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

Abstract

The present disclosure provides compounds of Formula (I) useful for the activation of Triggering Receptor Expressed on Myeloid Cells 2 ("TREM2") expressed on myeloid cells. The present disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treating, for example, neurodegenerative diseases. Furthermore, the present disclosure provides intermediates useful for the synthesis of compounds of Formula (I)

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 019,768, filed May 4, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure provides compounds that can be used to activate trigger receptor 2 (“TREM2”) expressed on myeloid cells. This disclosure also provides pharmaceutical compositions comprising said compounds, uses of said compounds, and compositions for treating, for example, neurodegenerative diseases. Furthermore, this disclosure provides intermediates that can be used in the synthesis of compounds of formula I. Background Technology

[0004] Microglia are innate immune cells residing in the brain and are important for maintaining homeostasis in the central nervous system. (Hickman et al. 2018, Li and Barres 2018). These resident macrophages express a variety of receptors that enable them to sense changes in their microenvironment and alter their phenotype, thereby mediating responses to invading pathogens, protein toxicity stress, cellular damage, and other infarcts 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), neurites (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 a variety of physiological processes. Because microglia can proliferate rapidly in response to stimuli, they characteristically exhibit myeloid cell functions such as phagocytosis, cytokine / chemokine release, antigen presentation, and migration. (Colonna and Butovsky 2017). Further specialized functions of microglia include pruning synapses from neurons and the ability to communicate directly with their highly dendritic cellular processes that monitor the area surrounding the neuronal cell body. (Hong et al. 2016, Sellgren et al. 2019).

[0005] Microglial plasticity and its distinct states, described by single-cell RNA-Seq profiling, are thought to arise from the integration of signaling from a variety of cell surface receptors. (Hickman et al., 2013). These receptors, collectively termed microglial "sensoroids," are responsible for transducing activated or inhibited intracellular signaling and include families of proteins such as sialic acid-binding immunoglobulin-type lectins (“SIGLEC”), Toll-like receptors (“TLR”), Fc receptors, nucleotide-binding oligomerization domains (“NOD”), and purinergic G protein-coupled receptors. (Doens and Fernandez, 2014; Madry and Attwell, 2015; Hickman and ElKhoury, 2019). Similar to other cells in the bone marrow lineage, the composition of microglial sensoroids is dynamically regulated and acts to recognize molecular patterns that guide phenotypic responses to homeostatic changes in the central nervous system (“CNS”). (Ibid.) One of the receptors selectively expressed by microglia in the brain is TREM2, which consists of a single transmembrane domain, an extracellular stem region, and an extracellular immunoglobulin variable region (“IgV”)-like domain responsible for ligand interactions. Kleinberger et al. (2014). Because TREM2 lacks intracellular domains for mediating signal transduction, biochemical analysis indicates that interactions with adaptor proteins DAP10 and DAP12 mediate downstream signal transduction after ligand recognition. Peng et al. (2010), Jay et al. (2017). The TREM2 / DAP12 complex can particularly serve as a signal transduction unit characterized by pre-activation of microglia phenotypes as well as peripheral macrophages and osteoclasts. Otero et al. (2012), Kobayashi et al. (2016), Jaitin et al. (2019). In the CNS, signal transduction via TREM2 has been studied in the context of ligands such as phospholipids, cellular debris, apolipoproteins, and myelin. Wang et al. 2015, Kober and Brett 2017, Shirotani et al. 2019. In mice lacking functional TREM2 expression or mutant forms expressing the receptor, a key observation was the sluggish microglial response to injury, such as oligodendrocyte demyelination, stroke-induced brain tissue damage, and in vivo protein toxicity contents. Cantoni et al. 2015, Wu et al. 2017.

[0006] In genome-wide association studies (GWAS) in humans, coding variants at the TREM2 locus have been associated with late-onset Alzheimer's disease ("LOAD"), linking receptor function loss to an increased risk of disease. (Jonsson et al. 2013, Sims et al. 2017). In the CNS, genetic variations in other genes selectively expressed by microglia (e.g., CD33, PLCg2, and MS4A4A / 6A) have reached genome-wide significance due to their association with LOAD risk. (Hollingworth et al. 2011, Sims et al. 2017, Deming et al. 2019). In summary, these genetic findings are linked in a putative biochemical circuit, highlighting the importance of microglia's innate immune function in LOAD. Furthermore, an increase or elevation of the soluble form of TREM2 ("sTREM2") in the cerebrospinal fluid (CSF) of human subjects has been associated with disease progression and the presence of pathological markers of LOAD, including phosphorylated tau protein. Suarez-Calvet et al. 2019. Furthermore, natural history and human biology studies have shown that baseline sTREM2 levels in the CSF can stratify the rate of temporal lobe volume reduction and episodic memory decline in longitudinal monitoring cohorts. Ewers et al. 2019.

[0007] In addition to human genetic evidence supporting the role of TREM2 in LOAD, homozygous loss-of-function mutations in TREM2 are the cause of early-onset dementia syndromes known as polycystic fat membrane-like dysplasia with sclerotic leukoencephalopathy (“PLOSL”) or Nasu-Hakola disease (“NHD”). Golde et al. 2013, Dardiotis et al. 2017. This progressive neurodegenerative disease typically ends in the 3rd year of life. 个 Over a decade, the pathological features of this disease have manifested as loss of myelin in the brain, accompanied by glial proliferation, persistent neuroinflammation, and brain atrophy. Typical neuropsychiatric manifestations usually precede bone abnormalities such as bone cysts and decreased peripheral bone density (Bianchin et al. 2004, Madry et al. 2007, Bianchin et al. 2010). Given that osteoclasts in the bone marrow lineage also express TREM2, PLOSL-related symptoms of wrist and ankle pain, swelling, and fractures suggest that TREM2 may act on specific signaling pathways parallel to microglia in the CNS to regulate bone homeostasis (Paloneva et al. 2003, Otero et al. 2012). The correlation between TREM2 function and PLOSL demonstrates the importance of the receptor in key physiological aspects of maintaining myeloid cell function in the human body.

[0008] Work has been done to mimic the biology of TREM2 in mice, thereby promoting the generation of TREM2 knockout (“KO”) mice and LOAD-associated TREM2 R47H loss-of-function mutant transgenic mice. Ulland et al. 2017, Kang et al. 2018. Although the neurological manifestations of PLOSL could not be reproduced, TREM2 KO mice showed bone ultrastructural abnormalities. Otero et al. 2012. When TREM2 KO or mutant mice were crossed with a background of transgenic mice with familial Alzheimer’s disease (such as 5XFAD amyloid mutant strains), distinct phenotypes have been observed. Ulrich et al. 2017. These in vivo phenotypes of TREM2 loss of function in the CNS include increased plaque burden and decreased levels of secreted microglial cytokines SPP1 and osteopontin, which are characteristic of microglial responses to amyloid pathology. Ulland et al. 2017. Other rodent studies have shown that TREM2 loss leads to reduced microglial clustering around plaques and less compact plaque morphology in familial AD amyloid models. Parhizkar et al. 2019. Regarding tau protein pathology observed in LOAD, a familial tau protein disease model in mice showed enhanced diffusion of pathological human tau aggregates from the injection site to the mouse brain in TREM2 KO mice. Leyns et al. 2019. Furthermore, single-cell RNASeq studies in aged TREM2 KO mice, 5XFAD familial Alzheimer's disease model mice, and ALS SOD1 mutant mice have shown that TREM2 receptor function is crucial for a conserved set of phenotypic transformations within microglial populations in response to CNS pathology. Keren-Shaul et al. 2017.

[0009] In rodent models with elevated TREM2 expression levels, brain amyloid pathology in 5XFAD transgenic mice showed reduced plaque volume and morphological changes (Lee et al. 2018). Changes in brain amyloid pathology-related immunohistochemical markers were also associated with weakened dystrophic neurites when TREM2 was overexpressed (ibid.). Therefore, pharmacological activation of TREM2 is a target of interest for the treatment or prevention of neurodegenerative and other diseases. While numerous attempts have been made to target pathological markers of LOAD with anti-amyloid and anti-tau therapies to alter disease progression, TREM2 activators are still needed to address, for example, the genetically related neuroimmunological aspects of LOAD. Such TREM2 activators could be suitable as therapeutic agents and remain relevant given the significant and ongoing social burden of diseases such as Alzheimer's disease that have not yet been alleviated. Summary of the Invention

[0010] First, this paper provides compounds of formula I.

[0011]

[0012] Or its tautomers, or a pharmaceutically acceptable salt of said compound or said tautomers, wherein

[0013] X 1 It is (1) CH or N and b is a single bond; or (2) C and b are double bonds;

[0014] X 2 It is CH2, CHF, CF2, O, or NH;

[0015] Wherein, R 5 It does not exist and X 2 CR 6 The group forms a 5- or 6-membered heteroaryl group, wherein the 5-membered heteroaryl group contains only one ring atom selected from N, O, and S and optionally only one additional N ring atom, and wherein the 6-membered heteroaryl group contains only one or only two N ring atoms, and wherein the 5- or 6-membered heteroaryl group is optionally affected by a halogen, C 1-3 Alkyl or C 1-3 Alkyl substitution;

[0016] X 3 It is CH or N independently each time it appears;

[0017] R 1 It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl;

[0018] R 2 It is H, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0019] R 3 Is it H or C? 1-3 alkyl;

[0020] R 4 Is it H or C? 1-3 alkyl;

[0021] R 5 Is it H or C? 1-3 alkyl;

[0022] R 6 It is C 2-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3Alkylamino, -C(=O)O(C 1-6 Alkyl), C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; wherein

[0023] (1)C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups are optionally substituted with C=O.

[0024] (2) The phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally substituted by 1 to 3 independent substituents selected from the following: 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 groups, -CN, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl and C 3-6 Heterocyclic alkyl groups; wherein

[0025] The C in segment (2) 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with OH; and wherein

[0026] The C in segment (2) 3-6 The heterocyclic alkyl group is optionally substituted with 1 to 3 substituents selected from halogens, C... 1-3 Alkyl groups and -C(=O)O(C 1-6 alkyl);

[0027] R 7 It is C 5-6 cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, phenyl, or 6-membered heteroaryl; wherein R 7 Further optionally selected by 1 to 4 independently chosen from halogen, C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups; and

[0028] n is 0 or 1; the prerequisite is that when X 1 When X is N and n is 0, 2 It is neither NH nor O.

[0029] Second, this article provides a pharmaceutical composition comprising a compound of formula I or a tautomer thereof, or a pharmaceutically acceptable salt of the compound or the tautomer thereof, and a pharmaceutically acceptable excipient.

[0030] Third, this article provides compounds of Formula I as described above, or tautomers thereof, or pharmaceutically acceptable salts of said compounds or tautomers, or pharmaceutical compositions, which may be used to treat or prevent conditions associated with loss of function of TREM2 in humans.

[0031] Fourth, this document provides compounds of Formula I as described above, or tautomers thereof, or pharmaceutically acceptable salts of said compounds or tautomers, or pharmaceutical compositions, which may be used to treat or prevent Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prions, or stroke.

[0032] Reference will now be made in detail to embodiments of this disclosure. While certain embodiments of this disclosure will be described, it should be understood that it is not intended to limit the embodiments of this disclosure to those described. Rather, reference to embodiments of this disclosure is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of embodiments of this disclosure as defined by the appended claims. Detailed Implementation

[0033] As an implementation scheme 1, this document provides compounds of formula I.

[0034]

[0035] Or its tautomers, or a pharmaceutically acceptable salt of said compound or said tautomers, wherein

[0036] X 1 It is (1) CH or N and b is a single bond; or (2) C and b are double bonds;

[0037] X 2 It is CH2, CHF, CF2, O, or NH;

[0038] Wherein, R 5 It does not exist and X 2 CR 6 The group forms a 5- or 6-membered heteroaryl group, wherein the 5-membered heteroaryl group contains only one ring atom selected from N, O, and S and optionally only one additional N ring atom, and wherein the 6-membered heteroaryl group contains only one or only two N ring atoms, and wherein the 5- or 6-membered heteroaryl group is optionally affected by a halogen, C1-3 Alkyl or C 1-3 Alkyl substitution;

[0039] X 3 It is CH or N independently each time it appears;

[0040] R 1 It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl;

[0041] R 2 It is H, C 1-3 Alkyl, C 1-3 Halogenated alkyl or C 3-6 cycloalkyl;

[0042] R 3 Is it H or C? 1-3 alkyl;

[0043] R 4 Is it H or C? 1-3 alkyl;

[0044] R 5 Is it H or C? 1-3 alkyl;

[0045] R 6 It is C 2-6 Alkyl, C 1-6 Halogenated alkyl, di-C 1-3 Alkylamino, -C(=O)O(C 1-6 Alkyl), C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl; wherein

[0046] (1)C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups are optionally substituted with C=O.

[0047] (2) The phenyl, 5-membered heteroaryl, or 6-membered heteroaryl group is optionally substituted by 1 to 3 independent substituents selected from the following: 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 1-3Alkyl)(C 1-3 Alkyl groups, -CN, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl and C 3-6 Heterocyclic alkyl groups; wherein

[0048] The C in segment (2) 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with OH; and wherein

[0049] The C in segment (2) 3-6 The heterocyclic alkyl group is optionally substituted with 1 to 3 substituents selected from halogens, C... 1-3 Alkyl groups and -C(=O)O(C 1-6 alkyl);

[0050] R 7 It is C 5-6 cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, phenyl, or 6-membered heteroaryl; wherein R 7 Further optionally selected by 1 to 4 independently chosen from halogen, C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups; and

[0051] n is 0 or 1; the prerequisite is that when X 1 When X is N and n is 0, 2 It is neither NH nor O.

[0052] As an embodiment 2, this document provides the compound or its tautomer according to embodiment 1, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is not

[0053] 5-(5-chloro-3-methyl-2-pyridyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0054] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-methyl-3-phenyl-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; or

[0055] 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.

[0056] As an embodiment 3, this document provides a compound or tautomer thereof according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of formula II.

[0057]

[0058] As an embodiment 4, this document provides a compound or tautomer thereof according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of formula IIA.

[0059]

[0060] As embodiment 5, this document provides a compound or tautomer thereof according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of formula IIB.

[0061]

[0062] As an embodiment 6, this document provides a compound or tautomer thereof according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of formula IIC.

[0063]

[0064] As embodiment 7, this document provides a compound or tautomer thereof according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of formula IID.

[0065]

[0066] As embodiment 8, this document provides a compound or tautomer thereof according to embodiment 1 or embodiment 2, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of formula IIE.

[0067]

[0068] As embodiment 9, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0069] X 1 It is CH.

[0070] As embodiment 10, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0071] X 1 It is N.

[0072] As embodiment 11, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0073] X 2 It is CH2, CF2, or O.

[0074] As embodiment 12, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0075] X 2 It is O.

[0076] As embodiment 13, this document provides a compound or tautomer thereof according to embodiment 1, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein formula I Part of it is

[0077] As embodiment 14, this document provides a compound or tautomer thereof according to embodiment 1, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein formula I Part of it is

[0078] As embodiment 15, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0079] X 3 It is CH.

[0080] As embodiment 16, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0081] X 3 It is N.

[0082] As embodiment 17, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0083] R 1 It is methyl, ethyl, propyl, -CH2CF3, cyclopropyl, or cyclohexyl.

[0084] As embodiment 18, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0085] R 1 It is a methyl group.

[0086] As embodiment 19, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0087] R 2 It is H, methyl, trifluoromethyl or cyclopropyl.

[0088] As embodiment 20, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 18, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0089] R 2 It is a methyl group.

[0090] As embodiment 21, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0091] R 3 It is H or methyl.

[0092] As embodiment 22, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 20, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0093] R 3 It's H.

[0094] As embodiment 23, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 22, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0095] R4 It is H or methyl.

[0096] As embodiment 24, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 22, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0097] R 4 It's H.

[0098] As embodiment 25, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 22, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0099] R 4 It is a methyl group.

[0100] As embodiment 26, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 25, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0101] R 5 It is H or methyl.

[0102] As embodiment 27, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 25, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0103] R 5 It's H.

