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

Abstract

To provide compounds useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 ("TREM2").SOLUTION: The present invention provides compounds of Formula (I). This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a neurodegenerative disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 019,768, filed May 4, 2020, which is incorporated herein by reference in its entirety.

[0002] The present disclosure provides compounds useful for activating triggering receptor expressed on myeloid cells 2 ("TREM2"). The present disclosure also provides pharmaceutical compositions containing the compounds, uses of the compounds, and compositions for treating, for example, neurodegenerative disorders. Additionally, the present disclosure provides intermediates useful for synthesizing compounds of Formula I. [Background technology]

[0003] Microglia are resident innate immune cells in the brain and are critical for maintaining homeostasis in the central nervous system (Hickman et al. 2018, Li and Barres 2018). These resident macrophages express various receptors that enable them to sense changes in their microenvironment and modify their phenotype to mediate responses to invading pathogens, proteotoxic stress, cellular injury, and other infarctions that can occur in health and disease (ibid.). Microglia reside in the parenchyma of the brain and spinal cord, where they interact with neuronal cell bodies (Cserep et al. 2019), neural processes (Paolicelli et al. 2011, Ikegami et al. 2019), and other types of glial cells (Domingues et al. 2016, Liddelow et al. 2017, Shinozaki et al. 2017), playing a role in numerous physiological processes. Microglia, with their ability to rapidly proliferate in response to stimuli, exhibit characteristic myeloid cell functions such as phagocytosis, cytokine / chemokine release, antigen presentation, and migration (Colonna and Butovsky 2017). More unique functions of microglia include their ability to sever synapses from neurons and directly communicate with highly arborized cellular processes that survey the area surrounding the neuronal cell body (Hong et al. 2016; Sellgren et al. 2019).

[0004] The plasticity of microglia and its diverse states, as described through single-cell RNASeq profiling, is thought to arise from the integration of signaling from a diverse array of cell surface receptors (Hickman et al. 2013). Collectively known as the microglial "sensome," these receptors are involved in transmitting activating or inhibiting intracellular signaling and include protein families such as sialic acid-binding immunoglobulin-type lectins ("SIGLECs"), Toll-like receptors ("TLRs"), Fc receptors, nucleotide-binding oligomerization domain ("NOD"), and purinergic G protein-coupled receptors (Doens and Fernandez 2014; Madry and Attwell (2015), Hickman and El Khoury (2019). Like other cells of the myeloid lineage, the composition of the microglial sensome is dynamically regulated and acts to recognize molecular patterns that direct phenotypic responses to homeostatic changes in the central nervous system (CNS). Ibid. One receptor selectively expressed by brain microglia is TREM2, which consists of a single-pass transmembrane domain, an extracellular stalk region, and an extracellular immunoglobulin variable domain (IgV)-like domain involved in ligand interaction. Kleinberger et al. (2014). Because TREM2 lacks an intracellular signaling mediator domain, biochemical analysis has shown that its interaction with the adaptor proteins DAP10 and DAP12 mediates downstream signaling following ligand recognition. Peng et al. (2010), Jay et al. (2017). In particular, TREM2 / DA The P12 complex acts as a signaling unit that can be characterized as a promoter of activation of microglial phenotypes in addition to peripheral macrophages and osteoclasts. Otero et al. 2012, Kobayashi et al. 2016, Jaitin In the CNS, TREM2-mediated signaling has been studied in the context of ligands such as phospholipids, cell debris, apolipoproteins, and myelin (Wang et al. 2015, Kober and Brett 2017, Shirotani et al. 2019). A central observation in mice lacking functional TREM2 expression or expressing mutant forms of the receptor is a blunted microglial response to insults such as oligodendrocyte demyelination, stroke-induced tissue damage in the brain, and proteotoxic inclusions in vivo (Cantoni et al. 2015, Wu et al.2017.

[0005] Coding variants at the TREM2 locus have been associated with late-onset Alzheimer's disease ("LOAD") in human genome-wide association studies, linking loss of receptor function with increased disease risk (Jonsson et al. 2013, Sims et al. 2017). Genetic variations in other genes selectively expressed by microglia in the CNS, such as CD33, PLCg2, and MS4A4A / 6A, reached genome-wide significance for their association with LOAD risk (Hollingworth et al. 2011, Sims et al. 2017, Deming et al. 2017). al. 2019. Together, these genetic findings are linked with putative biochemical circuits that highlight the importance of microglial innate immune function in LOAD. Additionally, increased or elevated levels of the soluble form of TREM2 ("sTREM2") in the cerebrospinal fluid (CSF) of human subjects are associated with disease progression and the emergence of pathological hallmarks of LOAD, including phosphorylated tau. Suarez-Calvet et al. 2019. Furthermore, natural history and human biology studies have shown that baseline sTREM2 levels in CSF can stratify rates of temporal lobe volume loss and episodic memory decline in longitudinally monitored cohorts. Ewers et al. 2019.

[0006] In addition to human genetic evidence supporting a role for TREM2 in LOAD, homozygous loss-of-function mutations in TREM2 are responsible for an early-onset dementia syndrome known as polycystic lipomembranous dysplasia with sclerosing leukoencephalopathy (PLOSL) or Nasu-Hakola disease (NHD) (Golde et al. 2013, Dardiotis et al. 2017). This progressive neurodegenerative disease typically manifests in the third decade and is pathologically characterized by loss of myelin in the brain accompanied by gliosis, unexplained neuroinflammation, and brain atrophy. The presentation of typical neuropsychiatric symptoms often precedes bone abnormalities such as bone cysts and loss of peripheral bone density (Bianchin et al. 2004, Madry et al. 2007, Bianchin et al. 2010). Considering that osteoclasts of the myeloid lineage are also known to express TREM2, PLOSL-associated symptoms such as wrist and ankle pain, swelling, and fractures indicate that TREM2 may act to regulate bone homeostasis through defined signaling pathways that parallel those of microglia in the CNS (Paloneva et al. 2003, Otero et al. 2012). The link between TREM2 function and PLOSL demonstrates the importance of the receptor in maintaining key physiological aspects of myeloid cell function in the human body.

[0007] In addition to LOAD-associated TREM2 R47H loss-of-function mutation transgenic mice, efforts have been made to model TREM2 biology in mice, prompting the generation of TREM2 knockout ("KO") mice (Ulland et al. 2017, Kang et al. 2018). While it is not possible to reproduce the neurological symptoms of PLOSL, TREM2 KO mice exhibit abnormalities in bone ultrastructure (Otero et al. 2012). TREM2 KO or mutant mice have been shown to be more efficient than the 5XFAD amyloidogenic mutant strain. When crossed with a familial Alzheimer's disease transgenic mouse background, striking phenotypes have been observed (Ulrich et al. 2017). These in vivo phenotypes of TREM2 loss of function in the CNS include elevated plaque burden and reduced levels of the secreted microglial factors SPP1 and osteopontin, which are characteristic of the microglial response to amyloid pathology (Ulland et al. 2017). Other rodent studies have demonstrated that loss of TREM2 leads to reduced microglial clustering around plaques and the appearance of less compact plaque morphology in a familial AD amyloid model (Parhizkar et al. 2019). Regarding the tau protein pathology observed in LOAD, a familial tauopathy model in mice showed enhanced spread of pathological human tau aggregates from the injection point into the mouse brain in TREM2 KO mice (Leyns et al. 2019). Furthermore, single-cell RNA-Seq studies using TREM2 KO mice in aging scenarios, 5XFAD familial Alzheimer's disease model mice, and amyotrophic lateral sclerosis SOD1 mutant mouse backgrounds indicate that TREM2 receptor function is critical for a conserved set of phenotypic transformations within microglial populations in response to CNS pathology. et al.2017.

[0008] In a rodent model with elevated TREM2 expression levels, cerebral amyloid pathology in 5XFAD transgenic mice showed reduced plaque volume and altered morphology (Lee et al. 2018). Changes in immunohistological markers associated with cerebral amyloid pathology were also accompanied by the presence of attenuated dystrophic neurites when TREM2 was overexpressed (Ibid.). Therefore, pharmacological activation of TREM2 is a target for treating or preventing neurological, neurodegenerative, and other diseases. Despite numerous attempts to modify disease progression by targeting the pathological hallmarks of LOAD via anti-amyloid and anti-tau therapeutics, TREM2 activators are needed, for example, to address neuroimmune aspects related to the genetics of LOAD. Such TREM2 activators may be suitable for use as therapeutic agents, given the significant societal burden that continues unabated from diseases such as Alzheimer's disease. Summary of the Invention

[0009] First, provided herein is a compound of formula I [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: X 1 is (1) CH or N and b is a single bond, or (2) C and b are a double bond; X 2 is CH2, CHF, CF2, O, or NH; Optionally, R 5 But it doesn't exist, X 2 CR 6 The groups form a 5- or 6-membered heteroaryl, the 5-membered heteroaryl containing only one ring atom selected from N, O, and S, and optionally only one further N ring atom, and the 6-membered heteroaryl containing only one or only two N ring atoms. wherein the 5- or 6-membered heteroaryl is selected from the group consisting of halogen, C 1~3 Alkyl or C 1~3optionally substituted with alkoxy; X at each occurrence 3 are independently CH or N; R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~6 is cycloalkyl, R 2 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 3~6 is cycloalkyl, R 3 But H or C 1~3 is alkyl, R 4 But H or C 1~3 is alkyl, R 5 But H or C 1~3 is alkyl, R 6 But C 2~6 Alkyl, C 1~6 Haloalkyl, DiC 1~3 Alkylamino, -C(=O)O(C 1~6 alkyl), C 3~6 Cycloalkyl, C 3~6 heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; (1)C 3~6 Cycloalkyl or C 3~6 heterocycloalkyl is optionally substituted with C=O; (2) The phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is independently selected from the group consisting of halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -(C 1~3 alkyl)O(C 1~3 alkyl), -(C 1~3 alkyl)NH2, -(C 1~3 alkyl)NH(C 1~3 alkyl), -(C 1~3 alkyl)N[(C 1~3 Alkyl)(C 1~3alkyl)], -CN, C 2~4 Alkenyl, C 3~6 Cycloalkyl, phenyl, and C 3~6 optionally substituted with 1 to 3 substituents selected from heterocycloalkyl; Subsection (2) C 1~6 Alkyl and C 1~6 haloalkyl is optionally substituted with OH; Subsection (2) C 3~6 Heterocycloalkyl is halogen, C 1~3 Alkyl, and -C(=O)O(C 1~6 alkyl), R 7 But C 5~6 Cycloalkyl, C 5~8 Spiroalkyl, C 5~8 tricycloalkyl, phenyl, or 6-membered heteroaryl; R 7 Furthermore, independently, halogen, C 1~3 Alkyl, and C 1~3 optionally substituted with 1 to 4 substituents selected from haloalkyl; n is 0 or 1, provided that X 1 is N and n is 0, then X 2 is not NH or O, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0010] Second, provided herein is a pharmaceutical composition comprising a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, and a pharmaceutically acceptable excipient.

[0011] Third, provided herein is a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition as described above, for use in treating or preventing a condition associated with loss of function of human TREM2.

[0012] Fourth, provided herein is a compound of Formula I or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition described above, for use in the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0013] Reference will now be made in detail to the embodiments of the present disclosure. While particular embodiments of the present disclosure will be described, it should be understood that they are not intended to limit the embodiments of the present disclosure to these described embodiments. On the contrary, reference to embodiments of the present disclosure is intended to cover alternatives, modifications, and equivalents, which may be included within the spirit and scope of the embodiments of the present disclosure as defined by the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0014] Provided herein as embodiment 1 is a compound of formula I [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: X 1 is (1) CH or N and b is a single bond, or (2) C and b are a double bond; X 2 is CH2, CHF, CF2, O, or NH; Optionally, R 5 But it doesn't exist, X 2 CR 6 The groups form a 5- or 6-membered heteroaryl, the 5-membered heteroaryl containing only one ring atom selected from N, O, and S, and optionally only one further N ring atom, and the 6-membered heteroaryl containing only one or two N ring atoms, and the 5- or 6-membered heteroaryl containing only one or two N ring atoms, and 1~3 Alkyl or C 1~3 optionally substituted with alkoxy; X at each occurrence 3are independently CH or N; R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~6 is cycloalkyl, R 2 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 3~6 is cycloalkyl, R 3 But H or C 1~3 is alkyl, R 4 But H or C 1~3 is alkyl, R 5 But H or C 1~3 is alkyl, R 6 But C 2~6 Alkyl, C 1~6 Haloalkyl, DiC 1~3 Alkylamino, -C(=O)O(C 1~6 alkyl), C 3~6 Cycloalkyl, C 3~6 heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; (1)C 3~6 Cycloalkyl or C 3~6 heterocycloalkyl is optionally substituted with C=O; (2) The phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is independently selected from the group consisting of halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -(C 1~3 alkyl)O(C 1~3 alkyl), -(C 1~3 alkyl)NH2, -(C 1~3 alkyl)NH(C 1~3 alkyl), -(C 1~3 alkyl)N[(C 1~3 Alkyl)(C 1~3 alkyl)], -CN, C 2~4 Alkenyl, C 3~6Cycloalkyl, phenyl, and C 3~6 optionally substituted with 1 to 3 substituents selected from heterocycloalkyl; Subsection (2) C 1~6 Alkyl and C 1~6 haloalkyl is optionally substituted with OH; Subsection (2) C 3~6 Heterocycloalkyl is halogen, C 1~3 Alkyl, and -C(=O)O(C 1~6 alkyl), R 7 But C 5~6 Cycloalkyl, C 5~8 Spiroalkyl, C 5~8 tricycloalkyl, phenyl, or 6-membered heteroaryl; R 7 Furthermore, independently, halogen, C 1~3 Alkyl, and C 1~3 optionally substituted with 1 to 4 substituents selected from haloalkyl; n is 0 or 1, provided that X 1 is N and n is 0, then X 2 is not NH or O, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0015] Provided herein as embodiment 2 is a compound comprising: 5-(5-chloro-3-methyl-2-pyridinyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-methyl-3-phenyl-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, or The compound of embodiment 1, which is not 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(1-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0016] Provided herein as embodiment 3 is a compound of embodiment 1 or embodiment 2, wherein the compound is a compound of formula II, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0017] Provided herein as embodiment 4 is a compound of embodiment 1 or embodiment 2, wherein the compound is a compound of formula IIA, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0018] Provided herein as embodiment 5 is a compound according to embodiment 1 or embodiment 2, wherein the compound is a compound of formula IIB, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0019] Provided herein as embodiment 6 is a compound of embodiment 1 or embodiment 2, wherein the compound is a compound of formula IIC, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0020] Provided herein as embodiment 7 is a compound according to embodiment 1 or embodiment 2, wherein the compound is a compound of formula IID, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. [ka]

[0021] Provided herein as embodiment 8 is a compound according to embodiment 1 or embodiment 2, wherein the compound is a compound of formula IIE, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer. [ka]

[0022] Provided herein as embodiment 9 is X 1 is CH; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0023] Provided herein as embodiment 10 is X 1 is N, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0024] Provided herein as embodiment 11 is X 2 is CH2, CF2, or O; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0025] Provided herein as embodiment 12 is X 2is O, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0026] Provided herein as embodiment 13 is a compound of formula I [ka] The part is, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0027] Provided herein as embodiment 14 is a compound of formula I [ka] The part is, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0028] Provided herein as embodiment 15 is X 3 is CH; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0029] Provided herein as embodiment 16 is X 3 is N, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0030] Provided herein as embodiment 17 is R1 is methyl, ethyl, propyl, —CH2CF3, cyclopropyl, or cyclohexyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0031] Provided herein as embodiment 18 is R 1 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0032] Provided herein as embodiment 19 is R 2 is H, methyl, trifluoromethyl, or cyclopropyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0033] Provided herein as embodiment 20 is R 2 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0034] Provided herein as embodiment 21 is R 3 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0035] Provided herein as embodiment 22 is R 3 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0036] Provided herein as embodiment 23 is a method for treating a pulmonary arthritis (PA) comprising: R 4 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0037] Provided herein as embodiment 24 is R 4 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0038] Provided herein as embodiment 25 is R 4 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0039] Provided herein as embodiment 26 is R 5 is H or methyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0040] Provided herein as embodiment 27 is R 5 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0041] Provided herein as embodiment 28 is R 6is difluoromethyl, trifluoromethyl, —CHCF, dimethylamino, —C(═O)OCHCH, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxetanyl, optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted 1,3-oxazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted 1,3,4-oxadiazolyl, optionally substituted thiophenyl, optionally substituted thiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, or optionally substituted pyrimidinyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0042] In some embodiments, R 6 is difluoromethyl. In some embodiments, , R 6 is trifluoromethyl. In some embodiments, R 6 is —CH 2 CF 3 . In some embodiments, R 6 is dimethylamino. In some embodiments, R 6 is —C(═O)OCH2CH3. In some embodiments, R 6 is optionally substituted cyclopropyl. In some embodiments, R 6 is an optionally substituted cyclobutyl. In some embodiments, R 6 is an optionally substituted oxetanyl. In some embodiments, R 6 is an optionally substituted azetidinyl. In some embodiments, R 6 is optionally substituted tetrahydrofuranyl. In some embodiments, R 6 is an optionally substituted pyrrolidinyl. In some embodiments, R 6 is optionally substituted phenyl. In some embodiments, R 6is an optionally substituted pyrazolyl. In some embodiments, R 6 is an optionally substituted imidazolyl. In some embodiments, R 6 is an optionally substituted 1,3-oxazolyl. In some embodiments, R 6 is an optionally substituted 1,2,4-oxadiazolyl. In some embodiments, R 6 is an optionally substituted 1,3,4-oxadiazolyl. In some embodiments, R 6 is an optionally substituted thiophenyl. In some embodiments, R 6 is an optionally substituted thiazolyl. In some embodiments, R 6 is an optionally substituted pyridinyl. In some embodiments, R 6 is an optionally substituted pyridazinyl. In some embodiments, R 6 is an optionally substituted pyrimidinyl.

[0043] Provided herein as embodiment 29 is R 6 difluoromethyl, trifluoromethyl, -CH2CF3, dimethylamino, -C(=O)OCH2CH3, cyclopropyl, cyclobutyl, oxetan-2-yl, azetidin-1-yl, tetrahydrofuran-3-yl, [ka] phenyl, [ka] [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0044] Provided herein as embodiment 30 is R 6difluoromethyl, trifluoromethyl, -CH2CF3, dimethylamino, -C(=O)OCH2CH3, cyclopropyl, cyclobutyl, oxetan-2-yl, azetidin-1-yl, tetrahydrofuran-3-yl, [ka] phenyl, [ka] [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0045] Provided herein as embodiment 31 is R 6 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0046] Provided herein as embodiment 32 is R 7 is arbitrarily substituted C 5~6 cycloalkyl, optionally substituted phenyl, or optionally substituted 6-membered heteroaryl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0047] Provided herein as embodiment 33 is R 7 is arbitrarily substituted C 5~6cycloalkyl, optionally substituted phenyl, or optionally substituted pyridinyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0048] Provided herein as embodiment 34 is R 7 is optionally substituted phenyl; or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0049] Provided herein as embodiment 35 is R 7 is optionally substituted pyridinyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0050] Provided herein as embodiment 36 is R 7 is arbitrarily substituted C 5~6 cycloalkyl; or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or said tautomer.

