Agonists of TREM2 activity

Abstract

The present disclosure is directed to compounds of Formula I and their use as TREM2 agonists for treatment and prevention of a neurodegenerative disorder associated with a loss of function of human TREM2. The disclosed TREM2 agonists may be useful for the treatment of Alzheimer's Disease and associated neurological conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 692,981, filed September 10, 2024, and 63 / 612,010, filed December 19, 2023, the contents of each of which are incorporated herein by reference in their entireties. FIELD OF THE INVENTION

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

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

[0004] Triggering Receptor Expressed on Myeloid cells-2 (TREM2), an immunoglobulin-like transmembrane receptor, appears to play a key role in AD pathology7. Heterozy gous mutations in the TREM2 gene have been found to increase the risk of AD by up to 3-fold (Guerreiro et al. (2013), N Eng! J Med, 368: 117-127; Jonsson et al. (2013) NEnglJMed, 368: 107-116),and increase the rate at which brain volume shrinks (Rajagopalan et al. (2013) N Engl J Med, 369: 1565-1567). Even individuals without AD who carry7 a heterozy gous TREM2 mutation show7 impaired cognition compared to individuals with two normal TREM2 alleles. In the context of AD pathology. TREM2 expression impacts amyloid pathology, modulates neuritic dystrophy, tau hyperphosphorylation and aggregation, and affects synaptic and neuronal loss (Jay et al. (2017) Mol Neurodegener, 12(1):56). In addition, it has been shown that TREM2 plays a key role in limiting the development of peri-plaque tau pathologies (Leyns et al. (2019) Nat Neurosci). Recent mouse genetic model studies also strongly support a key role for TREM2 in AD, with loss or deficiency of TREM2 being associated with increased pathology (Cheng-Hathaway et al. (2018) Mol Neurodegener. 13(1):29; Wang et al. (2015) Cell, 160: 1061-1071; Wang et al. (2016) J Exp Med, 213:667-675: Yuan et al. (2016) Neuron, 90:724-739).

[0005] As reflected in its name, TREM2 is expressed primarily on myeloid lineage cells, including microglia (Colonna & Wang (2016) Nat Rev Neurosci, 17:201-207). Microglia are resident macrophages of the central nervous system (CNS) that, when activated appropriately, are thought to serve an important protective role in Alzheimer’s disease through their housekeeping functions such as facilitating clearance of cellular debris through phagocytosis, as well as secretion of growth factors. In the CNS, TREM2 is exclusively expressed on microglia. It has been shown that TREM2 expression regulates microglial chemotaxis and phagocytosis, and enhances microglial cell survival, proliferation, and differentiation. In addition, it is well known that TREM2 is required to sustain microglial trophic function in the aging brain, and studies showed that an overlap exists between aged microglia phenotype and microglial molecular signatures found in animal models of AD, which include TREM2 pathways (Krasemann et al. (2017) Immunity, 47(3):566-581).

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

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

[0008] The present invention is directed to certain carbonyl-substituted fused heteroaryl derivative compounds. These compounds are shown to exhibit agonism of the TREM2 receptor, surprisingly and advantageously. The present invention is further directed to the use of these compounds in the treatment or prevention of a neurodegenerative disorder, in a subject in need thereof. The present invention provides compounds that may be adapted for pharmaceutical compositions that may be administered to a subject suffering from a neurodegenerative disorder.

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

[0010] In some aspects, provided herein are compounds having the Formula (I): (I) or a pharmaceutically acceptable salt thereof, wherein: X1 isCorN; X2 is C or N. provided that both X1 and X2 are not N; X3 isCorN; X4 is C orN; X5 is C orN; X6 is selected from -CH2-, -N(CHs)- and -0-, and y is 0 or 1; R1 is a -Ci-10 alkyl, -(CH2)z-OH, or -(CH2)-N(CH?); R2 is a -C1-10 alkyl, or a -OC1-6 alkyl; wherein the C1-10 alkyl of R1 and R2and the -OC1-6 alkyl of R2 are unsubstituted or independently substituted by one or more halo, Ci-3alkyl, or C3-6 cycloalkyl groups; or, alternatively, R1 and R2 are linked together to form a C3-7 cycloalkyl or three to seven membered heterocyclyl group, wherein the C3-7 cycloalkyl or three to seven membered heterocyclyl group is unsubstituted or substituted with one or more halo, Ci-3alkyl, or C3-6 cycloalkyl groups; provided that when X1 is C and X2 is N, then R1 and R2 must be linked together to form the C3-7 cycloalkyl or the three to seven membered heterocyclyl group; A is selected from (i) a C3-7Cycloalkyl and (ii) a heterocyclyl comprised of: (1) seven carbon atoms and one N atom, (2) six carbon atoms and (i) one O atom, (ii) one N atom, or (iii) one each of O and N, (3) four carbon atoms and one N atom, or d6 'Y^Y2 RS'kJ D16a' p16b (4) R                wherein: Y1 is CH, CF, OorN; Y2 is CH orN; Y3 is CH orN; R5 is selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C1-10 alkyl, -C(=0)-Ci-io alkyl, -C(=O)-C3-8Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclyl, -CH2-heteroaryl, -C(=O)heteroaryl, -C(=O)-C(CH3)2-heteroaryl, fluoro and =0; wherein the -C(=O)-C3-8cycloalkyl of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-2 alkyl unsubstituted or substituted with one or two fluoro atoms, a heteroaryl, -NH-C(=0)-0-Ci-io alkyl, -OCH3, -CH2CH2OCH3, and -SCH3; wherein the -SO2C1-10 alkyl or -C(=0)-Ci-io alkyl of R5 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl. isopropenyl, or one, two or three fluoro; wherein the -C(=O)-aryl, -C(=O)-heterocyclyl, -CH2-heleroan l. -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl of R5 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from a -C1-10 alkyl, -OC1-10 alkyl, -C(=0)-0-Ci-io alkyl, a -C3-scycloalkyl, methylbenzyl, -CF3, fluoro, and =0; R16a and R16b are independently hydrogen, fluoro, or methyl; R6 is selected from hydrogen, a C3-7cycloalkyl, a heterocyclyl, and a heteroaryl, wherein the C3-7cycloalkyl moiety of R6 is unsubstituted or substituted with a heteroaryl or one or two fluoro atoms, wherein the heterocyclyl or heteroaryl of R6 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from a -Ci-io alkyl, -OCi-io alkyl, -C(=0)-0-Ci-io alkyl, a-Cs-scycloalkyl, methylbenzyl, -CF3, fluoro, and =0; R3 is selected from the group consisting of: R7 and R9are independently selected from hydrogen, methyl, and halo; R8, R10 and R11 are independently selected from hydrogen, halo, a -C1-4 alkyl, -CF3, and-SCH3; X7 is C or N; R12and R12 are each independently selected from hydrogen, -CF3, -OCF3, -(CH3)2, and fluoro; R13and R13 are each independently selected from hydrogen and fluoro; R4, R14 and R17are each independently selected from hydrogen and fluoro; wherein R17is fluoro when X4 is C; and R4is hydrogen when X5 is N.

[0011] All structural Formulas, embodiments and classes thereof described herein include the pharmaceutically acceptable salts of the compounds defined therein. Reference to the compounds of Formula (I) herein encompass the compounds of each of Formulas (II)-(VI), and all embodiments and classes thereof. Reference to the compounds of this invention as those of a specific formula or embodiment, e.g., Formula (I), (II), (III), (IV), (V), or (VI), or embodiments thereof, or any other generic structural formula or specific compound described or claimed herein, is intended to encompass the specific compound or compounds falling within the scope of the Formula or embodiment, including salts thereof, particularly pharmaceutically acceptable salts, solvates (including hydrates) of such compounds and solvated salt forms thereof, where such forms are possible, unless specified otherwise.

[0012] The invention also encompasses pharmaceutical compositions comprising an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION

[0013] The present disclosure is directed to compounds of Formula (I) including compounds of Formulas (II)-(IX), which exhibit activity as agonists of TREM2 receptor. Also provided herein are pharmaceutical preparations comprising any of these compounds and a pharmaceutically acceptable carrier. Further provided herein are methods of treatment and prevention of a neurodegenerative disorder comprising the administration of any of these compounds to a subject. Also provided herein are methods of treatment and prevention of a condition associated with a loss of function of human TREM2 in a subject. Compounds of the Disclosure

[0014] In some embodiments of the compounds of Formula (I), R3 is selected from the group consisting of:

[0015] In one embodiment, the compound of Formula (1) has the Formula (II) F F , and R10 O             (II) wherein: X1 is C orN; X2 is C or N, wherein X2is C when X1 is N, provided that both X1 and X2 are not N; Y1 is O orN; Y2 is CH orN; R1 is a -Ci-4 alkyl; wherein the Ci-4alkyl moiety of R1 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl, isopropenyl, or one, two or three fluoro; R2 is a -Ci-4 alkyl or a -OC1-4 alkyl; wherein the Ci-4alkyl moiety of R2 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl, isopropenyl, or one, two or three fluoro; or R1 and R2 are linked together to form a three to seven membered cycloalkyl or heterocyclyl group; wherein said three to seven membered cycloalkyl or heterocyclic group is optionally substituted with one of more halo, C1-3 alkyd or Cs-ecycloalkyl; and provided that when X1 is C and X2 is N, then R1 and R2 must be linked together to form the three to seven membered cycloalkyl or heterocyclyl group; R10 is selected from hydrogen, halo, a -C1-3 alkyl, -CF3, and -SCH3; R7, R8, R9, R10, and R11 are independently selected from hydrogen, methyl, and halo; R5 is selected from hydrogen, -SO2N(CH3)2, -SO2C1-10 alkyl, -C(=0)-Ci-io alky l, -C(=O)-C3-8cycloalky1, -C(=O)-ary 1. -C(=O)-heterocyclyl, -C(=O)-heteroaryl and -C(=O)-C(CH3)2-heteroaryl; wherein R5 is absent when Y1 is O; wherein the -C(=O)-C3-scycloalkyl of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-2 alkyl unsubstituted or substituted with one or two fluoro, a heteroary 1, -NH-C(=0)-0-Ci-io alkyl, -OCH3, -CH2CH2OCH3, -SCH3, and one or two fluoro, wherein the -C(=O)-aryl, -C(=O)-heterocyclyl, -C(=O)-heteroaryl or -C(=O)-C(CH3)2-heteroaryl of R3 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-10 alkyl, -C(=0)-0-C1-10 alkyl, -CF3, and fluoro; wherein the -SO2C1-10 alkyl or -C(=0)-Ci-io alkyl of R5 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl, isopropenyl, or one, two or three fluoro; R6 is selected from hydrogen and a heteroaryl: wherein the heteroary 1 of R6 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-10 alkyl, -C(=0)-0-Ci-io alkyl, -CF3, and fluoro; and y is 0 or 1.

[0016] In some embodiments of the compounds of Formula (I) or (II), X1 is C, X2is N, and R1 and R2 are linked together to form a three to seven membered cycloalkyl or heterocyclyl group, which is unsubstituted or substituted with one or more halo. Ci-3alkyl, or C3-6 cycloalkyl groups, wherein said alkyl, cycloalkyl or heterocyclic group is optionally substituted with one of more halo, C1-3 alkyl or Cs-ecycloalkyl.

[0017] In other embodiments of the compounds of Formula (I) or (II), X1 is N.

[0018] In some embodiments of the compounds of Formula (I) or (II), R1 and R2 are each methyl.

[0019] In other embodiments of the compounds of Formula (I) or (II), R1 and R2 are taken together to form a C5-8 cycloalkyl or a heterocyclyl comprising one O atom.

[0020] In some embodiments of the compounds of Formula (I) or (II), R5 is selected from the group consisting of -C(=O)-heterocyclyl, -CH2-heteroaryl, -C(=O)heteroaryl, and -C(=O)-C (CH3)2-heteroary 1; wherein the -CFh-heteroaryl, -C(=O(heteroary 1, or -C(_O)-C(CH3)2-hcteroan l (i.e., the heteroaryl moiety of such radicals) of R5is comprised of: (1) four carbon atoms and one of O, (2) three carbon atoms and (i) N and O, (ii) N and S, or (iii) N and NH; (3) two carbon atoms and three of N; (4) seven carbon atoms and N and O; and wherein the -C(=O)-heterocyclyl (i.e., the heterocyclyl moiety of such radical) of R5is comprised of: (1) three, four, five, six or seven carbon atoms and one O, (2) four carbon atoms and (i) two of 0 or (ii) N and 0, or (3) six carbon atoms and two of 0 and one of N.

[0021] In certain embodiments of the compounds of Formula (I) or (II), R6 is a pyrazole substituted at the 1-position with a -Ci-io alky l.

[0022] In specific embodiments of the compounds of Formula (I) or (II), R10 is fluoro or chloro, R9 is fluoro, and R7 is hydrogen.

[0023] In other specific embodiments of the compounds of Formula (I) or (II), R10 is chloro, R9 is fluoro, and R7 is hydrogen.

[0024] In some embodiments, the compound of Formula (I) has the Formula (IV) wherein: X1 is C orN; X2 is C or N, provided that both X1 and X2 are not N; Rl and R2 are independently Cl-3 alkyl, or, alternatively, Rl and R2, together with the carbon atoms to which they are attached, form a ring CZ; wherein ring CZ is: (i) a non-aromatic, partially unsaturated 5- to 6-membered cycloalkyd; (ii) a 5- to 6-membered heterocycloalkyl, wherein said 5- to 6-membered heterocycloalky l is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N, O and S; or (iii) a 9 to 10-membered bicyclic heterocycloalkyl wherein said 9- to 10-membered bicy clic heterocycloalky1 is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N. O and S; wherein ring CZ is unsubstituted or substituted by 1 to 2 RZ substituents independently selected from the group consisting of Cl-3 alkyl, Cl-3 fluoroalkyl, and halo; provided that when X1 is C and X2 is N, then R1 and R2, together with Xl and X2, must form ring CZ; Y2 is C(H) orN; Y4 is CH2 or O; R6 is: (a) ring C6, wherein ring C6 is: (i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S; (ii) a 4- to 6-membered saturated, monocyclic heterocycloalkyl containing one heteroatom selected from the group consisting of N, O and S; (hi) a 6-to 10-membered fused or bridged heterobi cyclic system containing 1 to 2 heteroatoms independently selected from the group consisting of N, 0 and S; wherein said 6-to 10-membered heterobicyclic system is: (a) fully saturated or (b) contains 1 aromatic ring and one partially unsaturated ring; (iv) a C3-7 saturated cycloalkyl; or (v) phenyl; wherein ring C6 is unsubstituted or substituted by 1 to 2 R6a substituents independently selected from the group consisting of halo, cyano, Cl-3 alkyl, Cl-3 alkoxy, or R6ac; wherein R6ac is -(CH2)y-Cac; Cacis (I) C3-6 monocyclic cycloalkyl; (II) C7-12 bicyclic cycloalkyl; (III) a 3- to 6-membered monocyclic heterocycloalkyl, wherein the 3- to 6membered monocyclic heterocycloalkyl is saturated, and contains 1 to 2 heteroatoms independently selected from the group consisting of N, 0, and S; (IV) a 6- to 10-membered bicyclic heterocycloalkyl, wherein the 6- to 10membered bicyclic heterocycloalkyl is saturated or partially saturated, and contains 1 to 2 heteroatoms independently selected from the group consisting of N, O, and S; (V) a 5- to 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S; (VI) a 6- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S; or (VII) phenyl or naphthyl; wherein Cac is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of halo, amino, oxo, Ci-12 alkyl, Ci-3 fluoroalkyl, Ci-3 alkydamino, Ci-3 dialkylamino, Cl-3 alkoxy, and Cl-3 alkoxy(Ci-3) alkyl; (b) Ci_6 alkyl; (c) Ci-6 fluoroalkyl; (d) Ci-6 alkoxy; (e) C1-3 alkoxy(C1-3) alkyl; (f) Cl-3 hydroxyalky l; each RAis independently fluoro Ci-3 alkyl, or C1-3 alkoxy; R7, R8, and Rl 1 are independently H or halo; R10 is halo, methyl, or trifluoromethyl; q is 1 or 2; r is 0, 1, or 2; s is 0 or 1; and v is 0, 1 or 2.

[0025] In certain embodiments, the compound of Formula (I) has the Formula (V) wherein: ^I6a Rl and R2 are independently Ci-3 alkyl, or, alternatively, Rl and R2, together with the carbon atoms to which they are attached, form a ring CZ; wherein ring CZ is: (i) a non-aromatic. partially unsaturated 5- to 6-membered cycloalkyl; or (ii) a 5- to 6-membered heterocycloalkyl, wherein said 5- to 6-membered heterocycloalkyl is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N, O and S; wherein ring CZ is unsubstituted or substituted by 1 to 2 RZ substituents independently selected from the group consisting of Ci-3 alkyl, Ci-3 fluoroalkyl, and halo; Y2 is C(H) orN; R6 is (a) ring C6, which is: (i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, 0 and S; (ii) a 4- to 6-membered saturated heterocycloalkyl containing one heteroatom selected from the group consisting of N, 0 and S; (iii) a 6-to 10-membered fused or bridged heterobi cyclic system containing 1 to 2 heteroatoms independently selected from the group consisting of N. 0 and S; wherein said 6-to 1 O-membered heterobicyclic system is: (a) fully saturated or (b) contains 1 aromatic ring and one partially unsaturated ring; or (iv) a C3-6 cycloalkyl; wherein ring C$ is unsubstituted or substituted by 1 to 2 R6a substituents independently selected from the group consisting of halo, cyano, Ci-3 alkyl, Ci-3 fluoroalkyl, Cl-3 alkoxy, orRbac; wherein R6ac is -(CH2)y-Cac; Cacis (I) C3-6 monocyclic cycloalkyl; (II) a 3- to 6-membered monocyclic heterocycloalkyl, wherein the 3- to 6membered monocyclic heterocycloalkyl is saturated, and contains 1 to 2 heteroatoms independently selected from the group consisting of N, 0, and S; or (III) a 5- to 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O and S; wherein Cac is unsubstituted or substituted by 1 to 2 substituents selected from halo, amino, cyano, oxo, Ci-12 alkyl, Ci-3 fluoroalkyl, Ci-3 alkylamino, Ci-3 dialkylamino, Ci-3 alkoxy, Ci-3 alkoxy(Ci-3) alkyl, (b) Ci-g alkyl;(c) C1-3 hydroxyalkyl; (d) Ci-3 haloalkyl; or (e) cyano; R.7, RS, and Rl 1 are independently H or halo; R10 is halo; and R16aand R16b are independently H, fluoro, Ci-3 alkyl or Ci-3 fluoroalkyd; or, alternatively. R16a and R1 ^b together with the carbon atom to which they are attached, form aC3-6 cycloalkyl; and y is 0 or 1.

[0026] In some embodiments of the compound of Formula (V), Rl and R2, together with the carbon atoms to which they are attached, form the ring C^.

[0027] In specific embodiments of the compound of Formula (V), the moiety            O is.            O O              ; and wherein p is 0, 1, or 2.

[0028] In certain embodiments of the compound of Formula (V), Y2 is N. In other embodiments, Y2 is C(H).

[0029] In some embodiments of the compound of Formula (V),

[0030] In particular embodiments of the compound of Formula (V), R6 is unsubstituted or substituted pyrazolyl, pyridyl, or tetrahydrofuryl.

[0031] In certain embodiments of the compound of Formula (V),

[0032] In other embodiments, the compound of Formula (I) has the Formula (VI) wherein: Y2 is C(H) orN; Y4 is C(H) or O; each RZ is independently selected from the group consisting of Ci-3 alkyl, Ci-3 fluoroalkyl, and halo; R6 is: (a) ring C6, wherein ring C6 is: (i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, 0 and S; (ii) a -5 to 6-membered saturated heterocycloalkyl containing one heteroatom selected from the group consisting of N, 0 and S; or (iii) a C3-7 cycloalkyl; wherein ring C$ is unsubstituted or substituted by 1 to 2 R6a substituents independently selected from the group consisting of halo, Ci-3 alkyl, cyano, Ci-3 alkoxy, or C3-6 cycloalkyl; or (b) C1-6 alkyl; RA is fluoro or Ci-3 alkyl; R?, R8, and Rl 1 are independently H or halo; R10 is halo; and p is 0, 1, or 2; q is 1 or 2; r is 0, 1, or 2; and s is 0 or 1.

[0033] In some embodiments of the compound of Formula (VI),

[0034] In particular embodiments of the above-illustrated moieties, R6 is unsubstituted or substituted pyrazolyl, pyridyl, or tetrahydrofuryl.

[0035] In other embodiments of the compound of Formula (VI),

[0036] In specific embodiment of the compound of Formula (VI).

[0037] In other embodiments, the compound of Formula (I) has the Formula (VII) wherein: ring Cz is a cyclopentenyl, cyclohexenyl, dihydrofuran, or dihydropyran ring; each RZ is independently selected from the group consisting of Cl-3 alkyl. Cl-3 fluoroalkyl, and halo; ring C6 is (i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, 0 and S; (ii) a -5 to 6-membered saturated mono- or bicyclic heterocycloalkyl containing one 0 heteroatom; or (iii) a C3-7 cycloalkyl; each R6a is independently selected from the group consisting of halo, Ci-3 alkyl, cyano, Ci-3 alkoxy, and C3-6 cycloalkyl; or each RA is independently fluoro or C1-C3 alkyl; R7, r8, and Rl 1 are independently H or halo; R10 is halo; methyl or trifluoromethyl; p is 0, 1, or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

[0038] In some embodiments of the compound of Formula (VII), the moiety

[0039] In certain embodiments of the compound of Formula (VII),

[0040] In specific embodiments of the compound of Formula (VII),

[0041] In other embodiments, the compound of Formula (I) has the Formula (VIII) R10 wherein: ring Cz is a cyclopentene, cyclohexene dihydrofuran, or dihydropyran ring; each RZ is independently selected from the group consisting of C1-3 alkyl, Ci-3 fluoroalkyl, and halo; Y4 is C(H2) or O; ring C6 is (i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S; (ii) a -5 to 6-membered saturated heterocycloalkyl containing one O heteroatom; or (iii) a C3-7 cycloalkyl; each R6a is independently selected from the group consisting of halo, Ci-3 alkyl, cyano, Ci-3 alkoxy, and C3-6 cycloalkyl: or each RA is independently fluoro or C1-C3 alkyl; R?, R&, and Rl 1 are independently H or halo; R10 is halo; methyl or trifluoromethyl; pis 0, 1, or2; q is 1 or 2; r is 0, 1, or 2; and t is 0, 1, or 2.

[0042] In some embodiments of the compound of Formula (VIII),

[0043] In other embodiments, the compound of Formula (I) has the Formula (IX) wherein: Rl and R2 are independently Cl-3 alkyl, or, alternatively, Rl and R2, together with the carbon atoms to which they are attached, form a ring CZ; wherein ring CZ is: (i) a non-aromatic. partially unsaturated 5- to 6-membered cycloalkyl; or (ii) a 5- to 6-membered heterocycloalkyl, wherein said 5- to 6-membered heterocycloalkyl is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N, O and S; wherein ring CZ is unsubstituted or substituted by 1 to 2 RZ substituents independently-selected from the group consisting of C]-3 alkyl, C]-3 fluoroalkyl, and halo; R5 is selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C1-10 alkyl, -C(=0)-Ci-io alkyl, -C(=O)-C3-8Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclyl, -CH2-heteroary l, -C(=O)heteroaryl, -C(=O)-C(CH3)2-heteroaryl, fluoro and =0; wherein the -C(=O)-C3-8cycloalkyl of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-2 alkyl unsubstituted or substituted with one or two fluoro atoms, a heteroaryl, -NH-C(=0)-0-Ci-io alkyl, -OCH3, -CH2CH2OCH3, and -SCH3; wherein the -SO2C1-10 alkyl or -C(=0)-Ci-io alkyl of R5 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl, isopropenyl, or one, two or three fluoro; wherein the -C(=O)-aryl, -C(=O)-heterocyclyl, -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl of R5 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from a -C1-10 alkyl, -OC1-10 alkyl, -C(=0)-0-Ci-io alkyl, a -Cs-scycloalkyL methylbenzyl, -CFs, fluoro, and =0; R16a and R16b are independently H, fluoro, Ci-3 alkyl or Ci-3 fluoroalky l; or, alternatively, R16a and R16b, together with the carbon atom to which they are attached, form a C3-6 cycloalkyl; R?. R8, and Rl 1 are independently H or halo; and R10 is halo; methyl or trifluoromethyl.

[0044] In some aspects, the present application provides the compounds having the Formula (I), wherein: X1 is C or N; X2 is C or N, provided that both X1 and X2 are not N; X3 is C or N; X4 is C or N; X5 is C or N; X6 is selected from -CH2-, -N(CH3)- and -0-, and y is 0 or 1; R1 is a -C1-10 alkyl, -(CH2)z-0H, or -(CH2)-N(CH3); R2 is a -Ci-10 alkyl, or a -OC1-6 alkyl; or R1 and R2 are linked together to form a three to seven membered cycloalkyl or heterocyclyl group, which is unsubstituted or substituted with one or more halo, Ci-salkyl, or C3-6 cycloalkyl groups, wherein said alkyl, cycloalkyl or heterocyclic group is optionally substituted with one of more halo, C1-3 alkyl or Cs-ecycloalkyl, and provided that when X1 is C and X2 is N, then R1 and R2 must be linked together; A is selected from (i) a C3-7cycloalkyl and (ii) a heterocyclyl comprised of: (1) seven carbon atoms and one N atom, (2) six carbon atoms and (i) one O atom, (ii) one N atom, or (iii) one each of O and N, (3) four carbon atoms and one N atom, or ...            p16          ,    . (4)          r\ . wherein: Y1 is CH, CF, OorN; Y2 is CH orN; Y3 is CH orN; R5 is selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C1-10 alkyl, -C(=0)-Ci-io alkyl, -C(=O)-C3-8Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclyl, -C(R13)z-heteroaryl, fluoro and =0, wherein R15is selected from hydrogen. (=0)- and (=0)-C(CH3)-, and z is 0 or 1, and wherein any cycloalkyl of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-2 alkyl unsubstituted or substituted with one or two fluoro atoms, a heteroaryl, -NH-C(=0)-0-Ci-io alkyl, -OCH3, -CH2CH2OCH3, -SCH3, and fluoro; and R16 is hydrogen or methyl; R6 is selected from hydrogen, a C4-7Cycloalkyl, aheterocyclyl, and a heteroaryl, wherein any cycloalkyd moiety of R6 is unsubstituted or substituted with a heteroaryl or one or two fluoro atoms, wherein any heteroaryl or heterocyclyl moiety of R5 and R6 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from a -C1-10 alkyd, -OC1-10 alkyl, -C(=0)-0-Ci io alkyl, a -Cs-scycloalkyl, methylbenzyl, -CF3, fluoro, and =0, and wherein any -C1-10 alkyl moiety7 of R1, R2 and R3 is unsubstituted or substituted with -OC1-3 alkyd, cyclopentanyl, isopropenyl, or one, two or three fluoro; R3 is selected from the group consisting of wherein R7 and R9are independently selected from hydrogen, methyl, and halo, and R8, R10 and R11 are independently selected from hydrogen, halo, a -C1-4 alkyl, -CF3, and -SCH3, and X7 is C or N, and R12and R12 are each independently selected from hydrogen. -CF3, -OCF3, -(CH3)2, and fluoro, and R13and R13 are each independently selected from hydrogen and fluoro; and R4, R14 and R17are each selected from hydrogen and fluoro, wherein R17is fluoro when X4 is C, and R4is hydrogen when X5 is N.

[0045] In some embodiments are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X3 and X4 are N. In some embodiments are compounds of Formula (I) wherein X3, X4 and X1 are N. In some embodiments are compounds of Formula (I) wherein X3, X4 and X2 are N.

[0046] In other aspects, the present application provides the compounds having the Formula (II), wherein: X1 is C or N; X2 is C or N, wherein X2is C when X1 is N, provided that both X1 and X2 are not N; Y1 is O orN; Y2 is CH orN; R1 is a -Ci-4 alkyl; R2 is a -Ci-4 alkyl or a -OCi-4 alkyl; or R1 and R2 are linked together to form a three to seven membered cycloalkyd or heterocyclyl group, which is unsubstituted or substituted with one or more halo, Ci-3alkyl, or C3-6 cycloalkyl groups, wherein said alkyl, cycloalkyl or heterocyclic group is optionally substituted with one of more halo. C1-3 alkyl or Cs-ecycloalkyl, and provided that when X1 is C and X2 is N, then R1 and R2 must be linked together; R10 is selected from hydrogen, halo, a -C1-3 alkyl, -CF3, and -SCH3; R7 and R9are independently selected from hydrogen, methyl, and halo; R8 and R11 are both H; R5 is selected from hydrogen, -SO2N(CH3)2, -SO2C1-10 alkyl, -C(=0)-Ci-io alkyl, -C(=O)-C3-8cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclyl, -C(=O)-heteroaryl and -C(=O)-C(CH3)-heteroaryl; and R6 is selected from hydrogen and a heteroaryl. wherein any heteroaryl or heterocyclyl moiety of R5 and R6 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-10 alkyl, -C(=O)-O-C1-10 alkyl, -CF3, and fluoro, wherein any cycloalkyl moiety of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-2 alkyl unsubstituted or substituted with one or two fluoro, a heteroaryl, -NH-C(=0)-0-Ci-io alkyl, -OCH3, -CH2CH2OCH3, -SCH3, and one or two fluoro, wherein any alkyl moiety of R1, R2 and R5 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl, isopropenyl, or one, two or three fluoro; and y is 0 or 1.

[0047] In various embodiments are compounds of Formula (I) and (II) wherein y is 0. In some embodiments are compounds of Formulas (I) and (II) wherein y is 1 and X6 is -CH2-. In other embodiments, y is 1 and X6 is -N(CH?)-.

[0048] In some embodiments, the compounds of Formula (I) and Formula (II) are bicyclic. In a sub-embodiment of these embodiments are compounds of Formula (I) and Formula (II), wherein R1 and / or R2 are Ci-4alkyl. In some such sub-embodiments, R1 and / or R2 are methyl. In some such sub-embodiments, R1 and R2 are both methyl. In such a sub-embodiment are compounds such as the below exemplary compound Cl O or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the compounds of Formula (I) and Formula (II) are tricyclic. In a sub-embodiment of these embodiments are compounds of Formula (I) and Formula (II), wherein R1 and R2 are taken together to form a C5-8 cycloalkyl or a heterocyclyl that is unsubstituted or substituted with one or two fluoro or a methyl. In a sub-embodiment, R1 and R2 are taken together to form a C5-8 cycloalkyd that is unsubstituted. In a sub-embodiment, R1 and R2 are taken together to form a five- to eight-membered heterocyclyl containing one O atom. In a subembodiment. R1 and R2 are taken together to form a five- to eight-membered heterocyclyl containing one N atom. In such sub-embodiments are compounds such as the below exemplary compounds: Cl                                 Cl pharmaceutically acceptable salt thereof.

[0050] In a sub-embodiment of these tricyclic compound embodiments are compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are taken together with multiple intervening atoms (e.g., two intervening atoms) to form a spiro, caged or bridged five- to eight-membered cycloalkyl or heterocyclyl. In such sub-embodiments are compounds such as the below exemplary compounds: or a pharmaceutically acceptable salt thereof. In a sub-embodiment of these tricyclic compound embodiments are compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are taken together with multiple intervening atoms to form ci , or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the invention is directed to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X1 is C, X2is N, and R1 and R2 are linked together to form a three to seven membered cycloalkyl or heterocyclyl group, which is unsubstituted or substituted with one or more halo, Ci-3alkyl, or C3-6 cycloalkyl groups, wherein said cycloalkyl or heterocyclic group is optionally substituted with one of more halo, C1-3 alkyd or Cs-ecycloalkyl.

[0052] In some embodiments are compounds of Formula (I), or a pharmaceutically acceptable salt thereof wherein A is Ri $     , wherein Y1, Y2, Y3, R5. R6 and R16 are defined as above. In some embodiments, R16is hydrogen. In some embodiments, Y2 is N. In some embodiments, Y1 is O, Y2 is N, and Y3 is CH. In some embodiments, Y1 is N, Y2 is N, and Y3 is CH. In some embodiments, Y1 is CH.

[0053] In some embodiments are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5 is a 4- to 8-membered cycloalkyl or heterocyclyl. In some embodiments, R5 is a 4- to 8-membered spiro, caged or bridged 4- to 8-membered cycloalkyl or heterocyclyl. In some embodiments, R5 is a 5- to 8-membered heterocyclyl containing at least one O atom. In some embodiments, R5 is a 5- to 8-membered heterocyclyl containing at least one N atom. In some embodiments, R5 is a spiro, caged or bridged 5- to 8-membered heterocyclyl containing at Cl least one N atom, such as the compound                            .

[0054] In some embodiments are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R5 is selected from -C(=0)-Ci-io alkyl, -C(=O)-C3-8cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclyl, and -C(R15)z-heteroaryl, wherein z is 1, and R15 is hydrogen or (=0)-. In sub-embodiments of these embodiments, the -C(R15)-heteroaryl of R5 is a four- to nine-five heterocyclyl. In sub-embodiments of these embodiments, the -C(R15)-heteroaryl of R5 is a four-to nine-membered heteroaryl. In one embodiment of these embodiments, the -C(R15)-heteroaryl of R5 is a five-membered heteroaryl.

[0055] In some embodiments are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein any cycloalkyl moiety of R5 is substituted with 1 or 2 substituents wherein each substituent is a -C1-2 alkyl unsubstituted or substituted with one or two fluoro atoms or a heteroaryl. In sub-embodiments of these embodiments, a cycloalkyl moiety of R5 is substituted with a -Ci-2 alkyl substituted with a five- to six-membered heteroaryl.

[0056] In some embodiments are compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, wherein R5 is a four- to eight-membered heteroaryl. Any such heteroaryl moiety of R5may be comprised of '                               -26 - (1) four carbon atoms and one of O, (2) three carbon atoms and (i) N and 0, (ii) N and S, or (iii) N and NH; (3) two carbon atoms and three of N; (4) seven carbon atoms and N and 0.

[0057] In some embodiments are compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, wherein R5 is a four- to eight-membered heterocyclyl. Any such heterocyclyl moiety7 of R5may be comprised of: (1) three, four, five, six or seven carbon atoms and one 0, (2) four carbon atoms and (i) two of 0 or (ii) N and 0, or (3) six carbon atoms and two of 0 and one of N.

[0058] In some embodiments are compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, wherein R6 is a five- to eight-membered heteroaryl, e.g., a five- to eight-membered heteroaryl containing one or two N atoms. This heteroaryl may be substituted with a -Ci-io alkyl. In sub-embodiments of these embodiments, R6 is a pyrazole that is unsubstituted or substituted at the 1-position with a -Ci-io alkyl. In one sub-embodiment, R6 is a pyrazole substituted at the 1-position with a methyl.

[0059] In other sub-embodiments of these embodiments, R6 is a six-membered heteroaryl containing one N atom. This heteroaryl may be substituted with a -Ci-io alkyl, e.g.. a methyl. In N= / some such sub-embodiments, R6 is ' . F J^F F

[0060] In some embodiments are compounds of Formula (I) wherein R3 is

[0061] In some embodiments are compounds of Formula (I), or a pharmaceutically acceptable R10 Rl^X7 R11 r9^4^r7 salt thereof, wherein R3 is T^ . In sub-embodiments of these embodiments, X7 is C. In further sub-embodiments of these embodiments, R8 and R11 are each hydrogen, such that R10 R3 is R .

[0062] In some embodiments of such sub-embodiments are compounds of Formula (I) and Formula (II). wherein R9 is fluoro. In some embodiments of such sub-embodiments are compounds of Formula (I) and Formula (II), wherein R10 is chloro. In some embodiments of such sub-embodiments are compounds of Formula (I) and Formula (II), wherein R7 is hydrogen. Accordingly, in some embodiments, R10 is chloro. R9 is fluoro, and R7 is hydrogen.

[0063] In still other aspects, the present application provides the compounds having the Formula (III), R10 wherein X1, X2, R1, R2 and R10 are defined above.

[0064] In particular embodiments, the compound is selected from the group of Example Nos. 11 - 1-259, 2-1 - 2-235, 3-1 - 3-98, 4-1 - 4-30, 5-1 - 5-2, 6-1 - 6-9. and 7-1 - 7-5. In specific embodiments, the compound is selected from the group of Example Nos. 1-1 - 1-259, 2-1-2235, 4-1 - 4-30, 5-1 - 5-2, 6-1 - 6-9, and 7-1 - 7-5.

[0065] In some embodiments, provided herein are pharmaceutically acceptable salts of any of the disclosed compounds (e.g., hydrochloride salts). In other embodiments, the compounds provided herein are isolated as trifluoroacetate salts. In some embodiments, the phase of any of the disclosed compounds is crystalline. In some embodiments, the phase of any of the disclosed compounds is amorphous.

[0066] In some embodiments, any of the disclosed compounds exhibit high potency in activating the TREM2 receptor, e.g., the human TREM2 receptor. Activation of the TREM2 receptor may be measured using any of several assays known in the art. For example, activation of TREM2 may be measured using a phosphorylation of Spleen Tyrosine Kinase (pSYK) assay. In addition to the pSYK assay, activation of TREM2 may be measured in vivo (e.g., in a subject) using other biomarkers including, but not limited to, interaction of TREM2 with adaptor protein DAP12, pDAP12 elevation, TREM2 clustering, and cytokine elevation, e.g., IP10 or CCL4 cytokine elevation. Several of these biomarkers, such as DAP 12, constitute proteins that are activated in the TREM2 pathway downstream of, and following binding of a ligand to. the TREM2 receptor. Potencies of activation may be expressed as ICso or ECso. Activation of TREM2 may be measured in vitro. Treatment Of Neurodegenerative Disorders

[0067] The disclosed compounds and pharmaceutical compositions are useful for treatment and / or prevention of one or more neurodegenerative disorders. For instance, they may be useful for treatment or prevention of one or more of Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, demyelination disorder, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis (ALS). tauopathy disease. Nasu-Hakola disease, or adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). In some embodiments, the disclosed compounds and compositions are useful for treatment of Alzheimer’s Disease. In some embodiments, the disclosed compounds and compositions are useful for treatment of dementia, such as frontotemporal dementia.

[0068] In some aspects, any of the disclosed compounds and compositions may be administered to a subject suffering from Alzheimer’s Disease. In various embodiments, the subject is human. Administration of these compositions may improve cognitive and / or functional benefit by stabilizing amyloid negative status or further modulating multiple biomarkers of Alzheimer’s disease pathology or progression in the subject. In certain embodiments, the disclosed compositions promote the stabilization amyloid negative status in the subj ect. Modulation of biomarkers of Alzheimer’s disease pathology7 or progression in the subject may be observed by measuring any of the following biomarkers in a sample of the subject's blood, plasma and / or cerebrospinal fluid: Ab42 / 40 ratio, pTau and / or total Tau, NfL, GFAP, soluble Trem2 (sTrem2) and YKL-40. In some embodiments, any of the disclosed compounds improve (i.e., reduce) the subject’s Ab42 / 40 ratio, pTau and / or total Tau, NfL, GFAP, sTrem2 and / or YKL-40 in plasma or cerebrospinal fluid (CSF). In some embodiments, administration of any of the disclosed compounds improve the subject’s Ab42 / 40 ratio. In some embodiments, administration of any of the disclosed compounds reduce the sTREM2 in the subject’s CSF.

[0069] Modulation of the Ab42 / 40 ratio, pTau and / or total Tau in a subject may be measured using imaging markers, including positron emission tomography (PET) of amyloid or tau protein, respectively. Accordingly, in some embodiments, following administration of any of the disclosed compositions, an amyloid PET and / or tau PET of the subject or subject’s sample is performed.

[0070] Accordingly, further provided herein are methods of treatment and prevention comprising administration of any of the disclosed compounds. Further provided herein are uses of these compounds as medicaments for treatment or prophylaxis of a neurodegenerative disorder, such as Alzheimer’s Disease. In certain embodiments, a compound of Formula (I), or pharmaceutically acceptable salt thereof, is used in the preparation of a medicament for: (a) therapy (e.g.. of the human body), (b) medicine, (c) activation of TREM2 receptor, (d) treatment or prevention of Alzheimer’s Disease and / or neurological symptoms thereof, (e) treatment or prevention of dementia, or (I) treatment, prevention of, or delay in the onset or progression of Alzheimer's Disease, dementia, and / or neurological symptoms thereof. In these uses, the compounds of the present invention can optionally be employed in combination with one or more other active agents, such as an amyloid-beta targeting therapy or tau targeting therapy.

[0071] Further provided herein are methods for the treatment or prevention of a condition associated with a loss of function of human TREM2 in a subject (e.g., a human subject). In some embodiments, the condition associated with a loss of function of human TREM2 is dementia or cognitive impairment associated with Alzheimer’s Disease. In some embodiments, this condition is cognitive impairment associated with Parkinson’s Disease. In some embodiments, this condition is cognitive impairment associated with frontotemporal dementia, demyelination disorder, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis (ALS), tauopathy disease, Nasu-Hakola disease, or adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

[0072] The disclosure further provides methods of administering any of the disclosed compounds or compositions to a subject. In some embodiments, the disclosed methods may bring about in the subject (i) a reduction in amyloid plaques, (ii) an elevation in disease-associated microglia (DAM) mRNA expression, (iii) an elevation in lipid metabolism, (iv) an elevation in DAM chemotaxis, DAM proliferation, DAM pro-inflammatory cytokine secretion, or DAM phagocytic activity, and / or (v) a reduction in dystrophic neurites. In some embodiments, the disclosed methods bring about a reduction in amyloid plaques. In some embodiments, the presently disclosed methods bring about an elevation in disease-associated microglia (DAM) mRNA expression. In some embodiments, the presently disclosed methods bring about an elevation in lipid metabolism in the subject. In some embodiments, the disclosed methods bring about an elevation in DAM chemotaxis, DAM proliferation, DAM pro-inflammatory cytokine secretion, or DAM phagocytic activity, and / or a reduction in dystrophic neurites.

[0073] In some aspects, provided herein are methods for the treatment or prophylaxis of abnormal motor symptoms associated with Parkinson’s disease (including but not limited to bradykinesia, rigidity and resting tremor). Another embodiment provides a method for the treatment or prophylaxis of abnormal non-motor symptoms associated with Parkinson’s disease (including but not limited to cognitive dysfunction, autonomic dysfunction, emotional changes and sleep disruption), Lewy body dementia, and L-Dopa induced dyskinesias.

