TREM2 modulator

Abstract

The present invention relates to compounds useful for regulating Triggering Receptor Expressed on Myeloid Cells 2 (hereinafter referred to as "TREM2") expressed in myeloid cells. The present invention also relates to compounds for use in the treatment of conditions associated with loss of function of TREM2, such as neurodegenerative diseases, and pharmaceutical compositions containing such compounds.

Description

Technical Field

[0001] The present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) expressed in myeloid cells. The present invention also relates to compounds for use in the treatment of conditions associated with loss of function of TREM2, such as neurodegenerative diseases, and pharmaceutical compositions containing such compounds.

Background Art

[0002] Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) expressed in myeloid cells is a transmembrane receptor belonging to the immunoglobulin superfamily and is encoded by the TREM2 gene mapped to human chromosome 6p21. TREM2 consists of an extracellular portion containing a single immunoglobulin domain and a short extracellular domain, a single transmembrane helix, and a short cytosolic tail (Colonna, M. et al. (2016)).

[0003] Insight into the role of TREM2 is obtained from its restricted expression pattern. It is expressed exclusively on myeloid lineage cells such as macrophages, microglia, dendritic cells, and osteoclasts. It plays a role as a pathological sensor in specific tissues and an inducer of innate immune signaling in tissue maintenance. In the brain, TREM2 is expressed exclusively in microglia and is functionally required, for example, in the phagocytosis of cell debris, but has also been assigned roles in limiting inflammation and promoting cell survival (Deczkowska, A. et al. (2020)).

[0004] TREM2 has a wide range of ligands including bacterial anionic molecules / endotoxins, phospholipids including phosphatidylserine, lipoproteins, apolipoproteins including ApoE, and oligomeric Aβ (Hammond, T.R. (2019)).

[0005] Signaling through TREM2 is well - described through the co - receptor DAP12. The adapter molecule DAP12 is expressed as a homodimer on the surface of various cells involved in innate immune responses, including microglia, macrophages, granulocytes, NK cells, and dendritic cells. After ligation of TREM2, phosphorylation of the ITAM (immunoreceptor tyrosine - based activation motif) tyrosine of DAP12 by SRC family kinases drives the recruitment and activation of Syk kinase and / or ZAP70 kinase. Downstream of TREM2 / DAP12 / Syk, several signaling pathways involved in cell survival, cell activation and differentiation, and control of the actin cytoskeleton have been described.

[0006] Proteolytic cleavage of the extracellular domain of TREM2 by metalloproteinases, including ADAM10 and ADAM17, and possibly matrix metalloproteinases, results in shedding of soluble TREM2 (sTREM2), which can be detected in human cerebrospinal fluid (CSF). sTREM2 has been suggested as a potential biomarker for microglial activity in early Alzheimer's disease (Suarez - Calvet, M. et al. (2016)).

[0007] Deficiency of either TREM2 or DAP12 leads to attenuation of the microglial response to pathogens. The effects of TREM2 deficiency in vitro have been shown in relation to stimulation with typical TLR ligands such as LPS. Loss-of-function gene variants of TREM2 have been associated with neurodegenerative diseases, supporting a central role of microglial function in the disease pathogenesis. Homozygous loss-of-function TREM2 variants cause Nasu-Hakola disease (Yamazaki, K. et al. (2015), Paloneva BM, J. et al. (2001), Ulrich J.D. et al. (2017)), while heterozygous loss-of-function TREM2 variants are associated with an increased risk of several neurological and neurodegenerative disorders such as Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), Parkinson's disease, FTLD-like syndromes, and amyotrophic lateral sclerosis (ALS). The most widely seen mutation associated with AD is the loss-of-function mutation R47H, which has been shown to inhibit ligand binding and phagocytosis (Atagi, Y. et al. (2015), Kleinberger, G. et al(2014)).

[0008] Neurodegenerative disorders that can be treated by modulating the activity and / or signaling of TREM2 include, but are not limited to, Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), FTLD-like syndromes, Parkinson's disease, Huntington's disease, Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), multiple sclerosis (MS), Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, and amyotrophic lateral sclerosis (ALS). Therefore, there is a high unmet medical need for TREM2 modulators to address these indications. SUMMARY OF THE INVENTION

[0009] The present invention relates to compounds that modulate TREM2.

[0010] In one aspect, the present invention provides a compound of formula LXI:

Chemical formula

Chemical formula

[0011] In one aspect, the present invention relates to a compound of formula LXI as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases associated with loss of function of TREM2, such as neurodegenerative diseases.

[0012] Definitions As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0013] The terms "about" and "approximately" as used herein are synonyms. In some embodiments, "about" refers to the recited amount, value, or duration ±20%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.5%.

[0014] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure unless otherwise specified.

[0015] As used herein, the terms "C1-3 alkyl", "C1-5 alkyl", and "C1-6 alkyl" refer to straight or branched hydrocarbon chains containing 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. Representative examples of C1-3 alkyl, C1-5 alkyl, and C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, and hexyl.

[0016] As used herein, the term "C2-4 alkenyl" refers to a saturated hydrocarbon containing 2 to 4 carbon atoms with at least one carbon-carbon double bond. Alkenyl groups include both straight and branched portions. Representative examples of C2-4 alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.

[0017] As used herein, the term "C3-6 cycloalkyl" refers to a saturated carbocyclic molecule having a cyclic framework of 3 to 6 carbon atoms. Representative examples of C3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0018] As used herein, the term "di-C1-3 alkylamino" refers to -NR*R**, where R* and R** each independently represent C1-3 alkyl as defined herein. Representative examples of di-C1-3 alkylamino include, but are not limited to, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -N(CH2CH2CH3)2, and -N(CH(CH3)2)2.

[0019] As used herein, the terms "C1-3 alkoxy" and "C1-6 alkoxy" refer to -OR#, where R# represents a C1-3 alkyl and a C1-6 alkyl group as defined herein, respectively. Representative examples of C1-3 alkoxy and C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.

[0020] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0021] As used herein as a prefix to another term representing a chemical group, the term "halo" refers to a modification of the chemical group in which one or more hydrogen atoms are replaced by a halogen as defined herein. The halogen is independently selected in each instance. For example, the term "C1-6 haloalkyl" refers to a C1-6 alkyl as defined herein in which one or more hydrogen atoms are replaced by a halogen. Representative examples of C1-6 haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3). Further, for example, the term "C1-6 haloalkoxy" refers to a C1-6 alkoxy as defined herein in which one or more hydrogen atoms are replaced by a halogen. Representative examples of C1-6 haloalkoxy include, but are not limited to, -OCH2F, -OCHF2, -OCF3, -OCHFCl, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, -OCF(CHF2)2, and -OCH(CH2F)(CF3).

[0022] The term "CN" is used herein to denote the cyano group

Chem.

[0023] As used herein, the terms "5-membered heteroaryl" or "6-membered heteroaryl" refer to a 5- or 6-membered carbocyclic ring having two or three double bonds and containing one ring heteroatom selected from N, S, and O, and optionally one or two additional ring N atoms, in place of one or more ring carbon atoms (if any). Representative examples of 5-membered heteroaryl include, but are not limited to, furyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of 6-membered heteroaryl include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl.

[0024] As used herein, the term "C3-6 heterocycloalkyl" refers to a saturated carbocyclic molecule having a cyclic framework with 3 to 6 carbons, where one or more carbon atoms are substituted with heteroatoms (if any) selected from N, O, and S. In some embodiments, "C3-6 heterocycloalkyl" refers to a saturated carbocyclic molecule having a cyclic framework with 3 to 6 carbons, where one carbon atom is substituted with a heteroatom selected from N, O, and S. When the C3-6 heterocycloalkyl group is C6 heterocycloalkyl, one or two carbon atoms are substituted with heteroatoms independently selected from N, O, and S. Representative examples of C3-6 heterocycloalkyl include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0025] As used herein, the term "spiro compound" refers to a compound having one atom (usually a quaternary carbon) as the only common member of two rings. As used herein, "C5-8 spiroalkyl" refers to a bicyclic system containing 5 to 8 carbon atoms in which the two rings are connected through a single shared carbon atom. Representative examples of C5-8 spiroalkyl include, but are not limited to, spiro[2.2]pentanyl, spiro[3.2]hexanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, and spiro[2.5]octanyl.

[0026] As used herein, the term "C5-8 tricycloalkyl" refers to a tricyclic system in which all three cycloalkyl rings share two identical ring atoms. Representative examples of C5-8 tricycloalkyl include, but are not limited to, tricyclo[1.1.1.01,3]pentanyl, tricyclo[2.1.1.01,4]hexanyl, tricyclo[3.1.1.01,5]hexanyl, and tricyclo[3.2.1.01,5]octanyl.

[0027] As used herein, the term "C5-8 bicycloalkyl" refers to a bicyclic system in which both cycloalkyl rings share two identical ring atoms. The term "C5-8 bicycloalkyl" includes bridged bicyclic compounds, i.e., those in which the two rings share more than three atoms and are separated by a bridge containing at least one atom between two bridgehead atoms. For example, the term "C5-8 bicycloalkyl" includes bicyclo[1.1.1]pentyl. For example, the term "C5-8 bicycloalkyl" [Chemical formula] including.

[0028] The term "aryl", when used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of 4 to 14 ring members, at least one of the rings in the system being aromatic and each ring in the system containing 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, etc., which may have one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.

[0029] The terms "heteroaryl" and "heteroar-" when used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", Groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; groups having 6, 10, or 14 π electrons shared in a cyclic arrangement; and groups having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" in the context of "heteroaryl" specifically includes, but is not limited to, nitrogen, oxygen, or sulfur, and any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaral-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The heteroaryl ring may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", and any of these terms includes a ring optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with heteroaryl, and both the alkyl and heteroaryl moieties are independently optionally substituted.

[0030] When described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise specified, an "optionally substituted" group may have a suitable substituent at one or more substitutable positions of the group, and in any given structure, if more than one position is substituted with more than one substituent selected from the specified group, the substituents may each be the same or different at all positions, i.e., the substituents may be selected individually / independently from the group of substituents. Combinations of substituents envisioned by the present invention preferably result in the formation of stable or chemically possible compounds.

[0031] As used herein, the term "stable" refers to compounds that do not substantially change when subjected to the conditions necessary for their production, detection, and in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0032] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and that have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

DETAILED DESCRIPTION OF THE INVENTION

[0033] In one aspect, the invention provides a compound of formula LXI:

CHEMICAL

Chemical formula

[0034] In one aspect, the present invention provides a compound of formula LXI:

Chemical formula

Chemical formula

[0035] In one aspect, the present invention provides a compound of formula LXI:

Chemical formula

Chemical formula

[0036] In one aspect, the present invention is a compound of formula IX:

Chemical formula

Chemical formula

[0037] In one aspect, the present invention provides a compound of formula IX: [Chemical formula] wherein, X1 is N or CH, X2 is N or CH, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R10, Ra is H or C1-6 alkyl, Rb is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohex-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, One methylene group of the C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, The azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally replaced by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R10 is selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and phenyl, and the phenyl is optionally replaced by 1 to 5 substituents individually selected from -O-C1-6 alkyl, R23 has the formula XX: [Chemical formula] wherein, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is C(H)(R7) or C(O), X11 is C(R4) or N, X12 is C(R6)(R6b), R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) The C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen, (b) The phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, The C1-6 alkyl or the C1-6 haloalkyl in subcategory (b) is optionally substituted with -OH, The C3-6 heterocycloalkyl in subcategory (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), (c) The C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl, and -N(R30)(R31), R6 is H, halogen, or C1-3 alkyl, R6b is H, halogen, or C1-3 alkyl, Here, when R6 and R6b are C1-3 alkyl, R6 and R6b are optionally linked together to form a 3- to 6-membered ring, and / or Here, when R6 and R6b are C1-3 alkyl, one methylene group is optionally replaced by -O- or -N(R35)-, where R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, R7 is H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl, or C1-6 haloalkyl, and the C1-6 alkyl, the -C(O)-C1-6 alkyl, or the -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy, R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen, R29 is a bond, -O-, or a C1-6 hydrocarbon chain in which one methylene group is optionally replaced by -O-, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl, n is 0, 1, or 2, v is 1 or 2, relates to the compound, or a pharmaceutically acceptable salt thereof.

[0038] In one aspect, the present invention is a compound of formula IX:

Chemical formula

Chemical formula

[0039] In one aspect, the present invention relates to a compound of formula IX:

Chemical formula

Chemical formula

[0040] In some embodiments, the compound is of formula I: [Chemical formula] wherein, X1 is N or CH, X2 is N or CH, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is C(H)(R7) or C(O), R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R10, Ra is H or C1-6 alkyl, Rb is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), The C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohexa-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, The azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, (a) The C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with oxo (=O), (b) The phenyl, the 5-membered heteroaryl, or the 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, The C1-6 alkyl or the C1-6 haloalkyl in sub-category (b) is optionally substituted with -OH, The C3-6 heterocycloalkyl in sub-category (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), R6 is H or C1-3 alkyl, R7 is H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C3-6 cycloalkyl, -C(O)-C1-6 alkyl, C1-6 alkyl-O-C1-6 alkyl or C1-6 haloalkyl, R10 is selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, R11 is selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, n is 0, 1, or 2; or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, R23 is of formula XLVII, wherein R5, R8, R29, X4, X10, X11, X12, n, and v are as defined herein. In some embodiments, R23 is of formula XLVIII, wherein R5, R8, R29, X4, X10, X11, X12, n, and v are as defined herein. In some embodiments, R23 is of formula XLIX, wherein R4, R5, R29, X4, X10, X12, X13, n, and v are as defined herein. In some embodiments, R23 is of formula L, wherein R4, R5, R29, X4, X10, X12, X13, n, and v are as defined herein. In some embodiments, R23 is of formula LI, wherein R4, R5, R8, R29, X4, X10, X12, X13, n, and v are as defined herein. In some embodiments, R23 is of formula LII, wherein R4, R5, R8, R29, X4, X10, X12, X13, n, and v are as defined herein. In some embodiments, R23 is of formula LIII, wherein R4, R5, R8, R29, X4, X10, X12, X13, n, and v are as defined herein. In some embodiments, R23 is of formula LIV, wherein R4, R5, R8, R29, X4, X10, X12, X13, n, and v are as defined herein.

Chem.

[0042] In some embodiments, R23 is of formula Xa, where R4, R5, R6, X3, X4, X10, and n are as defined herein; or a pharmaceutically acceptable salt thereof. In some embodiments, R23 is of formula Xb, where R4, R5, R6, X3, X4, X10, and n are as defined herein; or a pharmaceutically acceptable salt thereof. In some embodiments, R23 is of formula XXa, where R4, R5, R29, X3, X4, X10, X12, n, and v are as defined herein; or a pharmaceutically acceptable salt thereof. In some embodiments, R23 is of formula XXb, where R4, R5, R29, X3, X4, X10, X12, n, and v are as defined herein; or a pharmaceutically acceptable salt thereof. In some embodiments, R23 is of formula XXc, where R4, R5, R8, R29, X4, X10, X12, n, and v are as defined herein; or a pharmaceutically acceptable salt thereof. In some embodiments, R23 is of formula XXd, where R4, R5, R8, R29, X4, X10, X12, n, and v are as defined herein; or a pharmaceutically acceptable salt thereof. In some embodiments, R23 is of formula XXe, where R4, R5, R8, R29, X4, X10, X12, n, and v are as defined herein; or a pharmaceutically acceptable salt thereof. In some embodiments, R23 is of formula XXf, where R4, R5, R8, R29, X4, X10, X12, n, and v are as defined herein; or a pharmaceutically acceptable salt thereof.

Chem.

[0043] In some embodiments, the compound is of formula Ia or formula Ib:

Chemical formula

[0044] In some embodiments, X1 is N. In some embodiments, X1 is C(R42), where R42 is H or halogen. In some embodiments, R42 is H, i.e., X1 is CH. In some embodiments, R42 is halogen. In some embodiments, R42 is F, i.e., X1 is CF. In some embodiments, X1 is CH. In some embodiments, X2 is N. In some embodiments, X2 is CH. In some embodiments, X14 is N. In some embodiments, X14 is CH. In some embodiments, X1 is N and X2 is CH. In some embodiments, X1 is CH and X2 is N. In some embodiments, X1 is CH and X2 is CH. In some embodiments, X1 is N and X2 is N. In some embodiments, X1 is N, X2 is N, and X14 is N. In some embodiments, X1 is N, X2 is N, and X14 is CH. In some embodiments, X1 is N, X2 is CH, and X14 is N. In some embodiments, X1 is CH, X2 is N, and X14 is N. In some embodiments, X1 is CH, X2 is CH, and X14 is N. In some embodiments, X1 is CH, X2 is N, and X14 is CH. In some embodiments, X1 is N, X2 is CH, and X14 is CH. In some embodiments, X1 is CH, X2 is CH, and X14 is CH. In some embodiments, X1 is CF, X2 is N, and X14 is N.

[0045] In some embodiments, the compound is of formula II: [ka] wherein R1, R2, R3, R4, R5, R6, X3, X4, X10, and n are as defined herein; or a pharma- ceutically acceptable salt thereof.

[0046] In some embodiments, the compound is of formula II, wherein: X1 is N or CH; X2 is N or CH; R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R10; Ra is H or C1-6 alkyl; Rb is H or C1-6 alkyl; R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11; R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl); the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopent-1-en-1-yl, the cyclohex-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl; one methylene group of said C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-; R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, the azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R10 is selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is CH2, R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with oxo (=O), (b) the phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, in sub - group (b), the C1 - 6 alkyl or the C1 - 6 haloalkyl is optionally substituted by - OH, in sub - group (b), the C3 - 6 heterocycloalkyl is optionally substituted by 1 - 3 substituents each independently selected from the group consisting of halogen, C1 - 3 alkyl, and - C(O)O(C1 - 6 alkyl), (c) the C1 - 6 alkyl is optionally substituted by - N(H)C(O)R24, - oxo(=O), - O - C1 - 3 alkyl, and - N(R30)(R31), R6 is H or C1 - 3 alkyl, R8 is selected from the group consisting of H, - OH, - O - alkyl, and halogen, R9 is C1 - 6 alkyl, - C(O)-C1 - 6 alkyl, or - C(O)-C3 - 6 cycloalkyl, R24 is C1 - 6 alkyl or aryl, and the C1 - 6 alkyl is optionally substituted by C1 - 3 alkoxy or halogen, n is 1; or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted with one to three individually selected substituents R10, Ra is H or C1-6 alkyl, Rb is H or C1-6 alkyl, and R10 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and halogen. In some embodiments, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted with R10, Ra is H or C1-6 alkyl, Rb is H or C1-6 alkyl, and R10 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and halogen. In some embodiments, R1 is C1-6 alkyl optionally substituted with one to three individually selected substituents R10. In some embodiments, R1 is C1-6 alkyl optionally substituted with R10 as defined herein. In some embodiments, R1 is C1-3 alkyl optionally substituted with one to three individually selected substituents R10. In some embodiments, R1 is C1-3 alkyl optionally substituted with R10 as defined herein. In some embodiments, R1 is -CH3. In some embodiments, R10 is individually selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and halogen. In some embodiments, R10 is a halogen such as F. In some embodiments, R1 is -CF3. In some embodiments, R1 is C3-6 cycloalkyl optionally substituted with R10 as defined herein. In some embodiments, R1 is H.