[0104] As embodiment 28, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 27, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0105] R 6 It is difluoromethyl, trifluoromethyl, -CH2CF3, dimethylamino, -C(=O)OCH2CH3, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxacyclobutyl, optionally substituted azacyclobutyl, 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.

[0106] In some implementation schemes, R 6It is difluoromethyl. In some embodiments, R 6 It is trifluoromethyl. In some implementations, R 6 It is -CH2CF3. In some implementations, R 6 It is dimethylamino. In some embodiments, R 6 It is -C(=O)OCH2CH3. In some implementations, R 6 It is an optionally substituted cyclopropyl group. In some embodiments, R 6 It is an optionally substituted cyclobutyl group. In some embodiments, R 6 It is an optionally substituted oxocyclic butyl group. In some embodiments, R 6 It is an optionally substituted nitrogen-containing heterocyclic butyl group. In some embodiments, R 6 It is an optionally substituted tetrahydrofuranyl group. In some embodiments, R 6 It is an optionally substituted pyrroleyl group. In some embodiments, R 6 It is an optionally substituted phenyl group. In some embodiments, R 6 It is an optionally substituted pyrazolyl group. In some embodiments, R 6 It is an optionally substituted imidazole group. In some embodiments, R 6 It is an optionally substituted 1,3-oxazolyl group. In some embodiments, R 6 It is an optionally substituted 1,2,4-oxadiazolyl group. In some embodiments, R 6 It is an optionally substituted 1,3,4-oxadiazolyl group. In some embodiments, R 6 It is an optionally substituted thiophene group. In some embodiments, R 6 It is an optionally substituted thiazolyl group. In some embodiments, R 6 It is an optionally substituted pyridyl group. In some embodiments, R 6 It is an optionally substituted pyridazinyl group. In some embodiments, R 6 It is an optional substituted pyrimidinyl group.

[0107] As embodiment 29, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 27, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0108] R 6 It is difluoromethyl, trifluoromethyl, -CH2CF3, dimethylamino, -C(=O)OCH2CH3, cyclopropyl, cyclobutyl, oxetane-2-yl, azirane-1-yl, tetrahydrofuran-3-yl, phenyl,

[0109] As embodiment 30, this document provides a compound or a tautomer thereof according to any one of embodiments 1 to 27, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0110] R 6 It is ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, -CH2CF3, dimethylamino, -C(=O)OCH2CH3, cyclopropyl, cyclobutyl, oxetane-2-yl, azirane-1-yl, tetrahydrofuran-3-yl, phenyl,

[0111]

[0112] As embodiment 31, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 27, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0113] R 6 yes

[0114] As embodiment 32, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0115] R 7 C is an optional substitute 5-6 Cycloalkyl, optionally substituted phenyl, or optionally substituted 6-membered heteroaryl.

[0116] As embodiment 33, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0117] R 7 C is an optional substitute 5-6 Cycloalkyl, optionally substituted phenyl, or optionally substituted pyridyl.

[0118] As embodiment 34, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0119] R 7 It is an optional substituted phenyl group.

[0120] As embodiment 35, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0121] R 7 It is an optional substituted pyridinyl group.

[0122] As embodiment 36, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0123] R 7 C is an optional substitute 5-6 Cycloalkyl.

[0124] As embodiment 37, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0125] R 7 yes

[0126] As embodiment 38, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0127] R 7 yes

[0128] As embodiment 39, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 31, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0129] R 7 yes

[0130] As embodiment 40, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 12 and embodiments 15 to 39, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0131] n is 0.

[0132] As embodiment 41, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 39, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein

[0133] n is 1.

[0134] As an embodiment 42, this document provides a compound or tautomer thereof according to embodiment 1, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is

[0135] 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;

[0136] 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;

[0137] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone;

[0138] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone;

[0139] 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;

[0140] 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;

[0141] 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;

[0142] 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;

[0143] 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;

[0144] 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;

[0145] 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;

[0146] 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;

[0147] 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;

[0148] 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;

[0149] 5-(5-chloro-3-fluoro-2-pyridinyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-4(3H)-quinazolinone;

[0150] 2,3-Dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)-5-(6-(trifluoromethyl)-3-pyridyl)pyridino[4,3-d]pyrimidin-4(3H)-one;

[0151] 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;

[0152] 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;

[0153] 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;

[0154] ±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;

[0155] 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;

[0156] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0157] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(1-ethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0158] 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;

[0159] 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;

[0160] 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;

[0161] 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;

[0162] 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;

[0163] 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;

[0164] 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;

[0165] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-cyclopropyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0166] 5-(4-chloro-2-fluorophenyl)-7-(2-cyclobutyl-4-morpholino)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0167] 5-(4-chloro-2-fluorophenyl)-7-((2S,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0168] 5-(4-chloro-2-fluorophenyl)-7-((2S,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0169] 5-(4-chloro-2-fluorophenyl)-7-((2R,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0170] 5-(4-chloro-2-fluorophenyl)-7-((2R,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0171] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2R)-2-oxetane)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0172] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2S)-2-oxetane)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0173] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2S)-2-oxetane)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0174] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2R)-2-oxetane)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0175] 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;

[0176] 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;

[0177] 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;

[0178] 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;

[0179] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0180] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0181] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(4-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0182] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(4-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0183] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-pyridazinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0184] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(5-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0185] 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;

[0186] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2,2,2-trifluoroethyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0187] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(thiophen-3-yl)morpholine)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0188] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-thienyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0189] 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;

[0190] 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;

[0191] 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;

[0192] 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;

[0193] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(6-methyl-3-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0194] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-4-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0195] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-methyl-4-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0196] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2-methyl-4-pyrimidinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0197] 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;

[0198] 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;

[0199] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0200] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1,5-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0201] 5-(4-chloro-2-fluorophenyl)-7-(2-(1,3-dimethyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0202] 5-(4-chloro-2-fluorophenyl)-7-(2-(5-fluoro-3-pyridinyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0203] 5-(4-chloro-2-fluorophenyl)-7-(2-(5-ethyl-1,3,4-oxadiazol-2-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0204] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6S)-2-methyl-6-(3-thienyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0205] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6R)-2-methyl-6-(3-thienyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0206] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6S)-2-methyl-6-(3-thienyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0207] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,6R)-2-methyl-6-(3-thienyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0208] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-methyl-1,3-thiazolyl-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0209] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2,6-dimethyl-4-pyridyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0210] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2,6-dimethyl-4-pyridyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0211] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0212] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0213] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0214] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0215] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0216] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0217] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0218] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0219] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-chlorophenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0220] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-chlorophenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0221] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-chloro-4-pyridyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0222] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-chloro-4-pyridyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0223] 4-(4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyridino[4,3-d]pyrimidin-7-yl)-2-morpholinyl)benzylnitrile;

[0224] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-(trifluoromethyl)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0225] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-(trifluoromethyl)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0226] 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;

[0227] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(2-(trifluoromethyl)-4-pyridinyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0228] 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;

[0229] 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;

[0230] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-(trifluoromethoxy)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0231] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-(trifluoromethoxy)phenyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0232] 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;

[0233] 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;

[0234] 5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,6-naphthidin-2(1H)-yl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0235] 5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,7-naphthidin-2(1H)-yl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0236] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(1-methyl-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)pyridolo[4,3-d]pyrimidin-4(3H)-one;

[0237] 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;

[0238] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(5-oxo-3-pyrrolidinyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0239] 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;

[0240] 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;

[0241] 5-(4-chloro-2-fluorophenyl)-7-(3-(dimethylamino)-1-piperidinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0242] 7-(3-(1-azacyclobutyl)-1-piperidinyl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0243] 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;

[0244] 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;

[0245] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3S)-3-(4-pyridyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0246] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(4-pyridyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0247] 7-(8-chloro-3,4-dihydro-2,7-naphthidin-2(1H)-yl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0248] 5'-(4-chloro-2-fluorophenyl)-4-methoxy-2',3'-dimethyl-7,8-dihydro-5H-[6,7'-bipyrido[4,3-d]pyrimidine]-4'(3'H)-one;

[0249] 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;

[0250] 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;

[0251] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(trifluoromethyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0252] 5-(4-chloro-2-fluorophenyl)-7-(3-(difluoromethyl)-1-pyrrolidinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0253] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(3-pyridyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0254] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0255] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0256] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(3-oxetane)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0257] 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;

[0258] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0259] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0260] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0261] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoro-2-hydroxyethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0262] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0263] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0264] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,3-difluoro-2-propyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0265] 2-Methyl-2-propyl 3-(4-((2S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyridino[4,3-d]pyrimidin-7-yl)-2-morpholino)-1H-pyrazol-1-yl)-1-azacyclobutane carboxylate;

[0266] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,2-difluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0267] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0268] 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-vinyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0269] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azacyclobutane)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0270] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0271] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0272] 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;

[0273] 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;

[0274] 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;

[0275] 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;

[0276] 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;

[0277] 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;

[0278] 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;

[0279] 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;

[0280] 5-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(2-methyl-4-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0281] 5-(2,4-difluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(2-methyl-4-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0282] 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;

[0283] 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;

[0284] 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;

[0285] 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;

[0286] 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;

[0287] 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(difluoromethyl)-4-morpholino)-2-methyl-3-propylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0288] 5-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S)-2-phenyl-4-morpholinyl)-3-propylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0289] 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;

[0290] 5-Cyclohexyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0291] 5-Cyclopentyl-2,3-dimethyl-7-((2S)-2-(1-methyl-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0292] 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;

[0293] 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;

[0294] 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;

[0295] 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;

[0296] 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one;

[0297] 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;

[0298] (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-carboxylic acid ethyl ester 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-carboxylic acid ethyl ester;

[0299] (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 ethyl ester 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-carboxylic acid ethyl ester;

[0300] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(2-methyl-4-pyridyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0301] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(2-methyl-4-pyridyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0302] 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;

[0303] 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0304] 5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0305] 5-(4-chloro-2-fluorophenyl)-7-((2R,4R)-2-(2-methoxy-4-pyridyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0306] 5-(4-chloro-2-fluorophenyl)-7-((2S,4S)-2-(2-methoxy-4-pyridyl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0307] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4R)-2-(3-pyridyl)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-pyridyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0308] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(3-pyridyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one; or

[0309] 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,4R)-2-(3-pyridyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one.

[0310] As an embodiment 43, this document provides a compound or a tautomer thereof according to embodiment 1, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of Table A.

[0311] As an embodiment 44, this document provides the compound or its tautomer according to embodiment 1, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is not

[0312] 5-(2,4-difluorophenyl)-2,3-dimethyl-7-(2-(2-methylpyridin-4-yl)morpholine)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0313] 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;

[0314] 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;

[0315] 5-(2,4-Difluorophenyl)-7-(2-(2-methoxypyridin-4-yl)morpholine)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one;

[0316] 2,3-Dimethyl-7-(2-(2-methylpyridin-4-yl)morpholine)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrido[4,3-d]pyrimidin-4(3H)-one;

[0317] 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;

[0318] 2,3-Dimethyl-7-(2-(2-methylpyridin-4-yl)morpholine)-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[4,3-d]pyrimidin-4(3H)-one; or

[0319] 7-(2-(2-methoxypyridin-4-yl)morpholine)-2,3-dimethyl-5-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrido[4,3-d]pyrimidin-4(3H)-one.

[0320] As an embodiment 45, this document provides a compound or a tautomer thereof according to embodiment 1, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of formula II.

[0321]

[0322] in

[0323] n is 1;

[0324] X 1 It is CH or N;

[0325] X 2 It is O;

[0326] X3 It is N;

[0327] R 1 and R 2 They are all methyl groups;

[0328] R 3 R 4 and R 5 Each is H;

[0329] R 6 yes and

[0330] R 7 It is C 5-6 cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, phenyl, or 6-membered heteroaryl; wherein R 7 Further optionally selected by 1 to 4 independently chosen from halogen, C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups;

[0331] The prerequisite is R 7 no

[0332] As an embodiment 46, this document provides a compound or a tautomer thereof according to embodiment 1, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein said compound is a compound of formula II.

[0333]

[0334] in

[0335] n is 1;

[0336] X 1 It is CH or N;

[0337] X 2 It is O;

[0338] X 3 It is N;

[0339] R 1 and R 2 They are all methyl groups;

[0340] R 3 R 4 and R 5 Each is H;

[0341] R 6 yes and

[0342] R7 yes

[0343] As embodiment 47, this document provides a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is

[0344] As an embodiment 48, this document provides a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is

[0345] As embodiment 49, this document provides the compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is

[0346] As an embodiment 50, this document provides a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is

[0347] As an embodiment 51, this document provides a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is

[0348] As an embodiment 52, this document provides a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is

[0349] As embodiment 53, this document provides a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is

[0350] As an embodiment 54, this document provides a compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein said compound is

[0351] Exemplary compounds of the present invention are shown in Table A below. In some embodiments, the compounds of Formula I are those shown in Table A. In some embodiments, the present invention provides compounds as depicted in Table A or pharmaceutically acceptable salts thereof.

[0352] Table A. Exemplary Compounds

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404] The foregoing summarizes only certain aspects of this disclosure and is not intended to, nor should it be construed as, limiting this disclosure in any way.

[0405] Formulation and route of administration

[0406] While the compounds disclosed herein may be applied alone in the stated uses, they are typically provided as active ingredients in a pharmaceutical composition. Therefore, in one embodiment, a pharmaceutical composition is provided comprising the compounds disclosed herein with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants, etc., and, if desired, combinations of other active ingredients. See, for example, Remington: The Science and Practice of Pharmacy, Volumes I and II, 22nd Edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012; Pharmaceutical Dosage Forms (Vols. 1–3), edited by Liberman et al., Marcel Dekker, New York, NY, 1992; Handbook of Pharmaceutical Excipients (3rd Edition), edited by Arthur H. Kibbe, American Pharmaceutical Association, Washington, 2000; Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), 1st Edition, edited by GD Tovey, Royal Society of Chemistry, 2018. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of the compound disclosed herein.

[0407] One or more compounds disclosed herein may be administered via any suitable route in the form of a pharmaceutical composition suitable for such route and at a dose effective for the intended treatment. For example, the compounds and compositions provided herein may be administered orally, via mucosae, topically, transdermally, rectally, pulmonaryly, parenterally, intranasally, intravascularly, intravenously, intra-arterially, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally, or by infusion techniques in dosage units containing conventional pharmaceutically acceptable excipients.

[0408] Pharmaceutical compositions may be in the form of, for example, tablets, chewable tablets, small tablets, small capsules, pills, beads, hard capsules, soft capsules, gelatin capsules, granules, powders, lozenges, patches, creams, gels, small pouches, microneedle arrays, syrups, flavored syrups, fruit juices, drops, solutions for injection, emulsions, microemulsions, ointments, aerosols, aqueous suspensions, or oil suspensions. Pharmaceutical compositions are typically prepared in dosage units containing a specific amount of the active ingredient.

[0409] As embodiment 55, this document provides a pharmaceutical composition comprising a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.

[0410] As embodiment 56, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, which are used as pharmaceuticals.

[0411] Pharmaceutically acceptable compositions

[0412] According to some embodiments, this disclosure provides a composition comprising a compound of the present disclosure or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or mediator. The amount of the compound in the composition of the present disclosure is such that it is effective in measurably activating TREM2 protein or its mutants in a biological sample or patient. In some embodiments, the amount of the compound in the composition of the present disclosure is such that it is effective in measurably activating TREM2 protein or its mutants in a biological sample or patient. In some 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.

[0413] The compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or through a transplanted reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathic, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions disclosed herein can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspension media.

[0414] For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, can be used to prepare injectable formulations, as well as pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially their polyoxyethylated forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants, which are commonly used in pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens and Spans, as well as other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0415] The pharmaceutically acceptable compositions disclosed herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of oral tablets, common 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 an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavoring agents, or coloring agents may also be added.

[0416] Alternatively, the pharmaceutically acceptable compositions of this disclosure can be administered in the form of suppositories for rectal use. These can be prepared by mixing the pharmaceutical preparation with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thus melting in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0417] The pharmaceutically acceptable compositions disclosed herein can also be applied topically, especially when the target of treatment includes areas or organs easily accessible by topical application, including eye, skin, or lower intestinal diseases. Suitable topical formulations for each of these areas or organs can be readily prepared.