[0074] In some aspects, provided herein are methods for the treatment or prophylaxis of Alzheimer’s disease, mild cognitive impairment, the transition from mild cognitive impairment to Alzheimer’s disease, tauopathy disorders characterized by hyperphosphorylation of tau such as argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia, and Parkinson’s disease linked to chromosome 17. Additional indications include neuroinflammation, including neuroinflammation associated with of microglial inflammatory responses associated with multiple sclerosis, HIV-induced dementia. ALS, ischemic stroke, traumatic brain injury and spinal cord injury.

[0075] In some embodiments, any of the presently described compounds, compositions and methods provide a reduction in the likelihood or severity of symptoms of Alzheimer's Disease in one or more subjects. In some embodiments, any of these compounds, compositions, and methods may provide a partial or complete reduction / inhibition of one or more symptoms. Any of the disclosed compounds, compositions, and methods may provide a partial or complete activation of the TREM2 receptor. Any of the disclosed compounds, compositions, and methods may provide a partial or complete reversal of a loss of function of human TREM2 in a subject. Any of the disclosed methods may provide an improvement in cognitive function following administration of any of the disclosed compounds. Definitions

[0076] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0077] The terms used herein have their ordinary meaning and the meaning of such terms is independent at each occurrence thereof. That notwithstanding and except where stated otherwise, the following definitions apply throughout the specification and claims. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyd” applies to “alkyl” as well as the “alkyl” portions of “hydroxyalky l,” “haloalky1,” “-O-alky1,” etc.

[0078] As used herein, and throughout this disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0079] A “subject” is a human or non-human mammal. In one embodiment, a subject is a human. In another embodiment, a subject is a primate. In another embodiment, a subject is anon-human primate, e.g., a monkey. In some embodiments, a subject is a rhesus monkey. In still another embodiment, a subject is a rodent, such as a rat. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a laboratory animal.

[0080] The term “effective amount” as used herein, refers to an amount of compound and / or an additional therapeutic agent, or a composition thereof that is effective in agonizing the human TREM2 receptor and in producing the desired therapeutic, ameliorative, or preventative effect when administered to a subject suffering from a neurodegenerative disorder. In any of the combination therapies of the present disclosure, an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount.

[0081] The terms “treating” or “treatment” as used herein with respect to a neurodegenerative disorder, includes inhibiting the severity' of a neurodegenerative disorder, e.g., arresting or reducing the development of the neurodegenerative disorder or its clinical symptoms; or ameliorating or relieving symptoms of the neurodegenerative disorder, e.g., causing regression of the severity of the neurodegenerative disorder or its clinical symptoms. For example, the disclosed compounds, pharmaceutical compositions, and methods may be useful for arresting or reducing the development of, or relieving symptoms of, Alzheimer’s Disease or neurological conditions associated with Alzheimer's Disease.

[0082] The terms “preventing.” or “prophylaxis.” as used herein with respect to a neurodegenerative disorder, encompasses impeding the development or progression of clinical symptoms of the disease, disorder, or condition in a mammal that may be exposed to or predisposed to the disease, disorder or condition but does not yet experience or display symptoms of the disease, and the like.

[0083] ‘‘Alkyl’', as well as other groups having the prefix “alk”, such as alkoxy, and the like, means carbon chains which may be linear or branched, or combinations thereof, containing the indicated number of carbon atoms. For instance, a Ci-6 alkyl means an alkyl group having one (i.e., methyl) up to 6 carbon atoms (i.e., hexyl). In particular embodiments, linear alkyl groups have 1-6 carbon atoms and branched alkyl groups have 3-7 carbon atoms. Examples of alkyd groups include methy l, ethyl, propyl, isopropyl, butyl, sec- and Ze / 7-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

[0084] Alkoxy” and “alkyl-O-” are used interchangeably and refer to an alkyl group linked to oxy gen. “Haloalkoxy” means an alkoxy that is mono-or multiple-halo-substituted. The bond to the parent group is through the oxygen atom of the group.

[0085] “Hydroxyalky 1” means a HO-alkyl- group in which alkyl is as previously defined. The bond to the parent moiety is through one of the carbon atoms of the alkyl component. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalky l groups include hydroxymethyl and 2-hydroxy ethyl.

[0086] “Alkoxyalkyl” means a RO-alkyl group in which alkyl and alkoxy are as previously defined. The bond to the parent moiety is through one of the carbon atoms of the alkyl component. Non-limiting examples of suitable alkoxyalkyl groups include 2-ethoxyethyl and 2-methoxy ethyl.

[0087] “Cycloalkyl” means a cyclic hydrocarbon radical. Unless otherwise specified, “cycloalkyl” refers to a saturated cycloalkyl. In particular embodiments, the cycloalkyl group has 3-12 carbon atoms, forming 1-3 carbocyclic rings, wherein cyclic systems having 2-3 rings can be fused. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. In certain embodiments, e.g., the cycloalkyl is fused to a hetereraryl ring, the cycloalkyl may be a non-aromatic, partially unsaturated ring.

[0088] “Fluoroalkyl” includes mono-substituted as well as multiple fluoro-substituted alkyl groups, up to perfluoro substituted alkyl. For example, fluoromethyl, 1,1-difluoroethyl, trifluoromethyl or 1,1,1,2,2-pentafluorobutyl are included. The bond to the parent group is through one of the carbon atoms of the alkyl component.

[0089] Bicyclic ring system” refers to two joined rings. “Tricyclic ring system” refers to three joined rings. “Tetracyclic ring system” refers to four joined rings. Heterocyclic and cycloalkyl rings may be fused, i.e., share two adjacent atoms, or “spirocyclic”, i.e., share only a single atom, or ‘‘bridged”, i.e., share three or more atoms with two bridgehead atoms being connected by a bridge containing at least one atom. Heteroaryl rings may be fused.

[0090] The term “halo,” as used herein, means -F, -Cl, -Br or -I. A particular class of interest of halo substituents for compounds of Formula (I) and embodiments thereof, is each of fluoro (-F) and chloro (-C1). The term “haloalkyl” refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with halo (i.e., -F, -Cl, -Br and / or -I).

[0091] The term “substituted” means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By “stable compound’ or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. When any substituent or variable (e.g., R1) occurs more than one time in any constituent or in Formula I or Formula II, its definition on each occurrence is independent of its definition at every' other occurrence, unless otherwise indicated. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0092] When a functional group in a compound is termed “protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as. for example, T. W. Greene et al., Protective Groups in Organic Synthesis (1991), Wiley, New York.

[0093] When a moiety is noted as being “optionally substituted” in Formula (I) or any embodiment thereof, it means that Formula I or Formula II, or the embodiment thereof, encompasses both compounds that are substituted with the noted substituent (or substituents) on the moiety and compounds that do not contain the noted substituent (or substituents) on the moiety (i.e., wherein the moiety is unsubstituted). As one example, when Rl is a Ci-io alkyl group that can be optionally substituted with halo, then Rl can be Ci-io alkyl or Ci-io haloalkyl.

[0094] When any variable (e.g., Rl, Rx, RY) occurs more than one time in any constituent or in Formula (I), or in any other formula depicting and describing compounds of the present invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., cycloalkyl, aryl, or heteroaryl) provided such ring substitution is chemically allowed and results in a stable compound.

[0095] Unless expressly stated to the contrary, all ranges cited herein are inclusive of the recited endpoints and independently combinable. For example, the range of‘"between about 0.5 and about 95 percent7’ is inclusive of the endpoints (about) 0.5 percent and (about) 95 percent, and all intermediate values. The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0096] As used herein, "heteroaryl” or “heteroaromatic ring” refers to aromatic monocyclic, bicyclic, tricyclic, or tetracyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon. Heteroatoms are typically O, S, orN atoms. Examples of heteroaryl groups include pyrazolyl, oxadiazolonyl, pyridinyl, pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl, indolyl, benzoxazolyl, benzothiazolyl, and imidazolyl.

[0097] Heterocycloalkyl” or “heterocyclic ring” or “heterocycle” or “heterocyclyl” (when the ring is bonded to a parent moiety ) means a non-aromatic monocyclic, bicyclic, tricyclic or tetracyclic ring system comprising about 3 to about 17 ring atoms, preferably about 3 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphorus or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the ring system. In some embodiments, heterocycloalkyls contain about 5 to about 6 ring atoms. The prefix aza, oxa, phospha or thia before the heterocyclyl root name means that at least a nitrogen, oxygen, phosphorus or sulfur atom respectively is present as a ring atom. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like. “Spiroheterocycloalkyl” refers to a fused ring system in which the rings share only a single atom and at least one of the rings is a heterocycloalkyl.

[0098] In some embodiments, the compounds disclosed herein contain a heteroaryl substituent containing one nitrogen atom. It is also to be understood that any range cited herein includes within its scope all of the sub-ranges within that range. Thus, for example, a "‘heterocyclic” ring is intended to include as aspects thereof, heterocyclic rings containing 2 to 4 heteroatoms, 3 or 4 heteroatoms, 1 to 3 heteroatoms, 2 or 3 heteroatoms, 1 or 2 heteroatoms, 1 heteroatom, 2 heteroatoms, 3 heteroatoms, or 4 heteroatoms. For instance, the ring may contain one or more nitrogen atoms (e.g., 1 to 3 nitrogen atoms), one or more oxygen atoms, or one or more sulfur atoms. Any of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups described herein may be optionally substituted with one or more groups. As used herein, “optionally substituted with one to five groups’" is intended to include as aspects thereof, the cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with 1 to 5 substituents. 2 to 5 substituents. 3 to 5 substituents. 4 to 5 substituents, 5 substituents, 1 to 4 substituents, 2 to 4 substituents, 3 to 4 substituents, 4 substituents, 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent. Likewise, as used herein, “optionally substituted with one to three groups"’ is intended to include as aspects thereof, the cycloalkyl, heterocyclyl, aryl or heteroaryl substituted with 1 to 3 substituents, 2 to 3 substituents, 3 substituents, 1 to 2 substituents, 2 substituents, and 1 substituent.

[0099] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results from combination of the specified ingredients in the specified amounts.

[0100] The term “salt(s)”, as used herein, denotes acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Compounds can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise rious to the recipient thereof).

[0101] The compounds of Formula (I), which contain one or more basic groups, i.e., groups w hich can be protonated, can be used according to the invention in the form of their acid addition salts with inorganic or organic acids as, for example but not limited to, salts with hydrogen chloride, hydrogen fluoride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, benzenesulfonic acid, methanesulfonic acid. / Moluenesul fonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid. etc.

[0102] In some embodiments, one or more N atoms (e.g., an N atom in a heteroaryl or heterocyclyl ring, or an N atom in an NH2 group) of any of the compounds of Formula I is protonated in a salt form. In some embodiments, an N atom that is a ring member of a heteroaryl or heterocyclyl ring of any of the compounds of Formula (I) is protonated in a salt form. In some embodiments, this N atom is protonated in a salt form with trifluoroacetate. If the compounds of Formula (I) simultaneously contain acidic and basic groups in the molecule the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula (I) by customary’ methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts. The present disclosure also includes all salts of the compounds of Formula (I) which, ow ing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0103] The present disclosure encompasses any composition comprised of a compound of Formula (I) or a compound that is a salt thereof, including for example but not limited to, a composition comprised of said compound associated together with one or more additional molecular and / or ionic component(s) which may be referred to as a “co-crystal.” The term “cocrystal” as used herein refers to a solid phase (which may or may not be crystalline) wherein two or more different molecular and / or ionic components (generally in a stoichiometric ratio) are held together by non-ionic interactions including but not limited to hydrogen-bonding, dipole-dipole interactions, dipole-quadrupole interactions or dispersion forces (van der Waals). There is no proton transfer between the dissimilar components and the solid phase is neither a simple salt nor a solvate. A discussion of co-crystals can be found, e.g., in Aitipamula et al., Crystal Growth and Design, 2012, 12 (5), pp. 2147-2152.

[0104] Compounds of the present invention may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula (I) are intended to be included within the scope of the present invention. In addition, some of the compounds of the instant invention may form solvates with water (i.e., a hydrate) or common organic solvents. Such solvates and hydrates, particularly the pharmaceutically acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhydrous forms. Accordingly, the compounds within the generic structural formulas, embodiments and specific compounds described and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts thereof. Salts, Solvates and Stereoisomers

[0105] Solvates of the disclosed compounds of Formula (I) are contemplated herein. One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain situations, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate wherein the solvent molecule is water.

[0106] One or more compounds of Formula (I) may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al., J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al., AAPSPharmSciTech., 5(1), article 12 (2004); and A. L. Bingham et al., Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than room temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[0107] The compounds of Formula (I) can form salts which are also within the scope of this invention. In some embodiments, the salt is a pharmaceutically acceptable salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the compounds of Formula I and Formula II may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0108] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al.. Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

[0109] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogencontaining groups may be quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), arylalkyl halides (e g., benzyl and phenethyl bromides), and others.

[0110] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. [OlH] This disclosure includes individual diastereomers, particularly epimers, i.e., compounds having the same chemical formula but which differ in the spatial arrangement around a single atom. This disclosure also includes mixtures of diastereomers, particularly mixtures of epimers, in all ratios. This disclosure encompasses compounds of Formula (I) having either the R or S stereo-configuration at an asymmetric center and at any additional asymmetric centers that may be present in a compound of Formula (I), as w ell as stereo-isomeric mixtures thereof. Embodiments of this disclosure also include a mixture of enantiomers enriched with 51% or more of one of the enantiomers, including for example 60% or more, 70% or more, 80% or more, or 90% or more of one enantiomer. A single epimer is preferred. An individual or single enantiomer refers to an enantiomer obtained by chiral synthesis and / or using generally known separation and purification techniques, and which may be 100% of one enantiomer or may contain small amounts (e.g., 10% or less) of the opposite enantiomer. Thus, individual enantiomers are a subject of this disclosure in pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism this disclosure includes both the cis form and the trans form as well as mixtures of these forms in all ratios.

[0112] The preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be carried out at an intermediate step during the synthesis of a compound of Formula (I), or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Alternatively, absolute stereochemistry may be determined by Vibrational Circular Dichroism (VCD) spectroscopy analysis. The present disclosure includes all such isomers, as well as salts, solvates (which includes hydrates), and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0113] Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be directly separated using chiral chromatographic techniques.

[0114] It is also possible that the compounds of Formula I and / or Formula II may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. For example, each of the keto / enol and imine / enamine tautomeric forms of the disclosed compounds are encompassed within embodiments of the disclosed compounds that depict either form individually. As another example, both the hydroxypyridine and pyridinone forms of oxosubstituted pyridine substituents are encompassed within embodiments of the disclosed compounds that depict either form individually.

[0115] Unless otherwise indicated, all stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If a compound incorporates a double bond or a fused ring, both the cis- and transforms, as well as mixtures, are embraced within the scope of the invention.

[0116] When a substituent on a chiral carbon atom is depicted without specific stereochemistry (by using a straight-line bond to a chiral center), it is to be understood that both the alpha and beta configurations of said substituent group are to be considered part of the present invention. It is understood that a chiral center in a compound may exist in the S' or R absolute configuration, or as a mixture of both. Within a molecule, each bond drawn as a straight line from a chiral center includes both the R and S’ stereoisomers as well as mixtures thereof. An asterisk denotes a stereocenter in a single configuration, either R or S. Absolute stereochemistry of separate stereoisomers in the examples and intermediates may not have been determined unless stated otherwise in an example or explicitly in the nomenclature. Otherwise, for compounds in the Examples that contain a chiral center, isomer mixtures may have been separated, yielding the particular stereoisomer(s) depicted.

[0117] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S orR configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate" and the like, is intended to apply equally to the salt and solvate of enantiomers, stereoisomers, rotamers, tautomers or racemates of the disclosed compounds.

[0118] In the compounds of Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula (I). For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds of Formula (I) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates. In one embodiment, a compound of Formula (I) has one or more of its hydrogen atoms replaced with deuterium.

[0119] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry', and peptide chemistry are those well-known and commonly employed in the art.

[0120] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0121] As used herein, the term “about” when modifying a quantitative term refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules).

[0122] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 100 mg to 1500 mg” is inclusive of the endpoints, 100 mg and 1500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0123] As used herein, the term “comprising” may include the embodiments “consisting of' and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having.” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds. TREM2 Agonism and Neurodegenerative Conditions

[0124] Impairment in TREM2 receptor function has been linked to several human diseases. For instance, mutations in both TREM2 and DAP 12 have been linked to the autosomal recessive disorder Nasu-Hakola Disease, which is characterized by bone cysts, muscle wasting and demyelination phenotypes. Guerreiro et al. 2013. Variants in the TREM2 gene have been linked to increased risk for Alzheimer’s disease (AD) and other forms of dementia including frontotemporal dementia. (Jonsson et al. 2013, Guerreiro & Lohmann et al. 2013, and Jay & Miller et al. 2015.) In particular, the R47H variant has been identified in genome-wide studies as being associated with increased risk for late-onset AD with an overall adjusted odds ratio (for populations of all ages) of 2.3, second only to the strong genetic association of ApoE to AD. The R47H mutation resides on the extracellular IgV-set domain of the TREM2 protein and has been shown to impact lipid binding and uptake of apoptotic cells and amyloid-P (Wang et al. 2015; Yeh et al. 2016), suggestive of a loss-of-function linked to disease. Further, postmortem comparison of AD patients’ brains with and without the R47H mutation are supportive of a novel loss-of-microglial barrier function for the carriers of the mutation, with the R47H carrier microglia putatively demonstrating a reduced ability to compact plaques and limit their spread. Yuan et al. 2016. Impairment in microgliosis has been reported in animal models of prion disease, multiple sclerosis, and stroke, suggesting that TREM2 may play an important role in supporting microgliosis in response to pathology7 or damage in the CNS. Ulrich and Holtzman 2016.

[0125] In addition, knockdown of TREM2 has been shown to aggravate a-synuclein-induced inflammatory' responses in vitro and exacerbate dopaminergic neuron loss in response to adeno-associated viral (AAV) vectors encoding synuclein in vivo (a model of Parkinson's disease), suggesting that impaired microglial TREM2 signaling exacerbates neurodegeneration bymodulating microglial activation states. Guo et al. 2019. A variety of animal models also suggest that Toll-Like Receptor (TLR) signaling is important in the pathogenesis of Rheumatoid Arthritis (RA) via persistent expression of pro-inflammatory cytokines by macrophages. Signaling through TREM2 / DAP12 inhibits TLR responses by reducing MAPK (Erkl / 2) activation, suggesting that TREM2 activation may act as a negative regulator of TLR driven RA pathogenesis. Signaling through DAP 10 and DAP 12 also elicits recruitment of PI3K and SYK, which drive multiple doyvnstream events resulting in Ca2+ mobilization and activation of MAPK-mediated cascades as yvell as other pathyvays.

[0126] In vieyv of the data indicating that deficiency in TREM2 activity affects macrophage and microglia function, the TREM2 agonist compounds disclosed herein are of particular use in treating, preventing, and / or reducing the severity of disorders such as those described below, and in neurodegenerative disorders more generally.

[0127] TREM2 consists of a single-pass transmembrane domain, an extracellular stalk region, and extracellular immunoglobulin variable-like (IgV) domain responsible for ligand interaction (Kleinberger et al. Sci TranslMed, 2014). As TREM2 does not possess intracellular signal transduction-mediating domains, biochemical analysis has illustrated that interaction with adaptor proteins DAP 10 and DAP 12 mediate doyvnstream signal transduction following ligand recognition (Peng et al. Sci Signal 2010; Jay et al. Mol Neurodegener, 2017). TREM2 / DAP12 complexes in particular act as a signaling unit that can be characterized as pro-activation on microglial phenotypes in addition to peripheral macrophages and osteoclasts (Otero et al. J Immunol, 2012; Kobayashi et al. JNeurosci, 2016; Jaitin et al., Cell, 2019. In the CNS, signaling through TREM2 has been studied in the context of ligands such as phospholipids, cellular debris, apolipoproteins, and myelin (Wang et al. Cell, 2015; Kober and Brett, J Mol Biol, 2017; Shirotani et al., Sci Rep, 2019). In mice lacking functional TREM2 expression or expressing a mutated form of the receptor, a core observation is blunted microglial responses to insults such as oligodendrocyte demyelination, stroke-induced tissue damage in the brain, and proteotoxic inclusions in vivo (Cantoni et al., Acta Neuropathol, 2015, Wu et al., Mol Brain, 2017).

[0128] In rodent models where TRFM2 expression levels are elevated, brain amyloid pathology in the 5XF AD transgenic mice displayed reduced plaque volume and altered morphology (Lee et al. Neuron, 2018). The changes in immunohistological markers relating to brain amyloid pathology were also accompanied by an attenuated presence of dystrophic neurites when TREM2 was overexpressed. Id. As such, pharmacological agonism of TREM2 has gained interest in treating or preventing neurodegenerative disorders and conditions.

[0129] Genetic variation in the TREM2 locus has been associated with late onset al.zheimer's disease (“LOAD”) in human genome-wide association studies, linking a loss-of-receptor function to a gain in disease risk (Jonsson et al. N Engl J Med 2013, Sims et al. Nat Genet 2017). Genetic variation of other genes selectively expressed by microglia in the CNS, for example, CD33, PLCg2 and MS4A4A / 6A have reached genome-wide significance for their association with LOAD risk (Hollingworth et al. Nat Genet 2011, Sims et al. Nat Genet 2017, Deming et al. Sci TranslMed 2019). Together, these genetic findings link together in a putative biochemical circuit that highlights the importance of microglial innate immune function in LOAD. Additionally, increase or elevation in the soluble form of TREM2 (“sTREM2”) in the cerebrospinal fluid (CSF) of human subjects is associated with disease progression and emergence of pathological hallmarks of LOAD including phosphorylated Tau (Suarez-Calvet et al. Mol Neurodegener 2019). Furthermore, natural history and human biology studies indicate that baseline sTREM2 levels in the CSF can stratily the rate of temporal lobe volume loss and episodic memory decline in longitudinally monitored cohorts (Ewers et al. Sci Transl Med 2019). Additional studies have revealed that CSF sTREM2 levels are elevated in the earlier course of AD and attenuated in the dementia stage (Liu etal., 2018), and are elevated following brain amyloidosis, CSF phosphorylation, and total tau protein increases (Halaas et al., 2020).

[0130] Accordingly, provided herein are methods of administering any of the disclosed compounds, or a pharmaceutically acceptable salt thereof, for treatment or prevention of LOAD. Further provided herein are methods for treatment or prevention of a condition associated with a loss of function of human TREM2, human DAP12 or human DAP10. Further provided herein are methods for reducing the amount of sTREM2 in the CSF of a subject.

[0131] In addition to human genetic evidence supporting a role of TREM2 in LOAD, homozygous loss-of-function mutations in TREM2 are causal for an early onset dementia syndrome known as Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (“PLOSL’') or Nasu-Hakola disease (“NHD”) (Golde et al. Alzheimers Res Tuer 2013, Dardiotis et al. Neurobiol Aging 2017). This progressive neurodegenerative disease typically manifests in the third decade of life and is pathologically characterized by loss of myelin in the brain concomitant with gliosis, unresolved neuroinflammation, and cerebral atrophy. Typical neuropsychiatric presentations are often preceded by osseous abnormalities, such as bone cysts and loss of peripheral bone density (Bianchin et al. Cell Mol Neurobiol 2004; Madry et al. Clin Orthop Relat Res 2007, Bianchin et al. Nat Rev Neural 2010). Given that osteoclasts of the myeloid lineage are also know n to express TREM2, the PLOSL-related symptoms of wrist and ankle pain, swelling, and fractures indicate that TREM2 may act to regulate bone homeostasis through defined signaling pathways that parallel the microglia in the CNS (Paloneva et al. J Exp Med 2003, Otero et al. J Immunol 2012). The link between TREM2 function and PLOSL / NHD and other adult-onset leukoencephalopathies has illustrated the importance of the receptor in sustaining key aspects of myeloid cell function in the human body.

[0132] Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously recognized as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmentary orthochromatic leukodystrophy (POLD). is an autosomal-dominant central nervous system disease that manifests in the form of variable behavioral, cognitive and motor function changes in patients suffering from the disease. ALSP is characterized by patchy cerebral white matter abnormalities visible by magnetic resonance imaging. However, the clinical symptoms and MRI changes are not specific to ALSP and are common for other neurological conditions, including Nasu-Hakola disease (NHD) and AD, making diagnosis and treatment of ALSP very difficult. Recent studies have discovered that ALSP is a Mendelian disorder in which patients carry' a heterozy gous loss of function mutation in the kinase domain of CSF-1R, suggesting a reduced level of signaling on the macrophage colony-stimulating factor (M-CSF) / CSF-1R axis. CSF-1R is a macrophage colony-stimulating factor (M-CSF), which regulates the survival, proliferation, differentiation and function of mononuclear phagocytic cells, including microglia of the central nervous system.

[0133] Accordingly, provided herein are methods of administering any of the disclosed compounds, or a pharmaceutically acceptable salt thereof, for treatment or prevention of PLOSL. Further provided herein are methods of administering any of the disclosed compounds for treatment or prevention of NHD. Further provided herein are methods of administering any of the disclosed compounds for treatment or prevention of adult-onset leukoencephalopathy, with or without axonal spheroids and pigmented glia. Further provided herein are methods of administering any of the disclosed compounds for treatment or prevention of ALSP.

[0134] Further provided herein are methods of administering any of the disclosed compounds, or a pharmaceutically acceptable salt thereof, for treatment or prevention of argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia, Parkinson’s disease linked to chromosome 17, HIV-induced dementia or neuroinflammation.

[0135] In addition to the CNS, TREM2 is expressed in myeloid lineage cells of the liver. In some embodiments, these compounds, or a pharmaceutically acceptable salt thereof, may be useful to treat or prevent a liver disease associated with impaired TREM2 function. In some embodiments, these compounds are useful to treat or prevent alcoholic liver disease (ALD) or non-alcoholic steatohepatitis (NASH).

[0136] In various embodiments of any of the disclosed methods, the subject suffers from the disorder or condition being treated. In various embodiments, the subject is human.

[0137] In other embodiments, the subject is a non-human mammal. In some embodiments, the subject is a companion animal. In some embodiments, the subject is a laboratory animal. In some embodiments, the subject is a rodent. In some embodiments, the subject is anon-human primate. Formulations

[0138] When administered to a subject, any of the disclosed compounds of Formula I and Formula II. or a pharmaceutically acceptable salt thereof, may be administered as a component of a composition that comprises a pharmaceutically acceptable carrier. The present disclosure provides pharmaceutical compositions comprising an effective amount of at least one of the disclosed compounds and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, adapted for oral administration in the form of tablets or capsules, any of the disclosed compounds may be combined with any pharmaceutically acceptable inert carrier. Solid form preparations include powders, tablets, dispersible granules, capsules, sachets and suppositories. Tablets, powders, sachets and capsules may be suitable for oral administration. Powders and tablets may be comprised of between about 0.5 and about 95 percent of any of the disclosed pharmaceutical compositions.

[0139] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films.

[0140] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0141] Moreover, when desired or needed, suitable binders, glidants. lubricants, disintegrating agents and coloring agents may also be incorporated in the composition, particularly in formulations for oral administration. The compositions may be formulated for extended or controlled release. In other embodiments, the compositions are formulated for immediate or modified release.

[0142] In particular embodiments, the compositions of the present invention may be formulated in extended dosing, or sustained release, forms to provide a rate-controlled release of any one or more of the components or active ingredients to optimize therapeutic effects, i.e., TREM2 activation. Suitable dosage forms for sustained release include long-acting injectable and implant dosage forms. Other suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

[0143] Solid preparations suitable for oral administration (e.g., powders, pills, capsules and tablets) can be prepared according to techniques know n in the art and can employ such solid excipients as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. These preparations may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Liquid preparations suitable for oral administration (e.g., suspensions, syrups, elixirs and the like) can be prepared according to techniques known in the art and can employ any of the usual media such as water, glycols, oils, alcohols and the like.

[0144] In some embodiments, any of the disclosed pharmaceutical compositions comprise pharmaceutically acceptable carriers that are suitable or adapted for administration to the subject by injection. In some embodiments, these carriers are adapted for long-action injection. In some embodiments, these carriers are liquid form preparations that include solutions, suspensions, emulsions, or nano-emulsions for intramuscular or subcutaneous administration. In some embodiments, any of the disclosed pharmaceutical compositions are adapted for long-acting injectable formulations.

[0145] Any of the disclosed compositions may comprise pharmaceutically acceptable carriers that are suitable or adapted for administration parenterally, including subcutaneous, intravenous, intramuscular, intraperitoneal or intrastemal injection, or other infusion techniques (one or more injections or infusions may be administered at each dosing interval as needed to deliver the appropriate amount of active agent), in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and conventional pharmaceutically acceptable carriers, adjuvants and vehicles for the treatment of a subject suffering from a neurodegenerative disorder. The compositions may also be administered parenterally via an implantable drug delivery' composition or device adapted to provide an effective amount of the compound over an extended period of time. In some embodiments, the composition is administered parenterally once per month, once per every three months, once per every' six months, or once per every twelve months.

[0146] In some embodiments, the disclosed compositions are adapted for intramuscular administration. In some embodiments, the disclosed compositions are adapted for subcutaneous administration. In some embodiments, the disclosed compositions are adapted for intravenous administration. In some embodiments, the disclosed compositions are adapted for intraperitoneal administration. In some embodiments, the disclosed compositions are adapted for intracerebroventricular (ICV), intrathecal, or intracistemal administration. In some embodiments, the disclosed compositions may be adapted for inhalation spray, intranasal, vaginal, rectal, sublingual, buccal or topical routes of administration.

[0147] Parenteral compositions can be prepared according to techniques known in the art. These compositions may employ sterile water as a carrier and optionally other ingredients. A continuous dosing regimen may be used for subjects suffering from a neurodegenerative disease, such as Alzheimer’s Disease. Any of the disclosed pharmaceutical preparations for parenteral injection may comprise solutions, suspensions or emulsions that may include water, a suspending agent, a viscosity modifier, a tonicity modifier, and / or a pH modifier.

[0148] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions, emulsions and nano-emulsions. Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as a solubility aid. Injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose. Implantable compositions can be prepared according to methods known in the art wherein the carrier comprises the active chemical ingredient with polymers and suitable excipients, or utilizing an implantable device for drug delivery. Further description of methods suitable for use in preparing pharmaceutical compositions for use in the present disclosure and of ingredients suitable for use in said compositions is provided in Remington - The Science and Practice of Pharmacy, 22nd Edition, published by Pharmaceutical Press and Philadelphia College of Pharmacy at University of the Sciences. 2012, ISBN 978 0 85711-062-6 and prior editions.

[0149] Formulations of compounds of Formula I that result in drug supersaturation and / or rapid dissolution may be utilized to facilitate oral drug absorption. Formulation approaches to cause drug supersaturation and / or rapid dissolution include, but are not limited to, nanoparticulate systems, amorphous systems, solid solutions, solid dispersions, and lipid systems. Such formulation approaches and techniques for preparing them are known in the art. For example, solid dispersions can be prepared using excipients and processes as described in reviews (e.g., A.T.M. Serajuddin, JPharm Sci, 88:10, pp. 1058-1066 (1999)). Nanoparticulate systems based on both attrition and direct synthesis have also been described in reviews such as Wu et al. (F. Kesisoglou, S. Panmai, Y. Wu, Advanced Drug Delivery Reviews, 59:7 pp. 631-644 (2007)).

[0150] The compounds of Formula I may be administered in a dosage range of, e.g., 1 to 20 mg / kg, or 1 to 10 mg / kg, or about 5 mg / kg of mammal (e.g., human) body w eight per day, or at other time intervals as appropriate, in a single dose or in divided doses. The compounds of Formula I may be administered in a dosage range of 0.001 to 2000 mg per day in a single dose or in divided doses. Examples of dosage ranges are 0.01 to 1500 mg per day, or 0.1 to 1000 mg per day, administered orally or via other routes of administration in a single dose or in divided doses.

[0151] For oral (e.g.. tablets or capsules) or other routes of administration, the dosage units may contain 100 mg to 1500 mg of the active ingredient, for example but not limited to 0.1 mg to about 1500 mg of the active ingredient, for example but not limited to 0.1, 0.25, 0.5, 1, 2, 2.5, 5, 10, 15, 20, 25, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 500, 1000, 1250, or 1500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. Furthermore, the compound may be formulated in oral formulations for immediate or modified release such as extended or controlled release. When the compound of Formula I is administered as a salt, reference to an amount of the compound in milligrams or grams is based on the free form (i.e., the non-salt form) of the compound.

[0152] Daily administration can be via any suitable route of administration but is preferably via oral administration and can be a single dose or more than one dose at staggered times (divided daily doses) within each 24-hour period. Each dose may be administered using one or multiple dosage units as appropriate. In some embodiments, the disclosed compounds and compositions are administered once daily. In some embodiments, the disclosed compounds and compositions are administered twice daily.

[0153] The specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, the effect of other drugs the subject is taking, the severity of the particular condition, and the host undergoing therapy. In some cases, depending on the potency of the compound or the individual response, it may be necessary to deviate upwards or downwards from the given dose. The amount and frequency of administration will be regulated according to the judgment of the attending clinician considering such factors.

[0154] The compounds of this invention are also useful in the preparation and execution of screening assays for agonists of TREM2. Furthermore, the compounds of this invention may be useful in establishing or determining the binding site of other TREM2 agonists.

[0155] Additional embodiments of the present disclosure include the following: (a) a pharmaceutical composition comprising an effective amount of a compound of Formula I or II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and (b) a pharmaceutical composition which comprises the product prepared by combining (e.g., mixing) an effective amount of a compound of Formula I or II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0156] Additional embodiments of the present disclosure include each of the pharmaceutical compositions, methods and uses set forth in the preceding paragraphs, wherein the compound of Formula I or its salt employed therein in substantially pure. With respect to a pharmaceutical composition comprising a compound of Formula I or II or its salt and a pharmaceutically acceptable carrier and optionally one or more excipients, it is understood that the term "‘substantially pure7’ is in reference to a compound of Formula I or II or its salt per se. Combination Therapies

[0157] In some aspects, the present methods for treating or preventing a neurodegenerative disorder can further comprise the administration of one or more additional therapeutic agents that are not any of the disclosed compounds.

[0158] Examples of additional therapeutic agents that the compounds of this disclosure may also be combined with include, without limitation, treatments for Alzheimer’s disease, Parkinson's disease, rheumatoid arthritis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, demyelination disorder, Huntington’s disease, amyotrophic lateral sclerosis (ALS), tauopathy disease, adult-onset leukoencephalopathy, argyrophilic grain disease, Picks disease, corticobasal degeneration, progressive supranuclear palsy, HIV-induced dementia, or neuroinflammation.

[0159] Accordingly, in one embodiment, the present invention provides methods for treating a neurodegenerative disorder in a subject, the method comprising administering to the subject: (i) at least one compound of Formula I or Formula II (which may include two or more different compounds), or a pharmaceutically acceptable salt thereof, and (ii) at least one additional therapeutic agent that is other than any of the disclosed compounds, wherein the amounts administered are together effective to treat or prevent a neurodegenerative disorder.

[0160] In some embodiments, the additional therapeutic agent is a tau targeting therapy. In some embodiments, the additional therapeutic agent is an amyloid-0 targeting therapy. Administration of a tau targeting therapyor an amyloid-0 targeting therapy has been shown to improve cognitive function, reverse (partially) the neurodegenerative effects of Alzheimer’s Disease, and / or treat or prevent Alzheimer’s Disease. Accordingly, provided herein are methods of administering any of the disclosed compounds wherein the methods further comprise a step of administering a tau targeting therapyor an amyloid-0 targeting therapyto the subject. Such methods may be used to promote the treatment or prevention of a neurodegenerative disorder in a subject. Such methods may be used to promote the treatment or prevention of AD in a subject.

[0161] When administering a combination therapy of the invention to a subject, therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, a compound and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like). In some embodiments, any of the disclosed compounds or a pharmaceutically acceptable salt thereof, is administered orally, and the additional therapeutic agent is further administered orally. When administered orally, the compound and the other agent(s) may be administered simultaneously (i.e.. in separate compositions one right after the other) or sequentially.

[0162] In some embodiments, a disclosed compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours. 10 hours, 11 hours, 12 hours, 13 hours. 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a disclosed compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.

[0163] In one embodiment, at least one compound is administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.

[0164] In another embodiment, at least one compound and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy. In another embodiment, at least one compound and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy.

[0165] In some embodiments, the additional therapeutic agent(s) is present in a pharmaceutical composition. In one embodiment, this composition is suitable for subcutaneous administration. In another embodiment, this composition is suitable for intramuscular administration. In another embodiment, this composition is suitable for oral administration. In still another embodiment, this composition is suitable for intravenous administration.

[0166] The at least one compound and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and / or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of therapy without reducing the efficacy of therapy.

[0167] The doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a neurodegenerative disorder may be determined by the attending clinician, taking into consideration the approved doses and dosage regimen in the package insert; the age. sex and general health of the subject; and the type and severity of the neurodegenerative disease or neurological symptoms thereof. When administered in combination, the compound and the other agent(s) may be administered simultaneously (i.e., in the same composition or in separate compositions one right after the other) or sequentially. This is particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another component is administered every six hours, or when the pharmaceutical compositions are different, e.g., one is a tablet and one is a capsule. A kit comprising the separate dosage forms is therefore advantageous. Abbreviations

[0168] The abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise. ACN acetonitrile AcOH acetic acid aq aqueous Boc tert-butoxycarbamate BOC2O di-te / 7-butyl dicarbonate BPD bis(pinacolato)diboron BTMG 2-tert-butyl -1,1,3,3 -tetramethylguanidine Bu3SnCl tributyltin chloride °C degrees Celsius calc'd Calculated cataCXium A-Pd-G2 chloro[(di(l-adamantyl)-A-butylphosphine)-2-(2-aminobiphenyl)lpalladium(II) CDCI3 deuterated chlorofonn CD3OD deuterated methanol Cs2CO3 cesium carbonate CuTC Copper (I) thiophene-2-carboxylate cone concentrated DAST Diethylaminosulfur trifluoride DCM Dichloromethane DCE dichloroethane DIEA Diisopropylethylamine DMA Dimethylacetamide DMF Dimethylformamide DMSO Dimethylsulfoxide eq or equiv equivalents ESI electron spray ionization EtOAc ethyl acetate EtOH Ethanol h hours HC1 Hydrochloric acid 1HNMR proton nuclear magnetic resonance (data) HPLC high performance liquid chromatography IC50 inhibitory concentration at 50% maximum response In(OTf)3 Indium triflate iPrOH Isopropyl alcohol LCMS liquid chromatography mass spectrometry MeCN acetonitrile MeOH methanol MHz Megahertz min minutes MS mass spectrum (data) Nai Sodium iodide NaOAc sodium acetate Na2SO4 Sodium sulfate NBS N -bromosuccinimide Ni(II)C12 gEmc Nickel (II) chloride ethylene glycol dimethyl ether complex NMR nuclear magnetic resonance (data) KOAc potassium acetate K3PO4 potassium phosphate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) PdCl2(dppf) [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl2(dtbpI) [1,1 '-bis(di-rert-butylphosphino)ferrocene]dichloropalladium(II) PdC12(PPh3)4 bis(triphenylphosphine)palladium(II) dichloride Pd(Pli3)4 Tetrakis (triphenylphosphine)palladium (0) P(NMe2)3 tris(dimethylamino)phosphine POC13 Phosphoryl chloride PPA Polyphosphoric acid P(tBu)3 Pd G2 (Chloro [ (tri- tert -butylphosphine)-2- (2-aminobiphenyl)l palladium (II)) RT room temperature RuPhosPd G3 (2-Dicyclohexylphosphino- 2',6'-diisopropoxy-l,l'-biphenyl) [2- (2'-amino-l,l'-bipheny 1)1 palladium (II) methanesulfonate sat saturated SFC supercritical fluid chromatography TBAI Tetrabutylammonium iodide TEA triethylamine TFA trifluoroacetic acid TFAA Trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography %wt weight percentage XPhos 2-dicy clohexy lphosphino-2 ',46 '-triisopropy Ibipheny 1 XPhos-Pd-G2 chloro(2-dicyclohexy lphosphino-2 ’ .4’ ,6 ’ -triisopropy 1-1,1 '-biphenyl) [2-(2'-amino-1,1 '-biphenyl)lpalladium(II) XPhos-Pd-G3 methanesulfonato(2-dicyclohexylphosphino-2',4'.6'-triisopropyl-l.l'-biphenyl)[2-(2'-amino-l.l'-biphenyl)lpalladium(II) XPhos-Pd-G4 methanesulfonato(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-methylamino-l,T-biphenyl)]palladium(II) Zn Zinc GENERAL SYNTHETIC SCHEMES

[0169] The following reaction schemes and Examples illustrate methods which may be employed for the synthesis of the compounds of structural Formula I described in this invention. These reaction schemes and Examples are provided to illustrate the invention and are not to be construed as limiting the invention in any manner. All substituents are as defined above unless indicated otherwise. Several strategies based upon synthetic transformations known in the literature of organic synthesis may be employed for the preparation of the compounds of structural Formula I and II.