[0051] Provided herein as embodiment 37 is R 7 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0052] Provided herein as embodiment 38 is R 7 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0053] Provided herein as embodiment 39 is R 7 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0054] Provided herein as embodiment 40 is The compound according to any one of embodiments 1 to 12 and 15 to 39, wherein n is 0, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

[0055] Provided herein as embodiment 41 is The compound of any one of embodiments 1 to 39, wherein n is 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

[0056] Provided herein as embodiment 42 is a compound comprising: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone, 5-(4-chlorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chlorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-3-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2,4-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,3,4-trifluorophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,4,5-trifluorophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2,5-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2-fluoro-4-methylphenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2,3-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(5-chloro-3-fluoro-2-pyridinyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone, 2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(6-trifluoromethyl)-3-pyridinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-cyclohexyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-(2,2,2-trifluoroethyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, ±5-(5-chloro-3-fluoro-2-pyridinyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido-[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,5R)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,5R)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl) pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-cyclopropyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(2-cyclobutyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2R)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2S)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2S)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2R)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((3S)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((3S)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((3R)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((3R)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidine-4(3H) -on, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-pyridazinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2,2,2-trifluoroethyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(thiophen-3-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-thiophenyl)-4-morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2-methyl-4-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(2-(1,3-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(2-(5-fluoro-3-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(2-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6S)-2-methyl-6-(3-thiophenyl)-4-morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6R)-2-methyl-6-(3-thiophenyl)-4-morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6S)-2-methyl-6-(3-thiophenyl)-4-morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6R)-2-methyl-6-(3-thiophenyl)-4-morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-methyl-1,3-thiazol-2-yl)-4-morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2,6-dimethyl-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2,6-dimethyl-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidine-4( 3H)-On, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-chlorophenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-chlorophenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-chloro-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-chloro-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 4-(4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)-2-morpholinyl)benzonitrile, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-(trifluoromethyl)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-(trifluoromethyl)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(5-phenyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-(2,2,2-trifluoroethoxy)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-(2,2,2-trifluoroethoxy)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2- (3-(trifluoromethoxy)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-(trifluoromethoxy)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(1,3-oxazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(5-oxo-3-pyrrolidinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(3-(dimethylamino)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 7-(3-(1-azetidinyl)-1-piperidinyl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(4-pyridinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(4-pyridinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 7-(8-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyridin Mydin-4(3H)-one, 5'-(4-chloro-2-fluorophenyl)-4-methoxy-2',3'-dimethyl-7,8-dihydro-5H-[6,7'-bipyrido[4,3-d]pyrimidin]-4'(3'H)-one, 5-(4-chloro-2-fluorophenyl)-7-((3R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((3S)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(trifluoromethyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(3-(difluoromethyl)-1-pyrrolidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(3-pyridinyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(3-oxetanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoro-2-hydroxyethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,3-difluoro-2-propanyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 2-methyl-2-propanyl 3-(4-((2S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)-2-morpholinyl)-1H-pyrazol-1-yl)-1-azetidinecarboxylate, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,2-difluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-ethenyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azetidinyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2,4-difluorophenyl)-3-ethyl-2-methyl-7-((2S)-2- (2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,4-difluorophenyl)-3-ethyl-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(5-chloro-3-fluoro-2-pyridinyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R)-2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(difluoromethyl)-4-morpholinyl)-2-methyl-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-phenyl-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-cyclohexyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-cyclopentyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, (2R,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and ethyl (2S,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate, (2S,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and (2R,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(6-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,4R)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,4S)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, or 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

[0057] Provided herein as embodiment 43 is an embodiment wherein the compound is a compound of Table A. The compound according to embodiment 1 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer.

[0058] Provided herein as embodiment 44 is a compound comprising: 5-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2,4-difluorophenyl)-7-(2-(2-methoxypyridin-4-yl)morpholino)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)morpholino)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)morpholino)-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, or The compound of embodiment 1 is not 7-(2-(2-methoxypyridin-4-yl)morpholinyl)-2,3-dimethyl-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer.

[0059] Provided herein as embodiment 45 is a compound of Formula II, [ka] During the ceremony, n is 1, X 1 is CH or N, X 2 is O, X 3 is N, R 1 and R 2 But both are methyl, R 3 , R 4 , and R 5 are H, respectively, R 6 but, [ka] and R 7 But C 5~6 Cycloalkyl, C 5~8 Spiroalkyl, C 5~8tricycloalkyl, phenyl, or 6-membered heteroaryl; R 7 Furthermore, independently, halogen, C 1~3 Alkyl, and C 1~3 is optionally substituted with 1 to 4 substituents selected from haloalkyl, However, R 7 but [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, provided that:

[0060] Provided herein as embodiment 46 is a compound of Formula II, [ka] During the ceremony, n is 1, X 1 is CH or N, X 2 is O, X 3 is N, R 1 and R 2 But both are methyl, R 3 , R 4 , and R 5 are H, respectively, R 6 but, [ka] and R 7 but, [ka] or a tautomer thereof, wherein Pharmaceutically acceptable salts of the variants.

[0061] Provided herein as embodiment 47 is a compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0062] Provided herein as embodiment 48 is a compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0063] Provided herein as embodiment 49 is a compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0064] Provided herein as embodiment 50 is a compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0065] Provided herein as embodiment 51 is a compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0066] Provided herein as embodiment 52 is a compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0067] Provided herein as embodiment 53 is a compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0068] Provided herein as embodiment 54 is a compound comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0069] Exemplary compounds of the invention are set forth below in Table A. In some embodiments, the compound of Formula I is a compound set forth in Table A. In some embodiments, the invention provides a compound depicted in Table A or a pharmaceutically acceptable salt thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 [Table 1-44] [Table 1-45] [Table 1-46] [Table 1-47] [Table 1-48] [Table 1-49] [Table 1-50]

[0070] The foregoing merely summarizes certain aspects of the disclosure and is not intended, nor should it be construed, as limiting the disclosure in any way.

[0071] Formulation and route of administration In the uses described herein, although it may be possible to administer the compounds disclosed herein alone, the compounds typically administered will be present as an active ingredient in a pharmaceutical composition. Thus, in one embodiment, a pharmaceutical composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants, etc., and optionally other active ingredients, is provided herein. For example, see Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vol. 1-3), Liberman et al., Eds., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Ed.), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The See Science and Technology of Dosage Forms (Drug Discovery), first edition, edited by G.D. Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of any of the compounds disclosed herein. Contains compounds.

[0072] The compounds disclosed herein can be administered by any suitable route in the form of a pharmaceutical composition adapted for such a route, in a dose effective for the intended treatment. The compounds and compositions presented herein can be administered orally, mucosally, topically, transdermally, rectally, pulmonary, parenterally, intranasally, intravascularly, intravenously, intraarterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally, or by infusion techniques, for example, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.

[0073] The pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, mini-tablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drops, infusion, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension. Pharmaceutical compositions are typically made in the form of a dosage unit containing a particular amount of the active ingredient.

[0074] Provided herein as embodiment 55 is a pharmaceutical composition comprising a compound according to any one of embodiments 1 to 54, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, and a pharmaceutically acceptable excipient.

[0075] Provided herein as embodiment 56 is a compound of any one of embodiments 1 to 54, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition of embodiment 55, for use as a medicament.

[0076] Pharmaceutically acceptable compositions According to some embodiments, the present disclosure provides a composition comprising a compound of the present disclosure or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present disclosure is an amount effective to measurably activate TREM2 protein or a variant thereof in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present disclosure is an amount effective to measurably activate TREM2 protein or a variant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present disclosure is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present disclosure is formulated for oral administration to a patient.

[0077] The compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present disclosure may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques well known in the art. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media.

[0078] For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are particularly well known in the art. In the case of oxyethylated versions, natural pharmaceutically acceptable oils such as olive oil or castor oil are useful for preparing injections.These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions.Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0079] The pharmaceutically acceptable composition of the present disclosure can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If necessary, certain sweeteners, flavorings, or colorings can also be added.

[0080] Alternatively, the pharmaceutically acceptable compositions of the present disclosure can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0081] The pharmaceutically acceptable compositions of the present disclosure may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0082] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0083] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0084] For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated into an ointment such as petrolatum.

[0085] Pharmaceutically acceptable compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared in solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents. It can be prepared as follows:

[0086] Most preferably, the pharmaceutically acceptable compositions of the present disclosure are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present disclosure are administered with food.

[0087] The amount of the compounds of the present disclosure that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the provided compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0088] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated. The amount of a compound of the present disclosure in a composition will also depend on the particular compound in the composition.

[0089] How to use As discussed herein (see the section entitled "Definitions"), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing, or solvates of any of the foregoing. Accordingly, the scope of methods and uses provided in this disclosure should be understood to encompass methods and uses employing all such forms.

[0090] In addition to being useful for human treatment, the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, etc. For example, animals including horses, dogs, and cats may be treated with the compounds provided herein.

[0091] Without intending to be bound by any particular theory, it is noted that TREM2 is involved in several myeloid cell processes, including phagocytosis, proliferation, survival, and regulation of inflammatory cytokine production (Ulrich and Holtzman 2016). In recent years, TREM2 has been associated with several diseases. For example, mutations in both TREM2 and DAP12 are associated with Nasu-Hakola disease, an autosomal recessive disorder characterized by bone cysts, muscle wasting, and a demyelinating phenotype (Guerreiro et al. 2013). More recently, variants in the TREM2 gene have been associated with an increased risk of 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 associated with an increased risk of late-onset AD in genome-wide studies, with an overall adjusted odds ratio (for all age groups) of 2.3, second only to the strong genetic association between ApoE and Alzheimer's disease. The R47H mutation resides in the extracellular lg V-set domain of the TREM2 protein and has been shown to affect lipid binding and the uptake of apoptotic cells and Abeta (Wang et al. 2015; Yeh et al. 2016), suggesting a disease-related loss of function. Furthermore, postmortem comparison of AD patient brains with and without the R47H mutation supports the loss of novel microbarrier function in mutation carriers, showing that microglia in R47H carriers have a reduced ability to compact plaques and limit their spread (Yuan et al. 2016). Impaired microgliosis has been reported in animal models of prion disease, multiple sclerosis, and stroke. These findings suggest that TREM2 may play an important role in supporting microgliosis in response to central nervous system pathology or injury (Ulrich and Holtzman 2016). Furthermore, knockdown of TREM2 has been shown to exacerbate a-syn-induced inflammatory responses in vitro and dopaminergic neuron loss in response to AAV-SYN (a model of Parkinson's disease) in vivo, suggesting that impaired microglial TREM2 signaling exacerbates neurodegeneration by regulating the activation state of microglia (Guo et al. 2019). Various animal models also suggest that Toll-like receptor (TLR) signaling is important in the pathogenesis of rheumatoid arthritis (RA) through the sustained expression of proinflammatory cytokines by macrophages. Signaling through TREM2 / DAP12 inhibits TLR responses by reducing MAPK (Erk1 / 2) activation, suggesting that TREM2 activation may act as a negative regulator of TLR-driven RA pathogenesis (Huang and Pope 2009).

[0092] In view of data showing that loss of TREM2 activity affects macrophage and microglial function, the compounds disclosed herein are particularly useful in, for example, the disorders described in the embodiments above and below, as well as in neurodegenerative disorders generally.

[0093] Provided herein as embodiment 57 is a compound according to any one of embodiments 1 to 54, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 55, for use in treating or preventing a condition associated with loss of function of human TREM2.

[0094] Provided herein as embodiment 58 is a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 55, for use in the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0095] Provided herein as embodiment 59 is the use of a compound according to any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or the pharmaceutical composition according to embodiment 55, in the preparation of a medicament for treating or preventing a condition associated with loss of function of human TREM2.

[0096] Provided herein as embodiment 60 is the use of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 55, in the preparation of a medicament for treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0097] Provided herein as embodiment 61 is a method of treating or preventing a condition associated with loss of function of human TREM2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 55.

[0098] Provided herein as embodiment 62 is a method of treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1 to 54 or a tautomer thereof, or 56. A method comprising administering to a subject a pharmaceutically acceptable salt of the compound or the tautomer, or a pharmaceutical composition of embodiment 55.

[0099] In some embodiments, the condition associated with loss of function of human TREM2 is Parkinson's disease. In some embodiments, the condition associated with loss of function of human TREM2 is rheumatoid arthritis. In some embodiments, the condition associated with loss of function of human TREM2 is Alzheimer's disease. In some embodiments, the condition associated with loss of function of human TREM2 is Nasu-Hakola disease. In some embodiments, the condition associated with loss of function of human TREM2 is frontotemporal dementia. In some embodiments, the condition associated with loss of function of human TREM2 is multiple sclerosis. In some embodiments, the condition associated with loss of function of human TREM2 is a prion disease. In some embodiments, the condition associated with loss of function of human TREM2 is stroke.

[0100] CSF1R CSF1R is the cell surface receptor for the cytokine colony-stimulating factor 1 (CSF-1), which until recently was also known as macrophage colony-stimulating factor (M-CSF), and it regulates the survival, proliferation, differentiation, and function of mononuclear phagocytes, including microglia, in the central nervous system. CSF1R consists of a highly glycosylated extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. Binding of CSF-1 to CSF1R leads to the formation of receptor homodimers and subsequent autophosphorylation of several tyrosine residues in the cytoplasmic domain, particularly Syk. In the brain, CSF1R is primarily expressed in microglial cells. Microglia from CSF1R-positive patients have been found to be depleted and exhibit increased apoptosis (Oosterhof et al., 2018).

[0101] The present invention relates to the unexpected discovery that administration of a TREM2 agonist can rescue the loss of microglia in cells harboring a CSF1R mutation. The TREM2 agonist antibody 4D9 dose-dependently increased ATP luminescence (cell number and activity) when the level of M-CSF in the culture medium was reduced to 5 ng / mL (Schlepckow et al., 2014). It has previously been shown that TREM2 agonist AL002c increases ATP luminescence when M-CSF is completely removed from the culture medium (Wang et al., J. Exp. Med.; 2020, 217(9):e20200785). This finding suggests that TREM2 agonism can compensate for the defect in CSF1R signaling caused by reduced concentrations of its ligand. In the 5xFAD mouse Alzheimer's disease model of amyloid pathology, doses of CSF1R inhibitors that nearly completely eliminate microglia in the brains of wild-type animals exhibit surviving microglia clustered around amyloid plaques (Spangenberg et al., J. Exp. Med.; 2020, 217(9):e20200785). et al., Nature Communications 2019). Plaque amyloid has previously been shown to be a ligand for TREM2, and microglial engagement with amyloid has been shown to be dependent on TREM2 (Condello et al., Nat Comm., 2015). The present invention relates to the unexpected discovery that it is activation of TREM2 that rescues microglia in the presence of CSF1R inhibitors, an effect also observed in patients with microglial loss due to CSF1R mutations. This discovery has not previously been taught or suggested in the available art.

[0102] To date, no previous studies have demonstrated that TREM2 agonism can rescue microglial loss in cells where mutations in the CSF1R kinase domain reduce CSF1R activity, rather than the presence of a CSF1R inhibitor or lack of a CSF1R ligand. Furthermore, no previous studies have taught or suggested that reversing microglial loss due to CSF1R mutations via TREM2 agonism could be used to treat diseases or disorders caused by and / or associated with CSF1R mutations.

[0103] Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), previously recognized as hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) or pigmented normochromatic leukodystrophy (POLD), is an autosomal dominant central nervous system disorder that manifests as variable behavioral, cognitive, and motor changes in affected individuals. ALSP is characterized by patchy cerebral white matter abnormalities visible by magnetic resonance imaging. However, the clinical symptoms and MRI changes are not unique to ALSP and are shared with other neurological disorders, including Nasu-Hakola disease (NHD) and Alzheimer's disease, making diagnosis and treatment of ALSP extremely challenging.

[0104] Recent studies have found that ALSP is a Mendelian disorder in which patients carry heterozygous loss-of-function mutations in the kinase domain of CSF1R, suggesting a decrease in signaling levels in the macrophage colony-stimulating factor (M-CSF) / CSF1R axis (Rademakers et al., Nat Genet 2012, Konno In one aspect, the present invention relates to the surprising discovery that activation of the TREM2 pathway can rescue microglial loss and prevent microglial apoptosis in CSF1R+ / - ALSP patients, thereby treating the ALSP condition.

[0105] Provided herein as embodiment 63 is a compound according to any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 55, for use in treating or preventing a condition associated with dysfunction of colony-stimulating factor 1 receptor (CSF1R, also known as macrophage colony-stimulating factor receptor / M-CSFR, or cluster of differentiation 115 / CD115).

[0106] Provided herein as embodiment 64 is a compound according to any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 55, for use in the treatment or prevention of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS).

[0107] Provided herein as embodiment 65 is the use of a compound according to any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 55, in the preparation of a medicament for treating or preventing a condition associated with dysfunction of CSF1R.

[0108] Provided herein as embodiment 66 is the use of a compound of any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition of embodiment 55, in the preparation of a medicament for treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS).

[0109] Provided herein as embodiment 67 is a method of treating or preventing a disease or disorder associated with dysfunction of CSF1R in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of any one of embodiments 1 to 54, or a tautomer thereof. 55. A method for treating a subject comprising administering to a subject a compound, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition of embodiment 54. In some embodiments, the subject is selected for treatment based on a diagnosis comprising the presence of a mutation in the CSF1R gene that affects CSF1R function. In some embodiments, the mutation in the CSF1R gene is a mutation that causes reduced CSF1R activity or abolishes CSF1R activity. In some embodiments, the disease or disorder is caused by a heterozygous CSF1R mutation. In some embodiments, the disease or disorder is caused by a homozygous CSF1R mutation. In some embodiments, the disease or disorder is caused by a splice mutation in the csf1r gene. In some embodiments, the disease or disorder is caused by a missense mutation in the csf1r gene. In some embodiments, the disease or disorder is caused by a mutation in the catalytic kinase domain of CSF1R. In some embodiments, the disease or disorder is caused by a mutation in the immunoglobulin domain of CSF1R. In some embodiments, the disease or disorder is caused by a mutation in the ectodomain of CSF1R. In some embodiments, the disease or disorder is a disease or disorder resulting from altered (e.g., increased, decreased, or abolished) activity of CSF1R. In some embodiments, the disease or disorder is a disease or disorder resulting from decreased or abolished activity of CSF1R. CSF1R-associated activity that is altered in a disease or disorder includes, but is not limited to, decreased or loss of microglial function, increased microglial apoptosis, decreased Src signaling, decreased Syk signaling, decreased microglial proliferation, decreased microglial response to cellular debris, decreased phagocytosis, and decreased cytokine release in response to stimuli. In some embodiments, the disease or disorder is caused by a loss-of-function mutation in CSF1R. In some embodiments, the loss-of-function mutation results in a complete abolition of CSF1R function. In some embodiments, the loss-of-function mutation results in a partial loss of CSF1R function or decreased CSF1R activity.

[0110] Provided herein as embodiment 68 is a method of treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital absence of microglia, or brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1-54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 55. In some embodiments, the method treats or prevents ALSP, which is a term that encompasses and replaces both HDLS and POLD. In some embodiments, the disease or disorder is a homozygous mutation in CSF1R. In some embodiments, the method treats or prevents childhood-onset leukoencephalopathy. In some embodiments, the method treats or prevents a congenital deficiency of microglia. In some embodiments, the method treats or prevents brain abnormalities neurodegeneration and dysostotic osteosclerosis (BANDDOS).

[0111] Provided herein as embodiment 69 is a method of treating or preventing Nasu-Hakola disease, Alzheimer's disease, frontotemporal dementia, multiple sclerosis, Guillain-Barré syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, traumatic brain injury, spinal cord injury, systemic lupus erythematosus, rheumatoid arthritis, prion disease, stroke, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysostosis, Pyle's disease, autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, or metachromatic leukodystrophy in a subject in need thereof, wherein any of the above diseases or disorders is present in a patient exhibiting CSF1R dysfunction or having a mutation in a gene affecting CSF1R function, comprising administering a therapeutically effective amount of any of embodiments 1 to 54. 56. A method of treating a subject comprising administering to a subject a compound according to any one of embodiments 54 or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55.

[0112] ABCD1 The ABCD1 gene provides instructions for producing adrenoleukodystrophy protein (ALDP). ABCD1 (ALDP) maps to Xq28. ABCD1 is a member of the ATP-binding cassette (ABC) transporter superfamily. This superfamily contains membrane proteins that transport a wide range of substrates across extracellular and intracellular membranes, including metabolites, lipids, sterols, and drugs. ALDP is located in the membrane of cellular structures called peroxisomes, which are small intracellular sacs that process many types of molecules. ALDP transports a group of lipids called very long-chain fatty acids (VLCFAs) into peroxisomes, where they are degraded. Because ABCD1 is highly expressed in microglia, microglial dysfunction and its close interaction with other cell types may be actively involved in neurodegenerative processes (Gong et al., Annals of Neurology. 2017;82(5):813-827). Severe microglial loss and damage have been shown to be an early feature in patients with cerebral X-linked ALD (cALD) who harbor ABCD1 mutations (Bergner et al., Glia. 2019;67:1196-1209). ABCD1 deficiency also leads to impaired myeloid cell plasticity, reflected by the incomplete establishment of an anti-inflammatory response, and may therefore contribute to the devastating, rapidly progressive demyelination in cerebral adrenoleukodystrophy (Weinhor et al., BRAIN 2018:141;2329-2342). These findings highlight the role of microglia, monocytes, and macrophages as important therapeutic targets for preventing or halting myelin destruction in patients with X-linked adrenoleukodystrophy.

[0113] The present invention relates to the unexpected discovery that administration of a TREM2 agonist can rescue microglia loss in cells harboring mutations in the ABCD1 gene. It has previously been shown that the TREM2 agonist antibody 4D9 dose-dependently increases ATP luminescence (a measure of cell number and activity) when M-CSF levels in the culture medium are reduced to 5 ng / mL (Schlepckow et al., EMBO Mol Med., 2020), and that the TREM2 agonist AL002c increases ATP luminescence when M-CSF is completely removed from the culture medium (Wang et al., J. Exp. Med.; 2020, 217(9):e20200785). This finding suggests that TREM2 agonism can compensate for the lack of ABCD1 function, which leads to sustained microglial activation, proliferation, chemotaxis, and maintenance of an anti-inflammatory environment, as well as reduced astrocyte proliferation caused by reduced ABCD1 and VLCFA accumulation. The present invention relates to the unexpected discovery that activation of TREM2 can rescue microglia in the presence of ABCD1 mutations and increased VLCFAs, and that this effect can also be observed in patients with microglial loss due to ABCD1 mutations, a discovery not previously taught or suggested in the available art.