[0418] Local administration to the lower intestine can be achieved in rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches can also be used.

[0419] For topical application, the provided pharmaceutically acceptable compositions can be formulated as suitable ointments containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated as suitable lotions or creams containing an 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, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0420] For ophthalmic applications, the pharmaceutically acceptable compositions provided may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride, or preferably as solutions in isotonic, pH-adjusted sterile saline. Alternatively, for ophthalmic applications, the pharmaceutically acceptable compositions may be formulated as ointments such as petrolatum.

[0421] The pharmaceutically acceptable compositions disclosed herein can also be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0422] Most preferably, the pharmaceutically acceptable compositions of this disclosure are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this disclosure are administered in the absence of food. In other embodiments, the pharmaceutically acceptable compositions of this disclosure are administered with food.

[0423] The amount of the compounds disclosed herein, which can be combined with carrier materials to produce compositions in a single dosage form, will vary depending on the host being treated and the specific route of administration. Preferably, the provided compositions should be formulated such that a dose of the compound between 0.01 and 100 mg / kg body weight / day can be administered to patients receiving these compositions.

[0424] 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 used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, as well as the attending physician's judgment and the severity of the specific disease being treated. The amount of the disclosed compounds in the composition will also depend on the specific compound in the composition.

[0425] How to use

[0426] As discussed herein (see the section entitled “Definitions”), the compounds described herein should be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates of any of the foregoing substances. Therefore, the scope of the methods and uses provided in this disclosure should be understood to additionally cover methods and uses employing all of these forms.

[0427] In addition to their use in human treatment, the compounds described herein can also be used for veterinary treatment of companion animals, exotic animals, and farm animals, including mammals, rodents, and more. For example, the compounds described herein can be used to treat animals including horses, dogs, and cats.

[0428] Without being bound by any particular theory, the following should be noted: TREM2 is associated with several myeloid cell processes, including the regulation of phagocytosis, proliferation, survival, and the production of inflammatory cytokines. (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 the autosomal recessive genetic disorder Nasu-Hakola, characterized by bone cysts, muscle atrophy, and a demyelinating phenotype. (Guerreiro et al. 2013). More recently, variants of 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. Specifically, the R47H variant has been identified in genome-wide studies as associated with an increased risk of late-onset AD, with an overall adjusted odds ratio (OOP) of 2.3 (across all age groups), second only to the strong genetic association between ApoE and Alzheimer's disease. The R47H mutation, located on the extracellular 1gV-set domain of the TREM2 protein, has been shown to affect lipid binding and uptake by apoptotic cells and Abeta (Wang et al. 2015; Yeh et al. 2016), suggesting a disease-related loss of function. Furthermore, post-mortem comparisons of the brains of AD patients with and without the R47H mutation support a novel loss of microglial barrier function in mutation carriers, with R47H carrier microglia presumably exhibiting a reduced ability to compress plaques and limit plaque spread. Yuan et al. (2016) have reported impaired microglial proliferation in animal models of prion diseases, multiple sclerosis, and stroke, suggesting that TREM2 may play an important role in supporting microglial proliferation in response to pathology or injury of the central nervous system. Ulrich and Holtzman (2016) further showed that TREM2 knockdown exacerbates α-synuclear inflammatory responses in vitro and exacerbates the loss of dopaminergic neurons in response to AAV-SYN in vivo (Parkinson's disease model), suggesting that impaired microglial TREM2 signaling exacerbates neurodegeneration by modulating microglial activation status. Guo et al. (2019) have also shown in numerous animal models that persistent expression of pro-inflammatory cytokines via Toll-like receptor (TLR) signaling through macrophages plays an important role in the pathogenesis of rheumatoid arthritis (RA). The TREM2 / DAP12 signaling pathway inhibits the TLR response by reducing MAPK(Erk1 / 2) activation, suggesting that TREM2 activation can act as a negative regulator of the TLR-driven pathogenesis of RA. (Huang and Pope 2009).

[0429] Given the data showing that defects in TREM2 activity affect macrophage and microglial function, the compounds disclosed herein are particularly suitable for disorders such as those described above and in the following embodiments, as well as more general neurodegenerative diseases.

[0430] As embodiment 57, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, which are used to treat or prevent conditions associated with loss of function of human TREM2.

[0431] As embodiment 58, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, which are used to treat or prevent Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prions, or stroke.

[0432] As embodiment 59, this document provides the use of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, for the preparation of a medicament for the treatment or prevention of conditions associated with loss of function of human TREM2.

[0433] As embodiment 60, this document provides the use of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, for the preparation of a medicament for the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prions, or stroke.

[0434] As embodiment 61, this document provides a method for treating or preventing a condition in a subject of need related to loss of function of human TREM2, the method comprising administering a therapeutically effective amount of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject.

[0435] As embodiment 62, this document provides a method for treating or preventing Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prions, or stroke in a subject of need, the method comprising administering a therapeutically effective amount of a compound or its tautomer according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject.

[0436] In some embodiments, the condition associated with loss of TREM2 function in humans is Parkinson's disease. In some embodiments, the condition associated with loss of TREM2 function in humans is rheumatoid arthritis. In some embodiments, the condition associated with loss of TREM2 function in humans is Alzheimer's disease. In some embodiments, the condition associated with loss of TREM2 function in humans is Nasu-Hakola disease. In some embodiments, the condition associated with loss of TREM2 function in humans is frontotemporal dementia. In some embodiments, the condition associated with loss of TREM2 function in humans is multiple sclerosis. In some embodiments, the condition associated with loss of TREM2 function in humans is prion disease. In some embodiments, the condition associated with loss of TREM2 function in humans is stroke.

[0437] CSF1R

[0438] CSF1R, a cell surface receptor primarily targeting the cytokine colony-stimulating factor 1 (CSF-1) and only recently known as macrophage colony-stimulating factor (M-CSF), 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 a receptor homodimer and subsequent autophosphorylation of cytoplasmic tyrosine residues, particularly Syk, in the cytoplasmic domain. In the brain, CSF1R is primarily expressed in microglia. Microglia have been found to be knocked out in CSF1R+ / - patients, exhibiting increased apoptosis (Oosterhof et al., 2018).

[0439] This invention relates to the unexpected finding that administration of a TREM2 agonist can rescue microglia loss in cells with CSF1R mutations. Previous studies have shown that when M-CSF levels in culture medium are reduced to 5 ng / mL, the TREM2 agonist antibody 4D9 increases ATP luminescence (a measure of cell number and activity) in a dose-dependent manner (Schlepckow et al., EMBO Mol Med., 2020), and when M-CSF is completely removed from the culture medium, the TREM2 agonist AL002c increases ATP luminescence (Wang et al., J. Exp. Med.; 2020, 217(9):e20200785). This finding suggests that TREM2 agonism can compensate for defects in CSF1R signaling caused by reduced concentrations of its ligands. In a 5xFAD murine model of Alzheimer's disease with amyloid pathology, doses of CSF1R inhibitors that nearly completely eliminated microglia in the brains of wild-type animals showed that surviving microglia aggregated around amyloid plaques (Spangenberg et al., Nature Communications 2019). It has been previously shown that plaque amyloid is a ligand of TREM2, and that microglia binding to amyloid is TREM2-dependent (Condello et al., Nat Comm., 2015). This invention relates to the unexpected finding that activation of TREM2 in the presence of CSF1R inhibitors rescues microglia, and that this effect has also been observed in patients suffering microglia loss due to CSF1R mutations. This finding has not been previously taught or proposed in the art.

[0440] To date, previous studies have not demonstrated that TREM2 agonists can rescue microglia loss in cells in the presence of CSF1R inhibitors or CSF1R ligand defects that reduce CSF1R activity, rather than in cases where mutations in the CSF1R kinase domain reduce CSF1R activity. Furthermore, previous studies have not taught or suggested that reversing microglia loss due to CSF1R mutations through TREM2 agonism could be used to treat diseases or disorders caused by and / or associated with CSF1R mutations.

[0441] Adult-onset leukoencephalopathy with axonoglobulinization and pigmented gliomatosis (ALSP), previously thought to be hereditary diffuse leukoencephalopathy with axonoglobulinization (HDLS) or pigmented orthochromatic leukodystrophy (POLD), is an autosomal dominant inherited central nervous system disorder. Patients with this disease exhibit behavioral, cognitive, and motor function changes in variable forms. ALSP is characterized by patchy white matter abnormalities visible on magnetic resonance imaging (MRI). However, clinical symptoms and MRI changes are not specific to ALSP and are also common in other neurological disorders, including Nasu-Hakola disease (NHD) and Alzheimer's disease (AD), making the diagnosis and treatment of ALSP very challenging.

[0442] Recent studies have revealed that ALSP is a Mendelian genetic disorder in which patients carry a heterozygous loss-of-function mutation in the kinase domain of CSF1R, indicating reduced signaling levels along the macrophage colony-stimulating factor (M-CSF) / CSF1R axis (Rademakers et al., Nat Genet 2012; Konno et al., Neurology 2018). In one aspect, this invention relates to the unexpected finding that activation of the TREM2 pathway can rescue microglia loss in CSF1R+ / - ALSP patients, prevent microglia apoptosis, and thereby treat ALSP.

[0443] As embodiment 63, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, which are used to treat or prevent conditions associated with dysfunction of colony-stimulating factor 1 receptor (CSF1R, also known as macrophage colony-stimulating factor receptor / M-CSFR, or differentiation cluster 115 / CD115).

[0444] As embodiment 64, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, which are used to treat or prevent adult-onset leukoencephalopathy with axonoglobulinization and pigmented gliosis (ALSP), hereditary diffuse leukoencephalopathy with axonoglobulinization (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital microglia or abnormal neurodegeneration of the brain and osteosclerosis (BANDDOS).

[0445] As embodiment 65, this document provides the use of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 55, for the preparation of a medicament for the treatment or prevention of conditions associated with dysfunction of CSF1R.

[0446] As embodiment 66, this document provides the use of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, for the preparation of a medicament for the treatment or prevention of adult-onset leukoencephalopathy with axonoglobulinization and pigmented gliosis (ALSP), hereditary diffuse leukoencephalopathy with axonoglobulinization (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital microglia or abnormal neurodegeneration of the brain and osteosclerosis (BANDDOS).

[0447] As embodiment 67, this document provides a method for treating or preventing a disease or disorder related to CSF1R dysfunction in a subject of need, the method comprising administering a therapeutically effective amount of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject. In some embodiments, the subject is selected for treatment based on a diagnosis including the presence of a mutation in the CSF1R gene that affects the function of CSF1R. In some embodiments, the mutation in the CSF1R gene is a mutation that results in reduced or ceased 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 splicing 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 extracellular domain of CSF1R. In some embodiments, the disease or disorder is caused by an alteration (e.g., increase, decrease, or cessation) of CSF1R activity. In some embodiments, the disease or disorder is caused by a decrease or cessation of CSF1R activity. CSF1R-related activities altered in the disease or disorder include, but are not limited to: reduced or lost microglia function; increased microglia apoptosis; reduced Src signaling; reduced Syk signaling; reduced microglia proliferation; reduced microglia response to cell debris; reduced phagocytosis; and reduced release of cytokines in response to stimulation. 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 the complete cessation of CSF1R function. In some embodiments, the loss-of-function mutation results in partial loss of CSF1R function or a reduction in CSF1R activity.

[0448] As embodiment 68, this document provides a method for treating or preventing adult-onset leukoencephalopathy with axonoglobulinization and pigmented gliosis (ALSP), hereditary diffuse leukoencephalopathy with axonoglobulinization (HDLS), pigmented orthochromatic leukodystrophy (POLD), childhood-onset leukoencephalopathy, congenital microglia absence or abnormal neurodegeneration of the brain and osteosclerosis (BANDDOS) in a subject of need, said method comprising administering a therapeutically effective amount of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject. In some embodiments, said method treats or prevents ALSP, ALSP being a comprehensive and alternative name for both HDLS and POLD. In some embodiments, the disease or disorder is a homozygous mutation in CSF1R. In some embodiments, said method treats or prevents childhood-onset leukoencephalopathy. In some embodiments, said method treats or prevents congenital microglia absence. In some implementations, the method treats or prevents abnormal neurodegeneration and osteosclerosis of the brain (BANDDOS).

[0449] As an implementation scheme 69, this article provides a treatment or prevention for 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, prions, stroke, osteoporosis, osteosclerosis, osteoid sclerosis, skeletal dysplasia, bone dysplasia, Pyle's disease, autosomal dominant cerebral arteriosclerosis with subcortical infarction and leukoencephalopathy. A method for treating autosomal recessive cerebral arteriosclerosis with subcortical infarction and leukoencephalopathy, cerebral retinal vascular disease, or metachromatic leukodystrophy, wherein any of the aforementioned diseases or disorders exists in a patient exhibiting CSF1R dysfunction or having a gene mutation affecting CSF1R function, the method comprising administering a therapeutically effective amount of a compound or its tautomer according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject.

[0450] ABCD1

[0451] The ABCD1 gene provides instructions for the production of adrenoleukodystrophy protein (ALDP). ABCD1 (ALDP) is mapped to Xq28. ABCD1 is a member of the ATP-binding cassette (ABC) transporter superfamily. This superfamily contains membrane proteins that can translocate a variety of substrates to the extracellular and intracellular membranes, including metabolites, lipids and sterols, as well as drugs. ALDP is located in the membrane of a cellular structure called a peroxisome. Peroxisomes are small sacs within the cell that process many types of molecules. ALDP carries a group of fats called very long chain fatty acids (VLCFAs) into the peroxisome, where they are broken down. Because ABCD1 is highly expressed in microglia, microglia dysfunction and its close interactions with other cell types can be actively involved in neurodegenerative processes (Gong et al., Annals of Neurology. 2017; 82(5):813-827.). Studies have shown that severe microglial loss and damage are early characteristics of patients with the brain form of X-linked ALD (cALD) carrying ABCD1 mutations (Bergner et al., Glia. 2019; 67:1196–1209). Research has also shown that ABCD1 deficiency leads to impaired plasticity of bone marrow lineage cells, reflected in the incomplete establishment of anti-inflammatory responses, and may therefore contribute to the destructive, rapidly progressive demyelination in cerebral adrenoleukodystrophy (Weinhor et al., BRAIN 2018:141; 2329–2342). These findings highlight microglia / monocytes / macrophages as key therapeutic targets for preventing or halting myelination in patients with X-linked adrenoleukodystrophy.

[0452] This invention relates to the unexpected finding that administration of a TREM2 agonist can rescue microglia loss in cells with ABCD1 gene mutations. Previous studies have shown that when M-CSF levels in culture medium are reduced to 5 ng / mL, the TREM2 agonist antibody 4D9 increases ATP luminescence (a measure of cell number and activity) in a dose-dependent manner (Schlepckow et al., EMBO Mol Med., 2020), and when M-CSF is completely removed from the culture medium, the TREM2 agonist AL002c increases ATP luminescence (Wang et al., J. Exp. Med.; 2020, 217(9):e20200785). This finding suggests that TREM2 agonists can compensate for ABCD1 dysfunction, leading to sustained activation, proliferation, and chemotaxis of microglia, maintaining an anti-inflammatory environment, and reducing astrocyte proliferation caused by ABCD1 reduction and VLCFA accumulation. This invention relates to the unexpected discovery that activation of TREM2 in the presence of ABCD1 mutations and increased VLCFA can rescue microglia, and this effect can also be observed in patients suffering microglia loss due to ABCD1 mutations. This discovery has not been previously taught or proposed in the art.

[0453] To date, previous studies have not demonstrated that TREM2 agonism can rescue microglia loss in the presence of ABCD1 mutations and increased VLCFA. Previous research has not taught or suggested that reversing microglia loss due to ABCD1 mutations through TREM2 agonism could be used to treat diseases or disorders caused by and / or associated with ABCD1 mutations.

[0454] As embodiment 70, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, which are used to treat or prevent conditions associated with dysfunction of ATP-binding cassette transporter 1 (ABCD1).

[0455] As embodiment 71, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, which are used to treat or prevent X-linked adrenoleukodystrophy (x-ALD), globular cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriovenous arteriovenous disease with subcortical infarction and leukoencephalopathy (CADASIL), leukopenia disease (VWM), Alexander disease, fragile X-related tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[0456] As embodiment 72, this document provides the use of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 55, for the preparation of a medicament for the treatment or prevention of conditions associated with dysfunction of ABCD1.