[0170] The compounds of the present disclosure can be prepared according to the procedures of the following Examples, using appropriate materials. The compounds illustrated in the examples are not. however, to be construed as forming the only genus that is considered as the invention. The Examples further illustrate details for the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of protecting groups, as well as of the conditions and processes of the following preparative procedures, can be used to prepare these compounds. It is also understood that whenever a particular chemical reagent is not commercially available, such a chemical reagent can be readily prepared following one of numerous methods described in the literature. Scheme 1-1 H R4sN'R5S Palladium C-N coupling

[0171] A general synthetic approach to some of the chemical matter is outlined in Scheme 1-1. In the first step of Scheme 1-1, the R1 and R2groups are installed from commercial materials using a condensation reaction. In step two, R3 can be installed via a Suzuki reaction. The installation of the R4S and R5S groups is done through a palladium-catalyzed C-N coupling. Scheme 1-2 Nickel C-C coupling

[0172] A general synthetic approach to some of the chemical matter is outlined in Scheme 1-2. In the first step of Scheme 1-2, the R4S and R5Sgroups are installed through a Nickel-catalyzed C- C coupling. Scheme 2-1 Acid catalyzed condensation p3S r'nh r4S Pd-catalyzed C-N coupling R3 I ho"b'oh Pd-catalyzed C-C bond formation

[0173] A general synthetic approach to some of the chemical matter is outlined in Scheme 2-1. In the first step of Scheme 2-1, the R1 and R2groups are installed through an acid catalyzed condensation reaction with a ketoester, then a Pd-catalyzed C-N coupling reaction installs R3S and R4S. Finally, a Palladium-catalyzed C-C bond formation installs R3. Scheme 2-2

[0174] A general synthetic approach to some of the chemical matter is outlined in Scheme 2-2. In the first step of Scheme 2-2, the R3S and R4Sgroups are installed through nickel-catalyzed C-C bond formation, then a Pd-catalyzed C-C coupling reaction installs R3. R3 ho'b'oh Pd-catalyzed C-C bond formation R4S Pd-catalyzed C-N coupling OR Ni-catalyzed C-C coupling

[0175] A general synthetic approach to some of the chemical matter is outlined in Scheme 2-3. In the first step of Scheme 2-3, the R3 is installed via a Palladium-catalyzed C-C bond forming reaction. Finally, through a metal-catalyzed C-N or C-C bond forming reaction, R3S and R4S are installed. Scheme 3-1 dehydration R3 Palladium C-C coupling ho"b'oh + r4S'y'r5S Palladium C-N coupling OR Nickel C-C coupling^

[0176] A general synthetic approach to some of the chemical matter is outlined in Scheme 3-1. In the first step of Scheme 3-1, the R1 and R2groups are installed from commercial materials using a condensation reaction. In step two, R3 can be installed via a Suzuki reaction. Finally, through a metal-catalyzed C-N or C-C bond forming reaction, R3S and R4S are installed. SYNTHESIS OF INTERMEDIATES Intermediate 1: (S and R)-2.2-difluoro-6-(2-methylpvridin-4-yl)morpholine ch3no2 TEA PhCHO NaBHjCN, MeOH CICF2COONa NaH, TBAI THF, 65 °C Step 1: l-(2-methylpyridin-4-yl)-2-nitroethan-l-ol

[0177] To a solution of 2-methylisonicotinaldehyde (10 g, 83 mmol) in nitromethane (106 mL, 1981 mmol) was added TEA (23.01 mL, 165 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 5 h. The reaction solution was fdtered and concentrated in vacuo. The crude was immediately purified by flash silica gel chromatography (Eluent of 100% Ethyl acetate gradient) to give l-(2-methylpyridin-4-yl)-2-nitroethan-l-ol. MS (ESI) m / z: calc’d for C8H11N2O3 [M+H]+ 183.0, found: 183.2. 1HNMR(400 MHz, CDCh): 8 8.39 (d, J= 5.25 Hz, 1 H), 7.25 (s, 1 H), 7.17 (d, J= 5.01 Hz, 1 H), 5.46 (dd, J= 8.58, 4.05 Hz, 1 H), 4.52 - 4.58 (m, 2 H), 2.53 (s, 3 H). Step 2: 2-amino-l-(2-methylpvridin-4-yl)ethan-l-ol

[0178] To a solution of l-(2-methylpyridin-4-yl)-2-nitroethan-l-ol (10.2 g, 56.0 mmol) in THF (400 mL) / MeOH (50 mL) / AcOH (2 mL) was added Pd-C (5.96 g, 5.60 mmol) under N2. The mixture was stirred at 30 °C for 30 h under H2(30 psi). The reaction mixture was filtered, washed with THF / MeOH (200 mL x 3, V / V=l / 1) and concentrated under reduced pressure to give 2-amino-l-(2-methylpyridin-4-yl)ethan-l-ol which was used directly without purification. MS (ESI) m / z-. calcd for C8H13N2O [M+H]+: 153.2. found: 153.2. 'HNMR (CDCh, 400 MHz): 5 8.25-8.39 (m, 1H), 7.13-7.19 (m, 1H), 7.10 (br d, J= 5.1 Hz, 1H), 4.77 (br dd, J= 9.3, 2.6 Hz, 1H), 2.94-3.10 (m, 1H), 2.68-2.83 (m, 1H), 2.41-2.54 (m, 3H). Step 3: 2-(dibenzylamino)-l-(2-methvlpyridin-4-yl)ethan-l-ol

[0179] A solution of 2-amino-l-(2-methylpyridin-4-yl)ethan-l-ol (10 g, 46 mmol), AcOH (0.1 mL) in MeOH (100 mL) was stirred at 15 °C for 0.5 h, then NaBH3(CN) (5.8 g, 92 mmol) was added. The mixture was stirred at 15 °C for 1 h. The reaction mixture was poured into water (100 mL), and extracted with dichloromethane (3 x 80 mL). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 40% ethyl acetate / pet. ether gradient) to give 2-(dibenzylamino)-l -(2-methylpyridin-4-yl)ethan-l -ol. MS (ESI) m / z'. calc’d for C22H25N2O [M+H]+: 333.2, found [M+H]+: 333.2. 'H NMR (CDCls, 400 MHz): d 8.41 (d, J= 5.1 Hz, 1H), 7.28-7.41 (m, 10H), 7.04 (s, 1H), 6.97 (d, J= 5.2 Hz, 1H), 4.62 (dd, J= 10.2, 3.5 Hz, 1H), 3.91 (d, J= 13.5 Hz, 2H), 3.53 (d, J= 13.4 Hz, 2H), 2.66-2.72 (m, 1H), 2.58 (dd, J= 12.8, 10.3 Hz, 1H). 2.53 (s, 3H). Step 4: 2-(2-(dibenzvlamino)-l-(2-methvlpvridin-4-vl)ethoxv)-2.2-difluoroacetic acid

[0180] To a solution of 2-(dibenzylamino)-l-(2-methylpyridin-4-yl)ethan-l-ol (7.5 g, 22.6 mmol), TBAI (833 mg, 2.26 mmol) and sodium 2-chloro-2,2-difluoroacetate (4.47 g, 29.3 mmol) in THF (80 mL) was added NaH (1.81 g, 45.1 mmol) at 0 °C, and the resulting mixture was allowed to warm to 65 °C. The mixture was stirred at 65 °C for 3 d. The mixture was quenched with water (100 mL) and extracted with EtOAc (80 mL x 3). The organic layers were concentrated to give 2-(2-(dibenzylamino)-l-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetic acid. The water layer was concentrated under reduced pressure to give crude product 2-(2-(dibenzylamino)-l-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetic acid which was used directly. MS (ESI) m / z'. calc’d for C24H25F2N2O3 [M+H]+: 427.2, found: 427.2. Step 5: methyl 2-(2-(dibenzvlamino)-l-(2-methvlpvridin-4-vl)ethoxv)-2.2-difluoroacetate

[0181] To a solution of 2-(2-(dibenzylamino)-l -(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetic acid (7.5 g, 16.71 mmol) in DCM (90 mL) / MeOH (30 mL) was added (trimethylsilyl)diazomethane (8.35 mL, 16.71 mmol) at 0 °C. and the resulting mixture was stirred at 15 °C for 16 h under N2. The mixture was concentrated to give a residue which was purified by flash silica gel chromatography (eluent of 30% ethyl acetate / pet. ether gradient) to give methyl 2-(2-(dibenzylamino)-l-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetate. MS (ESI) m / z-. calc’d for C25H27F2N2O3 [M+H]+: 441.2. found: 441.2. 'H NMR (CDCh, 400 MHz): <5 8.40-8.46 (m, 1H), 7.27-7.32 (m, 4H), 7.22-7.27 (m, 6H), 6.86 (s, 2H), 5.18 (t, J = 6.3 Hz, 1H), 3.87 (s, 3H), 3.69-3.76 (m, 2H), 3.58-3.66 (m, 2H), 2.90-2.98 (m, 1H), 2.76-2.84 (m, 1H), 2.52 (s, 3H). Step 6: 2.2-difluoro-6-(2-methvlpvridin-4-yl)morpholin-3-one

[0182] To a solution of methyl 2-(2-(dibenzylamino)-l-(2-methylpyridin-4-yl)ethoxy)-2,2-difluoroacetate (3.4 g, 7.72 mmol) in DCM (80 mL) was added NIS (10.4 g, 46.3 mmol) at 15 °C under N2, the resulting mixture was stirred at 40 °C for 20 h. The mixture was poured into water (100 mL) and extracted with DCM (60 mL x 3). The combined organic fractions were washed with sat. Na2S03(100 mL) and brine (100 mL), dried overNa2SO4. filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (eluent of 5% MeOH / DCM gradient) to give 2,2-difluoro-6-(2-methylpyridin-4-yl)morpholin-3-one. MS (ESI) mz: calc’d for C10H11F2N2O2 [M+H]+: 229.1, found [M+H]+: 229.1. 'HNMR (CDCL, 400 MHz): 3 8.54-8.59 (m, 1H), 7.22 (s, 1H), 7.13 (br d, J= 4.6 Hz, 1H), 5.41 (dd, J= 10.2, 3.9 Hz, 1H), 3.57-3.75 (m, 2H), 2.62 (s, 3H). StypJ7AAjmtyJf)2L22dif[uoro262C22mdhvlj3vn^^

[0183] To a solution of 2,2-difluoro-6-(2-methylpyridin-4-yl)morpholin-3-one (590 mg, 2.59 mmol) in THF (15 mL) was added BH3.DMS (0.776 mL, 7.76 mmol) under N2 at 0 °C. The reaction mixture was stirred at 55 °C for 3 h. After cooling to 0 °C, 10 mL of MeOH was added drop wise and the mixture was stirred at 55 °C for 2 h. The reaction mixture was allowed to cool to RT and the mixture was concentrated. The residue was purified by flash silica gel chromatography (eluent of 5% MeOH / DCM gradient) to give (S and R)-2,2-difluoro-6-(2-methylpyridin-4-yl)morpholine. MS (ESI) m / z'. calc’d for C10H13F2N2O [M+H]+: 215.2, found [M+H]+: 215.1. ’HNMR^DCh, 400 MHz): <5 8.48-8.54 (m, 1H), 7.16 (s, 1H), 7.06 (brd, J= 4.6 Hz, 1H), 5.09 (dd, J= 11.1, 2.7 Hz, 1H), 3.35 (br d, J= 13.6 Hz, 1H), 3.13-3.21 (m, 1H), 2.98-3.10 (m, 1H). 2.69-2.80 (m, 1H), 2.58 (s. 3H). Intermediate 2: (S and R)-4-(4.4-difluoropiperidin-3-vl)-2-methvlpvridine Step 1: tert-butyl 3-(2-methylpyridin-4-yl)-4-oxopiperidine-l-carboxylate

[0184] To a solution of 4-bromo-2-methylpyridine (10 g, 58.1 mmol) in THF (200 mL) were added tert-butyl 4-oxopiperidine-l-carboxylate (18.5 g, 93 mmol), XPhos (2.77 g, 5.81 mmol), Pd(OAc)2 (0.653 g, 2.91 mmol), sodium tert-butoxide (16.8 g, 174 mmol) at 25 °C. The mixture was stirred at 45 °C for 16 h under N2 protection. The solvent was removed under reduced pressure and the residue was dissolved in water (200 mL) and EtOAc (100 mL). The organic layer was separated and the aqueous was re-extracted with EtOAc (100 mL><3) and the combined organic layers were washed with brine (30 mLx3), dried over anhydrous MgSO4, fdtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 47% ethyl acetate / pet. ether gradient) to give tert-butyl 3-(2- methylpyridin-4-yl)-4-oxopiperidine-l-carboxylate. MS (ESI) m / z'. calc’d for C16H23N2O3 [M+H]+: 291.2, found [M+H]+: 290.9. Step 2: te / 7-butyl 4.4-difluoro-3-(2-methylpvridin-4-vl)piperidine-l-carboxylate

[0185] A mixture of tert-butyl 3-(2-methylpyridin-4-yl)-4-oxopiperidine-l-carboxylate (1 g, 3.44 mmol) in DCM (10 mL) was added DAST (4.55 mL, 34.4 mmol) at 0 °C dropwise. The resulting mixture was stirred at 20 °C for 1 h. The reaction mixture was added dropwise to aq. NaHCOs (200 mL) in ice water and adjusted pH~9. The mixture was extracted with DCM (50 mLx3). The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC (water (0.1%TFA) / MeCN) to give tert-butyl 4,4-difluoro-3-(2-methylpyridin-4-yl)piperidine-l-carboxylate. MS (ESI) m / z: calc’d for C16H23F2N2O2 [M+H]+: 313.2, found [M+H]+: 312.9. Step 3: (S and R)-4-(4.4-difluoropiperidin-3-yl)-2-methylpyridine

[0186] A mixture of tert-butyl 4.4-difluoro-3-(2-methylpyridin-4-yl)piperidine-l-carboxylate (100 mg, 0.320 mmol) in HCl-dioxane (2 mL) was stirred at 20 °C for 1 h. The solvent was removed under reduced pressure to give the crude product (S and R)-4-(4,4-difluoropiperidin-3-yl)-2-methylpyridine which was used directly to the next step without further w ork up. MS (ESI) m / z-. calc’d for C11H15F2N2 [M+H]+: 213.0, found [M+H]+: 212.9. Intermediate 3: 4-iodo-2-(tetrahvdrofuran-3-vl )tetrahvdro-2 / / -pvran Step 1: 2-(tetrahvdrofuran-3-vl)tetrahvdro-2 / / -pvran-4-ol

[0187] To a solution of tetrahydrofuran-3-carbaldehyde (1.0 g, 9.99 mmol) and but-3-en-l-ol (0.504 g, 6.99 mmol) in DCM (13 mL) at 0 °C was added TFA (5.94 mL, 80 mmol) dropwise. The solution was slowly warmed to 20 °C for 12 h. Upon completion, the reaction mixture was poured into sat. aq. NaHCOsand extracted with DCM (30 mL*3). The organic layer was dried over MgSOr. filtered and concentrated. The crude product was purified by flash silica gel chromatography 0-20% EtOAc / Pet.ether to give 2-(tetrahydrofuran-3-yl)tetrahydro-2 / / -pyran-4-ol. Step 2: 4-iodo-2-(tetrahydrofuran-3-yl)tetrahydro-2 / / -pvran

[0188] To a mixture of 2-(tetrahydrofuran-3-yl)tetrahydro-277-pyran-4-ol (1.0 g, 5.81 mmol) and Imidazole (0.514 g, 7.55 mmol), PPh3 (1.83 g, 6.97 mmol) in DCM (25 mL) was added I2 (1.77 g, 6.97 mmol) at 0 °C. The resulting mixture was gradually warmed to 25 °C over 2 h. The solvent w as removed under reduced pressure and the residue w as diluted with EtOAc (25 mL) -61 - and washed with water (10 mL x 3). The organic layer was separated and the aqueous layer was re-extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SOr, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography 10% ethyl acetate / pet.ether to give 4-iodo-2-(tetrahydrofuran-3-yl)tetrahydro-2 / / -pyran. MS (ESI) m / z'. calc’d for C9H16IO2 [M+H]+ 283.0, found [M+H]’ 283.0. Intermediate 4: 4-(4,4,5,5-tetraethvl-1.3.2-dioxaborolan-2-vl)-5.6-dihvdro-2H-pyran-2-one Pd(dppf)CI2 (5 mol %) TsCI (1.1 equiv)                            B2Epin2 (1.2 equiv) NEt3 (1.15 equiv)                      KOAc (2.0 equiv) O^^.BfEpin) CH2CI2                               dioxane, 70 °C 0 °C to rt                                    ON Step 1: 6-oxo-3.6-dihvdro-2H-pvran-4-vl 4-methvlbenzenesulfonate

[0189] A 50 mL round bottom flask with a stir bar was charged with dihydro-2H-pyran-2,4(3H)-dione (3.00 g, 26.3 mmol), DCM (10.0 mL), and triethylamine (3.06 g, 4.21 mL, 30.2 mmol). The mixture was cooled to 0 °C. p-Toluenesulfonyl chloride (5.51 g, 4.40 mL, 28.9 mmol) was added. After 30 min. the mixture was washed with water (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (0-60% EtOAc in hexanes) to afford (6-oxo-3,6-dihydro-2H-pyran-4-yl 4-methylbenzenesulfonate . Step 2: 4-(4,4,5,5-tetraethvl-L3.2-dioxaborolan-2-vl)-5.6-dihvdro-2H-pyran-2-one

[0190] To a 500 mL round bottom flask with a stir bar was charged 6-oxo-3,6-dihydro-2H-pyran-4-yl 4-methylbenzenesulfonate (6.40 g, 23.9 mmol), Pd(dppf)Ch (995 mg, 1.36 mmol), potassium acetate (4.68 g, 47.7 mmol), and 4,4,4',4',5,5.5',5'-octaethyl-2,2'-bi(l,3,2-dioxaborolane) (13.1 g, 35.8 mmol). The mixture was purged with N2 and degassed 1,4-Dioxane (128 mL) was added. The mixture was heated to 70 °C for 16 h. The mixture was allowed to cool to rt, filtered and concentrated under reduced pressure. The resulting crude mixture was purified by flash chromatography (0 to 55% ethyl acetate in hexanes) to afford 4-(4,4,5,5-tetraethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-one. Intermediate 5: (S)- 4-(9-(2.4-Difluorophenyl)-2.3-dimethvl-4-oxo-4EI-pvrazino[l.2-a]pvrimidin-7-vl)-3.4-dihvdro-2H-pvran-6-vl trifluoromethanesulfonate and (R)- 4-(9-(2.4-Difluorophenyl)-2.3-dimethyl-4-oxo-4H-pyrazino[l.2-a1pyrimidin-7-vl)-3.4-dihvdro-2H-pvran-6-vl trifluoromethanesulfonate toluene / tBuOH rt, ON Pd(PPh3)4 (5 mol %) Na2CO3 (2.5 equiv) toluene / MeOH 80 °C Step 2 Me (5.0 equiv) MSA (5.0 equiv) toluene 100 °C, 5 h Step 3 XPhos Pd G2 (10mol%) K2CO3 (3.0 equiv) dioxane / H2O 70 °C, ON Step 4 Cu(OAc)2*H2O (10 mol %) DPPB (2 mol %) PMHS (4.3 equiv) THE -78 °C to rt Step 5 □ HMDS (1.1 equiv) Tf2O (1.2 equiv) Step 1: 5-bromo-3-(2.4-difluorophenyl)pyrazin-2-amine

[0191] 3,5-dibromopyrazin-2-amine (10.0 g, 39.5 mmol), difluorophenyl)boronic acid (6.24 g, 39.5 mmol), tetrakis(triphenylphosphine)palladium(0) (2.28 g, 1.98 mmol), and sodium carbonate (10.5 g, 98.9) was added to a 500 mL round bottom flask with a stir bar. The flask was purged with N2 then toluene (160 mL) and water (5.5 mL) was added. The reaction was stirred for 18 h. The aqueous layer was removed, the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. To the crude mixture was added ethyl acetate (60 mL). DCM (60 mL). and hexanes (30 mL). The mixture was stirred at rt then filtered to collect 5-bromo-3-(2,4-difluorophenyl)pyrazin-2-amine. The mother liquor was collected and concentrated under reduced pressure. To collect a second crop of product, ethyl acetate (20 rnL), DCM (20 mL), and hexanes (30 rnL) was added. The mixture was stirred at rt and filtered to collect the solid 5-bromo-3-(2,4-difluorophenyl)pyrazin-2-amine. MS (ESI, m-z): calc’d for CioH?BrF2N3 [M+H]+ 285.9, found 285.9. Step 2: 7-bromo-9-(2.4-difluorophenvl)-2.3-dimethvl-4H-pvrazino[L2-a1pvrimidin-4-one

[0192] A 40 mL vial with a stir bar was charged with 5-bromo-3-(2,4-difluorophenyl)pyrazin-2-amine (2.30 g, 8.04 mmol), toluene (46.0 mL), methanesulfonic acid (3.86 g. 40.2 mmol). Ethyl 2-methyl-3-oxobutanoate (5.80 g, 5.69 mL, 40.2 mmol) was added and the reaction was heated to 100 °C for 5 h. When SM was consumed, the reaction was cooled to room temperature and the reaction mixture was poured into 10 mL H2O. The layers were separated and the aq. layer was extracted with 60 mL ethyl acetate. The combined organic layers were washed with NaHCOs, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was dissolved in 20 mL DCM, then 20 mL EA and 10 mL hexanes was added. The solution was filtered and washed with hexanes to afford 7-bromo-9-(2,4-difluorophenyl)-2,3- dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one. MS (ESI, m / z): calc’d for Ci5HnBrF2N3O [M+H]+ 366.0, found 366.0. Step 3: 9-(2.4-Difluorophenyl)-2.3-dimethyl-7- (6-oxo-3.6-dihydro-2H-pyran-4-yl)-4H-pyrazino[l.2-a1pyrimidin-4-one

[0193] A 40 mL vial with a stir bar was charged with 7-bromo-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one (1.00 g, 2.46 mmol) and XPhos Pd G2 (193 mg, 246 pmol). The mixture was purged with N2 and 4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-one (1.38 g, 4.92 mmol) was added as a solution in 1,4-Dioxane (20.0 mL). Aq. potassium carbonate (2.95 mL, 2.50M, 7.37 mmol) was added and the mixture was heated to 70 °C for 18 h. The reaction was cooled to room temperature and filtered. The aqueous layer was removed and the organic layer was concentrated under reduced pressure. The crude mixture was purified on silica gel (0-100% ethyl acetate in hexanes) to afford a crude solid. DCM (5 mL) and hexanes (1 mL) were added and the mixture was stirred for 1 h then filtered. The solid was washed with hexanes then dried under vacuum with a N2 sweep to afford 9-(2,4-difluorophenyl)-2,3-dimethyl-7- (6-oxo-3,6-dihydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one. MS (ESI, m / z); calc’d for C20H16F2N3O3 [M+H]+ 384.0, found 384.0. Step 4: 9-(2.4-difluorophenyl)-2.3-dimethyl-7-(2-oxotetrahydro-2H-pyran-4-yl)-4H-pyrazinof 1.2-a]pyrimidin-4-one

[0194] A 20-mL vial with a stir bar was charged with copper(II) acetate monohydrate (39.3 mg, 197 pmol) and l,2-bis(diphenylphosphanyl)benzene (17.56 mg, 39.3 pmol). The mixture was purged with N2 and tert-butanol (564 pL, 5.90 mmol) and toluene (15.1 mL) were added. The mixture was stirred for 20 min at rt. PMHS (2.493 g, 2.479 mL. 9.83 mmol) was added. A 40-mL vial with a stir bar was charged with 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(6-oxo-3,6-dihydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one (754 mg, 1.97 mmol) and the vial was purged with N2. The Cu solution w as added to this solution then heated to 50 °C overnight. The mixture was cooled to room temperature and water (10 mL) was added. The layers were separated, and the aq. layer was extracted with ethyl acetate (10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (0-100% EtOAc in hexanes) to afford 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-oxotetrahydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one. MS (ESI, m'z): calc'd for C20H18F2N3O3 [M+H]+ 386.0, found 386.0. Step 5: (S)-4-(9-(2.4-Difluorophenyl)-2.3-dimethvl-4-oxo-4H-pyrazino[1.2-a]pyrimidin-7-yl)-3.4-dihydro-2H-pyran-6-yl trifluoromethanesulfonate and (R)- 4-(9-(2.4-Difluorophenyl)-2.3- dimethvl-4-oxo-4H-pvrazino[1.2-alpvrimidin-7-vl)-3.4-dihvdro-2H-pvran-6-vl trifluoromethanesulfonate

[0195] 9-(2,4-Difluorophenyl)-2,3-dimethyl-7-(2-oxotetrahydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one (300 mg, 778 pmol) added to 40 mL vial with stir bar and purged with N2. THF (4.50 mL) was added and the mixture was cooled to -78 °C. LiHMDS (570.9 pL, 1.50 M in THF, 856 pmol) was added dropwise and the mixture was stirred for 15 min at -78 °C. TfzO (157 pL, 934 pmol) was added dropwise, and the mixture continued to stir at -78 °C for 15 min then allowed to warm to rt. The mixture was quenched with 15% aq. Na2CO3 and diluted with CH2CI2. The mixture was filtered through a phase separator and concentrated under reduced pressure. The crude mixture was purified by flash chromatography (0-100% EtOAc in hexanes) to afford 4-(9-(2,4-difluorophenyl)-2,3-dimethyl-4-oxo-4H-pyrazino[l,2-a]pyrimidin-7-y 1)-3,4-dihydro-2H-pyran-6-yl trifluoromethanesulfonate. The final material was submitted for chiral SFC separation: Column & Dimensions: Lux-3, 21x250 mm, 5um; UV Wavelength: 215nm; Flow Rate: 70 ml / min; Modifier: 10% MeOH w / 0.1% NH4OH to afford (S or R)- 4-(9-(2.4-Difluorophenvl)-2.3-dimethyl-4-oxo-4H-pyrazino|T.2-a1pyrimidin-7-yl)-3.4-dihvdro-2H-pyran-6-vl trifluoromethanesulfonate SFC Peak 1 (desired) and (R or S)- 4-(9-(2.4-Difluorophenyl)-2,3-dimethyl-4-oxo-4H-pyrazino|T.2-a]pvrimidin-7-vl)-3.4-dihvdro-2H-pvran-6-yl trifluoromethanesulfonate SFC Peak 2 (undesired). Analytical data matched for both enantiomers. MS (ESI, m / z): calc’d for C21H17F5N3O5S [M+H]+ 518.1, found 518.1. *HNMR (300 MHz, DMSO-d6,) 6 8.53 (s, 1H), 7.73 (td, J= 8.4, 6.7 Hz, 1H), 7.43 (td, J= 9.9, 2.5 Hz, 1H), 7.27 (td, 7=8.4, 2.6 Hz, 1H), 5.26 (d, 7= 3.9 Hz, 1H), 4.43-4.24 (m, 2H), 4.01 (q,7=5.2 Hz, 1H), 2.36 (s, 3H), 2.21 (s, 1H), 2.18 (s, 3H), 2.08 (d,7= 15.2 Hz, 1H). Intermediate 6; 7-((2R.4S)-2-(lH-pyrazol-4-yl)tetrahvdro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-4H-pvrazinon.2-a1pyrimidin-4-one and 7-((2S,4R)-2-(lH-pyrazol-4-yl)tetrahvdro-2H-pvran-4-vl)-9-(4-chloro-2-fluorophenvl)-2.3-dimethvl-4H-pvrazino| 1,2-a]pvrimidin-4-one Step 1: 7-(2-(lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-4H-pvrazino[1.2-a]pvrimidin-4-one

[0196] To a stirred mixture of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(l-((2-(trimethy lsilyl)ethoxy)methyl)-1 H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[ 1,2-a]pyrimidin-4-one (60 mg, 0.103 mmol) in TFA (1 mL) and DCM (0.200 mL). The mixture was stirred at 60 °C for 1 h. Upon completion, the reaction mixture was quenched with aqueous sodium hydrogen carbonate (1 mL) and extracted with DCM (2 mL x 3). The combined organic phases were washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (silica gel, ethyl acetate / pet. ether = 20mL / 20mL, v / v) to give 7-(2-(lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[ 1,2-a]pyrimidin-4-one. Step 2: 7-((2R.4S)-2-(lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-vl)-9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-4H-pyrazinolL2-a]pyrimidin-4-one and 7-((2S.4R)-2-(lH-pvrazol-4-yl)tetrahvdro-2H-pvran-4-vl)-9-(4-chloro-2-fluorophenvl)-2.3-dimethvl-4H-pvrazino[L2-a1pyrimidin-4-one

[0197] The 7-(2-(lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one was resolved by Chiral-SFC (Column DAICEL CHIRALCEL OD (250mm x 30mm, lOum); Condition: CO2-EtOH (0.1%NH3H2O); Begin B 35 End B 35 Gradient; Time (min): 1; 100%B Hold Time 1; Flow Rate (mL / min): 150) to give (SFC Peak 1): 7-((2R,4S or 2S,4R)-2-(lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[l,2-a]pyrimidin-4-one (tr= 1.777 min), and (SFC Peak 2): 7-((2S,4R or 2R,4S)-2-(lH-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-4H-pyrazino[L2-a]pyrimidin-4-one (tr = 2.118 min). SFC Peak 1: MS (ESI) m / z: calc’d for C23H24C1FN5O2[M+H]+: 454.1 / 456.1, found 454.1 / 456.1. 'H NMR (400 MHz, CDCh-d) 5 ppm 8.59 (s, 1 H), 7.65 - 7.76 (m, 1 H), 7.60 (t, 7=7.87 Hz, 1 H), 7.29 - 7.34 (m, 2 H), 7.23 - 7.26 (m, 1 H), 4.60 - 4.67 (m, 1 H), 4.26 - 4.34 (m, 1 H), 3.76 -3.86 (m, 1 H), 3.17 - 3.29 (m, 1 H), 2.45 (s, 4 H), 2.29 (s, 3 H), 2.00 - 2.07 (m, 2 H) SFC Peak 2: MS (ESI) m / z: calc’d for C23H24C1FN5O2[M+H]+: 454.1 / 456.1, found 454.1 / 456.1. 'H NMR (400 MHz, CDCh-d) 5 ppm 8.58 (s, 1 H), 7.57 - 7.69 (m, 3 H), 7.28 - 7.33 (m, 1 H), 7.23 - 7.26 (m, 1 H), 4.62 (br d, J=\ 1.21 Hz, 1 H), 4.28 (br d, J=11.44 Hz, 1 H), 3.76 - 3.87 (m, 1 H), 3.17 - 3.27 (m, 1 H), 2.45 (s, 3 H), 2.30 - 2.36 (m, 1 H), 2.29 (s, 3 H), 2.17 - 2.23 (m, 1 H), 2.01 -2.07 (m,2H), 1.92-2.00 (m, 1 H). Intermediate 7: 4-methyl-N-(2-oxo-2-(l-((2-(trimethylsilvl)ethoxv)methvl)-lH-pyrazol-4- yl)ethyl)benzenesulfonamide Pd(OAc)2, dppp, K2CO3, DMF, H2O, 100 °C, 16 h 1) Pyrrolidone hydrotribromide, 2-pyrrolidinone, THF, 70 °C,1 h 2) DIPEA, 25 °C, 1 h TsNHNCHPh Cs2CO3, MeCN 20 °C, 10 min Step 1 Step 2 Step 4 dioxane, 25 °C 4 h (S)-MeCBS(3.0 eq), BH3 SMe2(3 eq) Et3N,DCM 40 °C, 16h OHTf -^SP^ Step 3 Step 5 Step 5 Step 6 Step 1: 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pvrazole

[0198] A mixture of 4-bromo-lH-pyrazole (10 g, 68.0 mmol) in THF (120 mL) was added NaH (4.08 g, 102 mmol, 60%W) at 0 °C. The mixture was stirred at 0 °C for 3 h. The mixture was treated with (2-(chloromethoxy)ethyl)trimethylsilane (14.4 mL, 82 mmol) at 0 °C. The resulting mixture was stirred at 0-25 °C for 2 h. The reaction mixture was quenched with water (125 mL) and extracted with EtOAc (120 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole. MS (ESI) m / z: calc'dfor C9Hi7BrN2OSi [M+H]+: 277.0 / 279.0, found 277.0 / 279.0 Step 2: 1-(1 -((2-(trimethvlsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)ethan-l -one

[0199] A mixture of 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole (30 g, 108 mmol)), l,3-bis(diphenylphosphino)propane (4.46 g, 10.8 mmol)), (butyloxy)ethylene (70.0 mL, 541 mmol), Palladium(II) acetate (1.21 g, 5.41 mmol) and K^COs (17.9 g, 130 mmol)) in DMF (200 mL)) and water (40 mL) was stirred at 100 °C for 16 hour. The reaction mixture was quenched with water (1000 mL) and extracted with EtOAc (1000 mL x 3). The combined organic phases were washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 60 % ethyl acetate / petroleum ether gradient) to give 1 -(1 -((2-(trimethylsilyl)ethoxy)methyl)-IH-pyrazol-4-yl)elhan-l-one.'H NMR (400MHz, CDCL-d) 5 8.05 (s, 1H), 7.94 (s, 1H), 5.44 (s, 2H), 3.55-3.61 (m, 2H), 2.45 (s, 3H). 0.89-0.94 (m, 2H). 0.00 (s, 9H). MS (ESI) m / z: calc’d for CnH2oN202Si [M+H]+: 241.1, found 183.1. Step 3: 2-bromo-l-(l-((2-(trimethvlsilvl)ethoxv)methvl)-lH-pvrazol-4-vl)ethan-l -one

[0200] A mixture of l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)ethan-l-one (2.00 g, 8.32 mmol), 2-pyrrolidinone (1.41 g, 16.6 mmol) and pyrrolidone hydrotribromide (5.42 g, 16.6 mmol) in THF (20 mL) was stirred at 70 °C for 1 h. The mixture was filtered, then diethylphosphonate (2.30 g, 16.6 mmol) and DIPEA (2.91 mL, 16.6 mmol) were added to the filtrate and stirred at 25 °C for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 30% ethyl acetate / petroleum ether gradient) to give 2-bromo-l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)ethan-l-one. 'H NMR (400MHz, CDCL-d) 8 8.17 (s, 1H), 8.02 (s, 1H), 5.47 (s, 2H), 4.20 (s, 2H), 3.593.64 (m, 2H), 0.91-0.96 (m, 2H), 0.00 (s, 9H). MS (ESI) m / z: calc’d for CnHi9BrN2O2Si [M+H]+: 319.0 / 321.0, found [M+H-58]+: 261.0 / 263.0 Step 4: 4-methvl-N-(2-oxo-2-(l-((2-(trimethylsilvl)ethoxv)methvl)-lH-pyrazol-4-yl)ethyl)benzenesulfonamide

[0201] To a solution of 2-bromo-l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)ethan-l-one (1 g, 3.13 mmol), Cs2CO3 (1.12 g, 3.45 mmol) in acetonitrile (10 mL) was added benzaldehyde tosylhydrazone (0.945 g, 3.45 mmol). The mixture was stirred for 10 min at 20 °C. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 100% ethyl acetate gradient) to give 4-methyl-N-(2-oxo-2-( 1-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4yl)ethyl)benzenesulfonamide. 'H NMR (400MHz, CDCh-d) 3 8.07 (s, 1H), 7.91 (s, 1H), 7.75-7.80 (m, 2H), 7.30 (d, J= 7.99 Hz, 2H), 5.51-5.58 (m, 1H), 5.43 (s, 2H), 4.23 (d, J-4.65 Hz, 2H), 3.53-3.62 (m, 2H), 2.41 (s, 3H), 0.88-0.95 (m, 2H), 0.00 (s, 9H). MS (ESI) m / z: calc'd for Ci8H27N3O4SSi [M+H]+: 410.1, found [M+H-58]4: 352.1. Step 5: (S)-N-(2-hvdroxv-2-(l-((2-(trimethvlsilvl)ethoxv)methvl)-lH-pyrazol-4-vl) ethyl)-4-methvlbenzenesulfonamide

[0202] To a solution of (s)-(-)-2-methyl-cbs-oxazaborolidine solution (1015 mg, 3.66 mmol) in 1,4-Dioxane (10 mL) was added BH3-S(CH3)2 (0.366 mL, 3.66 mmol) dropwise at 25 °C under N2 atmosphere. The mixture was stirred for 20 minutes at 25 °C. 4-methyl-N-(2-oxo-2-( 1-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)ethyl)benzenesulfonamide (500 mg. 1.22 mmol) was next added at 0°C and the mixture was stirred for 4 h at 25 °C. The mixture was quenched with water (10 mL), extracted with DCM (20 mL x 3), washed with brine (20 mL), dried over Na2SO4, fdtered and the filtrate was concentrated to give crude (S)-N-(2-hydroxy-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)ethyl)-4-methylbenzenesulfonamide (e.e.% = 92.78%). MS (ESI) m / z: calc’d for C18H29N3O4SS1 [M+H]+: 412.2, found 412.1. Step 6: (S)-4-tosvl-2-(l-((2-(trimethvlsilvl)ethoxv)methvl)-lH-pyrazol-4-vl) morpholine

[0203] To a solution of (S)-N-(2-hydroxy-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)ethyl)-4-methylbenzenesulfonamide (450 mg, 1.09 mmol). diphenyl(vinyl)sulfonium trifluoromethanesulfonate (396 mg, 1.09 mmol) in DCM (5 mL) was added tri ethylamine (0.456 mL, 3.28 mmol) at 0 °C under N2. The mixture was stirred for 16 h at 40 °C. The reaction mixture was quenched with water (5 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 40% ethyl acetate / petroleum ether gradient) to give (S)-4-tosyl-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)morpholine.1H NMR (400MHz, CDCh-d) 5 7.63 (d, J= 8.34 Hz, 2H), 7.51 (s, 1H), 7.47 (s, 1H), 7.34 (d, J= 7.99 Hz, 2H), 5.37 (s, 2H), 4.584.66 (m, 1H), 3.94-4.01 (m, 1H), 3.75-3.85 (m, 1H), 3.66-3.72 (m, 1H), 3.49-3.58 (m, 3H), 2.53 (dt. 7=3.34. 11.27 Hz, 1H). 2.44 (s. 3H). 2.38(dd,7 = 10.01. 11.44 Hz, 1H), 0.84-0.92 (m, 2H), 0.00 (s, 9H). MS (ESI) m / z: calc’d for C2oH3iNs04SSi[M+H]+: 438.2, found 438.2. Step 7: (S)-2-(l-((2-(trimethvlsilvl)ethoxv)methvl)-lH-pvrazol-4-vl)morpholine

[0204] To a solution of (S)-4-tosyl-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl) morpholine (300 mg, 0.686 mmol) in MeOH (15 mL) was added magnesium (117 mg. 4.80 mmol) at 25 °C. The mixture was stirred for 16 h at 25 °C. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Cl 8 Column (eluent of 50% MeCN / water gradient) to give (S)-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)morpholine. 'H NMR (400MHz. CDCh-d) 5 9.71-10.14 (m. 2H), 7.59 (s. 1H), 7.54 (s, 1H), 5.40 (s, 2H), 4.84-4.92 (m, 1H), 4.00-4.20 (m, 2H), 3.50-3.59 (m, 2H), 3.42 (d, J=12.40 Hz, 1H), 3.28-3.36 (m, 1H), 3.13-3.23 (m, 1H), 3.02-3.11 (m, 1H), 0.84-0.94 (m, 2H), 0.06 (s, 9H). MS (ESI) m / z: calc’d for Ci3H25N3O2Si [M+H]+: 284.2, found 284.2. Intermediate 8: (S)-3-(2-(lH-pvrazol-4-vl)morpholino)-l-(4-chloro-2-fluorophenvl)-8.9- dihvdropvrido[3.4-d1pvrrolo[l.2-a1pyrimidin-5(7H)-one Step 1: (S)-l-(4-chloro-2-fluorophenyl)-3-(2-(l-((2-(trimethylsilyl)ethoxv)methyl)-lH-pyrazol-4-yl)morpholino)-8.9-dihydropyrido[3.4-dlpyrrolo[l.2-a1pvrimidin-5(7H)-one

[0205] To a solution of 3-chloro-l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one (1.3 g, 3.71 mmol) in dioxane (18.56 mL) were added (S)-2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)morpholine (1.37 g, 4.83 mmol), CS2CO3 (3.63 g, 11.1 mmol) and rac-BINAP Pd G4 (0.747 g, 0.742 mmol). The resulting mixture was stirred at 80 °C under N2 protection for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (10 mLx3). The organic layer was washed dried overNa2SO4. After filtration and concentration. The residue was purified by flash silica gel chromatography (Eluent of 0 ~ 50% Ethyl acetate / Petroleum ether gradient) to give (S)-l-(4-chloro-2-fluorophenyl)-3-(2-(l-((2-(trimethylsilyl)ethoxy)methyl)-114-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z: calc'd for C29H35ClFN6O3Si [M+H]+: 597.2 / 599.2, found 597.1 / 599.2. *HNMR (400 MHz, CDCls) 5 ppm 7.63 (d, 7=8.34 Hz, 2 H), 7.53 - 7.57 (m, 1 H), 7.37 (s, 1 H), 7.24 (br d, 7=1.67 Hz, 1 H), 7.20 (dd, 7=9.54, 1.91 Hz, 1 H), 5.42 (s, 2 H), 4.68 (dd, 7=10.25, 2.50 Hz, 1 H), 4.39 (br d, 7=12.28 Hz. 1 H). 4.12 - 4.20 (m. 4 H). 3.84 - 3.91 (m. 1 H). 3.55 - 3.61 (m. 2 H). 3.15 - 3.22 (m. 1 H). 3.05 - 3.13 (m, 3 H), 2.22 - 2.30 (m, 2 H), 0.89 - 0.95 (m, 2 H), -0.01 (s, 9 H). Step 2: (S)-3-(2-(lH-pyrazol-4-yl)morpholino)-l-(4-chloro-2-fluorophenyl)-8.9-dihvdropvrido[3.4-d1pvrrolo[1.2-alpvrimidin-5(7H)-one

[0206] A mixture of (S)-l-(4-chloro-2-fluorophenyl)-3-(2-(l-((2-(trimethylsilyl)ethoxy) methyl)-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one (1.7 g, 2.85 mmol) in TFA (4.17 mL) and DCM (20.8 mL) was stirred at 60 °C for 2 h. The reaction mixture was quenched with aqueous sodium hydrogen carbonate (10 mL) and extracted with DCM (20 mL x 3). The combined organic phases were dried over Na2SO4, Filtered and concentrated. The residue was purified by flash silica gel chromatography (30%MeCN / H2O, no TFA) to give (S)-3-(2-(lH-pyrazol-4-yl)morpholino)-l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z: calc'd for C23H21CIFN6O2 [M+H]+: 467.1 / 469.1. found 467.0 / 469.0. 'H NMR (400 MHz, CDCh) 5 ppm 7.73 (s,2H), 7.52 - 7.57 (m, 1 H), 7.38 (s, 1 H), 7.18-7.26 (m, 2 H), 4.73 (dd,7=10.13, 2.74 Hz, 1 H), 4.41 (br d, 7=13.11 Hz, 1 H), 4.17 (brd, 7=7.27 Hz, 3 H), 3.86 - 3.93 (m, 1 H), 3.19 - 3.24 (m, 1 H), 3.06 - 3.15 (m, 4 H), 2.23 - 2.29 (m, 2 H). Intermediate 9: 3-Chloro-l-(3-(trifluoromethvl)bicvclol 1.1.1 |pentan-l-vl)-8,9- dihvdropvrido[3.4-d]pvrrolo[1.2-a]pyrimidin-5(7H)-one THF, 45 °C, 1 h

[0207] Step 1: To a suspension of magnesium (10.2 mg, 0.420 mmol) in THF (2 mL) was added 1,2-dibromoethane (3.29 pl, 0.038 mmol) in glove box. The suspension was stirred for 30 min at 25 °C. l-iodo-3-(trifluoromethyl)bicyclo[l.l.l]pentane (100 mg, 0.382 mmol) in THF (2 mL) was then added to the suspension dropwise. The resulting mixture was heated to 75 °C and stirred for 1 h. The resulting solution was added to another vial charged with zinc chloride (0.210 mL, 0.420 mmol) in 2-methyltetrahydrofuran and stirred for 1 h at 25 °C. The solution was used directly for the next step. Step 2: To a solution of l,3-dichloro-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pynmidin-5(7H)-one (20.5 mg. 0.080 mmol) in THF (2 mL) was added bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.42 mg, 7.63 pmol) in a glove box. The solution of Step 1 was added to the second solution in dropwise. The reaction was stirred for 1 h at 45 °C. The mixture was concentrated in vacuo to give the residue. Water (5 mL) was added and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC (water (0.1%TFA)-ACN) to give 3-chloro-l-(3-(trifluoromethyl)bicyclo[Ll.l]pentan-l-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one. MS (ESI)m / z: calc’d for C16H14CIF3N3O [M+H]+: 356.0 / 358.0 found 355.9. Intermediate 10: 3-chloro-l-(4.4-difluorocyclohexyl)-8.9-dihydropyrido[3.4-d1pyrrolo[l.2-a1pvrimidin-5(7H)-one t-Bu              t-Bu O

[0208] A solution of nickel(II) bromide ethylene glycol dimethyl ether complex (48.2 mg, 0.156 mmol) and 4,4'-di- / e / 7-butyl-N-cyano-[2,2'-bipyridine]-6-carboximidamide (52.4 mg, 0.156 mmol) in DMA (4 mL) at 25 °C was stirred for 1 h. Then zinc (153 mg, 2.34 mmol), TBAI (288 mg, 0.781 mmol), 4-bromo-l,l-difluorocyclohexane (233 mg, 1.17 mmol), 1,3-dichloro-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one (200 mg, 0.781 mmol) were added and the resulting mixture was stirred at 40 °C for 2 h. The mixture was cooled, quenched with water (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic fractions were washed with brine (10 mL x 3), dried over Na2SO4, and filtered. The organic layer was concentrated in vacuo and purified by prep. HPLC (water(0.1%TFA)-ACN) to give 3-chloro-l-(4,4-difluorocyclohexyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z: calc'd for C16H17CIF2N3O [M+H]+: 340.0 / 342.0, found 339.9 / 341.9.

