No. 55754-728.601Y(A( B )(I)wherein,Ring A is a 6-membered aryl or heteroaryl ring system;RingB is a 5- or 6-membered heteroaryl ring system;X is H or -CH2-O-P(O)(OR1)2;R1is selected from H, or optionally substituted C1-C6 alkyl;G is described by Formula (a):wherein,Q is O, N-R12, C(R13)2, or SO2;T is C(R30)(R31) or O;V is C(R23)(R24), N-R14, or O;U is N, C-H or C-F;R10is selected from optionally substitutedCl-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted carbocyclyl;R11is selected from H, D, halogen, or optionally substituted Cl -C6 alkyl; or R10and R11join to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;R12and R14are each independently selected from H, optionally substituted Cl -C6 alkyl, -CO(optionally substituted C1-C6 alkyl), or -SO2(optionally substituted C1-C6 alkyl);each R13is independently selected from H, halo, or optionally substituted Cl -C6 alkyl; R15is selected from H or optionally substituted C1-C6 alkyl;R23and R24are independently selected from H, halo, optionally substituted Cl -C6 alkyl, or optionally substituted C1-C6 alkoxy; orR23and R24are both optionally substitutedCl-C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R23and R24form an oxo or an =N-OR15; or R12and R23are both optionally substituted Cl -C6 alkyl and join to form a carbocyclicWSGR Docket No. 55754-728.601ring or a heterocyclic ring; or R11and R23are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R23and R30are both optionally substituted C1-C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R30and R32are both optionally substituted C1-C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring;R30and R31are independently selected from H, D, or optionally substituted Cl -C6 alkyl; or R30and R31are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring;R32and R33are independently selected from H, D, or optionally substituted Cl -C6 alkyl; or R32and R33are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; andRa, Rb, Rc, and Rdare each independently selected from H, D, F, Cl, Br, -CN, CH3, CF3, or -OCF3.

[0083] One embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the Ring A-RingB bicyclic system is selected from the group consisting of:WSGR Docket No. 55754-728.601wherein,R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.

[0084] One embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (la):wherein,Z1is selected from N or C-H;R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionallyWSGR Docket No. 55754-728.601substituted aminoalkyl, or -SO2(optionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.

[0085] Another embodiment provides the compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is N. Another embodiment provides the compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is C-H.

[0086] One embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (lb):wherein,Y1is selected from N or C-H;Y2is selected from N or C-H;Y3is selected from N or C-H;Y4is selected from N or C-H;R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.

[0087] Another embodiment provides the compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y1isN. Another embodiment provides the compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y2is N. Another embodiment provides the compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y3is N. Another embodiment provides the compound of Formula (lb), ora pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y4is N. Another embodiment provides the compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y1is C-H. Another embodiment provides the compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y2is C-H. Another embodimentWSGR Docket No. 55754-728.601provides the compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y3is C-H. Another embodiment provides the compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y4is C-H.

[0088] One embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ic):wherein,Z1is selected from N or C-H;R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.

[0089] Another embodiment provides the compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is N. Another embodiment provides the compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is C-H.

[0090] One embodiment provides the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Id):wherein,WSGR Docket No. 55754-728.601R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.

[0091] One embodiment provi d es the compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope th e<r eof, having the structure of Formula (le):<>wherein,R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl).

[0092] One embodiment provides a TREM2 agonist compound, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having a structure presented in Table 1.Table 1WSGR Docket No. 55754-728.601WSGR Docket No. 55754-728.601> <<<WSGR Docket No. 55754-728.601><<WSGR Docket No. 55754-728.601" "<>WSGR Docket No. 55754-728.601< <WSGR Docket No. 55754-728.601<WSGR Docket No. 55754-728.601<<WSGR Docket No. 55754-728.601<> >> <<WSGR Docket No. 55754-728.601<<Preparation of Compounds

[0093] The compounds used in the synthetic chemistry reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (MiltonPark, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz& Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), PierceWSGR Docket No. 55754-728.601Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0094] Suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books andtreatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C."Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley -VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley -VCH, ISBN: 3-527-29871-l;Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[0095] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference useful for the preparation and selection of pharmaceuticalWSGR Docket No. 55754-728.601salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.Pharmaceutical Compositions

[0096] In certain embodiments, the TREM2 agonist compound described herein is administered as a pure chemical. In other embodiments, the TREM2 agonist compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0097] Provided herein is a pharmaceutical composition comprising at least one TREM2 agonist compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or the patient) of the composition.

[0098] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0099] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0100] In certain embodiments, the TREM2 agonist compound as described by Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is substantially pure, in that it contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0101] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

[0102] One embodiment provides a method of preparing a pharmaceutical composition comprising mixing a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable carrier.

[0103] In certain embodiments, the TREM2 agonist compound as described by Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is substantially pure, in that itWSGR Docket No. 55754-728.601contains less than about 5%, or less than about 2%, or less than about 1%, or less than about 0.5%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0104] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0105] In some embodiments, the TREM2 agonist compound as described by Formula (I), or Table 1, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based formulation, such as sesame oil, or the like.

[0106] The dose of the composition comprising at least one TREM2 agonist compound as described herein differs depending upon the subject or patient's (e.g., human) condition. In some embodiments, such factors include general health status, age, and other factors.

[0107] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease -free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0108] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Methods of Treatment

[0109] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.WSGR Docket No. 55754-728.601

[0110] One embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cardiovascular disease or disorder. Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of neurodegenerative disease or disorder. Another embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of metabolic disease or disorder.

[0111] One embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cardiovascular disease or disorder. Another embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of neurodegenerative disease or disorder. Another embodiment provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of metabolic disease or disorder.

[0112] One embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cardiovascular disease or disorder. Another embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of neurodegenerative disease or disorder. Another embodiment provides a use of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of metabolic disease or disorder.

[0113] In some embodiments is provided a method of treating an inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to theWSGR Docket No. 55754-728.601patient a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient. One embodiment provides a method of treating an inflammatory disease or disorder. Another embodiment provides a method of treating an autoimmune disease or disorder.

[0114] In some embodiments the inflammatory and autoimmune disease or disorder is selected from, but not limited to rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, lupus nephritis, systemic lupus erythematosus, psoriasis, Crohn's disease, colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, Alzheimer’s disease, Graves' disease, cutaneous lupus, ankylosing spondylitis, cryopyrin-associated periodic syndromes (CAPS), gout, gouty arthritis, Wegener’s granulomatosis, sarcoidosis, familial Mediterranean fever (FMF), neuropathic pain, and adult onset stills.

[0115] In some embodiments is provided a method of treating a cardiovascular disease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating cardiovascular disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0116] In some embodiments the cardiovascular disease or disorder is selected from, but not limited to: high blood pressure, heart disease, rheumatic heart disease, pericarditis, endocarditis, myocarditis and atherosclerosis.

[0117] In some embodiments is provided a method of treating a neurodegenerative disease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating neurodegenerative disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0118] In some embodiments the neurodegenerative disease or disorder is selected from, but not limited to: Alzheimer's disease, Parkinson's disease, frontotemporal dementia, primary progressive aphasia, Huntington's disease, amyotrophic lateral sclerosis, and paraneoplastic disorders.WSGR Docket No. 55754-728.601

[0119] In some embodiments is provided a method of treating a metabolic disease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating metabolic disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0120] In some embodiments the metabolic disease or disorder is selected from, but not limited to: Type 2 diabetes mellitus, obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and metabolic encephalopathies.

[0121] One embodiment provides a compound of Table 1 , or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of cardiovascular disease or disorder. Another embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of neurodegenerative disease or disorder. Another embodiment provides a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of metabolic disease or disorder.

[0122] One embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of cardiovascular disease or disorder. Another embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of neurodegenerative disease or disorder. Another embodiment provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient for use in a method of treatment of metabolic disease or disorder.

[0123] One embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of inflammatory or autoimmune disease or disorder. Another embodiment provides a useWSGR Docket No. 55754-728.601of a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of cardiovascular disease or disorder. Another embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of neurodegenerative disease or disorder. Another embodiment provides a use of a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, in the manufacture of a medicament for the treatment of metabolic disease or disorder.

[0124] In some embodiments is provided a method of treating an inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating inflammatory or autoimmune disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient. One embodiment provides a method of treating an inflammatory disease or disorder. Another embodiment provides a method of treating an autoimmune disease or disorder.

[0125] In some embodiments the inflammatory and autoimmune disease or disorder is selected from, but not limited to: rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, lupus nephritis, systemic lupus erythematosus, psoriasis, Crohn's disease, colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, multiple sclerosis, Alzheimer’s disease, Graves' disease, cutaneous lupus, ankylosing spondylitis, cryopyrin-associated periodic syndromes (CAPS), gout, and gouty arthritis, Wegener’s granulomatosis, sarcoidosis, familial Mediterranean fever (FMF), neuropathic pain, and adult onset stills.

[0126] In some embodiments is provided a method of treating a cardiovascular disease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Table 1 , or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating cardiovascular disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0127] In some embodiments the cardiovascular disease or disorder is selected from, but not limited to, high blood pressure, heart disease, rheumatic heart disease, pericarditis, endocarditis, myocarditis and atherosclerosis.WSGR Docket No. 55754-728.601

[0128] In some embodiments is provided a method of treating a neurodegenerative disease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating neurodegenerative disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1 , or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0129] In some embodiments the neurodegenerative disease or disorder is selected from, but not limited to: Alzheimer's disease, Parkinson's disease, frontotemporal dementia, primary progressive aphasia, Huntington's disease, amyotrophic lateral sclerosis, and paraneoplastic disorders.

[0130] In some embodiments is provided a method of treating a metabolic disease or disorder, in a patient in need thereof, comprising administering to the patient a compound of Table 1 , or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof. In some embodiments is provided a method of treating metabolic disease or disorder, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

[0131] In some embodiments the metabolic disease or disorder is selected from, but not limited to: Type 2 diabetes mellitus, obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and metabolic encephalopathies.

[0132] Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection.

[0133] One embodiment provides a method of modulating TREM2 receptor activity comprising contacting the TREM2 receptor with a compound of Formula (I), or Table 1. Another embodiment provides the method of modulating TREM2 receptor activity, wherein the TREM2 receptor is contacted in an in vivo setting. Another embodiment provides the method of modulating TREM2 activity, wherein the TREM2 receptor is contacted in an in vitro setting.

[0134] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.WSGR Docket No. 55754-728.601EXAMPLESI. Chemical Synthesis

[0135] In some embodiments, the TREM2 agonist compound disclosed herein are synthesized according to the following examples. As used below, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:ACN acetonitrile°C degrees CelsiusbHchemical shift in parts per million downfield from tetramethylsilane DCM dichloromethane (CH2CI2)DI D diisopropyl azodicarboxylateDIEA diisopropylethylamineDMF dimethylformamideDMSO dimethylsulfoxideEA ethyl acetateEtOAc ethyl acetateESI electrospray ionizationEt ethylg gram(s)h hour(s)HPLC high performance liquid chromatographyHz hertzJ coupling constant (in NMR spectrometry)LCMS liquid chromatography mass spectrometrymicrom multiplet (spectral); meter(s); milliM molarM+parent molecular ionMe methylMsCl methanesulfonyl chlorideMHz megahertzmin minute(s)mol mole(s); molecular (as in mol wt)mL milliliterMS mass spectrometryWSGR Docket No. 55754-728.601nm nanometer(s)NMR nuclear magnetic resonancepH potential of hydrogen; a measure of the acidity or basicity of an aqueous solutionPE petroleum etherRT room temperatures singlet (spectral)t triplet (spectral)SFC Supercritical fluid chromatographyT temperatureTFA trifluoroacetic acidTHF tetrahydrofuranTPP triphenylphosphineExperimental Procedures

[0136] Intermediate 1 - 2-(2-Chloro-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenolStep 1: l-Bromo-2-(methoxymethoxy)-4-(trifluoromethyl)benzeneTo a solution of 2-bromo-5-(trifluoromethyl)phenol (400 g, 1.66 mol) and Cs2CO3 (656 g, 1.99 mol) in DMF (4.0 L) at 0 °C was added MOMCI (218.4 g, 2.32 mol) dropwise over 20 min and the mixture was then stirred atRT for 2 h. The mixture was diluted with water (4.0 L), extracted with EtOAc (4.0 L x 2) and the combined organic phases washed with brine (1.0 L x 3), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100% Pet. ether) to give 1 (440 g, 93%) as a yellow oil. LCMS (Agilent Acid): no m / z 1HNMR (400 MHz, DMSO-d6) 87.88 - 7.82 (m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.33 - 7.28 (m, 1H), 5.41 (s, 2H), 3.42 (s, 3H).Step 2: 2-(2-(Methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolaneTo a solution of l-bromo-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (430 g, 1.51 mol) in 1,4-dioxane (3.9 L) were added B2pin2 (460 g, 1.81 mol), Pd(dppf)C12 (22.1 g, 0.03 mol) andWSGR Docket No. 55754-728.601KO Ac (444 g, 4.53 mol) and the mixture was purged three times with N2 then heated at 100 °C for 16 h. The mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 10% THF / Pet. ether) to give 2 (448 g, 89%) as a yellow oil. LCMS (Agilent Acid): nom / z 1HNMR (400 MHz, DMSO-d6) 67.72 (d, J = 8.0 Hz, 1H), 7.35 -7.33 (m, 2H), 5.27 (s, 2H), 3.41 (s, 3H), 1.30 (s, 12H).Step 3: 2,4-Dichloro-6,7-dimethylpteridineTo a solution of 2,6-dichloropyrimidine-4,5-diamine (200 g, 1.12 mol) in EtOH (1.1 L) was added biacetyl (136 g, 1.56 mol) and the mixture was stirred at 30 °C for 16 h. The mixture was concentrated under reduced pressure and the residue triturated with Et2O (200 mL) to give 2,4-Dichloro-6,7-dimethylpteridine (230 g, 90%) as a yellow solid. LCMS (Agilent Acid): m / z 229.1, 231.0 [M+H]+.Step 4: 2-Chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpteridine To a solution of 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (468 g, 1.41 mol) in THF (12.8 L) and water (2.1 L) were added 2,4-dichloro-6,7-dimethylpteridine (215 g, 0.94 mol), Pd(dppf)C12.DCM (76.6 g, 0.09 mol) and K2CO3 (389 g, 2.82 mol) and the mixture was purged three times with N2 then stirred at RT for 16 h under a N2 atmosphere. The mixture was diluted with water (12.8 L), extracted with EtOAc (12.8 L x 2) and the combined organic phases washed with brine (3.0 L), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 17% THF / Pet. ether) to give the crude product. The crude product was dissolved in EtOAc (1.2 L) and Pet. ether (16.8 L) was added dropwise atRT over 1 h. The resulting precipitate was collected by filtration to give the title compound (119 g, 32%) as a yellow solid. LCMS (Agilent Acid): m / z 399.1 [M+H]+. 1HNMR (400 MHz, DMSO- d6) 87.72 (d, J = 8.0 Hz, 1H), 7.62 - 7.60 (m, 1H), 7.59 - 7.53 (m, 1H), 5.19 (s, 2H), 3.25 (s, 3H), 2.80 (s, 3H), 2.64 (s, 3H).Step 5: 2-(2-Chloro-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol key intermediate To a solution of 2-Chloro-4-(2-(m ethoxymeth oxy)-4-(trifluoromethyl)phenyl)-6, 7-dimethylpteridine (4.00 g, 10.1 mmol) in DCM (60 mL) was added TFA (8 mL) and the mixture was stirred at RT for 1 h. The mixture was adjusted to pH 8 with a saturated aqueous NaHCO3 solution and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 80 / 20) to give the title compound (2.1 g, 59%) as a yellow solid. LCMS (Agilent Acid): m / z 355.1 [M+H]+.

[0137] Example 1 - 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601Step 1: To a solution of 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[2,3-d]pyrimidine (40 mg, 0.1 mmol) in dioxane (2 mL) was added water (0.5 mL), l-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (60 mg, 0.15 mmol), PdC12 (dppf).CH2C12 (10 mg, 0.012 mmol), K2CO3 (28 mg, 0.2 mmol). The mixture was degassed with N2 gas and stirred at 100°C under N2 overnight. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The mixture was purified on silica gel column to give 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine (47 mg).Step 2: To a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine (45 mg) in MeOH (30mL was added Pd / C (10%, 9mg). The mixture as degassed with N2 gas and hydrogenated at 45psi H2 for 20hr. The catalyst was removed by filtration. The mixture was dried in vacuo and the residue was dissolved in DCM (lOmL). To the mixture was added Mn02 (0.15 g), the resulting mixture was stirred atRT for 3.5 hr. Then Mn02 was removed over celite-pad. The crude mixture was purified on silica-gel column to provide 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine (35 mg).Step 3: To a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidine (35mg) in DCM (ImL) was added 4N HC1 in dioxane (ImL). The mixture was stirred at RT for Ihr, then diluted with DCM (30mL), washed with saturated NaHCO3. The crude mixture was purified on silica-gel column to afford cis-racemate, 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-yl)-5-(trifluoromethyl)phenol (20mg).

[0138] Example 2 - 8-(2-hydroxy-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-oneWSGR Docket No. 55754-728.601To a solution of 3-amino-2,6-dichloroisonicotinic acid (2 g, 10 mmol) in DMF (15 ml) was added HBTU (7.8 g, 20 mmol) at 0°C. The mixture was stirred for 10 minutes, DIEA (5.5 mL, 30 mmol) and methylamine hydrochloride (1.35 g, 20 mmol) were added. The mixture was stirred at room temperature overnight, diluted with EtOAc, washed with water (3x5 OmL), brine, and dried over Na2SO4. The solvent was removed under vacuum and residue was purified on silica gel to afford 3-amino-2,6-dichloro-N-methylisonicotinamide (1 g).To a solution of 3-amino-2,6-dichloro-N-methylisonicotinamide(400mg, 1.8 mmol) in AcOH (10 ml) was added 1,1,1 -triethoxy ethane (2.5 g). The mixture was stirred at 110°C for 3 hours and cooled to room temperature. The solid was filtered and washed with mixture of hexanes / EtOAc(95:5) to afford 6,8-dichloro-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (270 mg). To a solution of 6,8-dichloro-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (145 mg, 0.6 mmol) in dioxane (5 mL) was added water (1 mL), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane(200 mg, 0.6 mmol), PdC12 (dppf).CH2C12 (40 mg, 0.05 mmol), K2CO3 (210 mg, 1.5 mmol). The mixture was degassed and stirred at 85°C under N2 for 2 hours. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and residue was purified on silica gel to afford 6-chloro-8-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3 -dimethylpyrido[3 ,4-d]pyrimidin-4(3H)-one (92 mg).The mixture of 6-chloro-8-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (92 mg, 0.22 mmol), 2-(l-methyl-lH-pyrazol-4-yl)morpholine (37 mg, 0.22 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), BINAP (37 mg, 0.06 mmol) and Cs2CO3 (150 mg, 0.46 mmol) in toluene (5 mL) was degassed with N2 gas and heated at 100°C for 16 hours. The mixture was diluted with EtOAc, washed with water, brine and dried over Na2SO4. The solvent was removed under vacuum andresidue was purified on silica gel to provide 8-(2-(meth oxymeth oxy)-4-(trifluoromethyl)phenyl)-2, 3 -dimethyl-6-(2-(l -methyl-1 H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one (100 mg).WSGR Docket No. 55754-728.601To a solution of 8-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one (100 mg) in DCM (1 ml) was added HC1 (1 ml, 4N in dioxane) at room temperature. The mixture was stirred for Ihour and concentrated. The residue was stirred in DCM and hexane (1:2), filtered and solid was collected. The solid was added to saturated NaHCO3 and extracted with DCM twice. The combined organic layer was dried overNa2SO4. The solvent was removed under vacuum and residue was purified on silica gel to give 8-(2 -hydroxy -4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one (70 mg).

[0139] Example 3 - 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4-yl)-5-(trifluoromethyl)phenolStep 1: To a solution of 5,6-dimethylpyridin-3-qmine (2.44g, 20 mmol) in acetone (30 mL) was added dropwise the solution of NBS (3.6 g, 20mmol) in acetone (40 ml) at -5°C and the mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was diluted with DCM and water. The aqueous phase was extracted with DCM twice. The combined organic layer was dried overNa2SO4. The solvent was removed under vacuum and residue was purified by flash chromatography on silica gel to give 2-bromo-5,6-dimethylpyridin-3-amine (2.8g).To a solution of 2-bromo-5,6-dimethylpyridin-3-amine (1 g, 5 mmol) in DMF (15 mL) was added Zn(CN)2 (1.2 g, 10 mmol) and zinc powder (0.15g), PdC12 (dppf).CH2C12 (0.4 g, 0.49 mmol). The mixture was degassed with N2 gas and heated at 110°C for 24 hours. The mixture was diluted with EtOAc, washed with water, brine and dried overNa2SO4. The solvent was removed under vacuum and residue was purified by flash chromatography on silica gel to Afford 3 -amino-5,6-dimethylpicolinonitrile (450mg).Step 2: A mixture of 3-amino-5,6-dimethylpicolinonitrile (450 mg, 3 mmol) in methanol / DCM (1 / 2, 12 mL) was treated with tetrabutylammonium bromide (350 mg, 1.1 mmol) and 30% aq. Hydrogen peroxide (3 mL). The mixture was cooled to 0°C and 5N NaOH in water (10 mL, 5 mmol). After the addition was completed, methanol / DCM (1:2, 10 mL) was added. The reaction was warmed to room temperature and stirred overnight. After completion, the aqueous phase was extracted with DCM (3 times). The combined organic layer was dried overNa2SO4. The solventWSGR Docket No. 55754-728.601was removed under vacuum and the residue was triturated in MeOH to afford 3 -amino-5,6-dimethylpicolinamide (300 mg).Step 3: To a solution of 3-amino-5,6-dimethylpicolinamide(300 mg, 1.82 mmol) in dioxane (5mL) was added triphosgene (270mg, 0.9 mmol). The mixture was heated at 110°C for 2 hours. After completion, the solvent was removed under vacuum to give crude 6,7-dimethylpyrido[3,2-d]pyrimidine-2,4(lH,3H)-dione (400 mg) which was used for next step without purification. Step 4: To the crude 6,7-dimethylpyrido[3,2-d]pyrimidine-2,4(lH,3H)-dione (400 mg) in POC13 (5 mL) was added DIEA (ImL) dropwise and the mixture was heated at 100°C for 1 hour. After completion, POC13 was removed under vacuum, the residue was quenched with ice water and extracted with EtOAc. The combined organic layer was dried overNa2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel to give 2,4-dichloro-6,7-dimethylpyrido[3,2-d]pyrimidine (240 mg).Step 5: To a solution of 2,4-dichloro-6,7-dimethylpyrido[3,2-d]pyrimidine (170 mg, 0.75 mmol) in dioxane (6 mL) was added water (2 mL), 2 -(2-(meth oxymeth oxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane(250 mg, 0.75 mmol), PdC12 (dppf).CH2C12 (60 mg, 0.74 mmol), K2CO3 (230 mg, 1.67 mmol). The mixture was degassed and stirred at 75°C under N2 for 2.5 hours. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and residue was purified by flash chromatography on silica gel to give 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[3,2-d]pyrimidine (140 mg).Step 6: To the solution of 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[3,2-d]pyrimidine (80 mg, 0.2 mmol) in NMP(2ml) was added 2 -(1 -methyl- 1H-pyrazol-4-yl)morpholine (34 mg, 0.2 mmol), DIEA (0.2 ml). The mixture was degassed by nitrogen and heated at 105°C for 3 hours. The mixture was diluted with EtOAc, washed with water (3 times), brine and dried over Na2SO4. The solvent was removed under vacuum and residue was purified by flash chromatography on silica gel to afford 4-(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[3,2-d]pyrimidin-2-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (80 mg).Step 7: To a solution of 4-(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[3,2-d]pyrimidin-2-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (80 mg) in DCM (1 ml) was added HC1 (1 ml, 4N in dioxane) at room temperature. The mixture was stirred for Ihourand concentrated. The residue was stirred in DCM and hexane (1:2), filtered and solid was collected. The solid was added to saturated NaHCO3 and extracted with DCM twice. The combined organic layer was dried over Na2SO4. The solvent was removed under vacuum and residue was purified by flash chromatography on silica gel to provide 2-(6,7-dimethyl-2-(2-(l-WSGR Docket No. 55754-728.601methyl- lH-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4-yl)-5-(trifluoromethyl)phenol (60 mg).

[0140] Example 4 - 8-(2-hydroxy-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-oneStep 1: To a degassed solution of l-methyl-lH-pyrazole-4-carbaldehyde (2.2 g 20 mmol) in anhydrous DCM (30 mL) was added but-3-yn-l-ol (2.3 mL, 30 mmol) under nitrogen. The solution was cooled to 0°C, triflic acid (2.1 ml, 24 mmol) was added slowly. The reaction mixture was warmed to room temperature and stirred for 6 hours. The reaction mixture was cooled to 0°C, triflic acid (2.1 ml, 24 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by slowly addition of saturated NaHCO3 aqueous solution. The aqueous phase was extracted with DCM. The combined organic layer was dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography on silica gel to give 2,7 grams of 6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate.Step 2: The mixture of 6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (2.7 g, 9 mmol), bis(pinacolato)diboron (3.4 g, 13.5 mmol), KOAc (3.6 g, 36.7 mmol), PdC12 (dppf).CH2C12 (700 mg, 0.86 mmol) in dioxane (35 ml) was degassed and heated to 90°C under nitrogen for 3 hours. The mixture was cooled to room temperature and filtered through a pad of celite, the solid was washed with EtOAc. The solvent was removed under reduced pressure, the residue was purifiedby silica gel column to afford oil 1 -methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (1.1 g).Step 3: To a solution of 6-chloro-8-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one (165 mg, 0.4 mmol) in dioxane (8 mL) was addedWSGR Docket No. 55754-728.601water (2 mL), l-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran- 2-yl)-lH-pyrazole (174mg, 0.6 mmol), PdC12 (dppf).CH2C12 (32 mg, 0.04 mmol), K2CO3 (138 mg, 1 mmol). The mixture was degassed with N2 gas and stirred at 100°C under N2 overnight. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The mixture was purified on silica gel column to give 8-(2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (170 mg).Step 4: To a solution of 8-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(l- methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (170 mg) in MeOH (60mL) was added Pd / C (10%, 34mg). The mixture was degassed with N2 and hydrogenated at 40 psi H2 for 16hr. The catalyst was removed by filtration. The mixture was dried in vacuo and the residue was dissolved in DCM (20mL). To the mixture was added Mn02 (0.5g), the resulting mixture was stirred atRT for 2hr. Then Mn02 was removed over celite-pad. The crude mixture was purified on silica-gel column to afford 8-(2-(methoxymethoxy)-4- (trifluoromethyl)phenyl)-2, 3 -dimethyl-6-(2-(l -methyl- lH-pyrazol-4-yl)tetrahydro-2H-pyran-4- yl)pyrido[3,4-d]pyrimidin-4(3H)-one (105mg).Step 5: To a solution of 8-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(l- methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (105mg) in DCM (2mL) was added 4N HC1 in dioxane (2mL). The mixture was stirred at RT for Ihr, then diluted with DCM (80mL), washed with saturated NaHCO3. The crude mixture was purified on silica-gel column to afford 8-(2-hydroxy-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(l-methyl- lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (82mg).