[0048] In some embodiments, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, where R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and phenyl, and the phenyl is optionally substituted by 1 to 5 substituents individually selected from -O-C1-6 alkyl. In some embodiments, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and phenyl, and the phenyl is optionally substituted by 1 to 5 substituents individually selected from -O-C1-6 alkyl. In some embodiments, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl. In some embodiments, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, where R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl. In some embodiments, R2 is a C1-6 alkyl optionally substituted by R11 as defined herein. In some embodiments, R2 is a C1-3 alkyl optionally substituted by R11 as defined herein. In some embodiments, R2 is -CH3. In some embodiments, R2 is a C3-6 cycloalkyl optionally substituted by R11 as defined herein. In some embodiments, R11 is -O-C1-6 alkyl such as -O-CH3. In some embodiments, R2 is H. In some embodiments, R2 is a C1-3 alkyl substituted by R11, and R11 is -O-C1-6 alkyl. In some embodiments, R2 is -CH2CH2OCH3. In some embodiments, R2 is a C1-6 alkyl substituted by phenyl, and the phenyl is optionally substituted by -O-C1-6 alkyl.In some embodiments, R2 is C1-alkyl substituted with phenyl, and the phenyl is substituted with -O-C1-6 alkyl such as -O-C1-3 alkyl, for example, -O-C1 alkyl.

[0049] In some embodiments, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), wherein the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohexa-1-en-1-yl, the phenyl, the 6-membered heteroaryl, or the 5-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, and CN, wherein one methylene group of the C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, wherein R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, and wherein the azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.

[0050] In some embodiments, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohexa-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, C1-3 alkyl, and C1-3 haloalkyl, one methylene group of the C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, the azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.

[0051] In some embodiments, R3 is phenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, and CN; or a pharmaceutically acceptable salt thereof.

[0052] In some embodiments, R3 is phenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, -CN, C1-3 alkyl, and C1-3 haloalkyl.

[0053] In some embodiments, R3 is of formula III:

Chemical formula

[0054] In some embodiments, R3 is of formula III, wherein X5 is C(R15) or N, X6 is CH or N, R12 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R13 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R14 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, and R15 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl.

[0055] In some embodiments, R3 is of formula III, wherein X5 is C(R15) or N, X6 is CH, R12 is H or halogen, R13 is H or halogen, R14 is H, halogen, or C1-3 haloalkyl, and R15 is H or halogen; or a pharmaceutically acceptable salt thereof.

[0056] In some embodiments, X5 is C(R15) and X6 is CH. Thus, in some embodiments, R3 is of formula IV:

Chemical formula

[0057] In some embodiments, R3 is of formula IV, in which R12 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R13 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R14 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, and R15 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl.

[0058] In some embodiments, X5 is N and X6 is CH. In some embodiments, X5 is CH and X6 is N.

[0059] In some embodiments, R12 is H. In some embodiments, R12 is halogen such as F or Cl. In some embodiments, R12 is C1-3 alkyl such as -CH3. In some embodiments, R12 is CN.

[0060] In some embodiments, R13 is H. In some embodiments, R13 is halogen such as F.

[0061] In some embodiments, R14 is a halogen such as F or Cl. In some embodiments, R14 is a C1-3 alkyl such as -CH3. In some embodiments, R14 is a C1-3 haloalkyl. In some embodiments, R14 is -CF3. In some embodiments, R14 is -CHF2. In some embodiments, R14 is CN.

[0062] In some embodiments, R15 is H. In some embodiments, R15 is a halogen such as F.

[0063] In some embodiments, R3 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0064] In some embodiments, R3 is a 5-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3 is a 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3 is pyrazolyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3 is

Chemical formula

[0065] In some embodiments, R3 is C3-6 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl.

[0066] In some embodiments, R3 is of formula V:

Chemical formula

[0067] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R16 is H. In some embodiments, R16 is a halogen such as F. In some embodiments, R16 is a C1-3 alkyl such as -CH3. In some embodiments, R16 is a C1-3 haloalkyl such as -CF3 or -CHF2. In some embodiments, R17 is H. In some embodiments, R17 is a halogen such as F. In some embodiments, R17 is a C1-3 alkyl such as -CH3. In some embodiments, R17 is a C1-3 haloalkyl such as -CF3 or -CHF2. In some embodiments, R3 is [Chemical Formula] . In some embodiments, R3 is [Chemical Formula] . In some embodiments, R3 is [Chemical Formula] . In some embodiments, R3 is [Chemical Formula] . In some embodiments, R3 is [Chemical Formula] . In some embodiments, R3 is [Chemical Formula] . In some embodiments, R3 is [Chemical Formula] . In some embodiments, R3 is [Chemical Formula] It is. In some embodiments, R3 is

Chem.

Chem.

Chem.

Chem.

[0068] In some embodiments, R3 is a C1-3 haloalkyl such as -(CH2)2CF3.

[0069] In some embodiments, R3 is a C5-8 spiroalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3 is

Chem.

[0070] In some embodiments, R3 is a C5-8 tricycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3 is a C5-8 bicycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3 is bicyclo[1.1.1]pentyl optionally substituted with CF3 or C1 alkyl; or a pharmaceutically acceptable salt thereof. In some embodiments, R3 is

Chem.

[0071] In some embodiments, R3 is of Formula VI:

Chemical formula

[0072] In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, r is 1. In some embodiments, r is 2.

[0073] In some embodiments, R18 is H. In some embodiments, R18 is a halogen such as F. In some embodiments, R18 is a C1-3 alkyl such as -CH3. In some embodiments, R18 is a C1-3 haloalkyl such as -CF3 or -CHF2.

[0074] In some embodiments, R19 is H. In some embodiments, R19 is a halogen such as F. In some embodiments, R19 is a C1-3 alkyl such as -CH3. In some embodiments, R19 is a C1-3 haloalkyl such as -CF3 or -CHF2.

[0075] In some embodiments, R3 is

Chemical formula

Chemical formula

[0076] In some embodiments, R3 is -OCH2-(C3-6 cycloalkyl) optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.

[0077] In some embodiments, R3 is [Chemistry] is.

[0078] In some embodiments, R3 is C3-6 cycloalkyl in which one or more methylene groups are replaced by -O-. In some embodiments, R3 is [Chemistry] is.

[0079] In some embodiments, R3 is C3-6 cycloalkyl in which one or more methylene groups are replaced by -N(R28)-, where R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl. In some embodiments, R3 is of formula XV: [Chemistry] and in the formula, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl; or a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, R3 is

Chemical Formula

[0081] In some embodiments, R23 is of formula XLVI:

Chemical Formula

[0082] In some embodiments, R23 is a 6-membered ring, i.e., X3, (X13)v, X11, X4, X12, and (X10)n together form a 6-membered ring. For example, in some embodiments, R23 is of formula XLVI, wherein n is 1, v is 1, and there is no bond. In some embodiments, R23 is of formula XLVI, wherein X3 is N, X4 is O, X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 1. In some embodiments, R23 is of formula XLVI, wherein X3 is N, X4 is NH or NR9, X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 1. In some embodiments, R23 is of formula XLVI, wherein X3 is N, X4 is C(R38)(R39), X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 1. In some embodiments, R23 is of formula XLVI, wherein X3 is N, X4 is a bond, X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 2. In some embodiments, R23 is of formula XLVI, wherein X3 is C(R8), X4 is O, X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 1.

[0083] In some embodiments, R23 is a 5-membered ring, i.e., X3, (X13)v, X11, X4, X12, and (X10)n together form a 5-membered ring. For example, in some embodiments, R23 is of formula XLVI, wherein n is 1, v is 1, and X4 is a bond, or n is 0, v is 1, and X4 is not a bond. In some embodiments, R23 is of formula XLVI, wherein X3 is N, X13 is C(R40)(R41), X11 is C(R4), X4 is C(R38)(R39), X12 is C(R6)(R6b), and n is 0.

[0084] In some embodiments, R23 is a 4-membered ring, i.e., X3, (X13)v, X11, X4, X12, and (X10)n together form a 4-membered ring. For example, in some embodiments, R23 is of formula XLVI, wherein n is 0, v is 1, and X4 is a bond, or n is 1, v is 0, and X4 is a bond. In some embodiments, R23 is of formula XLVI, wherein X3 is N, X4 is a bond, n is 0, X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), and v is 1.

[0085] In some embodiments, X3 is N. In some embodiments, X3 is C(R8), where R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen. In some embodiments, R8 is H. In some embodiments, X3 is C(H).

[0086] In some embodiments, X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, where R9 is as defined herein. In some embodiments, X4 is CH2, O, CHF, NH, or NR9, where R9 is as defined herein. In some embodiments, X4 is O. In some embodiments, X4 is CF2. In some embodiments, X4 is CH2. In some embodiments, X4 is CHF. In some embodiments, X4 is NR9, where R9 is as defined herein. In some embodiments, R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, or -C(O)-C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, X4 is C(R38)(R39), where R38 is H or F, and R39 is H or F. In some embodiments, R38 is H. In some embodiments, R38 is F. In some embodiments, R39 is F. In some embodiments, R39 is F. In some embodiments, R38 is H and R39 is H. In some embodiments, R38 is F and R39 is F. In some embodiments, R38 is H and R39 is F.

[0088] In some embodiments, R4 is C1-3 alkyl. In some embodiments, R4 is H.

[0089] In some embodiments, R23 is of formula XVI, wherein X3 is N, X10 is CH2, n is 1, v is 1, R6 is H, X4 is O, and X11 is C(H). In some embodiments, R23 is of formula XX, wherein X3 is N, X10 is CH2, n is 1, v is 1, X4 is O, and X11 is C(H). In some embodiments, R23 is of formula XX, wherein X3 is N, X10 is CH2, n is 1, v is 1, X4 is O, X11 is C(H), and X12 is C(R6)(R6b). In some embodiments, R23 is of formula XXXIV:

Chemical formula

[0090] In some embodiments, R23 is of formula XXXIV, R6 is C1-3 alkyl, R6b is C1-3 alkyl, and R6 and R6b are linked together to form a 3- to 6-membered ring. In some embodiments, R23 is of formula XXXIV, R6 is C1-3 alkyl, R6b is C1-3 alkyl, and R6 and R6b are linked together to form a 4-membered ring, for example, R6 is C1 alkyl and R6b is C2 alkyl, or R6 is C2 alkyl and R6b is C1 alkyl. In some embodiments, R23 is of formula XXXIV, R6 is C1-3 alkyl, R6b is C1-3 alkyl, and R6 and R6b are linked together to form a 3-membered ring, for example, R6 is C1 alkyl and R6b is C1 alkyl. In some embodiments, R6 and R6b are C1-3 alkyl, and R6 and R6b are linked together to form a 3- to 6-membered ring, and one methylene group is optionally replaced by -O-. In some embodiments, R6 and R6b are C1-3 alkyl, and R6 and R6b are linked together to form a 3- to 6-membered ring, and one methylene group is optionally replaced by -N(R35)-, where R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl. In some embodiments, R35 is H. In some embodiments, R35 is C1-3 alkyl. In some embodiments, R35 is -C(O)C1-3 alkyl. In some embodiments, R23 is of formula XLV: [Chemical Formula] wherein k is 1, 2, 3, or 4. In some embodiments, R23 is of formula XLV, wherein k is 1. In some embodiments, R23 is of formula XLV, wherein k is 2.

[0091] In some embodiments, R23 is of formula XLVI, where X3 is C(R8), R8 is C1 alkyl, X13 is C(R40)(R41), R40 is a bond, R8 and R40 are linked together to form a 3-membered ring, R41 is H, and v is 1. In some embodiments, R23 is of formula LV: [Chemical formula] wherein R5, R29, X4, X10, X12, and n are as defined herein.

[0092] In some embodiments, R23 is of formula LVI, wherein R5, R29, X4, X10, X12, and n are as defined herein. In some embodiments, R23 is of formula LVI, wherein R5, R29, X4, X10, X12, and n are as defined herein. In some embodiments, R23 is of formula LVIII, wherein R5, R29, X4, X10, X12, and n are as defined herein. In some embodiments, R23 is of formula LIX, wherein R5, R29, X4, X10, X12, and n are as defined herein. [Chemical formula]

[0093] In some embodiments, R23 is of formula XLVI, where X3 is C(R8), R8 is a bond, X13 is C(R40)(R41), R40 is C1 alkyl, R8 and R40 are linked together to form a 3-membered ring, R41 is H, v is 1, X11 is C(H), X4 is O, X12 is CH2, X10 is CH2, and n is 1. In some embodiments, R23 is of formula LX: [Chemical formula] wherein R5 and R29 are as defined herein.

[0094] In some embodiments, R23 is of formula XLVI, wherein X12 is C(R6)(R6b), R6b is H, R6 is C1-3 alkyl, n is 1, X10 is C(R37)(R7), R37 is H, R7 is a bond to R6, and thus a 3- to 5-membered ring is formed. In some embodiments, R23 is of formula XLVI, wherein X3 is N, X13 is CH2, v is 1, X11 is C(H), X4 is O, X12 is C(R6)(R6b), R6b is H, R6 is C1 alkyl, n is 1, X10 is C(R37)(R7), R37 is H, R7 is a bond to R6, and a 3-membered ring is formed. In some embodiments, R23 is of formula LXIII:

Chemical formula

[0095] In some embodiments, R23 is of formula XVI, wherein X3 is N, X10 is CH2, n is 1, v is 1, R6 is H, X4 is C(R33)(R34), R33 is H or F, R34 is H or F, and X11 is C(H). In some embodiments, R23 is of formula XXXV:

Chemical formula

[0096] In some embodiments, R23 is of formula XVI, where X3 is N, n is 0, v is 1, R6 is H, X4 is CH2, and X11 is C(H). In some embodiments, R23 is of formula XXXVI: [Chemical formula] wherein R5 and R29 are as defined herein.

[0097] In some embodiments, R23 is of formula XVI, where X3 is N, X10 is CH2, n is 1, v is 1, R6 is H, X4 is N(R9), and X11 is C(H). In some embodiments, R23 is of formula XXXVII: [Chemical formula] wherein R5, R9, and R29 are as defined herein.

[0098] In some embodiments, R23 is of formula XVI, where X3 is C(H), X10 is CH2, n is 1, v is 1, R6 is H, X4 is O, and X11 is C(H). In some embodiments, R23 is of formula XXXVIII: [Chemical formula] wherein R5 and R29 are as defined herein.

[0099] In some embodiments, R23 is of formula XVI, where X3 is C(H), X10 is CH2, n is 1, v is 1, R6 is H, X4 is C(R33)(R34), R33 is H or F, R34 is H or F, and X11 is N. In some embodiments, R23 is of formula XXXIX: [Chemical formula] wherein R5 and R29 are as defined herein, R33 is H or F, and R34 is H or F. In some embodiments, R23 is of formula XXXIX, R33 is H, and R34 is H. In some embodiments, R23 is of formula XXXIX, R33 is F, and R34 is F.

[0100] In some embodiments, R23 is of formula XVI, wherein X3 is N, n is 0, v is 1, R6 is H, X4 is a bond, and X11 is C(H). In some embodiments, R23 is of formula XL:

Chemical formula

[0101] In some embodiments, R23 is of formula XVI, wherein X3 is N, X10 is CH2, n is 1, v is 2, R6 is H, X4 is a bond, and X11 is C(H). In some embodiments, R23 is of formula XLI:

Chemical formula

[0102] In some embodiments, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen, (b) the phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, the C1-6 alkyl or the C1-6 haloalkyl in subcategory (b) is optionally substituted with -OH, the C3-6 heterocycloalkyl in subcategory (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo (=O), and -N(R30)(R31), wherein R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl.

[0103] In some embodiments, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with oxo (=O), (b) the phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, the C1-6 alkyl or the C1-6 haloalkyl in subcategory (b) is optionally substituted with -OH, the C3-6 heterocycloalkyl in subcategory (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), (c) the C1-6 alkyl is optionally substituted with -N(H)C(O)R24, where R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen.

[0104] In some embodiments, R5 is C3-6 cycloalkyl or C3-6 heterocycloalkyl, and the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen.

[0105] In some embodiments, R5 is C3-6 cycloalkyl or C3-6 heterocycloalkyl, and the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted by oxo (=O); or a pharmaceutically acceptable salt thereof. In some embodiments, R5 is C1-6 alkyl, and the C1-6 alkyl is optionally substituted by -N(H)C(O)R24, where R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted by C1-3 alkoxy or halogen; or a pharmaceutically acceptable salt thereof. In some embodiments, R5 is C1-6 alkyl, and the C1-6 alkyl is optionally substituted by -oxo (=O). In some embodiments, R5 is C1-6 alkyl, and the C1-6 alkyl is optionally substituted by -N(R30)(R31), where R30 is H or C1-3 alkyl, and R31 is H or C1-3 alkyl. In some embodiments, R30 is H. In some embodiments, R30 is C1-3 alkyl such as C1 alkyl. In some embodiments, R31 is H. In some embodiments, R31 is C1-3 alkyl such as C1 alkyl. In some embodiments, R30 is C1-3 alkyl such as C1 alkyl and R31 is H. In some embodiments, R30 is C1-3 alkyl such as C1 alkyl and R31 is C1-3 alkyl such as C1 alkyl.