[0209] Examples shown in Example Table 1-1 below, were prepared according to procedures analogous to those outlined for Intermediate 10 procedure above using the appropriate starting materials. Table 1-1 Example Structure Name Found Mass [M+H]+ Int-11 F. F 0 3-chl oro-1-(6,6-difluorospiro[3.3]heptan-2-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 352 Intermediate 12: 4,4,5,5-tetraethvl-2-(6-(tetrahvdrofuran-3-vl)-3,6-dihvdro-2H-pvran-4-vl)- 1,3,2-dioxaborolane k2co3 Pd(dppf)CI2 dioxane,80°C Step 1: Synthesis of 6-(tetrahvdrofuran-3-vl)-3,6-dihvdro-2H-pvran-4-vl trifluoromethanesulfonate

[0210] To a solution of tetrahydrofuran-3-carbaldehyde (1 g, 9.99 mmol) in DCM (20 mL) under N2 in three-necked flask was added but-3-yn-l-ol (1.050 g. 14.98 mmol) and dropwise trifluoromethanesulfonic acid (2.396 mL, 30.0 mmol) at 0 °C. The mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was quenched with sat. aq. NaHCOs (200 mL) and extracted with DCM (100 mL x 3). The combined organic fractions were washed with brine (200 mL), dried over Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-40% ethyl acetate / petroleum ether gradient) to give 6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate as a desired product. MS (ESI) m / z: calc'd for C10H14F3O5S [M+H]+: 303.1, found 303.1. Step 2: Synthesis of 4,4,5,5-tetraethvl-2-(6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-1,3.2-dioxaborolane

[0211] To a solution of 6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1 g, 3.31 mmol) in 1,4-dioxane (8 ml) was added 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.242 g, 0.331 mmol), 4,4,4',4',5,5,5',5'-octaethyl-2,2'-bi(1.3.2-dioxaborolane) (1.454 g, 3.97 mmol) and potassium acetate (0.649 g, 6.62 mmol). Then the mixture was purged with N2 three times and stirred for 1 h at 80 °C. Upon completion, the mixture was filtered and the filtrate was concentrated. The crude product was purified by flash silica gel chromatography (eluent of 0-40% EtOAc / Petroleum ether gradient) to afford 4,4,5,5-tetraethyl-2-(6-(tetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-l,3,2-dioxaborolane as a desired product. MS (ESI) m / z: calc'd for C19H34BO4 [M+H]+: 337.1. found 337.1. Intermediate 13; (cis)-2-methyl-6-(2-methvlpyridin-4-yl)morpholine Step 1 Pd(PPh3)4,dioxane, 110 °C,16 h 3M HCI Bnx N J H4a OH DIPEA, THE, 25 3C,16 h Step 4 TMSOTf DCE, 0 oC -80 oC, 16 h Step 5 0 oC - 25 oC, 12 h Step 2 Pd(OH)2, HCOONH, MeOH, reflux, 16 h Step 6 Step 1: Synthesis of 4-(1-ethoxyvinyl)-2-methylpvridine

[0212] 4-bromo-2-methylpyridine (2.4 kg, 13.95 mol) was stirred into 1,4-dioxane (26.4 L), and Tributyl(l-ethoxyvinyl)tin (5.78 Kg, 16.00 mol, 1.15 equiv) was added to obtain amixture degassed with argon, followed by the addition of tetrakis (triphenylphosphine) palladium (800.0 g, 692.28 mmol, 0.05 equiv). The resulting mixture was heated to 110 °C for 6 hours, then filtered and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to obtain crude 4-(1-ethoxyvinyl)-2-methylpyridine. The raw material was used directly in the next step without further purification. Step 2: Synthesis of l-(2-methvlpvridin-4-vl) ethan-l-one

[0213] To a stirred material of crude 4-(1-ethoxy vinyl)-2-methylpyridine (13 kg) at 0 °C was added HC1 (26 L, 2 V, 6M) and the resulting solution was stirred at 25 °C for 2 h. The reaction mixture w as quenched with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash silica gel chromatography (eluent of 0-30% Ethyl acetate / Petroleum ether) to give l-(2-methylpyridin-4-yl) ethan-l-one as a desired product. Step 3: Synthesis of 2-bromo-l-(2-methvlpyridin-4-yl)ethan-l-one

[0214] A mixture of l-(2-methylpyridin-4-yl)ethan-l-one (450 g, 3.33 mol), DIPEA (538 g, 4.16 mol) and TMSOTf (888 g, 3.99 mol) in DCM (4.5 L, 10V) was stirred at 0-5 °C for 0.5 h, followed by the addition of NBS (711 g, 3.99 mol) and stirred at 0-5 °C for an additional 0.5h. The reaction was quenched with aqueous NaHCOs (8%, 10V, 4.5L). The separated organic layer was concentrated under vacuum and used directly in the next step. Step 4: Synthesis of 2-(benzvl(2-hvdroxvpropvl)amino)-l-(2-methvlpvridin-4-vl)ethan-l-one

[0215] A mixture of 2-bromo-l-(2-methylpyridin-4-yl)ethan-l-one hydrobromide (4) (712 g, 3.33 mol) and l-(benzylamino)propan-2-ol (550 g, 3.33 mol), N,N-Diisopropylethylamine (645 g, 4.99 mol) in THF (4500 mL) was stirred at 10 °C for 1 h. Upon completion, the reaction mixture was quenched with water (4500 mL) and extracted with EtOAc (2000 mL*3). The combined organic phases were washed with brine (2000 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 100% Ethyl acetate / Petroleum ether gradient) to give 2-(benzyl(2-hydroxypropyl)amino)-l-(2-methylpyridin-4-yl)ethan-l-one as a desired product. Step 5: Synthesis of 4-benzvl-2-methvl-6-(2-methylpvridin-4-vl)-3.4-dihvdro-2H-l,4-oxazine

[0216] TMSOTf (1.25 kg, 5.63 mol) was added to 2-(benzyl (2-hydroxypropyl) amino)-l -(2-methylpyridin-4-yl) ethan-l-one (5) (560 g, 1.88 mol) and DCE (11.2 L, 20V) at 0 °C. The resulting mixture w as heated to 90 °C for 16 h, then quenched with sodium bicarbonate (8%, 5.6 L, 10 V) and extracted with 10% methanol in dichloromethane. The organic layer was washed with brine (10%, 5.6 L, 10V), dried on anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 4-benzyl-2-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydro-2H-l,4-oxazine, which was used directly for the next step w ithout additional purification. Step 6: Synthesis of (cis)-2-methvl-6-(2-methvlpvridin-4-vl)morpholine

[0217] The solution of 4-benzyl-2-methyl-6-(2-methylpyridin-4-yl)-3,4-dihydro-2H-l,4-oxazine (6) (600 g, 2.14 mol) in MeOH (6 L) was added Pd(OH)2 (240 g, 40% wt) and ammonium formate (675 g, 10.7 mol). The mixture was stirred at 85 °C under N2 atmosphere for 1 h. Upon completion, the reaction was filtered and the filtrate was concentrated in vacuo, then purified by prep HPLC (MeCN / water using 0.04% NH3H2O + 10 mM NH4HCO3) to give (cis)-2-methyl-6-(2-methylpyridin-4-yl)morpholine as a desired product. MS (ESI) m / z: calc'd for C11H17IN2O [M+H]+ 193, found 193. Intermediate 14: 4-(4-bromotetrahvdro-27 / -pvran-2-vl)-l-cvclopropvl-17 / -pyrazole HBr / AcOH DCM

[0218] Three reactions on the same scale were run in parallel. To a 40 mL vial containing 1-cyclopropylpyrazole-4-carbaldehyde (1.00 g, 7.3 mmol) and but-3-en-l-ol (583 mg, 0.70 mL, 8.08 mmol) was added DCM (12 mL). The reaction was cooled to 0 °C, then followed by the addition of HBr in acetic acid (3.9 mL, 33% wt, 22.0 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The three reaction mixtures were combined and diluted with DCM (20 mL) and carefully quenched with sat. NaHCOs (aq.) until the solution become slightly basic. Then the mixture was extracted with 2x50 mL DCM. The organic extracts w ere combined and concentrated. The crude residue was purified by column chromatography on silica gel eluting with 10% to 25% to 40% EtOAc in Hexanes to give the desired product 4-(4-bromotetrahydro-2 / / -pyran-2-yl)-l-cyclopropyl-l / / -pyrazole. The product was submitted for SFC purification using the following condition to yield the isomers as Peak 1 at 3.76 min, Peak 2 at 4.36 min and Peak 3 (mixture of two isomers) at 5.03 min. Peak 3 mixture was further separated through SFC. 1st SFC condition: Column & Dimensions: IG, 21x250 mm, 5 pm UV Wavelength: 215 nm Flow Rate: 90 ml / min. Modifier: 20% MeOH w / 0.1% NH4OH, Outlet Pressure: 100 bar, Sample Amount: 5800 mg, Diluent: 1:1 MeOH / CHsCN, Diluent Volume: 40 ml, Injection Volume: 0.3 ml; Instrument: Sepiatec 3

[0219] The Peak 3 mixture sample from above was separated via a second SFC run to yield one of the isomers as Peak 3-1 at 2.7 min and Intermediate 14 (Peak 3-2) at 3.3 min. 2nd SFC condition: Column & Dimensions: IB-N, 21x250 mm, 5 pm; UV Wavelength: 215 nm; Flow Rate: 70 ml / min; Modifier: 15% MeOH w / 0.1% NH4OH; Outlet Pressure: 100 bar; Instrument: Sepiatec 2

[0220] Examples shown in Example Table 1-2 below, were prepared according to procedures analogous to those outlined in 1-14 procedure above using the appropriate starting materials. Table 1-2 Example Structure Name Found Mass [M+H]+ Intermediate 15 F^F A Br 4-(4-bromotetrahy dro-2H-pyran-2-yl)-2-(difluoromethyl)pyridine 292 Intermediate 16 m / 0 2—' 4-(4-bromotetrahy dro-2H-pyran-2-yl)-2-methoxypyridine 272 Intermediate 17 m u.          0 4-(4-bromotetrahy dro-2H-pyran-2-yl)-2-(difluoromethoxy)pyridine 308 Intermediate 18 Q'^l 4-bromooctahydro-2H,2'H- 2,4'-bipyran 249 Intermediate 19 oA / O^J 4-bromo-2-(2.2-dimethyltetrahydrofuran-3-yl)tetrahydro-2H-pyran 263 Intermediate 20 m / 0 4-(4-bromo-6-methy Itetrahy dro-2H-pyran-2-yl)-2-methylpyridine 270 Intermediate 21; 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4H-pyrazino[l,2- a]pyrimidin-4-one

[0221] To a 250 mL RBF, 7-bromo-9-(2,4-difluorophenyl)-2.3-dimethyl-4H-pyrazino[L2-a]pyrimidin-4-one (10.0 g„ 27.3 mmol), potassium acetate (8.04 g, 81.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (10.4g, 40.9 mmol) and Pd(dppf)C12 (1.99 g, 2.731 mmol) were added. 1,4-Dioxane (200 mL) was added andthe reaction mixture was sparged with nitrogen for 5 min. The mixtuere was outfitted with a reflux condenser, which was kept under N2. The reaction was heated to 80 °C while stirring at 900 rpm. The mixture was cooled and filtered through a pad of activated carbon (G60) and Celite. Displacement wash with dioxane was done until no colored filtrate was observed exiting the filter. The filtrate was concentrated to dry ness by rotary evaporation. The solid was taken up as a suspension in diethyl ether (50 mL) and heptanes (100 mL) and concentrated to dryness. This was repeated with 100 mL heptanes. Next. 550 mL of 1:1 MeCN / water solution was added and the mixture agitated (overhead stirring; 385 rpm) at ambient temperature and allowed to age overnight with agitation. This mixture was filtered and the wet cake was washed with heptanes to afford 9-(2,4-difluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1.3.2-dioxaborolan-2-yl)-4H-pyrazino[l,2- a]pyrimidin-4-one. MS (ESI) m / z C15H13B2N3O3 [M+H]+ calc’d 332.1, found 332.1. Intermediate 22: 4-Methyl-N'-(2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4- ylidene)benzenesulfonohy dr azide NaBH4 EtOH 0 °C~ 20 "C, 1 h IBX EtOAc 80 °C, 3 h ZnCI2, toluene 80 °C,12 h then TFA, 0 °C, 2 h Step 1: (6-methvlpyrimidin-4-vl)methanol

[0222] A mixture of ethyl 6-methylpyrimidine-4-carboxylate (25.0 g, 150 mmol) in EtOH (300 mL) was added NaBH4 (6.89 g, 182 mmol) at 0 °C under N2 protection. The resulting mixture was stirred at 20 °C for 1 h. 2N HCl-MeOH (200 mL) was added to the mixture at 0 °C to adjust pH~4. The mixture was stirred at 20 °C for 0.5 h. The resulting mixture was concentrated in vacuo to give the residue. The residue was purified by flash silica gel chromatography (20% MeCN / H2O) to give (6-methylpyrimidin-4-yl)methanol. MS (ESI) m / z: calc’d for C6H9N2O [M+H]+: 125.1, found 125.0. Step 2: 6-methvlpyrimidine-4-carbaldehvde

[0223] A mixture of (6-methylpyrimidin-4-yl)methanol (11.0 g. 89 mmol) and IBX (49.6 g, 177 mmol) in DCE (100 mL) was stirred at 80 °C for 2 h. The mixture was cooled to RT, filtered, and the filtrate was concentrated under reduced pressure to give the crude 6-methylpyrimidine-4-carbaldehyde, which was not further purified. MS (ESI) m / z: calc’d for C6H7N2O [M+H]+: 123.0, found 123.0. Step 3: 2-(6-methylpyrimidin-4-yl)-2.3-dihydro-4H-pyran-4-one

[0224] To a solution of 6-methylpyrimidine-4-carbaldehyde (5g, 40.9 mmol), l-methoxy-3-trimethylsiloxy-l,3-butadiene (7.05 g, 40.9 mmol) in Toluene (50 mL) was added ZnCh (2.04 mL, 4.09 mmol) at 25 °C. The mixture was stirred at 80 °C for 12 h. The reaction was added TFA (3.15 mL. 40.9 mmol) at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (eluent of 60% ethyl acetate / petroleum ether gradient) to give 2-(6-methylpyrimidin-4-yl)-2,3-dihydro-4H-pyran-4-one. MS (ESI) m / z: calc’d for C10H11N2O2 [M+H]T 191.1, found 191.0. Step 4: 2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-one

[0225] To a solution of 2-(6-methylpyrimidin-4-yl)-2,3-dihydro-4H-pyran-4-one (2.2 g, 11.5 mmol) in EtOAc (30 mL) was added Pd-C (0.492 g, 0.463 mmol) under N2 atmosphere. The mixture was degassed and backfilled with H2 (three times). The resulting mixture was stirred under H2 (Pressure: 15 psi) at 25 °C for 12 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-one which was used in next step directly. MS (ESI) m / z: calc’d for C10H13N2O2 [M+H]+: 193.1, found 193.0. Step 5: 4-methvl-N'-(2-(6-methvlpyrimidin-4-yl)tetrahvdro-4H-pyran-4-ylidenejbenzenesulfonohydrazide

[0226] To a solution of 2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-one (2.0 g, 10.4 mmol) in MeOH (40 mL) was added 4-methylbenzenesulfonohydrazide (1.93 g, 10.40 mmol) and the resulting mixture was stirred at 20 °C for 1 h. The mixture was concentrated under reduced pressure to give the residue. The residue was purified by flash silica gel chromatography (eluent of 60% ethyl acetate / petroleum ether gradient) to give 4-methyl-N'-(2-(6-methylpyrimidin-4-yl)tetrahydro-4H-pyran-4-ylidene)benzenesulfonohydrazide. MS (ESI) m / z: calc'd for C17H21N4O3S [M+H]+361.1, found 361.0. Intermediate 23; 2-(6-(5,5-dimethvltetrahvdrofuran-3-vl)-3.6-dihvdro-2H-pvran-4-vl)-4.4.5.5- tetraethyl-1,3,2-dioxaborolane IBX 70 °C,3 h HBrDCM, 0 ~ 20 °C,12 h Step 1: 5,5-dimethyltetrahydrofuran-3-carbaldehyde

[0227] A solution of (5,5-dimethyltetrahydrofuran-3-yl)methanol (3.0 g, 23.0 mmol) and 1-hydroxy-l-oxo-115-benzo[d][l,2]iodaoxol-3(lH)-one (12.9 g, 46.1 mmol) inEtOAc (115 ml)was stirred at 70 °C for 3 h. The reaction solution was filtered and concentrated in vacuo to give crude 5,5-dimethyltetrahydrofuran-3-carbaldehyde, which used directly for the next step without additional purification. Step 2: 4-bromo-6-(5.5-dimethyltetrahydrofuran-3-vl)-3.6-dihydro-2H-pvran

[0228] To a solution of 5,5-dimethyltetrahydrofuran-3-carbaldehyde (2.5 g. 19.5 mmol) and but-3-yn-l-ol (2.05 g, 29.3 mmol) in DCM (20 ml) was added HBr (6.42 ml, 39.0 mmol) at 0 °C over 10 min. The resulting mixture was stirred for 3 h. The reaction mixture was quenched with water (10 mL) and adjust pH>8 by sat. NaHCOw extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep. HPLC (condition MeCN / water (0.1%TFA)) to give 4-bromo-6-(5.5-dimethyltetrahydrofuran-3-yl)-3.6-dihydro-2H-pyran. MS (ESI) m / z: calc'd for CnHi7BrO2[M+H]+: 261.0 / 263.0, found 261.2 / 263.2. Step 3: 2-(6-(5,5-dimethvltetrahvdrofuran-3-vl)-3.6-dihvdro-2H-pvran-4-vl)-4.4.5.5-tetraethvl-1,3,2-dioxaborolane

[0229] To a solution of 4-bromo-6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran (160 mg, 0.613 mmol) in 1,4-dioxane (5 ml) was added [l,T-bis(diphenylphosphino) ferrocene] di chi oropalladium(II) (44.8 mg, 0.061 mmol),4,4,4',4',5,5,5',5'-octaethyl-2,2'-bi(l,3,2-dioxaborolane) (224 mg. 0.613 mmol) and potassium acetate (120 mg, 1.225 mmol). Then the mixture was purged with N2 for three times and stirred for 2 h at 80 °C. The mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography to give 2-(6-(5,5-dimethyltetrahydrofuran-3-yl)-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetraethyl-l,3,2-dioxaborolane. MS (ESI) m / z: calc'd for C2iH3?BO4[M+H]+:365.2, found 364.9. Intermediate 24;3-methvl-7-(2-(2-methylpvridin-4-yl)tetrahvdro-2H-pyran-4-vl)-5- (methylthio)-l ,3-dihvdro-10H-furo[3.4-d1pyrazino[l ,2-a1pvrimidin-10-one NaH, THF, DMSO, 25 "C, 16 h MeOOC' XS HOAc. MgSO4, MeOH, 80 °C,16 h COOMe Ph2O, 280 °C ,4 h DMA. 40 °C ,2 h Step 1: methyl 5-methvl-4-oxotetrahvdrofuran-3-carboxvlate

[0230] A suspension of NaH (16.1 g, 403 mmol) in THF (500 mL) was stirred for 10 min and then a solution of methyl 2-hydroxypropanoate (40.0 g, 384 mmol) in THF (100 mL) was added dropwise over 15 min. DMSO (100 mL) was added and a solution of methyl acrylate (40.6 g, 471 mmol) in DMSO (100 mL) was added at 0 °C. The mixture was stirred at 25 °C for 16 h. The pH was adjusted to around 3-4 with 2M HC1. The reaction mixture was quenched with H2O (250 mL) and extracted with EtOAc (250 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of [0~30]% ethyl acetate / petroleum ether gradient) to give methyl 5-methyl-4-oxotetrahydrofuran-3-carboxylate. 'H NMR (400 MHz, CDCh) 5 ppm 4.47 - 4.56 (m, 1 H), 4.23 - 4.30 (m, 1 H), 3.84 - 3.97 (m, 1 H), 3.75 (s, 3 H). 3.48 - 3.55 (m. 1 H). 1.31 (dd, J=6.85. 1.01 Hz, 3 H) Step 2: methyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-5-methyl-2.5-dihydrofuran-3-carboxylate

[0231] A mixture of 5-bromo-3-(methylthio)pyrazin-2-amine (1.00 g, 4.54 mmol), AcOH (0.520 ml, 9.09 mmol), MgSO4 (5.47 g, 45.4 mmol) and methyl 5-methyl-4-oxotetrahydrofuran-3-carboxylate (0.719 g, 4.54 mmol) in MeOH (10 ml) was stirred at 80°C for 16 h. The reaction is performed ten times in parallel. The mixture was filtered and concentrated under reduced pressure, The residue was purified by flash silica gel chromatography (eluent of [0~30]% ethyl acetate / EtOH andether gradient) to give methyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-5-methyl-2,5-dihydrofuran-3-carboxylate. MS (ESI) m / z: calc’d forCi2Hi5BrN3O3S [M+H]? 327.9 / 329.9 found 327.8 / 329.8. Step 3: 7-bromo-3-methvl-5-(methylthio)-L3-dihydro-lOH-furo[3.4-d1pvrazino[ L2-a1pvrimidin-10-one

[0232] A mixture of methyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-5-methyl-2,5-dihydrofuran-3-carboxylate (2.8 g, 7.77 mmol) in diphenyl ether (25 ml) was stirred at 280 °C for 4 h by Sand bath. The residue was purified by silica column chromatography (ethyl acetate / petroleum ether = 1:3) to give 7-bromo-3-methyl-5-(methylthio)-l,3-dihydro-10H-furo[3,4-d]pyrazino[l,2-a]pyrimidin-10-one. MS (ESI) m / z: calc’d for CnHnBrN3O2S [M+H]+: 327.9 / 329.9 found 327.9 / 329.9. 'H NMR (400 MHz, CDCh) 5 ppm 8.62 (s, 1 H), 5.25 - 5.30 (m, 1 H), 5.10 - 5.22 (m, 2 H), 2.62 (s. 3 H). 1.57 (d, 7=6.56 Hz, 3 H). Step 4: 3-methyl-7-(2-(2-methylpvridin-4-yl)tetrahvdro-2H-pyran-4-yl)-5-(methvlthio)-1.3-dihvdro-1 OH-furo [ 3,4-dlpyrazino [ 1,2-a]py rimidin-10-one

[0233] A mixture of NiCb-DME (26.8 mg, 0.122 mmol) and picolinimidamide hydrochloride (19.2 mg, 0.122 mmol) in DMA (5 ml) was stirred at 25 °C for 0.5 h in glove box. Then zinc (159 mg. 2.438 mmol), tetrabutylammonium iodide (338 mg. 0.914 mmol), 7-bromo-3-methyl-5-(methylthio)-l,3-dihydro-10H-furo[3,4-d]pyrazino[l,2-a]pyrimidin-10-one (200 mg, 0.609 mmol),4-(4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine (203 mg, 0.792 mmol) was added. The mixture was stirred at 40 °C for 2 h. Three reactions were ran in parallel. The reaction mixture was quenched with aqueous ammonium chloride (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-40% ethyl ether / petroleum ether gradient) to give 3-methyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(methylthio)-l,3-dihydro-10H-furo[3,4-d]pyrazino[l,2-a]pyrimidin-10-one. MS (ESI) m / z: calc’d for C22H24N4O3S [M+H]+: 425.1 found 425.2. Intermediate 25; 2.4-dichloro-7,8-dihvdropvrimidor4.5-flindolizin-10(6H)-one Smp L methy]jLiodo22j22dJoxo2L2A7>;t44rahv(^^

[0234] To a solution of methyl orotate (9.0 g, 52.9 mmol) in MeOH (100 mL) was added iodine (2.69 g, 10.5 mmol), periodic acid (7.24 g, 31.7 mmol) and the resulting mixture was stirred at 70 °C for 16 h. The reaction solution was filtered and concentrated in vacuo then wash and filter solids with water to give crude methyl 5-iodo-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate which used directly for the next step without additional purification. MS (ESI) m / z: calc'd for C6H5IN2O4 [M+H]+: 296.9, found 296.7. Step 2: methyl 5-iodo-l,3-bis(4-methoxvbenzvl)-2.6-dioxo-1.2.3.6-tetrahydropyrimidine-4-carboxylate

[0235] To a solution of methyl 5-iodo-2.6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (13 g, 43.9 mmol). Na2COs (13.0 g, 123 mmol) in DMF (100 rnL) was slowly added 4-methoxybenzyl chloride (11.9 ml, 88 mmol) and the resulting mixture was stirred at 25 °C for 16 h. The mixture was treated with water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic fractions were washed with brine (50 mL), dried overNa2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography (eluent of 25 % Ethyl acetate / Petroleum ether gradient) to give methyl 5-iodo-l,3-bis(4-methoxybenzyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate. MS (ESI) m / z: calc'd for C22H21IN2O6 [M+H]+: 537.0, found 536.9. *HNMR (400 MHz, DMSO-d6) 5 ppm 7.25 - 7.25 (m, 1 H), 7.25 (d, J=8.58 Hz, 1 H), 7.16 (d, J=8.70 Hz, 2 H), 6.89 (t, J=8.76 Hz, 4 H), 4.99 (s, 2 H). 4.90 (s, 2 H). 3.78 - 3.83 (m. 3 H). 3.73 (d, J=4.29 Hz, 6 H) Step 3: methyl 5-(5-((tert-butoxvcarbonvl)amino)pent-l-vn-l-vl)-L3-bis(4methoxvbenzvl)-2.6-dioxo-1.2.3.6-tetrahvdropyrimidine-4-carboxylate

[0236] To a solution of methyl 5-iodo-l,3-bis(4-methoxybenzyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (10.0 g, 18.65 mmol) in dioxane (93 mL) was added TEA (5.20 ml, 37.3 mmol), dichlorobis(triphenylphosphine)palladium(ii) (1.31 g, 1.86 mmol), Copper(I) iodide (0.710 g, 3.73 mmol), tert-butyl pent-4-yn-l-ylcarbamate (4.10 g, 22.3 mmol) and the resulting mixture was stirred at 80 °C under nitrogen protection for 12 h. The reaction solution was filtered and concentrated in vacuo and purified by flash silica gel chromatography (eluent of 0 - 35 % Ethyl acetate / Petroleum ether gradient) to give methyl 5-(5-((tert-butoxycarbonyl)amino)pent-l-yn-l-yl)-l,3-bis(4-methoxybenzyl)-2,6-di oxo-1.2,3.6-tetrahydropyrimidine-4-carboxylate. MS (ESI) m / z: calc'd for C32H37N30s[M+H]+: 592.2, found 592.2. Step 4: methyl 5-(5-aminopent-l-vn-l-vl)-1.3-bis(4-methoxybenzyl)-2.6-dioxo-l,2.3.6-tetrahy dropy rimidine-4-carboxy late

[0237] A solution of methyl 5-(5-((tert-butoxycarbonyl)amino)pent-l-yn-l-yl)-1.3-bis(4-methoxybenzyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (5.50 g, 9.30 mmol) in MeOH (50 ml) / Hydrochloric Acid, 37% (5.00 ml)was stirred at 25 °C for 6 h. The reaction solution was filtered and concentrated in vacuo to give crude methyl 5-(5-aminopent-l-yn-l-yl)-l,3-bis(4-methoxybenzyl)-2.6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate, which was used directly for the next step without additional purification. MS (ESI) m / z: calc'd for C27H29N3O6[M+H]+: 492.2, found 492.1. Step 5: 1.3-bis(4-methoxvbenzyd)-1.6.7.8-tetrahydropyrimido[4.5-f|indolizine-2.4.10(3H)-trione

[0238] To a solution of methyl 5-(5-aminopent-l-yn-l-yl)-l,3-bis(4-methoxybenzyl)-2,6-dioxo-l,2,3,6-tetrahydropyrimidine-4-carboxylate (4.5 g, 9.15 mmol) in DMF (45.8 mL) was added CS2CO3 (11.93 g, 36.6 mmol) and the resulting mixture was stirred at 80 °C for 6 h. The reaction solution was filtered and concentrated in vacuo. The mixture was purified by reversed phase column (60% MeCN / H2O, TFA modifier) to give l,3-bis(4-methoxybenzyl)-l,6,7,8-tetrahydropyrimido[4,5-f]indolizine-2,4,10(3H)-trione. MS (ESI) m / z: calc'd for C26H25N3O5 [M+HJ+: 460.1, found 460.0. Step 6: 1.6.7.8-tetrahydropyrimido[4.5-f|indolizine-2.4.10(3H)-trione

[0239] To a solution of l,3-bis(4-methoxybenzyl)-l,6,7,8-tetrahydropyrimido[4,5-f]indolizine-2,4,10(3H)-trione (550 mg, 1.19 mmol) in TFA (2 mL) was added trifluoromethanesulfonic acid (1.79 mg, 0.012 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 2 h. The mixture was purified by reversed phase column (80%MeCN / H2O) to give 1,6,7,8-tetrahydropyrimido[4,5-f|indolizine-2,4,10(3H)-trione. MS (ESI) m / z: calc'd for CioH9N303[M+H]+: 220.0. found 220.0. Step 7: 2.4-dichloro-7,8-dihvdropvrimido[4.5-flindolizin-10(6H)-one

[0240] To a solution of l,6,7,8-tetrahydropyrimido[4,5-f|indolizine-2,4,10(3H)-trione (450 mg, 2.05 mmol) in MeCN (10 mL) was added DIPEA (0.359 ml, 2.05 mmol), POCk (1.14 ml, 12.2 mmol) at 0 °C and stirred at 25 °C for 15 min. Then the resulting mixture was stirred at 100 °C for 2 h. Then Lithium chloride (174 mg, 4.11 mmol) was added and the resulting mixture was stirred at 100 °C for 2 h. The mixture was quenched with sat.NaHCO? aq. (8 mL) and extracted with EtOAc (10 mL x 3). The combined organic fractions were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 100% Ethyl acetate gradient) to give 2,4-dichloro-7,8-dihydropyrimido[4,5-f]indolizin-10(6H)-one. MS (ESI) m / z: calc'd for C10H7CI2N-OIM+HI : 256.0, found 255.9. 'H NMR (400 MHz, CDCh) 5 ppm 6.67 (s, 1 H), 4.28 - 4.33 (m, 2 H), 3.24 (td, J=7.72, 1.25 Hz, 2 H), 2.31 (quin, J=7.48 Hz, 2 H). SYNTHESIS OF EXAMPLE COMPOUNDS Example 1-1; (5)-l-(4-chloro-2-fluoropheny 1)-3-(2-(1-methyl-U7-pyrazol-4-yl)morpholino)-8,9- dihydropyrido[3.4-tZ]pyrrolo[l.2-a1pyrimidin-5(7 / 7)-one Pd(dppf)CI2-CH2CI2 Dioxane / Water K2CO3 2 h, 40 °C POCI3 Toluene 2-pyrrolidone 2 h, 90 °C Step 1: L3-dichloro-8.9-dihydropyrido[3.4-<7]pyrrolo[1.2-a1pvrimidin-5(777)-one

[0241] A suspension of 3-amino-2,6-dichloroisonicotinic acid (500 mg. 2.415 mmol) and pyrrolidin-2-one (226 mg, 2.66 mmol) was made by adding toluene (5 mL). Then POCI3 (1.351 mL, 14.49 mmol) was added slowly. Then the reaction was put under nitrogen, and was allowed to stir for 15 minutes. Then the reaction was stirred at 90 °C under nitrogen for 2 h. After LCMS showed the reaction was completed, the reaction mixture was slowly pipetted into a flask containing 50 mL sat. sodium bicarbonate. The mixture was extracted with EtOAc (30 mLx3). The organic layer was dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel chromatography (eluent of 0-100% hexanes: EtOAc) to provide L3-dichloro-8,9-dihydropyrido[3,4-c / ]pyrrolo[L2-a]pyrimidin-5(777)-one. MS (ESI) m / z C10H8CI2N3O [M+H]+ calc’d 255.9, found 256.0. Step 2: 3-chloro-l-(4-chloro-2-fluorophenvD-8.9-dihydropyrido[3.4-<7]pyiTolo[L2-a1pyrimidin-5(7 / 7)-one

[0242] A vial was charged with l,3-dichloro-8,9-dihydropyrido[3,4-J]pyrrolo[l,2-a]pyrimidin-5(7 / 7)-one (0.95 g, 3.7 mmol), (4-chloro-2-fluorophenyl)boronic acid (0.65 g, 3.7 mmol), potassium carbonate (1.5 g, 11 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.30 g, 0.37 mmol). Then 1.4-dioxane (13 mL) and water (1.3 mL) were added and the reaction was sparged for 15 minutes with nitrogen. The reaction was then heated to 40 °C for 2 h, then cooled to room temperature and concentrated. The residue was dissolved in water 5 mL and 5 mL of DCM. The organic layer was passed through a phase separator, the aqueous layer rinsed with DCM (3x5 mL) and the combined organic layers concentrated. The crude residue was purified by flash silica gel chromatography (0-100% EtOAc / hexanes) to provide 3-chloro-l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-«]pyrimidin-5(777)-one. MS (ESI) m / z C16H11CI2FN3O [M+H]+ calc’d 350.0, found 350.0. Step 3: (,S,)-l-(4-chloro-2-fluorophenyl)-3-(2-(l-methvl-lH-pyrazol-4-vl)morpholino)-8.9-dihydropyrido [ 3.4-<7]pyrrolo[ 1,2-^1 py rimi din-5 (77 / )-one

[0243] A vial was charged with RuPhos Pd G3 (8.55 mg, 10.2 pmol), potassium phosphate (65.1 mg, 307 pmol), 3-chloro-l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-<7|pyrrolo[l,2-a]pyrimidin-5(777)-one (35.8 mg, 102 pmol) and (<S)-2-(l-methyl-l / 7-pyrazol-4-yl)morpholine (34.2 mg, 204 pmol). Then 1,4-Dioxane (2.04 mL) was added, the solution was sparged for 15 min with nitrogen and then the reaction was heated for 2 h at 65 °C. The reaction was filtered and concentrated, then the crude material was purified by flash silica gel chromatography (0-100% EtOAc / hexanes gradient) which provided (S)-l-(4-chloro-2-fluorophenyl)-3-(2-(l-methyl-l / Z-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-i / ]pynolo[L2-a]pyrimidin-5(77 / )-one. MS (ESI) m / z C24H23CIFN6O2 [M+H]+ calc’d 481.1, found 481.0. 'H NMR (499 MHz, DMSO) 5 7.74 (s, 1H), 7.58 - 7.48 (m, 2H), 7.46 (s, 1H), 7.39 (dd, J= 8.2, 2.0 Hz, 1H), 7.36 (s, 1H), 4.56 (dd, J= 10.4, 2.6 Hz, 1H), 4.29 (d, J= 11.7 Hz, 1H), 4.13 (d, J= 12.5 Hz, 1H), 4.06 -3.98 (m, 3H), 3.81 (s, 3H). 3.75 - 3.66 (m, 1H), 3.01 (td, J= 12.5, 3.5 Hz, 1H), 2.98-2.87 (m, 3H), 2.13 (p. J =7.7 Hz. 2H). Examples 1-2 and 1-3; l-(4-chloro-2-fluorophenyl)-3-[(2R.4S)-2-(2-methylpvridin-4-yl)oxan-4-yl]-8.9-dihydropyrido[3.4-<7]pyrrolo[L2-a]pyrimidin-5(7 / 7)-one and l-(4-chloro-2-fluorophenyl)-3- [(25.45')-2-(2-methvlpvridin-4-vl)oxan-4-vll-8.9-dihvdropvridor3.4-51pvrrolo[l,2-alr)vrimi din- 5(7#)-one SFC Peak 1                            SFC Peak 2

[0244] To a mixture of 3-chloro-l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-r / |pyrrolo[l,2-a]pyrimidin-5(7 / / )-one (20 mg, 0.057 mmol), 4-(4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine (29.3 mg, 0.114 mmol), Nickel(II) chloride ethylene glycol dimethyl ether complex (1.255 mg, 5.71 pmol). zinc (7.47 mg, 0.114 mmol), sodium iodide (2.140 mg, 0.014 mmol), picolinimidamide hydrochloride (0.900 mg, 5.71 pmol) in DMA (5 ml) was added TFA (0.440 pl, 5.71 pmol) at 20 °C and the mixture was stirred at 60 °C for 16 h under N2 atmosphere. LCMS showed the reaction was completed. After filtration and concentration, the mixture was purified by pre-HPLC (water / MeCN with TFA modifier) to give rac-l-(4-chloro-2-fluoropheny I )-3-((25,48 and 28. 45)-2-(2-methylpyridin-4-yl)tetrahydro-27 / -pyran-4-yl)-8,9-dihy dropy rido [3,4-<7]pyrrolo[ 1,2-a] pyrimi din-5 (75Z)-one. 1 -(4-chloro-2-fluoropheny 1)-3 -(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one (35 mg, 0.071 mmol) was separated by chiral SFC and dried by lyophilization to afford 1 -(4-chloro-2-fluorophenyl)-3-((25.45)-2-(2-methylpyridin-4-yl)tetrahy dro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one (Rt =1.104min, ee>99.99%) 1-2, l-(4-chloro-2-fluorophenyl)-3-((25,45)-2-(2-methylpyri din-4-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one (Rt =2.021min, ee>99.99%), 1-3. Example 1-2 - Peak 1: l-(4-chloro-2-fluorophenyl)-3-((25,45)-2-(2-methylpyridin-4-yl)tetrahydro-2 / 7-pyran-4-yl)-8,9-dihydropyrido[3,4-5|pyrrolo[l,2-a]pyrimidin-5(777)-one: 'H NMR (CDCW, 400 MHz) d = 8.79 (d, J= 6.0 Hz, 1H), 8.00 (s, 1H), 7.68 - 7.65 (m, 1H), 7.64 -7.61 (m, 1H), 7.52 0,5=7.9 Hz, 1H), 7.31 (d, J= 1.4 Hz, 1H), 7.23 (dd, J= 1.8, 9.4 Hz, 1H), 4.72 (br d, J= 11.2 Hz, 1H), 4.46 - 4.36 (m, 1H), 4.23 (t, J= 7.3 Hz, 2H), 3.93 - 3.79 (m, 1H), 3.45 - 3.35 (m. 1H), 3.15 (t, J = 8.0 Hz, 2H), 2.85 (s, 3H). 2.43 - 2.37 (m. 1H), 2.34 - 2.26 (m, 2H), 2.15 - 2.06 (m, 2H), 1.85 - 1.73 (m, 1H). MS (ESI) m / z: calc’d for C27H24C1FN4O2+ [M+H]+: 490.9, found [M+H]+: 491.1 Example 1-3 - Peak 2: l-(4-chloro-2-fluorophenyl)-3-((27?,- / S)-2-(2-methylpyridin-4-yl)tetrahydro-2 / / -pyran-4-yl)-8,9-dihydropyrido[3,4-<7|pyrrolo[l,2-a]pyrimidin-5(7 / 7)-one: 'H NMR (CDCh-d, 400 MHz) 8 = 8.70 (d, J= 6.0 Hz, 1H), 7.91 (s, 1H), 7.58 (s, 1H), 7.55 (br d, J= 5.7 Hz, 1H), 7.43 (t, .7= 7.9 Hz, 1H), 7.22 (d,J = 1.8 Hz, 1H), 7.14 (dd, J= 1.8, 9.5 Hz, 1H), 4.63 (brd.. / ~ 10.0 Hz, 1H), 4.36-4.29 (m, 1H), 4.14 (t, J - 7.3 Hz, 2H), 3.80-3.71 (m, 1H), 3.35 - 3.29 (m, 1H), 3.06 (t, J= 7.9 Hz, 2H), 2.77 (s, 3H). 2.30 (br d, J= 13.5 Hz, 1H). 2.21 (Id, J = 7.6, 14.9 Hz. 2H), 2.05 - 1.97 (m, 2H), 1.76 - 1.64 (m, 1H). MS (ESI) m / z: calc’d for C27H24C1FN4O2+ [M+H]+: 490.9, found [M+H]+: 491.1