[0141] Example 5 - 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pteridin- 4-yl)-5-(trifluoromethyl)phenolStep 1: To a solution of 2,6-dichloropyrimidine-4,5-diamine (358 mg, 2 mmol) in dry ethanol (7 ml) was added 2,3 -Butanedione (200 mg, 2.4 mmol) and the mixture was heated to 45°C for 5 hours. After cooling to room temperature, the solvent was removed, and the residue was treated with MTBE to afford 2,4-dichloro-6,7-dimethylpteridine (300 mg).Step 2: To a solution of 2,4-dichloro-6,7-dimethylpteridine (176 mg, 0.77 mmol) in THF (6 mL) was added water (1 mL), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (256 mg, 0.77 mmol), PdC12 (dppf).CH2C12 (56 mg, 0.07 mmol), K2CO3 (276 mg, 2 mmol). The mixture was degassed and stirred at room temperature under N2 for 16WSGR Docket No. 55754-728.601hours. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed under vacuum, and residue was purified on silica gel to give 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpteridine (150 mg).Step 3 and 4: To a solution of 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpteridine (55 mg) in DCM (1 ml) was added HC1 (1 ml, 4N in dioxane) at room temperature. The mixture was stirred for Ihour and concentrated to afford 2-(2-chloro-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol which was used without purification. To the solution of 2-(2-chloro-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenolin NMP (2ml) was added 2-(l-methyl-lH-pyrazol-4-yl)morpholine (33 mg, 0.2 mmol), DIEA (0.2 ml). The mixture was degassed by nitrogen and heated at 100°C for 6 hours. The mixture was diluted with EtOAc, washed with water (3 times), brine and dried overNa2SO4. The solvent was removed under vacuum and residue was purified by on silica gel to afford 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pteridin-4-yl)-5-(trifluoromethyl)phenol (20 mg).

[0142] Example 6 - 2-(2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)quinoxalin-5-yl)-5-(trifluoromethyl)phenolStep 1 : To a solution of 5-bromo-3-chlorobenzene-l,2-diamine (443 mg, 2 mmol) in ethanol (7 ml) was added 2,3-Butanedione(215 mg, 2.5 mmol) and the mixture was heated to 90°C for 4 hours. After cooling to room temperature, the solvent was removed, and the residue was treated with EtOAc / Hexane to give 7-bromo-5-chloro-2, 3 -dimethylquinoxaline (450 mg).Step 2: The mixture of 7-bromo-5-chloro-2,3-dimethylquinoxaline (82 mg, 0.3 mmol), 2-(l-methyl-lH-pyrazol-4-yl)morpholine (50 mg, 0.3 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), BINAP (37 mg, 0.06 mmol) and Cs2CO3 (200 mg, 0.62 mmol) in toluene (8 mL) was degassed by nitrogen and heated at 95°C for 16 hours. The mixture was diluted with EtOAc, washed with water, brine and dried overNa2SO4. The solvent was removed under vacuum and residue was purified by flash chromatography on silica gel to afford4-(8-chloro-2,3-dimethylquinoxalin-6-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (100 mg).Step 3: To a solution of 4-(8-chloro-2,3-dimethylquinoxalin-6-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (100 mg, 0.28 mmol) in dioxane (4 mL) was added water (ImL), (2 -hydroxy -4-(trifluoromethyl)phenyl)boronic acid (70 mg, 0.34 mmol), Pd2(dba)3 (27.5 mg, 0.03 mmol), XPhos (29mg, 0.06mmol) andK2CO3 (97 mg, 0.7 mmol). The mixture was degassed and stirred at 100°C under N2 overnight. The mixture was diluted with EtOAc, washed with brine and dried overWSGR Docket No. 55754-728.601anhydrousNa2SO4. The solvent was removed, andresidue was purified by flash chromatography on silica gel to afford2-(2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)quinoxalin-5-yl)-5-(trifluoromethyl)phenol (90 mg).

[0143] Example 7 - 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4-yl)-5-(trifluoromethyl)phenolStep 1: To a solution of 2,4-dichloro-6,7-dimethylpyrido[2,3-d]pyrimidine (200 mg, 0.9 mmol) in dioxane (8 mL) was added water (2 mL), 2 -(2-(meth oxymeth oxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane(300 mg, 0.9 mmol), PdC12 (dppf).CH2C12 (72 mg, 0.09 mmol), K2CO3 (276 mg, 2 mmol). The mixture was degassed and stirred at 45°C under N2 for 1 hour. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and residue was purified by flash chromatography on silica gel to give 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[2,3-d]pyrimidine (250 mg).Step 2: To the solution of 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[2,3-d]pyrimidine (80 mg, 0.2 mmol) in NMP (2ml) was added 2 -(1 -methyl- 1H-pyrazol-4-yl)morpholine (33 mg, 0.2 mmol), DIEA (0.2 ml). The mixture was degassed with N2 gas and heated at 100°C for 6 hours. The mixture was diluted with EtOAc, washed with water (3 times), brine and dried over Na2SO4. The solvent was removed under vacuum and residue was purified on silica gel to give 4-(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (80 mg).Step 3: To a solution of 4-(4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpyrido[2,3-d]pyrimidin-2-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (80 mg) in DCM (1 ml) was added HC1 (1 ml, 4N in dioxane) at room temperature. The mixture was stirred for Ihourand concentrated. The residue was stirred in DCM and hexane (1:2), filtered and solid was collected. The solid was added to saturated NaHCO3 and extracted with DCM twice. The combined organic layer was dried over Na2SO4. The solvent was removed under vacuum and residue was purified on silica gel to give 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4-yl)-5-(trifluoromethyl)phenol (40 mg).

[0144] Example 8 - 9-(4-Fluoro-2-hydroxyphenyl)-7-(2-(2-methoxypyridin-4-yl)morpholino)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-oneWSGR Docket No. 55754-728.601Step 1 : To a solution of 4-iodo-2 -methoxypyridine (10 g, 42.6 mmol) in THF (120 mL) at -78 °C under a N2 atmosphere was added i-PrMgCI-LiCI (39 mL, 1.3 M in THF, 51.1 mmol) and the mixture was allowed to warm to 0 °C and stirred for 30 min. The mixture was re -cooled to -78 °C, 2-chloro-N-methoxy-N-methylacetamide (8.7 g, 63.8 mmol) was added and the mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched by the addition of a saturated aqueous NH4C1 solution (10 mL) and water (30 mL) and the mixture extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10 - 90% EtOAc / Pet. ether) to give the title compound (4.5 g, 57%) as a white solid. LCMS (ES-API): tR= 1.897 min, m / z 186.1 [M+H]+.Step 2: To a solution of 2-chloro-l-(2-methoxypyridin-4-yl)ethan-l-one (3.0 g, 16.2 mmol) in acetone (100 mL) atRT was added 2-(benzylamino)ethan-l-ol (3.7 g, 24.3 mmol), K2CO3(6.7 g, 48.6 mmol) and KI (2.7 g, 16.2 mmol) and the mixture was stirred at RT for 2 h. The mixture was diluted with water (30 mL), extracted with EtOAc and the organic extracts washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20 - 80% EtOAc / Pet. ether) to give the title compound (4.0 g, 82%) as a colorless oil. LCMS (ES-API): tR= 1.412 min, m / z 301.2 [M+H]+.Step 3 : To a solution of 2-(benzyl(2-hydroxyethyl)amino)-l-(2-methoxypyridin-4-yl)ethan-l-one (4.0 g, 13.3 mmol) in MeOH (30 mL) at 0 °C was added NaBH4(608 mg, 16.0 mmol) and the mixture was allowed to warm to RT and stirred for 1 h. The reaction was quenched with water (2 mL) and the mixture concentrated under reduced pressure. The residue was purified by silica gelWSGR Docket No. 55754-728.601chromatography (50% EtOAc / Pet. ether) to give the title compound (3.5 g, 87%) as a colorless oil. LCMS (ES-API): tR= 1.455 min, m / z 303.2 [M+H]+.Step 4: To a solution of 2-(benzyl(2 -hydroxy ethyl)amino)-l-(2-methoxypyridin-4-yl)ethan-l-ol (3.5 g, 11.6 mmol) in toluene (30 mL) was added CMBP (11.2 g, 46.4 mmol) and the mixture heated at reflux for 2 h. The mixture was diluted with water (50 mL), extracted withEtOAc and the organic extracts washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20 - 80% EtOAc / Pet. ether) to give the title compound (2.6 g, 79%) as a colorless oil. LCMS (ES-API): tR= 1.574 min, m / z 285.2 [M+H]+.2-(2-Methoxypyridin-4-yl)morpholineStep 5: To a solution of 4-benzyl-2-(2-methoxypyridin-4-yl)morpholine (2.6 g, 9.2 mmol) in EtOH (30 mL) was added cone. HC1 (0.2 mL) and 10% Pd / C (300 mg) and the mixture was stirred at RT under a hydrogen atmosphere (1 atm) for 4 h. The mixture was filtered through celite and the filtrate concentrated under reduced pressure to give the title compound (1.3 g, 73%) as a yellow oil. LCMS (ES-API): tR= 1.206 min, m / z 195.1 [M+H]+.Step 6: A mixture of 9-bromo-7-chloro-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one (300 mg, 1.05 mmol), (2-(benzyloxy)-4-fluorophenyl)boronic acid (307 mg, 1.25 mmol), CS2CO3 (1.02 g, 3.13 mmol) and Pd(dppf)C12'DCM (82 mg, 0.1 mmol) in dioxane (12 mL) and water (2 mL) was heated at 80 °C under a N2atmosphere for 3 h. The mixture was diluted with water (20 mL), extracted with EtOAc and the organic extracts washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (20 -80% EtOAc / Pet. ether) to give the title compound (180 mg, 42%) as a yellow solid.LCMS (ES-API): tR= 2.313 min, m / z 410.1 [M+H]+.Step 7 : A mixture of 9-(2-(benzyloxy)-4-fluorophenyl)-7-chloro-2,3 -dimethyl-4H-pyrazino[l ,2-a] pyrimidin-4-one(180 mg, 0.44 mmol), 2-(2-methoxypyridin-4-yl) morpholine (94 mg, 0.48 mmol), Cs2CO3(430 mg, 1.32 mmol), RuPhos (41 mg, 0.088 mmol) and RuPhosG3Pd (74 mg, 0.088 mmol) in toluene (5 mL) was heated at 120 °C under aN2atmosphere in a microwave reactor for 2 h. The mixture was diluted with water (10 mL), extracted with EtOAc and the organic extracts washed with brine, dried overNa2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc / Pet. ether) to give the title compound (90 mg, 36%) as a yellow solid. LCMS (ES-API): tR= 2.311 min, m / z 568.3 [M+H]+.9-(4-Fluoro-2-hydroxyphenyl)-7-(2-(2-methoxypyridin-4-yl)morpholino)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one Step 8: To a solution of 9-(2-(benzyloxy)-4-fluorophenyl)-7-(2-(2-methoxypyridin-4-yl)morpholino) -2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one (70 mg, 0.12 mmol) in EtOH (30 mL) was added 20% Pd(OH)2 / C (18 mg) and the mixture was stirred at RT under a hydrogen atmosphere (1 atm) for 1 h. The mixture was filtered through celite and theWSGR Docket No. 55754-728.601filtrate concentrated under reduced pressure. The residue was purified by prep-HPLC (GILSON-281, Pn tulip sBP-C i8, 10 pm, 21.2 x 250 mm, eluting with a gradient of ACN in water with 0.2% Formic acid, at a flow rate of 25.0 mL / min, 55%-85% ACN over 18 min) to give the title compound (5.8 mg, 10%) LCMS (ES-API): tR= 2.260 min, m / z 478.2 [M+H]+.JH NMR (400 MHz, DMSO-d6) 610.9 (br s, 1H), 8.17 (d, J= 5.6Hz, 1H), 8.03 (s, lH), 7.59 (dd, J = 8.4, 2.8 Hz, 1H), 7.09 (d, J = 5.2 Hz, 1H), 6.90 (s, 1H), 6.80 - 6.72 (m, 2H), 4.70 (dd, J= 10.4, 2.4Hz, 1H), 4.17 (d, J= 11.6 Hz, 2H), 3.98 (d, J= 12.4 Hz, 1H), 3.86 (s, 3H), 3.84 - 3.81 (m, 1H), 3.04 - 2.99 (m, 1H), 2.77 (t, J = 11.2 Hz, 1H), 2.35 (s, 3H), 2.17 (s, 3H).

[0145] Example 9 - 9-(4-fluoro-2-hydroxyphenyl)-2,3-dimethyl-7-(2-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl) morpholino)-4H-pyrazino[l,2-a] pyrimidin-4-oneStep 1: To a stirred solution of 9-bromo-7-chloro-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (2.0 g, 6.9 mmol) and (4-fluoro-2-hydroxyphenyl)boronic acid (0.97 g, 6.2 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added K3PO4(4.6 g, 21 mmol) and purged with argon for 5 min. Then, Pd (dtbpf)Cl2(0.46 g, 0.69 mmol) was added, and reaction mixture was stirred at 80 °C for 2 h. Progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through celite bed and filtrate was concentrated under reduced pressure to obtain the crude. The crude material was purified by combi -flash chromatography by eluting with 20% of Ethyl acetate in heptane, to obtain title compound 7-chloro-9-(4-fluoro-2-hydroxyphenyl)-2,3-dimethyl-4H-pyrazino[l,2-a] pyrimidin-4-one (0.6 g, 27% Yield). TLC: 30% EtOAc in heptane, Rf 0.3, UV active. LCMS (ESI) m / z [M+H]+: 96.68%, tR= 2.33; (Calculated for CI5HI6C1FN3O2: 320.05); Observed: 320.2 [M+H] +. Method Details: Column: XSelect CSH-C 18(3.0 x 50mm,2.5 m) Mobile Phase: A: 0.05% FA in water Mobile Phase: B: 0.05% FA in ACN (Gradient) T / B%:0.0 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2. Flow rate:l ml / min. Column Temp.:40 °C Step 2: To a stirred solution of 7-chloro-9-(4-fluoro-2-hydroxyphenyl)-2,3-dimethyl-4H-pyrazino[l,2-a] pyrimidin-4-one(0.6 g, 1.87 mmol) in acetone (6 mL) was added K2CO3(0.78 g, 5.63 mmol) and reaction mixture was stirred at room temperature for 20 min. Then, chloro-methylWSGR Docket No. 55754-728.601methyl ether (0.19 g, 2.43 mmol) was added at 0 °C and allowed to stir for 2 h at room temperature. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction , the reaction mixture was filtered on celite bed, washed with dichloromethane, evaporated under vacuum to afford title compound 7 -chloro-9-(4-fluoro-2-(methoxymeth oxy) phenyl)-2,3-dimethyl-4H-pyrazino[l,2-a] pyrimidin-4-one(0.25 g, 36% yield) as an off-white solid. TLC: 30% EtOAc in heptane, Rf 0.4, UV active. LCMS (ESI) m / z [M+H]+: 79.45%, tR= 3.07; (Calculated for CI7HI6C1FN3O3: 364.08); Observed: 364.2 [M+H] +. Method Details: Column:XbridgeC18(4.6X50mm,3.5pm) Mobile Phase: A: 10111MNH4HCO3 in water, Mobile Phase: B: ACN (Gradient) T / B%:0.0 / 2, 0.3 / 2, 2.5 / 98, 4.0 / 98, 4.2 / 2, 5 / 2. Flow rate:l ml / min, Column Temp.:40 °C.Step 3: To a stirred solution of 7-chloro-9-[4-fluoro-2 (methoxymethoxy) phenyl] -2,3 -dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.25 g, 0.68 mmol) & l-methyl-5-morpholin-2-yl-pyridin-2-one (0.22 g, 0.68 mmol) in 1,4-dioxane (8 mL) was added CS2CO3 (0.67 g, 2.06 mmol) and purged with argon gas for 10 min, then RuPhos (0.065 g, 0.14 mmol) and RuPhos Pd G3 (0.06 g, 0.068 mmol) were added and reaction mixture was stirred at 90 °C for 2 h in microwave. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mixture was filtered and concentrated to get crude as brown solid. The crude was purified by combi flash chromatography by eluting with 0-10% MeOH / DCMto afford title compound 9 -[4 -fluoro -2-(methoxymethoxy)phenyl]-2,3-dimethyl-7-[2-(l-methyl-6-oxo-3 -pyridyl)morpholin-4-yl]pyrazino[l,2-a]pyrimidin-4-one (65 mg, 14.1% Yield) as a yellow colour solid. TLC: 10 % MeOH in DCM, Rf: 0.3, UV active. LCMS (ESI) m / z [M+H]+: 89.90%, rR: 1.88 (Calculated for: C27H29FN5O5: 522.2); Observed: 522.4 [M+H] +; Method Details: Column: X-Select CSH Cl 8, (50mm*3.0mm,2.5p) Mobile Phase A: 0.05% Formic Acid in Water Mobile Phase B: 0.05% Formic Acid in Acetonitrile Flow rate: 1.OmL / min. Column temperature: 40 °C Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2Step 4: To a stirred solution of 9-[4-fluoro-2-(methoxymethoxy)phenyl]-2,3-dimethyl-7-[2-(l-methyl-6-oxo-3-pyridyl) morpholin-4-yl] pyrazino[l,2-a]pyrimidin-4-one (0.065 g, 0.096 mmol) in 1,4-dioxane (2 mL) was added hydrogen chloride solution 4.0 M in dioxane (4 mL) at 0 °C. Then reaction mixture was brought to RT and stirred for 30 min. Progress of the reaction was monitored by TLC. After completion of reaction, reaction mixture was concentrated under reduced pressure to obtain crude. The crude was diluted with DCM (20 mL) washed with NaHCO3solution (5 mL). The organic layer was dried over anhydrous Na2SO4filtered and concentrated under reduced pressure to obtain crude compound. The crude was purified by prepHPLC to afford title compound 9-(4-fluoro-2-hydroxy -phenyl)-2, 3 -dimethyl-7-[2-(l-methyl-6-oxo-3 -pyridyl) morpholin-4-yl] pyrazino[l,2-a] pyrimidin-4-one (4.68 mg, 10.1% Yield). TLC: 5%MeOH / DCM, Rf: 0.4.WSGR Docket No. 55754-728.601Prep-HPLC method: Column Name: X-SELECT C18(250*30mm),5p Mobile Phase A: 0.1% Formic Acid in Water, Mobile Phase B: Acetonitrile Flow: 20 mL, Loading(mg / inj ection) 50 Gradient (Time / %B) 0 / 10,3 / 10,10 / 35,20 / 55,30 / 65,40 / 75,50 / 99, Sample Diluent: ACN + WATER + DMSO + THF. LCMS (ESI) m / z [M+H]+: 98.50%, tR= 1.73. (Calculated for: C25H25FN5O4: 478.18); Observed: 478.25 [M+H]+; Method Conditions: FA_XB_3.7MIN, Column: XBridge BEH 2.5um; 2.1x30mm, Mobile Phase A: 0.05% FA in Water, Mobile Phase B: 0.05% FA in ACN (Time / B%): 0_2,0.3_2,2_98,2.8_98,3_2,3.7_2. Flow rate:0.7ml / min (Gradient), Column Oven Temp:45 °C. HPLC: 99.66%, tR= 3.06 min; Column: BAKERBOND 1.8um C18,100 mm X 2.1 mm, Mobile Phase A: 0.05% FA in Water, Mobile Phase B: 0.05% FA in Acetonitrile, Colum Temperature: 50 °C, Flow Rate: 0.5 mL / min Gradient: 0 / 5,1 / 5,6 / 90,8.5 / 90,8.8 / 5,11 / 5, Diluent: ACN:Water (80:20). 'HNMR (400 MHz, DMSO-76): 8 ppm 10.78 - 10.89 (m, 1 H) 8.01 (s, 1 H) 7.80 (d, 7=2.25 Hz, 1 H) 7.63 - 7.48 (m, 2 H) 6.83 - 6.69 (m, 2 H) 6.40 (d, 7=9.26 Hz, 1 H) 4.45 (dd, 7=10.63, 2.38 Hz, 1 H) 4.19 - 4.02 (m, 2 H) 3.94 (brd, 7=12.13 Hz, 1 H) 3.81 - 3.70 (m, 1 H) 3.43 (s, 3 H) 3.09 - 2.93 (m, 1 H) 2.84 (d, 7=11.01 Hz, 1 H) 2.35 - 2.30 (m, 3 H) 2.17 (s, 3 H).

[0146] Example 10 - 9-(3,4-difluoro-2-hydroxyphenyl)-7-(2-(2-methoxypyridin-4-yl) morpholino)-2,3-dimethyl-4H-pyrazino[l,2-a] pyrimidin-4-oneStep 1: To a stirred solution of 9-bromo-7-chloro-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.5 g, 1.73 mmol) and (3,4-difhioro-2-hydroxy-phenyl)boronic acid (0.30 g, 1.73 mmol) in toluene (8 mL) andH2O (2 mL) at room temperature was added Cs2CO3(1.70 g, 5.21 mmol) and purged with argon gas for 10 min. AfterthatPd (dtbpf)Cl2(0.11 g, 0.17 mmol) was added and then stirred at 100 °C for 16 h in a sealed tube. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, solvents were evaporated to dryness to obtain crude. Crude was purified by combi flash column chromatography by eluting in 10-15% of EtOAC in heptane to afford title compound 7-chloro-9-(3,4-difluoro-2-hydroxy-phenyl)-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one(0.2 g, 34.2% Yield) as a yellow solid. TLC system: 20% EtOAc in heptane, UV active. Rf= 0.2. LCMS (ESI) m / z (M+H)+: 81.59 % / R= 1.34 min; (Calculated for:CI5HHC1F2N3O2: 338.05); found: 338.20 [M+H]+; Method Details: TFA BEH 2.5 MIN, Column:WSGR Docket No. 55754-728.601XBridge BEH Cl 8 (2.1 *30) mm, 2.5um. Flow rate: 0.85 mL / min., Mobile Phase A: 0.05% TFA in Water, Mobile Phase B: 0.05% TFA in Acetonitrile, Column Temp.: 45°C, Gradient Program Time / B: 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3Step 2: To a stirred solution of 7-chloro-9-(3,4-difluoro-2-hydroxy-phenyl)-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.18 g, 0.53 mmol) in acetone (lOmL) was added K2CO3(0.036 g, 0.26 mmol) and then stirred the reaction mixture for 30 min. Then MOM chloride (0.046 g, 0.53 mmol) was added and stirred the reaction mixture at RT for 2 h. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass was filtered, filtrate was collected and evaporated under reduce pressure to afford title compound 7-chloro-9-[3,4-difluoro-2-(methoxymethoxy) phenyl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.18 g, 88.45% Yield) as a light pink solid. TLC: 20% EtOAc in heptane, Rf 0.3, UV active.JH NMR (400 MHz, CDC13) 8 ppm: 8.79 (s, 1H), 7.26-7.21 (m, 1H), 7.06-7.02 (m, 1H), 5.10 (s, 2H), 3.25 (s, 3H), 2.42 (s, 3H), 2.17 (s, 3H).Step 3: To a solution of 7-chloro-9-[3,4-difluoro-2-(methoxymethoxy) phenyl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (100 mg, 0.26 mmol), 2-(2-methoxypyridin-4-yl) morpholine (0.061 g, 0.31 mmol) in 1,4-dioxane (10 mL) was added CS2CO3 (0.25 g, 0.78 mmol). Then reaction mixture was purged under argon for 5 min and then added RuPhos Pd G3 (0.035 g, 0.039 mmol) followed by RuPhos (0.018 g, 0.039 mmol). The resultant suspension was stirred at 90 °C for 2 h in MW. The progress of reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to obtain crude. Crude was purified by combi flash by eluting with 30% EtoAc in heptane to afford title compound 9-[3,4-difluoro-2-(methoxymethoxy) phenyl]-7-[2-(2-methoxy-4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (80 mg, 56.62% Yield) as a yellow solid. TLC :80% EtOAc in heptane, Rf 0.2, UV active. LCMS (ESI) m / z (M+H)+: 87.27 %= 2.51 min; (Calculated for: C27H28F2N5O5: 540.20); found: 540.44 [M+H] +; Method Details: FA BEH 4.2 MINS, Column: Acquity UPLC BEH Cl 8 (2.1*50) mm, 1 Yum Flow rate: 0.5 mL / min. Mobile Phase A: 0.05% FA in Water, Mobile Phase B: 0.05% FA in Acetonitrile, Column Temp.: 40°C, Gradient Program Time / B: 0.0 / 2, 0.3 / 2, 2.0 / 98, 3.5 / 98, 3.6 / 2, 4.2 / 2Step 4: To a stirred solution of 9-[3,4-difluoro-2-(methoxymethoxy) phenyl]-7- [(2 methoxy -4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.070 g, 0.13 mmol) in 1,4-dioxane (2 mL) at RT was added HC1 in dioxane (0.05 mL, 0.2 mmol, 4 mol / L) at 0 °C. Reaction mixture was then stirred atRT for 1 h. Progress of the reaction was monitored by TLC and LCMS. Then, the solvents were evaporated under reduced pressure to get crude compound. The crude was purified by prep HPLC, fractions were lyophilized to afford title compound 9-(3,4-difluoro-2-hydroxy-phenyl)-7-[2-(2 -methoxy -4-pyridyl) morpholin-4-yl]-2,3-dimethyl-WSGR Docket No. 55754-728.601pyrazino[l,2-a] pyrimidin-4-one (0.027 g, 42.8% Yield) as a pale yellow solid. TLC: DCM, Rf: 0.7, UV active. Prep-HPLC condition: COLUMN XTIMATE Cl 8(250*21.2mm_5um), Mobile Phase A: 10 mM ABC in water, Mobile Phase B: 100 % ACN Flow rate 18ml / min Gradient (Time / %B) 0 / 30,3 / 30,8 / 70,22 / 80,23 / 100. LCMS (ESI) m / z (M+H)+: 99.47 % tR= 2.08 min; (Calculated for: C25H24F2N5O4: 496.32); found: 540.44 [M+H] +; Method Conditions: FA_XB_3.7MIN Column: XBridge BEH 2.5um; 2.1x30mm Mobile Phase A:0.05% FA in Water, Mobile Phase B: 0.05% FA in CAN (Time / B%): 0_2,0.3_2,2_98,2.8_98,3_2,3.7_2. Flow rate:0.7ml / min (Gradient), Column Oven Temp: 45 °C. HPLC: 99.82%, tR:6.23 min, Method Conditions: Column: BAKERBOND 1 ,8um C18,100 mm X 2.1 mm, Mobile Phase A: 0.05% FA in Water, Mobile Phase B: 0.05% FA in Acetonitrile, Colum Temperature: 50°C Flow Rate: 0.5 mL / min Gradient:0 / 5,1 / 5,6 / 90,8.5 / 90,8.8 / 5,11 / 5 Diluent:ACN:H2O (80:20). !HNMR(400 MHz, DMSO-d6) 8 ppm: 11.7 (bs, 1H), 8.17 (d, J= 5.2 Hz, 1H), 8.06 (s, 1H), 7.43 (t, J= 5.2 Hz, 1H), 7.10 (d, J= 5.2 Hz, 1H), 6.95-6.90 (m, 2H), 4.71 (d, J = 10.4 Hz, 1H), 4.16 (d, J= 11.2 Hz, 2H), 4.00 (d, J= 12 Hz, 1H), 3.85 (s, 3H), 3.80 (d, J =2.6 Hz, 1H), 3.05-2.99 (m, 1H), 2.77 (t, J= 11.4 Hz, 1H), 2.37 (s, 3H), 2.17 (s, 3H).