[0106] In some embodiments, R5 is C3-6 heterocycloalkyl optionally substituted by 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen. In some embodiments, R5 is C4 heterocycloalkyl optionally substituted by 1 to 3 substituents independently selected from C1-3 alkoxy and halogen. In some embodiments, R5 is azetidine optionally substituted by 1 to 3 substituents independently selected from C1-3 alkoxy and halogen. In some embodiments, R5 is

Chemical formula

Chemical formula

[0107] In some embodiments, R5 is selected from the group consisting of phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), and the phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, the C1-6 alkyl or the C1-6 haloalkyl is optionally substituted by -OH, the C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl).

[0108] In some embodiments, R5 is a 5-membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, the C1-6 alkyl or the C1-6 haloalkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halogen, and -OH, The C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl).

[0109] In some embodiments, R5 is a 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, the C1-6 alkyl or the C1-6 haloalkyl is optionally substituted with -OH, and the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents each independently selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl).

[0110] In some embodiments, R5 is of formula XXI:

Chemical formula

[0111] In some embodiments, R5 is of formula XXII:

Chemical formula

[0112] In some embodiments, R5 is of formula XXII:

Chemical formula

[0113] In some embodiments, R5 is of formula XXIII:

Chemical formula

[0114] In some embodiments, R5 is of formula XXIV:

Chemical formula

[0115] In some embodiments, R5 is of formula XLIII:

Chemical formula

[0116] In some embodiments, R5 is

Chemical formula

Chemical formula

[0117] In some embodiments, R5 is of formula VII:

Chemical formula

[0118] In some embodiments, R5 is of formula VII:

Chemical formula

[0119] In some embodiments, R5 is of formula VII:

Chemical formula

[0120] In some embodiments, R5 is of formula XXV:

Chemical formula

[0121] In some embodiments, R5 is of formula XXVI:

Chemical formula

[0122] In some embodiments, R5 is of formula XXVII:

Chemical formula

[0123] In some embodiments, R5 is of formula XXVIII:

Chemical formula

[0124] In some embodiments, R5 is of formula XXIX:

Chemical formula

[0125] In some embodiments, R5 is of formula XXX:

Chemical formula

[0126] In one embodiment, R5 is of formula XLII:

Chemical formula

[0127] In some embodiments, R5 is of formula XXXI:

Chemical formula

[0128] In some embodiments, R5 is of formula XXXII:

Chemical formula

[0129] In some embodiments, R5 is of formula XXXIII:

Chemical formula

[0130] In some embodiments, R20 is a C1-3 alkyl such as -CH3. In some embodiments, R20 is a C1-3 alkyl substituted with a C1-6 alkoxy. In some embodiments, R20 is a C1-2 alkyl optionally substituted with a C1 alkoxy. In some embodiments, R20 is -CH2CH2OCH3. In some embodiments, R20 is a C3-6 cycloalkyl such as C3 cycloalkyl. In some embodiments, R20 is H. In some embodiments, R20 is a C1-3 alkyl optionally substituted with 1 to 3 halogens such as F. In some embodiments, R20 is a methyl optionally substituted with 1 to 3 halogens such as F. In some embodiments, R20 is -CF3.

[0131] In some embodiments, R5 is

Chemical formula

Chemical formula

[0132] In some embodiments, R5 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0133] In some embodiments, R5 is

Chemical formula

Chemical formula

[0134] In some embodiments, R5 is

Chemical formula

Chemical formula

[0135] In some embodiments, R5 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0136] In some embodiments, R5 is

Chemical formula

Chemical formula

[0137] In some embodiments, R5 is

Chemical formula

[0138] In some embodiments, R5 is a 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or the C1-6 haloalkyl is optionally substituted with -OH, and the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl).

[0139] In some embodiments, X12 is CH2, R29 is a bond, and R5 is pyrazolyl optionally substituted with C1-6 alkyl or C3-6 cycloalkyl. In some embodiments, X12 is CH2, R29 is a bond, and R5 is pyrazolyl substituted with a C3-6 cycloalkyl such as cyclopropyl.

[0140] In some embodiments, R5 is of formula XLIV:

Chemical formula

[0141] In some embodiments, R5 is of Formula VIII:

Chemical formula

Chemical formula

[0142] In some embodiments, R5 is a C1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo(=O), and -N(R30)(R31), wherein R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl.

[0143] In some embodiments, R5 is of Formula XIII:

Chemical formula

[0144] In some embodiments, R4 and R5 are linked together to form a ring, thus producing a spiro compound. In some embodiments, R4 is C1-3 alkyl and R5 is C1-3 alkyl. In some embodiments, R4 is C1-3 alkyl and R5 is C1-3 alkyl, and R4 and R5 are linked together to form a 3- to 6-membered ring. In some embodiments, R4 is C2 alkyl and R5 is C2 alkyl, and R4 and R5 are linked together to form a 4-membered ring.

[0145] In some embodiments, R6 is C1-3 alkyl. In some embodiments, R6 is H. In some embodiments, R6 is halogen. In some embodiments, R6b is C1-3 alkyl. In some embodiments, R6b is H. In some embodiments, R6b is halogen. In some embodiments, R6 and R6b are H. In some embodiments, R6 is halogen and R6b is halogen. In some embodiments, R6 is H and R6b is halogen. In some embodiments, R6 and R6b are C1-3 alkyl such as C1 alkyl. In some embodiments, R6 and R6b are linked together to form a ring, thus generating a spiro compound. In some embodiments, R6 and R6b are C1-3 alkyl, and R6 and R6b are linked together to form a 3- to 6-membered ring such as a 4-membered ring or a 3-membered ring. In some embodiments, R6 and R6b are C1 alkyl, and R6 and R6b are linked together to form a 3-membered ring. In some embodiments, R6 is C1 alkyl and R6b is C2 alkyl, or R6 is C2 alkyl and R6b is C1 alkyl, and R6 and R6b are linked together to form a 4-membered ring. In some embodiments, R6 and R6b are C1-3 alkyl, and R6 and R6b are linked together to form a 3- to 6-membered ring, and one methylene group is optionally replaced by -O-. In some embodiments, R6 and R6b are C1-3 alkyl, and R6 and R6b are linked together to form a 3- to 6-membered ring, and one methylene group is optionally replaced by -N(R35)-, where R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl. In some embodiments, R35 is H. In some embodiments, R35 is C1-3 alkyl. In some embodiments, R35 is -C(O)C1-3 alkyl.

[0146] In some embodiments, X10 is C(H)(R7) or C(O). In some embodiments, X10 is C(H)(R7), where R7 is H or C1-3 alkyl. In some embodiments, X10 is individually C(R37)(R7), where R7 is individually H or C1-3 alkyl and R37 is individually H or C1-3 alkyl. In some embodiments, R7 is H. In some embodiments, R37 is H. In some embodiments, R7 is H and R37 is H. In some embodiments, X10 is C(H)2. When R7 is a bond, it forms a bond between the C of X10 and another atom such as the C of R6. In some embodiments, R7 is a bond, and then R6 is C1-3 alkyl, and R7 and R6 together are linked to form a 3- to 5-membered ring.

[0147] In some embodiments, X13 is C(R40)(R41), where R40 is individually H, C1-3 alkyl, or a bond, and R41 is individually H or C1-3 alkyl. In some embodiments, R40 is H. In some embodiments, R41 is H. In some embodiments, R40 is H and R41 is H. In some embodiments, X13 is CH2. When R40 is a bond, it forms a bond between the C of X13 and another atom such as the C of R8. In some embodiments, when R40 is a bond, R8 is C1-3 alkyl, and R8 and R40 together are linked to form a 3- to 5-membered ring.

[0148] In some embodiments, R23 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0149] In some embodiments, R23 is

Chem.

[0150] In some embodiments, R23 is

Chem.

[0151] In some embodiments, R23 is of formula XVI, wherein X3 is N, X4 is O, R4 is H, R6 is H, X10 is C(H)(R7), R7 is H, and n is 1. In some embodiments, R23 is of formula XVI, wherein X3 is CH, X4 is O, R4 is H, R6 is H, X10 is C(H)(R7), R7 is H, and n is 1. In some embodiments, R23 is of formula XVI, wherein X3 is N, X4 is a bond, R4 is H, R6 is H, and n is 0.

[0152] In some embodiments, R23 is of formula XI:

Chem.

[0153] In some embodiments, R23 is of formula XIX:

Chem.

[0154] In some embodiments, R23 is of formula XII:

Chemical formula

[0155] In some embodiments, R26 is R5. In some embodiments, R26 is a 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or the C1-6 haloalkyl is optionally substituted with -OH, and the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl).

[0156] In some embodiments, R26 is of formula VII:

Chemical formula

[0157] In some embodiments, R23 is

Chemical formula

[0158] In some embodiments, R23 is of formula XIV:

Chemical formula

[0159] In some embodiments, R23 is of formula XVII:

Chemical formula

[0160] In some embodiments, v is 0. In some embodiments, v is 2. In some embodiments, v is 1. In some embodiments, X11 is C(R4). In some embodiments, R23 is of formula XVIII:

Chemical formula

[0161] In some embodiments, R23 is a three-membered ring, i.e., X3, (X13)v, X11, X4, X12, and (X10)n together form a three-membered ring. For example, in some embodiments, R23 is of formula XLVI, where n is 0, v is 0, and X4 is a bond. In some embodiments, R23 is of formula XLVI, where X3 is C(R8), X4 is a bond, n is 0, X11 is C(R4), X12 is C(R6)(R6b), and v is 0.

[0162] In some embodiments, X3 is C(H), X12 is C(H)2, X4 is a bond, X11 is C(H), n is 0, and v is 0. In some embodiments, R23 is of formula LXII:

Chemical formula

[0163] In some embodiments, R23 is of formula LXIIa or formula LXIIb:

Chemical formula

[0164] In some embodiments, R23 is

Chemical formula

[0165] In some embodiments, R29 is a bond, i.e., R29 is absent.

[0166] In some embodiments, R23 is of formula X:

Chemical formula

[0167] In some embodiments, R29 is C1-3 alkoxy. In some embodiments, R29 is -O-C1-3 alkyl. In some embodiments, R29 is -OCH2-, -CH2O-, -CH2-, or O.

[0168] In some embodiments, X11 is N. In some embodiments, X11 is C(R4). In some embodiments, X11 is C(H). In some embodiments, X11 is C(CH3).

[0169] In some embodiments, n is 0. In some embodiments, n is 1.

[0170] In some embodiments, v is 1. In some embodiments, v is 2.

[0171] In some embodiments, the compound is of formula LXI, wherein X1 is N, X2 is N, X14 is N, R1 is -CF3, R2 is C1-6 alkyl such as CH3, R3 is of formula IV:

Chemical formula

[0172] In some embodiments, R12 is a halogen, R13 is H, R14 is a halogen, and R15 is H. For example, R12 is F and R14 is Cl. In some embodiments, R23 is of formula XXXIV: [Chemical formula] wherein R6 is H, a halogen, or C1-3 alkyl, R6b is H, a halogen, or C1-3 alkyl, and R29 is a bond.

[0173] In some embodiments, R6 is H and R6b is H. In some embodiments, R5 is of formula XXII: [Chemical formula] wherein R20 is C1-3 alkyl or C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof. In some embodiments, R5 is of formula VII: [Chemical formula] wherein R20 is C1-3 alkyl or C3-6 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, R23 is [Chemical formula] as follows.

[0175] In some embodiments, the compound is of formula LXI, wherein X1 is N, X2 is N, X14 is N, R1 is -CH3, R2 is C1-6 alkyl such as CH3, R3 is of formula IV: [Chemical formula] which is of the formula, wherein R12 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R13 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R14 is H, halogen, C1-3 alkyl, -CN, or C1-3 haloalkyl, R15 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl.

[0176] In some embodiments, R12 is halogen, R13 is H, R14 is haloalkyl, and R15 is H. In some embodiments, R12 is F and R14 is CF3. In some embodiments, R23 is of the formula XXXIV: [Chemical formula] which is of the formula, wherein R6 is H, halogen, or C1-3 alkyl, R6b is H, halogen, or C1-3 alkyl, R29 is a bond; or a pharmaceutically acceptable salt thereof.

[0177] In some embodiments, R6 is H and R6b is H. In some embodiments, R5 is of the formula VIII: [Chemical formula] which is of the formula, wherein X7 is N or CH, X8 is N or C(R21), X9 is N or C(R22), R21 is C1-3 alkyl such as -CH3, R22 is C1-3 alkyl such as -CH3.

[0178] In some embodiments, R5 is

Chem.

Chem.

[0179] In one aspect, the present invention provides a compound of formula LXI:

Chem.

Chemical formula

[0180] In some embodiments, the compound is

Chemical formula

[0181] In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methylpyridin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methylpyridin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methylpyrimidin-5-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methylpyrimidin-5-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(6-methylpyridazin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(6-methylpyridazin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2R,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(2S,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-{6,6-difluorospiro[3.3]heptan-2-yl}-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-{6,6-difluorospiro[3.3]heptan-2-yl}-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2... -(1-Methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)pyridin-3-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)pyridin-3-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,3,4-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,3,4-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(3,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(3,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(3,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(3,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,4r)-4-methylcyclohexyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,4r)-4-methylcyclohexyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(oxan-4-yl)-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(oxan-4-yl)-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4,4-difluoropiperidin-1-yl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluoropiperidin-1-yl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-{3-[(1-methyl-1H-pyrazol-4-yl)oxy]azetidin-1-yl}-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3R)-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3S)-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1s,4s)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4r)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)methoxy)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimid[5,4-d]pyrimidin. It is 4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-(1-methyl-1H-pyrazol-4-yl)-4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(4-(2-methoxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyrimidin-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-3-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1H-pyrazol-4-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(4-methylthiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(3-methyl-1H-1,2,4-triazol-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1H-pyrazol-3-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl. It is pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(thiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-2-yl)-N-methylmorpholine-2-carboxamide or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-2-yl)-N,N-dimethylmorpholine-2-carboxamide or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2-(methoxymethyl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2-((dimethylamino)methyl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-oxa-9-azaspiro[4.5]decan-9-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-methyl-2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1,2,4-oxadiazol-3-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-(4-methoxybenzyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-chloro-4-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((R)-2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4R)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((S)-2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4S)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(6,6-difluorospiro[3.3]heptan-2-yl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-1,2,3-triazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-morpholinopiperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(3-(3-methoxyazetidin-1-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(3-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1H-imidazol-2-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-imidazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-((3-methylpyridin-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2,3-dihydrospiro[indene-1,2'-morpholin]-4'-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5,6,7,9-tetrahydro-8H-pyrido[3,. 4-c](azepin-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(piperidin-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro(3,5)nonan-8-yl)pyrimido(5,4-d)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,2-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)quinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro(2,5)octan-7-yl)pyrimido(5,4-d)pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-dimethylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. One implementation. In one form, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2,2-dimethylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((4S,6S)-2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((4R,6R)-2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)(R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-8(7H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]heptan-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((1S,2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]heptan-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((1R,2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]heptan-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol... (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(2-methylpyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(2-methylpyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,2-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,2-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharma- ceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-one. (R)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((1R,2S)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((1R,2R)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorop. 8-(2,4-difluorophenyl)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (trans-racemate), or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(6-(difluoromethyl)pyridin-3-yl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(6-(difluoromethyl)pyridin-3-yl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-6-(2,2-difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoro... It is methyl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (8-(2,4-difluorophenyl)-2,3-dimethyl-6-((2R,4S,6R)-2-methyl-6-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-3-methyl-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-3-methyl-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-3-methyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-3-methyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(2,4-difluorophenyl)-3-methyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 5-chloro-2-(6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 4-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.In one embodiment, the compound is 2-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-(trifluoromethyl)benzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is 2-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-(trifluoromethyl)benzonitrile, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (R)-8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is (S)-8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, or a pharmaceutically acceptable salt thereof.

[0182] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the accompanying movement of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonated states having the same empirical formula and total charge. Exemplary prototropic tautomers include keto-enol pairs, amide-imino acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in an equilibrium state or can be sterically fixed in one form by appropriate substitution. Tautomeric forms can also include methyltropic tautomers which result from the exchange of an adjacent double bond and the accompanying movement of a methyl group.

[0183] The compounds of the present invention also include all isotopes of atoms present in the intermediates or final compounds. Isotopes include atoms having the same atomic number but different mass numbers. In some embodiments, the compounds of the present invention include one or more isotopes of an atom in an amount exceeding the natural abundance of that isotope. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, the compounds of the present invention include at least one deuterium atom in an amount exceeding the natural abundance of deuterium (e.g., the compound is deuterium-enriched).

[0184] All compounds described herein, and their pharmaceutically acceptable salts, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates).

[0185] In one aspect, the present invention relates to intermediate compounds or pharmaceutically acceptable salts thereof that can be used in the synthesis of the compounds of the present invention. For example, in some embodiments, the intermediate compound is one of the intermediate compounds of any one of Examples 1 to 203 disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present invention is selected from any of the intermediate compounds disclosed in any one of Examples 1 to 203 herein, or a pharmaceutically acceptable salt thereof.

[0186] The compounds of the present invention may, for example, contain one or more asymmetric carbon atoms and thus may exist as stereoisomers, enantiomers, and diastereomers. Accordingly, the scope of the present invention includes all possible stereoisomers of the exemplified compounds, including stereochemically pure forms and mixtures of stereoisomers of any chemical structure disclosed herein, unless the stereochemical structure is specifically defined. If the stereochemical structure of a structure or a part of a structure is not specified, for example, by boldface or a broken line, the structure or the part of the structure should be interpreted as encompassing all its stereoisomers. If the stereochemical structure of a structure or a part of a structure is specified, for example, by boldface or a broken line, the structure or the part of the structure should be interpreted as encompassing only the specified stereoisomer.

[0187] As used herein, the term "stereoisomer" or "stereoisomerically pure" compound refers to one stereoisomer of a compound that substantially excludes other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will substantially exclude the mirror image enantiomer of that compound, and a stereoisomerically pure compound having two chiral centers will substantially exclude the other enantiomer and diastereomers of that compound. Typical stereoisomerically pure compounds contain greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.

[0188] In some embodiments, the compounds defined herein are stereoisomerically pure.

[0189] Mixtures of stereoisomers can be resolved, for example, using standard techniques such as chiral columns or chiral resolving agents, as outlined in the Examples section.

[0190] Pharmaceutical Compositions The present invention also relates to pharmaceutical compositions, for example, containing a pharmaceutically effective amount of a compound disclosed herein as an active ingredient. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient, and / or diluent.