[0245] Examples shown in Example Table 1-1 below, were prepared according to procedures analogous to those outlined in Example 1-1 to 1-3 above using the appropriate starting materials. Table 1-1: Examples 1-4 to 1-23 Example Structure IUPAC Name Exact Mass [M+HJ+ 1-4 Cl ,N==i o 1 -(4-chloro-2-fluoropheny 1)-3-[(27 / )-2-( 1 -methyl- 1 / 7-pyrazol-4-yl)morpholin-4-yl]-8,9- dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin- 5(7 / 7)-one 481 1-5 Cl N«, o 1 -(4-chloro-2-fluorophenyl)-3-1(2 / / )-2-(1 -methyl- lEf-py razol-4-y l)morpholin-4-yl] -7,8,9,10-tetrahydro-5 / / -dipyndo|l.2-a^'Y'-c / lpyrimidin-S-one 495 1-6 Cl f^y N N      Yr i Y^ N      n 0 1 -(4-chloro-2-fluoropheny 1)-3[(23)-2-( 1 -methyl-177-pyrazol-4-yl)morpholin-4-yl] -7,8,9,10-tetrahydro-5E7-dipyrido[ 1,2-a:3',4'-<7]pyrimidin-5-one 495 1-7 Cl : Y       F i N            n X  • N-N \ {R}-1 -(4-chloro-2- fluorophenyl)-9,9-difluoro-3-[2-(1 -methyl-1 H-py razol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin- 5(7 / / )-one 517 1-8 Cl JM F"T    F O N—N \ (S)-l-(4-chloro-2-fluorophenyl)-9,9-difluoro-3-[2-(1 -methyl- 17 / -pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-< / ]pyrrolo[l,2-a]pyrimidin-5(7 / / )-one 517 1-9 Cl 0 N-N 10-(4-chloro-2-fluoropheny 1)-8-[(2S)-2-( 1 -methyl- l / Z-pyrazol-4-yl)morpholin-4-yl]-3,4-dihydropyrido[3',4':4,5]pyrimid o [2,1 -cl [ 1,4] oxazin-6( l / 7)-one 497 1-10 Cl jfj \                       n \ O^J     o N-N (R or S)-l-(4-chloro-2-fluorophenyl)-7-methyl-3-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin- 5(7H)-one 495 1-11 Cl A ^aA^nJ* o^J     o N-N \ (S or / ?)-l-(4-chloro-2-fluorophenyl)-7-methyl-3-(2-( 1 -methyl-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin- 5(7H)-one 495 1-12 Cl NA^A O^J    o A? N—N \ (R or 5)-l-(4-chloro-2-fluorophenyl)-9-methyl-3-(2-( 1 -methyl-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 495 1-13 Cl ^nAA^A o A5? N-N^ (S or 7?)-l-(4-chloro-2-fluorophenyl)-9-methyl-3-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin- 5(7H)-one 1-14 Cl X) 'M^yy^AAXA o-A     o 1 -(4-chloro-2-fluoropheny 1)-3[(2S, 4R)-2-( 1 -methyl- 1H-pyrazol-4-yl)oxan-4-yl]-8,9-dihy dropy ri do [3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 480 1-15 Cl Xj NAVA 'nAAAA O^J     0 1 -(4-chloro-2-fluoropheny 1)-3-[(2R, 45)-2-(1 -methyl- IH-pyrazol-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4- < / ]pyrrolo[l,2-a]pyrimidin-5(7H)-one 480 1-16 F Xj F'Yp nA^ Y^nAA^A O^J     o N—N l-(2,4-difluorophenyl)-3-[(25)-2-( 1 -methyl- 14 / -pyrazol-4-yl)morpholin-4-yl]-8,9- dihydropyrido[3,4- < / ]pyrrolo[ 1,2-a]pyrimidin-5(7H)-one 465 1-17 Xj y^aA^A O^J    o A / N-N \ 1-(2-fl uoro-4-methylpheny 1)-3[(25)-2-(1 -methyl- IH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4- d]pyrrolo[1.2-ajpyrimidin-5(7 / 7)-one 461 1-18 FxL<F Xj aXUnU r N n o N-N^ l-[2-fluoro-4- (trifluoromethyl)phenyl]-3-[(25)-2-(1 -methyl-1 / / -py razol-4-yl)morpholin-4-yl]-8,9- dihy dropy ri do [3,4- < / ]pyrrolo[ 1,2-a]pyrimidin-5(7 / / )-one 515 1-19 Cl A oU   o JU N (A)-1-(4-chloro-2-fluorophenyl)-3-(2-(2-methylpyridin-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin- 5(7 / ^-one 492 1-20 Cl A Xn o / 0 N (S)-1 -(4-chloro-2-fluoropheny 1)-3-(2-(2-methylpyridin-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7 / / )-one 492 1-21 Cl A F^T nMyx -nUyyUUJ O^J     0 1 -(4-chloro-2-fluoropheny 1)-3-[(2R,4R or 2S, 4S)-2-( 1 -methyl-l / / -pyrazol-4-yl)oxan-4-yl]-8,9-dihy dropy rido[3,4- < / ]pyrrolo[l,2-a]pvrimidin- 5 (7 / <)-one       ' 480 1-22 Cl A N iT^YA -^xA^'UUUU O^J     O 1 -(4-chloro-2-fluoropheny 1)-3-[{2S,4S or 2R, 4 / ?)-2-(l-methyl-lH-pyrazol-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-< / ]pyrrolo[l,2-a]pyrimidin- 5 (7 / / )-one 480 1-23 O'^     0 —nU  H^iU f'Yi Cl ( / aS',9« / ?)-3-(4-chloro-2-lluorophenyl)-5-[(25)-2-(l-methyl- l / / -py razol-4-y l)morpholin-4-yl] -l,la,9,9a-tetrahydro-77 / - cy clopropa[3,4]pyrrolo[ 1.2-a]pyrido[3,4-6nPYrimidin-7-one 493 Example 24-24; (7?)-l-(4-chloro-2-fluorophenyl)-3-(3-(pvridin-4-yloxv)pvrrolidin-l-vl)-8.9-dihvdropvridor3.4- d1pvrrolo[l.2-a1pyrimidin-5(7 / 7)-one Step 1: (A>l-(4-chloro-2-nuorophenvl)-3-(3-hvdroxvpvrrolidin-l-vl)-8.9-dihvdropvrido|3.4-d]pvrrolo[ 1,2-a1pyrimidin-5(7 / D-one

[0246] To a 20 mL vial was added (<S)-pyrrolidin-3-ol, HC1 (123 mg, 1.00 mmol), 3-chloro-l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(77 / )-one (350 mg, 1.00 mmol), RuPhos G3 (20.9 mg, 25.0 pmol) and cesium carbonate (716 mg, 2.20 mmol) in dry 1,4-Dioxane (10 mL). The mixture was purged with bubbling N2 for 5 min and the mixture was sealed and heated to 80 °C for 5 h. The mixture was cooled, filtered, concentrated and loaded onto a silica cartridge and purified (50-100% EtOAc in hexanes). The fractions were collected and concentrated to afford (<S’)-l-(4-chloro-2-fluorophenyl)-3-(3-hydroxypyrrolidin-l-yl)-8,9-dihydropyrido[3.4-d]pyrrolo[l,2-a]pyrimidin-5(77 / )-one. MS (ESI)mZz: calc’dfor C20H19CIFN4O2 [M+H]+: 401.0, found [M+H]+: 401.0. Step 2: ( / ?)-!-(4-chloro-2-fluorophenyl)-3-(3-(pvridin-4-yloxy)pyiTolidin-l-yl)-8.9-dihvdropvrido [3,4-d] pvrrolol 1,2-alpvrimi din-5 (7 / 7)-one

[0247] In a 2 dram vial was added (S)-l-(4-chloro-2-fluorophenyl)-3-(3-hydroxypyrrolidin-l-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one (14.0 mg, 34.9 pmol), Triphenylphosphine (18.3 mg, 69.9 pmol) and pyridin-4-ol (4.15 mg, 43.7 pmol) which were dissolved in dry THF (582 pL). 200 pL DCM was added for enhanced solubility. DIAD (13.6 pL. 69.9 pmol) was added last and added in one portion at RT and the resulting mixture stirred for 3h. The solvent was evaporated and taken up in MeOH, filtered, and submitted to reverse phase purification: (MeCN / water with 0.1% TFA modifier) to afford (R)-l-(4-chl oro-2 -fluorophenyl)-3-(3-(pyridin-4-yloxy)pyrrolidin-l-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z: calc’d for C25H22CIFN5O2 [M+H]+: 478.1, found [M+H]+: 478.1. 1H NMR (499 MHz, DMSO) 5 8.68 (d, J = 6.8 Hz, 1H), 8.45 (d, J = 7.2 Hz, 1H), 7.56-7.47 (m, 3H), 7.40 (dd, J = 8.2, 2.0 Hz, 1H), 7.10 (d, J = 7.1 Hz, 1H), 5.55 (s, 1H), 4.10 (d, J = 7.5 Hz, 1H), 4.07 - 4.01 (m, 2H), 3.92 (dd, J = 12.5, 4.2 Hz, 1H), 3.76 (dd, J = 19.2, 10.7 Hz, 2H), 3.60 (d, J = 7.1 Hz, 2H), 2.94 (t, J = 7.8 Hz, 2H), 2.13 (dt, J = 15.1, 7.9 Hz, 2H). Example 1-25 and 1-26: (R or lS')-3-(4.4-difluoro-3-(2-methylpvridin-4-yl)piperidin-l-vl)-l-(2.4-difluorophenvl )-8,9-dihvdropvrido[3.4-d1pvrrolo[l.2-a1pvrimidin-5(7 / / )-one and (Sor / ?)-3-(4.4-difluoro-3-(2-methylpvridin-4-yl)piperidin-l-vD-l-(2,4-difluorophenvl)-8.9-dihydropyrido[3.4-dlpyrrolo|T.2- al pvrimi din-5 (7 / / )-one Step 1: 3-(4.4-difluoro-3-(2-methvlpyridin-4-vl)piperidin-l-yl)-l-(2.4-difluorophenyl)-8,9-dihy dropy rido [ 3,4-d1 pyrrolof 1.2-a1pvrimi din-5 (7 / / )-one

[0248] To a solution of 3-chloro-l-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7 / Z)-one (60 mg, 0.180 mmol) in Dioxane (3 mL) were added 4-(4,4-difluoropiperidin-3-yl)-2-methylpyridine (60 mg, 0.283 mmol). CS2CO3 (234 mg, 0.719 mmol), rac-BINAP Pd G4 (18.09 mg, 0.018 mmol) and the resulting mixture was stirred at 100 °C for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in water (20 mL). The aqueous layer was re-extracted with EtOAc (20 mL><3) and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (Water (0.05%NH3H20 + lOmM NH4HCO3)-MeCN) to give 3-(4,4-difluoro-3-(2-methylpyridin-4-yl)piperidin-l-yl)-l-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7 / Z)-one. The compound was resolved by chiral SFC [DAICEL CHIRALCEL OD (250 mm x 30 mm,10 pm); Condition: CO2-EtOH (0.1%NH3-H2O)] to give 1-25 (SFC Peak 1): (S orA)-3-(4.4-difluoro-3-(2-methylpyridin-4-yl)piperi din-1-yl)-l-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimi din-5(7E7)-one and 1-26 (SFC Peak 2): (R or S)-3-(4,4-difluoro-3-(2-methylpyridin-4-yl)piperidin-l-yl)-l-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(777)-one. Ex 1-25 (SFC Peak 1): MS (ESI) w / z: calc’d for C27H24F4N5O [M+H]+: 510.2, found [M+H]+: 510.2. 'H NMR (400MHz, CDCh)^ = 8.48 (d, J= 3.6 Hz, 1H), 7.61 - 7.54 (m, 1H), 7.45 (s, 1H), 7.16 (s, 1H), 7.11 (d, .7= 4.8 Hz, 1H), 6.99 (dt, J= 1.9, 8.2 Hz, 1H), 6.92 (dt, J= 2.4, 9.5 Hz, 1H), 4.62 - 4.53 (m, 2H), 4.18 (t, J = 7.2 Hz, 2H), 3.52 (1, J= 12.6 Hz. 1H), 3.45 -3.37 (m, 1H), 3.24 - 3.12 (m, 1H), 3.09 (t, J= 7.9 Hz, 2H), 2.58 (s, 3H), 2.28 - 2.24 (m, 2H), 2.22 -1.99 (m, 2H). Ex 1-26 (SFC Peak 2): MS (ESI) m / z’. calc’d for C27H24F4N5O [M+H]+: 510.2, found [M+H]+: 510.2. *HNMR (400MHz, CDCh)<5 = 8.55 - 8.41 (m, 1H), 7.61 - 7.54 (m, 1H). 7.45 (s, 1H), 7.17 (s, 1H), 7.12 (d, J = 4.6 Hz, 1H), 6.99 (dt. 7=2.1, 8.3 Hz, 1H), 6.92 (dt,7=2.3. 9.5 Hz, 1H), 4.62-4.52 (m, 2H), 4.18 (t, 7 = 7.3 Hz, 2H), 3.52 (t,7 = 12.5 Hz, 1H), 3.45 - 3.36 (m, 1H), 3.23 - 3.12 (m, 1H), 3.09 (t, J= 7.9 Hz, 2H), 2.58 (s, 3H), 2.28 - 2.24 (m, 2H), 2.22 - 1.99 (m, 2H). Example 1-27,1-28,1-29, and 1-30: l-(4-chloro-2-fluorophenvl)-3-((25,47? or 2RAS)-2-((S or 7?)-tetrahvdrofuran-3-vl)tetrahvdro-2H- pyran-4-yl)-8.9-dihydropyrido[3.4-d1pyrrolo[l.2-a1pyrimidin-5(7H)-one. l-(4-chloro-2- fluorophenyl)-3-((25.47? or 2RAS)-2-((R or >S)-tetrahydrofuran-3-yl)tetrahydro-2H-pvran-4-yl)- 8.9-dihydropyrido[3.4-dlpyrrolo[1.2-a]pyrimidin-5(7H)-one. l-(4-chloro-2-fluorophenyl)-3-((27745 or 2SAR}-2-((S or 7?)-tetrahvdrofuran-3-yl)tetrahvdro-2H-pvran-4-vl)-8.9- dihydropyrido[3.4-d1pvrrolo[l.2-a1pyrimidin-5(7H)-one. and l-(4-chloro-2-fluorophenyl)-3-((27?.45 or 2SAR)-2-((R or 5)-tetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8.9- dihvdropvrido[3.4-d1pvrroloIl.2-alpvrimidin-5(7H)-one. Step 1: l-(4-chloro-2-fluorophenyl)-3-(2-(tetrahydrofuran-3-yl)tetrahydro-277-pyran-4-yl)-8.9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(777)-one

[0249] To a vial containing 4-bromo-2-(tetrahydrofuran-3-yl)tetrahydro-2H-pyran (101 mg, 428 pmol) were added 3-chloro-l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(777)-one (100 mg, 286 pmol), Sodium iodide (10.7 mg, 71.4 pmol), Zinc powder (74.7 mg, 1.14 mmol), pyridine-2,6-bis(carboximidamide) dihydrochloride (13.5 mg, 57.1 pmol), and nickel (II) chloride DME adduct (12.5 mg, 57.1 pmol) in DMA (3.57 mL) and sparged with N2 for 15 min. The reaction was then heated under N2 60 °C for Ih. The reaction was quenched with water (10 mL) and extracted with EtOAC (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4. filtered and concentrated. The residue was purified by reverse phase prep-HPLC (MeCN / water with 0.1% NH3OH modifier) to give 1-(4-chloro-2-fluorophenyl)-3-(2-(tetrahydrofuran-3-yl)tetrahydro-2 / / -pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(77 / )-one as a mixture of isomers. MS (ESI) m / z: calc’d for C25H26CIFN3O3 [M+H]+ 470.2, found [M+H]+ 470.2.

[0250] The isomers were separated by chiral SFC using Chiral Column IH, 21 x 250mm. 5pm: Modifier: 20% MeOH w / 0.1%NH4OH to afford 1-27 SFC Peak 1: 1 -(4-chloro-2-fluorophenyl)-3-((25,477 or 277,45)-2-((5 or 7?)-tetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one, 1-28 SFC Peak 2: l-(4-chloro-2-fluoropheny1)-3-((25,477 or 277,45)-2-((5 or 7?)-tetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3.4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one, 1-29 SFC Peak 3: l-(4-chloro-2-fluoropheny1)-3-((25,47? or 277,45)-2-((5 or 7?)-tetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one, 1-30 SFC Peak 4: l-(4-chloro-2-fluoropheny1)-3-((25,477 or 277,45)-2-((5 or 7?)-tetrahydrofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3.4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one. Ex 1-27, SFC Peak 1: MS (ESI) m / z'. calc’d for C25H26CIFN3O3 [M+H]+ 470.2, found [M+H]+ 470.2. 'H NMR (499 MHz, DMSO) 5 7.91 (s, IH), 7.60 - 7.53 (m, 2H), 7.44 (dd, J= 8.3, 2.0 Hz, IH), 4.12-4.06 (m. 2H), 4.02 (dd, J= 11.3, 3.3 Hz, IH), 3.77 0, / = 8.0 Hz, IH), 3.71 (td, / =8.2, 4.4 Hz, IH), 3.63-3.48 (m, 3H), 3.18 (t, / = 11.9 Hz. IH), 3.03 (t, / =8.0 Hz, 2H), 2.27 - 2.18 (m, IH), 2.15 (d, / = 7.2 Hz, 2H), 2.04 - 2.00 (m, 2H), 1.91 - 1.84 (m, IH), 1.81 - 1.73 (m, IH), 1.61 - 1.38 (m, 3H). Ex 1-28, SFC Peak 2: MS (ESI) m / z\ calc’d for C25H26CIFN3O3 [M+H]+ 470.2, found [M+H]+ 470.2. 'H NMR (499 MHz, DMSO) 5 7.91 (s, IH). 7.56 (s, 2H), 7.44 (dd, / = 8.3. 2.0 Hz. IH), 4.12-3.99 (m. 2H), 3.75 - 3.66 (m, 2H), 3.61 (q, / = 7.5 Hz, IH), 3.57 - 3.50 (m, IH), 3.43 (dd, / = 15.9, 8.4 Hz, 2H), 3.21-3.12 (m, IH), 3.03 (t, / =7.9 Hz, 2H), 2.34 - 2.21 (m, IH), 2.16 (p, / = 7.9 Hz, 2H), 1.97- 1.69 (m, 2H), 1.51 (q, / = 12.2 Hz, 2H), 1.42-1.31 (m, 3H). Ex 1-29, SFC Peak 3: MS (ESI) m / z'. calc’d for C25H26CIFN3O3 [M+H]+ 470.2, found [M+H]+ 470.2. 'H NMR (499 MHz, DMSO) 5 7.91 (s, 1H), 7.60 - 7.53 (m, 2H), 7.44 (dd, J= 8.3, 2.0 Hz, 1H), 4.12-4.06 (m. 2H), 4.02 (dd, J= 11.3, 3.3 Hz, 1H), 3.77 0, / = 8.0 Hz, 1H), 3.71 (td, / =8.2, 4.4 Hz, 1H), 3.63-3.48 (m, 3H), 3.18(1, / = 11.9 Hz. 1H), 3.03 (1, / =8.0 Hz, 2H), 2.27 - 2.18 (m, 1H), 2.15 (d, / = 7.2 Hz, 2H), 2.04 - 2.00 (m, 2H), 1.91 - 1.84 (m, 1H), 1.81 - 1.73 (m, 1H), 1.61 - 1.38 (m, 3H). Ex 1-30, SFC Peak 4: MS (ESI) m / z'. calc’d for C25H26CIFN3O3 [M+H]+ 470.2, found [M+H]+ 470.2. 'H NMR (499 MHz, DMSO) 5 7.91 (s, 1H). 7.56 (s, 2H), 7.44 (dd, / = 8.3. 2.0 Hz. 1H), 4.12-3.99 (m. 2H), 3.75 - 3.66 (m, 2H), 3.61 (q, / = 7.5 Hz, 1H), 3.57 - 3.50 (m, 1H), 3.43 (dd, / = 15.9, 8.4 Hz, 2H), 3.21-3.12 (m, 1H), 3.03 (1, / =7.9 Hz, 2H), 2.34 - 2.21 (m, 1H), 2.16 (p, / = 7.9 Hz, 2H), 1.97- 1.69 (m, 2H), 1.51 (q, / = 12.2 Hz, 2H), 1.42-1.31 (m, 3H).

[0251] Examples shown in Example Table 1-2 below, were prepared according to procedures analogous to those outlined in Examples 1-1 to 1-3 and 1-23 to 1-30 above using the appropriate starting materials. Table 1-2: Examples 1-31 to 1-57 Example Structure IUPAC Name Exact Mass [M+HJ+ 1-31 Cl X ____ N      HE \ A^A^n-V O i / / N N— l-(4-chloro-2-fluorophenyl)-3-{(37?)-3-[(5-fluoropyrimidin-4-yl)oxy]pyrrolidin-l-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7 / ^-one 497 1-32 Cl A ___ N Y zA       0 \ z~F N= / l-(4-chloro-2-fluorophenyl)-3-{(37?)-3-[(3-fluoropyridin-4-yl)oxy ]pyrrolidin-1 -yl )-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(777)-one 496 1-33 Cl A X .N. __ N    ^T\ ° N=Z N 4-({(3 / ?)-l-[l-(4-chloro-2-fluorophenyl)-5-oxo-5,7,8,9-tetrahydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-3-yl]pyrrolidin-3-yl}oxy)pyridine-2-carbonitrile 503 1-34 z / _ ° \ '—(     n Z  \=x /  __ /  \_-n O=( z d 1 -(2,4-difluorophenyl)-3-((2R,4S, 2R,4R, 2S,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 475 1-35 F Xj 1 N |1           N |T o 1 -(2,4-difluorophenyl)-3-((2R,4S, 2R,4R. 2S,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 475 1-36 F Xj 1        F^^[ A___.N. N ll         N y A^X^^^^X< n ~v O^X o 1 -(2,4-difluorophenyl)-3-((2R,4S, 2R,4R, 2S,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 475 1-37 F Xj 1      F^^Y .A                 - N ||             N h N X O^J     0 1 -(2,4-difluorophenyl)-3-((2R,4S, 2R,4R, 2S,4S or 2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 475 1-38 n— z / _ ° \ '—(    n \—Z  \=x \   —C ff— O=( z d 1 -(2,4-difluoropheny 1)-3-((2R,4S,6R or 2R,4R,6S)-2-methyl-6-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d] pyrrole [l,2-a]pyrimidin- ’    5(7H)-one 489 1-39 z / _ ° \ \—Z \ --C / —"H O=< z d 1 -(2,4-difluoropheny 1)-3-((2R,4S,6R or 2R,4R,6S)-2-methyl-6-(2-melhylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 489 1-40 Cl XJ 0 l-(4-chloro-2,3-dilluorophenyl)-3-[(2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 509 1-41 Cl F^X N |TNV\ O^J     0 l-(4-chloro-2-fluorophenyl)-3-((2R,4S or 2S,4R)-2-((R or S)-tetrahy drofuran-3 -yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 470 1-42 Z )= O x=< z—? / ° o^ / l-(4-chloro-2-fluorophenyl)-3-((2R,4S or 2S,4R)-2-((R or S)-tetrahy drofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 470 1-43 ° \ Z  \=\ - o=< Z d l-(4-chloro-2-fluorophenyl)-3-((2R,4S or 2S,4R)-2-((R or S)-tetrahy drofuran-3 -yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 470 1-44 U-     z 2=0 5“O“X / '=\ z \ / ° ^oz l-(4-chloro-2,5-difluorophenyl)-3-((2R,4S or 2S,4R)-2-((R or S)-tetrahy drofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 488 1-45 O z )=\ \ “ O=( z     -n d l-(4-chloro-2,5-difluorophenyl)-3-((2R,4S or 2S,4R)-2-((R or S)-tetrahy drofuran-3-yl)tetrahydro-2H-pyran-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 488 1-46 Cl A N      J \—J      O 3-[(3 / ?)-3-tert-butoxypy rrolidin-1 -y 1] -1 -(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 457 1-47 Cl jlj I 1N*O '— / 'Y-J      o (S or R)-l-(4-chloro-2-fl uoropheny 1)-3 -(3-cyclohexylpyrrolidin-1 -yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-'    5 (770-one 467 1-48 \ ° o—( Q Z   Z=\ \ —C O=< z -n d l-(4-chloro-2-fluorophenyl)-3-((S or R)-2-((R or S)-tetrahydro-2H-pyran-3-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 485 1-49 \ ° o—( Q Z    / =\ \ —C O=< z m d l-(4-chloro-2-fluorophenyl)-3-((S or R)-2-((R or S)-tetrahydro-2H-pyran-3-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pvrimidin- 5(7H)-one 485 1-50 \ ° O—< Q \~z / =\ \ J—C O=< z m d l-(4-chloro-2-fluorophenyl)-3-((S or R)-2-((R or S)-tetrahydro-2H-pyran-3-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 485 1-51 \ ° O—( Q \—~z.    / =\ \  —C   “ O=< z -n b l-(4-chloro-2-fluorophenyl)-3-((S or R)-2-((R or S)-tetrahydro-2H-pyran-3-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 485 1-52 9 0 u Cl l-(4-chloro-2-fluorophenyl)-3-((S or R)-2-((S or R)-tetrahydrofuran-3-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 471 1-53 ? ex \ / — / z^ / =° b l-(4-chloro-2-fluorophenyl)-3-((S or R)-2-((S or R)-tetrahydrofuran-3-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 471 1-54 0 A. / k / NvzX-M-\ F -nX   n X F\J\ U Cl l-(4-chloro-2-fluorophenyl)-8,8-difluoro-3-[(25)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-ylJ-8,9-dihydropyrido|3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 517 1-55 Cl fj Xx o v / ^N y \--' \—1       o (R or S)-l-(4-chloro-2-fluorophenyl)-3-[3-(oxan-4-yl)pyrrolidin-1 -y 1] -8,9-dihy dropy ri do [3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 469 1-56 \ N-N Y 0 II                                                  ....... U Cl (87? or &S)-l-(4-chloro-2-fluorophenyl)-8-methyl-3-[(25)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 495 1-57 \-N Y O'>x|       0 N,   AY Y N Cl (85’ or S / ?)-l-(4-chloro-2-fluorophenyl)-8-methyl-3-[(25)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 495 Example 1-58: l-(4-chloro-2-fluorophenyl)-3-((2S)-2-(l-((R and S)-2.2-difluorocyclopropyl)-lH-pyrazol-4- vl)morpholino)-8.9-dihvdropvrido[3.4-d1pvrrolo[l.2-a1pvrimidin-5(7H)-one

[0252] A vial was charged with (S)-3-(2-(lH-pyrazol-4-yl)morpholino)-l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[1.2-a]pyrimidin-5(7H)-one (10.0 mg, 21.4 pmol), 2-bromo-l,l-difluorocyclopropane (5.3 pL, 64.25 pmol), and cesium carbonate (20.9 mg, 64.2 pmol). DMF (428 pL) was added and the reaction was stirred and heated to 80 °C for 16 h. The reaction was cooled, filtered and submitted for reverse phase purification (MeCN / fbO+NFUOH) to provide l-(4-chloro-2-fluorophenyl)-3-((2S)-2-(l-((R and S)-2,2-difluorocyclopropyl)-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one. MS (ESI) Wz: cak’d for C26H23CIF3N6O2 [M+H]+ 543.1, found 543.1. 'H NMR (499 MHz, DMSO) 5 7.97 (s, 1H), 7.61 (s, 1H), 7.58 - 7.48 (m, 2H), 7.41 - 7.33 (m, 2H), 4.59 (d, J= 10.4 Hz, 1H), 4.56 - 4.46 (m, 1H), 4.32 (d,J = 12.3 Hz, 1H),4.15 (s, 1H), 4.04 (q, 7= 6.9 Hz, 3H), 3.78-3.64 (m, 1H), 3.01 (s, 1H), 2.96(1, J = 7.9 Hz, 3H), 2.35-2.25 (m, 1H), 2.19 - 2.07 (m, 2H). Example 1-59: 7-((S)-2-(l-cvclopropvl-lH-pvrazol-4-vl)morpholino)-5-(2.4-difluorophenvl)-6-fluoro-2.3- dihvdropvrrolo[2.1-b]quinazolin-9(lH)-one Step 1. Methyl 2-amino-3.5-dibromo-4-fluorobenzoate

[0253] To a solution of methyl 2-amino-4-fluorobenzoate (19.5 g, 115 mmol) in anhydrous DMF (389 ml) was added NBS (51.3 g, 288 mmol) at 0 °C. The resulting mixture was stirred at 0-25 °Cfor 2 h. The mixture was concentrated under reduced pressure. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of [0-30]% ethyl acetate / petroleum ether gradient) to give methyl 2-amino-3.5-dibromo-4-fluorobenzoate. MS (ESI) m / z: calc’d for CsHvBnFNCh [M+HJ+: 325.8 / 327.8 found 325.9 / 327.9. ‘HNMR (400 MHz,CDCl3) 5 ppm 8.05 (d, 7=7.63 Hz, 1 H), 3.87 (s, 3H). Step 2, 2-amino-3.5-dibromo-4-fluorobenzoic acid

[0254] A solution of methyl 2-amino-3,5-dibromo-4-fluorobenzoate (10 g, 30.6 mmol), lithium hydroxide hydrate (5.13 g, 122 mmol) in THF (50 ml) and water (50.0 ml)was stirred at 40 °C for 16 h. The pH was adjusted to around 3-4 by 2M HC1. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2-amino-3,5-dibromo-4-fluorobenzoic acid, which was not further purified. MS (ESI) m / z: calc'd for C7H5Br2FNO2 [M+H]+ 311.9 / 313.9 / 315.9, found 312.0 / 314.1 / 316.0. Step 3, 5.7-Dibromo-6-fluoro-2.3-dihvdropvrrolo[2.1-blquinazolin-9(lH)-one

[0255] To a solution of 2-amino-3,5-dibromo-4-fluorobenzoic acid (8.0 g, 25.6 mmol) in Toluene (100 mL) was added POCls (7.15 mL, 77 mmol) at 0 °C and stirred for 20 min. Then pyrrolidin-2-one (4.35 g, 51.1 mmol) was added and the resulting mixture was stirred at 80 °C for 16 h under N2. The reaction solution was concentrated in vacuo. The mixture was treated with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic fractions were concentrated under reduced pressure. Then was added 3 mL EtOAc and stirred 30 min. The mixture was fdtered and the solid was concentrated under reduced pressure to give the crude 5,7-dibromo-6-fluoro-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one, which was not further purified. MS (ESI) m / z: calc'd for CiiH7Br2FN2O [M+H]+ 360.9 / 362.9 / 364.9, found 360.9 / 362.9 / 364.9. Step 4, (S)-5-bromo-7-(2-(l-cvclopropvl-lH-pvrazol-4-yl)morpholino)-6-fluoro-2.3-dihydropyrrolo[2.l-b1quinazolin-9(lH)-one

[0256] To a solution of 5,7-dibromo-6-fluoro-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one (300 mg, 0.829 mmol) in dioxane (10 mL) was added (S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)morpholine (320 mg, 1.65 mmol), CS2CO3 (810 mg, 2.486 mmol), rac-BINAP Pd G4 (83 mg, 0.083 mmol) and the resulting mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of [0-30]% ethyl acetate / petroleum ether gradient) to give (S)-5-bromo-7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)morpholino)-6-fluoro-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one. MS (ESI) m / z: calc'd for C2iH22BrFN5O2 [M+H]+ 474.0 / 476.0, found 474.1 / 476.1. Step 5: 7-((S)-2-d-cyclopropyl-lH-pyrazol-4-yl)morpholino)-5-(2,4-difluorophenyl)-6-fluoro-2.3-dihvdropyrrolo[2.l-b1quinazolin-9(lH)-one

[0257] A mixture of (S)-5-bromo-7-(2-(l-cyclopropyl-lH-pyrazol-4-yl)morpholino)-6-fluoro-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one (30 mg, 0.063 mmol), (2,4-difluorophenyl)boronic acid (14.9 mg, 0.095 mmol), Pd(PPh3)4 (7.31 mg, 6.32 pmol) and Na2CO3 (20.1 mg, 0.190 mmol) in dioxane (1 mL) and water (0.333 mL) was degassed and backfilled with N2 (x3). The mixture was heated to 60 °C for 16 h. After cooling to rt, the reaction mixture was poured into water (2 mL) and extracted with EtOAc (2mL*3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by Prep-HPLC (Water (0.05%NH3H20+10mM NH4HCO3)-ACN)to give 7-((S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)morpholino)-5-(2,4-difluorophenyl)-6-fluoro-2,3-dihydropyrrolo[2,l-b]quinazolin-9(lH)-one. MS (ESI) m / z: calc'd for C27H25F3N5O2 [M+H]+ 507.0, found 507.1. ’H NMR (400 MHz, CDCI3) 5 ppm 7.83 - 7.87 (m, 1 H), 7.49 - 7.56 (m, 2 H), 7.31 - 7.39 (m, 1 H), 6.92 - 7.04 (m, 2 H), 4.76 (d, 7=8.20 Hz, 1 H), 4.16-4.22 (m, 2 H), 4.06-4.13 (m, 1 H), 3.94-4.04 (m, 1 H), 3.49-3.62 (m,2H), 3.35 -3.46 (m, 1 H), 2.94 - 3.15 (m, 4 H), 2.20 - 2.29 (m, 2H), 1.08- 1.16 (m, 2 H), 0.98 - 1.06 (m, 2H). Example 1-60: l-(4-chloro-2-fluorophenyl)-8-cyclopropyl-3-((S)-2-(l-methyl-lH-pyrazol-4-yl)morpholino)-8,9- dihvdropvridof3.4-d1pvrrolo[l.2-alpvrimidin-5(7H)-one ci                                                            ci Step 1: 3-chloro-l-(4-chloro-2-fluorophenyl)-8-cvclopropyl-8.9-dihydropyrido[3,4- dlpyrrolo[1.2-alpynmidin-5(7H)-one

[0258] Synthesized in library format: To microwave vials containing monomer lactams (180 umol, 3.00 eq.) was added a solution of POCh (240 umol, 4.00 eq.) in 1 mL toluene. Then a solution of the core, 3-amino-6-chloro-2-(4-chloro-2-fluorophenyl)isonicotinic acid (60.0 umol, 1.00 eq.) in 1 mL toluene was added. The mixture was stirred at 100 °C for 2 h in micro wave. The mixture was concentrated and the resulting residue was purified by preparative TLC to give pure intermediates, which were used in the next step without further purification. Step 2: l-(4-chloro-2-fluorophenvl)-8-cvclopropvl-3-((S)-2-(l-methyl-lH-pvrazol-4-yl)morpholino)-8.9-dihydropyrido[3.4-dlpyrrolo[l.2-a1pvrimidin-5(7H)-one

[0259] To a solution of (S)-2-(l-methyl-lH-pyrazol-4-yl)morpholine, 3-chloro-l-(4-chloro-2-fluorophenyl)-8-cyclopropyl-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one (about 30.0 umol, 1.00 eq.) in Dioxane (0.500 ml) were added CS2CO3 (90.0 umol, 3.00 eq.) and BINAP G3 (1.50 umol, 0.05 eq.). The mixture was stirred at 80 °C for 16 h. The mixture was filtered and concentrated. The resulting residue was dissolved in MeCN and purified by preparative HPLC to give l-(4-chloro-2-fluorophenyl)-8-cyclopropyl-3-((S)-2-(l-methyl-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one. MS (ESI) m / z: calc'd for C26H27CIFN6O2 [M+H]+ 509.2, found 509.2.