[0147] Example 11 and 12 - 5-fluoro-2-[7-[(2~{S},6~{R})-2-(2 -methoxy -4-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-b]pyrazin-5-yl]phenolStep 1: To a solution of 7-chloro-5-[4-fluoro-2-(methoxymethoxy)phenyl]-2,3-dimethyl-pyrido[3,4-b]pyrazine (500 mg, 1.438 mmol), (2~{S},6~{R})-2-(2-methoxy-4-pyridyl)-6-methyl-morpholine (0.42 g, 2.01 mmol, obtained from SYNthesis) in 1,4-dioxane (8 mL) was added Cs2CO3(1.41 g, 4.32 mmol). Then reaction mixture was purged under argon gas for 5 min then added RuPhos Pd G3 (0.25 g, 0.29 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.1369 g, 0.2875 mmol) andagain purged under argon gas for 5 min. Then reaction mixture was stirred 90 °C for 2 h in MW. The progress of reaction was monitored by LCMS & TLC. After completion of reaction, reaction mass was poured into water (100 mL), extracted with EtOAc (2 xWSGR Docket No. 55754-728.601100 mL), organic layer was collected, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get crude. Crude was purified by combi chromatography by eluting at 25-40% EtOAc / heptane andfractions were concentrated to obtain title compound (2~{S},6~{R})-4-[5-[4-fluoro-2-(methoxymethoxy)phenyl]-2,3-dimethyl-pyrido[3,4-b]pyrazin-7-yl]-2-(2-methoxy-4-pyridyl)-6-methyl-morpholine (0.18 g, 24.10% Yield) as a pale yellow solid. TLC: 30% EtOAc in heptane, Rf 0.3, UV active. LCMS (ESI) m / z [M+H]+: 78.55%, tR= 2.30; (Calculated for C28H3iFN5O4: 520.23); Observed: 520.2 [M+H] +. Method Details: Column: X-Select CSH C18, (50mm*3.0mm,2.5p), Mobile Phase A: 0.05%Formic Acidin Water, Mobile PhaseB: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.OmL / min, Column temperature: 40 °C Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.Step 2: To a stirred solution of (2~{S},6~{R})-4-[5-[4-fluoro-2 -(methoxymethoxy )phenyl]-2, 3-dimethyl-pyrido[3,4-b]pyrazin-7-yl]-2-(2 -methoxy -4-pyridyl)-6-methyl-morpholine (0.15 g, 0.29 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL) at 0 °C. The resultant solution was then stirred at same temperature for 3 h. Progress of the reaction was monitored by LCMS & TLC. After completion of reaction, reaction mass was quenched with saturated aq. Solution of NaHCO3(15 mL), extracted with EtOAc (2 x 15 mL), two layers were separated and organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get crude. Crude was purified by combi flash chromatography by eluting at 25 -40% EtOAc / heptane and fractions were concentrated to afford title compound 5-fluoro-2-[7-[(2~{S},6~{R})-2-(2-methoxy-4-pyridyl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[3,4-b]pyrazin-5-yl]phenol (0.11 g, 80.13% Yield). LCMS (ESI) m / z [M+H]+: 94.57%,= 2.45; (Calculated for C26H27FN5O3: 476.20); Observed: 476.1 [M+H] +. Method Details: Column: X-Select CSH Cl 8, (50mm*3.0mm,2.5p) Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1. OmL / min, Column temperature: 40 °C, Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2. C-HPLC method development: Area- (50.05: 49.95) % at / R(1.7292.368); Method Conditions: Column Name: CHIRALPAK IH (150*4.6mm, 5pm), Column ID: M-ARD-CAL-047, Mobile Phase A: CO2, Mobile Phase B: 0.1% ME0NH3in ACN: MEOH (1 :1), A B: 70:30, Flow rate: 4g-40%.Step 3: Chiral SFC purification (Cis-rac)110 mg of racemic compound was subjected for chiral separation to isolate two isomers Example 12 (first eluted peak, 43.14 mg) and Example 11 (second eluted peak, 36.08 mg). SFC Purification method: No of Injections: 5 (22.0 mg / inj / 8.0 mins), Column: Chiralpak-IH (30*250mm,5pm), MP(A)CO2: 75.0 g / min, MP(B)Co-Solvent: 25.0 ml / min (0.1% MeONH2 IN MeOH), Total Flow rate (mL / min): 100g-25%, 115 bar, Diluent: MeOH, Detection : 260 nm.Characterization data for Example 12 (first eluted peak)WSGR Docket No. 55754-728.601LCMS (ESI) m / z [M+H]+: 99.68%, tR= 2.81; Calculated for C26H27FN5O3: 476.20; Observed: 476.43 [M+H] +. Method Details: FA BEH 4.2 MINS, Column: Acquity UPLC BEH C18 (2.1*50) mm, 1.7um, Flow rate: 0.5 mL / min, Mobile Phase A: 0.05% FA in Water, Mobile Phase B: 0.05% FA in Acetonitrile, Column Temp.: 40°C, Gradient Program Time / B: 0.0 / 2, 0.3 / 2, 2.0 / 98, 3.5 / 98, 3.6 / 2, 4.2 / 2. HPLC : 99.15 %,= 7.826 min; Column: X Bridge BEH Cl 8, 2.5 pm, 100 X 3 mm, Mobile Phase A: 0.05% TFA in Water, Mobile Phase B: 0.05% TFA in Acetonitrile, Colum Temperature: 50°C, Flow Rate: 0.5 mL / min, Gradient: 0 / 5,1 / 5,6 / 90,8.5 / 90,8.8 / 5,11 / 5. C-HPLC: 100%, tR: 1.718; Method Conditions: Column Name: CHIRALPAK IH (150*4.6mm, 5pm), Column ID: M-ARD-CAL-047, Mobile Phase A: CO2, Mobile Phase B: 0.1% MEONH3in MEOH, AB: 70:30, Flow rate: 3g-30%.1HNMR(400 MHz, DMSO-t / g) 8 ppm: 11.60 (s, IH), 8.18 (d, J = 5.2 Hz, IH), 8.00 (t, = 7.8 Hz, IH), 7.23 (s, IH), 7.12(d, J= 4 Hz, IH), 6.92 (s, IH), 6.80-6.75 (m, 2H), 4.74 (d, J= 10.8 Hz, IH), 4.43 (d, J= 12 Hz, IH), 4.32 (d, J= 11.2 Hz, IH), 3.91-3.89 (m, IH), 3.86 (s, 3H), 2.75-2.67 (m, 2H), 2.64 (s, 3H), 2.56 (s, 3H), 1.30 (d, J= 6 Hz, 3H). Characterization data for Example 11 (second eluted peak)LCMS (ESI) m / z [M+H]+: 99.88%, tR= 2.81; (Calculated for C26H27FN5O3: 476.20); Observed: 476.43 [M+H]+. Method Details: FABEH 4.2 MINS, Column: Acquity UPLC BEH C18 (2.1*50) mm, 1.7um Flow rate: 0.5 mL / min, Mobile Phase A: 0.05% FA in Water, Mobile Phase B: 0.05% FA in Acetonitrile, Column Temp: 40 °C, Gradient Program Time / B: 0.0 / 2, 0.3 / 2, 2.0 / 98, 3.5 / 98, 3.6 / 2, 4.2 / 2. HPLC : 99.35 %, tR= 7.812 min; Column: XBridge BEH C18, 2.5 pm, 100 X 3 mm, Mobile Phase A: 0.05% TFA in Water, Mobile Phase B: 0.05% TFA in Acetonitrile, Colum Temperature: 50 °C, Flow Rate: 0.5 mL / min, Gradient: 0 / 5,1 / 5,6 / 90,8.5 / 90,8.8 / 5,11 / 5. C-HPLC: 100%, tR: 2.35; Method Conditions: Column Name: CHIRALPAK IH (150*4.6mm, 5 pm), Column ID: M-ARD-CAL-047, Mobile Phase A: CO2, Mobile Phase B: 0.1% MEONH3in MEOH, A B: 70:30, Flow rate: 3g-30%. 'H NMR. (400 MHz, DMSO-tL) 6 ppm: 11.60 (s, IH), 8.18 (d, J= 5.2 Hz, IH), 8.00 (t, J= 7.8 Hz, IH), 7.23 (s, IH), 7.12 (d, J= 4 Hz, IH), 6.92 (s, IH), 6.80-6.75 (m, 2H), 4.74 (d, J= 10.8 Hz, IH), 4.43 (d, J= 12 Hz, IH), 4.32 (d, J= 11.2 Hz, IH), 3.91-3.89 (m, IH), 3.86 (s, 3H), 2.75-2.67 (m, 2H), 2.64 (s, 3H), 2.56 (s, 3H), 1.30 (d, J= 6 Hz, 3H).

[0148] Example 13 - 9-(4-chloro-2 -hydroxy -phenyl)-7-[2-(2 -meth oxy -4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-oneWSGR Docket No. 55754-728.601Step 1 : To a stirred solution of 9-bromo-7-chloro-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (3 g, 10.4 mmol) and (4-chloro-2-hydroxy-phenyl)boronic acid (1.61 g., 9.36 mmol) in 1,4-dioxane (30 mL) and H2O (8 mL) was added K3PO4(7 g, 31.19 mmol) and purged with argon for 10 min. Then, Pd (dtbpf)Cl2(II) (0.7 g, 1.04 mmol) was added and reaction mixture was stirred at 100 °C for 6 h. Progress of the reaction was monitored by TLC. After completion of reaction, reaction mass was poured into water (200 mL), extracted with EtOAc (2 x 200 mL), two layers were separated and organic layer was dried over anhydrous Na2SO4, filtered and concentrated to get crude. The crude was purified using combi flash chromatography by eluting with 15-20% ethyl acetate in heptane to afford title compound 7 -chloro-9-(4-chloro-2 -hydroxy-phenyl)-2, 3 -dimethyl-pyrazino[l,2-a]pyrimidin-4-one(l g, 26.89% Yield) as a yellow solid. TLC: 50% ethyl acetate in heptane Rf 0.6, UV active. LCMS (ESI) m / z [M+H]+: 94.55%, tR= 1.45; (Calculated for CI5HI2C12N3O2: 336); Observed: 336.21 [M+H] + Method Details: TFA BEH 2.5 MIN Column: XBridgeBEH Cl 8 (2.1*30) mm, 2.5um Flow rate: 0.85 mL / min. Mobile Phase A: 0.05% TFA in Water Mobile Phase B: 0.05% TFA in Acetonitrile. Column Temp.: 45°C Gradient Program Time / B: 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3Step 2: To a stirred solution of 7-chloro-9-(4-chloro-2-hydroxy-phenyl)-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (1 g, 2.97 mmol) in acetone (20 mL) was added K2CO3(1.23 g., 8.92 mmol) at RT and stirred for 20 min. Then chloromethyl methyl ether (0.76 g 8.92 mmol) was added drop wise to the reaction mixture at and stirring was continued at the same temp for 16 h. Progress of the reaction mass was monitored by LCMS and TLC. After completion of reaction, Reaction mass was filtered, filtrate was concentrated under vacuum to get crude. Crude was washed with ether and pentane to afford title compound 7 -chloro-9-(4-chloro-2-(m ethoxymethoxy )phenyl)-2, 3 -dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one (0.8 g, 55.18% Yield) as an off-white solid. TLC: 50% EtOAc in heptane, RR0.4, UV active. LCMS (ESI) m / z [M+H]+: 78%, tR= 2.14; (Calculated for CI7HI6C12N3O3: 380.05); Observed: 379.8 [M+H]+. Method Details: Column: X-Select CSH C18,WSGR Docket No. 55754-728.601(50mm*3.0mm,2.5p) Mobile Phase A: 0.05% Formic Acid in Water Mobile Phase B: 0.05% Formic Acid in Acetonitrile Flow rate: l.OmL / min. Column temperature: 40°C Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.Step 3 : To a stirred solution of 7-chloro-9-[4-chloro-2-(methoxymethoxy) phenyl] -2,3 -dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.25 g, 0.66 mmol) and 2-(2-methoxy-4-pyridyl) morpholine (0.128 g, 0.66 mmol) in toluene (4 mL) was added sodium tert-butoxide (0.19 g, 1.97 mmol) was added to the reaction mixture and purged with argon gas for 5 min at RT. Then, RuPhos Pd G3(0.056 g, 0.066 mmol) and RuPhos (0.062 g, 0.13 mmol) was added to the reaction mass and again purged with argon gas for 5 min. The resultant suspension was stirred at 110 °C for 1 h in MW. Progress of the reaction was monitored by TLC. After completion of reaction, reaction mass poured into water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude. Crude was purified by combi flash chromatography by eluting at 25 -40% EtOAc / heptane and fractions were concentrated to afford title compound 9-[4-chloro-2 -(methoxymethoxy )phenyl]-7-[2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (150 mg, 42.40% Yield) as a pale yellow solid. TLC: 30% EtOAc in heptane, Rf 0.3, UV active. LCMS (ESI) m / z [M+H]+: 57%, rR= 2.27, (Calculated for: C27H29C1N5O5: 538.18); Observed.: 538.1 [M+H] +; Method Details: Column: X-Select CSH Cl 8, (50mm*3.0mm,2.5p) Mobile Phase A: 0.05% Formic Acid in Water Mobile Phase B: 0.05% Formic Acid in Acetonitrile Flow rate: 1.0 mL / min. Column temperature: 40 °C Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.Step 4: To a stirred solution of 9-[4-chloro-2 (meth oxy meth oxy) phenyl]-7-[2-(2 -methoxy -4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (0.29 g, 0.54 mmol) in 1,4-dioxane (5 mL)was added hydrochloric acid (4 mol / L)in dioxane (2.5 mL, 10 mmol, 4 mol / L) at 0 °C. Then reaction mixture was brought to RT and stirred for 3 h. Progress of the reaction was monitored by TLC. After completion of reaction, reaction mass was quenched saturated solution of NaHCOs (20 mL) and extracted with EtOAc (2 x 20 mL). Combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to get crude. Crude was purified by prep HPLC, fractions were lyophilized to afford title compound 9 -(4-chloro-2 -hydroxy -phenyl)-7-[2-(2-methoxy-4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (60.5 mg, 22.7% Yield) as pale yellow solid. TLC: 30% DCM in EtOAc, Rf: 0.5, UV active. Prep-HPLC: Column: X Select CSH Cl 8 (250*30) mm, 5pm, Mobile Phase: A: 10 mM ABC IN WATER, Mobile Phase B: 100 % ACN, Flow Rate: 22 ml / min, Gradient:0 / 50,2 / 50,12 / 85,22 / 90,25 / 90,26 / 98,30 / 98,31 / 50,35 / 10. LCMS (ESI) m / z [M+H]+: 99.54%, tR= 2.71, (Calculated for: C25H25C1N5O4: 494.15); Observed: 494.43 [M+H]+.; Method Details: FAWSGR Docket No. 55754-728.601BEH 4.2 MINS, Column: Acquity UPLC BEH Cl 8 (2.1*50)mm, 1.7um, Flow rate: 0.5 mL / min, Mobile Phase A: 0.05% FA in Water, Mobile Phase B: 0.05% FA in Acetonitrile, Column Temp.: 40 °C, Gradient Program Time / B: 0.0 / 2, 0.3 / 2, 2.0 / 98, 3.5 / 98, 3.6 / 2, 4.2 / 2. HPLC : 99.84%, = 7.536 min; Column: X-Select CSH C182.5um, 100 mm X 3.0 mm, Mobile Phase A: 0.05% FA in Water, Mobile Phase B: 0.05% FA in Acetonitrile, Colum Temperature: 40°C, Flow Rate: 0.5 mL / min, Gradient: 0 / 5,1 / 5,6 / 90,8.5 / 90,8.8 / 5,11 / 5, Diluent:- ACN: Water (80:20). 'H NMR (400 MHz, DMS0 ) <5ppm: 10.69 (bs, 1H), 8.17(d, = 5.2Hz, 1H), 8.02 (s, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.09 (d, J= 5.6 Hz, 1H), 7.01-6.97 (m, 2H), 6.89 (s, 1H), 4.71 (d,10.4 Hz, 1H), 4.16 (d, J = 11.2 Hz, 2H), 3.96 (d, J= 12.4 Hz, 1H), 3.83 (s, 3H), 3.80 (d, J= 2.6 Hz, 1H), 3.04-2.97 (m, 1H), 2.76 (d, J= 11.2 Hz, 1H), 2.34 (s, 3H), 2.16 (s, 3H).

[0149] Example 14 - 2-(2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[3,4-b]pyrazin-5-yl)-5-(trifluoromethyl)phenolStep 1: (Chloromethoxy )methane (0.8 g, 10 mmol) was added dropwise to a suspension of 2-bromo-5-(trifluoromethyl)phenol (2 g, 8 mmol) and Cs2CO3 (3.26 g, lOmmol) in DMF (10 mL) at 0 °C. The reaction mixture was warmed to RT over 2 hours and diluted with EtOAc (20 mL) and Hexane (20mL). The mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated to afford intermediate l-bromo-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (2.1g) which was used without purification.Step 2: The mixture of l-bromo-2-(methoxymethoxy)-4-(trifluoromethyl)benzene (2 g, l.Oeq), bis(pinacolato)diborane (2.0 g, 1.12eq), Pd(OAc)2 (160 mg, 0.1 eq), KOAc (1.4 g, 2.0eq) in anhydrous Dioxane (50 mL) was degassed with N2 gas for 5 min then stirred at 100 °C for 10 hours. The mixture was filtered through celite-pad and concentrated in vacuo, the crude mixture was purified on silica-gel column (80g) to afford oil 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.75g, yield 75%).WSGR Docket No. 55754-728.601Step 3 : To a solution of 2,6-dichloropyridine-3,4-diamine (1g, 1.Oeq) in ethanol (15 ml) was added 2,3 -Butanedione (0.6g, 1 ,25eq) and the mixture was heated to 90°C for 4 hours. After cooling to room temperature, the solvent was removed, and the residue was treated with EtOAc / Hexane to give 5,7-dichloro-2,3-dimethylpyrido[3,4-b]pyrazine (1.0g, yield 79%).Step 4: 5,7-dichloro-2,3-dimethylpyrido[3,4-b]pyrazine (130mg, l.Oeq), 2-(2-(methoxymethoxy)4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (200mg, l.Oeq), Pd(PPh3)4 (66mg, 0.1 eq) and K2CO3 (160mg, 2. Oeq) were combined in THF (8mL) and water (3mL). The mixture was degassed with N2 gas for 5mints, then heated at 55°C for 30min. The reaction mixture was diluted with acetate, washed with brine. The crude mixture was purified on silica -gel column (12g) to afford 7-chloro-5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-b]pyrazine (180mg, yield 83%).Step 5: 7-chloro-5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-b]pyrazine (40 mgs, l.Oeq), 2-(l-methyl-lH-pyrazol-4-yl)morpholine (23mg, 1.3eq), Pd(OAc)2 (3mg, O.leq), Binap (14mg, 0.2eq) and Cs2CO3 (66mg, 2. Oeq) were combined in dry Toluene (8mL). The mixture was degassed with N2 gas and heated at 120oC for 4hr. The solvent was removed in vacuo, the residue was purified on silica-gel column (12g) to give 4-(5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-b]pyrazin-7-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (35mg, yield 65%).Step 6: To a solution of 4-(5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-b]pyrazin-7-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (30mg) in DCM (2mL) was added TFA (2mL). The resulting mixture was stirred atRT for Ihr. The mixture was dried in vacuo, and the crude mixture was purified on HPLC to afford 2-(2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[3,4-b]pyrazin-5-yl)-5-(trifluoromethyl)phenol (15mg, yield 55%).

[0150] Example 15 - 9-(4-Fluoro-2-hydroxyphenyl)-7-((2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholino)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-oneWSGR Docket No. 55754-728.601Step 1 : To a solution of 4-bromo-2-methoxypyridine (5.0 g, 26.6 mmol) in toluene (45.0 mL) was added tributyl(vinyl)stannane (9.3 g, 29.2 mmol) and Pd(PPh3)4(307 mg, 0.26 mmol) and the mixture was heated at 90 °C under N2for 10 h. KI (5 g) was added and stirring was continued at 25 °C for 3 h. The mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3) and the combined organic layers washed with brine (100 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc, 100 / 0 to 90 / 10) to give the title compound (3 g, 83%) as a colorless oil. LCMS (ES-API): tR = 1.672 min, m / z 136.2, [M+H]+.Step 2: To a solution of 2-methoxy-4-vinylpyridine (2.0 g, 14.8 mmol) in t-BuOH (40.0 mL) and water (40 mL) was added NBS (2.63 g, 14.8 mmol) and the mixture was heated at 40 °C under N2for 3 h. NaOH (1.77 g, 44.4 mmol) was added and stirring was continued at 25 °C for 3 h. The mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3) and the combined organic layers washed with brine (100 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc, 100 / 0 to 90 / 10) to give the title compound (1.04 g, 47%) as a pale yellow oil. LCMS (ES-API): tR= 1.527 min, m / z 152.1, [M+H]+.1HNMR (400MHz,DMSO-d6)88.13 (dd, J = 5.2, 0.7 Hz, 1H), 6.87 (dd, J = 5.3, 1.4 Hz, 1H), 6.76 -6.74 (m, 1H), 3.94 (dd, J = 4.2, 2.5 Hz, 1H), 3.14 (dd, J = 5.5, 4.2 Hz, 1H), 2.84 (dd, J = 5.6, 2.5 Hz, 1H).Step 3: A mixture of 2-methoxy-4-(oxiran-2-yl)pyridine (1.0 g, 6.61 mmol), 4-methylbenzenesulfonamide (2.27 g, 13.2 mmol), Cs2CO3(220 mg, 0.66 mmol) and TEBA (150 mg, 0.66 mmol) in dioxane (20.0 mL) was heated at 90 °C under N2for 4 h. The mixture was diluted with water, extracted with EtOAc (30 mL x 3) and the combined organic layers washed with brine (50 mL), dried overNa2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc, 100 / 0 to 60 / 40) to give the title compound (1.2 g, 57%) as a colorless oil. LCMS (ES-API): tR= 1.749 min, m / z 323.1 [M+H]+.Step 4: To a solution of N-(2 -hydroxy -2-(2-methoxypyridin-4-yl)ethyl)-4-methylbenzenesulfonamide (1.2 g, 3.72 mmol) in acetone (15.0 mL) at 0 °C was added 1 -WSGR Docket No. 55754-728.601chloropropan-2-one (414 mg, 4.47 mmol), K2CO3 (1.54 g, 11.2 mmol) and KI (680 mg, 4.09 mmol) and the mixture was stirred at 25 °C for 4 h. The mixture was diluted with water, extracted withEtOAc (50 mLx 3) and the combined organic layers washed with brine (80 mL), dried over Na2SC>4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc, 100 / 0 to 65 / 35) to give the title compound (1.1 g, 78%) as a white solid. LCMS (ES-API): tR= 2.005 min, m / z 379.1 [M+H]+.Step 5: To a solution of N-(2 -hydroxy -2-(2-methoxypyridin-4-yl)ethyl)-4-methyl-N-(2-oxopropyl)benzene sulfonamide (1.1 g, 2.91 mmol) in DCM (70.0 mL) at 0°C was added TES (4.73 g, 40.7 mmol) and TMSOTf (15.5 g, 69.8 mmol) andthe mixture was stirred at 25 °C for 12 h. The mixture was diluted with a saturated aqueous NaHCCL solution, extracted with EtOAc (100 mL x 3) and the combined organic layers washed with brine (150 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc, 100 / 0 to 90 / 10) to give the title compound (850 mg, 81%) as a colorless oil. LCMS (ES-API): tR= 2.167 min, m / z 363.1 [M+H]+.Step 6: A mixture of (2S,6R)-2-(2-methoxypyridin-4-yl)-6-methyl-4-tosylmorpholine (850 mg, 2.35 mmol) and Mg (855 mg, 35.2 mmol) in MeOH (35.0 mL) was heated at reflux under N2 for 12 h. The mixture was filtered through celite and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM / MeOH, 100 / 0 to 92 / 8) to give the title compound (320 mg, 66%) as a colorless oil. LCMS (ES-API): tR= 1.402 min, m / z 209.1 [M+H]+. Step 7: To a solution of 3-bromo-5-chloropyrazin-2-amine (5.0g, 24.0 mmol) in DCE (50.0 mL) at 0 °C was added ethyl 2-methyl-3-oxobutanoate (10.4 g, 72.0 mmol) and TfOH (18.0 g, 120 mmol) and the mixture was heated at 70 °C under N2for 4 h. The mixture was diluted with water (100 mL), extracted with EtOAc (50 mL x 3) and the combined organic layers washed with brine (100 mL), dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / DCM, 100 / 0 to 30 / 70) to give the title compound (3.2 g, 46%) as a yellow solid. LCMS (ES-API): tR= 2.044 min, m / z 287.9 / 289.9, [M+H]+.Step 8: To a solution of 9-bromo-7-chloro-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one (1 g, 3.48 mmol) in dioxane (15 mL) and water (3 mL) was added (4-fluoro-2-hydroxyphenyl)boronic acid (651 mg, 4.18 mmol), Cs2CO3(3.4 g, 10.4 mmol) and Pd(dppf)Cl2-DCM (284 mg, 0.35 mmol) and the mixture was heated at reflux under N2 for 3 h. The mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 3) and the combined organic layers washed with brine, dried over Na2SO4and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc, 5 / 1) to give the title compound (450 mg, 41%) as a yellow solid. LCMS (ES-API): tR= 2.212 min, m / z 320.1 [M+H]+.WSGR Docket No. 55754-728.601Step 9: To a solution of 7-chloro-9-(4-fhioro-2-hydroxyphenyl)-2,3-dimethyl-4H-pyrazino[l,2-a] pyrimidin-4-one (140 mg, 0.43 mmol) in DCM (5 mL) at 0°C was added DIEA (71 mg, 0.55 mmol) and chloro(m ethoxy )methane (43.8 mg, 0.55 mmol) and the mixture was stirred at RT for 2 h. The mixture was diluted with water (5 mL), extracted with EtOAc (10 mL x 3) and the combined organic layers washed with brine, dried overNa2SO4and concentrated under reduce pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc, 5 / 1) to give the title compound (110 mg, 70%) as a yellow solid. LCMS-E (ES-API): tR=2.154 min, m / z 364.0 [M+H]+. Step 10: To a solution of 7-chloro-9-(4-fhioro-2 -(methoxymethoxy )phenyl)-2,3-dimethyl-4El-pyrazino[l,2-a]pyrimidin-4-one (60 mg, 0.16 mmol) in dioxane (2 mL) was added (2S,6R)-2-(2-methoxypyridin-4-yl)-6-methylmorpholine (24 mg, 0.16 mmol), CS2CO3 (161 mg, 0.49 mmol), Ruphos (15 mg, 0.03 mmol) andRuphos-Pd-G3 (26 mg, 0.03 mmol) and the mixture was heated at 90 °C for 2 h under N2in a microwave reactor. The mixture was diluted with water (10 mL), extracted with EtOAc (20 mL x 3) and the combined organic layers washed with brine, dried over Na2SO4and concentrated under reduce pressure. The residue was purified by silica gel chromatography (Pet. ether / EtOAc, 3 / 1) to give the title compound (80 mg, 90%). LCMS (ES-API): tR= 2.251 min, m / z 536.2 [M+H]+.Step 11 : A mixture of 9-(4-fluoro-2 -(meth oxymethoxy )phenyl)-7-((2S, 6R)-2-(2-meth oxypyridin-4-yl)-6-methylmorpholino)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one (60 mg, 0.11 mmol) and a 4 M solution of HC1 in dioxane (2 mL) was stirred at RT for 2 h. The mixture was concentrated under reduced pressure and the residue purified by prep-HPLC (GILSON-281, Pntulips BP-C18, 10 pm, 21.2 x 250 mm, eluting with a gradient of ACN in water with 0.2% Formic acid, at a flow rate of 25.0 mL / min, 50%-80% ACN over 18 min) to give the title compound (30.5 mg, 63%). LCMS (ES-API): tR= 2.337 min, m / z 492.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 6 10.8 (br s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.59 - 7.56 (m, 1H), 7.09 (dd, J= 5.2, 1.2 Hz, 1H), 6.90 (s, 1H), 6.81 - 6.70 (m, 2H), 4.75 (dd, J = 10.8, 2.8 Hz, 1H), 4.23 -4.15 (m, 1H), 4.08 -4.04 (m, 1H), 3.96-3.89 (m, 1H), 3.86 (s, 3H), 2.68 - 2.58 (m, 2H), 2.34 (s, 3H), 2.16 (s, 3H), 1.30 (d, J = 6.4 Hz, 3H).