[0191] The compounds disclosed herein for use in therapy may be administered in the form of the raw chemical compound, but it is often preferred to incorporate the active ingredient, optionally in the form of a pharmaceutically acceptable salt, into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other conventional pharmaceutical auxiliaries.

[0192] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic ingredients known and used in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to its recipient.

[0193] A therapeutic amount or therapeutically effective amount or dose refers to the amount of an active ingredient, i.e., a compound or composition disclosed herein, that treats, alleviates, reduces, or lessens the severity of symptoms of a disease in a subject, e.g., improves one or more symptoms of the condition or the condition itself. The therapeutic amount of the compounds described herein can improve the survival rate of a patient, increase the survival time or survival rate, attenuate symptoms, make the patient more tolerable to injury, disease, or condition (e.g., neurodegenerative disease), slow down the rate of degeneration or decline, or improve the physical or mental health of the patient.

[0194] Therapeutic efficacy and toxicity, e.g., ED50, can be determined by standard pharmacological procedures in cell culture or experimental animals. The dose ratio between the therapeutic effect and the toxic effect is the therapeutic index, which can be represented by the ratio between the plasma level that produces the therapeutic effect and the plasma ratio that produces the toxic effect. Pharmaceutical compositions with a large therapeutic index are preferred. In some embodiments, the therapeutically effective dose of the compounds disclosed herein ranges from about 0.01 mg / kg to about 100 mg / kg body weight / day.

[0195] The dose to be administered will, of course, be carefully adjusted in accordance with the age, weight, and condition of the individual being treated, as well as the route of administration, dosage form, and regimen, and the desired result, and the exact dosage will, of course, be determined by the attending physician.

[0196] Administering refers to a method of delivering a drug, compound, or composition to a desired biological site of action. These methods include, but are not limited to, enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

[0197] Biological activity As demonstrated in Example 204, the compounds of the present invention can modulate TREM2. Thus, in some embodiments, the compounds of the present invention are TREM2 modulators such as TREM2 agonists. The ability of a compound to act as an agonist of TREM2 may be evaluated and characterized using the assays described in Example 204. In some embodiments, the compounds of the present invention are useful for activating TREM2. In some embodiments, the compounds of the present invention activate TREM2. In some embodiments, the compounds of the present invention enhance the activity of TREM2. In some embodiments, the compounds of the present invention induce phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, including but not limited to Syk, ZAP70, PI3K, Erk, AKT, and GSK3b. In some embodiments, the compounds of the present invention enhance or activate TREM2 signaling via DAP12. In some embodiments, the compounds of the present invention enhance or activate the TREM2-induced phosphorylation level of the Syk kinase. In some embodiments, the compounds of the present invention induce or enhance Syk phosphorylation when the Syk phosphorylation level in a sample treated with the compound is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more compared to a control value, for example, at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to a control value.

[0198] In some embodiments, the potency of the compounds of the present invention is expressed as an EC50, which corresponds to the concentration of a compound capable of activating the AlphaScreen signal of phospho-Syk up to 50% of the maximum response. In some embodiments, the compounds of the present invention have an EC50 value of less than 1000 nM, such as an EC50 value of 100 nM to 1000 nM, such as an EC50 value of 10 nM to 100 nM, such as an EC50 value of 1 nM to 10 nM, such as an EC50 value < 1 nM.

[0199] In some embodiments, the compounds of the present invention are capable of increasing the expression of one or more genes regulated by TREM2. In some embodiments, the compounds of the present invention increase the expression of one or more genes regulated by TREM2. In some embodiments, the compounds of the present invention are capable of increasing one or more genes regulated by TREM2 selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119 (see Example 205). In some embodiments, the compounds of the present invention increase the expression level of one or more genes regulated by TREM2, such as the expression level in the brain, selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119.

[0200] In some embodiments, the compounds of the present invention increase the expression level, such as the expression level in the brain, when the expression level of the gene in the sample treated with the compound is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, or more compared to the control value, for example, increased by at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, or more compared to the control value (e.g., untreated control / vehicle).

[0201] Medical Use As a modulator of TREM2, the compounds of the present invention are useful for the treatment of diseases and disorders in living organisms including humans. As used herein, the term "treatment" includes the treatment, prevention, and / or alleviation or amelioration of one or more diseases and disorders, or one or more symptoms of a disease or disorder. In one aspect, the compounds described herein are for use as medicaments.

[0202] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of conditions associated with loss of function of TREM2. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of conditions associated with mutations in TREM2.

[0203] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of neurodegenerative diseases.

[0204] In some embodiments, the compounds described herein are used in the treatment of neurodegenerative diseases characterized by loss of function of TREM2. In some embodiments, the compounds described herein are used in the treatment of neurodegenerative diseases characterized by mutations in TREM2.

[0205] In one aspect, the present invention relates to a method for enhancing or increasing TREM2 activity in a subject in need thereof, such as a subject having a neurodegenerative disease, the method comprising administering to the subject a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0206] In one aspect, the present invention relates to a method for performing one or more of: i) enhancing or activating TREM2 signaling via DAP12; ii) inducing phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, including but not limited to Syk, ZAP70, PI3K, Erk, AKT, and GSK3b; iii) enhancing the TREM2-induced phosphorylation level of Syk kinase; iv) increasing the expression level of one or more genes regulated by TREM2, such as the expression level in the brain; and / or v) increasing the expression level of one or more genes regulated by TREM2 selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119, such as the expression level in the brain, in a subject in need thereof, for example, in a subject having a neurodegenerative disease, the method comprising administering to the subject a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the neurodegenerative disease is a tauopathy. Tauopathies represent several neurodegenerative disorders characterized by tau deposition in the brain, with cognitive impairment and parkinsonian features. In some embodiments, the neurodegenerative disease is a tauopathy selected from the group consisting of primary age-related tauopathy (PART), globular glial tauopathy, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy, corticobasal degeneration, diffuse neurofibrillary tangles with calcification (DNTC), frontotemporal dementia (FTD), and FTD-17 with parkinsonism (FTD linked to chromosome 17 with parkinsonism; FTDP-17).

[0208] In some embodiments, the neurodegenerative disease is a neurodegenerative disorder associated with TDP-43 (TDP-43 proteinopathy or TDP-43 opathy). Pathogenic deposits containing the TAR DNA-binding protein 43 (TDP-43) are clearly evident in the brains and spinal cords of patients and are presented across a wide variety of neurodegenerative diseases.

[0209] In some embodiments, the neurodegenerative disease is a TDP-43 proteinopathy selected from the group consisting of amyotrophic lateral sclerosis (ALS), sporadic amyotrophic lateral sclerosis (sALS), familial amyotrophic lateral sclerosis (fALS), frontotemporal lobe degeneration / disease (FTLD), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), FTLD-tau, FTLD-FUS (bvFTLD), FTLD-TDP-43, or FTLD-U (type a, type b, and type c), facial onset sensory and motor neuronopathy (FOSMN), limbic-predominant age-related TDP-43 encephalopathy (LATE), cerebral age-related TDP-43 with sclerosis (CARTS), Guam Parkinson-dementia complex (G-PDC) and ALS (G-ALS), Kii Peninsula ALS / PDC, Guam amyotrophic lateral sclerosis / Parkinsonism-dementia complex (ALS-PDC), multisystem proteinopathy (MSP; also known as juvenile Paget's disease of bone and inclusion body myositis associated with FTLD dementia (IBM)), Perry disease, and disorders coexisting with TDP-43 pathology including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE).

[0210] In some embodiments, the neurodegenerative disease is a multisystem proteinopathy (MSP). MSP is a human autosomal dominant multisystem degenerative disorder that can affect muscle, bone, and / or the central nervous system. MSP can present clinically as classical amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myositis (IBM), Paget's disease of bone (PDB), or combinations of these disorders (IBMPFD, IBMPFD / ALS).

[0211] In some embodiments, the neurodegenerative disease is a synucleinopathy.

[0212] Synucleinopathy (also known as alpha-synucleinopathy) is a neurodegenerative disease characterized by abnormal accumulation of aggregates of alpha-synuclein protein in neurons, neurofibrils, or glial cells.

[0213] In some embodiments, the neurodegenerative disease is a synucleinopathy selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), axonal dystrophy, and Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD / ALB).

[0214] In some embodiments, the neurodegenerative disease is cognitive impairment and / or memory loss. In some embodiments, the neurodegenerative disease is dementia. In some embodiments, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease dementia, Huntington's disease dementia, vascular dementia, HIV dementia, frontotemporal dementia, Lewy body dementia, prion disease dementia, argyrophilic grain dementia, boxer dementia, parkinsonism with dementia in Guadeloupe, neurofibrillary change predominant dementia, neurofibrillary change type dementia (tangle only dementia), Down syndrome, semantic dementia, familial British dementia, familial Danish dementia, and other dementias caused by other medical conditions such as brain tumors, subdural hematomas, endocrine disorders, nutritional deficiencies, infections, immune disorders, liver failure or kidney failure, metabolic disorders such as Kufs disease, some leukodystrophies, some neurological disorders such as epilepsy, and multiple sclerosis.

[0215] Disorders of the peripheral nerves (peripheral neuropathy) are the most common neurological complication of systemic amyloidosis. In some embodiments, the neurodegenerative disease is peripheral amyloidosis (peripheral neuropathy in systemic amyloidosis).

[0216] In some embodiments, the neurodegenerative disease is a demyelinating disorder. In some embodiments, the neurodegenerative disease is a demyelinating disorder of the central nervous system (CNS). In some embodiments, the demyelinating disorder is a demyelinating or myelin-destroying disorder selected from the group consisting of, for example, multiple sclerosis, neuromyelitis optica (Devic's disease), and idiopathic inflammatory demyelinating diseases. In some embodiments, the demyelinating disorder is a leukodystrophy or hypomyelination disorder selected from the group consisting of, for example, CNS neuropathies such as vitamin B12 deficiency, central pontine myelinolysis, myelopathies such as tabes dorsalis (syphilitic myelopathy), leukencephalopathy, and leukodystrophy.

[0217] In some embodiments, the neurodegenerative disease is a demyelinating disorder of the peripheral nervous system (PNS). In some embodiments, the demyelinating disorder is selected from the group consisting of Guillain-Barré syndrome and its chronic equivalent, chronic inflammatory demyelinating polyneuropathy; anti-MAG peripheral neuropathy; Charcot-Marie-Tooth disease and its equivalents, hereditary pressure-sensitive neuropathy; copper deficiency-related conditions (peripheral neuropathy, myelopathy, and rarely optic nerve neuropathy); and progressive inflammatory neuropathy.

[0218] In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD). In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD) with the R47H mutation. In some embodiments, the neurodegenerative disease is early Alzheimer's disease. In some embodiments, the neurodegenerative disease is frontotemporal lobar degeneration (FTLD). In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the neurodegenerative disease is Parkinson's disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease (NHD). In some embodiments, the neurodegenerative disease is an FTLD-like syndrome. In some embodiments, the neurodegenerative disease is Huntington's disease. In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is multiple sclerosis (MS). In some embodiments, the neurodegenerative disease is Guillain-Barré syndrome. In some embodiments, the neurodegenerative disease is chronic inflammatory demyelinating polyneuropathy. In some embodiments, the neurodegenerative disease is progressive subcortical gliosis. In some embodiments, the neurodegenerative disease is Charcot-Marie-Tooth disease. In some embodiments, the neurodegenerative disease is a prion disease such as prion protein cerebral amyloid angiopathy. In some embodiments, the neurodegenerative disease is stroke. In some embodiments, the neurodegenerative disease is cerebral amyloid angiopathy (CAA). In some embodiments, the neurodegenerative disease is fragile X-associated tremor / ataxia syndrome (FXTAS). In some embodiments, the neurodegenerative disease is herpes simplex virus (HSV) encephalitis. In some embodiments, the neurodegenerative disease is HIV-associated neurocognitive disorder (HAND). In some embodiments, the neurodegenerative disease is progressive supranuclear palsy (PSP). In some embodiments, the neurodegenerative disease is corticobasal degeneration. In some embodiments, the neurodegenerative disease is Hallervorden-Spatz disease. In some embodiments, the neurodegenerative disease is pallido-ponto-nigral degeneration. In some embodiments, the neurodegenerative disease is post-encephalitic parkinsonism. In some embodiments, the neurodegenerative disease is subacute sclerosing panencephalitis (SSPE).In some embodiments, the neurodegenerative disease is a retinal degeneration (e.g., macular degeneration).

[0219] In some embodiments, the neurodegenerative disease is a leukodystrophy.

[0220] Leukodystrophy (leukodystrophy-like disease) is a term used to describe all white matter diseases of the brain, whether their molecular causes are known or unknown. In some embodiments, the neurodegenerative disease is a leukodystrophy selected from the group consisting of progressive multifocal leukoencephalopathy, toxic leukoencephalopathy, leukodystrophy with vanishing white matter, leukodystrophy with diffuse axonal spheroids, reversible posterior leukoencephalopathy syndrome, megalencephalic leukoencephalopathy with subcortical cysts, and hypertensive leukoencephalopathy. In some embodiments, the neurodegenerative disease is ALSP (Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia).

[0221] In some embodiments, the neurodegenerative disease is selected from the group consisting of autosomal dominant cerebral arteriopathy with subcortical infarcts or leukoencephalopathy; autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy; and retinal vasculopathy with cerebral leukoencephalopathy (or cerebroretinal vasculopathy).

[0222] In some embodiments, the neurodegenerative disease is a leukodystrophy. In some embodiments, the neurodegenerative disease is vanishing white matter disease (VWM). Leukodystrophy is a group of rare genetic diseases that affect the white matter of the brain. In some embodiments, the neurodegenerative disease is a leukodystrophy selected from the group consisting of metachromatic leukodystrophy (MLD, also known as globoid cell leukodystrophy), Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, type 7 of megalencephalic leukodystrophy with subcortical cysts (4H syndrome), Pelizaeus-Merzbacher disease, cerebrotendinous xanthomatosis, and leukencephalopathy with vanishing white matter. In some embodiments, the neurodegenerative disease is adult-onset autosomal dominant leukodystrophy (ADLD). In some embodiments, the neurodegenerative disease is X-linked adrenoleukodystrophy (X-ALD). In some embodiments, the neurodegenerative disease is Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL)).

[0223] In some embodiments, the neurodegenerative disease is a transmissible spongiform encephalopathy (TSE) including Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease (GSS), kuru, and fatal familial insomnia.

[0224] In one aspect, the present invention relates to a method for treating a neurodegenerative disease, the method comprising administering to a subject in need thereof a compound described herein, or a pharmaceutically acceptable salt thereof.

[0225] In one aspect, the present invention relates to a method for treating a neurodegenerative disease, the method comprising one or more steps of administering to a subject in need thereof a therapeutically effective amount of a compound defined herein, or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the subject is a mammal such as a human.

[0227] In one aspect, the present invention relates to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of neurodegenerative diseases.

[0228] In one aspect, the present invention relates to a compound defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with dysfunction of colony stimulating factor 1 receptor (CSF1R, also known as macrophage colony stimulating factor receptor / M-CSFR, or cluster of differentiation 115 / CD115). In some embodiments, the disease or disorder associated with CSF1R dysfunction is a neurodegenerative disease associated with CSF1R dysfunction.

[0229] In some embodiments, the disease or disorder is caused by a heterozygous CSF1R mutation, a homozygous CSF1R mutation, a splice mutation in the csf1r gene, a missense mutation in the csf1r gene, a mutation in the catalytic kinase domain of CSF1R, a mutation in the immunoglobulin domain of CSF1R, a mutation in the extracellular domain of CSF1R, a loss-of-function mutation in CSF1R. In some embodiments, the disease or disorder results from a change (e.g., increase, decrease, or cessation) in the activity of CSF1R and / or a decrease or cessation in the activity of CSF1R.

[0230] In some embodiments, the neurodegenerative disease associated with CSF1R dysfunction is leukodystrophy.

[0231] In some embodiments, the neurodegenerative disease associated with CSF1R dysfunction is Adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP), CSF1R-related leukodystrophy, Hereditary diffuse leukodystrophy with axonal spheroids (HDLS), Pigmented orthochromatic leukodystrophy (POLD), Pediatric-onset leukodystrophy, Congenital deficiency of microglia, Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS), and Autosomal dominant cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) selected from the group consisting of

[0232] In some embodiments, the neurodegenerative disease is a condition associated with dysfunction of ATP-binding cassette transporter 1 (ABCD1).

[0233] In one aspect, the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of lysosomal storage diseases (LSDs). Most lysosomal storage diseases cause progressive neurodegeneration and lead to early death.

[0234] In some embodiments, the LSD is a lipoidosis selected from the group consisting of, for example, cholesteryl ester storage disease, fucosidosis, Schindler disease, and Wolman disease.

[0235] In some embodiments, the LSD is a sphingolipidosis selected from the group consisting of, for example, Fabry disease, Gaucher disease, Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (types A, B, and C), Sandhoff disease, Farber disease, multiple sulfatase deficiency, and Tay-Sachs disease.

[0236] In some embodiments, the LSD is a mucopolysaccharidosis selected from the group consisting of, for example, Hunter syndrome, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome, and Natowicz syndrome.

[0237] In some embodiments, the LSD is selected from the group consisting of Batten disease, cystinosis, Danon disease, and Pompe disease.

[0238] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder of bone and / or joint. In some embodiments, the disease or disorder is selected from the group consisting of arthritis, rheumatoid arthritis, Paget's disease, osteoporosis, marble bone disease, osteopetrosis, skeletal dysplasia, and heterotopic ossification.

[0239] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of autism spectrum disorder, autism, and Asperger's syndrome.

[0240] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of traumatic brain injury (TBI) and spinal cord injury. Traumatic brain injury (TBI) may also be known as intracranial injury. Traumatic brain injury occurs when the brain is traumatically injured by an external force. Spinal cord injury (SCI) includes any injury to the spinal cord caused by trauma instead of a disease. In some embodiments, the TBI is chronic traumatic encephalopathy (CTE).

[0241] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of muscular dystrophies such as myotonic dystrophy (DM) (including type 1 DM (DM1) and type 2 DM (DM2)).

[0242] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammation. In some embodiments, the inflammation is selected from the group consisting of inclusion body myositis, systemic lupus erythematosus (SLE), RA, gout, and certain intestinal diseases including inflammatory bowel disease (IBD).