[0260] Examples shown in Example Table 1-3 below, were prepared according to procedures analogous to those outlined in Examples 1-1 to 1-3 and 1-23 to 1-30, and 1-58 to 1-60 above using the appropriate starting materials. Table 1-3: Examples 1-61 to 1-259 Example Structure IUPAC Name Exact Mass [M+H]+ 1-61 0 N" u Cl l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- ’    5(7H)-one 507 1-62 ° \ z O o—! / l-(4-chl oro-2-fluorophenyl)-(R or S)-8-methyl-3-[(2S)-2-(l-methyl-1 H-pyrazol-4-yl)morpholin-4-yl]-8,9- dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin- '   5(7H)-one 495 1-63 o / n Nx[ N / > U Cl l'-(4-chloro-2-fluorophenyl)-3'-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-y 1] -7',8'-dihydro-5'H-spiro [cyclopropane-1,9'-pyrido[3,4-d]pyrrolo[l,2-a]pyrimidinJ-5'-one 507 1-64 Cl oO"n\^k^ aJCnV N        n 0 S)-l-(4-chloro-2-fluoropheny 1)-3-(2-( 1 -(oxetan-3-yl)-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[ 1,2-a]pvrimidin- 5(7H)-one 523 1-65 Q ° \ z O o— / b 2 3-[(2S)-2-(l-cyclopropyl-lH-pyrazol-4-yl)morpholin-4-yl]-1 -(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[ 1,2-a]pyrimidin-5(7H)-one 491 1-66 Cl F\^L / F vy ,nT    iY'I S O^J     0 l-(4-chloro-3,5-difluorophenyl)-3-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3.4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 499 1-67 Cl X A od   o 1 -(4-chloro-2-fluoropheny 1)-3-[(2R,4S,6R or 2S,4R, 6S)-2-( 1 -cyclopropyl-1 H-py razol-4-yl)-6-methyloxan-4-yl]-8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 520 1-68 O—( 0 , XX oY z    -n d l-(4-chloro-2,5-difluorophenyl)-3-[(2S)-2-( 1 -methyl-1 H-py razol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 499 1-69 < A JY   x Y YA nJyJUUJ °\ /     O 3-[(2S,4R or 2R.4S)-{2-[l-(R or S)-(2,2-difluorocyclopropyl)- 1H-py razol-4-yl] oxan-4-yl} -1 -(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 526 1-70 F Xj X F rrVy O^J     0 1 -(2,4-difluoropheny 1)-3- [(2S,4R or 2R,4S)-[2-(l-methyl- lH-pyrazol-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- ’    5(7H)-one 464 1-71 F 'Ni   y ArVs ° 3-[(2S,4R or 2R,4S)-[2-(l-cy clobutyl-lH-pyrazol-4-y l)oxan-4-yl] -1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4- d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 504 1-72 <X O Xn f Yx 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(pyridin-3-yl)methyl]-lH-pyrazol-4-yl} morpholin-4-yl] -8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 558 1-73 F NYS         / 1 L II ___ L N— / J       L .0 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-( 1 -ethyl- 1H-pyrazol-4-yl)morpholin-4-yl] -8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 495 1-74 Cl o 1 -(4-chloro-2-fluoropheny 1)-3-[(2S,6R or 2R,6S)-2-(l-cyclopropyl-lH-pyrazol-4-y l)-6-methy lmorpholin-4-y 1] -8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 521 1-75 Cl FX W) Y n    y ° 1 -(4-chloro-2-fluoropheny 1)-3-[(2R,6S or 2S,6R)-2-(l-cyclopropyl-lH-pyrazol-4-y l)-6-methy lmorpholin-4-y 1] -8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 521 1-76 Cl JLJ n\nYA <5 (R or S)-l-(4-chloro-2-fluorophenyl)-3-[3-(l-methyl-lH-pyrazol-4-yl)pyrrolidin-1 -yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 465 1-77 Cl Xj r~{          o n^n (R or S)-l-(4-chloro-2-fluorophenyl)-3 - {3 - [ (6-methylpyrazin-2-yl)oxy]pyrrolidin-l-yl}-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 493 1-78 <02^ ,NY n^J1„ O Zn f ■gt. l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-{ l-[(naphthalen-2-yl)methyl] - lH-pyrazol-4-yl} morpholin-4-yl] -8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin-'    5(7H)-one 607 1-79 F F--F i F h F rV'n 0 l-[2,5-difluoro-4- (trifluoromethyl)phenyl]-3-[(2S)-2-(l-methyl-lH-py razol-4-yl)morpholin-4-y 1] -8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 533 1-80 ° \ —z     -n Vz )=\ \ \ o=\ z d 3-[(2S,6R or 2R,6S)-2-(l-cyclopropyl-lH-pyrazol-4-y l)-6-methy lmorpholin-4-y 1] -1 -(2,4-difluorophenyl)-8,9- dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 505 1-81 _z .....d , O=< z d 3-[(2R,6S or 2S,6R)-2-(l-cyclopropyl-lH-pyrazol-4-y l)-6-methy lmorpholin-4-y 1] -l-(2,4-diliuorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 505 1-82 Cl A a AAdW f^y N    y O^J    0 1 -(4-chloro-2-fluorophenyl)-3-[(2R,6R)-2-methyl-6-(trifluoromethyl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [1,2-a] pyrimidin-5(7H)-one 483 1-83 p O. 0 C) N ?yN kX l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(oxolan-3-yl)methyl]-lH-pyrazol-4-y 1} morpholin-4-yl] -8,9-dihydropyrido[3,4-d] pyrrolo [1,2-a] pyrimidin-5(7H)-one 551 1-84 <1. 0 () N F Ap 1 -(4-chloro-2-fluorophenyl)-3 - {(2S)-2- [ 1 -(oxan-4-y 1)- 1H-pyrazol -4-y 1] morpholin-4-y 1} -8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 551 1-85 Q 'N1 0 i^N F Ax 1 -(4-chloro-2-fluorophenyl)-3-{(2S)-2-[(R and S)-l-(oxolan-3-yl)-lH-pyrazol-4-yl] morpholin-4-yl} -8.9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 537 1-86 f        rN p 1  L II   O-7 <Y^N N'"y''^ / As. J cr 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(3- methoxycy clobutyl)methyl] -lH-pyrazol-4-yl}morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 565 1-87 9r° F NvA    rN     / 1 L II   1 ^|[ n' N^y''^7 xV J    k^O cr l-(4-chloro-2-fluorophenyl)-3-{(2S)-2-[l-(2-methoxy ethyl)-1 H-pyrazol-4-yl]morpholin-4-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 525 1-88 XO'V'^Z NvA. o F Oyx^yAJy yp ''An 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(lS,2R)-2-methoxy cyclobutyl] -1H-pyrazol-4-y 1} morpholin-4-y 1] -8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 551 1-89 r o r^N F l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(6-oxa-4-azaspiro [2.4]hept-4-en-5-yl)methyl]- lH-pyrazol-4-y 1} morpholin-4-yl] -8,9-dihydropyrido[3.4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 576 1-90 / 0 O o N i^N F pi. 3-((S)-2-(l-(((R and S)-2,5-di oxaspiro [3.4] octan-6-yl)methyl)-lH-pyrazol-4-yl)morpholino)-1 -(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 593 1-91 o / “tp Q z t 1 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[3- (methoxy methyl Jcyclobutyl | -1 H-pyrazol-4-y 1} morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 565 1-92 ■ -0.. o o N F 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[2-(2,4-dimethylphenyl)ethyl] - 1H-pyrazol-4-y 1} morpholin-4-y 1] -8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 599 1-93 F F--F k n *Yya 0 3-[(2S)-2-(l-methyl-lH-pvrazol-4-yl)morpholin-4-vl] -’              l-[3-           ' (trifluoromethyl)bicyclo[ 1.1.1 ]pentan-l-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 487 1-94 Cl 1      F'3x^ nA. nAt^^y, O^J    o l-(4-chloro-2-fluorophenyl)-3-[(2R,6S or 2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 506 1-95 z >=O ..... }—o ~^Q 1 -(4-chloro-2-fluoropheny 1)-3-[(2S,6R or 2R,6S)-2-methyl-6-(2-methylpyri din-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 506 1-96 o NJ u F (laS,9aR)-3-(2,4-difluorophenyl)-5-[(2S)-2-(l-methyl-lH-pyrazol-4-y l)morpholin-4-y 1] -l,la,9,9a-tetrahydro-7H-cyclopropa[3,4]pyrrolo[l,2-a]pyrido[3,4-d]pyrimidin-7- one 477 1-97 Cl f A3 X _N.___ JL ^L,N0 / = / \__J      0 ( / NY 0— l-(4-chloro-2-fluorophenyl)-3-{(3R)-3-[(2-methoxypyrimidin-4-yl)oxy]pyrrolidin-l-yl}-8.9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 509 1-98 o / ~Cp )= / o 0 0 A 1 1 -(4-chloro-2-fluoropheny 1)-3-((S)-2-(l-(((SandR)-3-(methoxymethyl)tetrahydrofur an-3-yl)methyl)-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 595 1-99 N0J„ 0 ^N^ An f yA 1 -(4-chloro-2-fluorophenyl)-3-((S)-2-(l-(((R and S)-4.4-difluorotetrahydrofuran-2-y l)methyl)- lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 587 1-100 7 o Vn F l-(4-chloro-2-fluorophenyl)-3-((S)-2-(l-(((R and S)-2,2-difluorocyclopropyl)methyl)-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-djpyrrololl,2-a]pyrimidin- 5(7H)-one 557 1-101 SV I 1 L II          L n—' W L l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-{[l-(3-methoxypropoxy)cyclopentyl | methyl} -1 H-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 637 1-102 0 NvX. O Vn f ethyl l-L(4-{(2S)-4-ll-(4-chloro-2-fluorophenyl)-5-oxo-5,7,8,9-tetrahydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-3- y 1] morpholin-2-yl} -1H- pyrazol-1 -yl)methyl]-2- oxabicyclo[2.1. l]hexane-4-carboxylate 635 1-103 N r £1 o c 3 N An f VYx 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-{[3-(methoxymethyl)-l,2,4-oxadiazol-5-yl]methyl}-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [1,2-a] pyrimidin-5(7H)-one 593 1-104 -N1 NvX. O Vn f 1 -(4-chloro-2-fluorophenyl)-3-((S)-2-(l-(((Rand S)-5-methoxy-2,3-dihydrobenzofuran-2-yl)methyl)-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 629 1-105 3 O. o C1 N <"N F UX 3-((S)-2-(l-(((3S,5S, 3R,5R, 3R,5S and 3S,5R)-2,7-dioxaspiro[4.4]nonan-3-yl)methyl)-lH-pyrazol-4-yl)morpholino)-1 -(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 607 1-106 o / Cp )= / o O—( n Y 1 -(4-chloro-2-fluoropheny 1)-3-((S)-2-(l-(((R and S)-3-isopropoxytetrahydrofuran-3-y l)methyl)- lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d] pyrrolo [1,2-a] pyrimidin-5(7H)-one 609 1-107 O.. O N F 3-((S)-2-(l-(((R and S)-l,4,8-trioxaspiro[4.5]decan-2-y l)methyl)- lH-pyrazol-4-yl)morpholino)-1 -(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 623 1-108 Cl A F^Y X ___ N   V\ oY^Y / ,—V-J       o \ N N=^ 1 -(4-chloro-2-fluorophenyl)-3-{(3R)-3-[(2-methylpyrimidin-4-yl)oxy ]pyrrolidin-1 -y 1} -8.9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 493 1-109 Cl A F^y^ N Y^ Y\ A J\,nP qYn^Y ,—( Y-1      O / A --\ N N=^ l-(4-chloro-2-fluorophenyl)-3-{(3R)-3-[(2.6-dimethylpyrimidin-4-yl)oxy]pyrrolidin-l-yl}-8.9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 507 1-110 ,j6 N^N O 1 -(2,4-difluoropheny 1)-3-[(2S,4R or 2R,4S)-{2-[2-(dimethylamino)pyrimidin-4-yl]oxan-4-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 505 1-111 o'Y     o f'Yi Cl l-(4-chloro-2-fluorophenyl)-3-((S or R)-2-((R or S)-tetrahy drofuran-3 -yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 471 1-112 Cl Y J 1 |i    N Y YY YvN Y o^J    o l-(4-chloro-2,3-difluorophenyl)-3-[(2R,4R and 2S,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin- 5(7H)-one 509 1-113 F 1         F T nY. N^YNiVY O^J     ° F F (R or S)-3-[2,2-difluoro-6-(2-methylpyridin-4-yl)morpholin-4-yl]-l-(2,4-di 11 uoropheny 1)-8.9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 512 1-114 Cl N ii    Ni YY o l-(4-chloro-2-fluorophenyl)-3-[(2R,4R and 2S,4S)-{2-[2-(trifluoromethyl)pyridin-4-yl]oxan-4-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 545 1-115 I oY Q , tY-Y oY z d l-(4-chl oro-2-11 uoropheny 1)-3-[(2S)-2-( lH-pyrazol-4-yl)morpholin-4-yl]-8,9- dihydropyrido[3,4- d]pyrrolo[l ,2-a]pyrimidin- 5(7H)-one 467 1-116 Cl JM 0'" / N     Y /         ° 3 - [(3 R,4R)-3 -tert-butoxy -4-methoxy py rrolidin-1 -y 1] -1-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 487 1-117 Cl Xj y fjuOo o— / N    Y o ■4 (R or S)-3-(4-lert-butoxy-3,3-difluoropy rrolidin-1 -yl)-1 -(4-chloro-2-fl uoropheny 1)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 493 1-118 z—Z   T 7 %__Z_-n ° \ O=< Z d 1 -(2,4-difluoropheny 1)-3-[(2S,4R or 2R,4S)-{2-[2-(trifluoromethyl)pyridin-4-yl]oxan-4-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 529 1-119 F YF fX ___ n p         n |Y o^J    o 1 -(2,4-difluorophenyl)-3-[(2R,4R and 2S,4SH2-[2-(trifluoromethyl)pyridin-4-yl]oxan-4-yl}-8,9- dihydropyrido[3.4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 529 1-120 X z >=O / ° ll / =\ 7 U-   Z—V l-(4-chloro-2-fluorophenyl)-3-[(2S,4R or 2R,4S)-{2-[2-(trifluoromethyl)pyridin-4-yl]oxan-4-yl}-8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 545 1-121 y, A? n       = / F °x__ /  N=\_7 O Cl l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(4-fluoro-2-oxabicyclo[2.1. l]hexan-l-yl)methyl]-lH-pyrazol-4-yl} morpholin-4-yl] -8,9-dihydropyrido[3.4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 581 1-122 z / _ ° \ '---(         T1     T1 z 5=( \ ~ O=< Z V l-(4-chloro-2,3-difluorophenyl)-3-[(2S,4R or 2R,4S)-[2-(2-methylpyridin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin- 5(7H)-one 509 1-123 F .___L-F Yj F^>^ O^J     O 3-[(2S)-2-(l-methyl-lH-py razol-4-yl)morpholin-4-y 1] -1-(1,1,4-trifluoro-2,3-dihydro-lH-inden-5-y 1)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 523 1-124 z—z / _ O , z \--» /  _ / \_-n O=( z    m d 3-[(2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)oxan-4-y 1] -1 -(2,4,5-trifluorophenyl)- 8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 493 1-125 F A ' Ynya nvY^JMvnV O^J     0 3-[(2S,4R or 2R,4S)-[2-(l-cyclobutyl-lH-pyrazol-4-y l)oxan-4-yl] -1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4- d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 504 1-126 z / _ 'z—z   \— \  —\ / “ O=( z     -n l-(4-chloro-2,5-difluorophenyl)-3-[(2S,4R or 2R.4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 509 1-127 Cl Xj F'^y ' i i T o 1 -(4-chloro-2-fluorophenyl)-3-[(2S,4R or 2R,4S)-[2-(l-methyl-6-oxo-1,6-dihy dropy ri din-3 -yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 507 1-128 Cl JU _ /        0^1     0 l-(4-chloro-2-fluorophenyl)-3-L(2S)-2-(l-dodecyl-lH-py razol-4-yl)morpholin-4-y 1] -8.9-dihydropyrido[3.4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 635 1-129 F A ’JU U^,vJJh o (laS.9aR)-3-(2,4-difluorophenyl)-5-[(2S,4R or 2R.4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-l,la,9,9a-tetrahydro-7H-cyclopropa[3,4]pyrrolo[l,2-a]pyrido[3,4-d]pyrimidin-7-one 487 1-130 Cl Y J f h nVyv U^ / ^XzUn^ h OxY    ° (laS,9aR)-3-(4-chloro-2,3-difluorophenyl)-5-((2S,4R or 2R,4S)-2-((R or S)-tetrahy drofuran-3 -yl)tetrahydro-2H-pyran-4-yl)-1,1 a,9,9a-tetrahy dro-7H-cyclopropa[3,41pyrrolo[ 1.2-a]pyrido[3,4-d]pyrimidin-7-one 500 1-131 Y° O-6H '—hi -n m Vz \=( \ ?—C / -- oY z I (laS,9aR)-3-(4-chloro-2,3-difluorophenyl)-5-((2S,4R or 2R,4S)-2-((R or S)-tetrahy drofuran-3 -yl)tetrahydro-2H-pyran-4-yl)-l,la.9,9a-tetrahydro-7H-cyclopropa[3,4]pyrrolo[l,2-a]pyrido[3,4-d]pyrimidin-7-one 500 1-132 Y° O—Ji '—6u T ti Vz ^=( \ —C   “ oY z I (laS,9aR)-3-(4-chloro-2,3-difluorophenyl)-5-((2S,4R or 2R,4S)-2-((R or S)-tetrahy drofuran-3 -yl)tetrahydro-2H-pyran-4-yl)-1,1 a,9,9a-tetrahy dro-7H-cyclopropa[3,4]pyrrolo[1.2-a]pyrido[3,4-d]pyrimidin-7-one 500 1-133 Y° o— '---4« I Tl Tl qYU oY z Y ZE (laS,9aR)-3-(4-chloro-2,3-difluorophenyl)-5-((2S,4R or 2R,4S)-2-((R or S)-tetrahy drofuran-3 -yl)tetrahydro-2H-pyran-4-yl)-1,1 a,9,9a-tetrahydro-7H-cyclopropa[3,4]pyrrolo[l,2- 500 a]pyrido[3,4-d]pyrimidin-7-one 1-134 Cl JU O'^     N     --\ 0 1 -(4-chloro-2-fluoropheny 1)3-[(2S or 2R)-2-(oxan-4-yl)morpholin-4-yl]-8.9- dihydropyrido[3,4-d]pvrrolo[l,2-a]pyrimidin- ’    5(7H)-one 485 1-135 Cl F J^Y o"^ Y N y o l-(4-chloro-2-fluorophenyl)-3-[(2S or 2R)-2-(oxan-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 485 1-136 F Uy o-M ° N-N \ (S or R)-1-(2,4-difluorophenyl)-9-methyl-3-[(2 S )-2-( 1 -methyl- 1H-pyrazol-4-yl)morpholin-4-yl] -8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin- 5(7H)-one 479 1-137 F Um i^A^yn^ 0 N-N^ (S or R)-1-(2,4-difluorophenyl)-9-methvl-3-[(2S)-2-(l-methyl-lH-py razol-4-yl)morpholin-4-y 1] -8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 479 1-138 OZY     o -nM mMY fY, Cl (laR,9aRand laS,9aS)-7-(4-chloro-2-fluorophenyl)-5-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-l,la,9,9a-tetrahydro-3H-cyclopropa[4,5]pyrrolo[l,2-a]pyrido[3,4-d]pyrimidin-3-one 493 1-139 ^N-N 0 fl y N FYi F 3-[(2S,4R or 2R,4S)-[2-(l-cyclopropyl-lH-pyrazol-4-y l)oxan-4-yl] -1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin- 5(7H)-one 490 1-140 ^N-N < A O"A     0 n>An<!A / ? F 3-[(2S,4R or 2R,4S)-[2-(l-cyclopropyl-lH-pyrazol-4-yl)oxan-4-yl] -1-(2,4-difluorophenyl)-8.9-dihydropyrido[3,4- d]pvrrolo[l,2-a]pyrimidin- ’    5(7H)-one 490 1-141 Cl “AAA0 oA 0 l-(4-chloro-2-fluorophenyl)-3-[(2S,4R or 2R,4S)-[2-(l-cyclopropyl-lH-pyrazol-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 506 1-142 Cl <AvA° oA ° l-(4-chloro-2-fluorophenyl)-3-[(2S,4R or 2R,4S)-[2-(l-cyclopropyl-lH-pyrazol-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- ’    5(7H)-one 506 1-143 i z V . b Z Ao p (1 aR,9aS)-3-(4-chloro-2-11 uoropheny 1)-5- [(2S)-2-( 1 -methyl -lH-pyrazol-4-y l)morpholin-4-y 1] -l,la,9,9a-tetrahydro-7H-cyclopropa[3,4]pyrrolo[l,2-a]pyrido[3,4-d]pyrimidin-7-one 493 1-144 F\ F k. rkn AaA oA ° 1 -(4,4-difluorocyclohexyl)-3-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pvrrolo[ 1,2-a]pyrimidin- ’    5(7H)-one 471 1-145 E / Vf \==< N=K I \=( N NW 0- / 1 -(2,4-difluoropheny 1)-3-[(2S,4R and 2R,4S or 2R,4R and 2S,4S)-{2-[l-(propan-2-y 1)-1 H-pyrazol-4-yl] oxan-4-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 492 1-146 F. \ / ~F '— / N=\ / / =( r / ~—( / )=N  O-^ —N \ l-(2,4-difluorophenyl)-3-{2-[2-(dimethylamino)pyrimidin-4-yl]oxan-4-yl}-8.9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-’    5(7H)-one 505 1-147 z-z _ o—( Q . z \—» \ —\ / - - O=( z ci l-(4-chloro-2-fluorophenyl)-3-[(2S,4R or 2R,4S)-2-(6-methylpyridazin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 492 1-148 R z    o / \ z \ LL    LL      Z— / O l-(4-chloro-2,3-difluorophenyl)-3-[(2S)-2-( 1 -methyl-1 H-py razol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 499 1-149 F / L. F JU X ' ArVy 0 3-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-1 -(2,4,5-trifluoropheny 1)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 483 1-150 Cl \    J / b-X    N'V-n o 1 -(4-chloro-2-fluoropheny 1)3-[(2S and 2R)-2-(3-methyl-1,2-oxazol-5-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 482 1-151 Cl / N F-y o-Vx j rNv-x o 1 -(4-chloro-2-fluorophenyl)-3-[(2S and 2R)-2-(l,3-oxazol-5 -y l)morphol in-4-y 1] -8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 468 1-152 Cl xp     / / o l-(4-chloro-2-fluorophenyl)-3-[(2S or 2R)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 508 1-153 X A o 1 -(2,4-difluoropheny 1)-3- [(2S,4R or 2R,4S)-[2-(2-methoxypyridin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 491 1-154 Cl xp    J / NS5        / A A nAa o 1 -(4-chloro-2-fluoropheny 1)3-[(2S or 2R)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-8,9- dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 508 1-155 Cl F^A. T J ¥ iT YA VvY^T o l-(4-chloro-2,3-difluorophenyl)-3-[(2S,4R or 2R,4S)-[2-(R or S)-(2,2-dimethyloxolan-3-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin- ’    5(7H)-one 516 1-156 Cl f AZA F-X. / ^N     O F l-(4-chloro-2-fluorophenyl)-3-[(2R)-2-(trifluoromethyl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 469 1-157 Cl fl zaf N \ N—' N       O 4 o^Z l-(4-chloro-2-fluorophenyl)-3-[(2S and 2R)-2-(2,2,2-trifluoroethyl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 483 1-158 Cl 0 JF a o / 0 F (2S,6R and 2R,6S)-l-(4-chloro-2-fluorophenyl)-3-[2-methyl-6-(2.2.2-trifluoroethyl)morpholin-4-yl]-8.9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 497 1-159 Cl C3~f ' ( N=(k n A / % O—i       ' ~~o o<j l-(4-chloro-2-fluorophenyl)-3-[(2S and 2R)-2-(S and R)-(oxan-3-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 485 1-160 Cl F\ / L 1J AnT1 VyY^y^ 0 l-(4-chloro-2,3-difluorophenyl)-3-[(2S,4R or 2R,4S)-12-(R or S)-(2,2-dimethyloxolan-3-yl)oxan-4-yl]-8.9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 516 1-161 Cl h-F ' f n=^a / =( N-J N \__ / .___t           /         O l-(4-chloro-2-fluorophenyl)-3-[(2S or 2R)-2-(oxan-4-y l)morpholin-4-y 1] - 8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 485 1-162 Cl \ / F '—<  N=fy / =(   N--7 N   —Z F                 '    0 1 -(4-chloro-2-fluorophenyl)-3-[(2S or 2R)-2-(3,3-difluorocyclobutyl)morpholin -4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 491 1-163 / O zQ uv J z o^\ J z \ 1 -(4-chloro-2-fluoropheny 1)3-[(S and R)-2-('methoxymethyl)-6-(S and R)-methylmorpholin-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- ’    5(7H)-one 459 1-164 Cl fl N / \ N—' —N     ° l-(4-chl oro-2-11 uoropheny 1)3-[(2S or 2R)-2-(S and R)-[(oxolan-2-yl)methyl]morpholin-4-yl} -8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 485 1-165 A / z 1 -(4-chloro-2-fluorophenyl)-3-[(2S and 2R)-2- ' (ethoxymethyl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 459 1-166 Cl \ " / F Z> \= /  N=\ J y~v o / —m <f”°X 1 -(4-chloro-2-fluoropheny 1)3-[(2S or2R)-{2-[(cyclopropylmethoxy)methyl ]morpholin-4-yl}-8,9-dihydropyrido|3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 485 1-167 Cl fl N^ / X N / \ N—' L / l N       O CP0^ 1 -(4-chloro-2-fluoropheny 1)3-[(2S or 2R)-{2-(R and S)-[(oxolan-2-yl)methyl]morpholin-4-yl} -8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin- ’    5(7H)-one 485 1-168 F Xj F^^p N |1             N H o 1 -(2,4-difluoropheny 1)-3- [(2S,4R or 2R,4S)-[2-(pyridin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 461 1-169 o—( Q , 2 5=\ \ —C   “ o= / z d l-(4-chloro-2-fluorophenyl)-3-((S and R)-2-((R and S)-2,2-difluorocyclopropyl)morpholi no)-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 477 1-170 Cl Xj F^^s^ o 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-8-(R and S)-(propan-2-yl)-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 523 1-171 - f nyS rN' ILL   XzN N N A. J       L .0 cr (6aS,10aS and 6aR,10aR)-l-(4-chl oro-2-fluoropheny 1)-3-[(2S)-2-(l-methyl-lH-py razol-4-yl)morpholin-4-y 1] -'      7,8,9,10,10a,11-    ' hexahydropyrido[3',4':4,5]pyr imido[l,2-a]indol-5(6aH)-one 535 1-172 / ^° o—41 '—Li m -n \—Z \= / \  —C   ~ O= / z d l-(4-chloro-2,3-difluorophenyl)-3-[(2S,4R or 2R.4S)-2-(R or S)-(oxolan-3-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [1,2-a] pyrimidin- 5(7H)-one 488 1-173 / ^o O— / n '— / n   n -n \— Z  ^= / \ J—C   ~ O=( z d l-(4-chloro-2,3-difluorophenyl)-3-[(2R,4S or 2S,4R)-2-(R or S)-(oxolan-3-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 488 1-174 F Xj Q i1^0 0 3-[(2S,4R or 2R,4S)-([2,2'-bioxan] -4-yl)-1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 468 1-175 ° \ \—z 5=( \ —C / — ~ O=\ Z d l-(4-chloro-2,3-difluorophenyl)-3-[(2S,4R or 2R,4S)-[2-(R or S)-(2,2-dimethyloxolan-3-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 516 1-176 F Xj X .hL__, N JL^LxN" / 0 hU 1 -(2,4-difluorophenyl)-3-{(3R)-3-[(5-methylpyrimidin-4-yl)oxy]pyrrolidin-l-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrirmdin-5(7H)-one 477 1-177 Cl A tL UyyUjA’H 0 (laS,9aR)-3-(4-chloro-2,3-difluorophenyl)-5-[(2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-1,1 a,9,9a-tetrahydro-7H-cyclopropa[3,4]pyrrolo[l,2-a]pyrido[3,4-d]pyrimidin-7-one 521 1-178 Cl JU fJ jTV) 0 1 -(4-chloro-2-fluoropheny 1) 3-[(2S and 2R)-[2-(l,l-difluoroethyl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pvrrolo[l,2-a]pyrimidin- '    5(7H)-one 465 1-179 F Xj F^Y n  Vx O^N^Y fJH     0 H J—( N F N= / 1 -(2,4-difluoropheny 1)-3-[(3R)-3-{[6-(trifluoromethyl)pyrimidin-4-yl]oxy}pyrrolidin-l-yl]-8,9-dihydropyrido[3,4-djpyrrolo[l,2-a]pyrimidin-5(7H)-one 531 1-180 F A F"]^ X .N*___x N Y V\ X^L^nY 0Y YT 0 N= / 3-{(3R)-3-[(6-cyclopropylpynmidin-4-y l)oxy ] py rrolidin-1 -yl} -1 -(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 503 1-181 F Xj X N   Y\ JL X\^N-Y \ p-Aj^^Y » »n N— 1 -(2,4-difluorophenyl)-3-{(3R)-3-[(5-fluoropyrimidin-4-yl)oxy]pyrrolidin-l-yl}-8,9-dihydropyrido[3,4-d] pyrrolo [1,2-a] pyrimidin-5(7H)-one 481 1-182 F FXX X. / N. N Y\ xJ-Y-k oXn^Y 7= / XX     o nY x F F 1 -(2,4-difluoropheny 1)-3-[(3R)-3-{[2-(trifluoromethyl)pyridin-4-yl]oxy}pyrrolidin-l-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 530 1-183 F Xj F^Y X^k^ X^x- / / Y oXjY \ 9— /            0 —\ N N= / 1 -(2,4-difluorophenyl)-3-{(3R)-3-[(quinazolin-4-yl)oxy ]pyrrolidin-1 -y 1} -8.9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 513 1-184 F Xj X.Y___ X^L / nY oXn^Y r Y / \__ /     o X / ZN N-^ 1 -(2,4-difluorophenyl)-3-{(3R)-3-[(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)oxy]pyrrolidin-l-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 503 1-185 F A N A Jk / N-y Oh     ° >.y 1 -(2,4-difluoropheny 1)-3-{(3R)-3-[(thieno[3,2-b]pyridin-7-yl)oxy]pyrrolidin-l-yl}-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin- 5(7H)-one 518 1-186 F fj F^^Y / = / X-J     0 ( J NY 3-{(3R)-3-[(2-tert-butylpyridin-4-yl)oxy]pyrrolidin-l-yl}-l-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 518 1-187 F A FZ^ / X ,N.___ o^n^Y ° NY O— 1 -(2,4-difluorophenyl)-3-{(3R)-3-[(2-methoxypyridin-4-y l)oxy] py rrolidin-1 -yl}-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 492 1-188 o \=<   z=<   / y\ 7 z 7—€ )= / o ZK z' l-(4-chloro-2-lluorophenyl)-3-[(2S)-2-(l-methyl-lH-py razol-4-yl)morpholin-4-y 1] -7,8,9,10-tetrahy dro-5H-dipyrido[l,2-a:3',4’-d]pyrimidin-5-one 495 1-189 p" Y a 1 L II                JI N xL J     k xO l-(4-chloro-2-fluorophenyl)-10,10-dimethyl-3-[(2S)-2-(l -methyl-1 H-py razol-4-yl)morpholin-4-yl]-7,8,9,10-tetrahy dro-5H-dipyrido[ 1,2-a:3',4'-d]pyrimidin-5-one 523 1-190 0 Y'^YlyOL nj   NY„ / '—\ F^xL         । u Cl l-(4-chloro-2-fluorophenyl)-9-(R and S)-ethyl-3-[(2S)-2-(1 -methyl- lH-pyrazol-4-yl)morpholin-4-yl]-7,8,9,10-tetrahydro-5H-dipyrido[l,2-a:3',4'-dJpyrimidin-5-one 523 1-191 f NrS   X 1 L II           O n N'y X. J      L n 8-(R and S)-tert-butyl-1-(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-methyl-lH-py razol-4-yl)morpholin-4-y 1] -7,8,9,10-tetrahydro-5H-dipyrido[l,2-a:3’,4'-d]pyrimidin-5-one 551 1-192 z / ° '=\ z \ U- l-(4-chloro-2-fluorophenyl)-3- [(3 S)-3-phenyl py nolidin-1 -yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 461 1-193 Cl JM F^'y / XX o-Z n   y ° (R and S)-l-(4-chloro-2-fluorophenyl)-3-(3-phenoxypyrrolidin-l-yl)-8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 477 1-194 o—( Q \-z   „ r y / x / xy O=< z d 1-(6,6-difluorospiro [3.3]heptan-2-yl)-3-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl] -8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 483 1-195 Cl Xj nX<NX—\ / -N^XyNj o? 0 (R and S)-3-(3-benzy Ipyrrolidin-1 -y 1)-1 -(4-chloro-2-fluorophenyl)-8.9-dihydropyrido[3,4-d]pvrrolo[l,2-a]pyrimidin- '    5(7H)-one 475 1-196 Cl Xj F^Y^ n\V\ ry^A^y (R and S)-l-(4-chloro-2-fluorophenyl)-3-[3-(thiophen-2-y l)py rrolidin-1 -y 1]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 467 1-197 Cl A F'^J X _N. - N c,^V ° n=n 1 -(4-chloro-2-fluorophenyl)-3-{(3R)-3-[(6-chloropyridazin-4-yl)oxy]pyrrolidin-l-yl}-8.9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin-'    5(7H)-one 513 1-198 Cl A X.N.___. N VJ 0 zN \ / N 1 -(4-chloro-2-fluorophenyl)-3-{(3R)-3-[(5-cyclopropyl-l,3,4-oxadiazol-2-yl)oxy Jpyrrolidin-1 -y 1} -8.9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 509 1-199 n— Z / %_ O \ '—6     ti m o=( z 3 l-(4-chloro-2,3-difluorophenyl)-3-[(2R,4S or 2S,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 509 1-200 F A _N. _ N || N | VA ° F F (R or S)-3-[2,2-difluoro-6-(2-methylpyridin-4-yl)morpholin-4-y 1] -1 -(2,4-difluoropheny 1)-8.9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- ’    5(7H)-one 512 1-201 Cl F^X. T J n FAn °\ / 0 l-(4-chloro-2,3-difluorophenyl)-3-[(2S,4R or 2R,4S)-[2S or 2R-(2,2-dimethyloxolan-3-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 516 1-202 Cl jO AV ^VNV) V-'      o 3-[(3R)-3- (benzyloxy)pyrrolidin-1 -y 1] -l-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 491 1-203 Cl 0 (R or S)-l-(4-chloro-2-fluorophenyl)-3-[3-(4-fluoropheny l)py rrolidin-1 -y 1] -8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 479 1-204 Cl F^A. T J 1     F^y^ A^N. N |i      N y AA n -A ° l-(4-chloro-2,3-difluorophenyl)-3-[(2S,4R or 2R,4S)-[2-(2-methylpyridin-4-yl)oxan-4-yl] -8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin- 5(7H)-one 509 1-205 F JM A F NANYA 0 3-[(2S,4R or 2R,4S)-[2-(l-cy clobuty 1-lH-pyrazol-4-yl)oxan-4-yl]-l-(2,4-difluorophenyl)-8,9- dihydropyrido[3.4- d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 504 1-206 Cl ^A / F X T 1     F^y^ N il       N iT AA n o^J o l-(4-chloro-2,5-difluorophenyl)-3-[(2R,4S or 2S,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 509 1-207 a z / =° “■ \ / ~c? ■o / ° 3-((8 or R)-2-((R or S)-2,2-difluorocyclopropyl)morpholi no)-1 -(2,4-difluoropheny 1)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 461 1-208 Cl A F^Y 11     1 L O^A     o 1 -(4-chloro-2-fluoropheny 1)-3-[(2S,4R or 2R,4S)-[2-(l-methyl-6-oxo-l,6- dihy dropy ri din-3 -yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 507 1-209 ^^N-N Y u F 3-[(2R,4R or2S,4S)-2-(l-cyclopropyl-lH-pyrazol-4-y l)oxan-4-yl] -1-(2,4-difluorophenyl)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 490 1-210 R \   / F Z^, \= /  N=\ J n-Z zK / 1 o nA J \ 1 -(2,4-difluoropheny 1)-3-[(2S,4R and 2R,4S)-[2-(l,l'-dimethyl[lH.l'H-[3,4'-bipy razole]] -4-yl)oxan-4-y 1] -8.9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 544 1-211 ci C>—rn 0 o— / 1 -(4-chloro-2-fluoropheny 1)3-((S or R)-2-((S or R)-[2-(oxolan-2-yl)morpholin-4-yl] -8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 471 1-212 Cl ' ( N=(A / =(  N—' N \__ / V / O—v       '       o OO 1 -(4-chloro-2-fluorophenvl)-3-((S orR)-2-((S orR)-tetrahydro-2H-pyran-3-yl)morpholino)-8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin- 5(7H)-one 485 1-213 f   ny^n>^ U Cl (7S,10R)-l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-( 1 -methyl-1 H-py razol-4-yl)morpholin-4-yl]-7,8,9,10-tetrahydro-5H-7,10-methanodipyrido[l,2-a:3',4'-d]pyrimidin-5-one 507 1-214 t "n    rN- 1 L II              JI n A, J       L -o cr 1 '-(4-chloro-2-fluorophenyl)-3'-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-7'H-spiro[cyclohexane-l,8'-pyrido[3,4-d]pyrrolo[l,2-a] pyrimidin] -5'(9'H)-one 549 1-215 Cl o^J o l-(4-chloro-2,3-difluorophenyl)-3-[(2S,4R or 2R,4S)-2-(R or S)-(oxolan-3-yl)oxan-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[ 1,2-a]pyrimidin- ’    5(7H)-one 488 1-216 F JM F'^^ Cl I O^J    0 3-[(2S,4R or 2R,4S)-((S or R)-|2,2'-bioxan] -4-yl)-1 -(2,4-difluorophenyl)-8,9-dihydropyrido[3,4- d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 468 1-217 Cl Xj f^t । N'Y^yto O^J     0 N-N 10-(4-chloro-2-fluorophenyl)-1-(R or S)-methyl-8-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-3,4-dihy dropy rido [3' ,4': 4,5] py rimi do[2,1 -c] [ 1,4] oxazin-6(l H)-one 511 1-218 z^\   / ° \ l >'"•<    ) \—z'     Tl ^Z 5=\ Z Z— ^oz 10-(4-chloro-2-fluorophenyl)-1-(R or S)-methyl-8-[(2S)-2-(1 -methyl-lH-pyrazol-4-yl)morpholin-4-yl]-3.4- dihydropyrido[3',4':4,5]pyrimi do[2,1 -c] [ 1,4] oxazin-6( 1H)-one 511 1-219 Cl ,NX      N'^Y'N<Y^0 O^J     o 10-(4-chloro-2-fluorophenvl)-8-[(2S or2R)-2-(l- ’ cyclopropyl-lH-pyrazol-4-yl)morpholin-4-yl]-3,4-dihydropyrido[3',4':4,5]pyrimi do[2,1 -c] [ 1,4] oxazin-6( 1H)-one 523 1-220 Cl JLJ 1 O^J    o Xj 10-(4-chloro-2-fluorophenyl)-1-(R or S)-methyl-8-((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-3,4-dihy dropy rido [31,4’: 4,5] py rimi do[2,1 -c] [ 1,4] oxazin-6( 1H)-one 521 1-221 Cl O^J     o Xj 10-(4-chloro-2-fluorophenyl)-1-(R or S)-methyl-8-((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrido[3',4':4,5]pyrimi do[2,1 -c] [ 1,4] oxazin-6( 1H)-one 521 1-222 Cl Xj nZ^n^Z-o O^J     0 mi 10-(4-chloro-2-fluorophenyl)-1-(R or S)-methyl-8-((R or S)-2-(2-methylpyridin-4-yl)morpholino)-3.4- dihydropyrido[3',4':4,5]pyrimi do[2,1 -c] [ 1,4] oxazin-6( 1H)-one 522 1-223 F Xj nX^^Xq NAjyLj O^J     o N-N 10-(2,4-difluorophenyl)-1 -(R or S)-methyl-8-[(2S)-2-(l-methyl-lH-pyrazol-4-y l)morpholin-4-y 1]-3,4-dihy dropy rido [ 3' .4': 4,5] py rimi do[2,1 -c] [ 1,4] oxazin-6(l H)-one 495 1-224 F Xj 1 N       T 0 N-N 10-(2.4-difluorophenyl)-8-[(2S)-2-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-3,4-          ’ dihy dropy rido [3' .4': 4,5] py rimi do[2,1 -c] [ 1,4] oxazin-6(l H)-one 481 1-225 Cl Xj F^^A    । n^n^o O^J     0 Xj 10-(4-chloro-2-fluorophenyl)-1-(S or R)-methyl-8-((2S,4R or 2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-3,4- dihy dropy rido [3' ,4': 4,5] py rimi do[2,1 -c] [ 1,4] oxazin-6(l H)-one 521 1-226 Cl Xj F^T     1 O^J     0 A N^" 10-(4-chloro-2-fluorophenyl)-1-(R or S)-methyl-8-((R or S)-2-(2-methylpyridin-4-y l)morpholino)-3,4- dihy dropy rido [ 3' .4': 4,5] py rimi do[2,1 -c] [ 1,4] oxazin-6(l H)-one 522 1-227 F Xj F^^f V XN<^ O^J     0 3-((S or R)-2-((R or S)-2,2-difluorocyclopropyl)morpholi no)-1 -(2,4-difluoropheny 1)-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 461 1-228 Cl A Nr"-, ^n.A^ aJ^nV N     Y °^X     0 F F (R or S)-l-(4-chloro-2-fluorophenyl)-3-[2,2-difluoro-6-(l-methyl-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihy dropy rido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 517 1-229 Cl aJSjn 0 l-(4-chl oro-2-11 uoropheny 1)-3-[(2S,4R or 2R,4S)-(octahydro-2H,2'H-[2,4'-bipyran]-4-yl)-8,9-dihydropyrido[3,4-d] pyrrole [ 1,2-a]pyrimidin-5(7H)-one 484 1-230 Cl O 1 -(4-chloro-2-fluorophenyl)-3-[(2S,4R or 2R,4S)-(octahydro-2H,2'H-[2,4'-bipyran]-4-yl)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 484 1-231 Cl F^^y ° F F (R or S)-l-(4-chloro-2-fluorophenyl)-3-[2.2-difluoro-6-(1 -methyl-IH-py razol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 517 1-232 A b O / ={ L / ==\ o 1 -(4-chloro-2-fluorophenvl)-3-[(2S)-2-(l-{[3- " (methoxymethyl)oxetan-3-y 1] methyl} - IH-py razol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4- djpyrrolo[l,2-a]pyrirmdin-5(7H)-one 581 1-233 o 2~cp }= / o o 0= 1 -(4-chloro-2-fluoropheny 1)-3-[(2S)-2-(l-{(S and R-[3-(difluoromethyl)oxolan-3-yl]methyl}-lH-pyrazol-4-yl)morpholin-4-yl]-8.9-dihydropyrido[3,4-d]pvrrolo[ 1,2-a]pyrimidin- ’    5(7H)-one 601 1-234 N^A„ o F pbb. 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(spiro [3.3]heptan-2-yl)methyl]-lH-pyrazol-4-y 1} morpholin-4-yl] -8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 575 1-235 3 0 An f 3-((S)-2-(l-(((R and S))-2-oxaspiro[4.4]nonan-3-y l)methyl)- lH-pyrazol-4-yl)morpholino)-1 -(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 605 1-236 o o c> ti 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-{[l-(difluoromethyl)cyclobutyl]m ethyl} -1 H-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 585 1-237 O 0 o / A 1 / =z   / =\ o 1 -(4-chloro-2-fluoropheny 1)-3-[(2S)-2-{l-[(3-methy loxetan-3 -yl)methyl] -lH-pyrazol-4-yl}morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 551 1-238 0 'N^l O ^N^ AN f "jA. l-(4-chloro-2-fluorophenyl)-3-((S)-2-(l-(2-((R and S)-2,2-difluorocyclopropoxy)ethyl)-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d] pyrrolo [1,2-a] pyrimidin-5(7H)-one 587 1-239 nA r -A O ^N^ An f A \        /                            ’-'I l-(4-chloro-2-fluorophenyl)-3-L(2S)-2-{ 1-1(4,5-dihydro-l,2-oxazol-3-yl)methyl] -1H-pyrazol-4-y 1} morpholin-4-y 1] -8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 550 1-240 0 )=\ p mV / = / N=<f J Cl 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(4-methyl-2-oxabicyclo[2.1.1]hexan-l-yl)methyl]-lH-pyrazol-4-yl} morph olin-4-yl] -8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 577 1-241 o / Cp )= / o O—( n 1 1 -(4-chloro-2-fluoropheny 1)-3-[(2S)-2-(l-{[l-(methoxymethyl)cyclopropyl] methyl} - IH-py razol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 565 1-242 V o o N An f 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(5,8- dioxaspiro[3.5]nonan-2-yl)methyl]-lH-pyrazol-4-yl} morpholin-4-yl] -8,9-dihydropyrido[3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 607 1-243 9y f f NrS A A> ILL ___ A A J l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-{[3-(fluoromethyl)oxetan-3-yl]methyl}-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido|3,4-d] pyrrolo [ 1,2-a] pyrimidin-5(7H)-one 569 1-244 Cl nANVA payj / ? v>     °xA     ° 0 3 l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(l-oxaspiro [3.3]heptan-6-y l)methyl] -1 H-py razol-4-y 1} morpholin-4-y 1] -8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 577 1-245 <X O A^ F oyYyS N.^N / y        ci 1 -(4-chloro-2-fluoropheny 1)-3-((S)-2-(l-(((R and S)-3-11 uorotet rahy drofuran-3 -yl)methyl)-lH-pyrazol-4-yl)morpholino)-8.9-dihydropyrido[3,4- d]pyrrolo[ 1,2-a]pyrimidin- '    5(7H)-one 569 1-246 o An f 1 -(4-chloro-2-fluoropheny 1)-3-[(2S)-2-{l-[(3-oxabicyclo[3.1.0]hexan-6-yl)methyl] - lH-pyrazol-4-y 1} morpholin-4-yl] -8,9-dihydropyrido[3,4-djpyrrolo[l,2-a|pyrimidin-5(7H)-one 563 1-247 Cl F'^y a Anya rNA,.^NAAJA o=K        i ?       i N-\ 0. J      0 /  \-F / j F F —0 2-(4- {(2S)-4-[ 1 -(4-chloro-2-fluorophenyl)-5-oxo-5,7,8,9-tetrahydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-3-yl]morpholin-2-yl}-lH-pyrazol-l-yl)-N-(4-methoxyphenyl)-N-(2,2,2-trifluoroethyl)acetamide 712 1-248 NU".. O ^N^ An f A?A 3-((S)-2-(l-(((S andR)-6-oxaspiro[3.4]octan-7-y l)methyl)- lH-pyrazol-4-yl)morpholino)-1 -(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 591 1-249 Cl F AyJ nANYA O.-i'        I N       T /       °A    ° 3-[(2S)-2-(l-{2-[(lS,2S)-[ 1,1' -bi(cy clopropane)]-2-y l]ethyl} - lH-pyrazol-4-y l)morpholin-4-y 1] -1-(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d] pvrrolo [ 1,2-a] pyrimidin- '    5(7H)-one 575 1-250 F, F x-f 0 3 0. 0 X1 N / S F ^ci 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-{2-[4- (tri 0 uoromethoxy )pheny 11 eth yl}-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 655 1-251 O                   O । z lJyz^o \=Z   \-- / o 3-[2-(4-{(2S)-4-[l-(4-chloro-2-fluorophenyl)-5-oxo-5,7,8,9-tetrahydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-3-y l]morpholin-2-yl} -1H-py razol-1 -y l)ethy 1] -1 lambda~6~-thietane-1,1-dione 599 1-252 0 NH F Ya. 2-(4- {(2S)-4-[l-(4-chloro-2-fluorophenyl)-5-oxo-5,7,8,9-tetrahydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-3-yl]morpholin-2-yl}-lH-pyrazol-l-yl)-N-(5-methyl-l,2-oxazol-3-yl)acetamide 605 1-253 E f -y\^\ o    o'Y     o XY^rYn N-J f'Y] Cl 1 -(4-chloro-2-fluorophenvl)-3-((S)-2-(l-(((R and S)-2,2-difluoro-6-oxaspiro[3.4]octan-7-yl)methyl)- lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4- d]pyrrolo[l,2-a]pyrimidin- 5(7H)-one 627 1-254 n O=< Z m z    O—' 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-{[(3aS,6aS)-hexahydro-6aH-cyclopenta[b]furan-6a-yl]methyl}-lH-pyrazol-4-yl)morpholin-4-yl]-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 591 1-255 O-J N-N 1 X O’^     o J\^F nr Cl l-(4-chloro-2-fluorophenyl)-3-((S)-2-(l-(((R and S)-2-methyloxetan-2-yl)methyl)-lH-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 551 1-256 F F N-N X o "Pfn NX^N^^7 u Cl l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[(S and R)-(2,2-difluorocy clopropyl)methy 1] -1 H-pyrazol-4-y 1} morpholin-4-yl]-8,9-dihydropyrido[3,4-d] pyrrole [ 1,2-a]pyrimidin-5(7H)-one 557 1-257 OO0 r\ r °yy A rrN n JI            L II 1 NYrA ck J     L^k 3-((S)-2-(l-(((3R,5R, 3S,5S, 3R.5S and 3S,5R)-2.7-di oxaspiro [4.4] nonan-3 -yl)methyl)- lH-pyrazol-4-yl)morpholino)-1 -(4-chloro-2-fluorophenyl)-8,9-dihydropyrido[3,4-d]pvrrolo[ 1,2-a]pyrimidin- ’    5(7H)-one 607 1-258 ^J-0 N-N X cr'"]       o A^F nr Cl l-(4-chloro-2-fluorophenyl)-3-[(2S)-2-{l-[2-(S andR)-(oxolan-2-yl)ethyl]-lH-pyrazol-4-y 1} morpholin-4-y 1] -8,9-dihydropyrido[3,4-d]pyrrolo[l,2-a]pyrimidin-5(7H)-one 565 1-259 1 -(4-chloro-2-fluorophenyl)-3-((S)-2-(l-(((2R,6R, 2S,6S, 2R,6S and 2S,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-2-yl)methyl)- 1H-pyrazol-4-yl)morpholino)-8,9-dihydropyrido[3,4-d]pyrrolo[l ,2-a]pyrimidin-5(7H)-one 633 Example 2-1 9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-7-[(2S)-2-(l-methyl-17f-pyrazol-4-yl)morpholin-4-yl]- 4 / / -Dvrazinol l.2-a1pvrimidin-4-one ethyl 2-methyl-3-oxobutanoate PPA 1 h, 100 °C P(tBu)3 Pd G2 Dioxane CS2CO3 2 h, 40 °C Cl

[0261] Step 1: To a solution of 5-bromo-3-(methylthio)pyrazin-2-amine (500 mg, 2.272 mmol), ethyl 2-methyl-3-oxobutanoate (1638 mg, 11.36 mmol) was added PPA (5 mL) at 20 °C. The resulting mixture was stirred at 100 °C for 1 h. LCMS showed the reaction was completed. The mixture was added to water (100 mL). The pH was adjusted to 7 by progressively adding solid NaHCOs. The reaction mixture was extracted with EtOAc (100 mL x3). The organic phase was concentrated to 50 ml, filtered and the cake was dried. The crude product was used in the next step without purification.