[0457] As embodiment 73, this document provides the use of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, for the preparation of a medicament for the treatment or prevention of X-linked adrenoleukodystrophy (x-ALD), globular cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriovenous arteriovenous disease with subcortical infarction and leukoencephalopathy (CADASIL), vesicular leukodystrophy (VWM), Alexander disease, fragile X-related tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX).

[0458] As embodiment 74, this document provides a method for treating or preventing a disease or disorder related to ABCD1 dysfunction in a subject of need, the method comprising administering a therapeutically effective amount of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject. In some embodiments, patients are 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 results in reduced or stopped 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 splicing 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 caused by an alteration in ABCD1 activity (e.g., an increase, a decrease, or a cessation). In some embodiments, the disease or disorder is caused by a reduction or cessation of ABCD1 activity. ABCD1-related activities altered in the disease or disorder include, but are not limited to, peroxisome input of fatty acids and / or fatty acyl-CoA and the 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 the complete cessation of ABCD1 function. In some embodiments, the loss-of-function mutation results in partial loss of ABCD1 function or a reduction in ABCD1 activity. 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 disease. In some embodiments, the disease or disorder is a neurodegenerative disease 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 immune disorder caused by and / or associated with ABCD1 dysfunction.

[0459] As embodiment 75, this document provides a method for treating or preventing X-linked adrenoleukodystrophy (x-ALD), globular cell leukodystrophy (also known as Krabbe disease), metachromatic leukodystrophy (MLD), cerebral autosomal dominant arteriovenous arteriovenous disease with subcortical infarction and leukoencephalopathy (CADASIL), vesicular leukopenia (VWM), Alexander disease, fragile X-related tremor ataxia syndrome (FXTAS), adult-onset autosomal dominant leukodystrophy (ADLD), and X-linked Charcot-Marie-Tooth disease (CMTX) in a subject of need, said method comprising administering a therapeutically effective amount of a compound or its tautomer according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject. In some embodiments, any of the aforementioned diseases is present in patients exhibiting ABCD1 dysfunction or having gene mutations affecting ABCD1 function. In some embodiments, the method treats or prevents X-linked adrenoleukodystrophy (x-ALD). In some embodiments, the brain form of X-linked ALD (cALD). In some embodiments, the method treats or prevents Addison's disease, wherein the patient has been found to have a mutation in one or more ABCD1 genes affecting ABCD1 function. In some embodiments, the method treats or prevents Addison's disease, wherein the patient has a loss-of-function mutation in ABCD1.

[0460] As embodiment 76, this document provides a method for treating or preventing Nasu-Hakola disease, Alzheimer's disease, frontotemporal dementia, multiple sclerosis, Guillain-Barré syndrome, amyotrophic lateral sclerosis (ALS), or Parkinson's disease, wherein any of the aforementioned diseases or disorders is present in a patient exhibiting ABCD1 dysfunction or having a gene mutation affecting ABCD1 function, the method comprising administering a therapeutically effective amount of a compound or its tautomer according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject.

[0461] Autism spectrum disorder

[0462] TREM2-deficient mice have been found to exhibit symptoms indicative of autism spectrum disorder (ASD) (Filipello et al., Immunity, 2018, 48, 979-991). Microglia knockout of the autophagy Aatg7 gene has also been found to lead to synaptic pruning defects and increased dendritic spine density, as well as abnormal social interactions and repetitive behaviors indicative of ASD (Kim et al., Molecular Psychiatry, 2017, 22, 1576-1584). Further research has shown that increased dendritic spine density detected in the post-mortem ASD brain may be due to synaptic pruning defects, leading to low circuit connectivity and behavioral deficits, and is a potential source of many neurodevelopmental disorders (Tang et al., Neuron, 2014, 83, 1131-1143). Without intending to be limited to any particular theory, these findings suggest that TREM2 activation can reverse microglia knockout, thereby correcting synaptic pruning defects crucial for neurodevelopmental disorders such as ASD. This invention relates to the unexpected discovery that TREM2 activation using the compounds of this invention can rescue microglia in subjects with ASD. This discovery has not been previously taught or proposed in the art.

[0463] As embodiment 77, this document provides a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, for the treatment of autism or autism spectrum disorder.

[0464] As embodiment 78, this document provides the use of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, for the preparation of a medicament for the treatment of autism or autism spectrum disorder.

[0465] As embodiment 79, this document provides a method for treating autism or autism spectrum disorder in a subject of need, the method comprising administering a therapeutically effective amount of a compound or tautomer thereof according to any one of embodiments 1 to 54, or a pharmaceutically acceptable salt of said compound or said tautomer, or a pharmaceutical composition according to embodiment 55, to said subject. In some embodiments, the method treats autism. In some embodiments, the method treats Asperger's syndrome.

[0466] In some embodiments, this disclosure provides a method for increasing the activity of TREM2, said method comprising contacting TREM2 with a compound of the disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the contact occurs in vitro. In some embodiments, the contact occurs in vivo. In some embodiments, TREM2 is human TREM2.

[0467] Combination therapy

[0468] Depending on the specific condition or disease to be treated, additional therapeutic agents typically used to treat that condition may be used in combination with the compounds and compositions disclosed herein. As used herein, additional therapeutic agents typically used to treat a specific disease or condition are referred to as “suitable for the disease or condition to be treated”.

[0469] In some embodiments, the provided combination or combinations thereof are administered in combination with another therapeutic agent.

[0470] In some embodiments, this disclosure provides a method of treating a disclosed disease or condition, the method comprising administering an effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof to a patient in need, and simultaneously or sequentially co-administering effective amounts 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 the disclosed compound and one or more additional therapeutic agents has a synergistic effect.

[0471] Examples of agents that can be combined with the combinations disclosed herein include, but are not limited to, the treatment of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prions, or stroke.

[0472] As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to this disclosure. For example, combinations of this disclosure may be administered simultaneously or sequentially with another therapeutic agent in a single unit dosage form or together with a single unit dosage form.

[0473] The amount of additional therapeutic agent present in the compositions disclosed herein will not exceed the amount normally applied in compositions containing the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will be in the range of about 50% to 100% of the amount normally present in the composition containing the pharmaceutical agent as the sole active agent.

[0474] One or more other therapeutic agents may be administered separately from the compounds or compositions of this disclosure as part of a multiple-dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of this disclosure in a single composition. If administered as a multiple-dose regimen, one or more other therapeutic agents and the compounds or compositions of this disclosure may be administered to each other simultaneously, sequentially, or over a period of time, such as 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. In some embodiments, one or more other therapeutic agents and the compounds or compositions of this disclosure are administered as a multiple-dose regimen over a period greater than 24 hours.

[0475] In one embodiment, this disclosure provides a composition comprising the provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. The therapeutic agent may be administered together with the provided compound or a pharmaceutically acceptable salt thereof, or may be administered before or after the administration of the provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below. In some 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 prior to the therapeutic agent. In other embodiments, the provided compound or its pharmaceutically acceptable salt 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 after the therapeutic agent.

[0476] definition

[0477] The following definitions are provided to help understand the scope of this disclosure.

[0478] Unless otherwise specified, all figures used in the specification or claims to indicate quantities of ingredients, reaction conditions, etc., should be understood to be modified by the term "about" in all cases. Therefore, unless stated to the contrary, the numerical parameters shown in the following specification and appended claims are approximations, which may vary depending on the standard deviation present in their respective test measurements.

[0479] As used in this article, if any variable appears more than once in a chemical formula, its definition for each occurrence is independent of its definition for every other occurrence. If there is a conflict between the chemical structure and the chemical name, the chemical structure determines the identity of the compound.

[0480] As used herein, unless otherwise specified, the following definitions shall apply. For the purposes of this disclosure, chemical elements are defined according to the Periodic Table, CAS Edition, Handbook of Chemistry and Physics, p. 101. 版 To identify. Additionally, the general principles of organic chemistry are found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 2005, and "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure," p. 8. 版 As described in Smith, MB (ed.), John Wiley & Sons, New York: 2019, the full contents of which are incorporated herein by reference.

[0481] Stereoisomers

[0482] The compounds disclosed herein 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 transisomers. Therefore, unless specifically identified by stereochemistry, the scope of this disclosure should be understood to cover all possible stereoisomers of the compounds shown, including pure stereoisomeric forms (e.g., geometrically pure, enantiomerically pure, diastereomerically pure, and transisomerically pure) and mixtures of stereoisomers (e.g., mixtures of geometrically pure, enantiomerically pure, diastereomerically pure, and transisomerically pure, or any of the foregoing) of any chemical structure (all or part) disclosed herein.

[0483] If the stereochemistry of a structure or part thereof is not indicated, for example, by bold or dashed lines, then the structure or part thereof shall be interpreted to cover all its stereoisomers. If the stereochemistry of a structure or part thereof is indicated, for example, by bold or dashed lines, then the structure or part thereof shall be interpreted to cover only the indicated stereoisomers. For example, 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one (Example 129) is intended to cover 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-((S)-1-fluoroethyl)-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one (Example 129) )-1H-pyrazol-4-yl)-4-morpholino)-2,3-dimethylpyrido[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-morpholino)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. Bonds drawn with wavy lines indicate the coverage of both stereoisomers. This should not be confused with wavy lines perpendicular to the bonds, which indicate the points of connection between the group and the rest of the molecule.

[0484] As used herein, the term "stereoisomer" or "stereoisopure" refers to a stereoisomer of a compound (e.g., a geometric isomer, enantiomer, diastereomer, and transisomer) that is substantially free of other stereoisomers of the compound. For example, a stereoisopure compound having one chiral center will be substantially free of its mirror-image enantiomers, while a stereoisopure compound having two chiral centers will be substantially free of other enantiomers and diastereomers of the compound. A typical stereoisomeric pure compound contains more than about 80% by weight of one stereoisomer of the compound and equal to or less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and equal to or less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and equal to or less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and equal to or less than about 3% by weight of other stereoisomers of the compound.

[0485] This disclosure also covers the use of pharmaceutical compositions comprising the stereoisomeric pure form and the stereoisomeric pure form of any compound disclosed herein. Furthermore, this disclosure covers pharmaceutical compositions comprising mixtures of stereoisomers of any compound disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof can be synthesized according to methods well known in the art and methods disclosed herein. Mixtures of stereoisomers can be resolved using standard techniques such as chiral chromatographic columns or chiral resolving agents. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725; Eliel, Stereochemistry of Carbon Compounds (McGrawHill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (Eliel ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0486] tautomer

[0487] As those skilled in the art will know, some of the compounds disclosed herein may exist in one or more tautomer forms. Because a chemical structure can be used to represent only one tautomer form, it should be understood that, for convenience, references to compounds having a given structural formula include other tautomers of said structural formula. For example, the following are examples of tautomers of compounds of formula I, where R... 1 It is H:

[0488]

[0489] Therefore, the scope of this disclosure should be understood to cover all tautomer forms of the compounds disclosed herein.

[0490] Isotope-labeled compounds

[0491] Furthermore, the scope of this disclosure includes all pharmaceutically acceptable isotopically labeled compounds of the compounds disclosed herein, such as compounds of formula I, wherein one or more atoms are substituted with atoms having the same atomic number, but with an atomic mass or mass number different from that commonly found in nature. Examples of isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as... 2 H and 3H, an isotope of carbon, such as 11 C 13 C and 14 C, isotopes of chlorine, such as 36 Cl, an isotope of fluorine, such as 18 F, an isotope of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, an isotope of oxygen, such as 15 O、 17 O and 18 O, isotopes of phosphorus, such as 32 P, and isotopes of sulfur, such as 35 S. Certain isotope-labeled compounds of formula I, such as those doped with radioactive isotopes, can be used for drug and / or substrate tissue distribution studies. Radioactive isotope tritium ( 3 H) and carbon-14 ( 14 C) They are particularly useful for this purpose due to their ease of incorporation and readily available detection methods. Using isotopes such as deuterium ( 2 H or D substitution can provide certain therapeutic advantages stemming from increased metabolic stability, such as increased in vivo half-life or reduced dose requirements, and can therefore be advantageous in some cases. Positron-emitting isotopes, such as... 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies, for example, to examine target occupancy. The isotopically labeled compounds disclosed herein can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described in the appended general synthetic schemes and examples, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

[0492] solvates

[0493] As discussed above, the compounds disclosed herein, their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing, may exist in solvated or non-solvated forms.

[0494] As used herein, the term "solvent" refers to a molecular complex comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules in stoichiometric or non-stoichiometric amounts. If the solvent is water, the solvate is referred to as a "hydrate".

[0495] Therefore, the scope of this disclosure should be understood to cover all solvents of the compounds disclosed herein, as well as their stereoisomers, tautomers, and isotopically labeled forms, or pharmaceutically acceptable salts of any of the foregoing.

[0496] Miscellaneous Definitions

[0497] This section defines additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.

[0498] As used in this article, the term "C" 1-3 Alkyl", C 1-5 "alkyl" and "C" 1-6 "Alkyl" refers to straight-chain or branched hydrocarbons containing 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. C 1-3 Alkyl, C 1-5 Alkyl or C 1-6 Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

[0499] As used in this article, the term "C" 2-4 "Alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms and having at least one carbon-carbon double bond. Alkenyl groups include both straight-chain and branched portions. 2-4 Representative examples of alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0500] As used in this article, the term "C" 3-6 "Cycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic skeleton has 3 to 6 carbon atoms. 3-5 Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0501] As used in this article, the term "two C" 1-3 "alkylamino" refers to -NR*R**, where R* and R** independently represent C as defined herein. 1-3 Alkyl group. Dicarbonyl group. 1-3 Representative examples of alkylamino groups include, but are not limited to, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH2CH2CH3)2 and –N(CH(CH3)2)2.

[0502] As used in this article, the term "C" 1-3 "alkoxy" and "C" 1-6 "Alkoxy" refers to -OR # , where R # Represented as C as defined in this article 1-3 Alkyl and C1-6 Alkyl group. C 1-3 Alkoxy or C 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0503] As used in this article, the term "halogen" refers to -F, -Cl, -Br, or -I.

[0504] The term "halogenated," as a prefix used herein as another term for a chemical group, refers to the modification of a chemical group in which one or more hydrogen atoms are replaced by a halogen as defined herein. The halogen is chosen independently each time it appears. For example, the term "C" 1-6 "Halogenated alkyl" refers to C as defined herein. 1-6 Alkyl group, wherein one or more hydrogen atoms are replaced by halogens. C 1-6 Representative examples of alkyl halides include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3). Furthermore, the term "C"... 1-6 "Haloalkoxy" refers, for example, to C as defined herein. 1-6 Alkoxy groups, in which one or more hydrogen atoms are replaced by halogens. C 1-6 Representative examples of haloalkoxy groups include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCHFCl, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, -OCF(CHF2)2 and -OCH(CH2F)(CF3).

[0505] As used herein, the terms "5-membered heteroaryl" or "6-membered heteroaryl" refer to a 5-membered or 6-membered carbon ring having two or three double bonds, wherein the carbon ring contains a cyclic heteroatom selected from N, S, and O and optionally one or two additional cyclic N atoms, rather than one or more cyclic carbon atoms. Representative examples of 5-membered heteroaryl groups include, but are not limited to, furanyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of 6-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazolyl, and pyridazinyl.

[0506] As used in this article, the term "C" 3-6 "Heterocyclic alkyl" refers to a saturated carbocyclic molecule in which the cyclic framework has 3 to 6 carbons, and one of the carbon atoms is replaced by a heteroatom selected from N, O, and S. If C 3-6 If the heterocyclic alkyl group is a C6 heterocyclic alkyl group, then one or two carbon atoms are substituted by heteroatoms independently selected from N, O, and S. 3-6Representative examples of heterocyclic alkyl groups include, but are not limited to, aziridinyl, aziridine, oxobutidine, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0507] As used in this article, the term "C" 5-8 "Spiroalkyl" refers to a bicyclic cyclic system in which the two rings are connected by a single common carbon atom. C 5-8 Representative examples of spiroalkyl groups include, but are not limited to, spiro[2.2]pentyl, spiro[3.2]hexyl, spiro[3.3]heptyl, spiro[3.4]octyl and spiro[2.5]octyl.