[0243] A decrease in functional TREM2 levels results in dysregulation of lipid metabolism. In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of dysregulation of lipid metabolism. In certain embodiments, the dysregulation of lipid metabolism includes an increase in the intracellular and / or extracellular accumulation of one or more lipids. In some embodiments, the dysregulation of lipid metabolism is atherosclerosis.

[0244] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of metabolic syndrome, and conditions associated with metabolic syndrome, such as obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver, and alcoholic and non-alcoholic steatohepatitis.

[0245] In one aspect, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of amyloidosis, including AL amyloidosis (immunoglobulin light chain amyloidosis), AA amyloidosis (secondary amyloidosis), familial amyloidosis, familial systemic amyloidosis, wild-type amyloidosis (senile systemic amyloidosis), and localized amyloidosis.

[0246] In some embodiments, the neurodegenerative disease is Alzheimer's disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease. In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the method includes administering to the subject a compound described herein, or a pharmaceutical composition comprising a compound described herein.

[0247] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures shown, unless otherwise specified. Accordingly, it should be understood that the methods and uses herein encompass methods and uses with all such forms.

[0248] Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated." In some embodiments, the provided combination, or composition thereof, is administered in combination with another therapeutic agent. In some embodiments, the present invention provides a method of treating a disclosed disease or condition, the method comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents. In some embodiments, the method comprises co-administering one or more additional therapeutic agents. Examples of therapeutic agents with which the combinations of the present invention may be further combined include, but are not limited to, therapeutic agents for Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Niemann-Pick disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke. In some embodiments, therapeutic agents with which the combinations of the present invention may be further combined include, but are not limited to, therapeutic agents for diseases selected from the group consisting of tauopathy, TDP-43 proteinopathy, synucleinopathy, dementia, amyloidosis, CNS demyelinating disorders, PNS demyelinating disorders, leukodystrophy, leukodystrophy, transmissible spongiform encephalopathy (TSE), and lysosomal storage disease (LSD). As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combinations of the present invention may be administered together, simultaneously or sequentially, with another therapeutic agent in separate unit dosage forms or in a single unit dosage form.

[0249] Manufacturing method Generally, the compounds of formula LXI described herein may be synthesized according to the following scheme.

[0250] All starting materials are either commercially available or known in the art and may be synthesized by using known procedures. The starting materials may also be synthesized by using the procedures disclosed herein. The reaction conditions such as reaction temperature, solvent, and reagents for the scheme in this section can be found in the experimental section of this specification.

[0251]

Chemical formula

[0252] In one aspect, the present invention relates to a method for manufacturing a compound of formula IX described herein, the method comprising (a) Reacting a compound of formula (R1CO)2O with 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid to produce a compound of formula A1;

Chem.

Chem.

Chem.

Chem.

[0253]

Chem.

[0254] In one aspect, the present invention relates to a method for producing a compound of formula B6, the method comprising (a) reacting R1COCl with a compound of formula B1 to form a compound of formula B2;

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0255] Alternatively, as shown in Scheme 3, the amino-amide substituted aryl starting material can be cyclized in the presence of an orthoacetic acid ester reagent (e.g., R1C(OEt)3). X and Y are Cl or Br leaving groups and can be the same or different from each other. For example, an R3 substituent is added via a cross-coupling reaction (wherein W is a boronic acid, boronic acid ester, or other organometallic coupling reagent such as an organomagnesium, organotin, or organozinc reagent). R3 can also be introduced via nucleophilic substitution of the X leaving group. Subsequently, the R23 substituent can then be introduced via either a second cross-coupling reaction or a second nucleophilic substitution reaction of the Y leaving group.

Chemical formula

[0256] In one aspect, the present invention relates to a method for producing a compound of formula C4, the method comprising (a) reacting a compound of formula C1 with an orthoacetic acid ester reagent (e.g., R1C(OEt)3) to form a compound of formula C2;

Chemical formula

Chemical formula

[0257] In a further alternative approach, as shown in Scheme 4, the R23 substituent may be introduced via either a cross-coupling reaction or a nucleophilic substitution reaction of a Y leaving group. The R3 substituent is then added via a second cross-coupling reaction (where W is a boronic acid, boronic ester, or other organometallic coupling reagent such as an organomagnesium, organotin, or organozinc reagent). R3 may also be introduced via a second nucleophilic substitution of an X leaving group. Subsequent reduction, hydrolysis, treatment with anhydride (R1CO)2O, and then cyclization with R2NH2 can provide the desired compound. [Chemical formula]

[0258] In one aspect, the present invention relates to a method for producing a compound of formula D6, the method comprising: (a) reacting a compound of formula D1 with R23W2 (where W2 is B(OH)2, OH, or NH) to produce a compound of formula D2; [Chemical formula] (b) reacting a compound of formula D2 with R3W1 (where W1 is B(OH)2, OH, or NH) to produce a compound of formula D3; [Chemical formula] (c) reducing and hydrolyzing a compound of formula D3 to produce a compound of formula D4; [Chemical formula] (d) Reacting the compound of formula D4 with (R1CO)2O to produce a compound of formula D5;

Chemical formula

Chemical formula

[0259] As shown in Scheme 5, following the metal-catalyzed coupling of alkyne R1CCH with a halo-substituted heterocyclic substituent, hydrolysis and cyclization of the ester can be carried out. Further treatment with amine R2NH2 and deprotection of the R group can afford pyrido[3,4-d]pyrimidine-2,4,8-trione. For example, activation with POCl3 or POBr3 gives 2,4-dihalo-pyrido[3,4-d]pyrimidin-8-one (wherein X is a Cl or Br leaving group). For example, an R3 substituent is added via a cross-coupling reaction (wherein W is a boronic acid, boronic acid ester, or other organometallic coupling reagent such as an organomagnesium, organotin, or organozinc reagent). R3 may also be introduced via nucleophilic substitution of an X leaving group. Subsequently, the R23 substituent may be introduced via either a second cross-coupling reaction or a second nucleophilic substitution reaction.

Chemical formula

[0260] In one aspect, the present invention relates to a method for producing a compound of formula E7, the method comprising: (a) Reacting a compound of formula E1 with R1CCH to produce a compound of formula E2;

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Table 1

[0261] Certain compounds of the examples were obtained as mixtures of stereoisomers and were then separated by chiral preparative HPLC. As noted in some of the examples, the assignment of the stereochemical structure is arbitrary. Thus, in the examples, the compounds obtained after chiral preparative HPLC are annotated based on order. For example, in Example 19, two stereoisomers are obtained. These are annotated as "19A", which is peak 1, and "19B", which is peak 2. The structures are arbitrarily assigned as (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one for 19A and (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one for 19B. This is noted in Example 19 as "absolute stereochemical structure is unknown". However, since the assignment of the stereochemical structure is arbitrary ("absolute stereochemical structure is unknown"), it is possible that the stereochemical structure is the opposite, i.e., for example, 19A is (S)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one and 19B is (R)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one. Importantly, the numbering (e.g., 19A for peak 1 in Example 19) is maintained in the biological evaluation.

[0262] LCMS conditions: Condition A LCMS column - Acquity BEH C18 (50×2.1 mm, 1.7 u), initially (held 90% [0.05% aqueous HCOOH solution] and 10% [0.05% HCOOH in CH3CN: water (90:10)] for 0.75 min, then to 50% [0.05% aqueous HCOOH solution] and 50% [0.05% HCOOH in CH3CN: water (90:10)] by 1.00 min, then to 2% [0.05% aqueous HCOOH solution] and 98% [0.05% HCOOH in CH3CN: water (90:10)] by 2.00 min, held this mobile phase composition for 2.25 min, and finally returned to the initial conditions by 2.60 min and held for 3.00 min). Flow rate: 0.60 ml / min.

[0263] Condition B LCMS column - YMC Triart C18 (33×2.1 mm, 3 u), initially (held 98% [0.05% aqueous HCOOH solution] and 2% [0.05% HCOOH in CH3CN: water (90:10)] for 0.75 min, then to 90% [0.05% aqueous HCOOH solution] and 10% [0.05% HCOOH in CH3CN: water (90:10)] by 1.00 min, then to 2% [0.05% aqueous HCOOH solution] and 98% [0.05% HCOOH in CH3CN: water (90:10)] by 2.00 min, held this mobile phase composition for 2.25 min, and finally returned to the initial conditions by 2.90 min and held for 3.00 min). Flow rate: 1.00 ml / min.

[0264] Condition C LCMS column - Acquity BEH C18 (50×2.1 mm, 1.7 u), initially (held 95% [0.05% aqueous HCOOH solution] and 5% [0.05% HCOOH in CH3CN: water (90:10)] for 0.75 min, then to 75% [0.05% aqueous HCOOH solution] and 25% [0.05% HCOOH in CH3CN: water (90:10)] by 1.50 min, then to 5% [0.05% aqueous HCOOH solution] and 95% [0.05% HCOOH in CH3CN: water (90:10)] by 3.00 min, held this mobile phase composition for 4.00 min, and finally returned to the initial conditions by 4.50 min and held for 5.10 min). Flow rate: 0.80 ml / min.

[0265] Condition D LCMS column - YMC Triart C18 (33×2.1 mm, 3u), initially hold (95% [aqueous solution of 0.05% HCOOH] and 5% [0.05% HCOOH in CH3CN: water (90:10)]) for 0.75 minutes, then change to 50% [aqueous solution of 0.05% HCOOH] and 50% [0.05% HCOOH in CH3CN: water (90:10)] by 1.20 minutes, then change to 2% [aqueous solution of 0.05% HCOOH] and 98% [0.05% HCOOH in CH3CN: water (90:10)] by 2.00 minutes, hold this mobile phase composition for 2.25 minutes, finally return to the initial conditions by 2.60 minutes and hold for 3.00 minutes). Flow rate: 0.60 ml / min.

[0266] Condition E Column - YMC TRIART C18 (33×2.1 mm, 3u), (mobile phase: hold 98% [aqueous solution of 0.05% HCOOH] and 2% [CH3CN] for 0.75 minutes, then change to 90% [aqueous solution of 0.05% HCOOH] and 10% [CH3CN] by 1.0 minute, then further change to 2% [aqueous solution of 0.05% HCOOH] and 98% [CH3CN] by 2.0 minutes, hold this mobile phase composition for 2.25 minutes, finally return to the initial conditions by 3.0 minutes). Flow rate = 1.5 ml / min

[0267] Condition F Column - Acquity BEH C18 (2.1×50 mm, 1.7u) (mobile phase: hold 90% [aqueous solution of 0.05% HCOOH] and 10% [0.05% HCOOH in CH3CN: water (90:10)]) for 0.75 minutes, then change to 50% [aqueous solution of 0.05% HCOOH] and 50% [0.05% HCOOH in CH3CN: water (90:10)] by 1.0 minute, then further change to 2% [aqueous solution of 0.05% HCOOH] and 98% [0.05% HCOOH in CH3CN: water (90:10)] by 2.0 minutes, hold this mobile phase composition for 2.25 minutes, finally return to the initial conditions by 2.60 minutes and hold this composition for 3.00 minutes). Flow rate = 0.60 ml / min

[0268] Condition G Column - Xbridge C18 (4.6×50 mm, 5u), mobile phase: from 90% [10 mM ammonium acetate aqueous solution] and 10% [CH3CN] to 70% [10 mM ammonium acetate aqueous solution] and 30% [CH3CN] in 1.5 minutes, then to 10% [10 mM ammonium acetate aqueous solution] and 90% [CH3CN] in 3.00 minutes, hold this mobile phase composition for 4.00 minutes, and finally return to the initial conditions in 5.00 minutes. Flow rate = 1.20 ml / min

[0269] Condition H Column - Acquity BEH C8 (2.1×50 mm, 1.7u) (mobile phase: hold 95% [0.05% HCOOH aqueous solution] and 5% [0.05% HCOOH in CH3CN: water (90:10)] for 0.75 minutes, then to 75% [0.05% HCOOH aqueous solution] and 25% [0.05% HCOOH in CH3CN: water (90:10)] in 1.5 minutes, then to 5% [0.05% HCOOH aqueous solution] and 95% [0.05% HCOOH in CH3CN: water (90:10)] in 3.00 minutes, hold this mobile phase composition for 4.00 minutes, finally return to the initial conditions in 4.50 minutes, and hold this composition for 5.10 minutes). Flow rate = 0.80 ml / min

[0270] Condition I Column - Acquity BEH C8 (2.1×50 mm, 1.7u) (mobile phase: hold 90% [0.05% HCOOH aqueous solution] and 10% [0.05% HCOOH in CH3CN: water (90:10)] for 0.75 minutes, then to 50% [0.05% HCOOH aqueous solution] and 50% [0.05% HCOOH in CH3CN: water (90:10)] in 1.0 minute, then to 2% [0.05% HCOOH aqueous solution] and 98% [0.05% HCOOH in CH3CN: water (90:10)] in 2.0 minutes, hold this mobile phase composition for 2.25 minutes, finally return to the initial conditions in 2.60 minutes, and hold this composition for 3.00 minutes). Flow rate = 0.80 ml / min

[0271] Condition J LCMS column - Acquity BEH C8 (50×2.1 mm, 1.7 u), initially (held 90% [0.05% aqueous HCOOH solution] and 10% [0.05% HCOOH in CH3CN: water (90:10)] for 0.75 min, then changed to 50% [0.05% aqueous HCOOH solution] and 50% [0.05% HCOOH in CH3CN: water (90:10)] by 1.00 min, then changed to 2% [0.05% aqueous HCOOH solution] and 98% [0.05% HCOOH in CH3CN: water (90:10)] by 2.00 min, held this mobile phase composition until 2.25 min, and finally returned to the initial conditions by 2.60 min and held until 3.00 min). Flow rate: 0.80 ml / min.

[0272] Condition K LCMS column - Acquity BEH C8 (50×2.1 mm, 1.7 u), initially (held 95% [0.05% aqueous HCOOH solution] and 5% [0.05% HCOOH in CH3CN: water (90:10)] for 0.75 min, then changed to 75% [0.05% aqueous HCOOH solution] and 25% [0.05% HCOOH in CH3CN: water (90:10)] by 1.50 min, then changed to 5% [0.05% aqueous HCOOH solution] and 95% [0.05% HCOOH in CH3CN: water (90:10)] by 3.00 min, held this mobile phase composition until 4.00 min, and finally returned to the initial conditions by 4.50 min and held until 5.10 min). Flow rate: 0.80 ml / min.

[0273] Condition L LCMS column - YMC Triart C18 column (3 μm, 33×2.1 mm), initially (held 95% [0.05% aqueous HCOOH solution] and 5% [0.05% HCOOH in CH3CN: water (90:10)] for 0.75 min, then changed to 70% [0.05% aqueous HCOOH solution] and 30% [0.05% HCOOH in CH3CN: water (90:10)] by 1.00 min, then changed to 2% [0.05% aqueous HCOOH solution] and 98% [0.05% HCOOH in CH3CN: water (90:10)] by 2.00 min, held this mobile phase composition until 2.25 min, and finally returned to the initial conditions by 2.50 min and held until 3.00 min). Flow rate: 1.00 ml / min.

[0274] Condition M LCMS column - Acquity BEH C8 (50×2.1 mm, 1.7 u), initially held at (90% [aqueous solution of 0.05% HCOOH] and 10% [0.05% HCOOH in CH3CN: water (90:10)]) for 0.75 min, then changed to 50% [aqueous solution of 0.05% HCOOH] and 50% [0.05% HCOOH in CH3CN: water (90:10)] by 1.00 min, then changed to 2% [aqueous solution of 0.05% HCOOH] and 98% [0.05% HCOOH in CH3CN: water (90:10)] by 2.00 min, the composition of this mobile phase was held for 2.25 min, and finally returned to the initial conditions by 2.60 min and held for 3.00 min). Flow rate: 0.60 ml / min.

[0275] Condition N Column - Xbridge C18 (50×4.6 mm, 5 u), (mobile phase: from 90% [aqueous solution of 10 mM NH4OAc] and 10% [CH3CN], changed to 70% [aqueous solution of 10 mM NH4OAc] and 30% [CH3CN] by 1.5 min, further changed to 10% [aqueous solution of 10 mM NH4OAc] and 90% [CH3CN] by 3.0 min, the composition of this mobile phase was held for 4.0 min, and finally returned to the initial conditions by 5.0 min). Flow rate = 1.20 ml / min

[0276] Condition O Column - YMC Triart C18 (33×2.1 mm, 3 u), (initially held at 98% [aqueous solution of 0.05% HCOOH] and 2% [0.05% HCOOH in ACN: water (90:10)] for 0.75 min, then changed to 90% [aqueous solution of 0.05% HCOOH] and 10% [0.05% HCOOH in ACN: water (90:10)] by 1.0 min, further changed to 2% [aqueous solution of 0.05% HCOOH] and 98% [0.05% HCOOH in ACN: water (90:10)] by 2.00 min, the composition of this mobile phase was held for 2.50 min, and finally returned to the initial conditions by 4.90 min and this composition was held for 3.0 min). Flow rate: 1.0 ml / min.

[0277] Condition P Column - Xbridge C18 column (3.5 μm, 50×3 mm), (initially hold 95% [5 mM NH4OAc aqueous solution] and 5% [5 mM NH4OAc in ACN: water (90:10)] for 0.75 minutes, then change to 70% [5 mM NH4OAc aqueous solution] and 30% [5 mM NH4OAc in ACN: water (90:10)] by 1.00 minute, and finally change to 2% [5 mM NH4OAc aqueous solution] and 98% [5 mM NH4OAc in ACN: water (90:10)] by 2.00 minutes, hold this mobile phase composition for 2.50 minutes, and finally return to the initial conditions by 2.75 minutes and hold this composition for 3.0 minutes). Flow rate: 1.20 ml / min.

[0278] Condition Q LCMS column - Xbridge C18 column (5 μm, 100×4.6 mm), initially hold 95% [10 mM NH4OAc aqueous solution] and 5% [ACN] for 1.50 minutes, then change to 60% [10 mM NH4OAc aqueous solution] and 40% [ACN] by 5.00 minutes, further change to 5% [10 mM NH4OAc aqueous solution] and 95% [ACN] by 2.50 minutes, and finally change to 2% [10 mM NH4OAc aqueous solution] and 98% ACN by 9.50 minutes, hold this mobile phase composition for 12.50 minutes, and finally return to the initial conditions by 14.00 minutes and hold this composition for 15.00 minutes. Flow rate: 1.00 ml / min.