[0262] Step 2: To a solution of crude 7-bromo-2,3-dimethyl-9-(methylthio)-47f-pyrazino[l,2-a]pyrimidin-4-one (800 mg, 2.67 mmol) in dioxane (16 mL) was added (5)-2-(1 -methyl-1 / / -pyrazol-4-yl)morpholine (560 mg, 3.35 mmol), CS2CO3 (2605 mg, 8.00 mmol), Chloro[(tri-ter / -butylphosphine)-2-(2-aminobiphenyl)] palladium(Ii) (273 mg, 0.533 mmol), and the resulting mixture was stirred at 60 °C for 1 h. LCMS showed the starting material was consumed and the desired compound was found. The mixture was added to water (10 mL) and extracted with EtOAc (20 mL * 3). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash silica gel chromatography (eluent of 0-100% EtOAc / Petroleum ether gradient @ 30mL / min) to give (S)-2,3-dimethyl-7-(2-(l-methyl-17 / -pyrazol-4-yl)morpholino)-9-(methylthio)-4 / 7-pyrazino[l,2-a]pyrimidin-4-one. MS (ESI) / Wz: calc’d for Ci8H23N6O2S+ [M+H]+: 387.1, found [M+H]+: 386.9

[0263] Step 3: To a solution (S)-2,3-dimethyl-7-(2-(l-methyl-l / / -pyrazol-4-yl)morpholino)-9-(methylthio)-4 / f-pyrazino[L2-a]pyrimidin-4-one (400 mg, 1.035 mmol) in THF (8 mL) were added copper(i) thiophene-2-carboxylate (592 mg, 3.10 mmol), Pd(PhsP)4 (120 mg, 0.103 mmol) and (4-chloro-2-fluorophenyl)boronic acid (180 mg, 1.035 mmol) in glove box. The reaction was heated to 60 °C and stirred for 1 h. The mixture was cooled to room temperature, and dissolved with DCM (10 mL) and filtered. The filtrate was washed with saturated NaHCO? solution. The organic phase was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the resulting crude product was purified by preparative HPLC (water (0.04%NH3H20+10mM NH4HCO3)-ACN) to give (5)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1 -methyl-l / 7-pyrazol-4-yl)morpholino)-4 / f-pyrazino[1.2-a]pyrimidin-4-one. MS (ESI) m / z-. calc’d for C23H23C1FN6O2+ [M+H]+: 469.2, found [M+H]+: 469.1. 'H NMR (CDC13-d, 400 MHz) 8 8.10 (s, 1H), 7.65 (t, 1H, J= 7.9 Hz), 7.56 (s, 1H), 7.46 (s, 1H), 7.32 (d, 1H, J= 1.8 Hz), 7.26 (dd, 1H, J= 1.8, 9.8 Hz), 4.72 (dd, 1H, J=2.7, 10.3 Hz), 4.1-4.2 (m. 2H), 3.9-4.0 (m, 1H), 3.93 (s, 3H), 3.91 (s, 1H), 3.1-3.2 (m. 1H), 3.0-3.1 (m, 1H), 2.45 (s, 3H), 2.30 (s, 3H) Example 2-2, 2-3, & 2-4: 9-(4-chloro-2-fluorophenyl)-2.3-dimethvl-7-((2J?,- / <ST)-2-(2-methylpyridin-4-yl)tetrahydro-2H- pvran-4-vl)-4H-pvrazinoll,2-a1pvrimidin-4-one. 9-(4-chloro-2-fluorophenvl)-2,3-dimethvl-7- ((25.47?)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[L2-a1pyrimidin-4-one. and 9-(4-chloro-2-fluorophenvl)-2.3-dimethvl-7-((25'.4S' and 27?, 47?)-2-(2-methvlpyridin-4- vl)tetrahvdro-2H-pvran-4-vl)-4H-pyrazino[l.2-a1pyrimidin-4-one Pd(PPh3)4 CuTC then SFC separation NiCI2glyme , Zr; TBAI. LI DMA. 40 °C.16 li

[0264] Step 1: To a mixture of 7-bromo-2,3-dimethyl-9-(methylthio)-477-pyrazino[ 1,2-a]pyrimidin-4-one (220 mg, 0.733 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (16.10 mg, 0.073 mmol), zinc (144 mg, 2.199 mmol), TBAI (271 mg. 0.733 mmol), benzamide hydrochloride (23.10 mg, 0.147 mmol) in DMA (3 mL) was added 4-(4-bromotetrahydro-2 / / -pyran-2-yl)-2-methylpyridine (225 mg, 0.879 mmol) at 20 °C and the mixture was stirred at 60 °C for 16 h under N2 atmosphere. LCMS showed the reaction was completed. After filtration and concentration, the mixture was purified by Pre-HPLC (water / MeCN with TFA modifier) to give 2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2 / / -pyran-4-yl)-9-(methylthio)-47 / -pyrazino[l,2-a]pyrimidin-4-one, as a mixture of 4 diastereomers. MS (ESI) wz: calc’d for C2iH24N4O2S+ [M+H]+: 396.5. found [M+H]+: 396.9

[0265] Step 2: To a solution 2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2 / / -pyran-4-yl)-9-(methylthio)-4 / f-pyrazino[l,2-a]pyrimidin-4-one (60 mg, 0.151 mmol) in THF (1.5 mL) were added (4-chloro-2-fluorophenyl)boronic acid (39.6 mg, 0.227 mmol), Pd(PPh3)4 (5.25 mg, 4.54 pmol) and CuTC (86.3 mg, 0.453 mmol) in glove box. The reaction was heated to 60 °C and stirred for 1 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (15 mL * 3). The organic layer was dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by preparative HPLC (water / MeCN using TFA modifier) to give 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(-2-(2-methylpyridin-4-yl)tetrahydro-27 / -pyran-4-yl)-4H-pyrazino| 1,2-<2|pyrimidin-4-one as a mix of four diastereomers. The material was separated by SFC (Column: Chiralcel OD-3 150*4.6mm I.D., 3pm, Mobile phase: 40% of methanol (0.05% DEA) in CO2 Flow rate: 2.5mL / min, Column temp.: 35 °C ABPR: 1500psi) to give 9-(4-chl oro-2-fluoropheny 1)-2,3-di met hyl-7-((2 / ?. 4R and 2S,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one (Rt. = 2.522 and 2.814). 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2A.4<S')-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one (Rt. = 3.137) and 9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-7-((2A- / / ?)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one (Rt. = 3.752). 9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-7-((2R, 4R and 2S, 4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one: ‘HNMR (CDCh-J, 400 MHz) <5 = 8.70 (d, J= 6.0 Hz, 1H), 8.65 (s, 1H), 7.64 (t, J= 7.9 Hz, 1H), 7.55 (s, 1H), 7.52 (d, J = 5.8 Hz, 1H), 7.30 - 7.20 (m, 2H), 4.96 (dd, J= 2.3, 10.0 Hz, 1H), 4.02 - 3.91 (m, 2H), 3.45 -3.36 (m, 1H), 2.77 (s, 3H). 2.53 (d, J= 13.7 Hz. 1H), 2.41 (s, 3H), 2.27 - 2.19 (m, 4H), 2.19 -2.11 (m, 1H), 2.07 - 1.98 (m, 1H); MS (ESI) m / z: calc’d for C26H24C1FN4O2+ [M+HJ+: 479.0, found [M+H]+: 479.1 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((27?, 45)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one: ’H NMR (CDCh-d, 400 MHz) 3 - 8.80 (d, 2= 6.0 Hz, 1H), 8.60 (s, 1H), 7.66 (s, 1H), 7.63 (d, 2= 5.8 Hz, 1H), 7.58 (t, J= 7.8 Hz, 1H). 7.31 (dd, 2 = 1.7, 8.3 Hz, 1H), 7.26 (dd,. / = 1.9, 9.7 Hz, 1H), 4.72 (dd, . / = 1.7, 11.3 Hz, 1H), 4.43 (d, J= 3.0, 11.2 Hz, 1H), 3.91 - 3.80 (m, 1H), 3.39 - 3.24 (m, 1H), 2.85 (s, 3H), 2.46 (s, 3H), 2.38 (d, J= 13.2 Hz, 1H), 2.30 (s, 3H), 2.13-2.06 (m, 2H), 1.78 (q, J= 12.0 Hz, 1H); MS (ESI) m / z: calc’d for C26H24C1FN4O2+ [M+H]+: 479.0, found [M+H]+: 479.1 9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-7-((2N.- / / ?)-2-(2-methylpyndin-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one:1H NMR (CDCh-d, 400 MHz) 3 = 8.80 (d, J = 6.0 Hz, 1H), 8.59 (s, 1H), 7.65 (s, 1H), 7.62 (d, J= 5.8 Hz, 1H), 7.58 (t, J= 7.8 Hz, 1H), 7.31 (dd, J= 1.8, 8.3 Hz, 1H), 7.26 (dd, J= 1.9, 9.7 Hz, 1H), 4.75 - 4.69 (m, 1H), 4.46 - 4.39 (m, 1H), 3.93 - 3.79 (m, 1H), 3.38 - 3.25 (m, 1H), 2.85 (s, 3H), 2.46 (s, 3H), 2.38 (d, J= 13.0 Hz, 1H), 2.30 (s, 3H), 2.14 - 2.06 (m, 2H), 1.83 - 1.72 (m, 1H); MS (ESI) m / z: calc’d for C26H24CIFN4O2 [M+H]+: 479.0, found [M+H]+: 479.1 Example 2-5: 9-(4-cvclopropyl-2-fluorophenyl)-2.3-dimethyl-7-[(2)S)-2-(l-methyl-177-pvrazol-4-yl)morpholin-4-yl] -4 / 7- pyrazi no[ 1,2-a1 py rimidin-4-one

[0266] To a solution of (<S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(l-methyl-lH-pyrazol-4-yl)morpholino)-4H-pyrazino[1.2-a]pyrimidin-4-one (50 mg, 0.107 mmol) in dioxane (1mL) and H2O (0.1 mL) were added Cs2COs (104 mg, 0.320 mmol), Chloro[(di(l-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (7.13 mg, 10.66 pmol) and potassium cyclopropyl-difluoromethylboranuide (77 mg, 0.533 mmol), and the resulting mixture was stirred at 80 °C under N2 for 1 hour. LCMS showed the reaction was completed. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (15mL><3). The organic layer was dried over Na2SO4. After filtration and concentration, the crude product was purified by pre-HPLC (water / MeCN with TFA modifier) to give (<S)-9-(4-cyclopropyl-2-fluorophenyl)-2,3-dimethyl-7-(2-( 1 -methyl- IH-py razol-4-yl)morpholino)-4H-py razino[ 1,2-a] py rimidin-4-one. 'H NMR (CDCh-d, 400 MHz) 5 = 8.00 (s. 1H). 7.55 - 7.46 (m. 2H), 7.39 (s, 1H), 6.92 (br d, J= 8.0 Hz, 1H), 6.80 (br d, J= 11.8 Hz, 1H), 4.63 (dd, J=2.4, 10.0 Hz, 1H), 4.15-4.03 (m, 2H), 3.86 (s, 3H), 3.85 - 3.79 (m, 2H), 3.04 (dt, J= 3.4, 12.1 Hz, 1H), 2.94 (dd, J= 10.5, 12.2 Hz. 1H), 2.37 (s, 3H), 2.21 (s, 3H), 1.95 - 1.86 (m, 1H), 1.06 - 0.95 (m, 2H), 0.77 - 0.66 (m, 2H). MS (ESI) m / z: calc’d for C26H27FN6O? [M+H]+: 474.5, found [M+H]+: 475.2 Example 2-6; (ff)-9-(4-chloro-2-fluorophenyl)-2-methvl-7-(2-(l-methyl-lEf-pvrazol-4-yl)morpholino)-3- (trinuoromethvl)-4 / / -pvrazino| 1.2-a]pyrimidin-4-one Cl Step 1: 7-bromo-2-methvl-9-(methylthio)-4 / 7-pvrazino[L2-<a1pyrimidin-4-one

[0267] To a solution of 5-bromo-3-(methylthio)pyrazin-2-amine (2 g. 9.09 mmol) and ethyl 3-oxobutanoate (5.91 g, 45.4 mmol) was added PPA (30 mL) at 20 °C. The resulting mixture was stirred at 100 °C for 2 h. LCMS showed the reaction was completed. The reaction was cooled to room temperature. The mixture was added to a solution of NaOH at 0 °C. The pH was adjusted to ~7 with solid NaOH at 0 °C. The reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude compound was purified by flash silica gel chromatography to give 7-bromo-2-methyl-9-(methylthio)-477-pyrazino[l,2-a]pyrimidin-4-one. MS (ESI) m / z: calc’dfor C9H9BrN3OS+ [M+H]+: 286.0 / 288.0, found [M+H]+: 285.7 / 287.7 Step 2: 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-4 / / -pvrazino[l.2-a1pyrimidin-4-one

[0268] To a suspension of 7-bromo-2-methyl-9-(methylthio)-477-pyrazino[l,2-a]pyrimidin-4-one (350 mg, 1.223 mmol) in THF (8 mL) were added Pd(PPhs)4 (42.4 mg, 0.037 mmol) and (4-chloro-2-fluorophenyl)boronic acid (320 mg, 1.835 mmol), CuTC (700 mg, 3.67 mmol). The reaction was heated to 60 °C and stirred for 1 h. LCMS showed the reaction was completed. The mixture was cooled to room temperature, then dissolved with DCM (10 mL) and filtered. The filtrate w as washed with saturated NaHCOs solution until the color changed from dark blue to light yellow. The organic phase was dried over anhydrous Na?SO4 and filtered. The filtrate was concentrated in vacuo to give the crude residue. The residue was purified by flash silica gel chromatography to give 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-4H-pyrazino[l,2-a]pyrimidin-4-one. MS (ESI) m / z: calc’d for CuHgBrClFNsCf [M+H]+: 368.0 / 370.0, found [M+H]+: 367.9 / 369.7 Step 3: 7-bromo-9-(4-chloro-2-nuorophenvl)-3-iodo-2-methvl-4 / / -pvrazinol L2-<7lovrimidin-4- one

[0269] To a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-477-pyrazino[l,2-a]pyrimidin-4-one (300 mg, 0.814 mmol) in AcOH (5 mL) was added NIS (366 mg, 1.628 mmol), and the resulting mixture was stirred at 80 °C for 1 hour. Upon completion, the reaction mixture was adjusted with aq. NaHCOs (10 mL) to pH~9 and washed with Na2SOs until the color faded. The mixture was extracted with EtOAc(10 mL x 3). The organic layer was dried over Na2SO4. After fdtration and concentration, the residue was suspended with EtOAc (2.0 mL) and the precipitate was collected to give 7-bromo-9-(4-chloro-2-fluorophenyl)-3-iodo-2-methyl-4H-pyrazino[L2-tf]pyrimidin-4-one. MS (ESI) m / z: calc’d for Ci4H8BrClFIN3O+ [M+14]+: 493.9 / 495.8, found [M+H]+: 493.7 / 495.7 Step 4: 7-bro mo-9-(4-chloro-2-fluoropheny l)-2-methyl-3-(trifl uoromethyl)-42 / -pyrazino [1,2-a]pyrimidin-4-one

[0270] To a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-3-iodo-2-methyl-4 / / -pyrazino[l,2-a]pyrimidin-4-one (130 mg, 0.263 mmol) in DMF (0.5 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (379 mg, 1.972 mmol) and copper(I) iodide (75 mg, 0.394 mmol), and the resulting mixture was stirred at 80 °C for 3 hours. Upon completion, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with water (10 mL x 3), then dried over Na2SO4. After filtration and concentration, the crude product was purified by prep-TLC (SiO2, Pet. ether: EtOAc = 5: 1, v / v) to give 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-3-(trifluoromethyl)-4H-pyrazino[l,2-a]pyrimidin-4-one. MS (ESI) m / z: calc’d for Ci5H8BrClF4N3O+ [M+H]+: 435.9 / 437.9, found [M+H]+: 435.7 / 437.7 Step 5: 0S)-9-(4-chloro-2-fluorophenyl)-2-methy 1-7-(2-(1-methyl-lEf-pvrazol-4-yl)morpholino)-3-(tri fl uoromethvl )-4 / / -pvrazinol 1.2-a]pyrimidin-4-one

[0271] To a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2-methyl-3-(trifluoromethyl )-47 / -pyrazino[l,2-a]pyrimidin-4-one (60 mg, 0.137 mmol) in anhydrous dioxane (6 mL) were added potassium phosphate tribasic (88 mg, 0.412 mmol), (2-Dicyclohexylphosphino-2',6'-diisopropoxy-l,T-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II) methanesulfonate (11.49 mg, 0.014 mmol) and (5)-2-(l-methyl-lH-pyrazol-4-yl)morpholine (30 mg, 0.179 mmol), and the resulting mixture was stirred at 80 °C under N2 for 4 hours. Upon completion, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (30 mL x 3). The organic layer was dried over Na2SO4. After filtration and concentration, the crude product was purified by prep-TLC (SiO2, Pet. ether: EtOAc =1:1, v / v) to give the crude product. The crude product was purified by pre-HPLC (water / MeCN with TFA modifier) to give (S)-9-(4-chloro-2-fluorophenyl )-2-methy 1-7-(2-( I -methyl-17 / -pyrazol-4-yl)morpholino)-3-(trifluoromethyl)-47 / -pyrazino[l,2-a]pyrimidin-4-one. 'H NMR (400MHz, CDCh) 5 = 8.21 (s, 1H), 7.65 - 7.60 (m, 1H). 7.59 (s, 1H), 7.46 (s. 1H), 7.31 (dd, J= 1.8,8.3 Hz, 1H), 7.26 (d, 7=1.9 Hz, 1H), 4.69 (dd,7=2.7, 10.2 Hz, 1H), 4.24 (d, J = 12.6 Hz, 1H), 4.17 (dd, J= 2.4, 11.4 Hz, 1H), 3.94 (s, 4H), 3.92 - 3.86 (m, 1H), 3.20 (dt, J = 3.6, 11.4 Hz, 1H), 3.09 (dd, J = 10.3, 12.6 Hz, 1H), 2.58 (q, 7= 2.7 Hz, 3H).MS (ESI) m / z: calc’d for C23H2oC1F4N602+ [M+H]+: 523.1 / 525.1, found [M+H]+: 523.1 / 525.1 Example 2-7; (5)-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-7-(2-(l-methyl-177-pyrazol-4- yl)morpholino)-477-pyrazino( 1.2-a]pyrimidin-4-one Step 1: Ethyl 4-methoxv-2-methvl-3-oxobutanoate

[0272] To a stirred mixture of ethyl 4-methoxy-3-oxobutanoate (10 g, 62.4 mmol) in THF (80 mL) were added K2CO3 (11.22 g, 81 mmol) and Mel (4.29 ml, 68.7 mmol) at 25 °C and the mixture was stirred at 80 °C for 16 h under N2 atmosphere. Upon completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (80 mL x 3). The organic layer was washed with brine (100 mL x 3), then dried over Na2SO4. After filtration and concentration, the crude product was purified by flash silica gel chromatography to give ethyl 4-methoxy-2-methyl-3-oxobutanoate. 'H NMR (400 MHz, CDC13) 5 4.19 (d, J= 7.2 Hz, 2H), 4.13 (d, 7= 2.4 Hz, 2H), 3.66 (d, J =7.2 Hz, 1H), 3.41 (s, 3H), 1.35 (d, J =7.2 Hz, 3H). 1.27 (t, J= 7.2 Hz. 3H) Step 2: 7-bromo-2-(methoxvmethvl)-3-methvl-9-(methvlthio)-477-pvrazino[L2-rz1pvrimidin-4- one

[0273] To a solution of 5-bromo-3-(methylthio)pyrazin-2-amine (4 g, 18.17 mmol) in toluene (100 mL) was added In(OTl)3 (10.21 g, 18.17 mmol), ethyl 4-methoxy-2-methyl-3-oxobutanoate (6.97 g, 40.0 mmol) and the resulting mixture was stirred at 125 °C for 12 h. Water (20 mL) was added to the reaction and the mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography the resultant product was then suspended with (Petroleum ether: EtOAc = 10:1) (10.0 mL) and the precipitate was collected to give 7-bromo-2-(methoxymethyl)-3-methyl-9-(methylthio)-4 / 7-pyrazino[l,2-a]pyrimidin-4-one. 1HNMR(400 MHz, CDC13) 6 8.52 (s, 1H), 4.57 (s, 2H), 3.49 (s, 3H), 2.60 (s, 3H), 2.31 (s, 3H). MS (ESI) m / z: calc’d for CnHi2BrN3O2S+ [M+H]+: 330.1 found [M+H]+: 329.7 Step 3: 7-bromo-2-(methoxvmethvl)-3-methvl-9-(methvlthio)-4 / 7-pvrazino| 1,2-aIpyrimidin-done

[0274] To a solution 7-bromo-2-(methoxymethyl)-3-methyl-9-(methylthio)-4H-pyrazino[l,2-a]pyrimidin-4-one (860 mg, 2.60 mmol) in THF (2 mL) were added copper(i) thiophene-2 -carboxylate (745 mg, 3.91 mmol). Pd(Ph3P)4 (90 mg, 0.078 mmol) and (4-chloro-2-fluorophenyl)boronic acid (681 mg, 3.91 mmol) in glove box. The reaction was heated to 60 °C and stirred for 2 h. Upon completion, the reaction mixture was quenched with saturated NaHCO? solution (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography to give 7-bromo-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-477-pyrazino[l,2-«]pyrimidin-4-one. MS (ESI) m / z: calc’d for Ci6Hi2BrClFN3O2+ [M+H]+: 412.0 / 414.0 found [M+H]+: 411.9 / 413.9 Step 4: (5)-9-(4-chloro-2-fluorophenyl)-2-(methoxvmethvl)-3-methyl-7-(2-(l-methyl-177-pvrazol-4-yl)morpholino)-4H-pyrazino[ 1.2-a]pyrimidin-4-one

[0275] To a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-477-pyrazino[l,2-a]pyrimidin-4-one (30 mg. 0.073 mmol) in dioxane (2 mL) was added 2-(1-methyl-lH-pyrazol-4-yl)morpholine (14.59 mg. 0.087 mmol), Cs2CO3 (71.1 mg. 0.218 mmol) and Chloro[(tri-terLbutylphosphine)-2-(2-aminobiphenyl)] palladium(II) (3.73 mg, 7.27 pmol) in glove box. The resulting mixture was stirred at 60 °C under N2 protection for 3 hours. Upon completion, this mixture was filtered and the filtrate was concentrated in vacuo to give the crude residue. The residue was purified by prep-TLC (Petroleum ether: EtOAc = 3:1) to give a residue, which was further purified by Prep-HPLC (water / MeCN with TFA modifier) to give (5)-9-(4-chloro-2-fluorophenyl)-2-(methoxymethyl)-3-methyl-7-(2-(l-methyl-177-pyrazol-4-yl)morpholino)-477-pyrazino[l,2-a]pyrimidin-4-one. 'H NMR (400 MHz, CDCh-d) 5 8.10 (s. 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 4.71 (d, J= 10.0 Hz, 1H), 4.49 (s, 2H), 4.17 (t,J= 10.0 Hz, 2H), 3.92 (s, 5H), 3.40 (s, 3H), 3.16 (d, J= 9.2 Hz, 1H), 3.01-3.07 (m, 1H), 2.35 (s, 3H). MS (ESI) m / z: calc’d for C24H24C1FN6O3+ [M+H]+:499.2 found [M+H]+: 499.2. Example 2-8 and 2-9: (1Sy9-(4-chloro-2-fluorophenyl)-2-(cyclopropvlmethyl)-3-methvl-7-(2-(l-methvl-l / / -pvrazol-4-yl)morpholino)-477-pyrazino[l.2-a1pyrimidin-4-one and CS4-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(l-methyl-l / / -pyrazol-4-vl)morpholino)-2-(2-methylallyl)-4 / / -pyrazino[1.2- alpvrimidin-4-one o HO B OH d , Pd(PPh3)4, CuTC THF, 60 ”C Step 1: 4-cvclopropyl-3-oxobutanoate

[0276] Under N2atmosphere, CDI (19.46 g, 120 mmol) was added to the THF (100 mL) solution of 2-cyclopropylacetic acid (10.01 g, 100 mmol) slowly. The mixture was stirred at 25 °C for 1 h. Next potassium 3-ethoxy-3-oxopropanoate (25.5 g, 150 mmol) and magnesium chloride (11.42 g, 120 mmol) were added to the above mixture, which was stirred at 25 °C for 16 h. Upon completion, the reaction was quenched by 1.0 N HC1. The mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine (30 mL), dried over with Na2SO4, filtered and the filtrate was concentrated. The crude product was purified by flash silica gel chromatography to afford ethyl 4-cyclopropyl-3-oxobutanoate. Step 2: Ethyl 4-cvclopropyl-2-methyl-3-oxobutanoate

[0277] Under N2 atmosphere, Mel (3.44 ml, 55.0 mmol) was added to the solution of ethyl 4-cyclopropyl-3-oxobutanoate (8.51 g, 50 mmol) and K2CO3 (10.37 g, 75 mmol) in anhydrous THF (100 mL). The mixture was heated to 75 °C and stirred for 16 h. Upon completion, the reaction was quenched by water (50 mL), separated, extracted with EtOAc (30 mL x 3) and the organic layers combined. The organic phase was dried with Na2SO4 and concentrated in vacuum. The crude product was purified by flash silica gel chromatography to afford ethyl 4-cyclopropyl-2-methyl-3-oxobutanoate. Step 3: 7-bromo-2-(cyclopropvlmethyl)-3-methyl-9-(methylthio)-4 / if-pyrazinoH.2-a1pyrimidin-4-one and 7-bromo-3-methyl-2-(2-methylallyl)-9-(methylthio)-4 / f-pvrazino[1.2-a]pvrimidin-4-one

[0278] A single neck flask equipped with Dean-Stark trap was charged with toluene (40 mL), 5-bromo-3-(methylthio)pyrazin-2-amine (600 mg, 2.73 mmol), ethyl 4-cyclopropyl-2-methyl-3-oxobutanoate (1507 mg, 8.18 mmol), and In(OTf)3 (1532 mg, 2.73 mmol). Then the mixture was stirred at 120 °C for 1 h. upon cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, then re-purified by prep. HPLC (water / MeCN with NH3H2O modifier) and separated by SFC to give 7-bromo-3-methyl-2-(2-methylallyl)-9-(methylthio)-4 / 7-pyrazino[l,2-a]pyrimidin-4-one (Rt=3.219 min) and 7-bromo-2-(cyclopropylmethyl)-3-methyl-9-(methylthio)-4 / / -pyrazino[l,2-£7]pyrimidin-4-one (Rt=3.959 min). 7-bromo-3-methyl-2-(2-methylallyl)-9-(methylthio)-477-pyrazino[l,2-a]pyrimidin-4-one1H NMR (400MHz, CDC13) 5 8.42 (s, 1H), 2.62 (d, J= 6.8 Hz, 2H), 2.49-2.54 (m, 3H), 2.19 (s, 3H), 1.03-1.13 (m, 1H). 0.41-0.51 (m, 2H), 0.24 (q, J= 4.8 Hz, 2H). 7-bromo-2-(cyclopropylmethyl)-3-methyl-9-(methylthio)-4 / f-pyrazino[l,2-a]pyrimidin-4-one 'H NMR (400MHz, CDC13) 5 8.42 (s. 1H), 5.45-5.63 (m. 2H), 3.41 (d. J = 4.4 Hz, 2H), 2.51 (s, 3H), 2.18 (s, 3H), 1.62 (d, J = 4.8 Hz, 3H). MS (ESI) m / z: calc’d for CisHuBrNsOS4 [M+2]+: 342.1, found [M+2]2 341.8. Prep SFC condition: Column DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 pm) Condition 0.I %NH3-H2O iPrOH Begin B 30 End B 30 Gradient Time (min) 1 100%B Hold Time 1 Flow Rate (mL / min) 80 Step 4: (M-2-(cyclopropvlmethyl)-3-methvl-7-(2-( 1 -methyl-lF / -pyrazol-4-vl)morpholino)-9-(methvlthio)-4 / / -pvrazino| l,2-a1pyrimidin-4-one

[0279] To a solution of 7-bromo-2-(cyclopropylmethyl)-3-methyl-9-(methylthio)-4 / / -pyrazino[l,2-a]pyrimidin-4-one (40 mg, 0.118 mmol) in dioxane (2 mL) were added (5)-2-(1-methyl-lH-pyrazol-4-yl)morpholine (30 mg, 0.179 mmol), CS2CO3 (115 mg, 0.353 mmol), chloro[(tri-terLbutylphosphine)-2-(2-aminobiphenyl)] palladium(II) (12.05 mg, 0.024 mmol) and the resulting mixture was stirred at 60 °C for 16 h. Upon completion, the mixture was treated with water (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic fractions were washed with brine (5 mL), dried over Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (SiO2, EtOAc) to give (5)-2-(cyclopropylmethyl)-3- methyl-7-(2-(l-methyl-1 / / -pyrazol-4-yl)morpholino )-9-(methylthio)-4Z / -pyrazino| 1,2-a]pyrimidin-4-one. MS (ESI) m / z: calc’d for C2iH26N6O2S+ [M+H]+: 427.1 found [M+H]+: 427.1 Step 5: (<S)-9-(4-chloro-2-fluoropheny l)-2-(cy clopropylmethyl)-3-methyl-7-(2-( 1 -methyl- 1H-pvrazol-4-vl>morpholino)-4 / 7-pvrazino| L2-a|pvrimidin-4-one

[0280] To a solution of (X)-2-(cyclopropylmethyl)-3-methyl-7-(2-( I-methyl-l / / -pyrazol-4-yl)morpholino)-9-(methyhhio)-477-pyrazino[l,2-a]pyrimidin-4-one (15 mg, 0.035 mmol) in THF (1 mL) were added (4-chloro-2-fluorophenyl)boronic acid (6.13 mg, 0.035 mmol), copper(i) thiophene-2-carboxylate (20.12 mg, 0.106 mmol). Pd(Ph3P)4 (4.06 mg, 3.52 pmol) under N2 and the resulting mixture was stirred at 60 °C for 1 h. Upon completion, the mixture was treated with water (5 mL) and extracted with EtOAc (2 mL x 3). The organic layer was concentrated in vacuo and purified by Prep-HPLC (water / MeCN using NH3 H2O modifier) to give (5)-9-(4-chloro-2-fluorophenyl)-2-(cyclopropylmethyl)-3-methyl-7-(2-(l-methyl-l / / -pyrazol-4-yl)morpholino)-4E / -pyrazino[l,2-a]pyrimidin-4-one. 'H NMR (400MHz, CDC13) 5 8.07 (s, 1H), 7.66 (t, J= 8.0 Hz, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.29 (d, J= 1.6 Hz, 1H), 7.24 (dd, J= 10.0, 2.0 Hz, 1H), 4.71 (dd, J= 10.4, 2.8 Hz, 1H), 4.12-4.20 (m, 2H), 3.88-3.96 (m, 4H), 3.07-3.15 (m, 1H), 3.01 (dd, J = 12.4, 10.4 Hz, 1H), 2.61 (d, J= 6.8 Hz, 2H), 2.31 (s, 3H), 1.01-1.10 (m, 1H), 0.43-0.50 (m, 2H), 0.18-0.24 (m, 2H). MS (ESI) m / z: calc’d for C26H26C1FN6O2+ [M+H]L 509.2 / 511.2, found [M+H]+: 509.1 / 511.1 Step 6: (.ST3-methvl-7-(2-(l-methvl-lZ / -pvrazol-4-vl)morpholino)-2-(2-methylallvl)-9-(methvl thi 0 )-4 / / -pvrazino [ L2-a1 pvrimidin-4-one

[0281] To a solution of 7-bromo-3-methyl-2-(2-methylallyl)-9-(methylthio)-47 / -pyrazino[l,2-a]pyrimidin-4-one (40 mg. 0.118 mmol) in Dioxane (2 mL) was added (5)-2-(1 -methyl-\H-pyrazol-4-yl)morpholine (23.59 mg, 0.141 mmol), Cs2CO3 (115 mg, 0.353 mmol), chloro[(tri-terLbutylphosphine)-2-(2-aminobiphenyl)] palladium(II) (12.05 mg, 0.024 mmol) and the resulting mixture was stirred at 60 °C for 16 h. Upon completion, the mixture was treated with water (5 mL) and extracted with EtOAc (3 mL x 3). The combined organic fractions were washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by Prep-TLC (SiO2, EtOAc) to give (5)-3-melhyl-7-(2-(l-melhyl-l / 7-pyrazol-4-yl)morpholino)-2-(2-methylallyl)-9-(mcthylthio)-4 / 7-pyrazino| 1.2-a]pyrimidin-4-one. MS (ESI) m / z: calc’d for C2iH2eN6O2S+ [M+H]+: 427.1, found [M+H]L 427.1. Step 7: LS)-9-(4-chloro-2-fluorophenvl)-3-methyl-7-(2-(l -methvl-lH-pvrazol-4-yl)morpholino)-2-(2-meth\lalhl )-4 / / -p\razino| 1.2-a]pyrimidin-4-one

[0282] To a solution of (S)-3-methyl-7-(2-(l-methyl-l / 7-pyrazol-4-yl)morpholino)-2-(2-methylallyl)-9-(methylthio)-4 / / -pyrazino[l,2-a]pyrimidin-4-one (15 mg, 0.035 mmol) in THF (1 mL) were added (4-chloro-2-fluorophenyl)boronic acid (6.13 mg, 0.035 mmol), copper(i) thiophene-2-carboxylate (20.12 mg, 0.106 mmol). Pd(PhsP)4 (4.06 mg, 3.52 pmol) under N2 and the resulting mixture was stirred at 60 °C for 1 h. Upon completion, the mixture was treated with water (5 mL) and extracted with EtOAc (2 mL x 3). The organic layer was concentrated in vacuo and purified by Prep-HPLC (water / MeCN with NH3 H2O modifier) to give (5)-9-(4-chloro-2-fluorophenyl)-3-methyl-7-(2-(l-methyl-17 / -pyrazol-4-yl)morpholino)-2-(2-methylallyl)-4 / 7-pyrazino[l,2-a]pyrimidin-4-one. 'H NMR (400MHz, CDC13) 5 8.07 (s, 1H), 7.66 (t. J = 8.0 Hz. 1H), 7.55 (s, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 7.24 (d, J= 10.0 Hz, 1H), 5.47-5.61 (m, 2H), 4.674.75 (m, 1H), 4.12-4.18 (m, 2H), 3.89-3.95 (m, 5H), 3.41 (d, J=4.8 Hz, 2H), 3.07-3.15 (m, 1H), 2.97-3.05 (m, 1H), 2.29 (s, 3H), 1.67 (d, J= 4.8 Hz, 3H). MS (ESI) m / z: calc’d for C26H26C1FN6O2+ [M+H]+: 509.2 / 511.2, found [M+H]+: 509.1 / 511.1 Example 2-10; 9-(4-chloro-2-fluorophenyl)-7-(4-(2.2-difluoroacetyl)piperazin-l-yl)-2.3-dimethyl-4 / / - pyrazinof 1,2-a 1 pyrimidin-4-one CuTc, Pd(PPh3)4 1,4-dioxane, 80 °C, 16 h DIPEA, HATU DMF, 25 °C, 16 h Step 1: Synthesis of terLbutvl 4-(2.3-dimethyl-9-(methylthio)-4-oxo-4 / 7-pyrazino[L2-a]pvrimidin-7-vl)piperazine-l-carboxylate

[0283] To a stirred solution of compound 7-bromo-2.3-dimelhyl-9-(methylthio)-4 / 7-pyrazino[l,2-a]pyrimidin-4-one (4.5 g, 14.99 mmol) in 1.4-dioxane (15 mL) were added tertbutyl piperazine-1-carboxylate (2.79 g, 14.99 mmol), cesium carbonate (14.65 g, 45.0 mmol) and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-l,r-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II) (1.164 g, 1.499 mmol) at room temperature in the glove box. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled at room temperature, quenched with water (250 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel chromatography to afford compound tert-butyl 4-(2,3-dimethyl-9-(methylthio)-4-oxo-4 / 7-pyrazino[l,2-tf]pyrimidin-7-yl)piperazine-l-carboxylate. MS (ESI) m / z: calcd. for Ci9H28NsO3S+ [M+H]+:406.18, found 406.28 Step 2: Synthesis of compound te / 7-butvl 4-(9-(4-chloro-2-fluorophenvl)-2.3-dimethvl-4-oxo- 4 / / -pyrazino|T.2-a]pyrimidin-7-yl)piperazine-l-carboxvlate

[0284] To a stirred solution of 4-(2,3-dimethyl-9-(methylthio)-4-oxo-47 / -pyrazino[L2-£7]pyrimidin-7-yl)piperazine-l-carboxylate (4.5 g, 11.10 mmol) in 1,4-dioxane (15 mL) were added (4-chloro-2-fluorophenyl)boronic acid (2.90 g, 16.65 mmol), copper(i) thiophene-2-carboxylate (3.17 g, 16.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.89 mmol) at room temperature in glove box. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with ethyl acetate (40 mL) and water (25 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography. Pure fractions were combined and concentrated under reduced pressure to afford compound / erLbutyl 4-(9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-4 / / -pyrazino[l,2-a]pyrimidin-7-yl)piperazine-l-carboxylate. LCMS (ESI) calcd. for C24H28C1FN5O3+ [M+H]+: 488.18, found 488.32 Step 3: Synthesis of compound 9-(4-chloro-2-fluorophenyl)-2.3-dimethyl-7-(piperazin-l-yl)-47 / -Pvrazino[L2-a]pyrimidin-4-one hydrochloride

[0285] To a stirred solution compound tert-butyl 4-(9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-477-pyrazino[l,2-a]pyrimidin-7-yl)piperazine-l-carboxylate (2.0 g, 4.10 mmol) in 1,4 -dioxane (40 mL) was added 4M 1,4-dioxane hydrochloride (0.486 ml, 4.10 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Reaction mixture was concentrated under reduced pressure. Crude compound was triturated with diethyl ether (500 mL) and concentrated under reduced pressure to afford compound 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(piperazin-l-yl)-4 / / -pyrazino[l,2-a]pyrimidin-4-one hydrochloride. LCMS (ESI) calcd. for Ci9H2oClFN50+ [M+H]+:388.13, found 388.11. 1HNMR(400 MHz, DMSO-de): 5 (ppm) 9.25 (br s, 2H), 8.08 (s, 1H), 7.72 (t. J = 7.60 Hz, 1H), 7.63 (dd, J = 2.00, 9.60 Hz, 1H), 7.48 (dd, J = 2.00, 8.20 Hz, 1H), 3.69 (t, J = 5.20 Hz, 4H), 3.25 (s, 4H), 2.34 (s, 3H), 2.18 (s, 3H). Step 4: Synthesis of compound 9-(4-chloro-2-fluorophenyl)-7-(4-(2.2-difluoroacetyl)piperazin-l-yl)-2.3-dimethvl-4 / / -pyrazino[L2-a1pyrimidin-4-one ci

[0286] To a stirred solution 9-(4-chloro-2-fluorophcnyl)-2.3-dimcthyl-7-(pipcrazin-l-yl)-4H-pyrazino[l,2-a]pyrimidin-4-one hydrochloride (15 mg 35.35 pmol, 1.0 eq) in DMF (1500 pl) were added DIPEA (18 pl. 106.05 pmol, 3.0 eq), HATU (20.16 mg, 53.02 pmol, 1.5 eq) and 2,2-difluoroacetic acid (3.39 mg, 35.35 pmol, 1.0 eq) at RT. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by Prep HPLC purification. Fraction was collected and lyophilized to afford 9-(4-chloro-2-fluorophenyl)-7-(4-(2,2-difluoroacetyl)piperazin-1 -y 1)-2,3-dimethyl-4H-pyrazino[ 1,2-a]pyrimidin-4-one. LCMS (ESI) calcd. for C2iH2oClF3N502+ [M+H]+:466.12, found 466.19.¾ NMR (400 MHz, DMSO-de): 5 (ppm) 8.01 (s. 1H), 7.72 (t, J = 8.0 Hz, 1H), 7.62 (dd, J = 2.00. 10.0 Hz, 1H), 7.47 (dd, J = 2.00, 8.4 Hz, 1H), 6.8 (t, J = 52.8 Hz, 1H). 3.70 (br s, 4H), 3.51 (br s, 4H), 2.32 (s, 3H), 2.17 (s. 3H).