[0151] Example 16 - 9-(4-fluoro-2-hydroxy-phenyl)-7-[2-(2 -methoxy -4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrido[l,2-a] pyrimidin -4-oneWSGR Docket No. 55754-728.601Step 1: To a stirred solution of 9-bromo-7-chloro-2,3-dimethyl-pyrido[l,2-a] pyrimidin-4-one (0. 5 g, 1.74 mmol) and (4-fluoro-2-hydroxy -phenyl) boronic acid (0.35 g, 2.26 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was added potassium carbonate (0.60 g, 4.34 mmol) atRT, and it was purged with argon gas for 10 min. Then, [1, T bis(diphenylphosphino) ferrocene] dichloropalladium (II) (0.13 g, 0.17 mmol) was added to the reaction mixture and resultant suspension was stirred at 80 °C for 16 h. Progress of the reaction was monitored by TLC. Crude was purified by combi flash chromatography by eluting at 20-30% EtOAc / heptane and fractions were concentrated afford title compound 7-chloro-9-(4-fluoro-2-hydroxy-phenyl)-2, 3 -dimethyl-pyrido[l,2-a] pyrimidin-4-one (0.28 g, 50.52% Yield) as white solid. TLC: 40% EtOAc in heptane, Rf 0.4, UV active. LCMS (ESI) m / z [M+H] +: 99.52%, rR= 2.06; (Calculated for C16H13CIFN2O2: 318); Observed: 318.8 [M+H]+. Column: X-SelectCSH Cl 8, (50mm*3.0mm, 2.5p) Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile Flow rate: 1.0 mL / min. Column temperature: 40 °C Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2Step 2: To a stirred solution of 7-chloro-9-(4-fluoro-2 -hydroxy -phenyl)-2,3-dimethyl-pyrido[l, 2-a]pyrimidin-4-one (0.095 g, 0.29 mmol) in acetone (5 mL) was added K2CO3(0.17 g, 1.25 mmol) at 0 °C and stirred for 20 min at the same temp. Then, chloromethyl methyl ether (0.036 mL, 0.45 mmol) was added to and the reaction mixture was then stirred at RT for 3 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was filtered and washed with DCM, filtrate was concentrated to get crude. Crude was triturated with n-heptane (3 mL), filtered and dried under vacuum to obtain title compound 7 -chloro-9-[4-fluoro-2-(methoxymethoxy)phenyl]-2,3-dimethyl-pyrido[l,2-a]pyrimidin-4-one (0.105 g, 97.09% Yield) as a pale yellow solid. TLC: 20% EtOAc in heptane, RR0.3, UV active. LCMS (ESI) m / z [M+H]+: 98.72%, / R= 2.47; (Calculated for CI8HI7C1FN2O3: 363.08); Observed: 363.3 [M+H] +. Method Details:FA BEH 4.2MINS Column: Acquity UPLC BEH C18 (2.1*50)mm, 1 ,7um Flow rate: 0.5 mL / min. Mobile Phase A: 0.05%FA in Water Mobile Phase B: 0.05% FA in Acetonitrile Column Temp.: 40 °C Gradient Program Time / B: 0.0 / 2, 0.3 / 2, 2.0 / 98, 3.5 / 98, 3.6 / 2, 4.2 / 2WSGR Docket No. 55754-728.601Step 3: To a stirred solution of 9-[4-fluoro-2 -(methoxymethoxy) phenyl]-7-[2-(2-methoxy-4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrido[l,2-a] pyrimidin-4-one (0.1 g, 0.28 mmol), 2-(2-methoxy-4-pyridyl)morpholine(0.075 g, 0.39 mmol) in 1,4-dioxane (1.5 mL) was added CS2CO3 (0.27 g, 0.83 mmol). Then reaction mixture was purged under argon gas for 5 min. Then RuPhos Pd G3 (0.049 g, 0.055 mmol) RuPhos (0.026 g, 0.055 mmol) were added, andreaction mixture was again purged under argon gas for 5 min. Then reaction mixture was stirred at 90 °C for 2 h in MW. The progress of reaction was monitored by LCMS and TLC. After completion of reaction, reaction mass was poured into water (20 mL), extracted with EtOAc (2 x 20 mL), two layers were separated and organic layer was dried over anhydrousNa2SO4, filtered and concentrated to get crude. Crude was purified by combi chromatography by eluting at 40-50% EtOAc / heptane and fractions were concentrated to afford title compound 9 -[4-fluoro-2-(methoxymethoxy )phenyl]-7-[2-(2 -methoxy -4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrido[l,2-a]pyrimidin-4-one (92 mg, 64.11% Yield) as an off white solid. TLC: 30% EtOAc in heptane, R : 0.3, UV active. LCMS (ESI) m / z [M+H]+: 91.46%, rR: 2.03 (Calculated, for: C28H3oFN405: 521.2); Observed: 521 [M+H]+; Method Details: Column: X-SelectCSH C18, (50mm*3.0mm,2.5p) Mobile Phase A: 0.05% Formic Acid in Water Mobile Phase B: 0.05% Formic Acid in Acetonitrile Flow rate: 1.0 mL / min. Column temperature: 40 °C Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.Step 4: To a stirred solution of 9-[4-fluoro-2-(methoxymethoxy) phenyl]-7-[2-(2 -methoxy -4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrido[l,2-a] pyrimidin-4-one (0.085 g, 0.16 mmol) in 1,4-dioxane (2 mL) was added HC1 (0.8 mL, 3 mmol, 4 mol / L) in dioxane at 0 °C. Then it was brought to RT and stirred for 30 min. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was quenched saturated NaHCO3solution (10 mL), extracted with EtOAc (2 x 10 mL), organic layer was collected and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get crude. Crude was triturated with di ethyl ether (3 mL) and n-pentane ( 5 mL), filtered and dried under vacuum to afford title compound 9-(4-fluoro-2-hy droxy-phenyl)-7-[2-(2 -methoxy -4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrido[l, 2-a]pyrimidin-4-one (65.96 mg, 84.78% Yield) as a pale yellow solid. TLC: 5% DCM in EtOAc, Rf 0.5, UV active. LCMS (ESI) m / z [M+H]+: 95.43%, tR= 3.17. (Calculated for: C26H26FN4O4: 477.19); Observed: 477.2 [M+H]+; Method Conditions: Column: XbridgeC18 (4.6X50mm, 3.5pm) Mobile Phase: A: 10 mM NH HCO3 in water Mobile Phase: B: ACN (Gradient) T / B%:0.0 / 2, 0.3 / 2, 2.5 / 98, 4.0 / 98, 4.2 / 2, 5 / 2. Flow rate:l ml / min, Column Temp: 40 °C. HPLC: 97.76%, tR= 5.09 min; Column: X Bridge BEH C18, 2.5 pm, 100 X 3 mm Mobile Phase A: 0.05% TFA in Water Mobile Phase B: 0.05% TFA in Acetonitrile Colum Temperature: 50 °C Flow Rate: 0.5 ml / min Gradient: 0 / 5, 1 / 5, 6 / 90, 8.5 / 90, 8.8 / 5, 11 / 5. !HNMR (400 MHz, DMSO-t / 6) ppm: 9.97 (s, 1H), 8.27 (d, = 2.8 Hz, 1H), 8.15 (d, J= 5.2 Hz, 1H), 8.00 (d, = 2.8 Hz, 1H), 7.27 (t, J =WSGR Docket No. 55754-728.6017.6 Hz, 1H), 7.12-7.10 (m, 1H), 6.91 (s, 1H), 6.75-6.70 (m, 2H), 4.71 (d, 10.4 Hz, 1H), 4.19 (dd, J= 10.8, 2 Hz, 1H), 3.98 (d, J= 12.4 Hz, 1H), 3.87 (d, J= 9.6 Hz, 1H), 3.83 (s, 3H), 3.60 (d, J = 12.4 Hz, 1H), 2.92-2.87 (m, 1H), 2.60-2.58 (m, 1H), 2.26 (s, 3H), 2.12 (s, 3H).

[0152] Example 17 - 9-(4,5-difluoro-2-hydroxy-phenyl)-7-[2-(2-methoxy-4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-oneStep 1 : To a stirred solution of 9-bromo-7-chloro-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (1 g, 3.46 mmol) and (4,5 -difluoro-2-hydroxy -phenyl) boronic acid (0.54 g, 3.12 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was added K3PO4(1.83 g, 8.62 mmol). Then reaction mixture was purged with argon gas for 5 min atRT. Then, Pd(dtbpf) Cl2(0.22 g, 0.34 mmol) was added to the reaction mass, and it was stirred at 100 °C for 1 h. Progress of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was diluted with water, extracted with EtOAc (2 x 15 mL). Organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain crude. Crude was purified by combi flash chromatography by eluting at 16-18% EtOAc:heptane to afford title compound 7-chloro-9-(4,5-difluoro-2-hydroxy-phenyl)-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.2 g, 17% yield) as a yellow solid. TLC: 20% EtOAc in heptane, UV active. Rf = 0.4. LCMS (ESI) m / z [M+H]+:96.30%, tR= 1.41 min; (Calculated for: Ci5HnClF2N3O2: 338.04); found: 338.20 [M+H]+; Method Details: TFA BEH 2.5 MIN Column : X-Bridge BEH Cl 8 (2.1*30)mm, 2.5um Flow rate: 0.85 mL / min. Mobile Phase A: 0.05% TFA in Water Mobile Phase B: 0.05% TFA in Acetonitrile Column Temp.: 45°C Gradient Program Time / B: 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3.Step 2: To a stirred solution of 7-chloro-9-(4,5-difluoro-2-hydroxy-phenyl)-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.2 g, 0.59 mmol) in acetone (4 mL) was added K2CO3(0.24 g, 1.77 mmol) and reaction mass was stirred at room temperature for 20 min. Then, chloro-methyl methyl ether (0.076 g, 0.89 mmol) was added at 0 °C and allowed to stir for 2 h at room temperature. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction , the reaction mixture was filtered on celite bed, washed with dichloromethane, evaporated under vacuum to afford 7-chloro-9-[4,5-difluoro-2-(methoxymethoxy) phenyl]-2,3-dimethyl-WSGR Docket No. 55754-728.601pyrazino[l,2-a] pyrimidin-4-one (170, 74% yield) as an off-white solid. TLC : 30% EtOAc in heptane, UV active. Rf = 0.4. LCMS (ESI) m / z [M+H]+: 89.77%, tR= 2.1 min; (Calculated for: C17H15CIF2N3O3: 382.07); found: 381.8 [M+H]+; Method details: Column: X-Select CSH C18, (50mm*3.0mm,2.5p), Mobile Phase A: 0.05% Formic Acid in Water, Mobile Phase B: 0.05% Formic Acid in Acetonitrile, Flow rate: 1.0 mL / min. Column temperature: 40 °C, Gradient Program (B%) :0.01 / 2, 0.3 / 2, 2.0 / 98, 2.8 / 98, 3.0 / 2, 3.7 / 2.Step 3 : To a stirred solution of 7-chloro-9-[4,5-difhioro-2-(methoxym ethoxy )phenyl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (0.17 g, 0.53 mmol) and 2 -(2 -methoxy -4-pyridyl) morpholine (0.101 g, 0.52 mmol) in 1,4-dioxane (4 mL) was added Cs2CO3(0.43 g, 1.31 mmol) followed by RuPhos Pd G3 (0.092 g, 0.10 mmol) and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (0.049 g, 0.10 mmol ) and was purged with argon gas for 10 min. The reaction mixture was stirred at 90 °C for 2 h in microwave. Progress of the reaction mass was monitored by LCMS and TLC. After completion of reaction, the reaction mass was poured into water (10 mL), extracted with EtOAc (2 x 15 mL), organic layer was dried with Na2SO4and concentrated under reduced pressure to get the crude compound. Crude compound was purified by combi flash chromatography using by eluting at 30-35% EtOAc / heptane to afford title compound 9-[4,5-difluoro-2 -(methoxymethoxy) phenyl]-7-[2-(2-methoxy -4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.012 g, 42.46% Yield) as a yellow solid. TLC: 100% EtOAc, UV active, Rf= 0.4. LCMS (ESI) m / z [M+H] +: = 1.49 min; (Calculated for: C27H28F2N5O5: 540.2); found: 540.44 [M+H]+; Method Details: FABEH 2.5 MIN Column : X-BridgeBEH Cl 8 (2.1*30)mm, 2.5um Flow rate: 0.85 mL / min. Mobile Phase A: 0.05% FA in Water Mobile Phase B: 0.05% FA in Acetonitrile Column Temp.: 45 °C Gradient Program Time / B: 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3.Step 4: To a stirred solution of 9-[4,5-difluoro-2 (methoxy methoxy) phenyl]-7-[2-(2-methoxy-4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.12 g, 0.22 mmol) in 1,4-dioxane (5 mL) was drop-wise added HC1 (1.2 mL, 4 mol / L). The resultant solution was stirred at 0 °C for 1 h. Progress of reaction was monitored by TLC and LCMS. After completion of reaction, the solvents were evaporated under reduced pressure, diluted with water (5 mL) and extracted with EtOAC (2 x 20 mL). Combined organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude. Crude was purified by combi- flash chromatography by eluting at 45-50 % EtOAc / heptane to afford title compound 9-(4,5-difluoro-2-hydroxy-phenyl)-7-[2-(2-methoxy-4-pyridyl) morpholin-4-yl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (85 mg, 77.27% yield). TLC: 30% EtOAc in heptane, UV active, Rf= 0.2. LCMS (ESI) m / z [M+H]+: 99.22%, tR= 1.42 min; (Calculated for: C25H24F2N5O4: 496.17); found: 496.37 [M+H]+; Method Details: TFA BEH 2.5 MIN Column: X-BridgeBEH C18 (2.1*30)mm, 2.5um Flow rate: 0.85 mL / min. Mobile PhaseWSGR Docket No. 55754-728.601A: 0.05% TFA in Water Mobile Phase B: 0.05% TFA in Acetonitrile Column Temp.: 45 °C Gradient Program Time / B: 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3. HPLC: 98.89%. tR:6.43 min, Method Conditions: Column: X Bridge BEH C18, 2.5 pm, 100 X 3 mm. Mobile Phase A: 0.05% TFA in Water, Mobile Phase B: 0.05% TFA in Acetonitrile Colum Temperature: 50 °C Flow Rate: 0.5 ml / min Gradient: 0 / 5, 1 / 5, 6 / 90, 8.5 / 90, 8.8 / 5, 11 / 5. !HNMR(400 MHz, DMSO-d6) 8 ppm: 11.80 (s, 1H), 8.17 (d, J= 5.2 Hz, 1H), 8.04 (s, 1H), 7.67-7.61 (m, 1H), 7.10 (dd, J= 5.2, 0.8 Hz, 1H), 6.96-6.90 (m, 2H), 4.72 (dd, J= 10.4, 2 Hz, 1H), 4.18 (d, J= 11.6 Hz, 2H), 3.97 (d, J = 12.4 Hz, 1H), 3.85 (s, 3H), 3.83-3.81 (m, 1H), 3.02 (t, J = 6 Hz, 1H), 2.79 (t, J = 11.4 Hz, 1H), 2.35 (s, 3H), 2.17 (s, 3H).

[0153] Example 18 - 9-(2 -hydroxy -4-(trifluoromethyl)phenyl)-7-(2-(2-methoxypyridin-4-yl)morpholino)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-oneStep 1: To a stirred solution of 9-bromo-7-chloro-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (0.5 g, 1.73 mmol) and [2-hydroxy-4-(trifluoromethyl)phenyl]boronic acid (0.36 g, 1.73 mmol) in toluene (8 mL) and H2O (2 mL) was added Na2CO3(0.37 g, 3.47 mmol) at RT and it was purged with argon gas for 5 min at the same temp. Then, Pd (PPh3)4(0.20 g, 0.17 mmol) was added to the reaction mass and reaction mixture was stirred at 100 °C for 12 h. Progress of the reaction was monitored by LCMS and TLC. After completion of reaction, reaction mass was diluted with water and extracted by EtOAc (2 x 20 mL). Combined organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude. Crude Was purified using combi flash column chromatography by eluting at 20 -30% EtOAc in heptane to obtain title compound 7 -chloro-9-[2 -hydroxy -4-(trifluoromethyl) phenyl]-2,3-dimethyl-pyrazino[l,2-a] pyrimidin-4-one (0.2 g, 23.73% Yield) as a dark yellow solid. TLC: (20% EtOAc / heptane), UV active, RR0.4. LCMS (ESI) m / z [M+H]+: 76.93%, tR= 1.44 min; (Calculated for: CI6HI2C1F3N3O2: 370.05); found: 370.23.20 [M+H]+; Method Details: TFABEH 2.5 MIN Column : XBridge BEHC18 (2.1*30)mm, 2.5um Flow rate: 0.85 mL / min. Mobile Phase A: 0.05% TFA in Water Mobile Phase B: 0.05%WSGR Docket No. 55754-728.601TFA in Acetonitrile Column Temp.: 45°C Gradient Program Time / B: 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3Step 2: To a stirred solution of in 7-chloro-9-[2-hydroxy-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (0.2 g, 0.54 mmol) in acetone (5 mL) was added K2CO3 (0.15 g, 1.08 mmol) followedby chloromethyl methyl ether (0.088 g, 1.08 mmol) were added and stirred at RT for 12 h. Progress of the reaction was monitored by TLC and LCMS. Upon completion of reaction, reaction mass was diluted in water and extracted with EtOAc (2 x 10 mL). Combined organic layer was dried over anhydrous Na2SO4, filtered and evaporated to get 7-chloro-9-[2-(methoxymethoxy)-4-(trifluoromethyl)phenyl]-2,3-dimethyl-pyrazino[l,2-a]pyrimidin-4-one (0.2 g, 68.79% Yield) as dark orange solid. TLC : 20% EtOAc in heptane, UV active. Rf = 0.3. LCMS (ESI) m / z [M+H] +: 77.69%,= 1.46 min; (Calculated, for: CI8HI6C1F3N3O3: 414.08); found: 414.26 [M+H]+; Method Details: TFA BEH 2.5 MIN, Column : XBridge BEH C18 (2.1*30)mm, 2.5um Flow rate: 0.85 mL / min. Mobile Phase A: 0.05% TFA in Water, Mobile Phase B: 0.05% TFA in Acetonitrile Column Temp: 45 °C Gradient Program Time / B: 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3Step 3 : To a stirred solution of in 7-chloro-9-(2-(methoxymethoxy)-4 (trifluoromethyl) phenyl)-2,3-dimethyl-4H-pyrazino[l,2-a] pyrimidin-4-one (200 mg, 0.48 mmol) and 2-(2-methoxypyridin-4-yl)morpholine (0.11 g, 0.58 mmol)in 1,4-dioxane (3 mL) was added Cs2CO3(0.47 g, 1.45 mmol) at RT and purged with argon gas for 10 min. Then, RuPhos (0.046 g, 0.096 mmol) and RuPhos Pd G3 (0.080 g, 0.096 mmol) were added to the reaction mass and again purged for 5 min and reaction mixture was stirred at 90 °C for 2 h in MW. The progress of the reaction was monitored by LCMS and TLC. After completion of reaction, reaction mass was diluted in water and extracted with EtOAc (2 x 10 mL). Combined organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude. Crude was purified by using combi flash chromatography by eluting at 20-40% EtOAC in heptane to afford title compound 9-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(2-(2-methoxypyridin-4-yl)morpholino)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one (0.15 g, 48.32% Yield) as a yellow solid.TLC: 30% EtOAc / heptane, UV active, Rf: 0.4. LCMS (ESI) m / z [M+H]+: 89%, tR= 1.46 min; (Calculated, for: C28H29F3N5O5: 572.2); found: 572.39 [M+H] +; Method Details: TFA BEH 2.5 MIN, Column: XBridge BEH Cl 8 (2.1*30)mm, 2.5um Flow rate: 0.85 mL / min. Mobile Phase A: 0.05% TFA in Water Mobile Phase B: 0.05% TFA in Acetonitrile Column Temp.: 45°C, Gradient Program Time / B: 0.0 / 3, 0.1 / 3,1.4 / 97, 2.0 / 97, 2.05 / 3,2.5 / 3.Step 4: To a stirred solution of 9-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-(2-(2-methoxypyridin-4-yl) morpholino)-2,3-dimethyl-4H-pyrazino[l,2-a] pyrimidin-4-one (0.13 g, 0.23 mmol) in 1,4-dioxane (2 mL) was added HC1 in dioxane (0.057 mL, 0.23 mmol, 4 mol / L) at 0 °C.WSGR Docket No. 55754-728.601Reaction mixture was then stirred atRT for 30 min. Completion of the reaction was monitored by TLC and LCMS. After completion of reaction, reaction mass was dissolved in water (5 mL) and neutralised with NaHCO3solution and extracted with EtOAC (2 x 10 mL). Combined organic layer was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure to get crude. Crude was purified by combiflash chromatography by eluting at 40-50% EtOAc in heptane to afford title compound 9-(2 -hydroxy -4-(trifluoromethyl)phenyl)-7-(2-(2 -methoxypyridin-4-yl)morpholino)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one(100mg, 82.91% Yield) as apale yellow solid. TLC: 50% EtOAc in heptane, UV active, Rf = 0.2. LCMS (ESI) m / z [M+H]+: 99.47%, ZR= 2.67 min; (Calculated for: C26H25F3N5O4: 528.18); found: 528.41 [M+H] +; Method Details: FA BEH 4.2 MINS Column : Acquity UPLCBEH Cl 8 (2.1*50)mm, 1.7 urn Flow rate: 0.5 mL / min. Mobile Phase A: 0.05% FA in Water Mobile Phase B: 0.05% FA in Acetonitrile Column Temp.: 40 °C Gradient Program Time / B: 0.0 / 2, 0.3 / 2, 2.0 / 98, 3.5 / 98, 3.6 / 2, 4.2 / 2. HPLC: 99.82%. ZR:6.64 min, Method Conditions: Column: X Bridge BEH Cl 8, 2.5 pm, 100 X 3 mm. Mobile Phase A: 0.05% TFA in Water, Mobile Phase B: 0.05% TFAin Acetonitrile Column Temperature: 50 °C Flow Rate: 0.5 ml / min Gradient: 0 / 5, 1 / 5, 6 / 90, 8.5 / 90, 8.8 / 5, 11 / 5.JH NMR (400 MHz, CDC13) 6 ppm: 12.74 (s, 1H), 8.20 (dd, J= 5.2, 0.4 Hz, 1H), 8.16 (s, 1H), 8.20 (d, J= 8 Hz, 1H), 7.36 (s, 1H), 7.24 (d, J= 1.2Hz, 1H), 6.95 (dd, J= 5.2, 1.2 Hz, 1H), 6.84 (s, 1H), 4.67 (dd, J= 10.4, 2.8 Hz, 1H), 4.28-4.20 (m, 2H), 4.02 (d, J= 12.4 Hz, 1H), 3.97 (s, 3H), 3.96-3.20 (td, J= 12, 4 Hz, 1H), 2.93-2.87 (m, 1H), 2.55 (s, 3H), 2.33 (s, 3H).