[0114] To date, no previous studies have demonstrated that TREM2 agonism can rescue microglial loss in cells with ABCD1 mutations and increased VLCFAs. No previous studies have taught or suggested that reversing microglial loss due to ABCD1 mutations via TREM2 agonism could be used to treat diseases or disorders caused by and / or associated with ABCD1 mutations.

[0115] Provided herein as embodiment 70 is a method for treating or preventing a condition associated with dysfunction of ATP-binding cassette transporter 1 (ABCD1), comprising administering to a subject in need thereof an ATP-binding cassette transporter 1 (ABCD1) in an amount of 1000 mg / kg / day. 54. A compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of the compound or tautomer; or a pharmaceutical composition according to embodiment 55.

[0116] Provided herein as embodiment 71 is a compound or a tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 55, for use in the treatment or prevention of X-linked adrenoleukodystrophy (x-ALD), globoid cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), vanishing white matter disease (VWM), Alexander disease, Fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[0117] Provided herein as embodiment 72 is the use of a compound of any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or the pharmaceutical composition of embodiment 55, in the preparation of a medicament for treating or preventing a condition associated with dysfunction of ABCD1.

[0118] Provided herein as embodiment 73 is the use of a compound or a tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition according to embodiment 55, in the preparation of a medicament for treating or preventing X-linked adrenoleukodystrophy (x-ALD), globoid cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), vanishing white matter disease (VWM), Alexander disease, Fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[0119] Provided herein as embodiment 74 is a method of treating or preventing a disease or disorder associated with dysfunction of ABCD1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or tautomer thereof described in any one of embodiments 1-54, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 55. In some embodiments, the patient is selected for treatment based on a diagnosis including the presence of a mutation in the ABCD1 gene that affects the function of ABCD1. In some embodiments, the mutation in the ABCD1 gene is a mutation that causes reduced ABCD1 activity or abolished ABCD1 activity. In some embodiments, the disease or disorder is caused by a heterozygous ABCD1 mutation. In some embodiments, the disease or disorder is caused by a homozygous ABCD1 mutation. In some embodiments, the disease or disorder is caused by a splice mutation in the ABCD1 gene. In some embodiments, the disease or disorder is caused by a missense mutation in the ABCD1 gene. In some embodiments, the disease or disorder is a disease or disorder resulting from an altered (e.g., increased, decreased, or abolished) activity of ABCD1. In some embodiments, the disease or disorder is a disease or disorder resulting from reduced or abolished activity of ABCD1. ABCD1-related activities that are altered in the disease or disorder include, but are not limited to, peroxisomal import of fatty acids and / or fatty acyl-CoA, and production of adrenoleukodystrophy protein (ALDP). In some embodiments, the disease or disorder is caused by a loss-of-function mutation in ABCD1. In some embodiments, the loss-of-function mutation results in a complete abolition of ABCD1 function. In some embodiments, the loss-of-function mutation results in a complete abolition of ABCD1 function. In some embodiments, the disease or disorder is caused by a homozygous mutation in ABCD1. In some embodiments, the disease or disorder is a neurodegenerative disorder. In some embodiments, the disease or disorder is a neurodegenerative disorder caused by and / or associated with ABCD1 dysfunction. In some embodiments, the disease or disorder is an immune disorder. In some embodiments, the disease or disorder is an immunological disorder caused by and / or associated with ABCD1 dysfunction.

[0120] Provided herein as embodiment 75 is a method of treating or preventing X-linked adrenoleukodystrophy (x-ALD), globoid cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), vanishing white matter disease (VWM), Alexander disease, Fragile X-associated tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or tautomer thereof described in any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 55. In some embodiments, any of the above diseases is present in a patient who exhibits ABCD1 dysfunction or has a mutation in a gene affecting ABCD1 function. In some embodiments, the method treats or prevents X-linked adrenoleukodystrophy (x-ALD). In some embodiments, the x-ALD is cerebral x-linked ALD (cALD). In some embodiments, the method treats or prevents Addison's disease in which the patient is known to have a mutation in one or more ABCD1 genes that affects ABCD1 function. In some embodiments, the method treats or prevents Addison's disease in which the patient has a loss-of-function mutation in ABCD1.

[0121] Provided herein as embodiment 76 is a method of treating or preventing Nasu-Hakola disease, Alzheimer's disease, frontotemporal dementia, multiple sclerosis, Guillain-Barré syndrome, amyotrophic lateral sclerosis (ALS), or Parkinson's disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition of embodiment 55, wherein any of the above diseases or disorders is present in patients who exhibit ABCD1 dysfunction or have a mutation in a gene that affects ABCD1 function.

[0122] Autism spectrum disorder TREM2-deficient mice have been found to exhibit symptoms reminiscent of autism spectrum disorder (ASD) (Filipello et al., Immunity, 2018, 48, 979-991). Microglial depletion of the autophagy gene Aatg7 has also been found to result in synaptic pruning defects, increased dendritic spine density, and abnormal social interactions and repetitive behaviors indicative of ASD (Kim et al., Molecular Psychiatry, 2017, 22, 1576-1584). Further studies have shown that the increased dendritic spine density detected in postmortem ASD brains is likely caused by synaptic pruning defects, leading to reduced circuit connectivity and behavioral impairments, potentially contributing to many neurodevelopmental disorders (Tang et al., Immunity, 2018, 48, 979-991). (Al., Neuron, 2014, 83, 1131-1143). Without intending to be limited to a particular theory, these findings suggest that TREM2 activation can reverse microglial depletion and therefore correct the synaptic pruning defects central to neurodevelopmental disorders such as ASD. The present invention provides evidence that activation of TREM2 using compounds of the present invention rescues microglia in subjects with ASD. This discovery relates to the unexpected discovery that it is possible to fabricate a holographically oriented ...

[0123] Provided herein as embodiment 77 is a compound or tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, of any one of embodiments 1 to 54, or a pharmaceutical composition of embodiment 55, for use in treating autism or an autism spectrum disorder.

[0124] Provided herein as embodiment 78 is the use of a compound of any one of embodiments 1 to 54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or the pharmaceutical composition of embodiment 55, in the preparation of a medicament for treating autism or an autism spectrum disorder.

[0125] Provided herein as embodiment 79 is a method of treating autism or an autism spectrum disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described in any one of embodiments 1-54 or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutical composition described in embodiment 55. In some embodiments, the method treats autism. In some embodiments, the method treats Asperger's syndrome.

[0126] In some embodiments, the disclosure provides a method of increasing the activity of TREM2, comprising contacting TREM2 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting occurs in vitro. In some embodiments, the contacting occurs in vivo. In some embodiments, the TREM2 is human TREM2.

[0127] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the present disclosure. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease, or condition, being treated."

[0128] In certain embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent.

[0129] In some embodiments, the present disclosure provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of a disclosed compound and an additional therapeutic agent or agents acts synergistically.

[0130] Examples of drugs with which the combinations of the present disclosure may be combined include, but are not limited to, treatments for Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke.

[0131] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, a combination of the present disclosure may be administered together, simultaneously or sequentially, in separate unit dosage forms or in a single unit dosage form. It may be administered in conjunction with another therapeutic agent.

[0132] The amount of additional therapeutic agent present in the compositions of the present disclosure will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0133] One or more other therapeutic agents may be administered separately from the compounds or compositions of the present disclosure as part of a multiple dosing regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the present disclosure in a single composition. When administered as a multiple dosing regimen, one or more other therapeutic agents and the compounds or compositions of the present disclosure may be administered simultaneously, sequentially, or within a period of each other, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours of each other. In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present disclosure are administered partially within a period of more than 24 hours as a multiple dosing regimen.

[0134] In one embodiment, the present disclosure provides a composition comprising a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. The therapeutic agents may be administered together with the provided compound or a pharmaceutically acceptable salt thereof, or may be administered before or after administration of the provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below. In certain embodiments, the provided 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 provided compound, or a pharmaceutically acceptable salt thereof, can 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 after the therapeutic agent.

[0135] definition The following definitions are provided to aid in understanding the scope of the present disclosure.

[0136] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification or claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending on the standard deviation found in their respective testing measurements.

[0137] As used herein, when any variable occurs more than once in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. When the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.

[0138] As used herein, the following definitions shall apply unless otherwise indicated: For the purposes of this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 101 st In addition, the general principles of organic chemistry are identified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 2005, and "March's Advanced Organic Chemistry" try:Reactions Mechanisms and Structure”,8 th Ed., Ed.: Smith, MB, John Wiley & Sons, New York: 2019, the entire contents of which are incorporated herein by reference.

[0139] stereoisomer Compounds of the present disclosure may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with hindered rotation, and thus may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers (E / Z)), enantiomers, diastereomers, and atropoisomers. Accordingly, the scope of the present disclosure should be understood to encompass all possible stereoisomers of the exemplified compounds, including stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomers pure) and stereoisomeric mixtures (e.g., mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixtures of any of the foregoing) of any chemical structure (in whole or in part) disclosed herein, unless the stereochemistry is specifically specified.

[0140] If the stereochemistry of a structure or portion of a structure is not shown, for example, with bold or dashed lines, then the structure or portion of a structure should be interpreted as encompassing all stereoisomers thereof. If the stereochemistry of a structure or portion of a structure is shown, for example, with bold or dashed lines, then the structure or portion of a structure should be interpreted as encompassing only the stereoisomer shown. For example, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrimido[4,3-d]pyrimidin-4(3H)-one (Example 129) is 5-(4-chloro-2-fluorophenyl)-7-((2S)-1-(1-(S)-1-fluoroethyl)-1H-pyrazole The term "pyrimidin-4-yl" is intended to encompass 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-((R)-1-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrimido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-((R)-1-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrimido[4,3-d]pyrimidin-4(3H)-one. A bond drawn with a wavy line indicates that both stereoisomers are encompassed. This should not be confused with the wavy line drawn perpendicular to the bond indicating the point of attachment of the group to the rest of the molecule.

[0141] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer (e.g., geometric isomer, enantiomer, diastereomer, and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror-image enantiomer of the compound, and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers and diastereomers of the compound. A typical stereoisomerically pure compound will contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound.

[0142] The present disclosure also encompasses pharmaceutical compositions comprising stereomerically pure forms and the use of stereomerically pure forms of any compound disclosed herein. Additionally, the present disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compound disclosed herein and the use of such pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods well known in the art and disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques, such as chiral columns or chiral resolving agents. For example, Jacques et al.,Enantiomers,Racemates and Resolutions(Wiley--Interscience,New See, Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (Eliel, Ed., University of Notre Dame Press, Notre Dame, IN, 1972).

[0143] tautomers As will be readily apparent to those skilled in the art, certain compounds disclosed herein may exist in one or more tautomeric forms. Because a chemical structure may be used to represent only one tautomeric form, for convenience, reference to a compound of a given structural formula is understood to include other tautomers of that structural formula. For example, the following illustrates tautomers of compounds of Formula I, where R 1 is H. [ka]

[0144] Therefore, the scope of the present disclosure should be understood to encompass all tautomers of the compounds disclosed herein.

[0145] isotope labeled compounds Additionally, the scope of the present disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of Formula I, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, e.g., 2 H and 3 H, isotopes of carbon, e.g. 11 C. 13 C, and 14 C, an isotope of chlorine, e.g. 36 Cl, isotopes of fluorine, e.g. 18F, an isotope of iodine, e.g. 123 I and 125 I, isotopes of nitrogen, e.g. 13 N and 15 N, isotopes of oxygen, e.g. 15 O. 17 O, and 18 O, isotopes of phosphorus, e.g. 32 P, as well as sulfur isotopes, e.g., 35 Certain isotopically labeled compounds of Formula I, for example, compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 ( 14 C) is particularly useful for this purpose in view of its ease of incorporation and ease of detection. 2 Substitution with isotopes such as H or D may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be advantageous in some circumstances. 11 C. 18 F, 15 O, and 13 Substitution with positron-emitting isotopes, such as N, can be useful, for example, in Positron Emission Topography (PET) studies to examine target occupancy. Isotopically labeled compounds of the compounds disclosed herein can generally be prepared by conventional techniques readily known to those of skill in the art, or by processes analogous to those described in the accompanying general synthetic schemes and examples, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0146] solvate As noted above, the compounds disclosed herein, as well as the stereoisomers, tautomers, and isotopically labeled forms thereof, or pharmaceutically acceptable salts of any of the foregoing, can exist in solvated or unsolvated forms.

[0147] The term "solvate," as used herein, refers to a molecular complex comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules, in either a stoichiometric or non-stoichiometric amount. When the solvent is water, the solvate is referred to as a "hydrate."

[0148] Therefore, the scope of the present disclosure should be understood to encompass all solvates of the compounds disclosed herein, as well as their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing.

[0149] Various definitions This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0150] As used herein, "C 1~3 Alkyl," "C 1~5 alkyl," and "C 1~6 The term "alkyl" refers to a straight or branched chain hydrocarbon containing 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. 1~3 Alkyl, C 1~5 Alkyl or C 1~6 Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0151] As used herein, "C 2~4 The term "alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon double bond. Alkenyl groups include both straight-chain and branched moieties. 2~4 Representative examples of alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0152] As used herein, "C 3~6The term "cycloalkyl" refers to a saturated carbocyclic molecule whose ring structure contains 3 to 6 carbon atoms. 3~5 Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0153] As used herein, "di-C" 1~3 The term "alkylamino" refers to -NR*R**, where R* and R** are independently C alkylamino groups as defined herein. 1~3 Represents alkyl. DiC 1-3 Representative examples of alkylamino include, but are not limited to, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH2CH2CH3)2, and -N(CH(CH3)2)2.

[0154] As used herein, "C 1~3 Alkoxy" and "C 1~6 The term "alkoxy" refers to the -OR # refers to R # are C as defined herein, respectively. 1~3 Alkyl and C 1~6 Represents an alkyl group. 1~3 Alkoxy or C 1~6 Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0155] As used herein, the term "halogen" refers to -F, -CI, -Br, or -I. Point.

[0156] The term "halo," as used herein as a prefix of another term for a chemical group, refers to a modification of a chemical group in which one or more hydrogen atoms are replaced with a halogen, as defined herein. The halogens are independently selected at each occurrence. For example, "C 1~6 The term "haloalkyl" refers to a C 1~6 C refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen.1-6 Representative examples of haloalkyl include, but are not limited to, -CHF, -CHF, -CF, -CHFCl, -CHCF, -CFHCF, -CFCF, -CH(CF), -CF(CHF), and -CH(CHF)(CF). 1~6 The term "haloalkoxy" refers to, for example, C as defined herein. 1-6 It refers to an alkoxy group in which one or more hydrogen atoms are replaced with halogen. 1~6 Representative examples of haloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCHFCl, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, -OCF(CHF2)2, and -OCH(CH2F)(CF3).

[0157] As used herein, the term "5-membered heteroaryl" or "6-membered heteroaryl" refers to a 5- or 6-membered carbocyclic ring having two or three double bonds and containing one ring heteroatom selected from N, S, and O, and optionally one or more additional ring N atoms replacing one or more ring carbon atoms. Representative examples of 5-membered heteroaryls include, but are not limited to, furyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of 6-membered heteroaryls include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl.

[0158] As used herein, "C 3~6 The term "heterocycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic framework has 3 to 6 carbons and one carbon atom is replaced with a heteroatom selected from N, O, and S. 3~6 When the heterocycloalkyl group is a C6 heterocycloalkyl, one or two carbon atoms are independently replaced with a heteroatom selected from N, O, and S. 3~6Representative examples of heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0159] As used herein, "C 5~8 The term "spiroalkyl" refers to a bicyclic ring system in which the two rings are joined through a single common carbon atom. 5~8 Representative examples of spiroalkyl include, but are not limited to, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, and spiro[2.5]octanyl.

[0160] As used herein, "C 5~8 The term "tricycloalkyl" refers to a tricyclic ring system in which all three cycloalkyl rings share the same two ring atoms. 5~8 Representative examples of tricycloalkyl include tricyclo[1.1.1.0 1,3 ]pentanyl, [ka] Tricyclo[2.1.1.0 1,4 ]hexanyl, tricyclo[3.1.1.0 1,5 ]hexanyl, and tricyclo[3.2.1.0 1,5 ]octanyl.

[0161] Alone or in the form of "aralkyl", "aralkoxy", or "aryloxyalkyl" The term "aryl" when used as part of a larger moiety, such as "," refers to a monocyclic or bicyclic ring system having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl.

[0162] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as heteroaralkyl or heteroaralkoxy, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, groups having 6, 10, or 14 pi electrons shared in a cyclic array, and groups having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" in the context of "heteroaryl" includes, but is not limited to, nitrogen, oxygen, or sulfur, including any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, with the radical or point of attachment being on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl rings may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted.The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently can be optionally substituted.

[0163] As described herein, compounds of the present disclosure may contain "substituted" moieties. Generally, the term "substituted" means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted with one or more substituents selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" refers to a compound that remains substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0164] As used herein, the term "pharmaceutically acceptable" means generally recognized for use in subjects, particularly humans.

[0165] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like, or (2) salts formed when an acidic proton present in either parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, dicyclohexylamine, and the like. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). Also, Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, 2 nd See also Revised Edition (2011).

[0166] As used herein, the term "pharmaceutically acceptable excipient" refers to a wide variety of ingredients that can be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation. Typically, excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherents, glidants, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, etc.

[0167] As used herein, the term "subject" refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment, the subject is a human.

[0168] The term "therapeutically effective amount," as used herein, refers to an amount of a compound disclosed herein that will elicit the biological or medical response in a tissue, system, or subject that is desired by a researcher, veterinarian, physician, or other clinician.

[0169] General synthetic procedure The compounds provided herein can be synthesized according to the procedures described in this section and in the following sections. The synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized by other routes utilizing alternative synthetic strategies, as would be understood by one of ordinary skill in the art. It should be understood that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any way.

[0170] Generally, compounds of Formula I can be synthesized according to the following schemes. Unless otherwise specified, the variables used in the following schemes are those defined in Formula I. All starting materials are commercially available, for example, from Merck Sigma-Aldrich Inc. and Enamine Ltd., or are known in the art and can be synthesized by employing known procedures using ordinary skill. Starting materials can also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as solvents, reaction temperatures, and reagents, for the schemes discussed in this section can be found in the examples provided herein. [ka]

[0171] As will be appreciated by those of skill in the art, the synthetic schemes and representative examples described above are not intended to comprise a comprehensive list of all the ways in which the compounds described and claimed in this application may be synthesized. Additional methods will be apparent to those of skill in the art. Additionally, the various synthetic steps described above may be performed in alternate routes or orders to arrive at the desired compounds.

[0172] Methods for purifying the compounds described herein are known in the art and include, for example, crystallization, chromatography (eg, liquid and gas phase), extraction, distillation, trituration, and reverse phase HPLC.

[0173] The present disclosure further encompasses "intermediate" compounds, including structures produced from the described synthetic procedures, whether isolated or produced in situ and not isolated, prior to ultimately obtaining the desired compound. These intermediates are included within the scope of the present disclosure. Exemplary embodiments of such intermediate compounds are described in the Examples below. [Example]

[0174] This section provides specific examples of compounds of Formula I and methods for making them. [Table 2-1] [Table 2-2]

[0175] General analytical and purification methods This section provides a description of the general analytical and purification methods used to prepare certain compounds provided herein.

[0176] Chromatography: Unless otherwise indicated, the crude product-containing residue was purified by passing the crude material or concentrate over either flash silica (SiO2) or reverse-phase flash silica (C18) pre-packed Biotage brand silica gel columns and eluting the product from the column with a solvent gradient as indicated. For example, a reference to silica gel (0-40% EtOAc / hexanes) means that the product was obtained by eluting the silica-packed column with a solvent gradient of 0% to 40% EtOAc in hexanes.

[0177] Preparative HPLC method: Where so indicated, the compounds described herein were purified by reverse-phase HPLC using a Waters Fractionlynx semi-preparative HPLC-MS system utilizing one of two HPLC columns: (a) a Phenominex Gemini column (5 micron, C18, 150 x 30 mm), or (b) a Waters X-select CSH column (5 micron, C18, 100 x 30 mm).

[0178] A typical flow through the instrument involves eluting at 45 mL / min with a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) in water (0.1% formic acid) over 10 min; conditions can be varied to achieve optimal separation.

[0179] Proton NMR spectrum: Unless otherwise indicated, all 1 H NMR spectra were collected on a Bruker NMR instrument at 300, 400, or 500 MHz. When so characterized, all observed protons are reported as parts per million (ppm) downfield from tetramethylsilane (TMS) using the internal solvent peak as the reference.