[0287] The Examples shown in Table 2-1 below were prepared according to procedures analogous to those outlined in Example 2-1 to 2-10 above using appropriate starting materials. Table 2-1: Examples 2-11 to 2-78 Example Structure IUPAC Name Exact Mass [M+H]+ 2-11 Cl N-, n^.n^JU O^J     0 (S)-1 -(4-chloro-2-fluorophenyl)-3-[2-(l-methyl-l / / -pyrazol-4-y l)morpholin-4-yl]-7,10-dihydropyrano[3,4-< / ]pyrazino[ 1.2-a]pyrimidin-6(8 / / )-one 497 2-12 Cl F J'y 0 (S)-1 -(4-chloro-2-fluorophenyl)-3-[2-(l -methy 1- l / / -pyrazol-4-y l)morpholin-4-y 1] -7,8,9,10-tetrahy dro-6 / / -py razino [2,1-6]quinazolin-6-one 495 2-13 Cl JU O^P     o 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2 / ?)-2-(l-methyl- l / / -pyrazol-4-yl)morpholin-4-yl]-4 / / -pyrazino[l,2-a]pyrimi din-d one 469 2-14 F JU N^VV o^P     0 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[(2<S’)-2-(l -methyl- l / / -pyrazol-4-y l)morpholin-4-y 1] -4 / / -pyrazino[ 1.2-o|pynmi din-done 453 2-15 Cl JU \ F pY-o 0 ( / / )-1 -(d-chloro-2-fluorophenyl)-3-[2-(l-methyl- l / / -pyrazol-d-yl)morpholin-d-yl]-7.10-dihydropyrano[3,d- < / ]pyrazino[ 1,2-a]pyrimidin-6(8 / / )-one 497 2-16 p ( / ?)-! -(d-chloro-2-fluorophenyl)-3-|2-(l-methy 1- 1 / Z-py razol-4-y l)morpholin-d-y 1] -7.8.9.10-tetrahy dro-6Z / -py razino [2,1-6]quinazolin-6-one 495 2-17 Cl A A n        n o.^     o 9-(4-chloro-2-fluorophenyl)-7-[(2.7)-2-(l-cyclopropyl-1 / / -pyrazol-4-yl)morpholin-4-yl] -2,3-dimethy 1-4 / / -pyrazino[ 1,2-a]pyrimidin-4-one 495 2-18 Cl j0 0 9-(4-chloro-2- methylpheny 1)-2,3-dimethyl- 7-[(2S)-2-(l-methyl-1 / / - pyrazol-4-yl)morpholin-4-y 1] -4 / / -py razino| 1,2-alpyrimidin-4-one 465 2-19 Cl jA o 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2Z?, 4S)-2-(1 -methyl- 177-py razol-4-yl)oxan-4-yl]-4 / / - pyrazino[ 1.2-« |pyrimidin-4-one 468 2-20 Cl jA N-, nA>V O^J     0 9-(4-chloro-2-fluorophenyl)-2,3-dimethy l-7-[(2S, 4R)-2-(1 -methyl-1 / / -py razol-4-yl)oxan-4-yl]-477-pyrazino[ l,2-c?]pyrimi din-done 468 2-21 Cl jA h F rrn O^   0 ( / ?)-! -(4-chloro-2-fluorophenyl)-3-[2-(l-methy 1- 1 / 7-py razol-4-yl)morpholin-4-yl]-8,9-dihydrocyclopenta[< / ]pyrazin o[l,2-a]pvrimidin-6(7 / / )-one 481 2-22 A N=1    N^VNk< AWA 0 9-(2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(l-methy 1- 177-py razol-4-y l)morpholin-4-yl] -4H-pyrazino[ 1.2-0 |pyrimidin-4-one 435 2-23 Cl A o-A     o 9-(d-chloro-2-fluorophenyl)-7-[(2R, 4S)-2-(\ -cyclopropyl-l / / -pyrazol-4-yl)oxan-4-yl|-2.3-dimethyl-d / / - pyrazino[ 1,2-a]pyrimidin-4-one d9d 2-24 Cl Xj Fy^ m               .N. / o 9-(4-chloro-2-fluorophenyl)-7-[{2S, 4Ryi-(\-cy clopropyl-l / / -pyrazol-4-yl)oxan-4-yl]-2.3-dimethyl-4 / / - pyrazino[ l,2-a]pyrimi din-done d9d 2-25 Cl jO V    F nX^n 0 (5)-1 -(4-chloro-2-fluorophenyl)-3-[2-(l -methyl- 1 / Z-py razol-4-yl)morpholin-4-yl]-8,9-dihydrocyclopenta[t / ]pyrazin o[l,2-a]pvrimidin-6(7 / / )-one d81 2-26 Cl A F'yT o^J     o 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethy 1-7-((25)-2-( 1 -methyl- l / f-pyrazol-4-y l)morpholin-4-y 1] -4H-pyrazino[ 1.2-o|pynmi din-done d87 2-27 Cl A AA aA >1 n         n oj   0 9-(d-chloro-2-fluorophenyl)-2-ethyl-3-methyl-7-[(25)-2-(1 -methyl- IH-py razol-d-y l)morpholin-d-yl] -4H-pyrazinof 1,2-a]pyrimi din-done d83 2-28 Cl Xj N^V "n\A^ aU il / N     Y 0 0^   o 9-(d-chloro-2-fluorophenyl)-3-methoxy-2-methyl-7-[(25)-2-(1-methyl-l / / -pyrazol-d-y l)morpholin-d-y 1] -4H-pyrazino[ 1.2-o|pynmi din-done d85 2-29 b o . ( / )-1 -(4-chloro-2-fluorophenyl)-3-[2-(2-methylpyridin-4- yl)morpholin-4-yl]-7.10-dihydropyrano[3,4-b]pyrazino[ 1,2-a]pyrimidin-6(8 / / )-one 508 2-30 z # \\__ 0 . ° \ z 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methylpyridin-4- y l)morpholin-4-y 1] -4 / / -pyrazino[ l,2-«]pyrimi dinb one 480 2-31 ‘ O —b # z—' 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(27?)-2-(2-methylpyridin-4- y l)morpholin-4-yl] -4 / / -pyrazino[ 1,2-a]pyrimidin-4-one 480 2-32 p Q . z -n 9-[2,6-difluoro-4-(methylsulfanyl)phenyl]-2.3-dimethy 1-7-[(2S)-2-( 1 -methyl- 1 / Z-py razol-4-y l)morpholin-4-yl] -4 / / -pyrazino[ 1,2-a ]pyrimidin-4-one 499 2-33 Cl JM F^i —\ 0 ( / ?)-! -(4-chloro-2-fluorophenyl)-3-[2-(2-methylpyridin-4-yl)morpholin-4-yl]-8.9-dihydrocyclopenta[b|pyrazin o[l .2-<2]pyrimidin-6(7 / / )-one 492 2-34 Cl A NA N AApNAN^M oA ° (S)-l-(4-chloro-2-fluorophenyl)-3-[2-(2-methylpyridin-4-yl)morpholin-4-yl]-8,9-dihydrocyclopenta[d]pyrazin o [ 1,2-a] pvrimidin-6(7 / / )-one 492 2-35 Cl JO .N. |1                                 O OJ^^n^JO o (S)-1 -(4-chloro-2-fluorophenyl)-3-[2-(2-methylpyridin-4-yl)morpholin-4-yl]-7.10-dihydropyrano[3,4-< / ]pyrazino[ 1,2-a]pyrimidin-6(8 / / )-one 508 2-36 A 0^0     o 9-(2-fluoro-4-methylphenyl)-2.3-dimethyl-7-[(25>2-(l-methy 1- 177-py razol-4-y l)morpholin-4-y 1] -4H-pyrazino[ 1,2-a]pyrimidin-4-one 449 2-37 fJ0 JO F^\ M               .N. / N=,         Vs- V 0^0     0 9-[2-fluoro-4-(trifluoromethyl)phenyl] -2.3-dimethy 1-7-[(2S)-2-( 1 -methyl- l / / -pyrazol-4-y l)morpholin-4-yl] -4H-pyrazino[ l,2-a]pyrimi din-done 503 2-38 Cl - N~j   YV'O nj^n^0u 0^0     0 1 -(4-chloro-2-fluorophenyl)-3-[(2S)-2-(l-methyl-ltf-pyrazol-4-yl)morpholin-4-yl]-7,10-dihydropyrano[3,4-< / ]pyrazino[ 1,2-a]pyrimidin-6(87 / )-one 497 2-39 A ' N AV 0^0     o 9-(4-cyclopropyl-2- fluorophenyl)-2,3-dimethyl- 7-[(2<S')-2-(l-methyl-l / / -pyrazol-4-yl)morpholin-4-yl]-4 / f-pyrazino[ 1,2-al pyrimidin-4-one 475 2-40 o — 0 H' o 9-(4-chloro-2-fluorophenyl)- 7-[4-(furan-2- carbony l)piperazin-1 -y 1] -2.3-dimethy 1-477-py razino [ 1,2-al pyrimidin-4-one 482 2-41 0 -o 7-[4- (benzenecarbonyl)piperazin-1 -y 1] -9-(d-chloro-2- fluorophenyl)-2,3-dimethyl-d / / -py razmo| 1,2- a]pvrimidin-4-one d92 2-42 ,N=\ w 9-(d-chloro-2-fluorophenyl)-2,3-dimethyl-7-[4-(4-methyl-1.3-oxazole-5- carbony l)piperazin-1 -y 1] -4 / / -pyrazino[ 1.2-a]pyrimi din-d one d97 2-43 / —z Z'9. / II Ma o 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[4-(l,2- oxazole-5- carbony l)piperazin-1 -y 1]-AH-pyrazino[ 1.2-0 |pyrimidin-4- one d83 2-44 O\ a - o 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[4-(oxetane-2-carbonyl)piperazin-1 -yl] -47 / -pyrazino[ 1,2-alpyrimidin-4-one d72 2-45 >0 O y— z z o 9-(4-chloro-2-fluorophenyl)-7-[4-(cis-3-fluoro-3-methylcyclobutane-1 - carbonyl)piperazin-l-yl]-2.3-di methyl -4 / / -pyrazino [1,2-alpvrimidin-4-one 502 2-46 o o rac-9-(4-chloro-2- fluorophenyl)-2,3-dimethyl-7-[4-(spiro [2.4]heptane-1 -carbony l)piperazin-1 -yl] AH-pyrazino[ 1.2-a]pyrimi din-done 510 2-47 F. F X~F N=\ fyyci T Y VN^N 9-(d-chloro-2-fluorophenyl)-2,3-dimethyl-7-{4-[4- rnethyl-2-(trifluorornethyl)- l,3-oxazole-5- carbony 1J piperazin-1 -yl} - 477-pyrazino[ 1,2-a]pvrimidin-4-one 565 2-48 w qY^Y rac-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[d-(l-methyl-2-oxabicyclo[2.2. l]heptane-d-carbony l)piperazin-1 -yl] -4H-pyrazino[ 1,2-a]pyrimi din-done 526 2-49 Cl Y 0 kNV° r 0 cis and lrany-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[4-(6-methyloxane-2-carbony l)piperazin-1 -y 1] -4H-pyrazinol 1,2-aJpyrimi din-done 51d 2-50 o J3 o 9-(d-chloro-2-fluorophenyl)-7-{4-[(JR,2S)-2- (fluoromethyl)cyclopropane-1 -carbonyl] piperazin-1 -y 1} -2,3-dimethyl-d / f- pyrazino[ 1,2-a]pyrimi din-done d88 2-51 ... o JI '° 9-(d-chloro-2-fluorophenyl)-2,3-dimethyl-7-{d-[3- (trifluoromethyl)-1,2-oxazole-5- carbony 1] piperazin-1 -yl} - d / / -py razmo| 1,2-a]pvrimidin-d-one 551 2-52 \ II Q 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-{4-[l-(l / f-1,2,3-triazol-l- yl)cyclopropane-l-carbony 1] piperazin-1 -yl} -4 / / -py razino| 1,2-a]pyrimidin-4-one 523 2-53 0 1 o tert-butyl [QR2R,4R)-l-{4-[9-(4-chloro-2- fluorophenyl)-2,3-dimethyl-4-oxo-4 / 7-py razino[ 1,2-a]pyrimidin-7-yl]piperazine-1- carbonyl}bicyclo[2.2. l]hepta n-2-yl] carbamate 625 2-54 CT F^^CI ANY0Cr \v rac-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[4-(4-methyl-3- oxabicyclo[4.1.0]heptane-4-carbony l)piperazin-1 -yl] -4H-pyrazino[ 1.2-0 |py rirnidin-4-one 526 2-55 n fwci w 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-{4-[l-(1,3-thiazol-5-yl)cyclopropane-l-carbony 1J piperazin-1 -yl} -477-py razinof 1,2-alpvrimidin-4-one 539 2-56 -1 ■: o 9-(4-chloro-2-fluorophenyl)-7-[4-(4-                  ’ fluorobicyclo[2.2. l]heptane- 1 -carbonyl)piperazin-1 -yl] - 2.3-dimethyl-4H-pyrazino[l,2-a]pyrimi din-done 528 2-57 cr KI / k N ] J ^Nv° A 9-(4-chloro-2-fluorophenyl)- 7-(4-(7,7- difluorotricyclo[2.2.1.0-2,6- ]heptane-l- carbony l)piperazin-1 -y 1] -2,3-dimethy 1-477-py razino [1,2- a]pvrimidin-4-one 544 2-58 Cl XL tert-butyl (2S,6R)-2-{4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-d-oxo-d / / - pyrazino[ 1,2-a]pyrimi din-7 -yl] piperazine-1 -carbonyl} -6-methylmorpholine-d-carboxylate 615 2-59 ' / J 3¾ o 9-(d-chloro-2-fluorophenyl)-2,3-dimethyl-7-[4-(2-oxabicyclo[2.2.2]octane-l-carbony l)piperazin-1 -y 1] -4H-pyrazino[ 1.2-o|pynmi din-done 526 2-60 Fx 0b ^NYN00 XV 0VjX\ 9-(4-chloro-2-fluorophenyl)-7 - [4-(3 -fluorooxolane-3-carbonyl)piperazin-l-yl]-2.3-di methyl -4 / / -pyrazmo [ 1,2-alpvrimidin-4-one 50d 2-61 0 V Q 9-(4-chloro-2-fluorophenyl)- 7-{4-l(7A,2A)-2- (fluoromethyl)cyclopropane-1 -carbonyl] piperazin-1 -y 1} - 2,3-dimethyl-477- pyrazino[ 1.2-a]pyrimi din-d one d88 2-62 Cl w o     k___-N^° S03 1 9-(d-chloro-2-fluorophenyl)-2,3-dimethyl-7-{d-[l- (methylsulfanyl)cyclobutane-l-carbonyl]piperazin-l-yl}-4 / / -pyrazino[ 1.2-a]pyrimidin-d-one 516 2-63 0*0 °'0 cAq wci Y N^N 9-(d-chloro-2-fluorophenyl)-7-{d-l(26>l,d-dioxane-2-carbony 1] piperazin-1 -yl} -2.3-dimethyl-d / / - pyrazino[l,2-a]pyrimi din-done 502 2-64 Cl 0 0 1 9-(4-chloro-2-fluorophenyl)- 7-{4-[( / A, 25)-2-(2-methoxyethyl)cyclopropane-1 -carbonyl] piperazin- 1-yl} - 2.3-dimethyl-4 / / - pyrazino[ 1.2-0 |pyrimidin-4- one 514 2-65 FVVCI T T 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-{4-[( / 5,55)-3-oxabi cyclo [3.1,O]hexane-1 -carbonyl]piperazin-l -yl} -4H-pyrazino[l,2-a]pyrimidin-4-one 498 2-66 0 -¾ o 9-(4-chloro-2-fluorophenyl)-7-{4-[3-(2,2- difluoroethy l)bicy clo[ 1.1.1 ] p entane-1 -carbonyl] piperazin-1 -yl} -2.3-dimethyl-4J7-pyrazino[l,2-a]pyrimi din-done 546 2-67 -¾ c O—\ z—' O"1^ o 9-(4-chloro-2-fluorophenyl)-7-{4-[(2R)-l,4-dioxane-2-carbonyl] piperazin-1 -yl} -2.3-dimethyl-4 / f- py razin o| 1.2-a | py ri mi din-4-one 502 2-68 Cl ex yX o    0^N^O o\ / ■ac-9-(4-chloro-2-fluorophenyl)-7-[4-(2,3-dimethyloxolane-3-carbonyl)piperazin-l -yl]-2,3-dimethy 1 -47 / -py razino [1,2-a]pyrimidin-4-one 514 2-69 fl A XV of^f 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-{4-[l-(l,3-oxazol-2-yl)cy clopropane-1 -carbonyl] piperazin-1 -yl} -477-pyrazino[l,2-a]pyrimidin-4-one 523 2-70 Cl X V 0 ■''0 1 9-(4-chloro-2-fluorophenyl)-7-{4-[(7A, 277)-2- methoxy cyclopropane-1 - carbonyl] piperazin-1 -yl} - 2,3-dimethyl-477- pyrazino[ 1.2-a]pyrimi din-d one 486 2-71 AX yY \v 0Vj?V 9-(4-chloro-2-fluorophenyl)-7-{4-[( / K2A)-2-       ' (difluoromethyl)cyclopropan e-1 -carbonyl]piperazin-1 -yl}-2,3-dimethyl-4 / / -pyrazino[ 1.2-0 |pyrimidin-4-one 506 2-72 / =^ -^N^N of^ Vn^yVV XV of^f 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[4-(4-methyl-477-1,2,4-triazole-3- carbony l)piperazin-1 -yl] -477-pyrazino[ 1,2-a]pyrimidin-4- one 497 2-73 Vl° a. zf ✓ ° z 1 9-(4-ethyl-2-fluorophenyl)-2,3-dimethyl-7-[(25)-2-(l- methyl- 177-pyrazol-4- y l)morpholin-4-y 1] -477-pyrazino[ l,2-c?]pyrimidin-4- one 463 2-74 o vn O '■ o 7-(4-(2.1 -benzoxazole-3-carbony l)piperazin-1 -y 1] -9-(4-chloro-2-fluorophenyl)- 2.3-dimethyl-4 / / - pyrazino[ 1,2-a ]py rimidin-4-one 533 2-75 ° O FYVCI 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[4-(l,3,3-trimethyl-2- oxabicyclo[2.1. l]hexane-4-carbony l)piperazin-1 -yl] -4 / / -pyrazino[ 1,2-a]pyrimidin-4- one 540 2-76 g^ o . 0 ^=o 9-(4-chloro-2-fluorophenyl)-7-{4-[(lR,2R)-2-        ’ methoxy cyclobutane-1 -carbonyl] piperazin-1-yl} -2.3-dimethyl-47 / -pyrazino[l,2-a]pyrimidin-4-one 500 2-77 o J\p O ' o rac-9-(4-chloro-2-fluoropheny 1)-7- [4-(1,7-dioxa-2-azaspiro[4.4]non-2-ene-3 -carbony l)piperazin-1 -yl]-2,3-dimethyl-4 / f-pyrazino[l,2-a]pyrimidin-4-one 541 2-78 Cl X^F 0 N^° rac-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-{4-[2-(lH-pyrazol-5-y l)propanoyl] piperazin-1 -y 1} -4H-pyrazino [1.2-a]pyrimidin-4-one 510 Example 2-79: (1Sf)-5-(4-chloro-2-fluorophenyl)-7-(2-(l-methvl-lH-pvrazol-4-yl)morpholino)-1.3-dihvdro-10H- furo[3.4-d1pvrazino[l.2-a1pyrimi din-10-one Step 1: ethyl 4-((5-bromo-3-(methvlthio)pvrazin-2-vl)amino)-2.5-dihvdrofuran-3-carboxvlate

[0288] A mixture of 5-bromo-3-(methylthio)pyrazin-2-amine (2.0 g, 9.09 mmol) and ethyl 4-oxotetrahydrofuran-3-carboxylate (4.31 g, 27.3 mmol) in AcOH (30 mL) was stirred at 120 °C for 3 h. The mixture was filtered and the solid was concentrated under reduced pressure to give the crude ethyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-2,5-dihydrofuran-3-carboxylate, which was not further purified. MS (ESI) m / z: calc’d for C^isBrNsOsS [M+H]+: 360.1 / 362.1 found [M+H]+ 360.2 / 362.2. Step 2: 7-bromo-5-(methylthio)-1,3-dihvdro-10 / / -furo[3,4-d1pyrazino[l,2-a1pyrimidin-l0-one

[0289] A mixture of ethyl 4-((5-bromo-3-(methylthio)pyrazin-2-yl)amino)-2.5-dihydrofuran-3-carboxylate (900 mg, 2.498 mmol) in diphenyl ether (1 mL) was stirred at 280 °C for 20 min using sand bath. Upon completion, the mixture was filtered and the solid was concentrated under reduced pressure to give the crude 7-bromo-5-(methylthio)-l,3-dihydro-10Lf-furo[3,4-d]pyrazino[l,2-a]pyrimidin-10-one, which was not further purified. MS (ESI) m z: calc’d for CioH9BrN302S[M+H]+: 314.0 / 316.0.0, found [M+H]+314.1 / 316.1. Step 3: (5)-7-(2-( 1 -methyl- lH-pvrazol-4-vl)morpholino)-5-(methylthio)-1,3-dihydro-10H-furo[3....

Claims

1. A compound of Formula (I):(I)or a pharmaceutically acceptable salt thereof, wherein:X1 is C orN;X2 is C or N, provided that both X1 and X2 are not N;X3isCorN;X4isCorN;X5 isCorN;X6 is selected from -CH2-, -N(CH3)- and -0-, and y is 0 or 1;R1 is a -Ci-10 alkyl, -(CH2)z-0H, or -(CH2)-N(CH3);R2 is a -C1-10 alkyl, or a -OC1-6 alkyl;wherein the C1-10 alkyl of R1 and R2and the -OC1-6 alkyl of R2 are unsubstituted or independently substituted by one or more halo, Ci-3alkyl, or C3-6 cycloalkyl groups;or, alternatively, R1 and R2 are linked together to form a C3-7 cycloalkyl or three to seven membered heterocyclyl group,wherein the C3-7 cycloalkyl or three to seven membered heterocyclyl group is unsubstituted or substituted with one or more halo, Ci-3alkyl, or C3-6 cycloalkyl groups;provided that when X1 is C and X2 is N. then R1 and R2 must be linked together to form the C3-7 cycloalkyl or the three to seven membered heterocyclyl group;A is selected from (i) a C3-7cycloalkyl and (ii) a heterocyclyl comprised of:(1) seven carbon atoms and one N atom,(2) six carbon atoms and (i) one O atom, (ii) one N atom, or (iii) one each of O and N, or(3) four carbon atoms and one N atom, orY1 is CH, CF, OorN;Y2 is CH orN;Y3 is CH orN;R5 is selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C1-10 alkyl, -C(=0)-Ci-io alkyl, -C(=O)-C3-8cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclyl, -CH2-heteroaryl, -C(=O)heteroaryl, -C(=O)-C(CH3)2-heteroaryl, fluoro and =0;wherein the -C(=O)-C3-scycloalkyl of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-2 alkyl unsubstituted or substituted with one or two fluoro atoms, a heteroaryl, -NH-C(=0)-0-Ci-io alkyl, -OCH3, -CH2CH2OCH3, and -SCH3;wherein the -SO2C1-10 alkyl or -C(=0)-Ci-io alkyl of R5 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl. isopropenyl, or one, two or three fluoro;wherein the -C(=O)-aryl, -C(=O)-heterocyclyl, -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl of R5 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from a -C1-10 alkyl, -OC1-10 alkyl, -C(=0)-0-Ci-io alkyl, a -C3-5cycloalkyl. methylbenzyl, -CF3, fluoro, and =0;R16a and R16b are independently hydrogen, fluoro, or methyl;R6 is selected from hydrogen, a C3-7Cycloalkyl, a heterocyclyl, and a heteroaryl,wherein the C3-7Cycloalkyl moiety7 of R6 is unsubstituted or substituted with a heteroaryl or one or two fluoro atoms,wherein the heterocyclyl or heteroaryl of R6 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from a -C1-10alkyl, -OCi-io alkyl, -C(=0)-0-Ci-io alkyl, a -C3-5cycloalkyl, methylbenzyl, -CF3, fluoro, and =0;R3 is selected from the group consisting of:R7 and R9are independently selected from hydrogen, methyl, and halo;R8, R10 and R11 are independently selected from hydrogen, halo, a -Ci-4 alkyl, -CF3, and-SCH3;X7 is C or N;R12 and R12 are each independently selected from hydrogen, -CFs, -OCFs, -(CH3)2, and fluoro;R13and R13 are each independently selected from hydrogen and fluoro;R4, R14 and R17are each independently selected from hydrogen and fluoro;wherein R17is fluoro when X4 is C; andR4is hydrogen when X5 is N.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of:

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II):0 (II)or a pharmaceutically acceptable salt thereof, wherein:X1 isCorN;X2 is C or N, wherein X2is C when X1 is N, provided that both X1 and X2 are not N;Y1 is O or N;Y2 is CH orN;R1 is a -Ci-4 alkyl;wherein the Ci-4alkyl moiety of R1 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl, isopropenyl, or one, two or three fluoro;R2 is a -C1-4 alkyl or a -OC1-4 alkyl;wherein the Ci-4alkyl moiety of R2 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl, isopropenyl, or one, two or three fluoro;or R1 and R2 are linked together to form a three to seven membered cycloalkyl or heterocyclyl group;wherein said three to seven membered cycloalkyl or heterocyclic group is optionally substituted with one of more halo, C1-3 alkyd or Cs-ecycloalky 1;and provided that when X1 is C and X2 is N, then R1 and R2 must be linked together to form the three to seven membered cycloalky1 or heterocyclyl group;R10 is selected from hydrogen, halo, a -C1-3 alky l, -CF3, and -SCH3;R7, R8, R9, R10, and R11 are independently selected from hydrogen, methyl, and halo;R5 is selected from hydrogen, -SO2N(CH3)2, -SO2C1-10 alkyl, -C(=0)-Ci-io alky 1, -C(=O)-C3-8cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclyl, -C(=O)-heteroaiy1 and -C(=O)-C(CH3)2-heteroaryl;wherein R5 is absent when Y1 is O;wherein the -C(=O)-C3-8Cycloalkyl of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-2 alkyl unsubstituted or substituted with one or two fluoro, a heteroaryl, -NH-C(=0)-0-Ci-io alkyl, -OCH3, -CH2CH2OCH3, -SCH3, and one or two fluoro,wherein the -C(=O)-aryl, -C(=O)-heterocyclyl, -C(=O)-heteroaryl or -C(=O)-C(CH3)2-heteroaryl of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-10 alkyl, -C(=O)-O-C1-10 alkyl, -CF3, and fluoro;wherein the -SO2C1-10 alkyd or -C(=0)-Ci-io alkyl of R5 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentany l, isopropenyl, or one, two or three fluoro;R6 is selected from hydrogen and a heteroaryl;wherein the heteroaryl of R6 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-10 alkyl, -C(=0)-0-Ci-io alkyl, -CF3, and fluoro; andy is 0 or 1.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof,wherein X1 is C, X2 is N, and R1 and R2 are linked together to form a three to seven membered cycloalkyl or heterocyclyl group, which is unsubstituted or substituted with one or more halo, Cisalkyl, or C3-6 cycloalkyl groups, wherein said alky l, cycloalkyl or heterocyclic group is optionally substituted with one of more halo, C1-3 alkyd or C3-6cycloalkyl.

5. The compound of any one of claims 1-3. or a pharmaceutically acceptable salt thereof, wherein X1 is N.

6. The compound of any one of claims 1, 2, 3, and 5, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are each methyl.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are taken together to form a C5-8 cycloalkyd or a heterocyclyl comprising one O atom.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R5 is selected from the group consisting of -C(=O)-heterocyclyl, -CH2-heteroaryl, -C(=O)heteroaryl, and -C(=O)-C(CH3)2-heteroaryl;wherein the -CH2-heteroaryl, -C(=O)heteroaryl. or -C(=O)-C(CH3)2-heteroaryl of R5is comprised of(1) four carbon atoms and one of O,(2) three carbon atoms and (i) N and 0, (ii) N and S, or (iii) N and NH;(3) two carbon atoms and three of N;(4) seven carbon atoms and N and O; andwherein the -C(=O)-heterocyclyl of R5is comprised of:(1) three, four, five, six or seven carbon atoms and one 0,(2) four carbon atoms and (i) two of 0 or (ii) N and 0, or(3) six carbon atoms and two of 0 and one of N.

9. The compound of any one of claims 1 -7, or a pharmaceutically acceptable salt thereof, wherein R6 is a pyrazole substituted at the 1-position with a -C1-10 alkyl.

10. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R6 is pyridine substituted with a -C1-10 alkyd.

11. The compound of any one of claims 1 and 3, or a pharmaceutically acceptable salt thereof, wherein R10 is fluoro or chloro, R9 is fluoro, and R7 is hydrogen.

12. The compound of any one of claims 1 and 3, or a pharmaceutically acceptable salt thereof, wherein R10 is chloro, R9 is fluoro, and R7 is hydrogen.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (III):

14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (IV)wherein:X1 is C orN;X2 is C or N, provided that both X1 and X2 are not N;Rl and R2 are independently Ci-3 alkyl, or, alternatively, Rl and R2, together with the carbon atoms to which they are attached, form a ring CZ;wherein ring CZ is:(i) a non-aromatic, partially unsaturated 5- to 6-membered cycloalkyl;(ii) a 5- to 6-membered heterocycloalkyl, wherein said 5- to 6-membered heterocycloalkyl is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N, O and S; or(iii) a 9 to 10-membered bicyclic heterocycloalkyl wherein said 9- to 10-membered bicy clic heterocycloalkyl is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N. O and S;wherein ring CZ is unsubstituted or substituted by 1 to 2 RZ substituents independently selected from the group consisting of Ci-3 alkyl, Ci-3 fluoroalkyl, and halo;provided that when X1 is C and X2 is N, then R1 and R2, together with Xl and X2, must form ring CZ;Y2 is C(H) orN;Y4 is CH2 or O;R6 is:(a) ring C6, wherein ring C6 is:(i) a 5- to 6-membered monocyclic hctcroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S;(ii) a 4- to 6-membered saturated, monocyclic heterocycloalkyl containing one heteroatom selected from the group consisting of N, O and S;(iii) a 6-to 10-membered fused or bridged heterobicyclic system containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S;wherein said 6-to 10-membered heterobicyclic system is:(a) fully saturated or(b) contains 1 aromatic ring and one partially unsaturated ring;(iv) a C3-7 saturated cycloalkyl; or(v) phenyl;wherein ring C6 is unsubstituted or substituted by 1 to 2 R6a substituents independently selected from the group consisting of halo, cyano, Cl-3 alkyl, Cl-3 alkoxy, or R6ac;wherein R6ac is -(CH2)\-Cac;Cacis(I) C3-6 monocyclic cycloalkyl;(II) C7-12 bicyclic cycloalkyl;(III) a 3- to 6-membered monocyclic heterocycloalkyd, wherein the 3- to 6membered monocyclic heterocycloalkyl is saturated, and contains 1 to 2 heteroatoms independently selected from the group consisting of N, 0, and S;(IV) a 6- to 10-membered bicyclic heterocycloalky l, wherein the 6- to 10membered bicyclic heterocycloalkyl is saturated or partially saturated, and contains 1 to 2 heteroatoms independently selected from the group consisting of N, 0, and S;(V) a 5- to 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S;(VI) a 6- to 10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S; or(VII) phenyl or naphthyl;wherein Cac is unsubstituted or substituted by 1 to 2 substituents independently selected from the group consisting of halo, amino, oxo, Ci-12 alkyl, Ci-3 fluoroalkyl, Ci-3 alkylamino, Ci-3 dialkylamino, Ci-3 alkoxy, and Ci-3 alkoxy(Ci-3) alkyd;(b) Ci-6 alkyl;(c) Ci-6 fluoroalkyl;(d) Ci-6 alkoxy;(e) Ci-3 alkoxy(Ci-3) alkyl;(I) Ci-3 hydroxyalkyl;each RA is independently fluoro Ci-3 alkyl, or Ci-3 alkoxy;R?, R&, and Rl 1 are independently H or halo;R10 is halo, methyl, or trifluoromethyl;q is 1 or 2;r is 0, 1, or 2;s is 0 or 1; and v is 0, 1 or 2.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (V)R10wherein:Rl and R2 are independently Ci-3 alkyl, or, alternatively, Rl and R2, together with the carbon atoms to which they are attached, form a ring CZ;wherein ring CZ is:(i) a non-aromatic, partially unsaturated 5- to 6-membered cycloalkyd; or(ii) a 5- to 6-membered heterocycloalkyl, wherein said 5- to 6-membered heterocycloalkyl is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N, O and S;wherein ring CZ is unsubstituted or substituted by 1 to 2 RZ substituents independently selected from the group consisting of Cl-3 alkyl, Cj-3 fluoroalkyl, and halo;Y2 is C(H) orN;R6 is(a) ring C6, which is:(i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S;(ii) a 4- to 6-membered saturated heterocycloalkyl containing one heteroatom selected from the group consisting of N, O and S;(iii) a 6-to 10-membered fused or bridged heterobicyclic system containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S; wherein said 6-to 10-membered heterobicyclic system is:(a) fully saturated or(b) contains 1 aromatic ring and one partially unsaturated ring; or(iv) a C3-6 cycloalkyl;wherein ring C$ is unsubstituted or substituted by 1 to 2 R6a substituents independently selected from the group consisting of halo, cyano, Ci-3 alkyl, Ci-3 fluoroalkyl, Ci-3 alkoxy, orR6ac;wherein R6ac is (CH2)y-Cac;Cacis(I) C3-6 monocyclic cycloalkyl;(II) a 3- to 6-membered monocyclic heterocycloalkyl, wherein the 3- to 6membered monocyclic heterocycloalkyl is saturated, and contains 1 to 2 heteroatoms independently selected from the group consisting of N, 0, and S; or(III) a 5- to 6-membered monocyclic heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S;wherein Cac is unsubstituted or substituted by 1 to 2 substituents selected from halo, amino, cyano, oxo, Cl-12 alkyl, Cl-3 fluoroalkyl, Cl-3 alkylamino, Ci-3 dialkylamino, Ci-3 alkoxy, Ci-3 alkoxy(Ci-3) alkyl,(b) Cl-6 alkyl;(c) Cl-3 hydroxy alkyl;(d) C1-3 haloalkyl; or(e) cyano;R?, R&, and Rl 1 are independently H or halo;R10 is halo; andR16a and R16b are independently H, fluoro, Ci-3 alkyl or Ci-3 fluoroalkyl;or, alternatively, Riba and R16b? together with the carbon atom to which they are attached, form a C3-6 cycloalkyl; andy is 0 or 1.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein Rl and R2, together with the carbon atoms to which they are attached, form the ring C^.

17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, whereinandwherein p is 0, 1, or 2.

18. The compound of claim 15 or a pharmaceutically acceptable salt thereof, whereinY2 is N.

19. The compound of claim 15 or a pharmaceutically acceptable salt thereof, whereinY2 is C(H).

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein21. The compound of claim 15 or a pharmaceutically acceptable salt thereof, whereinR6 is unsubstituted or substituted pyrazolyl, pyridyl, or tetrahydrofuryl.

22. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein23. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (VII)wherein:ring Cz is a cyclopentenyl, cyclohexenyl, dihydrofuran, or dihydropyran ring;each RZ is independently selected from the group consisting of Cl-3 alkyl, Cl-3 fluoroalkyl, and halo;ring C6 is(i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S;(ii) a -5 to 6-membered saturated mono- or bicyclic heterocycloalkyl containing one 0 heteroatom; or(iii) a C3-7 cycloalkyl;each R6a is independently selected from the group consisting of halo, Ci-3 alkyl, cyano, Ci-3 alkoxy, and C3-6 cycloalkyl: oreach RA is independently fluoro or C1-C3 alkyl;R?, R&, and Rl 1 are independently H or halo;R10 is halo; methyl or trifluoromethyl;pis 0, 1, or2;r is 0, 1, or 2; andt is 0, 1, or 2.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein25. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein26. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein27.    The compound of claim 1 or a pharmaceutically acceptable salt thereof, whereinthe compound is of Formula (VIII)wherein:ring Cz is a cyclopentene, cyclohexene dihydrofuran, or dihydropyran ring;each RZ is independently selected from the group consisting of C1-3 alkyl, Ci-3 fluoroalkyl, and halo;Y4 is CH2 or O;ring C6 is(i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, O and S;(ii) a -5 to 6-membered saturated heterocycloalkyl containing one O heteroatom; or (iii) a C3-7 cycloalkyl;each R6a is independently selected from the group consisting of halo, Cl-3 alkyl, cyano, Cl-3alkoxy, and C3-6 cycloalkyl; oreach RA is independently fluoro or C1-C3 alkyl;R?, R&, and Rl 1 are independently H or halo;R10 is halo; methyl or trifluoromethyl;p is 0, 1, or 2;q is 1 or 2;r is 0, 1, or 2; andt is 0. 1, or 2.

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, whereinthe compound is of Formula (VI)wherein:Y2 is C(H) orN;Y4 is C(H) or O;each RZ is independently selected from the group consisting of C1-3 alkyl, Ci-3 fluoroalkyl, andhalo;R6 is:(a) ring C6, wherein ring C6 is:(i) a 5- to 6-membered monocyclic heteroaryl containing 1 to 2 heteroatoms independently selected from the group consisting of N, 0 and S;(ii) a -5 to 6-membered saturated heterocycloalkyl containing one heteroatom selected from the group consisting of N, 0 and S; or(iii) a C3-7 cycloalkyl;wherein ring C6 is unsubstituted or substituted by 1 to 2 R6a substituents independently selected from the group consisting of halo, Ci-3 alkyl, cyano, Ci-3 alkoxy, or C3-6 cycloalkyl; or(b) Ci_6 alkyl;R.A is fluoro or Ci-3 alkyl;R?, R&, and Rl 1 are independently H or halo;R10 is halo; andp is 0, 1, or 2;q is 1 or 2;r is 0, 1, or 2; ands is 0 or 1.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein31.    The compound of claim 30 or a pharmaceutically acceptable salt thereof, whereinR6 is unsubstituted or substituted pyrazolyl. pyridyl, or tetrahydrofuryl.

33. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein34. The compound of claim 1 or a pharmaceutically acceptable salt thereof, whereinthe compound is of Formula (IX)wherein:Rl and R2 are independently Cl-3 alkyl, or, alternatively, Rl and R2, together with the carbon atoms to which they are attached, form a ring CZ;wherein ring CZ is:(i) a non-aromatic. partially unsaturated 5- to 6-membered cycloalkyl; or(ii) a 5- to 6-membered heterocycloalkyl, wherein said 5- to 6-membered heterocycloalkyl is non-aromatic and partially unsaturated and contains one heteroatom selected from the group consisting of N, O and S;wherein ring CZ is unsubstituted or substituted by 1 to 2 RZ substituents independently-selected from the group consisting of C]-3 alkyl, C]-3 fluoroalkyl, and halo;R5 is selected from hydrogen, methyl, -SO2N(CH3)2, -SO2C1-10 alkyl, -C(=0)-Ci-io alkyl, -C(=O)-C3-8Cycloalkyl, -C(=O)-aryl, -C(=O)-heterocyclyl, -CH2-heteroary l, -C(=O)heteroaryl, -C(=O)-C(CH3)2-heteroaryl, fluoro and =0;wherein the -C(=O)-C3-8cycloalkyl of R5 is unsubstituted or substituted with 1 or 2 substituents independently selected at each occurrence from a -C1-2 alkyl unsubstituted or substituted with one or two fluoro atoms, a heteroaryl, -NH-C(=0)-0-Ci-io alkyl, -OCH3, -CH2CH2OCH3, and -SCH3;wherein the -SO2C1-10 alkyl or -C(=0)-Ci-io alkyl of R5 is unsubstituted or substituted with -OC1-3 alkyl, cyclopentanyl, isopropenyl, or one, two or three fluoro;wherein the -C(=O)-aryl, -C(=O)-heterocyclyl, -CH2-heteroaryl, -C(=O)heteroaryl, or -C(=O)-C(CH3)2-heteroaryl of R5 is unsubstituted or substituted with 1, 2 or 3 substituents independently selected at each occurrence from a -C1-10 alkyl, -OC1-10 alkyl, -C(=0)-0-Ci-io alkyl, a -Cs-scycloalkyL methylbenzyl, -CFs, fluoro, and =0;R16a and R16b are independently H, fluoro, Ci-3 alkyl or Ci-3 fluoroalky l;or, alternatively, R16a and R16b, together with the carbon atom to which they are attached, form a C3-6 cycloalkyl;R?. R8, and Rl 1 are independently H or halo; andR10 is halo; methyl or trifluoromethyl.

35. The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of Example Nos. 1-1 - 1-259, 2-1 - 2-235, 4-1 -4-30, 5-1 - 5-2, 6-1 - 6-9, and 7-1 - 7-5.

36. A pharmaceutical composition comprising an effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1- 35, and a pharmaceutically acceptable carrier.

37. The pharmaceutical composition of claim 36, wherein the pharmaceutical composition is adapted for oral, injectable, intramuscular, subcutaneous, intravenous, or intraperitoneal administration.

38. The pharmaceutical composition of claim 36 or 37, wherein the pharmaceutical composition is adapted for oral administration.

39. A method for the activation of TREM2 receptor in a subject which comprisesadministering to the subject an effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-35, or pharmaceutical composition of any one of claims 36-38.

40. A method for the treatment or prevention of a condition associated with a loss offunction of human TREM2 in a subject, comprising administering to the subject an effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-35, or pharmaceutical composition of any one of claims 36-38.

41. A method for the treatment or prevention of a neurodegenerative disorder in asubject, comprising administering to the subject an effective amount of the compound or s pharmaceutically acceptable salt of any one of claims 1-35, or pharmaceutical composition of any one of claims 36-38.

42. The method of claim 41, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease, Parkinson's disease, frontotemporal dementia, demyelination disorder, multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis (ALS), tauopathy disease, Nasu-Hakola disease, or adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

43. The method of claim 41 or 42, wherein the neurodegenerative disorder is Alzheimer’s Disease.

44. The method of any one of claims 39-43, wherein the subject is human.

45. The method of any one of claims 39-43, further comprising the step ofadministering a tau targeting therapy or an amyloid-P targeting therapy46. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the treatment or prevention of a neurodegenerative disorder in a subject.

47. The compound of any of claims 1-35, or a pharmaceutically acceptable salt thereof, for use in therapy.