[0154] Example 19 - 2-(6,7-dimethyl-2-(2-(l-(methyl-d3)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601Step 1: Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (1.0g, 4.5mmol, l.Oeq), tetramethylstannane (4.0 g, 22 mmol, 5.0eq), Pd2(dba)3(0.42g, 0.45mmol, 0.1 eq) and XPhos (0.85g, 1.8mmol, 0.4eq) were combined in Dioxane (20mL). The mixture was degassed with N2for 5 min and heated at 115°C (oil bath) in a sealed tube for 16 hr. LCMS analysis showed clean reaction without remaining starting material. The mixture was diluted with DCM (lOOmL). To the mixture was added NaF (~50g) and Na2SC>4 (50g). The mixture was stirred at RT for 30 min. The inorganic was removed by filtration. The mixture was concentrated in vacuo and purified on ISCO (24g silica-gel column) to give methyl 3 -amino-5,6-dimethylpyrazine-2 -carboxylate (0.67g, yield 82%).Step 2: To a solution of l-(methyl-d3)-lH-pyrazole-4-carbaldehyde (1.11g, 10 mmol) and but-3-yn-l-ol (0.85 g, 12 mmol) in dry DCM (20 mL) at -10 °C was added TfOH (4.5 g, 30 mmol) dropwise over 30 mins under N2 and the mixture was then stirred at ~20 °C for 20 hr under N2 protection. The reaction was monitored by LCMS until aldehyde was completely consumed. The mixture was cooled with ice-water and quenched with ice-water and adjusted pH=8 by adding saturated aqueous NaHCO3and extracted with DCM (2x30 mL). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, added active carbon (2g), heated at refluxing for lOmints, filtered and concentrated to afford oil 6-(l-(methyl-d3)-lH-pyrazol-4-yl)-3,6-dihydro-2H-WSGR Docket No. 55754-728.601pyran-4-yl trifluoromethanesulfonate (2.51 g, yield -80%) as oil which was used without further purification.Step 3: To a solution of 6-(l-(methyl-d3)-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (2.5g, 8 mmol) and DIEA (3.1g, 24 mmol) in MeOH (50mL) was degassed under vacuo and backfilled with CO gas three times. Catalyst PdCl2(PPh3)2(0.28g, 0.4 mmol) was added. The resulting mixture was heated at 55 °C under CO ballon for 12 hr. LCMS analysis showed reaction went completion. Upon cooling to room temperature, the mixture was filtered through celite-pad to remove insoluble solid and washed celite pad with MeOH (2x10). The MeOH was then removed in vacuo till remaining vol (-30 mL). To the solution was added LiOH (580mgs, 24 mmol) in water (30mL). The mixture was stirred at RT for 1 hr. LCMS showed reaction went completion. Most MeOH was removed in vacuo. The residue was diluted with water (20mL) and extracted with DCM (3x40mL). The DCM phase was discarded. The aqueous phase was adjusted to pH 1-2 by adding 6N HC1, then extracted with mixture solvent (iPrOH / DCM=l / 8) (4x40mL). The combined organic phase was washed with brine and dried over Na2SO4to afford solid (1.3 g) which was suspended in Acetate (3ml) and Hexane (30mL) and stirred atRT for 30 min. The solid was collected by filtration and dried in high vacuo to give 6-(l-(methyl-d3)-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-carboxylic acid (1.2g, yield -71% over two steps) solid which was used without purification.Step 4: To a solution of 6-(l-(methyl-d3)-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-carboxylic acid (1.2 g) in MeOH (120 ml) was added Pd / C (10%, 600 mg). The mixture was degassed with N2gas and hydrogenated under H2(55 psi) at room temperature for 20 hr. LCMS analysis showed -15% starting material remained. Additional Pd / C (10%, 100 mg) was added. The mixture was hydrogenated at 55 psi (H2) for additional 20 hr. No starting material remained by LCMS analysis. The catalyst was removed by filtration through celite-pad and washed with MeOH (2x20mL). The solvent was removed in vacuo to afford white solid which was suspend in acetate (~10mL), sonicated for 2min and stirred at RT for 30min. The solid was collected by filtration to give cis-mixture of 2-(l-(methyl-d3)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-carboxylic acid (0.68g, yield 64%) which was used without further purification.Step 5: 2-(l-(methyl-d3)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-carboxylic acid (0.24g, 1.14mmol, l.Oeq) and methyl 3-amino-5,6-dimethylpyrazine-2-carboxylate (0.22g, 1.2mmol, 1 ,06eq) were combined in dry DCM (20mL) under N2. To the mixture was added pyridine (0.45g, 5.7mmol, 5.0eq). The mixture was cooled to OoC over ice-water bath. A solution of POC13(0.44g, 2.85mmol, 2.5eq) in DCM (4mL) was added dropwise over 5min. The resulting mixture was stirred at RT overnight under N2. LCMS analysis showed both starting materials remained (-10% by UV). Additional POC13(87mg, 0.57mmol, 0.5eq) was added at RT. The mixture was stirred at RT forWSGR Docket No. 55754-728.6015hr. The reaction mixture was concentrated in vacuo directly and the residue was suspended in MeOH (30mL) and transferred into a pressure bottle. The suspension solution was bubbled with NH3(gas) at 0°C until saturated. The mixture was heated at 90 °C in the sealed pressure bottle for 12hr. LCMS analysis showed clean reaction without remaining intermediate. The solvent was removed in vacuo, the residue was dissolved in DCM (100ml), the insoluble solid was removed by filtration and discarded. The crude mixture was purified on silica-gel column (12g) with mobile solvents 0-8% MeOH in DCM in 10 min to afford methyl 6,7-dimethyl-2-(2-(l-(methyl-d3)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4(3H)-one (0.31g, yield 78% in two steps). Step 6: To a solution of 6,7-dimethyl-2-(2-(l-(methyl-d3)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4(3H)-one (0.24g, 0.7mmol, l.Oeq) in dry THF (35mL) was added anhydride K2CO3 (0.58g, 4.2mmol, 6.0eq) and TosCl (0.3g, 1.56mmol, 2.2 eq). The resulting mixture was heated at 70°C under N2overnight. LCMS analysis showed clean reaction and no SM remained. The mixture was diluted with DCM (100ml), filtered through celite-pad to remove inorganic solid and concentrated in vacuo. The mixture was dissolved in DCM (lOmL) and loaded on silica-gel column (12g), washed off with acetate (~60mL) then CH3CN (~120ml) to afford 6,7-dimethyl-2-(2-(l-(methyl-d3)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl 4-methylbenzenesulfonate (0.29g, yield 83%).Step 7: 6,7-dimethyl-2-(2-(l-(methyl-d3)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl 4-methylbenzenesulfonate (50 mgs, O.lmmol, l.Oeq), (2 -hydroxy -4-(trifluoromethyl)phenyl)boronic acid (42mgs, 0.2mmol, 2.0eq), Na2CO3(22mgs, 0.2mmol, 2.0 eq), PdCl2(PPh3)2(7mgs, O.Olmmol, O.leq) were combined in THF (3ml) and DI water (1ml). The mixture was degassed with N2gas and heated at 70°C under N2for 1 ,5hr. LCMS analysis indicated no SM remained. The mixture was diluted with ethyl acetate (30mL), washed with water and brine. The crude mixture was purified on silica-gel column (4g) to afford cis-racemic 2-(6,7-dimethyl-2-(2-(l-(methyl-d3)-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (22 mgs, yield 44%).

[0155] Example 20 - 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601Step 1: To a solution of 2,6-dichloropyrimidine-4,5-diamine (358 mg, 2 mmol) in dry ethanol (7 ml) was added 2,3 -Butanedione (200 mg, 2.4 mmol) and the mixture was heated to 45°C for 5 hrs. After cooling to room temperature, the solvent was removed, and the residue was suspended in MTBE (lOmL) and stirred for 5min, filtered to afford 2,4 -dichloro-6,7-dim ethylpteridine (300 mg, yield 58%).Step 2: To a solution of 2,4-dichloro-6,7-dimethylpteridine (176 mg, 0.77 mmol) in THF (6 mL) was added water (1 mL), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (256 mg, 0.77 mmol), PdCl2(dppf).DCM (56 mg, 0.07 mmol), K2CO3(276 mg, 2 mmol). The mixture was degassed and stirred at room temperature under N2for 16 hours. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed under vacuum, and the crude mixture was purified on silica gel column to give 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dim ethylpteridine (150 mg, yield 49%).Step 3: To a solution of 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpteridine (100 mg, 0.25 mmol) in dioxane (4 mL)was added water (1 mL), 1 -methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (90 mg, 0.3 mmol), PdCl2(dppf) DCM (24 mg, 0.03 mmol), K2CO3(70 mg, 0.5 mmol). The mixture was degassed and stirred at 60°C under N2for 6 hours. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified on silica gel column to give 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (45 mgs, yield 34%).Step 4: To a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (45 mgs) in MeOH (40 mL) was added Pd / C (10%, 9 mgs). The mixture was degassed under vacuo and back filled with N2twice.WSGR Docket No. 55754-728.601The mixture was hydrogenated under 50 psiH2for 15hrs atRT. LCMS analysis showed no starting material remained. The catalyst was removed, and crude mixture was concentrated in vacuo to afford mixture which was dissolved in DCM (20mL) and added activated MnO2(-lOOmg). The resulting mixture was stirred atRT for 15hr. The mixture was filtered and was purified on silica -gel column (4g) with MeOH in ethyl acetate (0%~5%) in 10 mins to afford 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-(l -methyl- lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine (35mgs, -85% purity, yield -77%) cis-mixture.Step 5: To a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridine (35mgs, -85% purity) in DCM (2mL) was added TFA (0.5mL), the mixture was stirred atRT for 30 mints. The solvent was removed, and the crude mixture was purified on HPLC (mobile phase contains 0.1%TFA). The fractions of desired product were combined and adjusted pH -8 by adding saturated NaHCO3then extracted with DCM (2x25mL) to afford cis-racemic 2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (lOmgs, yield 31%).

[0156] Example 21 - 5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,6-naphthyridin-l(2H)-oneStep 1: To a solution of methyl 3 -aminoisonicotinate (10 g, 65.8 mmol) in DMF (20 mL) was added NCS (9.5 g, 133.5 mmol). The mixture was stirred at room temperature overnight and poured into water, the solid was filtered and washed with water and dried by air to afford methyl 3 -amino-2,6-dichloroisonicotinate (13 g, yield 89%) which was used without purification.Step 2: To a solution of methyl 3 -amino-2,6-dichloroisonicotinate (1.1 g, 5 mmol) in dry ACN (20 ml) was added tertbutyl nitrite (772 mg, 7.5 mmol) and Cui (4.75g, 25 mmol). The mixture wasWSGR Docket No. 55754-728.601stirred at 60°C for 6 hours. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica gel to give methyl 2,6 -dichloro-3 -iodoisonicotinate (800 mg, yield 48%). To a solution of methyl 2,6-dichloro-3-iodoisonicotinate (1.5g, 4.46 mmol) in dry THF (30 mL) was added Cui (190 mg, 1 mmol), PdC12(PPh3)2(300mg, 0.42 mmol) and TEA (5 mL). The mixture was degassed and propyne in DMF (8ml, 8mmol) was added. The mixture was stirred at room temperature under N2overnight and was diluted with EtOAc. The mixture was washed with water, brine and dried over anhydrous Na2SO4. The solvent was removed, and the crude mixture was purified on silica gel column to provide methyl 2,6-dichloro-3-(prop-l-yn-l-yl)isonicotinate (240 mg, yield -22%).Step 3: Methyl 2,6-dichloro-3-(prop-l-yn-l-yl)isonicotinate (240 mg, 1 mmol) was added to ammonia in MeOH (7N, 10 mL), and the mixture was stirred at 50°C in a pressure tube for 1 hour. The mixture was cooled to room temperature and concentrated in vacuo to give 2,6-dichloro-3-(prop-l-yn-l-yl)isonicotinamide (220 mg, yield 97%) as a white solid.Step 4: To a solution of 2,6-dichloro-3-(prop-l-yn-l-yl)isonicotinamide (220 mg, 0.96 mmol) in DMF (4mL) was added NaH (60%, 80 mg, 2 mmol). And the mixture was stirred at 60°C in a pressure tube for 1 hour. The mixture was cooled to room temperature and Mel (0.4ml) was added. The mixture was stirred at room temperature for 1 hour, was diluted with EtOAc, washed with water and brine, and dried over anhydrous Na2SO4. The solvent was removed, and the crude mixture was purified on silica gel column to give 5,7-dichloro-2,3-dimethyl-2,6-naphthyridin-l(2H)-one (220 mg, yield 94% over two-step).Step 5: To a solution of 5,7-dichloro-2,3-dimethyl-2,6-naphthyridin-l(2H)-one (210 mg, 0.86 mmol) in THF (8 mL) was added water (2 mL), 2 -(2-(meth oxymeth oxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (300 mg, 0.9 mmol), PdCl2(dppf).DCM(70 mg, 0.08 mmol), K2CO3(280 mg, 2 mmol). The mixture was degassed with N2gas and stirred at 60°C under N2for 1.5 hours. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the crude mixture was purified on silica gel column to give 7-chloro-5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-2,6-naphthyridin-l(2H)-one (190 mg, yield 53%).Step 6: To a solution of 7-chloro-5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-2,6-naphthyridin-l(2H)-one (lOOmg, 0.25 mmol) in dioxane (4 mL) was added water (1 mL), 1-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (87 mg, 0.3 mmol), PdCl2(dppf).DCM (24 mg, 0.03 mmol), K2CO3(70 mg, 0.5 mmol). The resulting mixture was degassed with N2gas and stirred at 100°C under N2for 14 hr. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the crude mixture was purified on silica gel column to provide 5 -(2-WSGR Docket No. 55754-728.601(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,6-naphthyridin-l(2H)-one (95 mgs, yield 72%).Step 7: To a solution of 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,6-naphthyridin-l(2H)-one (95mgs) in MeOH (lOOmL) was added Pd / C (10%, 20 mgs). The mixture was degassed under vacuo and back filled with N2 twice. The mixture was hydrogenated under 50 psi H2for 15hrs at RT. LCMS analysis showed no starting material remained. The catalyst was removed, and the crude mixture was purified on silica-gel column to afford 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,6-naphthyridin-l(2H)-one (45 mgs, yield 47%).Step 8: To a solution of 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,6-naphthyridin-l(2H)-one (45 mgs) in DCM (2mL) was added 4NHC1 in dioxane (ImL), the mixture was stirred atRT for Ihr. The solvent was removed, and the crude mixture was suspended in saturated NaHCO3, extracted with DCM (2x20mL). The combined organic was washed with brine and dried over Na2SO4. The solvent was concentrated in vacuo to afford crude mixture which was suspended in 5% acetate in hexane (~3mL) and stirred for 5 mins. The solid was collected by filtration and dried in high vacuo to afford cis-racemic 5-(2-hydroxy-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,6-naphthyridin-l(2H)-one (22 mgs, yield 53%).

[0157] Example 22 - 2-(2, 3 -dimethyl-7-(2-(l -methyl- lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazin-5-yl)-5-(trifluoromethyl)phenolStep 1 : To a solution of 2,6-dichloropyridine-3,4-diamine (1g, l.Oeq) in ethanol (15 ml) was added 2,3 -Butanedione (0.6g, 1 ,25eq) and the mixture was heated to 90°C for 4 hours. After cooling to room temperature, the solvent was removed, and the residue was treated with EtOAc / Hexane to give 5,7-dichloro-2,3-dimethylpyrido[3,4-b]pyrazine (1.0g, yield 79%).WSGR Docket No. 55754-728.601Step 2: 5,7-dichloro-2,3-dimethylpyrido[3,4-b]pyrazine (130mg, l.Oeq), 2-(2-(methoxymethoxy)4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (200mg, l.Oeq), Pd(PPh3)4(66mg, O.leq) and K2CO3 (160mg, 2.0eq) were combined in THF (8 mL) and water (3 mL). The mixture was degassed with N2 gas for 5 mints, then heated at 55 °C for 30min. The reaction mixture was diluted with acetate, washed with brine. The crude mixture was purified on silica -gel column (12g) to afford 7-chloro-5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-b]pyrazine (180mg, yield 83%).Step 3: To a solution of 7-chloro-5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-b]pyrazine(80 mg, 0.2 mmol) in dioxane (4 mL) was added water (1 mL), 1 -methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (88 mg, 0.3 mmol), PdCl2(dppf).DCM (24 mg, 0.03 mmol), K2CO3(70 mg, 0.5 mmol). The mixture was degassed and stirred at 60°C under N2for 6 hours. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified on silica gel column to give 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine (45 mgs, yield 43%).Step 4: To a solution of 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine(45 mgs) in MeOH (50 mL) was added Pd / C (10%, 10 mgs). The mixture was degassed under vacuo and back filled with N2gas twice. The mixture was hydrogenated under H2(50 psi) for 15hrs atRT. LCMS analysis showed no starting material remained. The catalyst was removed, and crude mixture was concentrated in vacuo to afford mixture which was dissolved in DCM(20 mL) and added activated MnCh (-lOOmg). The resulting mixture was stirred at RT for 15hr. The mixture was filtered and was purified on silica-gel column (4g) with MeOH in ethyl acetate (0%~5%) in 10 mins to afford 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine (36mgs, yield -78%) cis-mixture.Step 5: To a solution of 5-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazine (33mgs) in DCM (2mL) was added 4N HC1 in dioxane (0.5mL), the mixture was stirred at RT for Ihr. The solvent was removed, and the crude mixture was purified on HPLC. The fractions of desired product were combined and adjusted pH -8 by adding saturated NaHCO3 then extracted with DCM (2x25mL) to afford cis-racemic 2-(2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-b]pyrazin-5-yl)-5-(trifluoromethyl)phenol (17mgs, yield 56%).

[0158] Example 23 - 2-(2, 3 -dimethyl-6-(2-(l -methyl- lH-pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601Step 1: To a solution of 4,6-dichloropyridine-2,3-diamine (450 mg, 2.5 mmol) in ethanol (7 ml) was added 2,3 -Butanedione (260 mg, 3 mmol) and the mixture was heated to 85°C for 4 hours. After cooling to room temperature, the solvent was removed, and the residue was treated with EtOAc / Hexane to give 6,8-dichloro-2,3-dimethylpyrido[2,3-b]pyrazine (400 mgs, yield 69%) which was used without purification.Step 2: The mixture of 6,8-dichloro-2,3-dimethylpyrido[2,3-b]pyrazine (70 mg, 0.3 mmol), 2-(l-methyl-lH-pyrazol-4-yl)morpholine(45 mg, 0.27 mmol), Pd(OAc)2 (6.7 mg, 0.03 mmol), BINAP (37 mg, 0.06 mmol) and Cs2CO3(200 mg, 0.62 mmol) in toluene (8 mL) was degassed with N2gas and heated at 100°C for 16 hours. The mixture was diluted with EtOAc, washed with water, brine and dried overNa2SO4. The solvent was removedin vacuo, and the crude mixture was purified on silica gel column to provide 4-(8-chloro-2,3-dimethylpyrido[2,3-b]pyrazin-6-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (30 mgs, yield 27%)Step 3: To a solution of 4-(8-chloro-2,3-dimethylpyrido[2,3-b]pyrazin-6-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (30 mg, 0.08 mmol) in dioxane (2 mL) was added water (0.5mL), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (45 mg, 0.13 mmol), PdCl2(dppf).DCM(10 mg, 0.012 mmol), K2CO3(28 mg, 0.2 mmol). The mixture was degassed with N2gas and stirred at 100°C under N2overnight. The mixture was diluted with EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the crude mixture was purified on silica gel column to give 4-(8-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[2,3-b]pyrazin-6-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (30 mgs, yield 68%).Step 4: To a solution of 4-(8-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[2,3-b]pyrazin-6-yl)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (30 mg) in DCM (1 ml) was added HC1 (0.5 ml, 4N in dioxane) at room temperature. The mixture was stirred at RT for 1 hour and concentrated. The residue was stirred in DCM and hexane (2ml, 1 :2), filtered and solid was collected. The solid was added to saturated NaHCO3and extracted with DCM twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the crude mixtureWSGR Docket No. 55754-728.601was purified on silica gel column to give racemic 2-(2,3-dimethyl-6-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)phenol (15 mgs, yield 54%).

[0159] Example 24 - 2-(6,7-dimethyl-2-((2S,4R,6S)-2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol and Example 40 - 2-(6,7-dimethyl-2-((2R,4S,6R)-2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin- 4-yl)-5-(trifluoromethyl)phenolStep 1: (E)-triethyl(penta-l,3-dien-2-yloxy)silaneTo a solution of LDA (1 M, 65.4 mL, 131 mmol) in THF (55 mL) was added (E)-pent-3-en-2-one (10.0 g, 119 mmol) at -78 °C. After 15 minutes, TESC1 (19.65 g, 131 mmol) was added. The mixture was stirred at -78 °C for 30 minutes and 25 °C for 1 hour. The mixture was quenched with a saturated aqueous NaHCOs (100 mL), extracted with EtOAc (80 mL x 3) and the combined organic layers washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 100 / 0 to 80 / 20) to give (E)-triethyl(penta-l,3-dien-2-yloxy)silane (10.2 g, 43.26 %) as a colorless oil. LCMS (Agilent Acid): m / z 199.2 [M+H]+.Step 2: l-methyl-4-((2R,6R)-6-methyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-lH-pyrazoleWSGR Docket No. 55754-728.601To a solution of l-methyl-lH-pyrazole-4-carbaldehyde (925 mg, 8.4 mmol) in CHC13(20 mL) was added (E)-triethyl(penta-l,3-dien-2-yloxy)silane (5.0 g, 25.2 mmol) and Eu(fod)3(436 mg, 0.42 mmol). The mixture was stirred at 80 °C for 12 hours. The mixture was diluted with water (80 mL), extracted with EtOAc (50 mL x 3) and the combined organic layers washed with brine (80 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 100 / 0 to 70 / 30) to give l-methyl-4-((2R,6R)-6-methyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (700 mg, 27%) as a yellow oil.LCMS (Agilent Acid): m / z 309.2 [M+H]+.Step 3: 2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-4H-pyran-4-oneTo a solution of l-methyl-4-((2R,6R)-6-methyl-4-((triethylsilyl)oxy)-3,6-dihydro-2H-pyran-2-yl)-IH-pyrazole (700 mg, 2.5 mmol) in THF (2 mL) was added HC1 (IM, 8 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was diluted with water (30 mL), extracted with EtOAc (20 mL x 3) and the combined organic layers washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under vacuum to give 2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-4H-pyran-4-one (550 mg, crude) as a yellow oil. LCMS (Agilent Acid): m / z 195.1 [M+H]+.Step 4: 2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yltriflu orom eth an e sulf on ateTo a flask of LiHMDS (IM, 5.15 mL, 45.15 mmol) at -78 °C, 2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-4H-pyran-4-one (500 mg, 2.57 mmol) was dissolved in THF and dropped at -78 °C for 45 minutes. The N-(5-chloropyridin-2-yl)-l,l,l-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (2.02 g, 5.15 mmol) was dissolved in THF and dropped. The mixture was stirred at -78 °C for 15 minutes and 25 °C for 1 hour. The mixture was quenched with a saturated aqueous NH4C1 (30 mL), extracted with EtOAc (30 mL x 3) and the combined organic layers washed with brine (100 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by MPLC (Biotage Airs Science C18-M column eluting with 0% to 50% MeCN / H2O, 0.1% FA) to give 2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (310 mg, 36.9 %) as a yellow oil. LCMS (Agilent Base): m / z 327.1 [M+H]+.Step 5: l-methyl-4-(6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazoleTo a solution of 2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (310 mg, 0.950 mmol) in dry dioxane (5 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (362 mg, 1.43 mmol), Pd(dppf)Cl2»DCM (78 mg, 0.095 mmol) and AcOK (280 mg, 12.85 mmol). The mixture was stirred at 80 °C for 2 hours. The mixture was diluted with water (30 mL), extracted with EtOAc (20 mL x 3) and theWSGR Docket No. 55754-728.601combined organic layers washed with brine (30 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 100 / 0 to 75 / 25) to give l-methyl-4-(6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (300 mg, crude) as a yellow oil. LCMS (Agilent Base): m / z 305.3 [M+H]+.Step 6 : 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridineTo a solution of 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl) -6,7-dimethylpteridine (240 mg, 0.0.601 mmol) in dioxane (4 mL) and H2O (0.8 mL) was added 1-methyl-4-(6-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-IH-pyrazole (201 mg, 0.662 mmol), Cs2CO3(588 mg, 1.81 mmol), Pd(dppf)Cl2»DCM (74 mg, 0.090 mmol). The mixture was stirred at 100 °C under microwave for 1 hour. The mixture was diluted with water (50 mL), extracted with EtOAc (30 mL x 3) and the combined organic layers washed with brine (30 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 100 / 0 to 56 / 44) to give 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (350 mg, 65.66%) as a red oil. LCMS (Agilent Base): m / z 541.3 [M+H]+.Step 7: 2-(6,7-dimethyl-2-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (300 mg, 0.552 mmol) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred at 25 °C for 10 minutes. The mixture was quenched with a saturated aqueous NaHCCL (30 mL), extracted with EtOAc (20 mL x 3) and the combined organic layers washed with brine (30 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 100 / 0 to 50 / 50) to give 2-(6,7-dimethyl-2-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (180 mg, 55.99%) as a brown oil. LCMS (Agilent Acid): m / z 497.2 [M+H]+.Step 8 : 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridineTo a solution of 2-(6,7-dimethyl-2-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (130 mg, 0.261 mmol) in EtOH (1 mL) was added PtO2(40 mg). The mixture was stirred at 25 °C under H2atmosphere for 3 hours. The mixture was filtered and concentrated to give 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-WSGR Docket No. 55754-728.6012-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridine (180 mg, crude) as a brown oil. LCMS (Agilent Base): m / z 503.3 [M+H]+.Step 9: 2-(6,7-dimethyl-2-((2R,4S,6R)-2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 40 & 2-(6,7-dimethyl-2-((2S,4R,6S)-2-methyl-6-(l -methyl- lH-pyrazol-4-y l)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 24To a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridine (130 mg, 0.258 mmol) in DCE (2 mL) was added MnO2(450 mg, 5.17 mmol). The mixture was stirred at 25 °C 2 hours. The mixture was filtered and concentrated under vacuum. The residue was purified by MPLC (Biotage Airs Science C18-M column eluting with 0% to 50% MeCN / H2O, 0.1% FA) and SFC (separation condition: Column: OJ (30*250mm, 10pm); Mobile phase A: Supercritical CO2, Mobile phase B: 25% CH3OH (0.4% 7MNH3), 45g / min, 1.7mL, A:B = 80:20 at 45mL / min; Column Temp: 35 °C; BackPressure: lOOBar; Wavelength: 214 nm)), 45g / min, 1.7mL) to give 2-(6,7-dimethyl-2-((2R,4S,6R)-2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (38.2 mg, 32.22%) as the first eluting compound. LCMS (Agilent Acid): m / z 499.2 [M+H +TH NMR (400 MHz, DMSO-d6) 88.05 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 7.30-7.25 (m, 2H), 4.58 (d, J = 10.8 Hz, 1H), 3.79 (s, 4H), 3.49 (s, 1H), 2.77 (s, 3H), 2.66 (s, 3H), 2.26 (d, J = 12.4 Hz, 1H), 2.13 (d, J = 12.0 Hz, 1H), 1.86 (dd, J = 24.4, 12.0 Hz, 1H), 1.58 (dd, J = 24.0, 12.0 Hz, 1H), 1.21 (d, J = 6.0 Hz, 3H).Further elution gave 2-(6,7-dimethyl-2-((2S,4R,6S)-2-methyl-6-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (33.3 mg, 28.09 %) as the second eluting compound. LCMS (Agilent Acid): m / z 499.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 68.05 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 7.30 (d, J = 8.8 Hz, 2H), 4.58 (d, J = 10.0 Hz, 1H), 3.84 - 3.77 (m, 4H), 3.54 - 3.45 (m, 1H), 2.77 (s, 3H), 2.67 (s, 3H), 2.27 (d, J = 13.2 Hz, 1H), 2.13 (d, J = 12.8 Hz, 1H), 1.86 (dd, J = 24.4, 12.0 Hz, 1H), 1.58 (dd, J = 24.0, 12.0 Hz, 1H), 1.21 (d, J = 6.0 Hz, 3H).