[0508] As used in this article, the term "C" 5-8 "Tricyclic alkyl" refers to a tricyclic system in which all three cyclic alkyl rings share two common ring atoms. C 5-8 Representative examples of tricyclic alkyl groups include, but are not limited to, tricyclic [1.1.1.0] 1,3 Pentyl, Three Rings [2.1.1.0] 1,4 Hexyl, tricyclic [3.1.1.0] 1,5 Hexyl and tricyclic [3.2.1.0] 1,5 Octyl group.

[0509] The term "aryl," used alone or as part of a larger portion of "aralkyl," "aralkylkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic system having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aromatic ring." In certain embodiments of this disclosure, "aryl" refers to an aromatic ring system, including but not limited to phenyl, biphenyl, naphthyl, anthracene, etc., which may carry one or more substituents. As used herein, aromatic rings fused to one or more non-aromatic rings, such as indanyl, phthalimide, naphthimide, phenanthridine, or tetrahydronaphthyl, are also included within the scope of the term "aryl."

[0510] The terms "heteroaryl" and "heteroaryl-", used alone or as part of a larger portion such as "heteroarylalkyl" or "heteroarylalkoxy", refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; a group having 6, 10, or 14 π electrons in a cyclic array; and a group having one to five heteroatoms in addition to a carbon atom. In the context of "heteroaryl", the term "heteroatom" specifically includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indoleazinyl, purine, naphridinyl, and pteridinyl. As used herein, the terms “heteroaryl” and “heteroaryl-” also include groups in which the heteroaryl ring is fused to one or more aryl, alicyclic, or heterocyclic rings, wherein a radical or linker is located on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiopheneyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, terpineyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazolyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic or bicyclic. The heteroaryl ring can include one or more oxo (=O) or thio (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl family," or "heteroaryl family," any of which includes an optionally substituted ring. The term "heteroarylalkyl" refers to a family of alkyl groups substituted with heteroaryl groups, wherein the alkyl and heteroaryl portions are optionally substituted independently.

[0511] As described herein, the compounds of this disclosure may contain a “substituted” moiety. Generally, the term “substituted” means that one or more hydrogen atoms of the specified moiety are substituted by a suitable substituent. Unless otherwise specified, an “optionally substituted” group may have a suitable substituent at one or more substituted positions of the group, and when more than one position in any given structure is substituted by more than one substituent selected from the specified group, the substituent may be the same or different at each position. Combinations of substituents contemplated in this disclosure are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term “stable” means that the compound remains substantially unchanged when subjected to conditions of permissible compound production, detection, and, in some embodiments, recovery, purification, and use for one or more of the purposes disclosed herein.

[0512] As used in this article, the term "pharmaceutically acceptable" means that it is generally accepted for use in subjects, especially humans.

[0513] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has 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, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion or coordinated with an organic base, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion; and the organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, dicyclohexylamine, etc. Further examples of such salts can be found in Berge et al., J. Pharm. Sci. 66(1):1-19 (1977). See also Stahl et al., Pharmaceutical Salts: Properties, Selection, and Use, p. 2 版 Revised edition (2011).

[0514] As used herein, the term "pharmaceuticalally acceptable excipient" refers to a broad range of ingredients that can be combined with the compounds or salts disclosed herein to prepare pharmaceutical compositions or formulations. Excipients typically include, but are not limited to, diluents, colorants, mediators, anti-adhesion agents, flow aids, disintegrants, flavoring agents, coating agents, binders, sweeteners, lubricants, adsorbents, preservatives, and so on.

[0515] 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 implementation, the subject is a human.

[0516] As used herein, the term “therapeutic effective amount” refers to the amount of the compound disclosed herein that will elicit a biological or medical response in a tissue, system, or subject being sought by an investigator, veterinarian, physician, or other clinician.

[0517] General synthesis procedure

[0518] The compounds provided herein can be synthesized according to the procedures described in this section and the following sections. As will be understood by those skilled in the art, the synthetic methods described herein are merely exemplary, and the compounds disclosed herein can also be synthesized via alternative routes utilizing alternative synthetic strategies. It should be understood that the general synthetic procedures and specific examples provided herein are merely illustrative and should not be construed as limiting the scope of this disclosure in any way.

[0519] Generally, compounds of Formula I can be synthesized according to the following schemes. Unless otherwise stated, any 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 ordinary techniques using known procedures. Starting materials can also be synthesized using the procedures disclosed herein. For the schemes discussed in this section, suitable reaction conditions, such as solvents, reaction temperatures, and reagents, can be found in the examples provided herein.

[0520] Option 1

[0521]

[0522] As will be understood by those skilled in the art, the above synthetic schemes and representative embodiments are not intended to be a comprehensive list of all means by which compounds can be synthesized as described and claimed in this application. Other methods will be readily apparent to those skilled in the art. Furthermore, the various synthetic steps described above can be performed in an alternating sequence or order to obtain the desired compound.

[0523] Purification methods for the compounds described herein are known in the art and include, for example, crystallization, chromatography (e.g., liquid and gas chromatography), extraction, distillation, grinding, and reversed-phase HPLC.

[0524] This disclosure also covers “intermediate” compounds, which include structures produced from the described synthetic procedure prior to obtaining the final desired compound, whether isolated, in-situ generated, or not isolated. These intermediates are included within the scope of this disclosure. Exemplary embodiments of such intermediate compounds are shown in the following examples.

[0525] Example

[0526] This section provides specific examples of compounds of Formula I and their preparation methods.

[0527] List of abbreviations

[0528]

[0529]

[0530]

[0531] General analytical and purification methods

[0532] This section provides a description of general analytical and purification methods used to prepare the specific compounds presented herein.

[0533] Chromatography:

[0534] Unless otherwise specified, residues containing crude product are purified by passing the crude material or concentrate through a Biotage silica column pre-packed with fast silica (SiO2) or reversed-phase fast silica (C18), and eluting the product from the column using the solvent gradient indicated. For example, the description of silica (0-40% EtOAc / hexane) means obtaining the product by eluting from a silica-packed column using a solvent gradient of 0% to 40% EtOAc in hexane.

[0535] Preparative HPLC methods:

[0536] In the cases described herein, the compounds were purified by reversed-phase HPLC using a Waters Fractionlynx semi-preparative HPLC-MS system with one of the following two HPLC columns: (a) a Phenominex Gemini column (5 μm, C18, 150 x 30 mm) or (b) a Waters X-select CSH column (5 μm, C18, 100 x 30 mm).

[0537] Typical instrument operation involves elution over 10 minutes at a flow rate of 45 mL / min using a linear gradient of 10% (v / v) to 100% MeCN (0.1% v / v formic acid) aqueous solution (0.1% formic acid); conditions can be varied to achieve optimal separation.

[0538] Proton NMR spectroscopy:

[0539] Unless otherwise specified, all 1 1H NMR spectra were collected on Bruker NMR instruments at 300, 400, or 500 MHz. Under these characterization conditions, the internal solvent peak was used as a reference, and all observed protons were reported as parts per million (ppm) low field from tetramethylsilane (TMS).

[0540] Mass spectrometry (MS)

[0541] Unless otherwise specified, all mass spectrometry data for starting materials, intermediates, and / or exemplary compounds are reported as mass / charge (m / z) with [M+H]. + Molecular ions. The reported molecular ions were obtained using a Waters Acquity UPLC / MS system via an electrospray ionization detection method (commonly known as ESIMS). As will be understood by those skilled in the art, compounds having isotopic atoms such as bromine are typically reported based on the detected isotopic pattern.

[0542] Compound Name

[0543] The compounds disclosed and described in this paper have been named using the IUPAC naming function provided by Biovia Pipeline Pilot. Specific Implementation

[0545] This section provides procedures for synthesizing specific examples of the compounds provided herein. Unless otherwise specified, all starting materials are commercially available from Merck Sigma-Aldrich Inc. or are known in the art and can be synthesized using common techniques and known procedures.

[0546] Synthesis of the Implementation Examples

[0547] Method 1

[0548] 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

[0549]

[0550] Step 1: 5,7-Dichloro-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. Add 1100 mL of a pyridine solution of 4-amino-2,6-dichloronicotinic acid 2,2,2-trifluoroacetate (110 g, 343 mmol) and acetic anhydride (129 mL, 1371 mmol) to a 10-L four-necked round-bottom flask. Stir the reaction mixture at room temperature for 1 hour. Cool the reaction mixture to 0°C and add methylamine (2 M in THF, 1028 mL, 2056 mmol) dropwise. Remove the cold bath and stir the reaction mixture for 30 minutes. Cool the mixture to 0°C and add 2,4,6-tripropyl-1,3,5,2,4,6-trioxotriphosphate-2,4,6-trioxide (50% in EtOAc solution) (550 mL, 685 mmol). The cold 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 a brine solution (2.5 L). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (0-40% hexane solution of EtOAc) to give a yellow solid, which was dissolved in DCM (500 mL) and precipitated with petroleum ether. The obtained solid was filtered and dried to give 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 ¹H NMR (400 MHz, DMSO-d⁶) δppm 7.63 (s, 1H), 3.49 (s, 3H), 2.60 (s, 3H). m / z (ESI, +ive ions): 244.0 (M+H).

[0551] Step 2: 7-Chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one. Add 5,7-dichloro-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (100 g, 410 mmol), (4-chloro-2-fluorophenyl)boronic acid (71.4 g, 410 mmol), 1,4-dioxane (3000 mL), and water (1000 mL) to a 10-L four-necked round-bottom flask. Add cesium carbonate (400 g, 1229 mmol) to the mixture and purge the reaction mixture with nitrogen for 10 min. Add the PdCl2(dppf)-CH2Cl adduct (16.73 g, 20.49 mmol) and stir the reaction mixture at room temperature for 0.5 h. The reaction mixture was quenched with water (4 L) and extracted with DCM (2 x 3500 mL). The combined organic compounds were washed with a brine solution (4000 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was absorbed onto a 100–200 mesh silica gel stopper and purified chromatographically using a 100–200 mesh silica gel column, eluting with a gradient of 0% to 40% hexane solution of EtOAc. The obtained solid was ground in EtOAc (150 mL), filtered, and washed with anhydrous n-hexane 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 ¹H NMR (400MHz, DMSO-d⁶) δppm 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, +ive ions): 338.0 (M+H).

[0552] Step 3: (S)-5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholine)pyrido[4,3-d]pyrimidin-4(3H)-one. Add (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (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) to a 250 mL flask. Heat the reaction to 100 °C for 16 hours. Quench the reaction mixture with water and filter to obtain the crude product. The crude substance was purified using a silica gel column and eluted with a heptane solution of 0 to 100% EtOH / EtOAc (1:3). The collected fractions were concentrated and ground with hot isopropanol to give (S)-5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholine)pyrido[4,3-d]pyrimidin-4(3H)-one (9.91 g, 71.5% yield) as a white solid. The absolute stereochemical structure was determined by X-ray crystallography. 1 H NMR(500MHz,DMSO-d6)δppm 7.70-7.73(m,1H),7.44-7.46(m,1H),7.36

[0553] -7.41(m,2H),7.30-7.34(m,1H),6.81-6.83(m,1H),4.50-4.54(m,1H),4.36

[0554] -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

[0555] -2.55 (m, 3H). m / z (ESI, +ive ions): 469.0 (M+H) + .

[0556] Table 1. Compounds 2 to 122 were prepared according to the procedure described in steps 1 to 3 of Method 1 as follows:

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574] Method 2

[0575] Example 123: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one

[0576]

[0577] Cesium carbonate (0.093 g, 0.286 mmol) and 2-bromopropane (0.053 g, 0.040 mL, 0.429 mmol) were added to a DMF solution (0.572 mL) of (S)-7-(2-(1H-pyrazol-4-yl)morpholine)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (Examples 1-22, 0.065 g, 0.143 mmol). The reaction mixture was stirred overnight at 60 °C and then cooled to room temperature. The reaction mixture was diluted with 20 mL of DCM, washed with 2 x 15 mL of water, and the organic phase was separated and concentrated under vacuum. The crude product was purified by column chromatography by gradient elution with 0-10% MeOH (+0.1% NH3) in DCM solution to give 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propyl)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one (0.048 g, 0.097 mmol, 67.6% yield) as a grayish-white solid. 1 HNMR(500MHz,DMSO-d6)δ7.80(s,1H),7.46(s,1H),7.36-7.41(m,2H),7.31(dd,J=2.01,8.24 Hz,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 = 12.07 Hz, 1H), 3.97 (dd, J = 2.01, 11.61 Hz, 1H), 3.66 (dt, J = 2.47, 11.55 Hz, 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, +ive ions): 497.0 (M + Na).

[0578] Table 2. Compounds 124 to 134 were prepared according to the procedure described in Method 2 as follows:

[0579]

[0580]

[0581] Method 3

[0582] 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

[0583]

[0584] DAST solution (1M in DCM) (0.117 mL, 0.117 mmol) was slowly added to a DCM solution (0.0485 g, 0.094 mmol, 125604-46-1) of 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1-fluoro-2-hydroxyethyl)-1H-pyrazol-4-yl)morpholine)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (125604-46-1) at -78 °C. The reaction mixture was heated to room temperature and stirred for 4 hours. The reaction was quenched with saturated NaHCO3 solution and the phases were separated. The organic phase was concentrated under vacuum, and the crude product was purified by column chromatography by gradient elution with 0-10% MeOH (+1% NH3) DCM solution to give 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 (0.029 g, 0.056 mmol, 59.6% yield) as a white solid. 1 ¹H NMR (500MHz, DMSO-d⁶) δppm 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, +ive ions): 541 (M+H).

[0585] Method 4

[0586] 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

[0587]

[0588] A mixture of (S)-7-(2-(1H-pyrazol-4-yl)morpholine)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (Example 22, 0.2 g, 0.440 mmol), cyclopropylboronic 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) was stirred at 50 °C for 18 hours (the septum of the vial was punctured with two needles to allow air to enter). After cooling to room temperature, the mixture was filtered through diatomaceous earth. The filtrate was washed with NH4Cl, dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography and eluted 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 = 12.46 Hz, 1H), 3.98–4.04 m, 1H), 3.70 dt, J = 2.59, 11.55 Hz, 1H), 3.35 s, 3H), 2.99–3.11 m, 2.53 s, 3H. m / z (ESI, +ive ions): 481.0 (M+H).

[0589] Table 3. Compound 137 was prepared according to the procedure described in Method 4, as follows:

[0590]

[0591] Method 5

[0592] Example 138: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azacyclobutane)-1H-pyrazol-4-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one

[0593]

[0594] A solution of dioxane (0.3 mL, 1.2 mmol) of 4N hydrogen chloride was added to a vial containing (S)-3-(4-(4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholin-2-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (Example 134, 0.02 g, 0.033 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The solid residue was partitioned between saturated NaHCO3 and DCM. The organic phase was separated (using a phase separator) and concentrated under vacuum to give a crude intermediate that could be used in the next step without further purification. Sodium triacetoxyborate (10.4 mg, 0.049 mmol) was added to a 0.131 mL solution of intermediate paraformaldehyde (4.92 mg, 0.164 mmol) and triethylamine (3.32 mg, 4.57 μl, 0.033 mmol) in 1,2-dichloroethane. 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 under vacuum. The crude product was purified by column chromatography by gradient elution with 0-10% MeOH (+1% NH3) DCM solution to give 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azacyclobutyl)-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)δppm 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, +ive ions): 524.0 (M+H)

[0595] Method 6

[0596] Example 139: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one

[0597] Example 140: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one

[0598]

[0599] Step 1: Methyl 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholin-2-carboxylate. Add 5 mL of a dimethyl sulfoxide solution of 7-chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (1.014 g, 3 mmol), methyl morpholin-2-carboxylate, and n,n-diisopropylethylamine (1.939 g, 15.00 mmol) to a 10 mL vial. Stir the reaction 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 could be used in the next step without further purification.