[0180] Mass spectrum (MS) Unless otherwise indicated, all mass spectral data for starting materials, intermediates and / or exemplary compounds is given as [M+H] + The molecular ions are reported as mass / charge (m / z). The reported molecular ions were obtained using a Waters Acquity UPLC / MS system or electrospray detection method (commonly referred to as ESI MS). Compounds with isotopic atoms such as bromine are generally reported according to the detected isotopic pattern, as will be understood by those skilled in the art.

[0181] Compound name The compounds disclosed and described herein are named using the IUPAC nomenclature facility provided in Biovia Pipeline Pilot.

[0182] Specific Examples Provided in this section are procedures for synthesizing specific examples of the compounds provided herein. All starting materials, unless otherwise noted, are either commercially available from Merck Sigma-Aldrich Inc. or known in the art and can be synthesized by adapting known procedures using ordinary skill.

[0183] Synthesis of Examples Method 1 Example 1: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one [ka] Step 1: 5,7-Dichloro-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. To a 10 L four-neck round-bottom flask was added 4-amino-2,6-dichloronicotinic acid 2,2,2-trifluoroacetate (110 g, 343 mmol) and acetic anhydride (129 mL, 1371 mmol) in pyridine (1100 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, and methanamine (2 M in THF, 1028 mL, 2056 mmol) was added dropwise. The cold water bath was removed, and the reaction was stirred for 30 minutes. The mixture was cooled to 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% in EtOAc) (550 mL, 685 mmol) was added. The cold water bath was removed, and the reaction was stirred for 1 hour. The mixture was quenched with water (2.5 L) and extracted with EtOAc (2 L). The organic layer was washed with water (2 L) and brine solution (2.5 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified via silica gel chromatography (0-40% EtOAc in hexanes) to provide a yellow solid, which was dissolved in DCM (500 mL) and precipitated with petroleum ether. The resulting solid was filtered and dried to provide 5,7-dichloro-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (60 g, 246 mmol, 71.7% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ ppm 7.63 (s, 1H), 3.49 (s, 3H), 2.60 (s, 3H). m / z (ESI, cation): 244.0 (M+H).

[0184] Step 2: 7-chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. To a 10 L four-neck round-bottom flask were added 5,7-dichloro-2,3-dimethylpyrido-[4,3-d]pyrimidin-4(3H)-one (100 g, 410 mmol) and (4-chloro-2-fluorophenyl)boronic acid (71.4 g, 410 mmol), 1,4-dioxane (3000 mL), and water (1000 mL). To this mixture was added cesium carbonate (400 g, 1229 mmol), and the reaction mass was purged with nitrogen gas for 10 minutes. PdCl(dppf)-CHCl adduct (16.73 g, 20.49 mmol) was added, and the reaction mass was stirred at room temperature for 0.5 hours. The reaction mixture was quenched with water (4 L) and extracted with DCM (2 x 3500 mL). The combined organic layers were washed with brine solution (4000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by filtration through a 100-200 mesh silica gel column. The solid was absorbed onto a plug of PEG and purified by chromatography through a 100-200 mesh silica gel column eluted with a gradient of 0% to 40% EtOAc in hexanes. The resulting solid was triturated in EtOAc (150 mL), filtered, and washed with dry n-hexanes to give 7-chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (62.5 g, 185 mmol, 45.1% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ ppm 7.48~7.71 (m, 1H), 7.45~7.51 (m, 2H), 7.37~7.41 (m, 1H), 3.42 (s, 3H), 2.62 (s, 3H). m / z (ESI, cation): 338.0 (M+H).

[0185] Step 3: (S)-5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one. A 250 mL flask was charged with (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholino (Intermediate 3, 5.93 g, 35.5 mmol), 7-chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (10 g, 29.6 mmol), DMSO (74 mL), and 1,1′-dimethyltriethylamine (11.47 g, 89 mmol). The reaction was heated to 100° C. for 16 hours. The reaction was quenched with water and filtered to provide the crude material. The crude material was purified using a silica gel column eluted with 0-100% EtOH / EtOAc (1:3) in heptane. The collected fractions were concentrated and triturated with hot isopropanol to give (S)-5-(4-chloro-2-fluoropheny)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one (9.91 g, 71.5% yield) as a white solid. The absolute stereochemistry was assigned by X-ray crystallography. 1 H NMR (500MHz, DMSO-d6) δ ppm 7.70~7.73(m, 1H), 7.44~7.46(m, 1H), 7.36~7.41(m, 2H), 7.30~7.34(m, 1H), 6. 81~6.83(m, 1H), 4.50~4.54(m, 1H), 4.36~4.40(m, 1H), 4.19~4.24(m, 1H), 3.96 ~4.02(m, 1H), 3.78~3.82(m, 3H), 3.63~3.70(m, 1H), 3.34~3.37(m, 3H), 3.04~3 .11(m, 1H), 2.97~3.02(m, 1H), 2.52~2.55(m, 3H), m / z (ESI, cation): 469.0(M+H) + . [Table 3-1] [Table 3-2] Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 [Table 3-20] [Table 3-21] [Table 3-22] [Table 3-23] [Table 3-24] [Table 3-25]

[0186] Method 2 Example 123: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one [ka] To a solution of (S)-7-(2-(1H-pyrazol-4-yl)morpholino)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (Examples 1-22, 0.065 g, 0.143 mmol) in DMF (0.572 mL) was added cesium carbonate (0.093 g, 0.286 mmol) and 2-bromopropane (0.053 g, 0.040 mL, 0.429 mmol). The reaction mixture was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was diluted with 20 mL of DCM and washed with 2×15 mL of water, and the organic phase was separated and concentrated in vacuo. The crude product was purified by column chromatography eluting with a gradient of 0-10% MeOH (+0.1% NH) in DCM to give 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propanyl)-1H) as an off-white solid. To obtain (4,3-d-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one (0.048 g, 0.097 mmol, 67.6% yield). 1 H NMR (500MHz, DMSO-d6) δ7.80(s, 1H), 7.46(s, 1H), 7.36~7.41(m, 2H), 7.31(dd, J=2.01, 8.24H z, 1H), 6.84(s, 1H), 4.50(dd, J=2.53, 10.44Hz, 1H), 4.45(td, J=6.63, 13.33Hz, 1H), 4.39(br d, J=12.20Hz, 1H), 4.25(br d, J=12.07Hz, 1H), 3.97(dd, J=2.01, 11.61Hz, 1H), 3.66(dt, J=2.47, 11.55Hz , 1H), 3.34(s, 3H), 2.97~3.08(m, 2H), 2.52(s, 3H), 1.40(s, 3H), 1.38(s, 3H). m / z (ESI, cation): 497.0 (M+Na). [Table 4-1] [Table 4-2]

[0187] Method 3 Example 135: 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,2-difluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one [ka] To a solution of 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoro-2-hydroxyethyl)-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (0.0485 g, 0.094 mmol, 125604-46-1) in DCM (0.938 mL) was slowly added a solution of DAST (1 M in DCM) (0.117 mL, 0.117 mmol) at −78° C. The reaction mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was quenched with saturated NaHCO solution and the phases were separated. The organic phase was concentrated in vacuo and the crude material was purified by silica gel chromatography eluting with a gradient of 0–10% MeOH (+1% NH) in DCM to give 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,2-difluoroethyl)-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (0.029 g, 0.056 mmol, 59.6% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ ppm 8.15~8.18(m, 1H), 7.78~7.81(m, 1H), 7.37~7.41(m, 2H), 7.29~7.33(m, 1H), 6.86~6.88(m, 1H), 6.80~6.84(m, 1H), 4.86~4.93(m, 2H), 4.56~4.59(m, 1H), 4.41~4.45(m, 1H), 4.22~4.27(m, 1H), 3.98~4.02(m, 1H), 3.66~3.71(m, 1H), 3.33~3.35(m, 3H), 3.03~3.09(m, 1H), 2.96~3.02(m, 1H), 2.51~2.53(m, 3H). m / z (ESI, cation): 541 (M+H).

[0188] Method 4 Example 136: 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one [ka] (S)-7-(2-(1H-pyrazol-4-yl)morpholino)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (Example 22, 0.2 g, 0.440 mmol), cyclopropyl-boronic acid (0.084 g, 0.980 mmol), 2,2′-bipyridine (0.072 g, 0.464 mmol), and sodium carbonate (0.104 g, 0.980 mmol, Fisher) in 1,2-dichloroethane (1.912 mL) were stirred at 50° C. for 18 hours (the vial septum was pierced with two needles to allow air entry). After cooling to room temperature, the mixture was filtered over Celite. The filtrate was washed with NH4Cl, dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography eluting with 0-10% DCM / MeOH to give 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (0.113 g, 0.228 mmol, 51.9% yield). 1 H NMR (500MHz, DMSO-d6) δ8.13(s, 1H), 7.69(s, 1H), 7.37~7.44(m, 2H), 7.32(dd, J=2.01, 8.11Hz, 1H), 7.20(dd, J=8.89 , 15.64Hz, 1H), 6.86(s, 1H), 5.55(d, J=15.57Hz, 1H), 4.84(d, J=8.43Hz, 1H), 4.58(dd, J=2.66, 10.32Hz, 1H), 4.43(br d, J=12.20Hz, 1H), 4.27(br d, J=12.46Hz, 1H), 3.98~4.04(m, 1H), 3.70(dt, J=2.59, 11.55Hz, 1H), 3.35(s, 3H), 2.99~3.11(m, 2H), 2.53(s, 3H). m / z (ESI, cation): 481.0(M+H)+. [Table 5]

[0189] Method 5 Example 138: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azetidinyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one [ka] Into a vial containing tert-butyl (S)-3-(4-(4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholino-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Example 134, 0.02 g, 0.033 mmol), hydrogen chloride 4N in dioxane (0.3 mL, 1.2 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The solid residue was partitioned between saturated NaHCO3 and DCM. The organic phase was separated (phase separator) and concentrated in vacuo to give the crude intermediate, which was used in the next step without further purification. To a solution of the intermediate paraformaldehyde (4.92 mg, 0.164 mmol) and triethylamine (3.32 mg, 4.57 μl, 0.033 mmol) in 1,2-dichloroethane (0.131 mL) was added sodium triacetoxyborohydride (10.4 mg, 0.049 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with NaHCO3 solution. DCM was added and the organic phase was separated. The solvent was concentrated in vacuo. The crude material was purified by column chromatography eluting with a gradient of 0–10% MeOH (+1% NH) in DCM to give 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azetidinyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one (0.007 g, 0.013 mmol, 38.4% yield). 1H NMR (500MHz, CDCl3)δ ppm 7.59~7.63(m, 2H), 7.34~7.38(m, 1H), 7.22~7.25(m, 1H), 7.14~7.18(m, 1H), 6.62 ~6.64(m, 1H), 4.90~4.97(m, 1H), 4.60~4.65(m, 1H), 4.40~4.49(m, 1H), 4.18~4.2 5(m, 1H), 4.07~4.13(m, 1H), 3.77~3.93(m, 3H), 3.52~3.59(m, 2H), 3.46~3.49(m, 3H), 3.19~3.26(m, 1H), 3.11~3.19(m, 1H), 2.56~2.60(m, 3H), 2.46~2.53(m, 3H). m / z (ESI, cation): 524.0 (M+H)

[0190] Method 6 Example 139: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one Example 140: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one [ka] Step 1: Methyl 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholine-2-carboxylate. To a 10 mL vial was added 7-chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (1.014 g, 3 mmol), methyl morpholine-2-carboxylate, and n,n-diisopropylethylamine (1.939 g, 15.00 mmol) in dimethyl sulfoxide (5 mL). The reaction was stirred at 100° C. for 24 hours. The reaction mixture was partitioned between DCM and water and the organic phase was concentrated to give methyl 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholine-2-carboxylate, which was used in the next step without further purification.

[0191] Step 2: 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholine-2-carboxylic acid. Methyl 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholine-2-carboxylate (4.92 g, 11 mmol, 125373-9) and potassium trimethyl(oxide)-silane (1.693 g, 13.20 mmol) were combined in 1,4-dioxane (11 mL), and the reaction was stirred at 80 °C for 30 min. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO solution, and extracted with EtOAc. The aqueous phase was acidified to pH = 3 and extracted twice with EtOAc. The combined organics were dried and concentrated to give 1.9 g of crude product, which was further purified via reverse phase chromatography to provide 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholine-2-carboxylic acid (1.85 g, 38.5%). m / z (ESI, positive ion): 433.0 (M+H).

[0192] Step 3: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one. A small vial was added to 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholine-2-carboxylic acid (13 The vial was charged with bis(3,5-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)hexafluorophosphate (3.37 mg, 3.00 μmol), bis(3,5-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-hexafluorophosphate (3.37 mg, 3.00 μmol), bis(3,5-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-hexafluorophosphate (3.37 mg, 3.00 μmol), bis(3,5-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-hexafluorophosphate (3.37 mg, 3.00 μmol), and bis(3,5-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-hexafluorophosphate (3.37 mg, 3.00 μmol). The vial was evacuated and filled with nitrogen three times. N,N-Dimethylformamide (5000 μl) was added, and the reaction vial was irradiated for 3 hours at 450 nm using an integrated photoreactor (fan: 1500 rpm, stirring: 500 rpm, LED power: 100%). The reaction mixture was partitioned between EtOAc and water. The organic phase was dried, concentrated, and purified via reverse phase chromatography to give 18 mg of crude product. Chiral purification via SFC stacked Chiralcel OJ-H 2 x 25 cm and Chiralcel OJ-H 2 x 15 cm, 5 μm columns, 25% methanol mobile phase, F = 70 mL / min provided 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido(4,3-d)pyrimidin-4(3H)-one (Example 139) and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)-pyrido(4,3-d)pyrimidin-4(3H)-one (Example 140) as off-white solids. Absolute stereochemistry was arbitrarily assigned. 1H NMR (500MHz, CDCl3)δ ppm 8.56~8.58(m, 1H), 7.64~7.69(m, 1H), 7.34~7.39(m, 1H), 7.22~7.25(m, 1H), 7 .18~7.21(m, 1H), 7.14~7.17(m, 1H), 6.62~6.64(m, 1H), 4.60~4.65(m, 1H), 4.4 6~4.52(m, 1H), 4.24~4.31(m, 1H), 4.16~4.21(m, 1H), 3.85~3.91(m, 1H), 3.48 (s, 3H), 3.21~3.27(m, 1H), 2.97~3.03(m, 1H), 2.60(s, 3H), 2.57~2.58(m, 3H). m / z (ESI, cation): 480.0 (M+H).

[0193] Method 7 Example 141: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one [ka] Step 2 Step 1: (S)-7-(2-(1-(bromodifluoromethyl)-1H-pyrazol-4-yl)morpholino)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. To a solution of (S)-7-(2-(1H-pyrazol-4-yl)morpholino)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (Example 22, 0.065 g, 0.143 mmol, 124947-40-1) in DMF (0.572 mL) was added cesium carbonate (0.093 g, 0.286 mmol) and dibromodifluoromethane (0.039 mL, 0.09 g, 0.429 mmol). The reaction mixture was stirred overnight at room temperature, diluted with 10 mL of DCM, and washed with water. The organic phase was separated and concentrated in vacuo, and the crude product was purified by column chromatography eluting with a gradient of 0 to 30% EtOAc-EtOH (3:1) in heptane to give ((S)-7-(2-(1-(bromodifluoromethyl)-1H-pyrazol-4-yl)morpholino)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (0.025 g, 0.043 mmol, 30% yield) as an off-white solid. m / z (ESI, positive ion): 583.0 (M+H). + .

[0194] Step 2: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one. To a stirred solution of (S)-7-(2-(1-(bromodifluoromethyl)-1H-pyrazol-4-yl)morpholino)-5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-pyrido[4,3-d]pyrimidin-4(3H)-one (0.025 g, 0.043 mmol, 124947-42-10) in DCM (0.428 mL) was added silver(I) tetrafluoroborate (0.017 g, 0.086 mmol) at −78° C. The solution was then stirred at room temperature overnight. The mixture was diluted with DCM containing 5% MeOH, sonicated for 2–3 min, filtered, and concentrated. The crude material was purified by flash column chromatography eluting with a gradient of 0–10% MeOH (+0.1% ammonia) in DCM to give 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one (0.0169 g, 0.032 mmol, 75% yield). 1 H NMR (500MHz, DMSO-d6) δ8.55(s, 1H), 8.04(s, 1H), 7.36~7.43(m, 2H), 7.29~7.34(m, 1H), 6.91(s, 1H), 4.61~4.65(m, 1H), 4.46(br d, J=12.20Hz, 1H), 4.32(br d, J=13.10Hz, 1H), 3.99~4.06(m, 1H), 3.67~3.75(m, 1H), 3.34(s, 3H), 3.00~3.09(m, 2H), 2.52(s, 3H). m / z (ESI, cation): 523.0 (M+H) + .

[0195] Method 8 Example 142: 5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one. [ka] Step 1: tert-Butyl 4-amino-6-chloro-2-(4-chloro-2-fluorophenyl)nicotinate. To a 100 mL vial was added tert-butyl 4-amino-2,6-dichloronicotinate (2.5 g, 9.50 mmol, 125370-12), (4-chloro-2-fluorophenyl)boronic acid (2.319 g, 13.30 mmol), CsCO (7.74 g, 23.75 mmol), and PdCl(dtbpf) (0.310 g, 0.475 mmol) in 1,4-dioxane (25.3 mL) and water (6.33 mL). The mixture was flushed with N and stirred at 80 °C for 4 h. The resulting mixture was diluted with water and EtOAc and extracted twice with EtOAc. The organic layer was dried over MgSO, filtered, and concentrated. Purification on silica with 0-20% EtOAc in heptane gave tert-butyl 4-amino-6-chloro-2-(4-chloro-2-fluorophenyl)nicotinate as a pale orange solid. m / z (ESI, positive ion): 356.9 (M+H). + .

[0196] Step 2: (S)-tert-butyl 4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)nicotinate. To a solution of tert-butyl 4-amino-6-chloro-2-(4-chloro-2-fluorophenyl)nicotinate (500 mg, 1.400 mmol, 125370-40) in dimethyl sulfoxide (4666 μL) was added (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Intermediate 3, 234 mg, 1.400 mmol) and triethylamine (425 mg, 585 μL, 4.20 mmol). The mixture was stirred at 125° C. for 72 hours, then diluted with EtOAc and washed with water. The organic layer was dried over MgSO, filtered, and concentrated. Purification on silica gel (0-100% EtOAc in heptane) provided (S)-tert-butyl 4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)nicotinate as a yellow solid. m / z (ESI, positive ion): 488.0 (M+H). + .

[0197] Step 3: (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)nicotinic acid hydrochloride. In a 20 mL vial, tert-butyl (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)nicotinate (342 mg, 0.701 mmol, 125520-8) and 4 M HCl in dioxane (511 mg, 426 μL, 14.02 mmol) were combined. The mixture was heated at 60° C. for 90 minutes, allowed to cool to room temperature, and concentrated to dryness to give crude (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)nicotinate. (4-yl)morpholino)nicotinic acid hydrochloride, which was used in the next step without purification. m / z (ESI, positive ion): 467.8 (M+H) + .

[0198] Step 4: 5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one. To a solution of (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)nicotinic acid (25 mg, 0.058 mmol, 125520-12) in DCM (193 μL) was added cyclopropane-carboxylic acid chloride (30.3 mg, 0.289 mmol) and triethylamine (17.57 mg, 24.21 μL, 0.174 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and dissolved in 0.2 mL of pyridine. Aminomethane (57.9 μL, 0.116 mmol) and T3P (36.8 mg, 33.8 μL, 0.058 mmol) in DMF were added, and the mixture was stirred for 72 h at 70° C. The reaction mixture was concentrated using a silica gel column eluted with 0 to 100% EtOH / EtOAc (1:3) in heptane to provide 5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one as a light brown solid. 1 H NMR (500MHz, DMSO-d6) δ ppm 7.72(s, 1H), 7.45(s, 1H), 7.36~7.41(m, 2H), 7.29~7.33(m, 1H), 6.72(s, 1H), 4.50(dd, J=10.32, 2.53Hz, 1H), 4.36(br d, J=12.07Hz, 1H), 4.22(br d. s, 2H), 1.08(br dd, J=8.04, 3.24Hz, 2H). m / z (ESI, cation): 495.0 (M+H) + . [Table 6-1] [Table 6-2] [Table 6-3]

[0199] Method 9 Example 158: 5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one. [ka] Step 1: 5,7-Dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. 5,7-Dichloropyrido[4,3-d]pyrimidin-4(3H)-one (0.086 g, 0.4 mmol), cesium carbonate (0.261 g, 0.8 mmol), and iodomethane (0.170 g, 1.2 mmol) were combined in DMF (2 mL). The reaction mixture was stirred at room temperature for 24 hours and then partitioned between EtOAc and water. The organic phase was separated and dried over MgSO. The resulting solution was concentrated to provide crude 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one, which was used in the next step without further purification.