[0160] Example 25 - 2-(7-methyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601Step 1: 2,4-dichloro-7-methylpteridineTo solution of 2, 4-dichloro-7 -methylpteridine (1 g, 7.3 mmol), 2-oxopropanal (766.5 mg, 10.95 mmol) and CaSO4(766.5 mg, 10.95 mmol) in DCE (18 mL). The reaction mixture was stirred at RT for 16h. The reaction was filtered through a plug of celite and evaporated under reduced pressure to give 2, 4-dichloro-7-m ethylpteridine (230 mg) as a yellow solid. LCMS (Agilent Acid): m / z 215.0 [M+H]+.Step 2: 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-methylpteridineA mixture of 2,4-dichloro-7-methylpteridine (200 mg, 0.934 mmol), 2-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (341.3 mg, 1.028 mmol), Pd(dppf)C12 (114 mg, 0.141 mmol) and K2CO3 (386.8 mg, 2.804 mmol) in THF (2.4 mL) and H2O (0.4 mL). The reaction mixture was stirred at 25°C for 3hrs. The reaction was quenched with a saturated aqueous water (10 mL) solution and the mixture extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 30 / 70) to 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7 -methylpteridine (180 mg, 71.5%) as a yellow solid. LCMS (Agilent Acid): m / z 385.1 [M+H]+.Step 3 : 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-methyl-2-(6-(l-methyl-lH-pyrazoM-yl)-3,6-dihydro-2H-pyran-4-yl)pteridineTo a solution of 2-chloro-4-(2-(m ethoxymeth oxy)-4-(trifluoromethyl)phenyl)-7 -methylpteridine (160 mg, 0.417 mmol) and l-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (181.3 mg, 0.625 mmol) in dioxane (5 mL) and water (1 mL) was added Cs2CO3(407.3 mg, 1.250 mmol) and Pd(dppf)Cl2(51 mg, 0.063 mmol) at25°C. The reaction mixture was stirred at 100°C for Ihrs in a microwave reactor. The reaction was quenched with a saturated aqueous water (10 mL) solution and the mixture extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THFWSGR Docket No. 55754-728.601= 50 / 50) to give 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-7-methyl-2-(6-(l -methyl- 1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (186 mg, 87.3%) as a yellow oil. LCMS (Agilent Acid): m / z 513.2 [M+H]+.Step 4: 2-(7-methyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 4-(2-(m ethoxymethoxy)-4-(trifluoromethyl)phenyl)-7-methyl-2-(6-(l -methyl- 1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (180 mg, 0.352 mmol) in DCM (5 mL) was added TFA (3.0 mL) at 0°C. The reaction mixture was stirred at RT for 2h. The reaction was quenched with a saturated aqueous NaHCO3(10 mL) solution and the mixture extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 50 / 50) to give 2-(7-methyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenoll (86 mg, 52.5%) as a yellow solid. LCMS (Agilent Acid): m / z 469.2 [M+H]+.Step 5: 2-(7-methyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 2-(7-methyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenoll (80 mg, 0.171 mmol) in EtOH (2 mL) was added PtO2(26.8 mg, 0.119 mmol) at25°C. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 psi) at 25°C for 16hrs. The reaction mixture was filtered under reduced pressure to filter outPtO2to give 2-(7-methyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (60 mg) as a yellow oil, which was used in the next step without further purification. LCMS (Agilent Acid): m / z 475.3 [M+H]+.Step 6: 2-(7-methyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 25To a solution of 2-(7-methyl-2-(2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5, 6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (60 mg, 0.126 mmol) in DCE (5 mL) was added MnO2(230 mg, 2.532 mmol). The reaction mixture was stirred at RT for 6h. The reaction filtered under reduced pressure to filter out MnO2. The residue was purified by MPLC (Biotage Airs Science C18-M column eluting with 0% to 70% MeCN / H2O, 0.1% FA) to give 2-(7-methyl-2-(2-(1 -methyl- lH-pyrazol-4-yl)tetrahydro-2H-py ran -4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol Ex.25 (3.3 mg, 5.6%). LCMS (Agilent Base): m / z 471.2 [M+H]+.JHNMR(400 MHz, DMSO-d6) 8 11.06 (s, 1H), 8.97 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.66 (s, lH), 7.39 (s, 1H), 7.32 (d, J = 8.4 Hz,WSGR Docket No. 55754-728.6011H), 7.28 (s, 1H), 4.54 (d,J= 11.2 Hz, 1H), 4.11 (dd, J = 11.2, 4.4 Hz, 1H), 3.79 (s, 4H), 3.73 (t, J = 11.6 Hz, 1H), 3.55 -3.44 (m, 1H), 2.81 (s, 3H), 2.08 (d, J= 13.2 Hz, 1H), 1.99 - 1.88 (m, 2H).

[0161] Example 26 - 2-(2-(2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenolStep 1: 6-(2-methoxypyridin-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate A solution of 2-methoxyisonicotinaldehyde (1 g, 7.30 mmol) and but-3-yn-l-ol (766.5 mg, 10.95 mmol) in DCM (18 mL) which purged with Ar2was added drop wise TfOH (0.78 mL, 8.76 mmol) at 0 °C. After addition, the mixture was stirred at 25°C for 5h and then TfOH (0.78 mL, 8.759 mmol) was added dropwise stirred at 0°C. The resulting mixture was stirred at 25°C for 16h. The reaction was quenched with a saturated aqueous NaHCO3(50 mL) solution and the mixture extracted with DCM (60 mLx 3). The combined organic layers were washed with brine (50 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 80 / 20) to give 6-(2-methoxypyridin-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (800 mg, 32.4%). LCMS (Agilent Acid): m / z 340.1 [M+H]+. Step 2: 2-methoxy-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)pyridineTo a solution of 6-(2-methoxypyridin-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (300 mg, 0.89 mmol) in dioxane (3 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (337 mg, 1.33 mmol), KO Ac (347 m g, 3.54 mmol) and Pd(dppf)Cl2.DCM (72.3 mg, 0.09 mmol) at 25°C. The reaction mixture was stirred at 90°C for 4hrs. The reaction was quenched with a saturated aqueous water (20 mL) solution and the mixture extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 80 / 20) to give 2-methoxy-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-WSGR Docket No. 55754-728.601dihydro-2H-pyran-2-yl)pyridine(200 mg, 71.5%) as a yellow oil. LCMS (Agilent Acid): m / z 318.2 [M+H]+.Step 3 : 4-(2-(meth oxymeth oxy)-4-(trifluoromethyl)phenyl)-2-(6-(2-methoxypyridin-4-yl)-3, 6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridineTo a mixture of 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6, 7 -dimethylpteridine (113 mg, 1.136 mmol) and 2-methoxy-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)pyridine (180 mg, 0.568 mmol) in dioxane (3 mL) and water (0.6 mL) were added Cs2CO3(272 m g, 1.704 mmol) and Pd(dppf)C14» DCM(35.1 mg, 0.085 mmol) at25°C. The reaction mixture was stirred at 100°C for Ihrs in a microwave reactor. The reaction was quenched with a saturated aqueous water (10 mL) solution and the mixture extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 50 / 50) to give 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2-(6-(2-methoxypyridin-4-yl)-3,6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridine (108 mg, 34.5%) as a yellow oil. LCMS (Agilent Acid): m / z 554.3 [M+H]+.Step 4: 2-(2-(6-(2-methoxypyridin-4-yl)-3,6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-2-(6-(2-methoxypyridin-4-yl)-3,6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridine (200 mg, 0.362 mmol) in DCM (10 mL) was added TFA (3.0 mL) at 0°C. The reaction mixture was stirred at RT for 20 mins. The reaction was filtered through a plug of celite and evaporated under reduced pressure to give 2-(2-(6-(2-methoxypyridin-4-yl)-3,6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (105 mg) as a yellow solid, which was used in the next step without further purification. LCMS (Agilent Acid): m / z 510.2 [M+H]+.Step 5: 2-(2-(2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethyl-5, 6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 2-(2-(6-(2-methoxypyridin-4-yl)-3,6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (lOOmg, 0.196 mmol)in MeOH (10 mL) was added PtO2(34 mg, 0.137 mmol) at25°C. The suspension was degassed and purged with H2for 3 times. The mixture was stirred under H2(15 psi) at 25°C for 16hrs. The reaction mixture was filtered under reduced pressure to filter out PtO2to give 2-(2-(2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethyl-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (130 mg) as a yellow oil, which was used in the next step without further purification. LCMS (Agilent Acid): m / z 516.2 [M+H]+.Step 6: 2-(2-(2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-WSGR Docket No. 55754-728.601(trifluoromethyl)phenol Ex. 26To a solution of give 2-(2-(2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethyl- 5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (130 mg, 0.253 mmol) in DCE (5 mL) was added MnO2(1.32 g, 15.146 mmol). The reaction mixture was stirred atRT for 6h. The reaction filtered under reduced pressure to filter out MnO2. The residue was purified by MPLC (Biotage Airs Science C18-M column elutingwith 0% to 70% MeCN / H2O, 0.1% FA) to give 2-(2-(2-(2-methoxypyridin-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 26 (35.3 mg, 27.4%). LCMS (Agilent Base): m / z 512.2 [M+H]+.JH NMR (400 MHz, DMSO-d6) 68.11 (d, J = 5.3 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.8 Hz, 2H), 7.01 (dd, J = 5.2, 1.6 Hz, 1H), 6.80 (s, 1H), 4.62 (dd, J = 11.2, 2.0 Hz, 1H), 4.28 - 4.20 (m, 1H), 3.83 (s, 3H), 3.78 (td,J = 11.6, 2.0 Hz, 1H), 3.59-3.51 (m, 1H), 2.76 (s, 3H), 2.66 (s, 3H), 2.41-2.37 (m, 1H), 2.16 - 2.09 (m, 1H), 1.97-1.90 (m, 1H), 1.73 (q, J = 12.0 Hz, 1H).

[0162] Example 27 - 2-(6,7-dimethyl-2-((2S,4R)-2-(2-methyl-2H- 1,2,3 -triazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol and Example 28 - 2-(6,7-dimethyl-2-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolStep 1: (E)-2-methyl-4-styryl-2H-l,2,3-triazoleTo a solution of 4-bromo-2-methyl-2H-l,2,3-triazole (10.7 g, 66.05 mmol) in dry dioxane (86 mL) and H2O (22 mL) were added (E)-styrylboronic acid (11.73g, 79.26 mmol), Cs2CC>3(43.04 g, 132.1mmol) and Pd(dppf)Cl2(1.21g, 1.65 mmol) at rt. The mixture was heated at 80 °C for overnight. The mixture was filtered through filter paper and washed with EtOAc three times. The mixture was extracted with EtOAc (100 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by C.CWSGR Docket No. 55754-728.601(PE / EtOAc= 93% / 7%) to give (E)-2-methyl-4-styryl-2H-l, 2, 3 -triazole (11.4 g, 93%) as a white solid. LCMS (Agilent Acid): tR = 2.062 min, m / z 186.1 [M+H]+.Step 2: 2-methyl-2H-l,2,3-triazole-4-carbaldehydeTo a solution of (E)-2-methyl-4-styryl-2H- 1,2, 3 -triazole (10.4 g, 56.22 mmol) in THF (300 mL) and H2O (30 mL) were added NaIO4(48.1 g, 224.86mmol) and K2OsO4-2H2O (2.07g, 5.622mmol) at rt. The resulting mixture was stirred for 2 h at rt. The mixture was filtered through celite and extracted with DCM (100 mL x 3). The combine organic phases were washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum(20 °C). The residue was purified by C.C (PE / THF=90% / 10%) to give 2-methyl-2H-l,2,3-triazole-4-carbaldehyde (7.83 g (contain DCM)) as a yellow oil. LCMS (Agilent Acid): tR = 1.710 min, m / z 112.1 [M+H]+.Step 3: 6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate To a solution of 2-methyl-2H-l,2,3-triazole-4-carbaldehyde (2 g, 18.02 mmol) in DCM (20 mL) was added but-3-yn-l-ol (1.89g, 2.14mL,27.03mmol) atRT. Then TfOH (1.99mL, 3.24g, 21.62mmol) was added at 0 °C. The resulting mixture was stirred for 4 h at rt. Then TfOH (1.99mL, 3.24g, 21.62mmol) was added at 0 °C. The resulting mixture was stirred for overnight at rt. The mixture was quenched with NaHCOs solution and extracted with DCM (100 mL x 3). The combine organic phases were washed with brine, dried over anhydrous Na2SO4and concentrated under vacuum. The residue was purified by C.C(PE / THF= 80% / 20%) to give 6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (3.66 g, 64.9%) as a yellow oil. LCMS (Agilent Acid): tR = 2.026 min, m / z 314.0 [M+H]+.Step 4: 2-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-2H-1, 2, 3 -triazoleTo a solution of 6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (3.16 g, 10.09 mmol) in dry dioxane (30 mL) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (3.85g, 15.14 mmol), KOAc (3.96 g, 40.38mmol) andPd(dppf)Cl2DCM(824mg, 1.009 mmol) atrt. The mixture was heated at 90 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with EA (100 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum. The residue was purified by C.C (PE / THF= 70% / 30%) to give 2-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-2H-l,2,3-triazole (3 g, 90%) as a yellow oil. LCMS (Agilent Acid): tR = 1.971 min, m / z 292.1 [M+H]+.Step 5 : 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(2-methyl-2H-l ,2,3 -triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridineTo 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dim ethylpteridine (300 mg, 0.754mmol) in dry dioxane (6 mL) and H2O(1.2 mL) was added 2-methyl-4-(4-(4, 4,5,5-WSGR Docket No. 55754-728.601tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-2H-l,2,3-triazole (439g, 1.51 mmol), CS2CO3(737 g, 2.26mmol) andPd(dppf)Cl2DCM (92g, 0.11 mmol) at rt. The mixture was heated at 100 °C for 1 h under microwave reactor. The mixture was diluted with water (5 mL) and extracted with EA (50 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum and purified by c.c (PE / THF= 40% / 60%) to give 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (400 mg, 90%) as a purple solid. LCMS (Agilent Acid): tR= 2.181 min, m / z 528.1 [M+H]+.Step 6: 2-(6,7-dimethyl-2-(6-(2-methyl-2H- 1,2,3 -triazol-4-yl)-3, 6-dihy dro-2H-pyran-4-y l)pteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(2 -methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (380 mg, 0.720 mmol) was dissolved in dry DCM (10 mL) was added TFA (2 mL) atrt. The reaction mixture was stirred to rt for 0.5 hour. The mixture was concentrated to remove DCM. The pH of the resulting mixture was adjusted to 8 with saturated NaHCO3solution, extracted with DCM(20 mL x 3), dried over anhydrous Na2SO4and concentrated under vacuum and purified by c.c (PE / THF= 50% / 50%) to give 2-(6,7-dimethyl-2-(6-(2-methyl-2H-l, 2,3 -triazol-4-yl)-3, 6-dihy dro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (250 mg, 71.8%) as a yellow solid. LCMS (Agilent Acid): tR= 2.190 min, m / z 484.2 [M+H]+.Step 7: 2-(6,7-dimethyl-2-(2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 2-(6,7-dimethyl-2-(6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (240 mg, 0.497 mmol) in EtOH(15 mL) was added PtO2(85 mg, 0.348mmol). The mixture was evacuated and backfilled with hydrogen three times and then charged with hydrogen. The resulting mixture was stirred for 16 h at RT, then was filtered through celite and concentrated under vacuum to give 2-(6,7-dimethyl-2-(2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (257 mg, 90%) as a green oil. LCMS (Agilent Acid): tR= 2.143 min, m / z 490.3 [M+H]+.Step 8: 2-(6,7-dimethyl-2-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 28; 2-(6,7-dimethyl-2-((2S,4R)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 27; To a solution of 2-(6,7-dimethyl-2-(2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (257 mg, 0.526 mmol) in DCE (3 mL) was added MnO2(914 mg, 10.5 Immol). The resulting mixture was stirred for 16 h at RT. The mixture was filtered through celite and concentrated under vacuum. The residue was purified byWSGR Docket No. 55754-728.601MPLC(H2O(FA) / ACN= 50% / 50%) and purified by prep-HPLC (GILSON-281, Pntulips BP-C18, 10 pm, 21.2 x 250 mm, eluting with a gradient of ACN in water with 0.2% Formic acid, at a flow rate of 25.0 mL / min, 40%-50% ACN over 18 min) and SFC(135mg / 65mLMeOH / CH3CN(l / l),7M NH30.5mL, 45% CH3OH, 45g / min, 4.5mL, AD (30*250mm, 10pm)) to give 2-(6,7-dimethyl-2-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (54.5 mg, 40%) as the first eluting compound (LCMS (Agilent Acid): tR = 2.225 min, m / z 486.2 [M+H]+. !HNMR(400 MHz, DMSO-d6) 6 11.35 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.33 (d, J = 8.1 Hz, lH), 7.29 (s, 1H), 4.75 (dd, J= 11.4, 1.8 Hz, 1H), 4.19 - 4.08 (m, 4H), 3.79 (t, J= 11.0 Hz, 1H), 3.54 (ddd, J= 12.1, 8.4, 3.7 Hz, 1H), 2.78 (s, 3H), 2.68 (s, 3H), 2.38 (d, J= 13.1 Hz, 1H), 2.17 - 2.01 (m, 2H), 1.93 (ddd, J = 25.1, 12.5, 4.5 Hz, 1H).) and 2-(6,7-dimethyl-2-((2S,4R)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (54.8 mg, 40%) (LCMS (Agilent Acid): tR =2.225 min, m / z 486.2 [M+H]+.JH NMR (400 MHz, DMSO-d6) 611.34 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.72 (s, 1H), 7.33 (d, J = 8.2 Hz, lH), 7.29 (s, 1H), 4.75 (dd, J = 11.4, 1.8 Hz, 1H), 4.19 - 4.07 (m, 4H), 3.79 (t, J = 11.0 Hz, 1H), 3.54 (ddd, J= 12.0, 8.5, 3.7Hz, 1H), 2.78(s, 3H), 2.68(s, 3H), 2.38 (d, J= 13.1 Hz, 1H), 2.16 - 2.02 (m, 2H), 1.93 (ddd, J = 25.1, 12.6, 4.6 Hz, 1H).)

[0163] Example 29 - 2-(2-((2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol and Example 30 - 2-(2-((2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5- (trifluoromethyl)phenolStep 1: 6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate To a solution of l-cyclopropyl-lH-pyrazole-4-carbaldehyde (4.5 g, 33.1 mmol) in DCM (68 mL) were added but-3-yn-l-ol (3.5 g, 49.7 mmol) and TfOH (3.5 mL, 39.7 mmol) at 0 °C and the mixture was stirred atRT for 16 h. The reaction was quenched with a saturated aqueous NaHCO3to pH= 8 and the mixture extracted with DCM (80 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THFWSGR Docket No. 55754-728.601= 80 / 20) to give 6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (4.3 g, 38%) as a yellow oil. LCMS (Agilent Acid): m / z 339.1 [M+H]+. Step 2: l-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazoleTo a solution of 6-(l -cyclopropyl- lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (4.3 g, 12.7 mmol) in dioxane (86 mL) were added 4,4,4',4',5,5,5',5' -octamethyl-2,2'-bi(l,3,2-dioxaborolane) (4.8 g, 19.1 mmol), Pd(dppf)Cl2.DCM(l g, 1.2 mmol) and KO Ac (5 g, 50.8 mmol) and the mixture was stirred at 90 °C for 2 h. The mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 70 / 30) to give l-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (3.9 g, 97%) as a yellow oil. LCMS (Agilent Acid): m / z 317.2 [M+H]+.Step 3: 2-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpteridineTo a solution of 2-chloro-4-(2-(m ethoxymeth oxy)-4-(trifluoromethyl)phenyl)-6, 7-dimethylpteridine (400 mg, 1.0 mmol) in dioxane (15 mL) and water (3 mL) were added 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-lH-pyrazole (476 mg, 1.5 mmol) andPd(dppf)Cl2.DCM (123 mg, 0.1 eq) and the mixture was stirred at 100 °C for 1 h with microwave. The mixture was diluted with water (20 mL), extracted with EtOAc (20 mL x 2) and the combined organic layers washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 50 / 50) to give 2-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpteridine (620 mg, 89%) as a yellow solid. LCMS (Agilent Acid): m / z 553.2 [M+H]+.Step 4: 2-(2-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 2-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpteridine (600 mg) in DCM (2 mL) was added TFA (0.4 mL) and the mixture was stirred atRT for 1 h. The mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 20 / 80) to give 2-(2-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (230 mg, 38%) as a brown solid. LCMS (Agilent Acid): m / z 509.2 [M+H]+.Step 5: 2-(2-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethyl-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601To a solution of 2-(2-(6-(l-cyclopropyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (230 mg, 0.4 mmol) in EtOH (8 mL) were added PtO2.H2O (77 mg, 0.3 mmol) and the mixture was stirred at RT for 2 h under H2atmosphere. The mixture was filtered through Celite and the filtrate concentrated under vacuum to give 2-(2-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethyl-5,6,7,8-tetrahydropteri din-4-yl)-5-(trifluoromethyl)phenol (220 mg, 95%) as a brown solid. LCMS (Agilent Acid): m / z 515.2 [M+H]+.Step 6: 2-(2-((2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 30To a solution of 2-(2-(2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethyl-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (220 mg, 0.4 mmol) in DCE (40 mL) were added Mn02 (743 mg, 8.5 mmol) and the mixture was stirred atRT for 2 h. The mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by MPLC (FA, 0 to 70% ACN / water) to give the racemic product (120 mg, 54%) as a yellow solid. LCMS (Agilent Acid): m / z 511.2 [M+H]+. This racemate (120 mg) was purified by prep-SFC (separation condition: Column: OJ Daicel chemical Industries, Ltd, 250 x 30mm I D., lOum; Mobile phase A:Supercritical CO2, Mobile phase B: CH3OH (0.4% 7MNH3in CH3OH), A:B = 80:20 at45mL / min; Column Temp: 35 °C; BackPressure: lOOBar; Wavelength: 214 nm) to give 2-(2-((2R,4S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (35.2 mg, 29%). LCMS (Agilent Base): m / z 511.2 [M+H] .'H NMR (400 MHz, Methanol-d4) 69.14 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.52 - 7.49 (m, 1H), 7.28 (d, J = 7.6 Hz, 2H), 4.65 -4.62 (m, 1H), 4.25 - 4.21 (m, 1H),3.89 - 3.83 (m, 1H), 3.66 - 3.58 (m, 1H), 3.57 -3.51 (m, 1H), 2.85 (s, 3H), 2.83 (s, 3H), 2.46 - 2.38 (m, 1H), 2.21 - 2.03 (m, 3H), 1.08 - 0.99 (m, 4H). And 2-(2-((2S,4R)-2-(l-cyclopropyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (6.5 mg) LCMS (Agilent Base): m / z 511.2 [M+H]+.