[0600] 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-carboxylic acid (4.92 g, 11 mmol, 125373-9) and potassium trimethyl(oxo)silane (1.693 g, 13.20 mmol) were mixed 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 NaHCO3 solution, and extracted with EtOAc. The aqueous phase was acidified to pH 3 and extracted twice with EtOAc. The combined organic compounds were dried and concentrated to give 1.9 g of crude product, which was further purified by reversed-phase chromatography to give 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholino-2-carboxylic acid (1.85 g, 38.5%). m / z (ESI, +ive ion): 433.0 (M+H).

[0601] Step 3: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridyl)-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-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one. Add 4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl)morpholine-2-carboxylic acid (130 mg, 0.3 mmol, 125373-25), 5-bromo-2-methylpyridine (6.6 mg, 0.3 mmol), and nickel(II) chloride ethylene glycol dimethyl ether complex (6.59 mg, 0.030 mg) to the vial. 3,4'-di-tert-butyl-2,2'-bipyridine (12.08 mg, 0.045 mmol), cesium carbonate (293 mg, 0.900 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine, bis(3,5-difluoro-2-(5-(trifluoromethyl)pyridin-2-yl)phenyl)iridium(III) hexafluorophosphate (Ir catalyst, 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 vial was irradiated with 450 nm for 3 h using an integrated photoreactor (fan: 1500 rpm; stir: 500 rpm; LED power: 100%). The reaction mixture was partitioned between EtOAc and water. The organic phase was dried, concentrated, and purified by reversed-phase chromatography to give 18 mg of crude product. Chiral purification was performed using SFC-stacked Chiralcel OJ-H 2x25 cm and Chiralcel OJ-H 2x15 cm columns, 5 μm columns, with 25% methanol as the mobile phase and F = 70 mL / min, yielding 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(6-methyl-3-pyridyl)-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-pyridyl)-4-morpholinyl)-pyrido[4,3-d]pyrimidin-4(3H)-one (Example 140) as a grayish-white solid. Absolute stereochemical structures were arbitrarily specified. 1¹H NMR (500MHz, CDCl₃) δppm 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, +ive ions): 480.0 (M+H).

[0602] Method 7

[0603] 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

[0604]

[0605] Step 1: (S)-7-(2-(1-(bromodifluoromethyl)-1H-pyrazol-4-yl)morpholine)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyridano[4,3-d]pyrimidin-4(3H)-one. Cesium carbonate (0.093 g, 0.286 mmol) and dibromodifluoromethane (0.039 mL, 0.09 g, 0.429 mmol) were added to a DMF solution (0.572 mL) of (S)-7-(2-(1H-pyrazol-4-yl)morpholine)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyridano[4,3-d]pyrimidin-4(3H)-one (Example 22, 0.065 g, 0.143 mmol, 124947-40-1). 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 under vacuum, and the crude product was purified by column chromatography by a gradient elution of 0–30% EtOAc-EtOH (3:1) in heptane to give ((S)-7-(2-(1-(bromodifluoromethyl)-1H-pyrazol-4-yl)morpholine)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one (0.025 g, 0.043 mmol, 30% yield) as a grayish-white solid. m / z (ESI, +ive ion): 583.0 (M+H)+ .

[0606] 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. Silver tetrafluoroborate (I) (0.017 g, 0.086 mmol) was added to a stirred DCM solution (0.428 mL) of (S)-7-(2-(1-(bromodifluoromethyl)-1H-pyrazol-4-yl)morpholinyl)-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) at -78 °C. The solution was then stirred overnight at room temperature. The mixture was diluted with DCM containing 5% MeOH, sonicated for 2–3 minutes, filtered, and concentrated. The crude product was purified by rapid column chromatography, eluting with a gradient of 0–10% MeOH (+0.1% ammonia) in DCM solution 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,+ive ion):523.0(M+H) + .

[0607] Method 8

[0608] 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.

[0609]

[0610] Step 1: 4-Amino-6-chloro-2-(4-chloro-2-fluorophenyl)nicotinic acid tert-butyl ester. Add 4-amino-2,6-dichloronicotinic acid tert-butyl ester (2.5 g, 9.50 mmol, 125370-12), (4-chloro-2-fluorophenyl)boric acid (2.319 g, 13.30 mmol), Cs₂CO₃ (7.74 g, 23.75 mmol), PdCl₂(dtbpf) (0.310 g, 0.475 mmol), 1,4-dioxane (25.3 mL), and water (6.33 mL) to a 100 mL vial. Wash the mixture with N₂ and stir at 80 °C for 4 hours. Dilute the resulting mixture with water and EtOAc, and extract twice with EtOAc. Dry the organic layer with MgSO₄, filter, and concentrate. Purification on silica (0-20% EtOAc in heptane solution) yielded a pale orange solid of tert-butyl 4-amino-6-chloro-2-(4-chloro-2-fluorophenyl)nicotinic acid. m / z (ESI, +ive ions): 356.9 (M+H) + .

[0611] Step 2: (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholine) tert-butyl nicotinate. To a dimethyl sulfoxide solution (4666 μl) of 4-amino-6-chloro-2-(4-chloro-2-fluorophenyl) tert-butyl nicotinate (500 mg, 1.400 mmol, 125370-40), (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) were added. The mixture was stirred at 125 °C for 72 hours, then diluted with EtOAc and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated. Purification on silica gel (0-100% heptane solution of EtOAc) yielded (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholine) tert-butyl nicotinate, a yellow solid. m / z (ESI, +ive ions): 488.0 (M+H) + .

[0612] Step 3: (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholine)nicotinic acid salt. In a 20 mL vial, (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholine)nicotinic acid tert-butyl ester (342 mg, 0.701 mmol, 125520-8) and a dioxane solution of 4 M HCl (511 mg, 426 μl, 14.02 mmol) were mixed. The mixture was heated at 60 °C for 90 min, cooled to room temperature, and concentrated to dryness to give the crude product (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholine)nicotinic acid salt, which can be used in the next step without purification. m / z (ESI, +ive ions): 467.8 (M+H) + .

[0613] 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. Cyclopropane-carboxyl chloride (30.3 mg, 0.289 mmol) and triethylamine (17.57 mg, 24.21 μl, 0.174 mmol) were added to a DCM solution (193 μl) of (S)-4-amino-2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholinyl)nicotinic acid (25 mg, 0.058 mmol, 125520-12), 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. A solution of aminomethane (57.9 μl, 0.116 mmol) and T3P in DMF (36.8 mg, 33.8 μl, 0.058 mmol) was added, and the mixture was stirred at 70 °C for 72 h. The reaction mixture was concentrated and purified by silica gel column chromatography, eluting with a heptane solution of 0 to 100% EtOH / EtOAc (1:3) to give a pale brown solid of 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. 1H NMR(500MHz,DMSO-d6)δppm 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,J=12.07Hz,1H),3.94-4.00(m,1H),3.81(s,3H),3.62-3.70(m,1H),3.52(s,3H),2.95-3.08(m,2H),2.21-2.26(m,1H),1.15(br s,2H),1.08(br dd, J = 8.04, 3.24 Hz, 2H). m / z (ESI, +ive ions): 495.0 (M+H) + .

[0614] Table 4. Compounds 143 to 157 were prepared according to the procedures described in steps 1 to 4 of Method 8, as follows:

[0615]

[0616]

[0617]

[0618] Method 9

[0619] 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.

[0620]

[0621] 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 methyl iodoform (0.170 g, 1.2 mmol) were mixed 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 MgSO4. The resulting solution was concentrated to give the crude product 5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one, which could be used in the next step without further purification.

[0622] 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 mixed 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 min. The reaction mixture was cooled to room temperature and partitioned between DCM and water. The mixture was passed through a phase separation column and concentrated to give the crude product 7-chloro-5-(4-chloro-2-fluorophenyl)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one, which could be used in the next step without further purification. m / z (ESI, +ive ion): 324.0 (M+H) + .

[0623] 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 the reaction was stirred at 100 °C for 3 hours. After cooling to room temperature, the mixture was concentrated and the crude product was purified on silica gel by elution with a 0-100% EtOH / EtOAc (1:3) heptane solution 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 pale yellow solid (0.091 g, 0.2 mmol, 50% yield). 1H NMR(600MHz,DMSO-d6)δppm 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, +ive ions): 455.0 (M+H) + .

[0624] Method 10

[0625] 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.

[0626]

[0627] Step 1: 7-Chloro-5-(cyclohex-1-en-1-yl)-2,3-dimethylpyridano[4,3-d]pyrimidin-4(3H)-one. Add 2.5 mL of a 1,4-dioxane solution of 5,7-dichloro-2,3-dimethylpyridano[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-dioxoboronane (0.256 g, 1.229 mmol) and water (0.5 mL) to a glass microwave reaction vessel, followed by the addition of potassium carbonate (0.255 g, 1.844 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, then Pd(Ph3P)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 x 10 mL), and the organic extract was dried over Na2SO4. The solution was filtered and concentrated under vacuum to give a crude substance, which was purified by silica gel chromatography by elution with a 5-80% hexane solution of EtOAc to give 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, ~75% purity) as a yellow solid. m / z (ESI, +ive ions): 290.0 (M+H) + .

[0628] Step 2: (S)-5-(cyclohexyl-1-en-1-yl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholine)pyrido[4,3-d]pyrimidin-4(3H)-one. A 1,4-dioxane solution (6 mL) of (S)-2-(1-methyl-1H-pyrazol-4-yl)morpholine (intermediate 3) (0.270 g, 1.615 mmol) and 7-chloro-5-(cyclohexyl-1-en-1-yl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (0.360 g, 1.242 mmol) was added to a 25-mL round-bottom flask, followed by the addition of 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 under vacuum. The crude product was purified by reversed-phase preparative HPLC to give (S)-5-(cyclohex-1-en-1-yl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholine)pyrido[4,3-d]pyrimidin-4(3H)-one (0.21 g, 0.499 mmol, 40.2% yield) as a grayish-white solid. m / z (ESI, +ive ion): 421.1 (M+H)+ .

[0629] 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. A solution (5 mL) of (S)-5-(cyclohexyl-1-en-1-yl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazol-4-yl)morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one (200 mg, 0.476 mmol) in THF was added to a 25 mL round-bottom flask at room temperature, followed by the addition of 10% Pd-C (405 mg, 1.9 mmol). The mixture was stirred at room temperature under a hydrogen atmosphere for 8 hours, then filtered through a diatomaceous earth bed and concentrated under vacuum. The crude product was purified by HPLC to give 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 a grayish-white solid. 1 H NMR (400MHz, CDCl3) δppm7.53(s,1H),7.44(s,1H),4.59(dd,J=11.4,2.1Hz,1 H),4.28(dt,J=11.2,3.2Hz,1H),4.18(t,J=11.7Hz,1H),3.90(s,3H),3.83(dd d,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=13.5Hz,1H),2.32(d,J=8.2Hz,2H),2.12–2.23(m,5H),1.96–2.12(m,4H). m / z (ESI, +ive ions): 443.2 (M+H) + .

[0630] Table 5. Example 160 was prepared according to the procedure described in steps 1 to 3 of method 10, as follows:

[0631]

[0632] Method 11

[0633] Examples 161 to 163: 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 H)-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; 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.

[0634]

[0635] Step 1: 4-(4-Bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole. Add 1-methyl-1H-pyrazole-4-carboxaldehyde (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 a 100 mL flask. Add one part of hydrobromide-acetic acid (6.88 g, 5.08 mL, 28.1 mmol) to a vial. After 1 hour, 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 crude substance obtained was purified by silica gel chromatography and eluted with a heptane solution of 0% to 40% EtOAc / EtOH (3:1) to give a yellow oily substance (1.307 g, 5.33 mmol, 57% yield) of 4-(4-bromotetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (3.3:1 cis / trans mixture of diastereomers).

[0636] Major diastereomers (cis isomers): 1¹H NMR (500MHz, CDCl₃) δppm: 7.46 (s, ¹H), 7.36 (s, ¹H), 4.36 (dd, J = 11.3, 2.1Hz, ¹H), 4.25 (tt, J = 11.9, 4.5Hz, ¹H), 4.08 (ddd, J = 12.0, 4.8, 1.8Hz, ¹H), 3.89 (s, ³H), 3.58 (td, J = 12.1, 2.3Hz, ¹H), 2.52 (ddt, J = 12.9, 4.3, 2.1, 2.1Hz, ¹H), 2.12–2.26 (m, ³H). m / z (ESI, +ive ions): 245.0 (M+H) + .

[0637] Secondary diastereomers (trans isomers): 1 ¹H NMR (500MHz, CDCl₃) δppm: 7.46 (s, 1H), 7.35 (s, 1H), 4.93 (dd, J = 10.0, 2.9Hz, 1H), 4.79 (quintet, J = 3.1Hz, 1H), 4.12 (td, J = 11.6, 2.1Hz, 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, +ive ions): 245.0 (M+H) + .

[0638] Step 2: (2-(1-Methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II)bromide. Add Zn (0.320 g, 4.90 mmol) to a dried 50 mL flask, evacuate the flask, and backfill with nitrogen three times. Cover the flask with a rubber septum and insert a thermocouple probe. Add 0.5 M lithium chloride in anhydrous tetrahydrofuran solution (3.26 mL, 1.632 mmol), followed by 1,2-dibromoethane (0.015 g, 7.03 μL, 0.082 mmol), and heat the mixture at an internal temperature of 50 °C for 20 minutes. After cooling to room temperature, add trichlorosilane (8.86 mg, 10.36 μL, 0.082 mmol), and heat the mixture to an internal temperature of 50 °C for 20 minutes. After cooling to room temperature, add 0.1 mL of a THF solution containing diiodine (8.28 mg, 0.033 mmol) and heat the mixture to an internal temperature of 50 °C for 20 minutes. While still hot, add 1.5 mL of a THF solution containing 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). Stir the resulting mixture at 50 °C for 18 hours, then cool the reaction solution to room temperature and allow it to stand for 3 hours (zinc powder precipitation) to obtain a pale yellow solution, which can be used for the next step without further treatment.

[0639] 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. 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) were added to a 1 dallan vial. The vial was purged with nitrogen, and then 2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)zinc(II) bromide (~0.3M in THF, 0.47 mL, 0.141 mmol) was added, and the vial was stirred at room temperature. After 3 hours, 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 silica gel stopper and purified chromatographically using a 24 g silica gel column, eluting with a 0-100% EtOAc / EtOH 3:1 heptane solution to give the crude product as a 2.7:1 dr mixture (50 mg, 0.11 mmol, 60% yield). The single stereoisomer was obtained by SFC, Chiralpak AD-H 2x25 cm, 5 μm column (45% isopropanol, using F=80 mL / min) to produce peak 1 with 3 mg purity >99%, peak 2 with 9.3 mg ee >99%, and peak 3 with 8.0 mg ee >99%.

[0640] Peak 1 (Example 161): A 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, a yellow oil. LC / MS 1H NMR (500MHz, CDCl3) δppm 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) + .

[0641] 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. 1 H 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, +ive ions): 468.0 (M+H) + .

[0642] 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. 1H NMR(500MHz,CDCl3)δppm 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, +ive ions): 468.0 (M+H) + .

[0643] The absolute stereochemical structure can be arbitrarily specified. The relative stereochemical structure (cis / trans) is determined by NMR.

[0644] Method 12

[0645] 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.

[0646]

[0647] Step 1: 6-(1-Methyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl. Add 1-methyl-1H-pyrazol-4-carboxaldehyde (200 mg, 1.816 mmol), (2-hydroxyethyl)-acetylene (191 mg, 206 μl, 2.72 mmol), and DCM (3633 μl) to a 20 mL scintillation vial. Slowly add trifluoromethanesulfonic acid (327 mg, 194 μl, 2.180 mmol) at 0 °C and heat the mixture to room temperature. After 30 minutes, add additional trifluoromethanesulfonic acid (327 mg, 194 μl, 2.180 mmol) and stir the mixture at room temperature for 2 hours. Quench the reaction with saturated sodium bicarbonate solution and wash with DCM. Dry the combined organic layers with sodium sulfate, filter, and concentrate. The obtained substance was purified by silica gel chromatography and eluted with a heptane solution of 0-70% EtOAc to give 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. 1H NMR(500MHz,CDCl3)δppm 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).