[0200] Step 2: 7-chloro-5-(4-chloro-2-fluorophenyl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. 5,7-Dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (0.092 g, 0.4 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (0.015 g, 0.020 mmol), (4-chloro-2-fluorophenyl)boranediol (0.070 g, 0.400 mmol), and cesium carbonate (0.391 g, 1.200 mmol) were combined in a vial. 1,4-Dioxane (1.5 mL) and water (0.5 mL) were added, and the reaction was stirred at 60 °C for 30 minutes. The reaction mixture was cooled to room temperature and partitioned between DCM and water. The mixture was concentrated through a phase separation cartridge to give crude 7-chloro-5-(4-chloro-2-fluorophenyl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one, which was used in the next step without further purification. m / z (ESI, positive ion): 324.0 (M+H). + .

[0201] Step 3: 5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one. 7-Chloro-5-(4-chloro-2-fluorophenyl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (130 mg, 0.4 mmol), (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Intermediate 3) (80 mg, 0.480 mmol), and n,n-diisopropylethylamine (258 mg, 0.349 mL, 2.000 mmol) were combined in dimethyl sulfoxide (0.8 mL) and stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was concentrated and the crude product was purified by elution with 0-100% EtOH / EtOAc (1:3 ) to give 5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one as a pale yellow solid (0.091 g, 0.2 mmol, 50% yield). 1 H NMR (600MHz, DMSO-d6) δ ppm 8.31~8.35(m, 1H), 7.69~7.74(m, 1H), 7.42~7.47(m, 1H), 7.38~7.41(m, 2H), 7.29~7.35(m, 1H), 6.88~6.94(m, 1H), 4.49~4.54(m, 1H), 4.34~4.40(m, 1H), 4.20~4.26(m, 1H), 3.95~4.00(m, 1H), 3.79~3.81(m, 3H), 3.63~3.69(m, 1H), 3.28~3.30(m, 3H), 2.97~3.13(m, 2H). m / z (ESI, positive ion): 455.0 (M + H) + .

[0202] Method 10 Example 159: 5-Cyclohexyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one [ka] Step 1: 7-chloro-5-(cyclohex-1-en-1-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. A glass microwave reaction vessel was charged with 5,7-dichloro-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (Method 1—Step 1, 0.30 g, 1.229 mmol) and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.256 g, 1.229 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL), followed by potassium carbonate (0.255 g, 1.844 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, then Pd(Ph3)4 (0.142 g, 0.123 mmol) was added, and the reaction mixture was heated in a microwave at 100 °C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL), extracted with EtOAc (2 × 10 mL), and the organic extract was dried over Na2SO4. The solution was filtered and concentrated in vacuo to give a crude mineral, which was purified by silica gel chromatography eluting with 5–80% EtOAc in hexanes to provide 7-chloro-5-(cyclohex-1-en-1-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (0.360 g, 1.24 mmol, 101% yield, ca. 75% purity) as a yellow solid. m / z (ESI, positive ion): 290.0 (M+H). + .

[0203] Step 2: (S)-5-(cyclohex-1-en-1-yl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one. To a 25 mL round-bottom flask was added (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (Intermediate 3) (0.270 g, 1.615 mmol), 7-chloro-5-(cyclohex-1-en-1-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (0.360 g, 1.242 mmol) in 1,4-dioxane (6 mL), followed by DIPEA (0.434 mL, 2.485 mmol). The reaction mixture was heated at 100° C. for 16 hours, then cooled to room temperature and concentrated in vacuo. The crude product was purified by reverse-phase preparative HPLC to provide (S)-5-(cyclohex-1-en-1-yl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one (0.21 g, 0.499 mmol, 40.2% yield) as an off-white solid. m / z (ESI, positive ion): 421.1 (M+H). + .

[0204] Step 3: 5-Cyclohexyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one. To a 25 mL round-bottom flask was added (S)-5-(cyclohex-1-en-1-yl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one (200 mg, 0.476 mmol) in THF (5 mL), followed by 10% Pd—C (405 mg, 1.9 mmol) at room temperature. The mixture was stirred under a hydrogen gas atmosphere at room temperature for 8 hours, then filtered through a Celite bed and concentrated in vacuo. The crude product was purified by HPLC to provide 5-cyclohexyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one (56.6 mg, 0.134 mmol, 28.2% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ ppm 7.53(s, 1H), 7.44(s, 1H), 4.59(dd, J=11.4, 2.1Hz, 1H), 4.28(dt, J=11. 2, 3.2Hz, 1H), 4.18(t, J=11.7Hz, 1H), 3.90(s, 3H), 3.83(ddd, J=11.5, 8. 2, 5.3Hz, 1H), 3.41~3.52(m, 1H), 2.84(s, 3H), 2.80(s, 3H), 2.42(d, J=1 3.5Hz, 1H), 2.32(d, J=8.2Hz, 2H), 2.12~2.23(m, 5H), 1.96~2.12(m, 4H). m / z (ESI, positive ion): 443.2 (M + H) + . [Table 7]

[0205] Method 11 Examples 161 to 163: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydrofuran tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2 R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one.

[0206] [ka] Step 1: 4-(4-Bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole. A 100 mL flask was charged with 1-methyl-1H-pyrazole-4-carbaldehyde (1.03 g, 9.35 mmol), 3-buten-1-ol (0.708 g, 0.842 mL, 9.82 mmol), and DCM (18.71 mL). To the vial was added hydrogen bromide-acetic acid (6.88 g, 5.08 mL, 28.1 mmol) in one portion. After 1 h, the crude reaction was carefully quenched with saturated sodium bicarbonate solution and washed with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting crude material was purified by silica gel chromatography eluting with 0% to 40% EtOAc / EtOH (3:1) in heptane to provide 4-(4-bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (1.307 g, 5.33 mmol, 57% yield) as a pale yellow oil (3.3:1 cis / trans mixture of diastereomers).

[0207] Major diastereomer (cis isomer): 11H NMR (500 MHz, CDCl3) δ ppm 7.46 (s, 1H), 7.36 (s, 1H), 4.36 (dd, J = 11.3, 2.1 Hz, 1H), 4.25 (tt, J = 11.9, 4.5 Hz, 1H), 4.0 8 (ddd, J = 12.0, 4.8, 1.8 Hz, 1H), 3.89 (s, 3H), 3.58 (td, J = 12.1, 2.3 Hz, 1H), 2.52 (ddt, J = 12.9, 4.3, 2.1, 2.1 Hz, 1H), 2.12 - 2.26 (m, 3H). m / z (ESI, positive ion): 245.0 (M + H) + .

[0208] Trace diastereomer (trans isomer): 1 1H NMR (500 MHz, CDCl3) δ ppm 7.46 (s, 1H), 7.35 (s, 1H), 4.93 (dd, J = 10.0, 2.9 Hz, 1H), 4.79 (quin, J = 3.1 Hz, 1H), 4.12 (td, J = 11.6, 2.1 Hz, 1H), 3.92 - 3.99 (m, 1H), 3.89 (s, 3H), 2.16 - 2.29 (m, 3H), 1.93 - 2.02 (m, 1H). m / z (ESI, positive ion): 245.0 (M + H) + .

[0209] Step 2: (2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II) bromide. Zn (0.320 g, 4.90 mmol) was added to an oven-dried 50 mL flask, which was then evacuated and backfilled with nitrogen three times. The flask was capped with a rubber septum and a thermocouple probe inserted. A 0.5 M solution of lithium chloride in anhydrous tetrahydrofuran (3.26 mL, 1.632 mmol) was added, followed by 1,2-dibromoethane (0.015 g, 7.03 μL, 0.082 mmol), and the mixture was heated to an internal temperature of 50 °C for 20 min. After cooling to room temperature, chlorotrimethylsilane (8.86 mg, 10.36 μL, 0.082 mmol) was added, and the mixture was heated to an internal temperature of 50 °C for 20 min. After cooling to room temperature, diiodine (8.28 mg, 0.033 mmol) was added as a solution in 0.1 mL of THF, and the mixture was heated to an internal temperature of 50° C. for 20 minutes. While still hot, 4-bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (0.4 g, 1.632 mmol, a 3.3:1 mixture of cis / trans isomers) was added as a THF solution (1.5 mL). The resulting mixture was stirred at 50° C. for 18 hours, and the reaction solution was cooled to room temperature and allowed to stand for 3 hours (to allow zinc dust to settle) to provide a pale yellow solution, which was used in the next step without further treatment.

[0210] Step 3: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one. To a 1-dram vial was added palladium(II) acetate (1.992 mg, 8.87 μmol), 2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (7.75 mg, 0.018 mmol), and 7-chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (60 mg, 0.177 mmol). The vial was purged with nitrogen, then 2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II) bromide (approximately 0.3 M in THF, 0.47 mL, 0.141 mmol) was added, and the vial was stirred at room temperature. After 3 h, the reaction was quenched with saturated sodium bicarbonate solution and extracted four times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a 24 g silica gel column, eluting with 0–100% EtOAc / EtOH 3:1 in heptane, to provide the crude product as a 2.7:1 dr mixture (50 mg, 0.11 mmol, 60% yield). Single stereoisomers were obtained by SFC on a Chiralpak AD-H 2 x 25 cm, 5 um column (45% isopropanol using F = 80 mL / min) to yield 3 mg of peak 1 with >99% purity, 9.3 mg of peak 2 with >99% ee, and 8.0 mg of peak 3 with >99% ee.

[0211] Peak 1 (Example 161): Mixture of trans isomers 2R,4R and 2S,4S: 5- (4-Chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, yellow oil. LC / MS 1 H NMR(500MHz, CDCl3)δ ppm 7.47(s, 1H), 7.39~7.44(m, 2H), 7.26(s, 1H), 7.17(dd, J=1.95, 9.73Hz, 1H), 4.98(br t, J=4.80Hz, 1H), 3.89(s, 3H), 3.82~3.88(m, 2H), 3.53~3.55(m, 3H), 3.39~3.45(m, 1H), 2.65(s , 3H), 2.44 (dt, J=4.02, 8.82Hz, 1H), 2.30 (ddd, J=5.06, 5.19, 13.62Hz, 1H), 2.03~2.15 (m, 2H). (ESI+)=468.0(M+H) + .

[0212] Peak 2 (Example 162): 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one (9.3 mg, 0.020 mmol, 4.2% yield), yellow oil. 1H NMR (500MHz, CDCl3) δ7.48(s, 1H), 7.40(t, J=7.91Hz, 1H), 7.37(s, 2H), 7.26(s, 1H), 7.17(dd, J=1.88, 9.67Hz, 1H), 4.54(dd, J =1.88, 11.22Hz, 1H), 4.21~4.27(m, 1H), 3.87(s, 3H), 3.67~3.83(m, 1H), 3.53(s, 3H), 3.16~3.30(m, 1H), 2.64(s, 3H), 2.31(br d, J=12.98Hz, 1H), 2.02(br s, 1H), 1.80~2.00(m, 3H). m / z (ESI, cation): 468.0 (M+H) + .

[0213] Peak 3 (Example 163): 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one (8.0 mg, 0.017 mmol, 3.6% yield), yellow oil. 1 H NMR (500MHz, CDCl3)δ ppm 7.49(s, 1H), 7.39~7.43(m, 1H), 7.38(s, 2H), 7.26~7.28(m, 1H), 7.18(dd, J=9.6, 1.9Hz, 1H), 4.55(dd, J=11.3, 1.9Hz, 1H), 4 .22~4.28(m, 1H), 3.88(s, 3H), 3.78(td, J=11.7, 2.5Hz, 1H), 3.54(s, 3H), 3.27(tt, J=12.0, 3.8Hz, 1H), 2.65(s, 3H), 2.33(br d, J=13.0Hz, 1H), 1.88~2.07(m, 3H). m / z (ESI, cation): 468.0 (M+H) + .

[0214] Absolute stereochemistry was arbitrarily assigned. Relative stereochemistry (cis / trans) was determined by NMR.

[0215] Method 12 Example 164: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one [ka] Step 1: 6-(1-Methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl. To a 20 mL scintillation vial was added 1-methyl-1H-pyrazole-4-carbaldehyde (200 mg, 1.816 mmol), (2-hydroxyethyl)-acetylene (191 mg, 206 μL, 2.72 mmol), and DCM (3633 μL). Trifluoromethanesulfonic acid (327 mg, 194 μL, 2.180 mmol) was added slowly at 0°C, and the mixture was allowed to warm to room temperature. After 30 minutes, additional trifluoromethanesulfonic acid (327 mg, 194 μL, 2.180 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated sodium bicarbonate solution and washed with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting material was purified by silica gel chromatography eluting with 0 to 70% EtOAc in heptane to provide 6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (227 mg, 0.727 mmol, 40.0% yield) as a yellow oil. 1 H NMR (500MHz, CDCl3)δ ppm 2.45~2.60(m, 2H)3.82~3.88(m, 1H)3.91~3.94(m, 3H)3.98~4.04(m, 1H)5.20~5.23(m, 1H) 5.30~5.33(m, 1H)5.33~5.37(m, 1H)5.94~5.98(m, 1H)7.34~7.38(m, 1H)7.48~7.50(m, 1H).

[0216] Step 2: 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole. A 20 mL scintillation vial was charged with 6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (227 mg, 0.727 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with DCM (59.4 mg, 0.073 mmol), [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(ii), complex with DCM (59.4 mg, 0.073 mmol), and potassium acetate (285 mg, 2.91 mmol) and purged with N2. 1,4-Dioxane (2908 μL) was then added and the reaction was heated to 90 °C for 2 h. The reaction was then cooled to room temperature. The reaction mixture was diluted with EtOAc and a plug of silica gel was added. The crude product was filtered through a silica gel column and purified by chromatography eluting with 0% to 100% EtOAc in heptane to provide 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (87 mg, 0.300 mmol, 41.2% yield) as a red oil. 1 H NMR (CDCl3, 500MHz) δ7.48(s, 1H), 7.36(s, 1H), 6.61(q, 1H, J=1.9Hz), 5.20(q, 1H, J=2.6Hz), 3.9~3.9( m, 4H), 3.74 (ddd, 1H, J=4.5, 7.2, 11.4Hz), 2.30 (dt, 1H, J=2.5, 4.9Hz), 2.2~2.3 (m, 1H), 1.30 (s, 12H).

[0217] Step 3: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one. To a 20 mL scintillation vial equipped with a condenser was added 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (87 mg, 0.300 mmol, 125536-50-10), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with DCM (24.48 mg, 0.030 mmol), and cesium carbonate (293 mg, 0.899 mmol). The vial was sealed and purged with N for 20 min, and 1,4-dioxane (1124 μL) and water (375 μL) (degassed) were added. The flask was heated to 70° C. for 2 h, cooled to room temperature, and diluted with EtOAc and saturated sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated in vacuo to give the crude material as a brown oil. Purification by silica gel chromatography, eluting with 0-100% EtOAc / EtOH 3:1 in heptane, provided the crude product as a brown oil. The material was further purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN / HO, a gradient of 25-70% over 14 minutes, to provide racemic 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one (58.6 mg, 0.126 mmol, 41.9% yield). 1H NMR (CDCl3, 500MHz) δ7.52(s, 1H), 7.50(s, 1H), 7.4~7.5(m, 1H), 7.38(s, 1H), 7.2~7.3(m, 1H), 7.16(dd, 1H, J=1.9, 9.7H z), 7.13(s, 1H), 5.4~5.4(m, 1H), 4.1~4.1(m, 1H), 3.92(ddd, 1H, J=4.6, 7.2, 11.6Hz), 3.88(s, 3H), 3.54(s, 3H), 2.74(br s, 1H), 2.65(s, 4H). (ESI, cation):466.0(M+H) + .

[0218] Method 13 Example 165: 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one.

[0219] Example 166: 5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. [ka] Steps 1-3: 5-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. Steps 1-3 from Method 12 were followed using 1-cyclopropyl-1H-pyrazole-4-carbaldehyde as the starting material to provide 5-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-diethylpyrido[4,3-d]pyrimidin-4(3H)-one as a light brown solid. m / z (ESI, positive ion): 492.1 (M+H). + .

[0220] Step 4: (2R,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate. To a 50 mL round-bottom flask was added 5-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (300 mg, 0.610 mmol) and Pd / C (10%) (300 mg, 0.610 mmol) in EtOAc (30 mL). The reaction mixture was stirred under H gas at 42 PSI at room temperature for over 16 hours. After completion of the reaction, the reaction was filtered through Celite, washed with EtOAc (50 mL), and the filtrate was concentrated under reduced pressure and purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in EtOAc to provide a brown gummy solid (300 mg). The crude product was purified by SFC, Chiralpak AS-H 250 x 30 mm, 5 µm column (10% methanol, F = 80 mL / min) to yield 55.7 mg of peak 1 (>99% ee) and 52.1 mg of peak 2 (>99% ee) as off-white solids (35.5% combined yield).

[0221] Peak 1: Example 165 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. 1 H NMR (400MHz, methanol-d4) δ ppm 7.70(s, 1H), 7.56(s, 1H), 6.52(s, 1H), 5.61(dt, J=4.0, 2.2Hz, 1H), 4.62(dd, J=10.3, 2.8Hz, 1H), 4 .45(d, J=12.9Hz, 1H), 4.24(d, J=13.1Hz, 1H), 4.08(ddd, J=11.5, 3.6, 1.8Hz, 1H), 3.91(s, 3H), 3.8 0(td, J=11.5, 2.8Hz, 1H), 3.52(s, 3H), 3.06~3.21(m, 2H), 2.59(s, 3H), 2.16~2.31(m, 4H), 1.70~1.91(m, 4H). m / z (ESI, cation): 494.1 (M+H) + .

[0222] Peak 2: Example 166 5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. 1 H NMR (400MHz, methanol-d4) δ ppm 7.71(s, 1H), 7.57(s, 1H), 6.48(s, 1H), 4.63(d, J=9.3Hz, 1H), 4.40~4.53(m, 2H), 4.30(d, J=13.1Hz, 1H), 4.08(t, J=12.4Hz, 3H), 3.91(s, 3) H), 3.81(t, J=11.4Hz, 1H), 3.64(t, J=11.8Hz, 2H), 3.54(s, 3H), 3.18(dd, J=18.3, 12.0Hz, 2H), 2.58(s, 3H), 1.97(qd, J=12.7, 4.3Hz, 4H). m / z (ESI, positive ion): 494.1 (M + H) + .

[0223] Absolute stereochemistry was arbitrarily assigned.

[0224] Method 14 Example 167: (2R,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and (2S,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate (mixture of cis isomers) Example 168: (2S,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and (2R,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate (mixture of trans isomers). [ka]

[0225] Step 1: Ethyl 4-bromotetrahydro-2H-pyran-2-carboxylate. In a 20 mL vial, add ethyl 4-hydroxyoxane-2-carboxylate (675 mg, 3.87 (mmol, Aurum Pharmatech LLC) and DCM (7750 μl) were added, and the vial was cooled to 0 °C. Subsequently, triphenylphosphine (1118 mg, 4.26 mmol) and carbon tetrabromide (1285 mg, 3.87 mmol) were added. The reaction was warmed to room temperature and stirred for 16 h, then quenched with saturated sodium bicarbonate and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography eluting with 0 to 25% EtOAc in heptane to provide ethyl 4-bromotetrahydro-2H-pyran-2-carboxylate (0.49 g, 2.067 mmol, 53.3% yield) as a colorless oil. 1 H NMR (500MHz, CDCl3)δ ppm 1.30(t, J=7.14Hz, 3H), 1.89~1.96(m, 1H), 2.13~2.23(m, 2H), 2.25~2.37(m, 1H), 4.00(dd, J=7.7 9, 2.72Hz, 2H), 4.24(q, J=7.14Hz, 2H), 4.50(dd, J=10.12, 2.85Hz, 1H) 4.68(quin, J=3.76Hz, 1H).

[0226] Step 2: Ethyl 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate. To a 2-dram vial was added 7-chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (50 mg, 0.148 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (3.25 mg, 0.015 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl (3.97 mg, 0.015 mmol), lithium hydroxide (7.08 mg, 0.296 mmol), and (4,4′-di-tert-butyl-2,2′-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate (Ir catalyst, 1.66 mg, 1.479 μmol). The vial was flushed with N and 1,2-dimethoxyethane (1680 μL), tris(trimethylsilyl)silane (36.8 mg, 46.0 μL, 0.148 mmol), and 4-bromotetrahydro-2H-pyran-2-carboxylate (52.6 mg, 0.222 mmol) was added. After 3 hours of stirring and irradiation (Kessil lamp, full intensity, 800 rpm, fan on), the reaction was filtered and concentrated. The crude material was subjected to reverse-phase preparative HPLC using 0.1% TFA in CHCN / HO, a gradient of 25% to 70% TFA over 12 minutes, to give two peaks: Peak 1: Example 167, ethyl (2R,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and ethyl (2S,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate (mixture of cis isomers) as a white solid (5.7 mg, 0.012 mmol, 8.38% yield).1 H NMR (500MHz, DMSO-d6) δ7.40~7.46(m, 3H), 7.32~7.39(m, 1H), 4.04~4.17(m, 4H), 3.58(dt, J=2.72, 11.68Hz, 1H), 3.42(s, 3 H), 3.17~3.26(m, 3H), 2.60(s, 3H), 2.10~2.18(m, 1H), 1.76~1.87(m, 2H), 1.72(q, J=12.02Hz, 1H), 1.18(t, J=7.07Hz, 3H). m / z (ESI, cation): 460.0 (M+H) + .