[0279] Condition R Column - Gemini NX C18 (4.6×100 mm, 3u), mobile phase: hold 98% [10 mM ammonium acetate aqueous solution] and 2% [ACN] for 0.50 minutes, then change to 50% [10 mM ammonium acetate aqueous solution] and 50% [ACN] by 6.50 minutes, further change to 5% [10 mM ammonium acetate aqueous solution] and 95% [ACN] by 9.50 minutes, hold this mobile phase composition for 13.00 minutes, and finally return to the initial conditions by 14.00 minutes and hold this composition for 15.00 minutes. Flow rate = 1.00 ml / min

[0280] Example 1 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one Example 1A: Enantiomer peak 1, Example 1B: Enantiomer peak 2 Step 1 - Preparation of 2-methyl-4H-pyrimido[5,4-d][1,3]oxazine-4,6,8(5H,7H)-trione

Chemical formula

[0281] Step 2 - Preparation of 6,7-dimethyl-1,7-dihydropyrimido[5,4-d]pyrimidine-2,4,8(3H)-trione

Chemical formula

[0282] Step 3 - Preparation of 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one

Chemical formula

[0283] Step 4 - Preparation of 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one

Chemical Structure

[0284] Step 5 - Preparation of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one

Chemical Structure

[0285] Preparative HPLC was performed using a Waters automated purification instrument. Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate, B = acetonitrile; gradient profile: the initial composition of the mobile phase was 60% A and 40% B, then to 40% A and 60% B over 3 minutes, then to 20% A and 80% B over 20 minutes, then to 5% A and 95% B over 21 minutes, and this composition was held for 22 minutes for column washing, then returned to the initial composition over 23 minutes and held for 25 minutes. 1H NMR (400 MHz, DMSO D6) δ 7.74 (1 H, s) 7.68-7.64 (1 H, m) 7.61-7.59 (1 H, m), 7.45-7.44 (2 H, m), 4.63-4.60 (1 H, m), 4.52-4.49 (2 H, m), 4.01-3.99 (1 H, m), 3.81 (3 H, s), 3.66-3.63 (1 H, m), 3.51 (3 H, s), 3.18-3.12 (2 H, m), 2.44 (3 H, s). LCMS condition C: Rt = 2.86 minutes. m / z 470.27 [M+H]+.

[0286] Preparation of (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one [Example 1A] and (S)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one [Example 1B]

Chemical formula

[0287] Details of the chiral preparative HPLC method for separating enantiomers: Equipment: Agilent 1200 series equipment / Column: CHIRALPAK IC (250×21 mm) 5u / Flow rate: 21.0 ml / min / Mobile phase: hexane / dichloromethane / ethanol: 65 / 17.5 / 17.5 / Solvent: mixture of acetonitrile and dichloromethane / Wavelength: 295 nm / Run time: 36 minutes Example 1A (Peak 1): HNMR: 1H NMR (400 MHz, DMSO D6) δ 7.74 (1 H, s) 7.67 (1 H, t, J = 7.96 Hz) 7.62 - 7.59 (1 H, m), 7.46 - 7.44 (2 H, m), 4.62 (1 H, br d, J = 13.08 Hz), 4.52 - 4.59 (2 H, m), 4.01 - 3.99 (1 H, m), 3.81 (3 H, s), 3.66 - 3.65 (1 H, m), 3.51 (3 H, s), 3.18 - 3.12 (2 H, m), 2.44 (3 H, s). LCMS condition D: Rt = 1.87 min. m / z 470 [M+H]+. Example 1B (Peak 2) HNMR: 1H NMR (400 MHz, DMSO D6) δ 7.74 (1 H, s) 7.67 (1 H, t, J = 7.96 Hz) 7.62 - 7.59 (1 H, m), 7.45 - 7.44 (2 H, m), 4.62 (1 H, br d, J = 13.08 Hz), 4.52 - 4.59 (2 H, m), 4.01 - 3.99 (1 H, m), 3.81 (3 H, s), 3.66 - 3.65 (1 H, m), 3.51 (3 H, s), 3.18 - 3.12 (2 H, m), 2.44 (3 H, s). LCMS condition D: Rt = 3.03 min, m / z 470.3 [M+H]+. Analytical chiral HPLS: Chiralpak IC (4.6×250mm), 5μ, mobile phase: hexane / DCM / EtOH / IP amine: 60 / 20 / 20 / 0.1, flow rate: 1.0 ml / min. Solvent: MeOH, Rt = 12.62 min (for Peak 1) and Rt = 14.95 min (for Peak 2).

[0288] Example 2 8-(4-chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one Preparation of 1-Benzyl-4-bromo-1H-pyrazole

Chemical formula

[0289] Preparation of 1-Benzyl-4-(1-ethoxyvinyl)-1H-pyrazole

Chemical formula

[0290] Step 3 - Preparation of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one

Chemical formula

[0291] Preparation of 2-(Benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-one

Chem.

[0292] Preparation of 2-(Benzyl(2-hydroxyethyl)amino)-1-(1-benzyl-1H-pyrazol-4-yl)ethan-1-ol

Chem.

[0293] Step 6 - Preparation of the HCl salt of 4-benzyl-2-(1-benzyl-1H-pyrazol-4-yl)morpholine

Chemical formula

[0294] Step 7 - Preparation of 2-(1H-pyrazol-4-yl)morpholine

Chemical formula

[0295] Preparation of tert-Butyl 2-(1H-Pyrazol-4-yl)morpholine-4-carboxylate

Chemical Structure

[0296] Preparation of tert-butyl 2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholine-4-carboxylate

Chemical formula

[0297] Preparation of (1-Cyclopropyl-1H-pyrazol-4-yl)morpholine

Chem.

[0298] Preparation of 8-(4-Chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one

Chem.

[0299] Fractional HPLC was performed using a Waters automatic purification instrument. Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; gradient profile: the initial composition of the mobile phase was 40% A and 60% B, then to 20% A and 80% B by 20 minutes, then to 5% A and 95% B by 21 minutes, and this composition was held for 22 minutes for column washing, then returned to the initial composition by 23 minutes and held for 25 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1 H), 7.66 - 7.59 (m, 2 H), 7.45 - 7.44 (m, 2 H), 4.61 (d, J = 13.3 Hz, 1 H), 4.50 - 4.47 (m, 2 H), 4.00 (d, J = 11.4 Hz, 1 H), 3.69 - 3.67 (m, 2 H), 3.50 (s, 3 H), 3.18 - 3.13 (m, 2 H), 2.44 (s, 3 H), 1.02 - 1.00 (m, 2 H), 0.94 - 0.92 (m, 2 H). LCMS condition H: Rt = 2.94 minutes. m / z 496.32 [M+H]+.

[0300] Example 3 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one Step 1: Preparation of tert-butyl 2-(2-methylpyridin-4-yl)morpholine-4-carboxylate [Chemical formula] To a stirred solution of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (600 mg, 2.59 mmol) and 4-bromo-2-methylpyridine (444.15 mg, 2.59 mmol) in DMF (30 mL), cesium carbonate (2.5 g, 7.79 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridyl (104.42 mg, 0.39 mmol) were added and the mixture was degassed with argon. Nickel(II) chloride ethylene glycol dimethyl ether complex (57.07 mg, 0.26 mmol) and 4,4-bis(tert-butyl)-2,2-bipyridine]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl]phenyl]iridium(III) hexafluorophosphate (29.12 mg, 0.03 mmol) were added to the reaction product under an inert atmosphere. Using an integrated photoreactor, the resulting mixture was irradiated with 450 nm LED light for 72 h. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by combiflash chromatography (50-60% ethyl acetate in hexane) to afford tert-butyl 2-(2-methylpyridin-4-yl)morpholine-4-carboxylate (90 mg, yield 12.4%) as a gum. 1H NMR (400 MHz, DMSO) δ 8.39 (d, J = 22.2 Hz, 1 H), 7.25 (s, 1 H), 7.17-7.11 (m, 1 H), 4.38-4.23 (m, 1 H), 3.96-3.56 (m, 4 H), 2.50 (s, 3 H), 2.46-2.39 (m. 2 H), 1.42 (s, 9 H). LCMS condition E: Rt = 1.65 min. m / z 279.3 [M+H] +.

[0301] Step 2: Preparation of 2-(2-methylpyridin-4-yl)morpholine

Chemical Structure

[0302] Step 3: Preparation of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one [Chemical formula] To a stirred solution of 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (80 mg, 0.24 mmol) and 2-(2-methylpyridin-4-yl)morpholine (46.34 mg, 0.26 mmol, HCl salt) in DMSO (2 mL) was added DIPEA (0.21 mL, 1.18 mmol). The resulting mixture was heated at 100 °C for 16 hours. The reaction mixture was purified by reverse-phase preparative HPLC to afford 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one (75 mg, yield 65.8%) as a yellow solid.

[0303] Fractional HPLC was performed using a Waters automatic purification instrument. Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; gradient profile: the initial composition of the mobile phase was 70% A and 30% B, then to 40% A and 60% B in 3 minutes, then to 30% A and 70% B in 20 minutes, then to 5% A and 95% B in 21 minutes, and this composition was held for 22 minutes for column washing, then returned to the initial composition in 23 minutes and held for 25 minutes. 1H NMR (400 MHz, DMSO) δ 8.44 (d, J = 4.9 Hz, 1 H), 7.68 (t, J = 7.9 Hz, 1 H), 7.61 (d, J = 8.7 Hz, 1 H), 7.46 (d, J = 8.1 Hz, 1 H), 7.30 (s, 1 H), 7.23 (d, J = 4.6 Hz, 1 H), 4.70 (d, J = 13.0 Hz, 1 H), 4.68 - 4.57 (m, 2 H), 4.15 - 4.09 (m, 1 H), 3.76 - 3.71 (m, 1 H), 3.51 (s, 3 H), 3.23 - 3.18 (m, 1 H), 3.00 - 2.94 (m, 1 H), 2.49 (s, 3 H), 2.44 (s, 3 H). LCMS condition H: Rt = 1.65 minutes. m / z 279.3 [M+H]+.

[0304] Examples 4 - 10

Chemical formula

[0305] Condition B: A stirred solution of 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (1 mmol) and the corresponding boronic acid (0.9 mmol) in dioxane (6 mL) and water (2 mL) was added with sodium carbonate (1.5 mmol) and degassed with argon. PdCl2(dppf) (0.1 mmol) was added under an inert atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate, filtered through a short pad of celite, and washed with ethyl acetate. The combined organic phase portions were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (20 - 40% ethyl acetate - hexane) to give the corresponding desired product 3g.

[0306] Preparative HPLC method (using Waters automatic purification equipment): Example 4: Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; gradient profile: The initial composition of the mobile phase is 70% A and 30% B, then to 45% A and 55% B in 3 minutes, then to 20% A and 80% B in 20 minutes, then to 5% A and 95% B in 21 minutes, and this composition is held for 22 minutes for column washing, then returned to the initial composition in 23 minutes and held for 25 minutes.

[0307] Example 5: Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; gradient profile: The initial composition of the mobile phase is 70% A and 30% B, then to 50% A and 50% B in 3 minutes, then to 30% A and 70% B in 20 minutes, then to 5% A and 95% B in 21 minutes, and this composition is held for 22 minutes for column washing, then returned to the initial composition in 23 minutes and held for 25 minutes.

[0308] Example 6: Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; gradient profile: The initial composition of the mobile phase is 60% A and 40% B, then to 45% A and 55% B in 3 minutes, then to 20% A and 80% B in 20 minutes, then to 5% A and 95% B in 21 minutes, and this composition is held for 22 minutes for column washing, then returned to the initial composition in 23 minutes and held for 25 minutes.

[0309] Example 7: Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; Gradient profile: The initial composition of the mobile phase was 60% A and 40% B, then to 50% A and 50% B in 3 minutes, then to 25% A and 75% B in 20 minutes, then to 5% A and 95% B in 21 minutes, and this composition was held for 22 minutes for column washing, then returned to the initial composition by 23 minutes and held until 25 minutes.

[0310] Example 8: Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; Gradient profile: The initial composition of the mobile phase was 50% A and 50% B, then to 40% A and 60% B in 20 minutes, then to 5% A and 95% B in 21 minutes, and this composition was held for 22 minutes for column washing, then returned to the initial composition by 23 minutes and held until 25 minutes.

[0311] Example 9: Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; Gradient profile: The initial composition of the mobile phase was 50% A and 50% B, then to 20% A and 80% B in 20 minutes, then to 5% A and 95% B in 21 minutes, and this composition was held for 22 minutes for column washing, then returned to the initial composition by 23 minutes and held until 25 minutes.

[0312] Example 10: Column name: YMC-Actus C18 (250×20 mm, 5 μm), operated at ambient temperature, flow rate 16 mL / min. Mobile phase: A = 20 mM aqueous ammonium bicarbonate solution, B = acetonitrile; gradient profile: the initial composition of the mobile phase is 60% A and 40% B, then to 50% A and 50% B by 3 minutes, then to 30% A and 70% B by 20 minutes, then to 5% A and 95% B by 21 minutes, and this composition is held for 22 minutes for column washing, then returned to the initial composition by 23 minutes and held for 25 minutes.

[0313] General procedure for Step 2: To a stirred solution of the HCl salt of 2-(1-methyl-1H-pyrazol-4-yl)morpholine (0.59 mmol) in DMSO (2 mL), DIPEA (1.18 mmol) was added at room temperature and stirred for 15 minutes. The corresponding compounds 3a - 3g (0.29 mmol) were added thereto at room temperature. The resulting mixture was heated at 100 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by reverse-phase preparative HPLC to obtain the corresponding target compounds.

[0314] Information on the 1H NMR, LCMS, and yields of compounds 3a - 3g and Examples 4 - 10 are provided in the following table: [Table 2] TIFF2025521856000362.tif242151TIFF2025521856000363.tif226159

[0315] Example 11 8-(4,4-Difluorocyclohexyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one Step 1 - Preparation of 6-chloro-2,3-dimethyl-8-(1,4-dioxaspiro[4.5]decan-7-en-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one [Chemical formula] A stirred solution of 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (300 mg, 1.23 mmol) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]deca-7-en-8-yl)-1,3,2-dioxaborolane (294.4 mg, 1.107 mmol) in dioxane (4 mL) and water (1 mL) was added with sodium carbonate (258.3 mg, 2.46 mmol), and the resulting solution was degassed with argon. PdCl2(dppf) (90.0 mg, 0.123 mmol) was added under an inert atmosphere. The resulting mixture was heated at 80 °C for 2 h. The reaction mixture was diluted with ethyl acetate, filtered through a short pad of celit...

Claims

1. A compound of formula LXI: 【Chemical 1】 wherein, X1 is N or C(R42), R42 is H or halogen, X2 is N or CH, X14 is N or CH, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, wherein said C1-6 alkyl or said C3-6 cycloalkyl is optionally substituted by one to three individually selected substituents R10, Ra is H or C1-6 alkyl, Rb is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, wherein said C1-6 alkyl or said C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, C5-8 bicycloalkylcyclopenta-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), said C1-6 alkyl, said C3-6 cycloalkyl, said C5-8 spiroalkyl, said C5-8 tricycloalkyl, said cyclopenta-1-en-1-yl, said cyclohex-1-en-1-yl, said phenyl, said 6-membered heteroaryl, or said 5-membered heteroaryl is optionally substituted by one to four substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, and CN, one methylene group of said C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, The azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R10 is individually selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and halogen, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and phenyl, and the phenyl is optionally substituted with 1 to 5 substituents individually selected from -O-C1-6 alkyl, R23 is of formula XLVI: 【Chemical 2】 wherein, X3 is N or C(R8), X4 is C(R38)(R39), O, NH, NR9, or a bond, X10 is individually C(R37)(R7) or C(O), X11 is C(R4) or N, X12 is C(R6)(R6b), X13 is C(R40)(R41), R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen, (b) the phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl; the C1-6 alkyl or the C1-6 haloalkyl in subcategory (b) is optionally substituted with -OH; the C3-6 heterocycloalkyl in subcategory (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo(=O), -O-C1-3 alkyl, and -N(R30)(R31); R6 is H, halogen, or C1-3 alkyl; R6b is H, halogen, or C1-3 alkyl; wherein, when R6 and R6b are C1-3 alkyl, R6 and R6b are optionally linked together to form a 3- to 6-membered ring, and / or wherein, when R6 and R6b are C1-3 alkyl, one methylene group is optionally replaced by -O- or -N(R35)-, where R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl; R7 is individually H, C1-3 alkyl, or a bond; wherein, when R7 is a bond, R6 is C1-3 alkyl, and R7 and R6 are linked together to form a 3- to 5-membered ring; R37 is individually H or C1-3 alkyl; R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen; R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl, or C1-6 haloalkyl, and the C1-6 alkyl, the -C(O)-C1-6 alkyl, or the -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy, R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen, R29 is a bond, -O-, or a C1-6 hydrocarbon chain in which one methylene group is optionally replaced by -O-, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl, R38 is H or F, R39 is H or F, Each R40 is independently H, C1-3 alkyl, or a bond, wherein when R40 is a bond, R8 is C1-3 alkyl, and R8 and R40 are linked together to form a 3- to 5-membered ring, Each R41 is independently H or C1-3 alkyl, n is 0, 1, or 2, v is 0, 1, or 2, The compound, or a pharmaceutically acceptable salt thereof.