[0648] Step 2: 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole. Add 6-(1-methyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (227 mg, 0.727 mmol), a complex of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) with DCM (59.4 mg, 0.073 mmol), and a complex of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(ii) with DCM (59.4 mg, 0.073 mmol) and potassium acetate (285 mg, 2.91 mmol) to a 20 mL scintillation vial, which is then purged with N2. Then 1,4-dioxane (2908 μl) was added, and the reaction was heated to 90 °C for 2 hours, followed by cooling to room temperature. The reaction mixture was diluted with EtOAc and filtered through a silica gel stopper. The crude material was purified by chromatography using a silica gel column, eluting with a heptane solution of 0-100% EtOAc to give 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-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).

[0649] 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. Add 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (87 mg, 0.300 mmol, 125536-50-10), a complex of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) with DCM (24.48 mg, 0.030 mmol), and cesium carbonate (293 mg, 0.899 mmol) to a 20 mL scintillation vial equipped with a condenser. The vial was sealed and purged with N2 for 20 minutes. 1,4-Dioxane (1124 μl) and water (375 μl) were added (for degassing). The flask was heated to 70 °C for 2 hours, 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 under vacuum to give a crude brown oily product. Purification was achieved by silica gel chromatography, eluting with a 0-100% EtOAc / EtOH 3:1 heptane solution to give the crude brown oily product. The substance was further purified by reversed-phase preparative HPLC using a CH3CN / H2O solution of 0.1% TFA in a gradient of 25-70% over 14 minutes to give 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). 1 H 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,+ive ion):466.0(M+H) + .

[0650] Method 13

[0651] Example 165: 5-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one.

[0652] Example 166: 5-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one.

[0653]

[0654] Steps 1 to 3: 5-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethylpyridano[4,3-d]pyrimidin-4(3H)-one. Following steps 1 to 3 of Method 12, using 1-cyclopropyl-1H-pyrazol-4-carboxaldehyde as the starting material, we obtain 5-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-diethylpyridano[4,3-d]pyrimidin-4(3H)-one, a pale brown solid. m / z (ESI, +ive ions): 492.1 (M+H) + .

[0655] 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. Add a solution of 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) to a 50 mL round-bottom flask. Stir the reaction mixture at 42 PSI under H2 gas at room temperature for more than 16 hours. After the reaction was complete, the solution was filtered through diatomaceous earth and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and purified by silica gel chromatography, eluting with a gradient of 0-5% MeOH in EtOAc solution to give a brown gelatinous solid (300 mg). The crude product was purified by SFC, Chiralpak AS-H 250x30 mm, 5 μm column (10% methanol, F = 80 mL / min) to produce a grayish-white solid with peak 1 (>99% ee) at 55.7 mg and peak 2 (>99% ee) at 52.1 mg (35.5% overall yield).

[0656] 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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one. 1 ¹H NMR (400MHz, methanol-d⁴) δppm 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(dd d,J=11.5,3.6,1.8Hz,1H),3.91(s,3H),3.80(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, +ive ions): 494.1 (M+H) + .

[0657] 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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one. 1 H NMR (400MHz, methanol-d4) δppm 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, +ive ions): 494.1 (M+H) + .

[0658] Arbitrarily specify absolute stereochemical structures.

[0659] Method 14

[0660] 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 (a mixture of cis isomers)

[0661] Example 168: Ethyl (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 (a mixture of trans isomers).

[0662]

[0663] Step 1: Ethyl 4-bromotetrahydro-2H-pyran-2-carboxylate. Ethyl 4-hydroxyoxane-2-carboxylate (675 mg, 3.87 mmol, Aurum Pharmatech LLC) and DCM (7750 μl) were added to a 20-mL vial, and the vial was cooled to 0°C. Triphenylphosphine (1118 mg, 4.26 mmol) and carbon tetrabromide (1285 mg, 3.87 mmol) were then added. The reaction was heated to room temperature and stirred for 16 hours, 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 0–25% EtOAc in heptane to give ethyl 4-bromotetrahydro-2H-pyran-2-carboxylate (0.49 g, 2.067 mmol, 53.3% yield) as a colorless oil. 1 ¹H NMR (500MHz, CDCl₃) δppm 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 = 7.79, 2.72Hz, 2H) 4.24 (q, J = 7.14Hz, 2H) 4.50 (dd, J = 10.12, 2.85Hz, 1H) 4.68 (quintet, J = 3.76Hz, 1H).

[0664] 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. Add 7-chloro-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one (50 mg, 0.148 mmol), nickel(II) glycol dimethyl ether complex (3.25 mg, 0.015 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (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-pyridyl-N)phenyl-C]iridium(III) hexafluorophosphate (Ir catalyst, 1.66 mg, 1.479 μmol) to two tert-blue vials. The vial was rinsed with N2 and 1,2-dimethoxyethane (1680 μl), tris(trimethylsilyl)silane (36.8 mg, 46.0 μl, 0.148 mmol), and tris(trimethylsilyl)silane (36.8 mg, 46.0 μl, 0.148 mmol) and ethyl 4-bromotetrahydro-2H-pyran-2-carboxylate (52.6 mg, 0.222 mmol) were added. After stirring and irradiation (Kessil lamp, full intensity, 800 rpm, fan on) for 3 hours, the reaction was filtered and concentrated. The crude material was subjected to reversed-phase preparative HPLC using a 0.1% TFA solution in CH3CN / H2O with a gradient of 25% to 70% over 12 minutes, yielding two peaks:

[0665] Peak 1: 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 (a mixture of cis isomers) (5.7 mg, 0.012 mmol, 8.38% yield) white solids. 1H 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, 1H), 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,+ive ion):460.0(M+H) + .

[0666] 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-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 (a mixture of trans isomers) (7 mg, 0.014 mmol, 10.3% yield) white solids. 1 ¹H NMR (500MHz, DMSO-d⁶) δ 7.41–7.48 (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, +ive ions): 460.0 (M+H) + .

[0667] The absolute stereochemical structure can be arbitrarily specified. The relative stereochemical structure (cis / trans) is confirmed by NMR.

[0668] Table 6: Examples 169 to 178 were prepared according to the procedures described in steps 1 to 4 of method 14 as follows:

[0669]

[0670]

[0671]

[0672] Table B. Other compounds

[0673] The compounds disclosed in Table B below are prepared by the methods disclosed herein or similar methods. Suitable reagents, starting materials, and conditions required for the synthesis of the compounds in Table B will be apparent to those skilled in the art.

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694] Table C. Other compounds

[0695] The compounds disclosed in Table C below are prepared by the methods disclosed herein or similar methods. Suitable reagents, starting materials, and conditions required for the synthesis of the compounds in Table C will be apparent to those skilled in the art. Compounds marked "(+ / -)" are isolated as mixtures of diastereomers sharing the same relative stereochemical structure (i.e., cis or trans). Compounds marked "(rac)" are isolated as mixtures of all possible stereoisomers of the compounds shown.

[0696]

[0697]

[0698]

[0699] Table 7. Analytical Data

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717] Synthesis of intermediates

[0718] Method 15

[0719] Intermediate 1: (S)-2-(1H-pyrazol-4-yl)morpholine

[0720] Intermediate 2: (R)-2-(1H-pyrazol-4-yl)morpholine

[0721]

[0722] Step 1: 1-(1-Benzyl-1H-pyrazol-4-yl)-2-bromoethane-1-one. At room temperature, mono(N,N,N-trimethylphenylamine)tribromide (9.15 g, 23.60 mmol) was added in portions to a DCM solution (204 mL) of 1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-one (4.5 g, 22.47 mmol). 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 products were purified by column chromatography, eluting with a gradient of 0 to 30% heptane / EtOAc-EtOH (3 / 1) to give 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethane-1-one (9.9 g, 35.47 mmol, 79%) as a white solid. 1 ¹H NMR (400MHz, DMSO-d⁶) δppm 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, +ive ions): 279.0 (M+H) + .

[0723] Step 2: 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-one. 2-(benzylamino)ethane-1-ol (2.84 g, 18.81 mmol) was slowly added to a THF solution (46 mL) of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethane-1-one (4.45 g, 15.94 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then at room temperature for 6 h. Water was then added to the reaction mixture, and the aqueous phase was extracted with EtOAc (x3). The combined organic phases were dried over MgSO4, filtered, and concentrated. The reaction was repeated on the same scale. The combined crude material was absorbed onto a silica gel stopper and purified by chromatography using a silica gel column, eluting with a 0% to 10% DCM / MeOH gradient to give 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-one (8.3 g, 23.75 mmol, 75% yield). 1 ¹H NMR (400 MHz, DMSO-d⁶) δppm: 8.57 (s, 1H), 7.96 (s, 1H), 7.20–7.31 (m, 10H), 5.36 (s, 2H), 4.44 (t, J = 5.2 Hz, 1H), 3.68 (d, J = 3.1 Hz, 2H), 3.43–3.53 (m, 4H), 2.60 (d, J = 6.2 Hz, 2H). m / z (ESI, +ive ions): 350.0 (M + H) + .

[0724] Step 3: 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-ol. Sodium tetrahydroborate (1.797 g, 47.5 mmol) was added in portions to a methanol solution (79 mL) of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-one (8.30 g, 23.75 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then at room temperature for 2 h. 90% of the solvent was concentrated under vacuum. The reaction was quenched by adding ice-cold water dropwise. The reaction mixture was extracted with EtOAc (x3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-ol (8.35 g, 23.76 mmol, 100% yield) was used as is in the next step. 1¹H NMR (400MHz, DMSO-d⁶) δppm: 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 = 5.4Hz, 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, +ive ions): 352.2 (M+H) + .

[0725] Step 4: 4-Benzyl-2-(1-Benzyl-1H-pyrazol-4-yl)morpholine hydrochloride. A solution (61 mL) of 8.35 g of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethane-1-ol (6 N HCl) was heated at 110 °C for 2 hours. The reaction mixture was evaporated to dryness under reduced pressure. The resulting solid was ground with Et₂O to give 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine hydrochloride. The crude product was ready for use in the next step without any further purification. 1 H NMR(400MHz,DMSO-d6)δppm 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,+ive ion):334.2(M+H) + .

[0726] Step 5: 2-(1H-pyrazol-4-yl)morpholine. A suspension of 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine hydrochloride (23.75 mmol) and dihydroxypalladium (3.34 g, 4.75 mmol) in ethanol (120 mL) was placed under vacuum and washed with nitrogen. The reaction mixture was washed with hydrogen and stirred at atmospheric hydrogen pressure (25 psi) for 18 hours at room temperature. The catalyst was removed by diatomaceous earth filtration and washed several times with ethanol. The solvent was concentrated under vacuum. The crude product 2-(1H-pyrazol-4-yl)morpholine was purified by chiral SFC using an AD 30 x 250 mm, 5 μm column (mobile phase 20% ethanol, 0.2% diethylamine), F = 180 mL / min. Two isomers of pale brown solids were given. The absolute stereochemical structures of intermediates 1 to 4 are specified based on the independent synthesis of the two stereoisomers of Example 1 (pyrazole methylation, followed by SnAr coupling) and subsequent X-ray crystallography. The stereochemical indications of intermediates 5 to 15 in Table 8 below are arbitrarily specified.

[0727] Peak 1 (intermediate 1): (S)-2-(1H-pyrazol-4-yl)morpholine (1.67 g, 10.9 mmol, 46% yield, ee > 97%). 1 ¹H NMR (400MHz, CDCl₃) δppm 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, +ive ions): 154.2 (M+H) + .

[0728] Peak 2 (intermediate 2): (R)-2-(1H-pyrazol-4-yl)morpholine (1.59 g, 10.4 mmol, 44% yield, ee>89%). 1 ¹H NMR (400MHz, CDCl₃) δppm 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, +ive ions): 154.2 (M+H) + .

[0729] Table 8. Intermediates prepared using method 15

[0730]

[0731]

[0732] Method 16

[0733] Intermediate 17: 4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine.

[0734]

[0735] Step 1: 4,4-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidine-1-carboxylic acid tert-butyl ester. A solution of 3-(1-methyl-1H-pyrazol-4-yl)-4-oxopiperidin-1-carboxylic acid tert-butyl ester (1 g, 1.647 mmol) in DCM (40 mL) and DAST (2.2 mL, 16.47 mmol) was added to a 100-mL round-bottom flask at 0 °C. The reaction mixture was heated 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 Na₂SO₄. The solution was filtered and concentrated under vacuum to give a crude, orange oily substance. The crude substance was purified by silica gel chromatography and eluted with a 50% EtOAc hexane solution to give 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.

[0736] Step 2: 4,4-Difluoro-3-(1-methyl-1H-pyrazole-4-yl)piperidine hydrochloride. Add 4 mL of DCM solution (60 mg, 0.199 mmol) of 4,4-difluoro-3-(1-methyl-1H-pyrazole-4-yl)piperidine-1-carboxylic acid tert-butyl ester to a 10 mL round-bottom flask. Cool the mixture to 0 °C and add 0.5 mL of dioxane solution (2.000 mmol). Heat the reaction mixture to room temperature, stir for 2 hours, and then concentrate under vacuum to give a crude product. Wash the crude product with diethyl ether to give 4,4-difluoro-3-(1-methyl-1H-pyrazole-4-yl)piperidine hydrochloride (25 mg, 0.124 mmol, 62.4% yield) as a white solid (hygroscopic). 1 H NMR (400MHz, DMSO-d6): δppm 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).

[0737] Method 17

[0738] Intermediate 18: 4-(4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine.

[0739]

[0740] Add 2-methylisononical (5 g, 41.3 mmol), 3-buten-1-ol (3.13 g, 3.72 mL, 43.3 mmol), and DCM (83 mL) to a 500 mL flask. Stir the mixture at 0 °C and slowly add one part of hydrobromide-acetic acid (30.4 g, 22.42 mL, 124 mmol). After 5 minutes, heat the reaction mixture to room temperature and stir for 4 hours. Quench the mixture with saturated sodium bicarbonate solution and extract with DCM. Dry the combined organic layers with sodium sulfate, filter, and concentrate. Purify the crude product by silica gel chromatography, eluting with 0–30% EtOAc / EtOH (3:1) in heptane to give 4-(4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine, 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.

[0741] Product 1: 3.83 g of a mixture of cis isomers of 4-((2R,4S)-4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine and 4-((2S,4R)-4-bromotetrahydro-2H-pyran-2-yl)-2-methylpyridine. 1 H NMR(500MHz, CDCl3)δppm3.56-3.65(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).

[0742] 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 (a mixture of trans isomers): 1.69 g. 1H NMR(500MHz, CDCl3)δppm1.92-2.06(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)3.56-3.71(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).

[0743] The absolute stereochemical structure can be arbitrarily specified. The relative stereochemical structure (cis / trans) is confirmed by NMR.

[0744] Table 9. Intermediates prepared using method 17

[0745]

[0746] Biological assessment

[0747] This section provides biological assessments of the specific embodiments provided herein. See Examples A1 and A2 and Tables 10 and 11.

[0748] Example A1.

[0749] In vitro measurement of the activity of trigger receptor 2 expressed on myeloid cells using cellular phosphorylation assay with spleen tyrosine kinase (“Syk”).