[0227] Peak 2: Example 168, (2S,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylic acid as an off-white solid Ethyl and (2R,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate (mixture of trans enantiomers) (7 mg, 0.014 mmol, 10.3% yield). 1 H NMR (500MHz, DMSO-d6) δ7.41~7.48(m, 3H), 7.34~7.39(m, 1H), 4.52~4.62(m, 1H), 4.13~4.23(m, 2H), 3.79~3.88(m, 2H), 3.42~3 .44(m, 3H), 3.02~3.09(m, 1H), 2.59~2.62(m, 3H), 2.21~2.29(m, 1H), 2.07~2.17(m, 1H), 1.80~1.91(m, 2H), 1.20~1.28(m, 3H). m / z (ESI, cation): 460.0 (M+H) + .

[0228] The absolute stereochemistry was arbitrarily assigned. The relative stereochemistry (cis / trans) was confirmed by NMR. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0229] Table B. Additional Compounds The compounds disclosed below in Table B were made by the methods of the present disclosure or by analogous methods. The appropriate reagents, starting materials, and conditions required to synthesize the compounds of Table B will be apparent to one of ordinary skill in the art. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11] [Table 9-12] [Table 9-13] [Table 9-14] [Table 9-15] [Table 9-16] [Table 9-17] [Table 9-18] [Table 9-19] [Table 9-20] [Table 9-21] [Table 9-22] [Table 9-23] [Table 9-24]

[0230] Table C. Additional Compounds The compounds disclosed below in Table C were made by the methods of the present disclosure or by analogous methods. The appropriate reagents, starting materials, and conditions necessary to synthesize the compounds of Table C will be apparent to one of ordinary skill in the art. Compounds designated with "(+ / -)" were isolated as a mixture of diastereomers sharing the same relative stereochemistry (i.e., cis or trans). Compounds designated with "(rac)" were isolated as a mixture of all possible stereoisomers of the indicated compound. [Table 10-1] [Table 10-2] [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] [Table 11-7] [Table 11-8] [Table 11-9] [Table 11-10] [Table 11-11] [Table 11-12] [Table 11-13] [Table 11-14] [Table 11-15] [Table 11-16] [Table 11-17] [Table 11-18] [Table 11-19] [Table 11-20] [Table 11-21] [Table 11-22] [Table 11-23] [Table 11-24]

[0231] Synthesis of intermediates Method 15 Intermediate 1: (S)-2-(1H-pyrazol-4-yl)morpholine Intermediate 2: (R)-2-(1H-pyrazol-4-yl)morpholine [ka] Step 1: 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one. To a solution of 1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (4.5 g, 22.47 mmol) in DCM (204 mL) was added mono(N,N,N-trimethylbenzenaminium) tribromide (9.15 g, 23.60 mmol) in small portions at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered, and the solvent was evaporated. The reaction was repeated on the same scale (4.5 g). The combined crude was purified by column chromatography eluting with a gradient of 0 to 30% heptane / EtOAc-EtOH (3 / 1) to provide 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one (9.9 g, 35.47 mmol, 79%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ ppm 8.65 (s, 1H), 8.05 (s, 1H), 7.27~7.40 (m, 5H), 5.39 (s, 2H), 4.60 (s, 2H). m / z (ESI, cation):.279.0(M+H) + .

[0232] Step 2: 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one. To a solution of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one (4.45 g, 15.94 mmol) in THF (46 mL) at 0° C. was added 2-(benzylamino)ethan-1-ol (2.84 g, 18.81 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 6 hours. Water was then added to the reaction mixture, and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were dried over MgSO4, filtered, and concentrated. The reaction was repeated on the same scale. The combined crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column eluting with a gradient of 0% to 10% DCM / MeOH to provide 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (8.3 g, 23.75 mmol, 75% yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.57(s, 1H), 7.96(s, 1H), 7.20~7.31(m, 10H), 5.36(s, 2H), 4.44(t,J=5. 2Hz, 1H), 3.68(d,J=3.1Hz, 2H), 3.43~3.53(m, 4H), 2.60(d,J=6.2Hz, 2H). m / z (ESI, cation): 350.0 (M+H) + .

[0233] Step 3: 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one. To a solution of 2-(benzyl(2-hydroxypropyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one (8.30 g, 23.75 mmol) in methanol (79 mL) at 0° C. was added sodium borohydride (1.797 g, 47.5 mmol) in small portions. The reaction mixture was stirred at 0° C. for 30 minutes and then at room temperature for 2 hours. 90% of the solvent was concentrated under vacuum. Ice-cold water was added dropwise to quench the reaction. The reaction mixture was extracted with EtOAc (×3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-ol (8.35 g, 23.76 mmol, 100% yield) was used as such in the next step. 1 H NMR (400MHz, DMSO-d6) δ ppm 7.63(s, 1H), 7.25~7.35(m, 8H), 7.18~7.24(m, 3H), 5.26(s, 2H), 4.82(d, J=3.8Hz, 1H), 4.37(t, J=5.4 Hz, 2H), 3.68 (d, J=3.5Hz, 2H), 3.40~3.47 (m, 2H), 3.17 (d, J=5.3Hz, 1H), 2.64 (dd, J=6.4, 4.2Hz, 4H). m / z (ESI, cation): 352.2 (M+H) + .

[0234] Step 4: 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine, hydrochloride. A solution of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-ol (8.35 g) in 6 N HCl (61 mL) was heated at 110 °C for 2 h. The reaction mixture was evaporated to dryness under reduced pressure. The resulting solid was triturated with EtO to give 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine as the HCl salt. The crude material was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d) δ ppm 11.97(s, 1H), 7.87(s, 1H), 7.65(dt, J=7.5, 3.6Hz, 2H), 7.42~7.51(m, 4H), 7.31(dt, J=13.8, 6.7Hz, 3H), 7.19~7.24(m, 2H), 5.29( s, 2H), 4.97(dd, J=11.1, 2.3Hz, 1H), 4.27~4.39(m, 2H), 3.96~4.06(m, 2H), 3.37(d, J=12.1Hz, 1H), 3.14(dt, J=31.1, 11.0Hz, 3H). m / z (ESI, cation): 334.2 (M+H) + .

[0235] Step 5: 2-(1H-pyrazol-4-yl)morpholine. A suspension of 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine (23.75 mmol) as the HCl salt and dihydroxypalladium (3.34 g, 4.75 mmol) in ethanol (120 mL) was placed under vacuum and flushed with nitrogen. The reaction mixture was flushed with hydrogen and stirred at room temperature under hydrogen atm (25 psi) for 18 hours. The catalyst was removed by filtration over Celite and washed several times with ethanol. The solvent was concentrated under vacuum. The crude 2-(1H-pyrazol-4-yl)morpholine was purified by chiral SFC using an AD30 × 250 mm, 5-micron column (mobile phase 20% ethanol, 0.2% diethylamine), F = 180 mL / min, to provide two isomers as light brown solids. The absolute stereochemistry of intermediates 1-4 was assigned based on the independent synthesis (pyrazole methylation followed by SnAr coupling) and subsequent X-ray crystallography of both stereoisomers in Example 1. The stereochemistry indicators for intermediates 5-15 in Table 8 below have been arbitrarily assigned.

[0236] Peak 1 (Intermediate 1): (S)-2-(1H-pyrazol-4-yl)morpholine (1.67 g, 10.9 mmol, 46% yield, ee>97%). 1 H NMR (400MH z, CDCl3)δ ppm 7.58(s, 2H), 4.62(dd, J=10.3, 2.3Hz, 1H), 3.95~4.03(m, 1H), 3.78~3.87(m, 1H), 3.14(dd, J=12.4, 1.8Hz, 1H), 2.89~3.01(m, 3H). m / z (ESI, cation). 154.2(M+H) + .

[0237] Peak 2 (Intermediate 2): (R)-2-(1H-pyrazol-4-yl)morpholine (1.59 g, 10.4 mmol, 44% yield, ee>89%). 1 H NMR (400MHz, CDCl3)δ ppm 7.58(s, 2H), 4.62(dd, J=10.3, 2.3Hz, 1H), 3.93~4.03(m, 1H), 3.78~3.87(m, 1H), 3.16(dd, J=12.4, 1.8Hz, 1H), 2.89~3.01(m, 3H). m / z (ESI, cation): 154.2 (M+H) + . [Table 12-1] [Table 12-2]

[0238] Method 16 Intermediate 17: 4,4-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine. [ka] Step 1: tert-Butyl 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate. Tert-Butyl 3-(1-methyl-1H-pyrazol-4-yl)-4-oxopiperidine-1-carboxylate (1 g, 1.647 mmol) and DAST (2.2 mL, 16.47 mmol) in DCM (40 mL) were added to a 100 mL round-bottom flask at 0 °C. The reaction mixture was warmed to room temperature and stirred for 48 hours, then quenched with 10% sodium bicarbonate (50 mL) and extracted with DCM (30 mL). The organic extract was dried over Na SO . The solution was filtered and concentrated in vacuo to give the crude mineral as an orange oil. The crude material was purified by silica gel chromatography eluting with 50% EtOAc in hexanes to provide tert-butyl 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (500 mg, 1.1 mmol, 64.5% yield) as a yellow oil.

[0239] Step 2: 4,4-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine hydrochloride. To a 10 mL round-bottom flask was added tert-butyl 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylate (60 mg, 0.199 mmol) in DCM (4 mL). The mixture was cooled to 0 °C, and HCl in dioxane (0.5 mL, 2.000 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 hours, and then concentrated in vacuo to give the crude product, which was washed with diethyl ether to provide 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine hydrochloride (25 mg, 0.124 mmol, 62.4% yield) as a white solid (hygroscopic). 1 H NMR (400 MHz, DMSO-d): δ ppm 9.36(d, J=25.1Hz, 2H), 7.73(s, 1H), 7.41 (s, 1H), 3.82 (s, 4H), 3.57 (s, 2H), 3.18 (d, J=5.1Hz, 1H), 2.39 (d, J=11.9Hz, 2H).

[0240] Method 17 Intermediate 18: 4-(4-Bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine. [ka] To a 500 mL flask were added 2-methylisonicotinaldehyde (5 g, 41.3 mmol), 3-buten-1-ol (3.13 g, 3.72 mL, 43.3 mmol), and DCM (83 mL). The mixture was stirred at 0 °C, and hydrogen bromide-acetic acid (30.4 g, 22.42 mL, 124 mmol) was added slowly in one portion. The reaction mixture was warmed to room temperature after 5 minutes and stirred for 4 hours. The mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The resulting crude material was purified by silica gel chromatography eluting with 0% to 30% EtOAc / EtOH (3:1) in heptane to provide 4-(4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine as a mixture of four diastereomers (52% overall yield). A second silica gel column can be used to separate the cis and trans isomers of the product.

[0241] Product 1: 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine and 4-((2S,4R)-4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine (mixture of cis isomers): 3.83 g 1 H NMR (500MHz, CDCl3)δ ppm 3.56~3.65 (m, 1H) 4.01~4.10 (m, 1H) 4.11~4.19 (m, 1H) 4.37~4.42 (m, 1H) 4.52~4.58 (m, 1H) 4.76~4.83(m, 1H)4.84~4.95(m, 1H)7.00~7.09(m, 1H)7.09~7.19(m, 1H)8.43~8.49(m, 1H).

[0242] Product 2: 4-((2S,4S)-4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine and 4-((2R,4R)-4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine (mixture of trans isomers): 1.69 g. 1 H NMR (500MHz, CDCl3)δ ppm 1.92~2.06(m, 1H)2.12~2.24(m, 1H)2.25~2.35(m, 1H)2.47~2.55(m, 1H)2.56~2.62(m, 3H)3.56~3.7 1(m, 1H) 4.16~4.22(m, 1H) 4.23~4.39(m, 2H) 7.00~7.09(m, 1H) 7.11~7.18(m, 1H) 8.45~8.50(m, 1H).

[0243] The absolute stereochemistry was arbitrarily assigned. The relative stereochemistry (cis / trans) was confirmed by NMR. [Table 13]

[0244] Biological evaluation This section provides a biological evaluation of the specific examples provided herein. See Examples A1 and A2 and Tables 10 and 11.

[0245] Example A1. In vitro measurement of triggering receptor 2 activity expressed on myeloid cells using the cellular phosphorylation of spleen tyrosine kinase ("Syk") assay Pharmacological measurements of TREM2 signaling through DAP12 were performed using a single-cell cloned HEK293 stable cell line overexpressing TREM2 and DAP12 ("TREM2 / DAP12-HEK"). The readout for TREM2 signaling utilized PerkinElmer AlphaScreen / AlphaLISA technology, which monitors the phosphorylation level of Syk kinase. The TREM2 / DAP12-HEK cell line was cultured in DMEM-F12 (Corning 10-092-CM) supplemented with 1X penicillin / streptomycin (Corning 30-002-CI), 1X GlutaMAX (Gibco 35050-061), and 10% fetal bovine serum (Life Technologies 10099), referred to as "HEK culture medium." A suspension of TREM2 / DAP12-HEK cells was prepared in HEK culture medium and dispensed into 384-well poly-D-lysine-coated microplates (Corning 354661) at a density of 20,000 cells / well using a Multidrop Combi peristaltic microplate dispenser (Thermo), 25 μL of cell suspension / well. The plate containing the cells was then incubated for 20 hours in a humidified cell culture incubator (Thermo) at 37°C with 5% CO2. After incubation, the culture medium was removed from all wells of each microplate and replaced with 20 μL of "assay buffer" composed of DMEM-F12 (Corning 10-092-CM) supplemented with 1X penicillin / streptomycin (Corning 30-002-CI) and 0.1% Pluronic F-68 polyol (MP Biomedical 092750049) using a Bravo 384-well pipette-based liquid handling system (Agilent). The assay buffer contained diluted test substances (1% final DMSO concentration relative to the compound), or 100 nM anti-human / mouse TREM2 antibody (R&D Systems MAB17291) as a positive control, or 100 nM rat IgG2B isotype Ab (R&D Systems MAB0061) as a negative control. Plates were incubated with the test substances and controls for 45 min at room temperature, and then the medium was removed and plated.The plate was aspirated / removed from each well. Using a Multidrop Combi peristaltic liquid handler (Thermo), 15 μL / well of "Cell Lysis Immunoassay Buffer" was dispensed. The Cell Lysis Immunoassay Buffer contained M-PER Mammalian Protein Extraction Reagent (Pierce / ThermoFisher 78505), 1X Halt Phosphatase Inhibitor Cocktail (ThermoFisher #78427), 0.1875 nM anti-phospho-Syk (Tyr525 / 526) (C87C1) rabbit mAb (Cell Signaling Technologies, catalog #2710), and 1.5 nM biotinylated mouse anti-human Syk (4D10) antibody (BD Biosciences, catalog #624008). After adding the Cell Lysis Immunoassay Buffer, the plate was incubated at room temperature for 1 hour. Using a Multidrop Combi liquid handler, 15 μL of AlphaScreen acceptor bead solution containing 7.5 μg / mL anti-rabbit IgG (Fc-specific) AlphaLISA acceptor beads (Perkin Elmer AL104R) in 1X immunoassay buffer (Perkin Elmer AL000F) was dispensed into each well of the microplate. The plate was incubated for 2 hours at room temperature. After incubation with the AlphaLISA acceptor bead solution, 15 μL of AlphaScreen donor bead solution containing 30 μg / mL AlphaScreen streptavidin donor beads (Perkin Elmer 6760002B) in 1X immunoassay buffer (Perkin Elmer AL000F) was dispensed into each well of the microplate using a Multidrop Combi liquid handler (Thermo). Because the AlphaScreen reagents are light-sensitive, the microplate was incubated for 2 hours protected from light.Once the final incubation was complete, AlphaScreen signals were acquired from donor and acceptor beads using an Envision high-throughput multimodal microplate reader (Perkin Elmer) calibrated to the plate type, equipped with the AlphaScreen mirror and filter set, in 384-well mode at 680 nm excitation wavelength. The total measurement time per well was 550 ms with a 180 ms excitation time.

[0246] The AlphaScreen signal for each well of the microplate was read plate by plate, and each untreated test article well value (x) was normalized to a percent of control ("POC") value using the following formula: POC = ((x - μ n ) / (μ p -μ n ))*100, where (μ n ) is the average negative control well signal for a given plate, and (μ p ) is the mean positive control TREM2 antibody signal for a given plate. Each plate contained 12 of each type of control well, which were used to generate the mean values. For concentration-response curve analysis with test substances tested at various concentrations, % activation values ​​were analyzed using a four-parameter logistic or sigmoidal dose-response model using GeneData Screener (GeneData, AG) or GraphPad Prism7 (Graphpad Software, Inc.). Test article efficacy was expressed as EC50, which corresponds to the test article concentration capable of activating the phospho-Syk AlphaScreen signal to 50% of the maximal response.

[0247] For pharmacological evaluation of TREM2 signaling in a cell line that naturally expresses TREM2, we utilized human monocyte-derived macrophages, positively selected from large-scale apheresis of healthy human donors. +Monocytes (Lonza) were cultured in low-attachment bioprocess buffers for 9 days in RPMI-1640 medium (Gibco 11875093) supplemented with 10% fetal bovine serum (Gibco 10082139), 10 mM HEPES (Gibco 15630080), 1X penicillin-streptomycin (Gibco 15140122), 1X non-essential amino acids (Gibco 11140050), 1 mM sodium pyruvate (Gibco 11360070), 1X GlutaMAX (Gibco 35050-061), and 50 ng / mL M-CSF (Promocell C-60442A). The cells were differentiated into macrophages using a syringe (Saint-Gobain Performance Plastics). The macrophages were collected and stored in Banker (Wako / GC). The cells were cryopreserved in LYMPHOTEC 302-14681 / CS-02-001 and further quality-controlled for the expression of cell surface markers, including TREM2, using flow cytometry. The batches used for the phospho-Syk assay showed approximately 80–90% TREM2 expression by flow cytometry. + It was.

[0248] After macrophages recovered from freezing, a viable cell suspension was prepared at 100,000 cells / mL in "macrophage pSyk assay medium," which consisted of RPMI-1640 containing GlutaMAX medium (Gibco 61870036) supplemented with 10% fetal bovine serum (Gibco 10082139), 10 mM HEPES (Gibco 15630080), 1X penicillin-streptomycin (Gibco 15140122), 1X non-essential amino acids (Gibco 11140050), 1 mM sodium pyruvate (Gibco 11360070), and 10 ng / mL M-CSF (Promocell C-60442A). Using a Multidrop Combi peristaltic liquid handling instrument (Thermo), 50 μL / well of cell suspension (5,000 cells / well) was dispensed into a poly-d-lysine-coated 384-well plate (Corning 354661). After 30 min of incubation at room temperature, the plate was incubated for 16 h in a humidified cell culture incubator (Thermo) at 37°C with 5% CO2. To initiate the assay with test substances, the medium in each well of the assay plate was aspirated and replaced with 20 μL of assay buffer containing diluted test substances (1% final DMSO concentration relative to compound) or assay buffer containing 1% DMSO as a negative control. The remainder of the macrophage AlphaScreen phospho-Syk assay followed the procedure detailed above for the HEK cell line.

[0249] After reading the AlphaScreen signal for each well of the microplate containing macrophages, each untreated test article well value (x) was calculated by subtracting the background from the average negative control well signal for a given plate. Each plate contained 12–24 negative control wells, which were used to generate background-subtracted average values. For concentration-response curve analysis using test articles tested at various concentrations, values ​​were analyzed with a four-parameter logistic curve fit using GraphPad Prism 7 (Graphpad Software, Inc.). The efficacy of each test article was expressed as the EC50, which corresponds to the test article concentration capable of activating the background-subtracted phospho-Syk AlphaScreen signal to 50% of the maximal response.

[0250] The results presented in Table 10 were generated in the in vitro assay described above for Examples 1-275. This assay can be used to test any of the compounds described herein and to evaluate and characterize the ability of the compound to act as an agonist of TREM2.

[0251] Compounds designated as "A" exhibited an EC50 of ≦0.05 μM. Compounds designated as "B" exhibited an EC50 of >0.05 μM to ≦0.5 μM. Compounds designated as "C" exhibited an EC50 of >0.5 μM to ≦3.0 μM. Compounds designated as "D" exhibited an EC50 of >3.0 μM to ≦100 μM.