[0164] Example 31 - 2-(6,7-Dimethyl-2-((2S,6S)-2-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholino) pteridin-4-yl)-5-(trifluoromethyl)phenol and Example 32 - 2-(6,7-dimethyl-2-((2R,6R)-2-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholino)pteridin-4-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601Step 1: 2-Chloro-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-oneTo a solution of 4-bromo-2-methyl-2H-l,2,3-triazole (60 g, 370 mmol) in dry THF (300 mL) at -78 °C under aN2atmosphere was added n-BuLi (1.6 M in hexane, 347 mL, 555.5 mmol) dropwise over 2.5 h and the mixture was stirred at -78 °C for 1 h. A solution of 2-chloro-N-methoxy-N-methylacetamide (76.3 g, 555.5 mmol) in dry THF (300 mL) was then added dropwise and the mixture was stirred at -78 °C for a further 1 h. The reaction was quenched with a saturated aqueous NH4C1 (600 mL) solution and the mixture extracted with EtOAc (800 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 80 / 20) then triturated with Pet. ether / EtOAc = 10 / 1 to give 2-Chloro-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (20 g, 34%) as a yellow solid. LCMS (Agilent Acid): m / z 160.1 [M+H]+.Step 2: 2-(Benzyl(2-hydroxypropyl)amino)-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one To a solution of 2-chloro-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (20 g, 127.2 mmol) in acetone (200 mL) were added 1 -(benzylamino )propan-2-ol (21 g, 127.2 mmol), KI (21.1 g, 127.2 mmol) and K2CO3(52.7 g, 127.2 mmol) and the mixture was stirred atRT for 2 h. The mixture was filtered and the filtrate diluted with water (100 mL), extracted with EtOAc (100 mL x 3) and the combined organic layers washed with brine (100 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 75 / 25) to give 2-(Benzyl(2-hydroxypropyl)amino)-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (22.1 g, 60%) as a yellow oil. LCMS (Agilent Acid): m / z 289.2 [M+H]+.Step 3: l-(Benzyl(2 -hydroxy -2-(2-methyl-2H- 1,2, 3 -triazol-4-yl)ethyl)amino)propan-2-ol To a solution of 2-(benzyl(2-hydroxypropyl)amino)-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (19.1 g, 65.9 mmol) in MeOH (200 mL) at 0°C was added NaBH4(5.01 g, 131.9 mmol) portion wise and the mixture was stirred at RT for 1 h. The reaction was quenched with water (100 mL) and the mixture extracted with EtOAc (150 mL x 3). The combined organic layers were washedWSGR Docket No. 55754-728.601with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum to give 1-(Benzyl(2 -hydroxy -2-(2-methyl-2H-l, 2, 3-triazol-4-yl)ethyl)amino)propan-2-ol (19.8 g) as a yellow oil, which was used in the next step without further purification. LCMS (Agilent Acid): m / z 291.2 [M+H]+.Step 4: (cis)-4-Benzyl-2-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholineTo a solution of l-(Benzyl(2-hydroxy-2-(2-methyl-2H-l,2,3-triazol-4-yl)ethyl)amino)propan-2-ol (18.8 g, 64.8 mmol) in dry toluene (190 mL) was added CMBP (31.3 g, 129.6 mmol) and the mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was diluted with water (100 mL), extracted with EtOAc (150 mL x 3) and the combined organic layers washed with brine (200 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by MPLC (Biotage Airs Science C18-M column eluting with 0% to 50% MeCN / H2O, 0.1% NH4HCO3) to give (cis)-4-Benzyl-2-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholine (6 g, 35%) as a yellow oil as the first eluting compound. LCMS (Agilent Base): m / z 273.2 [M+H]+. iff NMR (400 MHz, DMSO-d6) 87.64 (s, 1H), 7.37 - 7.30 (m, 4H), 7.29- 7.21 (m, 1H), 4.66 (dd, J = 10.8, 2.4 Hz, 1H), 4.08 (s, 3H), 3.79-3.71 (m, 1H), 3.56 - 3.47 (m, 2H), 2.85 (dt, J= 11.2, 2.0 Hz, lH), 2.77 (dt, J= 11.2, 2.0 Hz, 1H), 2.11 (t, J= 10.8 Hz, 1H), 1.81 (dd, J = 11.2, 10.0 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H).Step 5: (2R,6R)-2-Methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholine and (2S,6S)-2-Methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholineTo a solution of (cis)-4-Benzyl-2-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholine (6 g, 22 mmol) in EtOH (60 mL) and water (60 mL) was added a 2 M aqueous HC1 solution (33 mL, 66 mmol) and 20% Pd(OH)2 / C (1.2 g) and the mixture was stirred for 8 h at RT under H2atmosphere (1 atm). The mixture was filtered through Celite and the filtrate concentrated under vacuum. The residue (4.7 g, HC1 salt) was diluted with ACN (60 mL) and treated with NH3(7 M solution in MeOH, 20 mL), then filtered. The filtrate was concentrated under vacuum and the residue (3.2 g, free base) was purified by prep-SFC (separation condition: Column: AD Daicel chemical Industries, Ltd, 250 x 30mm I.D., lOum; Mobile phase A: Supercritical CO2, Mobile phase B: CH3OH (0.4% 7MNH3in CH3OH), A:B = 80:20 at45mL / min; Column Temp: 35 °C; Back Pressure: lOOBar; Wavelength: 214 nm) to give (2R,6R)-2-Methyl-6-(2-methyl-2H- 1,2,3 -triazol-4-yl)morpholine (850 mg, 21%) as a colorless oil as the first eluting compound. LCMS (Agilent Base): m / z 183.2 [M+H] .'H NMR (400 MHz, DMSO-d6+ 1 drop cone. HC1) 6 10.2 - 9.97 (m, 1H), 9.97 - 9.73 (m, 1H), 7.81 (s, 1H), 5.06 (dd, J= 11.4, 2.4 Hz, 1H), 4.15 -4.06 (m, 4H), 3.37 (d, J = 12.6 Hz, 1H), 3.25 (d, J = 12.5 Hz, 1H), 3.17- 3.00 (m, 1H), 2.77 - 2.60 (m, 1H), 1.13 (d, J = 6.3 Hz, 3H). Further elution gave (2S,6S)-2-Methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholine (1.3 g, 33%) as a white solid as the second eluting compound. LCMS (Agilent Base): m / z 183.2WSGR Docket No. 55754-728.601[M+H]+. 'HNMR (400 MHz, DMSO-d6+ 1 drop cone. HC1) 610.2 - 10.1 (m, 1H), 9.97- 9.87 (m, 1H), 7.80 (s, 1H), 5.06 (dd, J = 11.3, 2.4 Hz, 1H), 4.15 - 4.05 (m, 4H), 3.34 (d, J = 12.4 Hz, 1H), 3.23 (d, J = 12.6 Hz, 1H), 3.16 - 3.00 (m, 1H), 2.73 - 2.60 (m, 1H), 1.12 (d, J = 6.3 Hz, 3H). Step 6: 2-(6,7-Dimethyl-2-((2S,6S)-2-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholino) pteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 2-(2-chloro-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (2.3 g, 6.6 mmol) in DMSO (20 mL) was added DIEA (2.56 g, 19.8 mmol) and (2S,6S)-2-Methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholine (1.2 g, 6.6 mmol) and the mixture was heated at 100 °C for 2 h. After cooling to RT, the mixture was diluted with water (50 mL), extracted with EtOAc (50 mL x 3) and the combined organic layers washed with brine (100 mL), dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by MPLC (Biotage Airs Science C18-M column, eluting with 0% to 50% MeCN / H2O 0.1% Formic acid) to give 2-(6,7-Dimethyl-2-((2S,6S)-2-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholino) pteridin-4-yl)-5-(trifluoromethyl)phenol (1.35 g, 41%). LCMS (Agilent Acid): m / z 501.2 [M+HJ+OH NMR (400 MHz, DMSO-d6) 6 10.8 (brs, 1H), 7.78 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.30 - 7.22 (m, 2H), 5.00 -4.85 (m, 1H), 4.79- 4.76 (m, 2H), 4.15 (s, 3H), 3.91 -3.80(m, 1H), 3.18 (dd, J = 13.2, 11.2 Hz, 1H), 2.84 (dd, J = 13.2, 10.8 Hz, 1H), 2.64 (s, 3H), 2.51 (s, 3H), 1.25 (d, J =6.0 Hz, 3H).Step 7: 2-(6,7-Dimethyl-2-((2R,6R)-2-methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholino) pteridin-4-yl)-5-(trifluoromethyl)phenol An identical procedure to step 6 was carried out using the enantiomer morpholine (2R,6R)-2-Methyl-6-(2-methyl-2H-l,2,3-triazol-4-yl)morpholineto prepare Example 32 (32 mg). LCMS (Agilent Acid): m / z 501.2 [M+H]+.

[0165] Example 33 - 2-(6,7-Dimethyl-2-((2R,4S)-2-(l -methyl- 1 H-pyrazol-4-yl)tetrahy dro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolStep 1: 6-(l-Methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulf onate. To a mixture of 1 -methyl- lH-pyrazole-4-carb aldehyde (20 g, 182 mmol) and but-3-yn-l-ol (19 g, 273 mmol) in DCM (400 mL) at 0 °C was added TfOH (32.7 g, 218 mmol) dropwise and theWSGR Docket No. 55754-728.601mixture was stirred at 25 °C for 1 h. The mixture was re-cooled to 0 °C, additional TfOH (32.7 g, 218 mmol) was added dropwise and the mixture allowed to warm to RT and stirred for a further 8 h. The mixture was adjusted to pH 7-8 with a saturated aqueous NaHCO3solution and extracted withDCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried overNa2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (25% THF / Pet. ether) to give the title compound (24.5 g, 43%) as a yellow oil. LCMS: m / z 313.1 [M+H]+.Step 2: l-Methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-IH-pyrazoleTo a solution of 6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (23 g, 73.7 mmol) in dioxane (230 mL) was added B2pin2(27.9 g, 111 mmol), Pd(dppf)Cl2(6.0 g, 7.3 mmol) and KOAc (17 g, 221 mol) and the mixture was heated at 90 °C under N2for 2 h. The mixture was filtered and the filtrate concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 40% THF / Pet. ether) to give the title compound (12 g, 53%) as a yellow oil. LCMS: m / z 291.2 [M+H]+.Step 3: 4-(2-(Methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridineTo a solution of 6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (38.2 g, 132 mmol) in dioxane (100 mL) and water (20 mL) were added 2-chloro-4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethylpteridine (35 g, 87.8 mmol), Pd(dppf)Cl2.DCM (10.7 g, 13.2 mmol) and Cs2CO3(85.5 g, 263.4 mmol) and the mixture was heated at 100 °C under a N2atmosphere for 4 h. The mixture was diluted with water (100 mL), extracted with EtOAc (100 mL x 3) and the combined organic phases washed with brine (100 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 55% THF / Pet. ether) to give 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (39 g, 84%) as a red solid. LCMS: m / z 527.2 [M+H]+.Step 4: 2-(6,7-Dimethyl-2-(6-(l-methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 4-(2-(methoxymethoxy)-4-(trifluoromethyl)phenyl)-6,7-dimethyl-2-(6-(l -methyl-lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridine (39 g, 74.1 mmol) in DCM (210 mL) was added TFA (58 mL) and the mixture was stirred atRT for 0.5 h. The mixture was adjusted to pH 8 with a saturated aqueous NaHCO3solution and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (0 to 60% THF / Pet. ether) toWSGR Docket No. 55754-728.601give 2-(6,7-Dimethyl-2-(6-(l -methyl- lH-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (25 g, 69%) as a yellow solid. LCMS: m / z 483.2 [M+H]+.Step 5: (+)-2-(6,7-Dimethyl-2-((2R,4S)-2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenolTo a solution of 2-(6,7-Dimethyl-2-(6-(l -methyl- lH-pyrazol-4-y l)-3, 6-dihydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (25 g, 53 ,8mmol) in EtOH (250 mL) was added PtO2X-H2O (12.2 g, 53.8 mmol) and the mixture was stirred atRT under a H2atmosphere (1 atm) for 2 h. The mixture was filtered through Celite and the filtrate concentrated under vacuum to give (+)-2-(6,7-Dimethyl-2-((2R,4S)-2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (24 g) as a yellow solid, which was used in the next step without further purification. LCMS: m / z 489.2 [M+H]+.Step 6: 2-(6,7-Dimethyl-2-((2R,4S)-2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 33To a solution of (+)-2-(6,7-Dimethyl-2-((2R,4S)-2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropteridin-4-yl)-5-(trifluoromethyl)phenol (24 g) in DCE (240 mL) was added MnO2(85.5 g, 984 mmol) and the mixture was stirred atRT for 1 h. Additional MnO2(85.5 g, 984 mmol) was added and stirring was continued atRT for 1 h. The mixture was filtered through Celite and the filtrate concentrated under vacuum. The residue was purified by MPLC (Biotage Airs Science C18-M column, eluting with 0% to 45% MeCN / H2O with 0.1% Formic acid), followed by further purification by chiral prep-SFC (Column: AD Daicel chemical Industries, Ltd, 250 x 30 mm I.D., lOum; Mobile phase A: Supercritical CO2, Mobile phase B: 40% (90%CH3OH (0.4% 7M NH3)+10%MeCN), 45g / min, 2.0mL; Column Temp: 35 °C; BackPressure: 100 Bar; Wavelength: 214 nm)to give 2-(6,7-Dimethyl-2-((2R,4S)-2-(l-methyl-lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol Ex. 33 (5.03 g, second eluting compound). LCMS: m / z 485.2 [M+H]+ 1HNMR(400 MHz, DMSO-d6) 6 11.5 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.65 (s, 1H), 7.38 (s, 1H), 7.35 - 7.25 (m, 2H), 4.53 (dd, J = 11.2, 2.0 Hz, 1H), 4.16 - 4.06 (m, 1H), 3.79 (s, 3H), 3.75 -3.68 (m, 1H), 3.49 - 3.43 (m, 1H), 2.77 (s, 3H), 2.67 (s, 3H), 2.33 - 2.28 (m, 1H), 2.11 - 2.02 (m, 1H), 1.97 - 1.86 (m, 2H).

[0166] Example 34 - 2-(6,7-dimethyl-2-((4R,8aR)-4-(2-methyl-2H-l,2,3-triazol-4-yl)hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601Step 1: 2-chloro-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-oneTo solution of 4-bromo-2-methyl-2H-l, 2, 3 -triazole (10 g, 61.728 mmol) in THF (30 mL) was added dropwise n-BuLi (1.6 M in hexane, 57.9 mL, 92.593 mmol) at -78 °C After addition, the mixture was stirred at for Ih and then 2-chloro-N-methoxy-N-methylacetamide (12.74 g, 92.593 mmol) in THF (20 mL) was added dropwise stirred at -78°C. The resulting mixture was stirred at -78°C for Ih. The reaction was quenched with a saturated aqueous NH4C1 (80 mL) solution and the mixture extracted with EtOAc (80 mLx 3). The combined organic layers were washed with brine (50 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 70 / 30) to give 2-chloro-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (3.8 g, 39%). LCMS (Agilent Acid): m / z 160.1 [M+H]+.Step 2: tert-butyl 2-(((4-methoxybenzyl)amino)methyl)pyrrolidine-l -carboxylateTo a solution of tert-butyl 2-(aminomethyl)pyrrolidine-l -carboxylate (3 g, 14.98 mmol) in THF (30 mL) was added 4-methoxybenzaldehyde (3.06 g, 22.47 mmol) and MgSO4(0.9 g, 7.49 mmol) at 0°C, the reaction mixture was stirred at 25°C for 4hrs. The reaction mixture was concentrated and add EtOH (30 mL) and NaBH4(198 mg, 5.24 mmol) at 0°C. The reaction mixture was stirred at 25 °C for overnight. The reaction was added H2O and concentrated undervacuum. The residue was purified by silica gel chromatography (Pet. ether / THF / DCM = 50 / 25 / 25) to give tert-butyl 2-(((4-methoxybenzyl)amino)methyl)pyrrolidine-l-carboxylate (2.3 g, 36%) as a yellow oil. LCMS (Agilent Acid): m / z 231.3 [M+H]+.Step 3: tert-butyl 2-(((4-methoxybenzyl)(2-(2-methyl-2H- 1,2,3 -triazol-4-yl)-2-oxoethyl)amino)methyl)pyrrolidine-l -carboxylateTo a solution of tert-butyl 2-(((4-methoxybenzyl)amino)methyl)pyrrolidine-l -carboxylate in ACN (80 mL) at 25°C were added 2-chloro-l-(2-methyl-2H-l,2,3-triazol-4-yl)ethan-l-one (994 mg, 6.25 mmol), K2CO3(2.59 g, 18.75 mmol), KI (1.04 g, 6.25 mmol). The mixture was stirred at RT for 1- Ill -WSGR Docket No. 55754-728.601h. The reaction was filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / EtOAc = 80 / 20)to give tert-butyl 2-(((4-methoxybenzyl)(2-(2-methyl-2H-1, 2, 3 -triazol-4-yl)-2-oxoethyl)amino)methyl)pyrrolidine-l -carboxylate (2.1 g, 75.8%) as a yellow oil. LCMS (Agilent Acid): m / z 444.3 [M+H]+.Step 4: 2-(4-methoxybenzyl)-4-(2-methyl-2H-l,2,3-triazol-4-yl)-2,3,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-5-iumTo a solution of tert-butyl 2-(((4-methoxybenzyl)(2-(2-methyl-2H-l,2,3-triazol-4-yl)-2-oxoethyl)amino)methyl)pyrrolidine-l -carboxylate (2 g, 4.515 mmol) in DCM (7.5 mL) was added TFA (5.0 mL) at 0°C. The reaction mixture was stirred atRT for 2hs. The reaction was filtered and concentrated under vacuum to give the title compound (1.4 g) as a yellow oil, which was used in the next step without further purification. LCMS (Agilent Acid): m / z 326.3 [M+H]+.Step 5: (4R,8aR)-2-(4-methoxybenzyl)-4-(2-methyl-2H-l,2,3-triazol-4-yl)octahydropyrrolo[l,2-a]pyrazineTo a solution of 2-(4-methoxybenzyl)-4-(2-methyl-2H-l,2,3-triazol-4-yl)-2,3,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-5-ium (1.4 g, 4.295 mmol) in DCE (10 mL) was added Na(OAc)BH3(481 mg, 12.883 mmol) atO°C. The reaction mixture was stirred at RT for 0.5h. The mixture was diluted with water (10 mL), extracted with DCM (15 mL x 3) and the combined organic layers washed with brine (20 mL), dried overNa2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Pet. ether / THF = 30 / 70) and MPLC (Ci8, water / ACN=50 / 50 with 0.1% HN4HCO3)to give (4R,8aR)-2-(4-methoxybenzyl)-4-(2-methyl-2H-l,2,3-triazol-4-yl)octahydropyrrolo[l,2-a]pyrazine (330 mg, 25%) as a yellow oil. LCMS (Agilent Base): m / z 328.3 [M+H]+.Step 6: (4R,8aR)-4-(2-methyl-2H-l,2,3-triazol-4-yl)octahydropyrrolo[l,2-a]pyrazineA mixture of (4R,8aR)-2-(4-methoxybenzyl)-4-(2-methyl-2H-l,2,3-triazol-4-yl)octahydropyrrolo[l,2-a]pyrazine (300mg, 0.917 mmol) andHCl (2N, 1.38 mL)in EtOH (5 mL) and H2O (5 mL) were added Pd(OH)2(60 mg) atRT. The mixture was stirred at RT for 12hrs. The reaction filtered under reduce pressure to filter out Pd(OH)2and concentrated under reduced pressure to give (4R,8aR)-4-(2-methyl-2H-l,2,3-triazol-4-yl)octahydropyrrolo[l,2-a]pyrazine (300 mg) as a yellow oil, which was used in the next step without further purification. LCMS (Agilent Acid): m / z 208.2 [M+H]+.Step 7: 2-(6,7-dimethyl-2-((4R,8aR)-4-(2-methyl-2H-l,2,3-triazol-4-yl)hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolA mixture of (4R,8aR)-4-(2-methyl-2H-l,2,3-triazol-4-yl)octahydropyrrolo[l,2-a]pyrazine (17.4 mg, 0.085 mmol), 2-(2-chloro-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (30 mg, 0.085 mmol) and DIEA (0.105 mL, 0.593 mmol) in DMSO (1 mL). The mixture was stirred at 100°C forWSGR Docket No. 55754-728.6013hrs. The mixture was diluted with water (10 mL), extracted with EtOAc (15 mL x 3) and the combined organic layers was MPLC (Biotage Airs Science Cl 8-M column eluting with 0% to 50% MeCN / H2O, 0.1% FA) to give 2-(6,7-dimethyl-2-((4R,8aR)-4-(2-methyl-2H-l,2,3-triazol-4-yl)hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (25.9 mg, 44%). LCMS (Agilent Base): m / z 526.3 [M+H]+. 'HNMR (400 MHz, DMSO-d6) 6 11.00 (s, 1H), 7.70 (d, J = 42.3 Hz, 2H), 7.25 (s, 2H), 4.92 (d, J = 64.8 Hz, 2H), 4.13 (s, 3H), 3.45 (s, 1H), 3.13 (t, J = 11.9 Hz, 1H), 2.88 (dd, J = 12.6, 10.6 Hz, 1H), 2.84 - 2.75 (m, 1H), 2.63 (s, 3H), 2.51 (s, 3H), 2.19 (s, 1H), 2.00-1.97 (m, 2H), 1.71-1.68 (m, 2H), 1.48 (s, 1H).

[0167] Example 35 - 2-(6,7-dimethyl-2-((4S,8aR)-4-(l-methyl-lH-pyrazol-4-yl)hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolStep 1: 2-bromo-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-oneTo a solution of 1-(1 -methyl- lH-pyrazol-4-yl)ethan-l -one (5 g, 40.3 mmol) in DCM (40 mL) and EtOH (10 mL) was added PyHBr3(12.9 g, 40.3 mmol). Then the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched by the addition of water (30 mL) and extracted with DCM (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by trituration with PE to give 2-bromo-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-one (6 g, 74 % yield). LCMS (Agilent Acid): tR= 1.514 min, m / z 203.0 [M+H]+.Step 2: tert-butyl 2-((((benzyloxy)carbonyl)(2-(l-methyl-lH-pyrazol-4-yl)-2-oxoethyl)amino)methyl)pyrrolidine-l -carboxylateTo a mixture of 2-bromo-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-one (990 mg, 4.9 mmol) and TEA (550 mg, 5.4 mmol) in DCM (30 mL) was added 2-bromo-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-WSGR Docket No. 55754-728.601one (1.0 g, 4.9 mmol). Then the mixture was stirred at room temperature for 30 min. TEA (1.5 g, 14.8 mmol) was added, followed by CBz-Cl (757 mg, 4.5 mmol). The resulting mixture was stirred at rtfor 2 h. The mixture was quenched by the addition of water (30 mL) and extracted with DCM (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EA / PE (30%:70%) to give tert-butyl 2-((((benzyloxy)carbonyl)(2-(l-methyl-lH-pyrazol-4-yl)-2-oxoethyl)amino)methyl)pyrrolidine-l -carboxylate (500 mg, 22 % yield). LCMS (Agilent Acid): tR= 2.094 min, m / z 357.2 [M-100+H]+.Step 3: 2-((benzyloxy)carbonyl)-4-(l-methyl-lH-pyrazol-4-yl)-2,3,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-5-iumTo a solution of tert-butyl 2 -((((benzyloxy )carbonyl)(2-(l-methyl-lH-pyrazol-4-yl)-2-oxoethyl)amino)methyl)pyrrolidine-l-carboxylate (1 g, 2.2 mmol) in DCM (15 mL) was added TFA (10 mL). Then the mixture was stirred at RT for 3 h. After the reaction was completed, the mixture was concentrated under vacuum. The crude product 2-((benzyloxy)carbonyl)-4-(l-methyl-lH-pyrazol-4-yl)-2,3,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-5-ium was used directly in the next step. LCMS (Agilent Base): tR= 2.002 min, m / z 339.2 [M+H]+.Step 4: benzyl (4R,8aS)-4-(l-methyl-lH-pyrazol-4-yl)hexahydropyrrolo[l,2-a]pyrazine-2(lH)-carboxylateTo a solution of 2-((benzyloxy)carbonyl)-4-(l-methyl-lH-pyrazol-4-yl)-2,3,6,7,8,8a-hexahydro-lH-pyrrolo[l,2-a]pyrazin-5-ium (745 mg, 2.2 mmol) in DCE (5 mL) was added NaBH(OAc)3(1.4 g, 6.6 mmol) and AcOH (3 drops) at rt. The reaction mixture was stirred at RT for 0.5 h. The mixture was quenched by the addition of saturated NaHCO3(10 mL) and extracted with ethyl acetate (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with PE / THF (70%:30%)to give benzyl (4R,8aS)-4-(l-methyl-lH-pyrazol-4-yl)hexahydropyrrolo[l,2-a]pyrazine-2(lH)-carboxylate (460 mg, 61% yield) as a colorless oil. LCMS (Agilent Base): tR= 1.891 min, m / z 341.3 [M+H]+.Step 5: (4S,8aR)-4-(l-methyl-lH-pyrazol-4-yl)octahydropyrrolo[l,2-a]pyrazineTo a solution of benzyl (4R,8aS)-4-(l-methyl-lH-pyrazol-4-yl)hexahydropyrrolo[l,2-a]pyrazine-2(lH)-carboxylate (400 mg, 1.2 mmol) in MeOH (10 mL) were added 10% Pd / C (50 mg), and AcOH (one drop). The reaction mixture was stirred at rt under H2(balloon pressure) for 2 h. The Pd / C was removed by filtration. The filtrate was concentrated under vacuum to give (4S,8aR)-4-(l-methyl-lH-pyrazol-4-yl)octahydropyrrolo[l,2-a]pyrazine (220 mg, crude) as a colorless oil. LCMS (Agilent Acid): tR= 0.408 min, m / z 207.2 [M+H]+.WSGR Docket No. 55754-728.601Step 6: 2-(6,7-dimethyl-2-((4S,8aR)-4-(l-methyl-lH-pyrazol-4-yl)hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)pteridin-4-yl)-5-(trifluoromethyl)phenolA mixture of (4S,8aR)-4-(l-methyl-lH-pyrazol-4-yl)octahydropyrrolo[l,2-a]pyrazine(20 mg, 0.09 mmol), 2-(2-Chloro-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (35 mg, 0.09 mmol), DIEA (58 mg, 0.45 mmol) and DMSO (2 mL) was stirred at 100 °C for 2 h. The mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate (10 mL X 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Pre-HPLC (GILSON-281, Pntulips BP-CI8, 10 pm, 21.2 x 250 mm, eluting with a gradient of ACN in water with 0.2% Formic acid, at a flow rate of 25.0 mL / min 30%-65% ACN over 18 min) to give 2-(6,7-dimethyl-2-((4S,8aR)-4-(l-methyl-lH-pyrazol-4-yl)hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl)pteridin-4-yl)-5-(trifluoromethyl)phenol (24.6 mg, 52% yield). LCMS (Agilent Acid): tR= 1.752 min, m / z 492.2 [M+H]+. 1H NMR (400 MHz, Methanol-d4) 88.54 - 8.50 (m, 1H), 7.69 (s, 1H), 7.58 (s, 1H), 7.30 - 7.23 (m, 2H), 5.08 (s, 2H), 3.93 (s, 3H), 3.40 -3.35 (m, 1H), 3.19 (s, 1H), 2.99 (d, J= 11.6 Hz, 2H), 2.72 (s, 3H), 2.66 (s, 3H), 2.31 (s, 1H), 2.11 (d, J= 9.2 Hz, 2H), 1.81 (t, J=3.6 Hz, 2H), 1.65 (s, 1H).