[0750] Pharmacological measurements of TREM2 signaling via DAP12 were performed using stable cell lines of HEK293 cells overexpressing TREM2 and DAP12, which had been cloned into single cells (“TREM2 / DAP12-HEK”). TREM2 signaling readings were performed using the Perkin Elmer AlphaScreen / AlphaLISA technique, which monitors the phosphorylation level of Syk kinase. The TREM2 / DAP12-HEK cell lines were cultured in DMEM-F12 (Corning 10-092-CM) (referred to as “HEK medium”) supplemented with 1X penicillin / streptomycin (Corning 30-002-CI), 1X GlutaMAX (Gibco 35050-061), and 10% fetal bovine serum (Life Technologies 10099). A suspension of TREM2 / DAP12-HEK cells was prepared in HEK 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), with a cell suspension volume of 25 μL / well. The plates containing the cells were then incubated in a humidified cell culture incubator (Thermo) at 37°C and 5% CO2 for 20 hours. After incubation, the culture medium was removed from all wells of each microplate using a Bravo 384-well pipette-based liquid handling system (Agilent), and replaced with 20 μL of "Assay Buffer" medium consisting 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). The Assay Buffer contained a diluted test sample (final DMSO concentration of 1% for the compound) or a 100 nM anti-human / mouse TREM2 antibody (R&D Systems MAB17291) positive control, and a 100 nM or rat IgG2B isotype Ab negative control (R&D Systems MAB0061). The plates were incubated with the test sample and control at room temperature for 45 minutes, and then the culture medium was aspirated / removed from each well of the plate. Use the Multidrop Combi peristaltic liquid processor (Thermo) to dispense 15 μL / well of “Cell Lysis Immunoassay Buffer”.The cell lysis immunoassay buffer contained M-PER mammalian protein extraction reagent (Pierce / ThermoFisher 78505), a 1X Halt phosphatase inhibitor mixture (ThermoFisher #78427), 0.1875 nM antiphosphorylated 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 plates were incubated at room temperature for 1 hour. Using a Multidrop Combi liquid processor, 15 μL of AlphaScreen receptor bead solution containing 7.5 μg / mL anti-rabbit IgG (Fc specific) AlphaLISA receptor beads (Perkin Elmer AL104R) in 1X immunoassay buffer (Perkin Elmer AL000F) was dispensed into each well of the microplate. The plates were incubated at room temperature for 2 hours. After incubation with the AlphaLISA receptor 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 processor (Thermo). Because the AlphaScreen reagent is photosensitive, the microplate was incubated in the dark for 2 hours. After the final incubation, the AlphaScreen signal was acquired from the donor and receptor beads using an Envision high-throughput multimode microplate reader (PerkinElmer), calibrated to plate type with AlphaScreen mirror and filter settings at 384-well mode, 680 nm excitation wavelength. The total measurement time per well was 550 ms, with an excitation time of 180 ms.

[0751] After reading the AlphaScreen signal for each well of the microplate, the original test specimen well value (x) was normalized to the percentage of the control (“POC”) on a plate-by-plate basis using the following formula: POC = ((x - μ) n ) / (μ p -μ n ))×100, where (μ n ) is the average negative control well signal of a given plate, (μ pThe mean positive control TREM2 antibody signal is represented by the value of the sample on a given plate. Each plate contains 12 control wells of each type, which are used to generate the mean. For concentration-response curve analysis of the test sample tested at different concentrations, the percentage of activation values ​​was analyzed using a 4-parameter logistic or sigmoid dose-response model with GeneData Screener (GeneData, AG) or GraphPad Prism 7 (Graphpad Software, Inc.). The potency of the test sample is expressed as EC50, which corresponds to the concentration of the test sample capable of activating the phosphorylated Syk AlphaScreen signal to 50% of its maximum response.

[0752] Pharmacological evaluation of TREM2 signaling in cell systems that naturally express TREM2 was performed using human monocyte-derived macrophages. CD14 + Monocytes were positively selected from large-scale apheresis (Lonza) of healthy human donors and differentiated into macrophages in low-adherence bioprocessing bags (Saint-Gobain Performance Plastics) in RPMI-1640 medium (Gibco 11875093) for 9 days. This medium was supplemented with 10% fetal bovine serum (Gibco10082139), 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). After differentiation, macrophages were harvested and cryopreserved in BamBanker (Wako / GC LYMPHOTEC 302-14681 / CS-02-001). Furthermore, flow cytometry was used for quality control of cell surface marker expression, including TREM2. As determined by flow cytometry, approximately 80-90% of the batches used for the phosphorylated Syk assay contained TREM2. + .

[0753] After cryopreservation of macrophages, a live cell suspension of 100,000 cells / mL was prepared in "macrophage pSyk assay medium". This medium consisted of RPMI-1640 supplemented with 10% fetal bovine serum (Gibco10082139), 10 mM HEPES (Gibco 15630080), 1X penicillin-streptomycin (Gibco15140122), 1X non-essential amino acids (Gibco11140050), 1 mM sodium pyruvate (Gibco11360070) and 10 ng / mL M-CSF (Promocell C-60442A) and GlutaMAX medium (Gibco 61870036). Using a Multidrop Combi peristaltic liquid handling instrument (Thermo), 50 μL / well of cell suspension (5,000 cells / well) was dispensed into poly-d-lysine-coated 384-well plates (Corning 354661). After incubation at room temperature for 30 minutes, the plates were incubated in a humidified cell culture incubator (Thermo) at 37°C and 5% CO2 for 16 hours. To begin the assay for the test sample, the culture medium in each well of the assay plate was aspirated and replaced with 20 μL of assay buffer containing diluted test sample (final DMSO concentration for the compound was 1%) or a negative control of assay buffer containing 1% DMSO. The remainder of the macrophage AlphaScreen phosphorylation Syk assay was performed according to the procedure described in detail above for the HEK cell line.

[0754] After reading the AlphaScreen signal from each well of a microplate containing macrophages, the original test sample well value (x) was extracted from the average negative control well signal of a given plate, on a plate-by-plate basis, by background subtraction. Each plate contained 12–24 negative control wells, which were used to generate the average background-subtracted value. For concentration-response curve analysis of the test samples tested at different concentrations, values ​​were analyzed using GraphPad Prism 7 (Graphpad Software, Inc.) with 4-parameter logistic curve fitting. The potency of each test sample is expressed as EC50, which corresponds to the test sample concentration that activates the background-subtracted phosphorylated Syk AlphaScreen signal to 50% of its maximum response.

[0755] The results provided in Table 10 were generated using the in vitro assays described above for Examples 1 through 275. These assays can be used to test any of the compounds described herein to assess and characterize their ability as TREM2 agonists.

[0756] Compounds labeled "A" exhibit an EC50 ≤ 0.05 μM. Compounds labeled "B" exhibit an EC50 > 0.05 μM and ≤ 0.5 μM. Compounds labeled "C" exhibit an EC50 > 0.5 μM and ≤ 3.0 μM. Compounds labeled "D" exhibit an EC50 > 3.0 μM and ≤ 100 μM.

[0757] Compounds marked with "++++" exhibit an Emax > 300. Compounds marked with "+++" exhibit an Emax > 200 and ≤ 300. Compounds marked with "++" exhibit an Emax > 100 and ≤ 200. Compounds marked with "+" exhibit an Emax > 45 and ≤ 100.

[0758] Table 10. hTREM2 EC50 data (HEK293 cells) of the examples provided herein.

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765] Example A2.

[0766] In vitro measurement of the activity of trigger receptor 2 expressed on myeloid cells was performed using cellular phosphorylation assays based on the spleen tyrosine kinase (“Syk”) assays used in Examples 276 to 283.

[0767] The efficacy of TREM2 agonists was measured using the HEK cell line (HEK293T-hTREM2 cells) expressing human TREM2 and DAP12. Binding of the small molecule to TREM2 and activation of TREM2 increase Syk phosphorylation. The resulting Syk phosphorylation levels were measured using the commercially available AlphaLisa kit. For the assay, HEK-hTREM2 cells were seeded at 14,000 cells per well in 25 μL of complete growth medium in 384-well plates and incubated at 37°C and 5% CO2 for 20–24 h. Prior to the assay, the test compound was diluted in assay buffer in the 384-well plates and equilibrated for 30 min. The growth medium was removed from the cell plates by inverting them onto absorbent paper, and 25 μL of the test compound in assay buffer was added to the cells. Cells were incubated at room temperature for 45 min. After 45 min, the assay buffer was removed, and 10 μL of lysis buffer was added. The plates were then shaken at 350 RPM for 20 min 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. A standard curve was generated using the intensity, and the percentage of activation was calculated. Curve fitting was performed using Prism v9 software, with log(agonist) versus response-variable slope (four parameters), and EC50 was calculated based on the curve fit.

[0768] The results provided in Table 11 were generated using the in vitro assays described above for Examples 276 to 283. These assays can be used to test any of the compounds described herein to assess and characterize their ability as TREM2 agonists.

[0769] Compounds labeled "A" exhibit an EC50 ≤ 0.05 μM. Compounds labeled "B" exhibit an EC50 > 0.05 μM and ≤ 0.5 μM. Compounds labeled "C" exhibit an EC50 > 0.5 μM and ≤ 3.0 μM. Compounds labeled "D" exhibit an EC50 > 3.0 μM and ≤ 100 μM.

[0770] Table 11. hTREM2 EC50 data (HEK293 cells) for Examples 276 to 283 provided herein.

[0771] 276 A 277 B 278 B 279 A 280 A 281 A 282 A 283 B

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[0826] All references cited in this article, such as scientific publications or patent application publications, are incorporated herein in their entirety by reference and for all purposes, to the extent that each reference is specifically and individually indicated as being incorporated herein in its entirety by reference for all purposes.

Claims

1. A compound of formula II II Or a pharmaceutically acceptable salt of the compound, wherein X 1 It is CH or N; X 2 It is CH2, CF2, or O; in, Optional, R 5 It does not exist and X 2 CR 6 The groups form 5- or 6-membered heteroaryl groups, wherein formula II Part of it is , , , , , , , , , or ; X 3 It is CH or N independently each time it appears; R 1 It is H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl; R 2 It is H, methyl, trifluoromethyl, or cyclopropyl; R 3 Is it H or C? 1-3 alkyl; R 4 Is it H or C? 1-3 alkyl; R 5 Is it H or C? 1-3 alkyl; R 6 It is difluoromethyl, trifluoromethyl, -CH2CF3, dimethylamino, -C(=O)OCH2CH3, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted oxacyclobutyl, optionally substituted azacyclobutyl, 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; wherein (1) The cyclopropyl, cyclobutyl, oxetane, azirane, tetrahydrofuranyl, and pyrrolidinyl groups are optionally substituted with C=O. (2) The phenyl, pyrazolyl, imidazolyl, 1,3-oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thienyl, thiazolyl, pyridyl, pyridinyl, pyridazinyl, or pyrimidinyl group is optionally substituted by one to three independent substituents selected from the following: 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)NH(C 1-3 alkyl), -(C 1-3 Alkyl)N[(C 1-3 Alkyl)(C 1-3 Alkyl groups, -CN, C 2-4 alkenyl, C 3-6 cycloalkyl, phenyl and C 3-6 Heterocyclic alkyl groups; wherein The C in segment (2) 1-6 Alkyl and C 1-6 The haloalkyl group is optionally substituted with OH; and wherein The C in segment (2) 3-6 The heterocyclic alkyl group is optionally substituted with 1 to 3 substituents selected from halogens, C... 1-3 Alkyl groups and -C(=O)O(C 1-6 alkyl); R 7 C is an optional substitute 5-6 Cycloalkyl, optionally substituted phenyl, or optionally substituted pyridyl; wherein R 7 Further optionally selected by 1 to 4 independently chosen from halogen, C 1-3 Alkyl and C 1-3 Substituents of haloalkyl groups; and n is 0 or 1; the prerequisite is that when X 1 When X is N and n is 0, 2 It's not O.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IIA. IIA.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IIB. IIB.

4. The compound according to claim 1 or a pharmaceutically acceptable salt of said compound, wherein... X 1 It is CH.

5. The compound according to claim 1 or a pharmaceutically acceptable salt of said compound, wherein... X 1 It is N.

6. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... X 2 It is O.

7. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... X 3 It is CH.

8. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... X 3 It is N.

9. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... R 1 It is methyl, ethyl, propyl, -CH2CF3, cyclopropyl, or cyclohexyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt of said compound, wherein... R 1 It is a methyl group.

11. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... R 2 It is a methyl group.

12. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... R 3 It is H or methyl.

13. The compound of claim 12 or a pharmaceutically acceptable salt of said compound, wherein... R 3 It's H.

14. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... R 4 It is H or methyl.

15. The compound of claim 14 or a pharmaceutically acceptable salt of said compound, wherein... R 4 It's H.

16. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... R 5 It is H or methyl.

17. The compound of claim 16 or a pharmaceutically acceptable salt of said compound, wherein... R 5 It's H.

18. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... R 6 It is difluoromethyl, trifluoromethyl, -CH2CF3, dimethylamino, -C(=O)OCH2CH3, cyclopropyl, cyclobutyl, oxetane-2-yl, azirane-1-yl, tetrahydrofuran-3-yl, , , , , , phenyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

19. The compound of claim 18 or a pharmaceutically acceptable salt of said compound, wherein... R 6 yes , , or .

20. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... R 7 It is an optionally substituted phenyl group, wherein the optionally substituted phenyl group is further optionally selected by 1 to 4 independently selected from halogens, C 1-3 Alkyl and C 1-3 Substitution of alkyl halogens.

21. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... R 7 yes , , , , , , , , , , , , , , , , , , , or .

22. The compound of claim 21 or a pharmaceutically acceptable salt of said compound, wherein... R 7 yes .

23. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... n is 0.

24. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein... n is 1.

25. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from...

26. The compound of claim 1 or a pharmaceutically acceptable salt of the compound, wherein 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-pyridyl)pyridino[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-dimethylpyridino[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-dimethylpyridino[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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-(2-cyclobutyl-4-morpholino)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2R,6R)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2R,6S)-2-cyclopropyl-6-methyl-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2R)-2-oxetane)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-((2S)-2-oxetane)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2S)-2-oxetane)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-((2R)-2-oxetane)-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-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(3-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(4-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(4-pyridyl)-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)morpholine)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(3-thienyl)-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-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(2-methyl-4-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(2-methyl-4-pyridyl)-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-dimethylpyridino[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-dimethylpyridino[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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-(2-(5-fluoro-3-pyridinyl)-4-morpholinyl)-2,3-dimethylpyridino[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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S,6S)-2-methyl-6-(3-thienyl)-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-thienyl)-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-thienyl)-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-thienyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(4-methyl-1,3-thiazolyl-2-yl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2,6-dimethyl-4-pyridyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2,6-dimethyl-4-pyridyl)-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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(3-methoxyphenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-methoxy-4-pyridinyl)-4-morpholinyl)-2,3-dimethylpyridino[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-dimethylpyridino[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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(4-chlorophenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(4-chlorophenyl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2R)-2-(2-chloro-4-pyridyl)-4-morpholinyl)-2,3-dimethylpyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(2-chloro-4-pyridyl)-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-dihydropyridino[4,3-d]pyrimidin-7-yl)-2-morpholinyl)benzylnitrile; 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-naphthidin-2(1H)-yl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-(3,4-dihydro-2,7-naphthidin-2(1H)-yl)-2,3-dimethylpyridino[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)pyridolo[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-azacyclobutyl)-1-piperidinyl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyridino[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-pyridyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((3R)-3-(4-pyridyl)-1-piperidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 7-(8-chloro-3,4-dihydro-2,7-naphthidin-2(1H)-yl)-5-(4-chloro-2-fluorophenyl)-2,3-dimethylpyridino[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]pyrimidine]-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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(3-(3-pyridyl)-1-pyrrolidinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(2-propyl)-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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(3-oxetane)-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-dimethylpyridino[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-dimethylpyridino[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-dimethylpyridino[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-dimethylpyridino[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-dimethylpyridino[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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,3-difluoro-2-propyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 2-Methyl-2-propyl 3-(4-((2S)-4-(5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-3,4-dihydropyridino[4,3-d]pyrimidin-7-yl)-2-morpholino)-1H-pyrazol-1-yl)-1-azacyclobutane carboxylate; 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-(1,2-difluoroethyl)-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[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-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-7-((2S)-2-(1-vinyl-1H-pyrazol-4-yl)-4-morpholinyl)-2,3-dimethylpyridino[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2S)-2-(1-(1-methyl-3-azacyclobutane)-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-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R)-2-(6-methyl-3-pyridyl)-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-pyridyl)-4-morpholinyl)pyrido[4,3-d]pyrimidin-4(3H)-one; 5-(2,4-difluorophenyl)-3-ethyl-2-methyl-7-((2S)-2-(2-methyl-4-pyridyl)-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-morpholino)-2-methyl-3-propylpyridino[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-dimethylpyridino[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-carboxylic acid ethyl ester 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-carboxylic acid ethyl ester; (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 ethyl ester 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-carboxylic acid ethyl ester; 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-((2R,4S)-2-(2-methyl-4-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-4(3H)-one.

27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is 。 28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 。 29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is 。 30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is 。 31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 。 32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is 。 33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is 。 34. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is 。 35. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, and a pharmaceutically acceptable excipient.

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