[0252] Compounds designated as "++++" exhibited an Emax of >300. Compounds designated as "+++" exhibited an Emax of >200 to ≦300. Compounds designated as "++" exhibited an Emax of >100 to ≦200. Compounds designated as "+" exhibited an Emax of >45 to ≦100. Table 10. hTREM2 EC50 data (HEK293 cells) for the examples provided herein. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6]

[0253] Example A2. In vitro measurement of triggering receptor 2 activity expressed on myeloid cells using the cellular phosphorylation of spleen tyrosine kinase ("Syk") assay used in Examples 276-283 The efficacy of TREM2 agonists was measured using a HEK cell line (HEK293T-hTREM2 cells) expressing human TREM2 and DAP12. Binding and activation of hTREM2 increases Syk phosphorylation. The resulting level of Syk phosphorylation was measured using a commercially available AlphaLisa reagent kit. To perform the assay, HEK-hTREM2 cells were seeded in 25 μL of complete growth medium at 14,000 cells per well in a 384-well plate and incubated at 37°C, 5% CO2 for 20–24 hours. Prior to the assay, test compounds were diluted in assay buffer in the 384-well plate and allowed to equilibrate for 30 minutes. Growth medium was removed from the cell plate by inversion onto blotting paper, and 25 μL of test compound in assay buffer was added to the cells. The cells were incubated for 45 minutes at room temperature. After 45 minutes, the assay buffer was removed and 10 μL of lysis buffer was added. The plate was shaken at 350 RPM for 20 minutes at room temperature. After complete lysis, AlphaLisa reagent was added to the lysate, and fluorescence intensity was measured using a Perkin Elmer Envision plate reader. Intensity was used to generate a standard curve and calculate percent activation. Curve fitting was performed using Prism v9 software, log (agonist) vs. response-variable slope (four parameters), and EC50 was calculated from the curve fit.

[0254] The results presented in Table 11 were generated in the in vitro assay described above for Examples 276-283. This assay can be used to test any of the compounds described herein and to evaluate and characterize the ability of the compound to act as an agonist of TREM2.

[0255] Compounds designated as "A" exhibited an EC50 of ≦0.05 μM. Compounds designated as "B" exhibited an EC50 of >0.05 μM to ≦0.5 μM. Compounds designated as "C" exhibited an EC50 of >0.5 μM to ≦3.0 μM. Compounds designated as "D" exhibited an EC50 of >3.0 μM to ≦100 μM. [Table 15]

[0256] References Bianchin,M.M.,H.M.Capella,D.L.Chaves,M.Steindel,E.C.Grisard,G.G.Ganev,J.P.da Silva Junior,S.Neto Evaldo,M.A.Poffo,R.Walz,C.G.Carlotti Junior and A.C.Sakamoto(2004).“Nasu-Hakola disease(polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy--PLOSL):a dementia associated with bone cystic lesions.From clinical to genetic and molecular aspects.”Cell Mol Neurobiol24(1):1-24. Bianchin,M.M.,K.C.Martin,A.C.de Souza,M. A.de Oliveira and C.R.Rieder(2010).“Nasu-Hakola disease and primary microglial dysfunction.”Nat Rev Neurol6(9):2 p following523. Cantoni,C.,B.Bollman,D.Licastro,M.Xie,R.Mikesell,R.Schmidt,C.M.Yuede,D.Galimberti,G.Olivecrona,R.S.Klein,A.H.Cross,K.Otero and L.Piccio(2015).“TREM2 regulates microglial cell activation in response to demyelination in vivo.”Acta Neuropathol129(3):429-447. Colonna,M.and O.Butovsky(2017).“Microglia Function in the Central Nervous System During Health and Neurodegeneration.” Annu Rev Immunol35:441–468. Cserep, C., B. Posfai, N. Lenart, R. Fekete, Z. Laszlo, Z. Lele, B. Orsolits, G. Molnar, S. Heindl, ADSchwarcz, K. Ujvari, Z. Kornyei, K. Toth, E. Szabadits, B. Sperlag h,M.Baranyi,L.Csiba,T.Hortobagyi,Z.Magloczky,B.Martinecz,G.Szabo,F.Erdelyi,R.Szipocs,MMTamkun,B.Gesierich,M.Duering,I.Katona,A.Liesz,G.Tamas and A.Denes(2019).“Microglia monitor and protect neuronal function via specialized somatic purinergic junctions.” Science10.1126 / science.aax6752:pp.1-18. Dardiotis, E., V. Siokas, E. Pantazi, M. Dardioti, D. Rikos, G. Xiromerisiou, A. Markou, D. Papadimitriou, M. Speletas and GMHadjigeorgiou(2017). of the literature.” Neurobiol Aging53:194.e13-194.e22. Deming,Y.,F.Filipello,F.Cignarella,C.Cantoni,S.Hsu,R.Mikesell,Z.Li,JLDel-Aguila,U.Dube,FGFarias,J.Bradley,J.Budde,L.Ibanez,MVFernandez,K.Blennow,H.Zetterberg,A.Heslegrave,PMJohanss on,J.Svensson,B.Nellgard,A.Lleo,D.Alcolea,J.Clarimon,L.Rami,JLMolinuevo,M.Suarez-Calvet,E.Morenas-Rodriguez,G.Kleinberger,M.Ewers,O.Harari,C.Haass,TJBrett,BABenitez,CMKarch,L.Piccio and C.Cruchaga (2019).“The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk.”Sci Transl Med11(505)eaau2291:pp.1-19. Doens,D.and PLFernandez(2014).“Microglia receptors and their implications in the response to amyloid beta for Alzheimer's r's disease pathogenesis.”J Neuroinflammation11:48(pp.1-14). Domingues, HS, CCPortugal, R. Socodato and JBRelvas (2016). “Oligodendrocyte, Astrocyte, and Microglia Crosstalk in Myelin Development, Damage, and Repair.”Front Cell Dev Biol4:71(pp.1-16). Ewers, M., N. Franzmeier, M. Suarez-Calvet, E. Morenas-Rodriguez, MAACaballero, G. Kleinberger, L. Piccio, C. Cruchaga, Y. Deming, M. Dichgans, JQ Trojanowski, LMShaw, MW Weiner, C. Haass and I. Alzheimer's Disease Neuroimaging(2019).“Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease.” Sci Transl Med11(507):eaav6221(pp.1-13). Golde,TE,WJStreit and P.Chakrabarty(2013).“Alzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease.” Alzheimers Res Ther5(3):24(pp.1-6). Guerreiro, R., A. Wojtas, J. Bras, M. Carrasquillo, E. Rogaeva, E. Majounie, C. Cruchaga, C. Sassi, JSKauwe, S. Younkin, L. Hazr you,J.Collinge,J.Pocock,T.Lashley,J.Williams,JCLambert,P.Amouyel,A.Goate,R.Rademakers,K.Morgan,J.Powell,P.St George-Hyslop,A.Singleton and J.Hardy(2013).“TREM2 Variants in Alzheimer's Disease.” N Engl J Med10(368):117-127. Guerreiro R.,E.Lohmann,J.M.Bras,J.R.Gibbs,J.D.Rohrer,N.Gurunlian,B.Dursun,B.Bilgic,H.Hanagasi,H.Gurvit,M.Emre,A.Singleton and J.Hardy(2013).“Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement.”JAMA Neurol70(1):78-84. Guo,Y.,X.Wei,H.Yan,Y.Qin,S.Yan,J.Liu,Y.Zhao,F.Jiang,H.Lou(2019).“TREM2 deficiency aggravates α-synuclein-induced neurodegeneration and neuroinflammation in Parkinson’s disease models.”FASEB J33(11):12164-12174. Hickman,S.,S.Izzy,P.Sen,L.Morsett and J.El Khoury(2018).“Microglia in neurodegeneration.”Nat Neurosci21(10):1359-1369. Hickman,S.E.and J.El Khoury(2019).“Analysis of the Microglial Sensome.”Methods M ol Biol2034:305-323. Hickman,S.E.,N.D.Kingery,T.K.Ohsumi,M.L.Borowsky,L.C.Wang,T.K.Means and J.El Khoury(2013).“The microglial sensome revealed by direct RNA sequencing.”Nat Neurosci16(12):1896-1905. Hollingworth,P.,D.Harold,R.Sims,A.Gerrish,JCLambert,MMCarrasquillo,R.Abraham,MLHamshere,JSPahwa,V.Moskvina,K.Dowzell,N.Jones,A .Stretton,J.Thomas,A.Richards,D.Ivanov,J.Widdowson,J.Chapman,S.Lovestone,J.Powell,P.Proitsi,MKLupton,J.Bryne,DCRubinsztein,M.G ill,B.Lawlor,A.Lynch,KSBrown,PAPassmore,D.Craig,B.McGuinness,S.Todd,C.Holmes,D.Mann,ADSmith,H.Beaumont,D.Warden,G.Wilcock,S.Love e,PGKehoe,NMHooper,ERVardy,J.Hardy,S.Mead,NCFox,M.Rossor,J.Collinge,W.Maier,F.Jessen,E.Ruther,B.Schurmann,R.Heun,H.Kolsch,H.van. man Bussche,I.Heuser,J.Kornhuber,J.Wiltfang,M.Dichgans,L.Frolich,H.Hampel,J.Gallacher,M.Hull,D.Rujescu,I. Giegling,AMGoate,JSKauwe,C.Cruchaga,P.Nowotny,JCMorris,K.Mayo,K.Sleegers,K.Bettens,S.Engelborghs,PPDe Dein,J.Van Broeckhoven,G.Livingston,NJBass,H.Gurling,A.McQuillin,R.William,P.Deloukas,A.Al-Chalabi,CEShaw,M.Tsolaki,AB Singleton,R.Guerreiro,TWMuhleisen,MMNothen,S.Moebus,KHJockel,N.Klopp,HEWichmann,VSPankratz,SBSando,JOAasly,M.Barcikowska,ZKWszolek,DWDickson,NRGraff-Radford,RCPetersen,I.Alzheimer's Disease Neuroimaging,CMvan Duijn,MMBreteler,MAIkram,ALDeStefano,ALFitzpatrick,O.Lopez,LJLauner,S.Seshadri,C.consortium,C.Berr,D.Campion,J.Epelbaum,JFDartigues,C.Tzourio,A.Alperovitch,M.L athrop,E.consortium,TMFeulner,P.Friedrich,J.Riehle,M.Krawczak,S.Schreiber,M.Mayhaus,S.Nicolhaus,S.Wagenpfeil,S.Steinberg,H.Stefansson,K.Stefansson,J.Snaedal,S. Bjornsson,PVJonsson,V.Chouraki,B.Genier-Boley,M.Hiltunen,H.Soininen,O.Combarros,D.Zelenica,M.Delepine,MJBullido,F.Pasquier,I.Mateo,A.Frank-Garcia,E.Porcellini, O.Hanon,E.Coto,V.Alvarez,P.Bosco,G.Siciliano,M.Mancuso,F.Panza,V.Solfrizzi,B.Nacmias,S.Sorbi,P.Bossu,P.Piccardi,B.Arosio,G.Annoni,D.Seripa,A.Pilotto,E.Scarpin. i,D.Galimberti,A.Brice,D.Hannequin,F.Licastro,L.Jones,P.A.Holmans,T.Jonsson,M.Riemenschneider,K.Morgan,S.G.Younkin,M.J.Owen,M.O’Donovan,P.Amouyel and J.Williams(2011).“Common variants at ABCA7,MS4A6A / MS4A4E,EPHA1,CD33 and CD2AP are associated with Alzheimer’s disease.”Nat Genet43(5):429-435. Hong,S.,L.Dissing-Olesen and B.Stevens(2016).“New insights on the role of microglia in synaptic pruning in health and disease.”Curr Opin Neurobiol36:128-134. Huang,Q.Q.and R.M.Pope(2009).“The role of toll-like receptors in rheumatoid arthritis.”Curr Rheumatol Rep11(5):357-364. Ikegami,A.,K.Haruwaka and H.Wake(2019).“Microglia:Lifelong modulator of neural circuits.”Neuropathology39(3):173-180. Jaitin,D.A.,L.Adlung,C.A.Thaiss,A.Weiner,B.Li,H.Descamps,P.Lundgren,C.Bleriot,Z.Liu,A.Deczkowska,H.Keren-Shaul,E.David,N.Zmora,S.M.Eldar,N.Lubezky,O.Shibolet,D.A.Hill,M.A.Lazar,M.Colonna,F.Ginhoux,H.Shapiro,E.Elinav and I.Amit(2019).“Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner.”Cell178(3):686-698.e14. Jay,T.R.,V.E.von Saucken and G.E.Landreth(2017).“TREM2 in Neurodegenerative Diseases.”Mol Neurodegener12(1):56(pp.1-33).Jay,T.R.,C.M.Miller,P.J.Cheng,L.C.Graham,S.Bemiller,M.L.Broihier,G.Xu,D.Margevicius,J.C.Karlo,G.L.Sousa,A.C.Cotleur,O.Butovsky,L.Bekris,S.M.Staugaitis,J.B.Leverenz,S.W.Pimplikar,G.E.Landreth,G.R.Howell,R.M.Ransohoff,B.T.Lamb(2015).“TREM2 deficiency eliminates TREM2 + inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models.”J Exp Med212(3):287-295. Jonsson,T.,H.Stefansson,S.Steinberg,I.Jonsdottir,P.V.Jonsson,J.Snaedal,S.Bjornsson,J.Huttenlocher,A.I.Levey,J.J.Lah,D.Rujescu,H.Hampel,I.Giegling,O.A.Andreassen,K.Engedal,I.Ulstein,S.Djurovic,C.Ibrahim-Verbaas,A.Hofman,M.A.Ikram,C.M.van Duijn,U.Thorsteinsdottir,A.Kong and K.Stefansson(2013).“Variant of TREM2 associated with the risk of Alzheimer’s disease.”N Engl J Med368(2):107-116. Kang,S.S.,A.Kurti,K.E.Baker,C.C.Liu,M.Colonna,J.D.Ulrich,D.M.Holtzman,G.Bu and J.D.Fryer(2018).“Behavioral and transcriptomic analysis of Trem2-null mice:not all knockout mice are created equal.”Hum Mol Genet27(2):211-223. Keren-Shaul,H.,A.Spinrad,A.Weiner,O.Matcovitch-Natan,R.Dvir-Szternfeld,T.K.Ulland,E.David,K.Baruch,D.Lara-Astaiso,B.Toth,S.Itzkovitz,M.Colonna,M.Schwartz and I.Amit(2017).“A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease.”Cell169(7):1276-1290.e17. Kleinberger,G.,Y.Yamanishi,M.Suarez-Calvet,E.Czirr,E.Lohmann,E.Cuyvers,H.Struyfs,N.Pettkus,A.Weninger-Weinzierl,F.Mazaheri,S.T ahirovic,A.Lleo,D.Alcolea,J.Fortea,M.Willem,S.Lammich,JLMolinuevo,R.Sanchez-Valle,A.Antonell,A.Ramirez,MTHeneka,K.Sleegers,J.van der Zee,JJMartin,S.Engelborghs,A.Demirtas-Tatlidede,H.Zetterberg,C.Van Broeckhoven,H.Gurvit,T.Wyss-Coray,J.Hardy,M.Colonna and C.Haass(2014). phagocytosis.” Sci Transl Med6(243):243ra286(pp.1-13). Kobayashi,M.,H.Konishi,A.Sayo,T.Takai and H.Kiyama(2016).“TREM2 / DAP12 Signal Elicits Proinflammatory Response in Microglia and Exacerbates Neuropathic Pain.”J Neurosci36(43):11138-11150. Kober,DLand TJBrett(2017).“TREM2-Ligand Interactions in Health and Disease.” J Mol Biol429(11):1607-1629. Lee,C.Y.D.,A.Daggett,X.Gu,L.L.Jiang,P.Langfelder,X.Li,N.Wang,Y.Zhao,C.S.Park,Y.Cooper,I.Ferando,I.Mody,G.Coppola,H.Xu and X.W.Yang(2018).“Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models.”Neuron97(5):1032-1048.e5. Leyns,C.E.G.,M.Gratuze,S.Narasimhan,N.Jain,L.J.Koscal,H.Jiang,M.Manis,M.Colonna,V.M.Y.Lee,J.D.Ulrich and D.M.Holtzman(2019).“TREM2 function impedes tau seeding in neuritic plaques.”Nat Neurosci22(8):1217-1222. Li,Q.and B.A.Barres(2018).“Microglia and macrophages in brain homeostasis and disease.”Nat Rev Immunol18(4):225-242. Liddelow,S.A.,K.A.Guttenplan,L.E.Clarke,F.C.Bennett,C.J.Bohlen,L.Schirmer,M.L.Bennett,A.E.Munch,W.S.Chung,T.C.Peterson,D.K.Wilton,A.Frouin,B.A.Napier,N.Panicker,M.Kumar,M.S.Buckwalter,D.H.Rowitch,V.L.Dawson,T.M.Dawson,B.Stevens and B.A.Barres(2017).“Neurotoxic reactive astrocytes are induced by activated microglia.”Nature541(7638):481-487. Madry,C.and D.Attwell(2015).“Receptors,ion channels,and signaling mechanisms underlying microglial dynamics.”J Biol Chem290(20):12443-12450. Madry,H.,J.Prudlo,A.Grgic and J.Freyschmidt(2007).“Nasu-Hakola disease(PLOSL):report of five cases and review of the literature.”Clin Orthop Relat Res454:262-269. Otero,K.,M.Shinohara,H.Zhao,M.Cella,S.Gilfillan,A.Colucci,R.Faccio,F.P.Ross,S.L.Teitelbaum,H.Takayanagi and M.Colonna(2012).“TREM2 and beta-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis.”J Immunol188(6):2612-2621. Paloneva,J.,J.Mandelin,A.Kiialainen,T.Bohling,J.Prudlo,P.Hakola,M.Haltia,Y.T.Konttinen and L.Peltonen(2003).“DAP12 / TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.”J Exp Med198(4):669-675. Paolicelli,R.C.,G.Bolasco,F.Pagani,L.Maggi,M.Scianni,P.Panzanelli,M.Giustetto,T.A.Ferreira,E.Guiducci,L.Dumas,D.Ragozzino and C.T.Gross(2011).“Synaptic pruning by microglia is necessary for normal brain development.”Science333(6048):1456-1458. Parhizkar,S.,T.Arzberger,M.Brendel,G.Kleinberger,M.Deussing,C.Focke,B.Nuscher,M.Xiong,A.Ghasemigharagoz,N.Katzmarski,S.Krasemann,S.F.Lichtenthaler,S.A.Muller,A.Colombo,L.S.Monasor,S.Tahirovic,J.Herms,M.Willem,N.Pettkus,O.Butovsky,P.Bartenstein,D.Edbauer,A.Rominger,A.Erturk,S.A.Grathwohl,J.J.Neher,D.M.Holtzman,M.Meyer-Luehmann and C.Haass(2019).“Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.”Nat Neurosci22(2):191-204. Peng,Q.,S.Malhotra,J.A.Torchia,W.G.Kerr,K.M.Coggeshall and M.B.Humphrey(2010).“TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.”Sci Signal3(122):ra38(pp.1-18). Sellgren, CM, J. Gracias, B. Watmuff, JDBiag, JMThanos, PB Whittredge, T. Fu, K. Worringer, HEBrown, J. Wang, A. Kaykas, R. Karmacharya, CPGoold, SDSheridan and RHPerlis(2019).“Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.” Nat Neurosci22(3):374-385. Shinozaki, Y., K. Shibata, K. Yoshida, E. Shigetomi, C. Gachet, K. Ikenaka, KFTanaka and S. Koizumi(2017). Shirotani, K., Y. Hori, R. Yoshizaki, E. Higuchi, M. Colonna, T. Saito, S. Hashimoto, T. Saito, TCSaido and N. Iwata(2019). Sims,R.,SJvan der Lee,ACNaj,J.Bellenguez,N.Badarinarayan,J.Jacobsdottir,BWKunkle,A.Boland,R.Raybould,JCBis,ERMartin,B. Grenier-Boley,S.Heilmann-Heimbach,V.Chouraki,ABKuzma,K.Sleegers,M.Vronskaya,A.Ruiz,RRGraham,R.Olaso,P .Hoffmann,MLGrove,BNVardarajan,M.Hiltunen,MMNothen,CCWhite,KLHamilton-Nelson,J.Epelbaum,W.Maier,SHCh oi,GWBeecham,J.Dulary,S.Herms,AVSmith,CCFunk,J.Derbois,AJForstner,S.Ahmad,H.Li,D.Bacq,D.Harold,CLSati zabal,O.Valladares,A.Squassina,R.Thomas,JABrody,L.Qu,P.Sanchez-Juan,T.Morgan,FJWolters,Y.Zhao,FSGarc ia,N.Denning,M.Fornage,J.Malamon,MCDNaranjo,E.Majounie,THMosley,B.Dombroski,D.Wallon,MKLupton,J.Dupui s,P.Whitehead,L.Fratiglioni,C.Medway,X.Jian,S.Mukherjee,L.Keller,K.Brown,H.Lin,LBCantwell,F.Panza,B.M cGuinness,S.Moreno-Grau,JDBurgess,V.Solfrizzi,P.Proitsi,HHAdams,M.Allen,D.Seripa,P.Pastor,LACupples,N .D.Price,D.Hannequin,A.Frank-Garcia,D.Levy,P.Chakrabarty,P.Caffarra,I.Giegling,ASBeiser,V.Giedraitis,H.Hampel,MEGarcia, X.Wang,L.Lannfelt,P.Mecocci,G.Eiriksdottir,PKCrane,F.Pasquier,V.Boccardi,I.Henandez,RCBarber,M.Scherer,L.Tarraga,PMAdam s, M. Leber, Y. Chen, M. S. Albert, S. Riedel-Heller, V. Emilsson, D. Beekly, A. Braae, R. Schmidt, D. Blacker, C. Masullo, H. Schmidt, R. S. Doody, G. Spalletta, W. T. Longstreth, Jr., T. J. Fairchild, P. Bossu, O. L. Lopez, M. P. Frosch, E. Sacchinelli, B. Ghetti, Q. Yang, R. M. Huebinger, F. Jessen, S. Li ,M.I.Kamboh,J.Morris,O.Sotolongo-Grau,M.J.Katz,C.Corcoran,M.Dunstan,A.Braddel,C.Thomas,A.Meggy,R.Marshall,A.Gerrish,J.Chapm an,M.Aguilar,S.Taylor,M.Hill,MDFairen,A.Hodges,B.Vellas,H.Soininen,I.Kloszewska,M.Daniilidou,J.Uphill,Y.Patel,JTHughes,J Lord, J. Turton, A.M. Hartmann, R. Cecchetti, C. Fenoglio, M. Serpente, M. Arcaro, C. Caltagirone, M.D. Orfei, A. Ciaramella, S. Pichler, M. Mayhaus, W. Gu, A. Leo, J. Fortea, R. Blesa, I.S. Barber, K. Brookes, C. Cupidi, R.G. Maletta, D. Carrell, S. Sorbi, S. Moebus, M. Urbano, A. Pilotto, J.Kornhuber,P.Bosco,S.Todd,D.Craig,J.Johnston,M.Gill,B.Lawlor,A.Lynch,NCFox,J.Hardy,A.Consortium,RLAlbin,LGApo stolova,SEArnold,S.Asthana,CSAtwood,CTBaldwin,LLBarnes,S.Barral,TGBeach,JTBecker,EHBigio,TDBird,BFBoeve,JDBo wen,A.Boxer,JRBurke,JMBurns,JDBuxbaum,NJCairns,C.Cao,CSCarlson,CMCarlsson,RMCarney,MMCarrasquillo,SLCarroll, CCDiaz,HCChui,DGClark,DHCribbs,EACrocco,C.DeCarli,M.Dick,R.Duara,DAEvans,KMFaber,KBFallon,DWFardo,MRFarlow,S .Ferris,TMForoud,DRGalasko,M.Gearing,DHGeschwind,JRGilbert,NRGraff-Radford,RCGreen,JHGrowdon,RLHamilton,LEHa rrell,LSHonig,MJHuentelman,CMHulette,BTHyman,GPJarvik,E.Abner,LWJin,G.Jun,A.Karydas,JAKaye,R.Kim,NWKowall,JH Kramer,FMLaFerla,JJLah,JBLeverenz,AILevey,G.Li,APLieberman,KLLunetta,CGLyketsos,DCMarson,F.Martiniuk,DCMash,E.Masliah,WCMcCormick,SMMcCurry,ANMcDavid,ACMcKee,M.Mesulam,BLMiller,CAMiller,JWMiller,JCMorris,JRMurrell,A.J.A lot. rs,S.O'Bryant,JMOlichney,VSPankratz,JEParisi,HLPaulson,W.Perry,E.Peskind,A.Pierce,WWPoon,H.Potter,JFQuinn,A.Raj,M.Raskind,B.Reisberg,C.Reitz,JMRingman,EDRoberson,E.Rogaev a,HJRosen,RNRosenberg,MASager,AJSaykin,JASchneider,LSSchneider,WWSeeley,AGSmith,JASonnen,S.Spina,RAStern,RHSwerdlow,RETanzi,TAThornton-Wells,JQTrojanowski,JCTroncoso,VMVan Deerlin,L.J.Van Eldik,HVVinters,JPVonsattel,S.Weintraub,KAWelsh-Bohmer,KCWilhelmsen,J.Williamson,TSWingo,RLWoltjer,CBWright,CEYu,L.Yu,F.Garzia,F.Golamaully,G.Septier,S.Engelborghs,R.Vandenberghe,PPDe Deyn,CMFernadez,YABenito,H.Thonberg,C.Forsell,L.Lilius,A.Kinhult-Stahlbom,L.Kilander,R.Brundin,L.Concari,S.Helisalmi,AMKoivisto,A.Haapasalo,V.Dermecourt,N.Fievet,O.Hanon,C.Dufouil,A. Brice,K.Ritchie,B.Dubois,JJHimali,CDKeene,J.Tschanz,ALFitzpatrick,WAKukull,M.Norton,T.Aspelund,EBLarson,R.Munger,JIRotter,RBLipton,MJBullido,A.Hofman,TJMontine,E.Coto,E.Boerwinkle,RCPetersen,V.Alvarez,F.Rivadeneira,EMReiman,M.Gallo,CJO'Donnell,JSReisch,ACBruni,DRRoyall,M.Dichgans,M.Sano,D.Galimberti,P.St George-Hyslop,E.Scarpini,DWTsuang,M.Mancuso,U.Bonuccelli,ARWinslow,A.Daniele,CKWu,CAEGerad / Perades, O.Peters,B.Nacmias,M.Riemenschneider,R.Heun,J.Brayne,DCRubinsztein,J.Bras,R.Guerreiro,A.Al-Chalabi, CEShaw,J.Collinge,D.Mann,M.Tsolaki,J.Clarimon,R.Sussams,S.Lovestone,MCO'Donovan,MJOwen,TWBehrens,S. Mead,AMGoate,AGUitterlinden,J.Holmes,J.Cruchaga,M.Ingelsson,DABennett,J.Powell,TEGolde,J.Graff,PLDe Jager,K.Morgan,N.Ertekin-Taner,O.Combarros,BMPsaty,P.Passmore,SGYounkin,J.Berr,V.Goodnason,D.Rujescu,D WDickson,JFDartigues,ALDeStefano,S.Ortega-Cubero,H.Hakonarson,D.Campion,M.Boada,JKKauwe,LAFarrer,C.Van Broeckhoven,MAIkram,L.Jones,JLHaines,C.Tzourio,LJLauner,V.Escott-Price,R.Mayeux,JFDeleuze,N.Amin,PAHolmans,MAPericak-Vance,P.Amouyel,CMvan Duijn,A.Ramirez,LSWang,JCLWilshammers,J. GDSche. llenberg(2017).“Rare coding variants in PLCG2,ABI3,and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease.”Nat Genet49(9):1373-1384. Suarez-Calvet,M.,E.Morenas-Rodriguez,G.Kleinberger,K.Schlepckow,M.A.Araque Caballero,N.Franzmeier,A.Capell,K.Fellerer,B.Nuscher,E.Eren,J.Levin,Y.Deming,L.Piccio,C.M.Karch,C.Cruchaga,L.M.Shaw,J.Q.Trojanowski,M.Weiner,M.Ewers,C.Haass and I.Alzheimer’s Disease Neuroimaging(2019).“Early increase of CSF sTREM2 in Alzheimer’s disease is associated with tau related-neurodegeneration but not with amyloid-beta pathology.”Mol Neurodegener14(1):1(pp.1-14). Ulland,T.K.,W.M.Song,S.C.Huang,J.D.Ulrich,A.Sergushichev,W.L.Beatty,A.A.Loboda,Y.Zhou,N.J.Cairns,A.Kambal,E.Loginicheva,S.Gilfillan,M.Cella,H.W.Virgin,E.R.Unanue,Y.Wang,M.N.Artyomov,D.M.Holtzman and M.Colonna(2017).“TREM2 Maintains Microglial Metabolic Fitness in Alzheimer’s Disease.”Cell170(4):649-663.e13. Ulrich,J.D.,D.M.Holtzman(2016).“TREM2 Function in Alzheimer’s Disease and Neurodegeneration.”ACS Chem Neurosci20(7):420-427. Ulrich,J.D.,T.K.Ulland,M.Colonna and D.M.Holtzman(2017).“Elucidating the Role of TREM2 in Alzheimer’s Disease.”Neuron94(2):237-248. Wang,Y.,M.Cella,K.Mallinson,J.D.Ulrich,K.L.Young,M.L.Robinette,S.Gilfillan,G.M.Krishnan,S.Sudhakar,B.H.Zinselmeyer,D.M.Holtzman,J.R.Cirrito and M.Colonna(2015).“TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model.”Cell160(6):1061-1071. Wu,R.,X.Li,P.Xu,L.Huang,J.Cheng,X.Huang,J.Jiang,L.J.Wu and Y.Tang(2017).“TREM2 protects against cerebral ischemia / reperfusion injury.”Mol Brain10(1):20(pp.1-13). Yeh,F.L.,Y.Wang,I.Tom ,L.C.Gonzalez,M.Sheng(2016).“TREM2 Binds to Apolipoproteins,Including APOE and CLU / APOJ,and Thereby Facilitates Uptake of Amyloid-Beta by Microglia.”Neuron91(2):328-340. Yuan,P.,C.Condello,C.D.Keene,Y.Wang,T.D. Bird, SM Paul, W. Luo, M. Colonna, D. Baddeley and J. Grutzendler (2016). “TREM2 Haplodeficiency in Mice and Humans Impairs the Microglia Barrier Function Leading to Decreased Amyloid Compaction and Severe Axonal Dystrophy.” Neuron90(4):724-739.