[0168] Example 36 - (R)-2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pteridin-4-yl)-5-(trifluoromethyl)phenol and Example 37 - (S)-2-(6,7-dimethyl-2-(2-(1 -methyl- lH-pyrazol-4-yl)morpholino)pteridin-4-yl)-5-(trifluoromethyl)phenolStep 1: 2-bromo-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-oneTo a solution of 1-(1 -methyl- lH-pyrazol-4-yl)ethan-l -one (5 g, 40.3 mmol) in DCM (40 mL) and EtOH (10 mL) was added PyHBr3(12.9 g, 40.3 mmol). Then the mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was quenched by the addition of water (30 mL) and extracted with DCM (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by trituration with PE toWSGR Docket No. 55754-728.601give 2-bromo-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-one (6 g, 74 % yield) as a yellow solid. LCMS (ES-API): tR= 1.514 min, m / z 203.0 [M+H]+.Step 2: 2-(benzyl(2-hydroxyethyl)amino)-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-oneTo a solution of 2-bromo-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-one (2 g, 9.8 mmol) in THF (30 mL) was added DIEA (2.5 g, 19.6 mmol) and 2-(benzylamino)ethan-l-ol (1.6 g, 10.8 mmol). Then the mixture was stirred at room temperature overnight. The mixture was quenched by the addition of water (30 mL) and extracted with EtOAc (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EA / PE (50%:50%) to give 2-(benzyl(2-hydroxyethyl)amino)-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-one(l g, 37 % yield) as a colorless oil. LCMS (ES-API): tR= 1.353 min, m / z 274.2 [M+H]+.Step 3: 2-(benzyl(2-hydroxyethyl)amino)-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-olTo a solution of 2-(benzyl(2-hydroxyethyl)amino)-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-one (1 g, 3.6 mmol) in MeOH (20 mL) was added NaBH4(166 mg, 4.4 mmol). Then the mixture was stirred atRT for 1 h. The mixture was quenched by the addition of water (30 mL) and extracted with EtOAc (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EA / PE (50%:50%)to give 2-(benzyl(2-hydroxyethyl)amino)-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-ol (800 mg, 79 % yield) as a colorless oil. LCMS (ES-API): tR= 1.319 min, m / z 276.2 [M+H]+. Step 4: 4-benzyl-2-(l -methyl- lH-pyrazol-4-yl)morpholineTo a solution of 2-(benzyl(2-hydroxyethyl)amino)-l-(l-methyl-lH-pyrazol-4-yl)ethan-l-ol (700 mg, 2.5 mmol) in toluene (10 mL) was added CMBP (1.2 g, 5.1 mmol) at rt. The reaction mixture was stirred at 120 °C for 4 h. The mixture was quenched by the addition of water (30 mL) and extracted with EtOAc (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with EA / PE (20%:80%) to give 4-benzyl-2-(l-methyl-lH-pyrazol-4-yl)morpholine (450 mg, 69 % yield) as a colorless oil. LCMS (ES-API): tR= 1.366 min, m / z 258.2 [M+H]+. Step 5: 2-(l-methyl-lH-pyrazol-4-yl)morpholineTo a solution of 4-benzyl-2-(l-methyl-lH-pyrazol-4-yl)morpholine (800 mg, 3.1 mmol) in EtOH (10 mL) and H2O (10 mL) was added 10% Pd(OH)2 / C (160 mg) and 2N HC1 (one drop). The reaction mixture was stirred at rt under H2(balloon pressure) for 4 h. ThePd(OH)2 / C was removed by filtration. The filtrate was concentrated under vacuum to give 2-(l-methyl-lH-pyrazol-4-yl)morpholine (300 mg, crude) as a yellow oil. LCMS (ES-API): tR= 0.455 min, m / z 168.1 [M+H]+.Step 6: (S)-2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pteridin-4-yl)-5-WSGR Docket No. 55754-728.601(trifluoromethyl)phenol (Example 37) and (R)-2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pteridin-4-yl)-5-(trifluoromethyl)phenol (Example 36)A mixture of 2-(l-methyl-lH-pyrazol-4-yl)morpholine (40 mg, 0.24 mmol), 2-(2-Chloro-6,7-dimethylpteridin-4-yl)-5-(trifluoromethyl)phenol (85 mg, 0.24 mmol), DIEA (155 mg, 1.2 mmol) and DMSO (2 mL) was stirred at 100 °C for 2 h. The mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate (10 mL X 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Pre-HPLC (GILSON-281, Pntulips BP-CI8, 10 pm, 21.2 x 250 mm, eluting with a gradient of ACN in water with 0.2% Formic acid, at a flow rate of 25.0 mL / min, 35%-65% ACN over 18 min) to give the racemic product (90 mg, 73% yield). The racemic product was purified by SFC (30% CH3OH (0.4% 7MNH3), 45g / min, 1.2mL OD (30*250mm, 10pm)) to give (S)-2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pteridin-4-yl)-5-(trifluoromethyl)phenol as the first eluting compound. LCMS (Agilent Acid): tR = 2.181 min, m / z 486.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 610.60 (s, 1H), 7.80 - 7.69 (m, 2H), 7.47 (s, 1H), 7.32 - 7.23 (m, 2H), 4.71 (d, = 11.2 Hz, 1H), 4.63 -4.50 (m, 2H), 4.02 (d, J= 11.6 Hz, 1H), 3.82 (s, 3H), 3.74 - 3.65 (m, 1H), 3.29 -3.15 (m, 2H), 2.65 (s, 3H), 2.50 (s, 3H). Further elution gave (R)-2-(6,7-dimethyl-2-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)pteridin-4-yl)-5-(trifluoromethyl)phenol as the second eluting compound. LCMS (Agilent Acid): tR= 2.181 min, m / z 486.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 610.68 (s, 1H), 7.88 - 7.75 (m, 2H), 7.53 (s, 1H), 7.39 - 7.27 (m, 2H), 4.77 (d, J= 11.2 Hz, 1H), 4.69 - 4.56 (m, 2H), 4.08 (d, J= 11.2 Hz, 1H), 3.88 (s, 3H), 3.74 (d, = 2.8 Hz, 1H), 3.34 - 3.22 (m, 2H), 2.71 (s, 3H), 2.56 (s, 3H).

[0169] Example 38 - 5-chloro-2-(2,3-dimethyl-7-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)quinoxalin-5-yl)phenolStep 1: 2-(7-bromo-2,3-dimethylquinoxalin-5-yl)-5-chlorophenolA solution of 7-bromo-5-iodo-2, 3 -dimethylquinoxaline (500 mg, 1.38 mmol) indioxane (5 mL) and H2O (0.5 mL) was added (4-chloro-2-hydroxyphenyl)boronic acid (357 mg, 2.07 mmol), Pd(dppf)C12 (202 mg, 0.27 mmol), and CS2CO3 (1350 mg, 4.15 mmol). The mixture was reacted at 80 °C for overnight. The reaction solution was diluted with water, extracted with DCM, dried over Na2SO4, filtered and the crude residue was purified silica gel chromatography (Pet. ether / EA= 100 / 0 to 86 / 14) to afford 2-(7-bromo-2,3-dimethylquinoxalin-5-yl)-5-chlorophenol (272 mg, 54.4% ) as white solid. LCMS (ES-API): tR2.297 min, m / z 363.0 [M+H]+.WSGR Docket No. 55754-728.601Step 2 (R)-5-chloro-2-(2,3-dimethyl-7-(6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)quinoxalin-5-yl)phenolA solution of 2-(7-bromo-2,3-dimethylquinoxalin-5-yl)-5-chlorophenol (100 mg, 0.27 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added 2-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-2H-l,2,3-triazole (80 mg, 0.27 mmol), Pd(dppf)C12.DCM(45 mg, 0.05 mmol), and K2CO3 (114 mg, 0.82 mmol). The mixture was reacted at 70 °C for 1 h under N2. The reaction solution was diluted with water, extracted with EA, dried overNa2SO4, filtered and the crude residue was purified silica gel chromatography (Pet. ether / THF = 100 / 0 to 60 / 40) to afford (R)-5-chloro-2-(2,3-dimethyl-7-(6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)quinoxalin-5-yl)phenol (105 mg, 85.3% ) as yellow solid. LCMS (ES-API): tR2.178 min, m / z 448.1 [M+H] +.Step 3: 5-chloro-2-(2,3-dimethyl-7-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)quinoxalin-5-yl)phenolA solution of (R)-5-chloro-2-(2,3-dimethyl-7-(6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)quinoxalin-5-yl)phenol (100 mg, 0.20 mmol) in EA (6 mL) was added Pd / C (70 mg) . The mixture was reacted at 25 °C for 2.5 h. The reaction solution was concentrated and the crude residue was purified by prep-HPLC (GILSON-281, Pntulips BP-C 18, 10 pm, 21.2*250mm, eluting with a gradient of ACN in water with 0.2% Formic acid, at a flow rate of 25.0 mL / min, 60-80% ACN over 18 min)to afford 5-chloro-2-(2,3-dimethyl-7-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)quinoxalin-5-yl)phenol (38.4 mg, 29.5%). LCMS (ES-API): tR2.178 min, m / z 450.1 [M+H] +. 1H NMR (400 MHz, DMSO) 89.80 (s, 1H), 7.82 (d, J = 1.9 Hz, 1H), 7.75 (d, J = 3.0 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.1, 2.1 Hz, 1H), 4.70 (d, J = 9.3 Hz, 1H), 4.17 - 4.10 (m, 4H), 3.75 (d, J = 2.2 Hz, 1H), 3.24 (s, 1H), 2.67 (d, J= 3.1 Hz, 3H), 2.56 (s, 3H), 2.18 (d, J = 13.1 Hz, 1H), 1.89 (ddd, J = 18.4, 16.8, 8.0 Hz, 3H).

[0170] Example 39 - 2-(2,3-dimethyl-7-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)quinoxalin-5-yl)-5-(trifluoromethyl)phenolWSGR Docket No. 55754-728.601Step 1: 5-bromo-3-iodobenzene-l,2-diamine 1A solution of 4-bromo-2-iodo-6-nitroaniline (5 g, 14.61 mmol), in EtOH (20 mL) was added SnCl22H2O (13 g, 58.44 mmol), 2NHC1 (2.2 mL). The mixture was reacted at 60 °C for overnight. The reaction solution was diluted with water, extracted with DCM, dried over Na2SO4, filtered and the crude residue was purified silica gel chromatography (Pet. ether / EA = 100 / 0 to 70 / 30) to afford 5-bromo-3-iodobenzene-l,2-diamine ( 4.2g, 93.3% ) as yellow solid. LCMS (ES-API): tR2.007 min, m / z 312.8 [M+H] +.Step 2: 7-bromo-5-iodo-2,3-dimethylquinoxalineA solution of 5-bromo-3-iodobenzene-l,2-diamine (2 g, 6.43 mmol) in DCE (20 mL) was added biacetyl (636 mg, 7.39 mmol), and CaSO4(2.2 g, 16.72 mmol). The mixture was reacted at r.t for overnight. The reaction solution was diluted with water, extracted with DCM, dried over Na2SO4, filtered and the crude residue was purified silica gel chromatography (Pet. ether / EA = 100 / 0 to 93 / 7) to afford 7-bromo-5-iodo-2, 3 -dimethylquinoxaline (1.7 g, 73.9) as yellow solid. LCMS (ES-API): tR2.388 min, m / z 362.8 [M+H] +.Step 3: 2-(7-bromo-2,3-dimethylquinoxalin-5-yl)-5-(trifluoromethyl)phenolTo a solution of 7-bromo-5-iodo-2, 3 -dimethylquinoxaline (500 mg, 1.38 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added (2 -hydroxy -4-(trifluoromethyl)phenyl)boronic acid (428 mg, 2.07 mmol), Pd(dppf)Cl2(101 mg, 0.13 mmol), and Cs2CC>3 (1350 mg, 4.15 mmol). The mixture was reacted at 65 °C for overnight. The reaction solution was diluted with water, extracted with DCM, dried overNa2SO4, filtered and the crude residue was purified silica gel chromatography (Pet. ether / EA = 100 / 0 to 86 / 14) to afford 2-(7-bromo-2,3-dimethylquinoxalin-5-yl)-5-(trifluoromethyl)phenol ( 251 mg, 45.8% ) as yellow solid. LCMS (ES-API): tR2.320 min, m / z 397.0 [M+H] +.WSGR Docket No. 55754-728.601Step 4: 2-(2,3-dimethyl-7-(6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)quinoxalin-5-yl)-5-(trifluoromethyl)phenolA solution of 2-(7-bromo-2,3-dimethylquinoxalin-5-yl)-5-(trifluoromethyl)phenol (150 mg, 0.37 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added 2-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-2H-l,2,3-triazole (110 mg, 0.37 mmol), Pd(dppf)C12.DCM(61 mg, 0.07 mmol), and K2CO3 (156 mg, 1.13 mmol). The mixture was reacted at 70 °C for 1 h under N2. The reaction solution was diluted with water, extracted with EA, dried overNa2SO4, filtered and the crude residue was purified silica gel chromatography (Pet. ether / THF = 100 / 0 to 55 / 45) to afford 2-(2,3-dimethyl-7-(6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)quinoxalin-5-yl)-5-(trifluoromethyl)phenol ( 118 mg, 64.8% ) as yellow solid. LCMS (ES-API): tR2.204 min, m / z 482.1 [M+H] +.Step 5: 2-(2,3-dimethyl-7-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)quinoxalin-5-yl)-5-(trifluoromethyl)phenolA solution of 2-(2,3-dimethyl-7-(6-(2-methyl-2H-l,2,3-triazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)quinoxalin-5-yl)-5-(trifluoromethyl)phenol (100 mg, 0.20 mmol) in EA (6 mL) was added Pd / C (70 mg) . The mixture was reacted at 25 °C for 1 h. The reaction solution was concentrated and the crude residue was purified by pre-HPLC (GILSON-281, Pntulips BP-C18, 10 pm, 21.2*250mm, eluting with a gradient of ACN in water with 0.2% Formic acid, at a flow rate of 25.0 mL / min , 60-80% ACN over 18 min)to afford 2-(2,3-dimethyl-7-((2R,4S)-2-(2-methyl-2H-l,2,3-triazol-4-yl)tetrahydro-2H-pyran-4-yl)quinoxalin-5-yl)-5-(trifluoromethyl)phenol (45.3 mg, 45.3%). LCMS (ES-API): tR2.198 min, m / z 484.2 [M+H] +. 1HNMR (400 MHz, DMSO) 69.98 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.81 - 7.70 (m, 1H), 7.63 (dd, J = 12.8, 1.8 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 6.2 Hz, 2H), 4.76 -4.64 (m, 1H), 4.12 (d, J = 10.3 Hz, 4H), 3.75 (dd, J = 11.6, 9.3 Hz, 1H), 3.25 (t, J = 12.0 Hz, 1H), 2.68 (s, 3H), 2.56 (s, 3H), 2.19 (d, J = 12.7 Hz, 1H), 2.O4 - 1.78 (m, 3H).II. Biological Evaluation

[0171] Example 1 : Evaluation of TREM2 agonist activity - Effect of compounds on SYK phosphorylation in TREM2 / DAP12 overexpressing HEK cellsHEK 293 T cells overexpressing TREM2 and DAP12 were seeded at 70000 cells / well in 200 pL DMEM (10% heat-inactivated FBS, 1% Pen / Strep) in Poly-D-Lysine coated 96-well plates and incubated overnight at 37°C, 5% CO2. After overnight incubation, the cell supernatant was replaced by 80 pLHBSS supplemented with 0.1%BSA(= assay buffer). Compounds were serially diluted in DMSO, followed by dilutions in assay buffer and 20 pL 5x compound stock was added to the cells. The conditions without compound were stimulated with vehicle (= 0,1 % DMSO final concentration). After 45 minutes incubation at 37°C, 5% CO2, the phosphoSYK and total SYKWSGR Docket No. 55754-728.601analyses were performed using an Alpha SureFire® Ultra™ Multiplex phospho-SYK (Tyr525 / 526) + Total SYK assay kit from Revvity . After removing the supernatant, the cells were lysed in 100 pL lx Lysis Buffer during 30 minutes shaking at room temperature.10 pL lysate was transferred to a white 384 -well plate (Proxiplate384 from Revvity), followed by the addition of 5 pL Acceptor Mix. This mix was incubated for 1 hour at room temperature, after which 5 pL Donor Mix was added for 1 hour at room temperature. The readout was performed at an excitation of 680 nmand an emission of 615 nm (phosphoSYK) and 545 nm (total SYK). The ratio phosphoSYK to totalSYK was calculated and the compound concentrations were converted into logarithm base 10. The EC50was calculated via a four-parameter logistic dose response equation in the GraphPad prism software. Table 2 provides the results of the biological evauation of compounds presented herein.

[0172] Activity is defined as “+” for EC50greater than 300 nM; “++” for EC50between 100 and 300 nM; “+++” for EC50 between 100 and 10 nM; and “++++” for EC50 less than 10 nM.Table 2WSGR Docket No. 55754-728.601WSGR Docket No. 55754-728.601

[0173] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to persons skilled in the art are to be included within the spirit and purview of this application and scope of the appended claims.

Claims

WSGR Docket No. 55754-728.601CLAIMSWhat is Claimed Is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof,wherein,Ring A is a 6-membered aryl or heteroaryl ring system;RingB is a 5- or 6-membered heteroaryl ring system;X is H or -CH2-O-P(O)(OR1)2;R1is selected from H, or optionally substituted C1-C6 alkyl;G is described by Formula (a):wherein,Q is O, N-R12, C(R13)2, or SO2;T is C(R30)(R31) or O;V is C(R23)(R24), N-R14, or O;U is N, C-H or C-F;R10is selected from optionally substitutedCl-C6 alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, or optionally substituted carbocyclyl;R11is selected from H, D, halogen, or optionally substituted Cl -C6 alkyl; or R10and R11join to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl;R12and R14are each independently selected from H, optionally substituted Cl -C6 alkyl, - CO(optionally substituted C1-C6 alkyl), or -SO2(optionally substituted C1-C6 alkyl);each R13is independently selected from H, halo, or optionally substituted Cl -C6 alkyl;WSGR Docket No. 55754-728.601R15is selected from H or optionally substituted C1-C6 alkyl;R23and R24are independently selected from H, halo, optionally substituted Cl -C6 alkyl, or optionally substituted Cl -C6 alkoxy; or R23and R24are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R23and R24form an oxo or an =N- OR15; orR12andR23are both optionally substituted C1-C6 alkyl and join to forma carbocyclic ring or a heterocyclic ring; or R11and R23are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R23and R30are both optionally substituted C1-C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; or R30and R32are both optionally substituted C1-C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring;R30and R31are independently selected from H, D, or optionally substituted Cl -C6 alkyl; or R30and R31are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring;R32and R33are independently selected from H, D, or optionally substituted Cl -C6 alkyl; or R32and R33are both optionally substituted Cl -C6 alkyl and join to form a carbocyclic ring or a heterocyclic ring; andRa, Rb, Rc, and Rdare each independently selected from H, D, F, Cl, Br, -CN, CH3, CF3, or -OCF3.2 The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein the Ring A-Ring B bicyclic system is selected from the group consisting of:WSGR Docket No. 55754-728.601wherein,R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.3 The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (la):wherein,Z1is selected from N or C-H;WSGR Docket No. 55754-728.601R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.4 The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is N.5 The compound of claim 3, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is C-H.6 The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (lb):wherein,Y1is selected from N or C-H;Y2is selected from N or C-H;Y3is selected from N or C-H;Y4is selected from N or C-H;R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.7 The compound of claim 6, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y1is N.8 The compound of claim 6 or 7, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y2is N.WSGR Docket No. 55754-728.6019. The compound of any one of claims 6-8, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y3is N.

10. The compound of any one of claims 6-9, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y4is N.

11. The compound of any one of claim 6, or 8-10 or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y1is C-H.

12. The compound of any one of claim 6, 7, or 9-11 or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y2is C-H.

13. The compound of any one of claims 6, 7, or 10-12, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y3is C-H.

14. The compound of any one of claims 6-9, or 11-13 or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Y4is C-H.

15. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Ic):wherein,Z1is selected from N or C-H;R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is N.

17. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Z1is C-H.

18. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (Id):WSGR Docket No. 55754-728.601wherein,R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); andR3is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl); or R2and R3join to form a carbocyclyl or heterocyclyl.

19. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, having the structure of Formula (le):wherein,R2is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl).

20. The compound of any one of claims 3-19, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is selected from optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.

21. The compound of any one of claims 3-19, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted alkyl.

22. The compound of any one of claims 3-19, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted carbocyclyl.WSGR Docket No. 55754-728.60123. The compound of any one of claims 3-19, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is selected from optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl).

24. The compound of any one of claims 3-18, or 20-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is selected from optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.

25. The compound of any one of claims 3-18, or 20-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is optionally substituted alkyl.

26. The compound of any one of claims 3-18, or 20-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is optionally substituted carbocyclyl.

27. The compound of any one of claims 3-18, or 20-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R3is selected from optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl).

28. The compound of any one of claims 3-18, or 20-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted alkyl; and R3is optionally substituted alkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2and R3join to form an optionally substituted carbocyclyl.

30. The compound of any one of claims 3-18, or 20-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is selected from optionally substituted alkoxy, optionally substituted aminoalkyl, or -SO2(optionally substituted alkyl); and R3is optionally substituted alkyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2and R3join to form an optionally substituted heterocyclyl.

32. The compound of any one of claims 3-18, or 20-23, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2is optionally substituted alkyl; and R3is selected from optionally substituted alkoxy, optionally substituted aminoalkyl, or -SChlpptionally substituted alkyl).

33. The compound of claim 32, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R2and R3join to form an optionally substituted heterocyclyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Rais H.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Rbis F, Cl, Br, -CN, CH3, CF3, or -OCF3.WSGR Docket No. 55754-728.60136. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Rbis F or Cl.

37. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Rbis CH3, CF3, or -OCF3.

38. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Rbis CF3.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Rcis H.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Rdis H.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (al):

42. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a2):<>wherein,U is C-H or C-F.

43. The compound of claim 41 or 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Q is O.

44. The compound of claim 41 or 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein Q is N-R12, C(R13)2, or SO2.

45. The compound of any one of claims 41-44, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R11is selected from H, D, or halogen.

46. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10is optionally substituted C1-C6 alkyl.

47. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10is optionally substituted heterocyclyl.WSGR Docket No. 55754-728.60148. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10is optionally substituted carbocyclyl.

49. The compound of any one of claims 41-45, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10is optionally substituted heteroaryl.

50. The compound of claim 49, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10is optionally substituted pyrazolyl.

51. The compound of claim 41 or 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10andRnjoin to form an optionally substituted carbocyclyl or an optionally substituted heterocyclyl.

52. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:, wherein R10is optionally substituted heteroaryl.

53. The compound of claim 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:, wherein R10is optionally substituted heteroaryl.

54. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:, wherein R10is optionally substituted pyridinone.

55. The compound of claim 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:, wherein R10is optionally substituted pyridinone.

56. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a3):WSGR Docket No. 55754-728.601wherein R10is optionally substituted heteroaryl.

57. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a4):wherein R10is optionally substituted heteroaryl.

58. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a5):wherein R23is optionally substituted C1-C6 alkoxy.

59. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a6):wherein R10is optionally substituted heteroaryl.

60. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a7):RyOA(a7),wherein R10is optionally substituted heteroaryl.

61. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a8):wherein R10is optionally substituted heteroaryl.WSGR Docket No. 55754-728.60162. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a9):wherein R10is optionally substituted heteroaryl.

63. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (a 10):wherein R10is optionally substituted heteroaryl.

64. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is described by Formula (all) or (al2):wherein R10is optionally substituted heteroaryl.

65. The compound of any one of claims 52, 53 or 56-64, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10is optionally substituted pyrazolyl.

66. The compound of any one of claims 52, 53 or 56-64, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10is optionally substituted triazolyl.

67. The compound of any one of claims 52, 53 or 56-64, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein R10is optionally substituted pyridinyl.

68. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:, wherein R10is optionally substituted carbocyclyl.

69. The compound of claim 42, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein G is:WSGR Docket No. 55754-728.601, wherein R10is optionally substituted carbocyclyl.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X is H.

71. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X is -CH2-O-P(O)(OH)2.

72. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, wherein X is -CH2-O-P(O)(OR1)2 and R1is optionally substituted Cl- C6 alkyl.

73. A compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Table 1.

74. A compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in Table 2.

75. A pharmaceutical composition comprising a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, as described in any one of claims 1 -74 and a pharmaceutically acceptable excipient.

76. A method of preparing a pharmaceutical composition comprising mixing a compound, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, of any one of claims 1 -74, and a pharmaceutically acceptable carrier.

77. A compound of any one of claims 1-74, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of the human or animal body.

78. A compound of any one of claims 1-74, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, for use in a method of treatment of a neurodegenerative disease, an inflammatory disease, cardiovascular disease or metabolic disease or disorder.

79. A method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a compound as described in any one of claims 1 -74, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof.

80. A method of treating a disease or disorder in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a compound as described in any one of claims 1-74, or pharmaceutically acceptable salt, solvate, or deuteroisotope thereof, and a pharmaceutically acceptable excipient.

81. The method of claim 79 or 80 wherein the disease or disorder is a neurodegenerative disease, an inflammatory disease, cardiovascular disease, or a metabolic disease or disorder.WSGR Docket No. 55754-728.60182. A method of modulating TREM2 receptor activity comprising contacting the TREM2 receptor with a compound, or deuteroisotope thereof, of any one of claims 1 -74, wherein the TREM2 receptor is contacted in an in vitro setting.

83. A method of modulating TREM2 receptor activity comprising contacting the TREM2 receptor with a compound, or deuteroisotope thereof, of any one of claims 1 -74, wherein the TREM2 receptor is contacted in an in vivo setting.

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