[0257] All references cited herein, for example, scientific publications or published patent applications, are hereby incorporated by reference for all purposes to the same extent as if each reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. The present invention includes, but is not limited to, the following aspects. [Aspect 1] Compounds of Formula I [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein: X 1 is (1) CH or N and b is a single bond, or (2) C and b are a double bond; X 2 is CH2, CHF, CF2, O, or NH; Optionally, R 5 But it doesn't exist, X 2 CR 6 The groups form a 5- or 6-membered heteroaryl, said 5-membered heteroaryl containing only one ring atom selected from N, O, and S, and optionally only one further N ring atom, said 6-membered heteroaryl containing only one or two N ring atoms, said 5- or 6-membered heteroaryl containing only one or two N ring atoms, and said 5- or 6-membered heteroaryl containing only one or two N ring atoms, and 1~3 Alkyl or C 1~3 optionally substituted with alkoxy; X at each occurrence3 are independently CH or N; R 1 But H, C 1~6 Alkyl, C 1~6 Haloalkyl, or C 3~6 is cycloalkyl, R 2 But H, C 1~3 Alkyl, C 1~3 Haloalkyl, or C 3~6 is cycloalkyl, R 3 But H or C 1~3 is alkyl, R 4 But H or C 1~3 is alkyl, R 5 But H or C 1~3 is alkyl, R 6 But C 2~6 Alkyl, C 1~6 Haloalkyl, DiC 1~3 Alkylamino, -C(=O)O(C 1~6 alkyl), C 3~6 Cycloalkyl, C 3~6 heterocycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; (1)C 3~6 Cycloalkyl or C 3~6 heterocycloalkyl is optionally substituted with C=O; (2) the phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is independently selected from the group consisting of halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, -(C 1~3 alkyl)O(C 1~3 alkyl), -(C 1~3 alkyl)NH2, -(C 1~3 alkyl)NH(C 1~3 alkyl), -(C 1~3 alkyl)N[(C 1~3 Alkyl)(C 1~3 alkyl)], -CN, C 2~4 Alkenyl, C3~6 Cycloalkyl, phenyl, and C 3~6 optionally substituted with 1 to 3 substituents selected from heterocycloalkyl; Subsection (2) C 1~6 Alkyl and C 1~6 haloalkyl is optionally substituted with OH; Subsection (2) C 3~6 Heterocycloalkyl is halogen, C 1~3 Alkyl, and -C(=O)O(C 1~6 alkyl), R 7 But C 5~6 Cycloalkyl, C 5~8 Spiroalkyl, C 5~8 Tricycloal alkyl, phenyl, or 6-membered heteroaryl; R 7 Furthermore, independently, halogen, C 1~3 Alkyl, and C 1~3 optionally substituted with 1 to 4 substituents selected from haloalkyl; n is 0 or 1, provided that X 1 is N and n is 0, then X 2 is not NH or O, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 2] The compound is 5-(5-chloro-3-methyl-2-pyridinyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-methyl-3-phenyl-1-piperidine)pyrido[4,3-d]pyrimidin-4(3H)-one, or A compound of embodiment 1 or a tautomer thereof that is not 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(1-methyl-1H-imidazol-2-yl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 3] 3. The compound of claim 1 or 2, wherein the compound is a compound of formula II, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. [ka] [Aspect 4] 3. The compound of claim 1 or 2, wherein the compound is a compound of formula IIA, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. [ka] [Aspect 5] 3. The compound of embodiment 1 or 2, wherein the compound is a compound of formula IIB, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer. [ka] [Aspect 6] X 1 is CH, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 7] X 1 is N, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 8] X 2 is CH2, CF2, or O; or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or said tautomer; [Aspect 9] X 2 is O, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 10] Formula I [ka] The part is, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 11] X 3 is CH, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 12] X 3 is N, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 13] R 1 is methyl, ethyl, propyl, —CH2CF3, cyclopropyl, or cyclohexyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 14] R 1 is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 15] R 2 is H, methyl, trifluoromethyl, or cyclopropyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 16] R 2is methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 17] R 3 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 18] R 3 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 19] R 4 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 20] R 4 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 21] R 5 is H or methyl, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 22] R 5 is H, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 23] R 6is difluoromethyl, trifluoromethyl, —CHCF, dimethylamino, —C(═O)OCHCH, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxetanyl, optionally substituted azetidinyl, optionally substituted tetrahydrofuranyl, optionally substituted pyrrolidinyl, optionally substituted phenyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted 1,3-oxazolyl, optionally substituted 1,2,4-oxadiazolyl, optionally substituted 1,3,4-oxadiazolyl, optionally substituted thiophenyl, optionally substituted thiazolyl, optionally substituted pyridinyl, optionally substituted pyridazinyl, or optionally substituted pyrimidinyl; or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 24] R 6 difluoromethyl, trifluoromethyl, -CH2CF3, dimethylamino, -C(=O)OCH2CH3, cyclopropyl, cyclobutyl, oxetan-2-yl, azetidin-1-yl, tetrahydrofuran-3-yl, [ka] phenyl, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, according to any one of Aspects 1 to 22, wherein: [Aspect 25] R 6 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, according to any one of Aspects 1 to 22, wherein: [Aspect 26] R 7 is arbitrarily substituted C 5~626. The compound of any one of Aspects 1-25, wherein R is cycloalkyl, optionally substituted phenyl, or optionally substituted 6-membered heteroaryl; or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 27] R 7 is arbitrarily substituted C 5~6 26. The compound of any one of Aspects 1-25, wherein R is cycloalkyl, optionally substituted phenyl, or optionally substituted pyridinyl; or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 28] R 7 is optionally substituted phenyl; or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 29] R 7 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, according to any one of Aspects 1 to 25, wherein: [Aspect 30] R 7 but, [ka] or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, according to any one of Aspects 1 to 25, wherein: [Aspect 31] A compound according to any one of aspects 1 to 9 and 11 to 30, wherein n is 0, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 32] 31. The compound according to any one of Aspects 1 to 30, wherein n is 1, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 33] 2. The compound or tautomer thereof of Aspect 1, wherein the compound is a compound of Table A, or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or tautomer thereof. [Aspect 34] The compound is 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone, 5-(4-chlorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chlorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-3-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2,4-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,3,4-trifluorophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,4,5-trifluorophenyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2,5-difluorophenyl)-2,3-dimethyl-7-((2S )-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2-fluoro-4-methylphenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2,3-difluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(5-chloro-3-fluoro-2-pyridinyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone, 2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(6-(trifluoromethyl)-3-pyridinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-cyclohexyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-(2,2,2-trifluoroethyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, ±5-(5-chloro-3-fluoro-2-pyridinyl)-2-methyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido-[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,5R)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,5R)-5-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6R)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6S)-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-methyl-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-cyclopropyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2-cyclobutyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2R)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2S)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2S)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2R)-2-oxetanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((3S)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((3S)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((3R)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((3R)-tetrahydro-3-furanyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-pyridanidyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2,2,2-trifluoroethyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(thiophen-3-yl)morpholino)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin ion-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2-methyl-4-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(2-(1,3-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(2-(5-fluoro-3-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(2-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6S)-2-methyl-6-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6R)-2-methyl-6-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6S)-2-methyl-6-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6R)-2-methyl-6-(3-thiophenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-methyl-1,3-thiazol-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2,6-dimethyl-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2,6-dimethyl-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-methoxyphenyl)- (phenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-chlorophenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-chlorophenyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-chloro-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-chloro-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 4-(4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)-2-morpholinyl)benzonitrile, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-(trifluoromethyl)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-(trifluoromethyl)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(5-phenyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-(2,2,2-trifluoroethoxy)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-(2,2,2-trifluoroethoxy)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-(trifluoromethoxy)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-(trifluoromethoxy)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(1,3-oxazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(5-oxo-3-pyrrolidinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(1H-pyrazol-4-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(3-(dimethylamino)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 7-(3-(1-azetidinyl)-1-piperidinyl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(4-pyridinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(4-pyridinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 7-(8-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5'-(4-chloro-2-fluorophenyl)-4-methoxy-2',3'-dimethyl-7,8-dihydro-5H-[6,7'-bipyrido[4,3-d]pyrimidin]-4'(3'H)-one, 5-(4-chloro-2-fluorophenyl)-7-((3R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((3S)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(trifluoromethyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-(3-(difluoromethyl)-1-pyrrolidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(3-pyridinyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(3-oxetanyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoro-2-hydroxyethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,3-difluoro-2-propanyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 2-methyl-2-propanyl 3-(4-((2S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)-2-morpholinyl)-1H-pyrazol-1-yl)-1-azetidinecarboxylate, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,2-difluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-ethenyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azetidinyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-2-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2R )-2-(5-methyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(2,4-difluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(2-methyl-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(2,4-difluorophenyl)-3-ethyl-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(5-chloro-3-fluoro-2-pyridinyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R)-2-(1-methyl-1H-pyrazol-5-yl)-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(difluoromethyl)-4-morpholinyl)-2-methyl-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-phenyl-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-3-methyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-cyclohexyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-cyclopentyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(6-(1-methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, (2R,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and ethyl (2S,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate, (2S,4S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate and (2R,4R)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)tetrahydro-2H-pyran-2-carboxylate, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(2-methyl-4-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(6-methylpyridin-3-yl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2R,4R)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-7-((2S,4S)-2-(2-methoxy-4-pyridinyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one and 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4S)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one, or 2. The compound of embodiment 1, wherein the compound is 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(3-pyridinyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one; or a tautomer thereof; or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 35] The compound is [ka] or a pharmaceutically acceptable salt thereof. [Aspect 36] The compound is [ka] or a pharmaceutically acceptable salt thereof. [Aspect 37] The compound is [ka] or a pharmaceutically acceptable salt thereof. [Aspect 38] The compound is [ka] or a pharmaceutically acceptable salt thereof. [Aspect 39] The compound is [ka] or a pharmaceutically acceptable salt thereof. [Aspect 40] The compound is [ka] or a pharmaceutically acceptable salt thereof. [Aspect 41] The compound is [ka] or a pharmaceutically acceptable salt thereof. [Aspect 42] The compound is [ka] or a pharmaceutically acceptable salt thereof. [Aspect 43] A pharmaceutical composition comprising a compound according to any one of Aspects 1 to 42, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient. [Aspect 44] A compound or a tautomer thereof according to any one of aspects 1 to 42, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to aspect 43, for use as a medicament. [Aspect 45] A compound or a tautomer thereof according to any one of aspects 1 to 42, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to aspect 43, for use in the treatment or prevention of a condition associated with loss of function of human TREM2. [Aspect 46] A compound or a tautomer thereof according to any one of Aspects 1 to 42, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Aspect 43, for use in the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke. [Aspect 47] 44. Use of a compound or a tautomer thereof according to any one of aspects 1 to 42, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to aspect 43, in the preparation of a medicament for treating or preventing a condition associated with loss of function of human TREM2. [Aspect 48] 44. Use of a compound or a tautomer thereof according to any one of Aspects 1 to 42, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to Aspect 43, in the preparation of a medicament for treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke. [Aspect 49] 43. A method of treating or preventing a condition associated with loss of function of human TREM2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of Aspects 1 to 42, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. [Aspect 50] 43. A method of treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Aspects 1 to 42, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer.

Claims

[Claim 1] The invention described in the specification.

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