2. The compound is of formula LXI: [Chemical Formula 3] wherein, X1 is N or C(R42), R42 is H or halogen, X2 is N or CH, X14 is N or CH, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NR a R b, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted with 1 to 3 individually selected substituents R10, R a is H or C1-6 alkyl, R b is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted with R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), wherein said C1-6 alkyl, said C3-6 cycloalkyl, said C5-8 spiroalkyl, said C5-8 tricycloalkyl, said cyclopenta-1-en-1-yl, said cyclohexa-1-en-1-yl, said phenyl, said 6-membered heteroaryl, or said 5-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, wherein one methylene group of said C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, wherein R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, wherein said azetidin-1-yl, said pyrrolidin-1-yl, said 3-azabicyclo[3.1.0]hexan-3-yl, said piperidin-1-yl, or said -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, wherein each R10 is independently selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and halogen, wherein R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and phenyl, and said phenyl is optionally substituted with 1 to 5 substituents independently selected from -O-C1-6 alkyl, R23 is of formula XLVI: [Chemical Formula 4] wherein in the formula, X3 is N or C(R8), X4 is C(R38)(R39), O, NH, NR9, or a bond, each X10 is independently C(R37)(R7) or C(O), X11 is C(R4) or N, X12 is C(R6)(R6b), X13 is C(R40)(R41), R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) said C3-6 cycloalkyl or said C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen, and (b) said phenyl, said -O-phenyl, said 5-membered heteroaryl, said -O-(5-membered heteroaryl), said 6-membered heteroaryl, or said -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, wherein said C1-6 alkyl or said C1-6 haloalkyl in subcategory (b) is optionally substituted with -OH, and said C3-6 heterocycloalkyl in subcategory (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), and (c) said C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl, and -N(R30)(R31), R6 is H, halogen, or C1-3 alkyl, R6b is H, halogen, or C1-3 alkyl, wherein when R6 and R6b are C1-3 alkyl, R6 and R6b are optionally linked together to form a 3- to 6-membered ring, and / or wherein when R6 and R6b are C1-3 alkyl, one methylene group is optionally replaced by -O- or -N(R35)-, wherein R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, R7 is individually H or C1-3 alkyl, R37 is individually H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl, or C1-6 haloalkyl, wherein the C1-6 alkyl, the -C(O)-C1-6 alkyl, or the -C(O)-C3-6 cycloalkyl is optionally substituted by 1 to 3 substituents independently selected from halogen and C1-3 alkoxy, R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted by C1-3 alkoxy or halogen, R29 is a bond, -O-, or a C1-6 hydrocarbon chain in which one methylene group is optionally replaced by -O-, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl, R38 is H or F, R39 is H or F, R40 is individually H, C1-3 alkyl, or a bond, wherein when R8 is a bond and R40 is C1-3 alkyl, R8 and R40 are optionally linked together to form a 3- to 5-membered ring, R41 is individually H or C1-3 alkyl, n is 0, 1, or 2, v is 0, 1, or 2, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound is of formula LXI: 【Chemical Formula 5】 wherein in the formula, X1 is N or C(R42), R42 is H or halogen, X2 is N or CH, X14 is N or CH, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NR a R b, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by 1 to 3 individually selected substituents R10, R a is H or C1-6 alkyl, R b is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), wherein the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohex-1-en-1-yl, the phenyl, the 6-membered heteroaryl, or the 5-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, wherein one methylene group of the C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, wherein the azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R10 is individually selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and halogen, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and phenyl, and the phenyl is optionally substituted by 1 to 5 substituents individually selected from -O-C1-6 alkyl, R23 is of formula XLVI: ​ wherein in the formula, X3 is N or C(R8), X4 is C(R38)(R39), O, NH, NR9, or a bond, X10 is individually C(R37)(R7) or C(O), X11 is C(R4) or N, X12 is C(R6)(R6b), X13 is C(R40)(R41), R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) said C3-6 cycloalkyl or said C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen, (b) said phenyl, said -O-phenyl, said 5-membered heteroaryl, said -O-(5-membered heteroaryl), said 6-membered heteroaryl, or said -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, wherein said C1-6 alkyl or said C1-6 haloalkyl in sub-category (b) is optionally substituted with -OH, wherein said C3-6 heterocycloalkyl in sub-category (b) is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), (c) said C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl, and -N(R30)(R31), R6 is H, halogen, or C1-3 alkyl, R6b is H, halogen, or C1-3 alkyl, wherein when R6 and R6b are C1-3 alkyl, R6 and R6b are optionally linked together to form a 3- to 6-membered ring, and / or wherein when R6 and R6b are C1-3 alkyl, one methylene group is optionally replaced by -O- or -N(R35)-, wherein R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, Each R7 is H or C1-3 alkyl, Each R37 is H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl, or C1-6 haloalkyl, wherein the C1-6 alkyl, the -C(O)-C1-6 alkyl, or the -C(O)-C3-6 cycloalkyl is optionally substituted by 1 to 3 substituents independently selected from halogen and C1-3 alkoxy, R24 is C1-6 alkyl or aryl, wherein the C1-6 alkyl is optionally substituted by C1-3 alkoxy or halogen, R29 is a bond, -O-, or a C1-6 hydrocarbon chain in which one methylene group is optionally replaced by -O-, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl, R38 is H or F, R39 is H or F, Each R40 is H, C1-3 alkyl, or a bond, wherein when R8 is a bond and R40 is C1-3 alkyl, R8 and R40 are optionally linked together to form a 3- to 5-membered ring, Each R41 is H or C1-3 alkyl, n is 0, 1, or 2, v is 1 or 2, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound is of formula IX: 【Chemical Formula 7】 wherein, X1 is N or CH, X2 is N or CH, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NR a R b, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by 1 to 3 individually selected substituents R10, R a is H or C1-6 alkyl, R b is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), wherein said C1-6 alkyl, said C3-6 cycloalkyl, said C5-8 spiroalkyl, said C5-8 tricycloalkyl, said cyclopenta-1-en-1-yl, said cyclohex-1-en-1-yl, said phenyl, said 6-membered heteroaryl, or said 5-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, wherein one methylene group of said C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, wherein R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, wherein said azetidin-1-yl, said pyrrolidin-1-yl, said 3-azabicyclo[3.1.0]hexan-3-yl, said piperidin-1-yl, or said -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, wherein each R10 is independently selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and halogen, wherein R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and phenyl, and said phenyl is optionally substituted with 1 to 5 substituents independently selected from -O-C1-6 alkyl, R23 is of formula XX: 【Chemical 8】 wherein in the formula, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is C(H)(R7) or C(O), X11 is C(R4) or N, X12 is C(R6)(R6b), R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), wherein (a) said C3-6 cycloalkyl or said C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen, wherein (b) said phenyl, said -O-phenyl, said 5-membered heteroaryl, said -O-(5-membered heteroaryl), said 6-membered heteroaryl, or said -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, wherein said C1-6 alkyl or said C1-6 haloalkyl in subcategory (b) is optionally substituted with -OH, wherein said C3-6 heterocycloalkyl in subcategory (b) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), wherein (c) said C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl, and -N(R30)(R31), R6 is H, halogen, or C1-3 alkyl, R6b is H, halogen, or C1-3 alkyl, wherein when R6 and R6b are C1-3 alkyl, R6 and R6b are optionally linked together to form a 3- to 6-membered ring, and / or wherein when R6 and R6b are C1-3 alkyl, one methylene group is optionally replaced by -O- or -N(R35)-, where R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, R7 is H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl, or C1-6 haloalkyl, and the C1-6 alkyl, the -C(O)-C1-6 alkyl, or the -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy, R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen, R29 is a bond, -O-, or a C1-6 hydrocarbon chain in which one methylene group is optionally replaced by -O-, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl, n is 0, 1, or 2, v is 1 or 2, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. The compound is of formula IX: ​ wherein, X1 is N or CH, X2 is N or CH, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NR a R b, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted with R10, R a is H or C1-6 alkyl, R b is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted with R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohexa-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, one methylene group of the C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, the azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, each R10 is independently selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, and phenyl, and the phenyl is optionally substituted with 1 to 5 substituents independently selected from -O-C1-6 alkyl, R23 is of formula XX: 【Chemical Formula 10】 wherein, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is C(H)(R7) or C(O), X11 is C(R4) or N, X12 is C(R6)(R6b), R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen; (b) the phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl; the C1-6 alkyl or the C1-6 haloalkyl of sub-category (b) is optionally substituted with -OH; the C3-6 heterocycloalkyl of sub-category (b) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl); (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl, and -N(R30)(R31); R6 is H, halogen, or C1-3 alkyl; R6b is H, halogen, or C1-3 alkyl; where, when R6 and R6b are C1-3 alkyl, R6 and R6b are optionally linked together to form a 3- to 6-membered ring, and / or where, when R6 and R6b are C1-3 alkyl, one methylene group is optionally replaced by -O- or -N(R35)-, where R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl; R7 is H or C1-3 alkyl; R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen; R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl, or C1-6 haloalkyl, and the C1-6 alkyl, the -C(O)-C1-6 alkyl, or the -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy, R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen, R29 is a bond, -O-, or a C1-6 hydrocarbon chain in which one methylene group is optionally replaced by -O-, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl, n is 0, 1, or 2, v is 1 or 2, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. The compound is of formula IX: 【Chemical 11】 wherein, X1 is N or CH, X2 is N or CH, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NR a R b, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R10, R a is H or C1-6 alkyl, R b is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), The C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohexa-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, One methylene group of the C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, The azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R10 is individually selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl, R23 is of formula XVI: 【Chemical 12】 wherein, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is C(H)(R7) or C(O), X11 is C(R4) or N, R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) The C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen, (b) the phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, the C1-6 alkyl or the C1-6 haloalkyl in sub-category (b) is optionally substituted with -OH, the C3-6 heterocycloalkyl in sub-category (b) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), (c) the C1-6 alkyl is optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo(=O), -O-C1-3 alkyl, and -N(R30)(R31), R6 is H or C1-3 alkyl, R7 is H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)-C3-6 cycloalkyl, or C1-6 haloalkyl, and the C1-6 alkyl, the -C(O)-C1-6 alkyl, or the -C(O)-C3-6 cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from halogen and C1-3 alkoxy, R24 is C1-6 alkyl or aryl, and the C1-6 alkyl is optionally substituted with C1-3 alkoxy or halogen, R29 is a bond, -O-, or a C1-6 hydrocarbon chain in which one methylene group is optionally replaced by -O-, R30 is H or C1-3 alkyl, R31 is H or C1-3 alkyl, n is 0, 1, or 2, v is 1 or 2, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. The compound is of formula IX: 【Chemical 13】 wherein, X1 is N or CH, X2 is N or CH, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R10, Ra is H or C1-6 alkyl, Rb is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, and the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohexa-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, one methylene group of the C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, the azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R10 is individually selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl, R23 is of formula X: 【Chemical Formula 14】 wherein, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is C(H)(R7) or C(O), R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) said C3-6 cycloalkyl or said C3-6 heterocycloalkyl is optionally substituted by oxo (=O), (b) said phenyl, said -O-phenyl, said 5-membered heteroaryl, said -O-(5-membered heteroaryl), said 6-membered heteroaryl, or said -O-(6-membered heteroaryl) is optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, said C1-6 alkyl or said C1-6 haloalkyl in sub-category (b) is optionally substituted by -OH, said C3-6 heterocycloalkyl in sub-category (b) is optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), (c) said C1-6 alkyl is optionally substituted by -N(H)C(O)R24, R6 is H or C1-3 alkyl, R7 is H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, or -C(O)-C3-6 cycloalkyl, R24 is C1-6 alkyl or aryl, said C1-6 alkyl being optionally substituted by C1-3 alkoxy or halogen, n is 0, 1, or 2, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. The compound is of formula I: 【Chemical Formula 15】 wherein, X1 is N or CH, X2 is N or CH, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is C(H)(R7) or C(O), R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R10, Ra is H or C1-6 alkyl, Rb is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohexa-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, the azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl, (a) said C3-6 cycloalkyl or said C3-6 heterocycloalkyl is optionally substituted by oxo (=O), (b) said phenyl, said 5-membered heteroaryl, or said 6-membered heteroaryl is optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, said C1-6 alkyl or said C1-6 haloalkyl of sub-category (b) is optionally substituted by -OH, said C3-6 heterocycloalkyl of sub-category (b) is optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), R6 is H or C1-3 alkyl, R7 is H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C3-6 cycloalkyl, -C(O)-C1-6 alkyl, C1-6 alkyl-O-C1-6 alkyl or C1-6 haloalkyl, R10 is selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, R11 is selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, n is 0, 1, or 2, A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

9. R23 is of formula Xa: 【Chemical Formula 16】 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is of the above formula.

10. R23 is of formula Xb: 【Chemical 17】 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is of the above formula.

11. R23 is of formula XXa: 【Chemical Formula 18】 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is of the above formula.

12. R23 is of formula XXb: 【Chemical Formula 19】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

13. R23 is of the formula XXc: 【Chemical 20】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

14. R23 is of the formula XXd: 【Chemical 21】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

15. R23 is of the formula XXe: 【Chemical 22】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

16. R23 is of the formula XXf: 【Chemical 23】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

17. The compound is of formula Ia or formula Ib: 【Chemical 24】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

18. X1 is N, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

19. X1 is C(R42), the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

20. R42 is H, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

21. R42 is halogen, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

22. R42 is F, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

23. X1 is CH, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

24. X1 is CF, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

25. X2 is N, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

26. X2 is CH, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

27. X14 is N, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

28. X14 is CH, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

29. The compound according to any one of the preceding claims, wherein X1 is N and X2 is N, or a pharmaceutically acceptable salt thereof.

30. The compound according to any one of the preceding claims, wherein X1 is N and X2 is CH, or a pharmaceutically acceptable salt thereof.

31. The compound according to any one of the preceding claims, wherein X1 is CH and X2 is N, or a pharmaceutically acceptable salt thereof.

32. The compound according to any one of the preceding claims, wherein X1 is CH and X2 is CH, or a pharmaceutically acceptable salt thereof.

33. The compound according to any one of the preceding claims, wherein X1 is N, X2 is N, and X14 is N, or a pharmaceutically acceptable salt thereof.

34. The compound according to any one of the preceding claims, wherein X1 is N, X2 is N, and X14 is CH, or a pharmaceutically acceptable salt thereof.

35. The compound according to any one of the preceding claims, wherein X1 is N, X2 is CH, and X14 is N, or a pharmaceutically acceptable salt thereof.

36. The compound according to any one of the preceding claims, wherein X1 is CH, X2 is N, and X14 is N, or a pharmaceutically acceptable salt thereof.

37. The compound according to any one of the preceding claims, wherein X1 is CH, X2 is CH, and X14 is N, or a pharmaceutically acceptable salt thereof.

38. The compound according to any one of the preceding claims, wherein X1 is CH, X2 is N, and X14 is CH, or a pharmaceutically acceptable salt thereof.

39. The compound according to any one of the preceding claims, wherein X1 is N, X2 is CH, and X14 is CH, or a pharmaceutically acceptable salt thereof.

40. The compound according to any one of the preceding claims, wherein X1 is CH, X2 is CH, and X14 is CH, or a pharmaceutically acceptable salt thereof.

41. The compound according to any one of the preceding claims, wherein X1 is CF, X2 is N, and X14 is N, or a pharmaceutically acceptable salt thereof.

42. The compound according to any one of the preceding claims, wherein the compound is of formula II: 【Chemical 25】 or a pharmaceutically acceptable salt thereof.

43. The compound is of formula II: 【Chemical 26】 wherein, R1 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, H, and NRaRb, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R10, Ra is H or C1-6 alkyl, Rb is H or C1-6 alkyl, R2 is selected from the group consisting of C1-6 alkyl, C3-6 cycloalkyl, and H, wherein the C1-6 alkyl or the C3-6 cycloalkyl is optionally substituted by R11, R3 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C5-8 spiroalkyl, C5-8 tricycloalkyl, cyclopenta-1-en-1-yl, cyclohex-1-en-1-yl, phenyl, 6-membered heteroaryl, azetidin-1-yl, pyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, piperidin-1-yl, and -OCH2-(C3-6 cycloalkyl), the C1-6 alkyl, the C3-6 cycloalkyl, the C5-8 spiroalkyl, the C5-8 tricycloalkyl, the cyclopenta-1-en-1-yl, the cyclohex-1-en-1-yl, the phenyl, or the 6-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, one methylene group of the C3-6 cycloalkyl is optionally replaced by -O- or -N(R28)-, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl, the azetidin-1-yl, the pyrrolidin-1-yl, the 3-azabicyclo[3.1.0]hexan-3-yl, the piperidin-1-yl, or the -OCH2-(C3-6 cycloalkyl) is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, R10 is selected from the group consisting of -O-C1-6 alkyl and C3-6 cycloalkyl, R11 is selected from the group consisting of -O-C1-6 alkyl, C3-6 cycloalkyl, and C1-6 haloalkyl, X3 is N or C(R8), X4 is CH2, O, CHF, CF2, NH, NR9, or a bond, X10 is CH2, R4 is H or C1-3 alkyl, R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, di-C1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) said C3-6 cycloalkyl or said C3-6 heterocycloalkyl is optionally substituted by oxo (=O), (b) said phenyl, said -O-phenyl, said 5-membered heteroaryl, said -O-(5-membered heteroaryl), said 6-membered heteroaryl, or said -O-(6-membered heteroaryl) is optionally substituted by one to three substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, said C1-6 alkyl or said C1-6 haloalkyl in subcategory (b) is optionally substituted by -OH, said C3-6 heterocycloalkyl in subcategory (b) is optionally substituted by one to three substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), (c) said C1-6 alkyl is optionally substituted by -N(H)C(O)R24, -oxo (=O), -O-C1-3 alkyl, and -N(R30)(R31), R6 is H or C1-3 alkyl, R8 is selected from the group consisting of H, -OH, -O-alkyl, and halogen, R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, or -C(O)-C3-6 cycloalkyl, R24 is C1-6 alkyl or aryl, said C1-6 alkyl is optionally substituted by C1-3 alkoxy or halogen, n is 1, A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

44. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6 alkyl optionally substituted by R10.

45. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-3 alkyl optionally substituted by R10.

46. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is -CH3.

47. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-6 alkyl optionally substituted by one to three individually selected substituents R10.

48. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is C1-3 alkyl optionally substituted by one to three individually selected substituents R10.

49. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R10 is a halogen such as F.

50. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is -CF3.

51. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is C3-6 cycloalkyl optionally substituted by R10.

52. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is H.

53. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-6 alkyl optionally substituted by R11.

54. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-3 alkyl optionally substituted by R11.

55. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is -CH3.

56. The compound according to any one of the preceding claims, wherein R2 is H.

57. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is C3-6 cycloalkyl optionally substituted by R11.

58. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R11 is -O-C1-6 alkyl such as -O-CH3.

59. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-3 alkyl substituted with R11 and R11 is -O-C1-6 alkyl.

60. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is -CH2CH2OCH3.

61. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-6 alkyl substituted with phenyl optionally substituted with -O-C1-6 alkyl.

62. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is C1 alkyl substituted with phenyl substituted with -O-C1-6 alkyl such as -O-C1-3 alkyl, for example -O-C1 alkyl.

63. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, and CN.

64. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl.

65. R3 is of formula III: 【Chemical 27】 wherein X5 is C(R15) or N, X6 is CH or N, R12 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or CN, R13 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or CN, R14 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or CN, R15 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or CN, The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

66. R3 is of formula III: 【Chemical 28】 wherein X5 is C(R15) or N, X6 is CH or N, R12 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R13 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R14 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R15 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

67. X5 is C(R15) or N, X6 is CH, R12 is H or halogen, R13 is H or halogen, R14 is H, halogen, or C1-3 haloalkyl, R15 is H or halogen, The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

68. X5 is N and X6 is CH, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

69. X5 is CH and X6 is N, the compound according to any one of the preceding claims.

70. R3 is of formula IV: 【Chemical Formula 29】 wherein, R12 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or CN, R13 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or CN, R14 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or CN, R15 is H, halogen, C1-3 alkyl, C1-3 haloalkyl, or CN, The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

71. R3 is of formula IV: [Chemical Formula 30] wherein, R12 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R13 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R14 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R15 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

72. R12 is H, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

73. The compound according to any one of the preceding claims, wherein R12 is a halogen such as F or Cl, or a pharmaceutically acceptable salt thereof.

74. The compound according to any one of the preceding claims, wherein R12 is a C1-3 alkyl such as -CH3, or a pharmaceutically acceptable salt thereof.

75. The compound according to any one of the preceding claims, wherein R12 is CN, or a pharmaceutically acceptable salt thereof.

76. The compound according to any one of the preceding claims, wherein R13 is H, or a pharmaceutically acceptable salt thereof.

77. The compound according to any one of the preceding claims, wherein R13 is a halogen such as F, or a pharmaceutically acceptable salt thereof.

78. The compound according to any one of the preceding claims, wherein R14 is a halogen such as F or Cl, or a pharmaceutically acceptable salt thereof.

79. The compound according to any one of the preceding claims, wherein R14 is a C1-3 alkyl such as -CH3, or a pharmaceutically acceptable salt thereof.

80. The compound according to any one of the preceding claims, wherein R14 is a C1-3 haloalkyl such as -CF3, or a pharmaceutically acceptable salt thereof.

81. The compound according to any one of the preceding claims, wherein R14 is a C1-3 haloalkyl such as -CHF2, or a pharmaceutically acceptable salt thereof.

82. The compound according to any one of the preceding claims, wherein R14 is CN, or a pharmaceutically acceptable salt thereof.

83. The compound according to any one of the preceding claims, wherein R15 is H, or a pharmaceutically acceptable salt thereof.

84. The compound according to any one of the preceding claims, wherein R15 is a halogen such as F, or a pharmaceutically acceptable salt thereof.

85. R3 is 【Chemical Formula 31】 The compound according to any one of the preceding claims, which is selected from the group consisting of

86. R3 is 【Chemical 32】 The compound according to any one of the preceding claims, which is

87. R3 is 【Chemical 33】 The compound according to any one of the preceding claims, which is selected from the group consisting of

88. R3 is 【Chemical Formula 34】 The compound according to any one of the preceding claims, which is

89. R3 is 【Chemical 35】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

90. R3 is a 5-membered heteroaryl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

91. R3 is a 5-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

92. R3 is a pyrazolyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

93. R3 is 【Chemical 36】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

94. R3 is a C3-6 cycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

95. R3 is of formula V: 【Chemical 37】 wherein R16 is H, halogen, C1-3 alkyl, and C1-3 haloalkyl, R17 is H, halogen, C1-3 alkyl, and C1-3 haloalkyl, m is 1, 2, or 3, p is 1, 2, or 3, The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

96. m is 1, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

97. m is 2, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

98. p is 1, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

99. p is 2, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

100. The compound according to any one of the preceding claims, wherein R16 is H, or a pharmaceutically acceptable salt thereof.

101. The compound according to any one of the preceding claims, wherein R16 is a halogen such as F, or a pharmaceutically acceptable salt thereof.

102. The compound according to any one of the preceding claims, wherein R16 is a C1-3 alkyl such as -CH3, or a pharmaceutically acceptable salt thereof.

103. The compound according to any one of the preceding claims, wherein R16 is a C1-3 haloalkyl such as -CF3 or -CHF2, or a pharmaceutically acceptable salt thereof.

104. The compound according to any one of the preceding claims, wherein R17 is H, or a pharmaceutically acceptable salt thereof.

105. The compound according to any one of the preceding claims, wherein R17 is a halogen such as F, or a pharmaceutically acceptable salt thereof.

106. The compound according to any one of the preceding claims, wherein R17 is a C1-3 alkyl such as -CH3, or a pharmaceutically acceptable salt thereof.

107. The compound according to any one of the preceding claims, wherein R17 is a C1-3 haloalkyl such as -CF3 or -CHF2, or a pharmaceutically acceptable salt thereof.

108. R3 is 【Chemical Formula 38】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

109. The compound according to any one of the preceding claims, wherein R3 is a C1-3 haloalkyl such as -(CH2)2CF3, or a pharmaceutically acceptable salt thereof.

110. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is a C5-8 spiroalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl.

111. R3 is 【Chemical 39】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is

112. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is a C5-8 tricycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl.

113. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is C5-8 bicycloalkyl optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, and C1-3 haloalkyl.

114. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is bicyclo[1.1.1]pentyl optionally substituted with CF3 or C1 alkyl.

115. R3 is 【Chemical 40】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

116. R3 is of formula VI: 【Chemical 41】 wherein R18 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R19 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, q is 1, 2, or 3, r is 1, 2, or 3, The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

117. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein q is 1.

118. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein q is 2.

119. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein r is 1.

120. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein r is 2.

121. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R18 is H.

122. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R18 is halogen such as F.

123. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R18 is C1-3 alkyl such as -CH3.

124. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R18 is C1-3 haloalkyl such as -CF3 or -CHF2.

125. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R19 is H.

126. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R19 is a halogen such as F.

127. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R19 is a C1-3 alkyl such as -CH3.

128. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R19 is a C1-3 haloalkyl such as -CF3 or -CHF2.

129. R3 is 【Chemical Formula 42】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

130. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is -OCH2-(C3-6 cycloalkyl) optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy.

131. R3 is 【Chemical 43】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is

132. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is a C3-6 cycloalkyl in which one or more methylene groups are replaced by -O-.

133. R3 is 【Chemical 44】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is

134. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is a C3-6 cycloalkyl in which one or more methylene groups are replaced by -N(R28)-, where R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl.

135. R3 is of formula XV: 【Chemical 45】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein in the formula, R28 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl.

136. R3 is 【Chemical 46】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

137. R23 is of formula XLVI: 【Chemical 47】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is

138. R23 is of formula XL VIII: 【Chemical 48】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

139. R23 is of formula XLIX: 【Chemical 49】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

140. R23 is of formula L: 【Chemical Formula 50】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

141. R23 is of formula LI: 【Chemical 51】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

142. R23 is of formula LII: 【Chemical 52】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

143. R23 is of formula LIII: 【Chemical Formula 53】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

144. R23 is of formula XLVI, wherein X3 is C(R8), R8 is a bond, X13 is C(R40)(R41), R40 is C1 alkyl, R8 and R40 are linked together to form a 3-membered ring, R41 is H, and v is 1; the compound according to any one of the preceding claims.

145. R23 is of formula LIV: 【Chemical 54】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

146. R23 is of formula LV: 【Chemical 55】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

147. R23 is of formula LVI: 【Chemical Formula 56】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

148. R23 is of formula LVII: 【Chemical Formula 57】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

149. R23 is of formula LVIII: 【Chemical 58】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

150. R23 is of formula LIX: 【Chemical Formula 59】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

151. R23 is a 6-membered ring; the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

152. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is N, X4 is O, X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 1.

153. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is N, X4 is NH or NR9, X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 1.

154. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is N, X4 is C(R38)(R39), X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 1.

155. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is N, X4 is a bond, X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 2.

156. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is C(R8), X4 is O, X10 is C(R37)(R7), X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), n is 1, and v is 1.

157. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is N.

158. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is C(R8).

159. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R8 is H.

160. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X4 is O.

161. The compound according to any one of the preceding claims, wherein X4 is CF2, or a pharmaceutically acceptable salt thereof.

162. The compound according to any one of the preceding claims, wherein X4 is CH2, or a pharmaceutically acceptable salt thereof.

163. The compound according to any one of the preceding claims, wherein X4 is CHF, or a pharmaceutically acceptable salt thereof.

164. The compound according to any one of the preceding claims, wherein R38 is H, or a pharmaceutically acceptable salt thereof.

165. The compound according to any one of the preceding claims, wherein R38 is F, or a pharmaceutically acceptable salt thereof.

166. The compound according to any one of the preceding claims, wherein R39 is F, or a pharmaceutically acceptable salt thereof.

167. The compound according to any one of the preceding claims, wherein R39 is F, or a pharmaceutically acceptable salt thereof.

168. The compound according to any one of the preceding claims, wherein R38 is H and R39 is H, or a pharmaceutically acceptable salt thereof.

169. The compound according to any one of the preceding claims, wherein R38 is F and R39 is F, or a pharmaceutically acceptable salt thereof.

170. The compound according to any one of the preceding claims, wherein R38 is H and R39 is F, or a pharmaceutically acceptable salt thereof.

171. The compound according to any one of the preceding claims, wherein R4 is H, or a pharmaceutically acceptable salt thereof.

172. The compound according to any one of the preceding claims, wherein R4 and R5 are linked together to form a ring, or a pharmaceutically acceptable salt thereof.

173. The compound according to any one of the preceding claims, wherein R23 is of formula XLVI, wherein X3 is C(R8), R8 is a bond, X13 is C(R40)(R41), R40 is C1 alkyl, R8 and R40 are linked together to form a three-membered ring, R41 is H, v is 1, X11 is C(H), X4 is O, X12 is CH2, X10 is CH2, and n is 1, or a pharmaceutically acceptable salt thereof.

174. R23 is of formula LX: 【Chemical Formula 60】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

175. X12 is C(R6)(R6b), R6b is H, R6 is C1-3 alkyl, n is 1, X10 is C(R37)(R7), R37 is H, and R7 is a bond to R6, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

176. R23 is of formula XLVI, wherein X3 is N, X13 is CH2, v is 1, X11 is C(H), X4 is O, X12 is C(R6)(R6b), R6b is H, R6 is C1 alkyl, n is 1, X10 is C(R37)(R7), R37 is H, and R7 is a bond to R6, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

177. R23 is of formula LXIII: 【Chemical Formula 61】 a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

178. R23 is of formula XVI, wherein X3 is N, X10 is CH2, n is 1, v is 1, R6 is H, X4 is O, and X11 is C(H), a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

179. R23 is of formula XX, wherein X3 is N, X10 is CH2, n is 1, v is 1, X4 is O, and X11 is C(H), a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

180. R23 is of formula XXXIV: 【Chemical Formula 62】 a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

181. R23 is of formula XXXIV, R6 is H, and R6b is H, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

182. R23 is of formula XXXIV, R6 is F, and R6b is F, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

183. R23 is of formula XXXIV, R6 is CH3, and R6b is CH3, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

184. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XXXIV, R6 is CH3, and R6b is H.

185. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XLV: 【Chemical Formula 63】 wherein k is 1, 2, 3, or 4.

186. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein k is 1.

187. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein k is 2.

188. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XVI, wherein X3 is N, X10 is CH2, n is 1, v is 1, R6 is H, X4 is C(R33)(R34), R33 is H or F, R34 is H or F, and X11 is C(H).

189. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XXXV: 【Chemical Formula 64】 wherein R33 is H or F, and R34 is H or F.

190. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XVI, wherein X3 is N, n is 0, v is 1, R6 is H, X4 is CH2, and X11 is C(H).

191. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XXXVI: 【Chemical Formula 65】

192. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XVI, wherein X3 is N, X10 is CH2, n is 1, v is 1, R6 is H, X4 is N(R9), and X11 is C(H).

193. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XXXVII: 【Chemical Formula 66】

194. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XVI, in which X3 is C(H), X10 is CH2, n is 1, v is 1, R6 is H, X4 is O, and X11 is C(H).

195. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XXXVIII: 【Chemical 67】

196. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XVI, in which X3 is C(H), X10 is CH2, n is 1, v is 1, R6 is H, X4 is C(R33)(R34), R33 is H or F, R34 is H or F, and X11 is N.

197. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XXXIX: in which R33 is H or F and R34 is H or F. 【Chemical Formula 68】

198. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R33 is H and R34 is H.

199. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R33 is F and R34 is F.

200. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XVI, in which X3 is N, n is 0, v is 1, R6 is H, X4 is a bond, and X11 is C(H).

201. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XL:

202. 【Chemical Formula 69】 A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XVI, in which X3 is N, X10 is CH2, n is 1, v is 2, R6 is H, X4 is a bond, and X11 is C(H).

203. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is of formula XLI:

204. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is a 5-membered ring. 【Chemical Formula 70】 ​ ​ ​

205. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1, v is 1, and X4 is a bond, or n is 0, v is 1, and X4 is not a bond.

206. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is N, X13 is C(R40)(R41), X11 is C(R4), X4 is C(R38)(R39), X12 is C(R6)(R6b), and n is 0.

207. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R23 is a 4-membered ring.

208. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0, v is 1, X4 is a bond, n is 1, v is 0, and X4 is a bond.

209. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3 is N, X4 is a bond, n is 0, X11 is C(R4), X12 is C(R6)(R6b), X13 is C(R40)(R41), and v is 1. R5 is selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, diC1-3 alkylamino, -C(O)-O-(C1-6 alkyl), C3-6 cycloalkyl, C3-6 heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen, (b) the phenyl, the -O-phenyl, the 5-membered heteroaryl, the -O-(5-membered heteroaryl), the 6-membered heteroaryl, or the -O-(6-membered heteroaryl) is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl. The C1-6 alkyl or the C1-6 haloalkyl of sub-part (b) is optionally substituted by -OH, the C3-6 heterocycloalkyl of sub-part (b) is optionally substituted by 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), (c) the C1-6 alkyl is optionally substituted by 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo (=O), and -N(R30)(R31), The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

210. R5 is a 5-membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, the C1-6 alkyl or the C1-6 haloalkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halogen, and -OH, the C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

211. R5 is a 5-membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, the C1-6 alkyl or the C1-6 haloalkyl is optionally substituted by -OH, and the C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

212. R5 is of formula XXI: 【Chemical 71】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

213. R5 is of formula XXII: 【Chemical Formula 72】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halogen, and -OH, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

214. R5 is of formula XXII: 【Chemical 73】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

215. R5 is of formula XXIII: 【Chemical 74】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

216. R5 is of formula XXIV: 【Chemical 75】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

217. R5 is of formula XIII: 【Chemical Formula 76】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

218. R5 is 【Chemical 77】 a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

219. R5 is 【Chemical 78】 a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

220. R5 is of formula VII: 【Chemical 79】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halogen, and -OH, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

221. R5 is of formula VII: 【Chemical Formula 80】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

222. R5 is of formula XXV: 【Chemical 81】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

223. R5 is of formula XXVI: 【Chemical 82】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

224. R5 is of formula XXVII: 【Chemical 83】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

225. R5 is of formula XXVIII: 【Chemical 84】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

226. R5 is of formula XXIX: 【Chemical 85】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

227. R5 is of formula XXX: 【Chemical 86】 wherein, R32 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

228. R5 is of formula XLII: 【Chemical 87】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

229. R5 is of formula XXXI: 【Chemical 88】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

230. R5 is of formula XXXII: 【Chemical 89】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

231. R5 is of formula XXXIII: 【Chemical Formula 90】 wherein, R20 is C1-3 alkyl, C3-6 cycloalkyl, H, or C3-6 heterocycloalkyl, and the C1-3 alkyl, the C3-6 cycloalkyl, or the C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C1-6 alkyl and C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

232. R20 is C1-3 alkyl such as -CH3, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

233. R20 is C1-3 alkyl optionally substituted with C1-6 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

234. R20 is C1-2 alkyl optionally substituted with C1 alkoxy, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

235. R20 is C1-3 alkyl optionally substituted with 1 to 3 halogens such as F, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

236. R20 is methyl optionally substituted with 1 to 3 halogens such as F, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

237. R20 is -CF3, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

238. R20 is -CH2CH2OCH3, a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

239. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R20 is a C3-6 cycloalkyl such as C3 cycloalkyl.

240. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R20 is H.

241. R5 is 【Chemical Formula 91】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of.

242. R5 is 【Chemical Formula 92】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is.

243. R5 is 【Chemical Formula 93】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is.

244. R5 is 【Chemical Formula 94】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of.

245. R5 is 【Chemical Formula 95】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of.

246. R5 is 【Chemical Formula 96】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of.

247. R5 is 【Chemical Formula 97】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is.

248. R5 is a 6-membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, wherein the C1-6 alkyl or the C1-6 haloalkyl is optionally substituted by -OH, and the C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

249. R5 is of formula XLIV: 【Chemical Formula 98】 wherein, X7 is N or CH, X8 is N or C(R21), X9 is N or C(R22), R21 is a C1-3 alkyl such as -CH3, R22 is a C1-3 alkyl such as -CH3, R36 is H or a C1-3 alkyl such as -CH3. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

250. R5 is of formula VIII: 【Chemical Formula 99】 wherein, X7 is N or CH; X8 is N or C(R21); X9 is N or C(R22); R21 is a C1-3 alkyl such as -CH3; R22 is a C1-3 alkyl such as -CH3. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

251. R5 is 【Chemical 100】 selected from the group consisting of, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

252. R5 is of formula XIII: 【Chemical 101】 wherein, R27 is C1-6 alkyl; u is 1, 2, or 3. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

253. R5 is a C1-6 alkyl optionally substituted with 1 to 3 substituents independently selected from -N(H)C(O)R24, -oxo(=O), -O-C1-3 alkyl, and -N(R30)(R31), the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

254. R5 is a C1-3 alkyl optionally substituted with -O-C1-3 alkyl such as -O-C1 alkyl, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

255. R5 is a C1-3 alkyl optionally substituted with -N(R30)(R31), where R30 and R31 are each independently selected from H and C1-3 alkyl such as C1 alkyl, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

256. R5 is 【Chemical 102】 selected from the group consisting of, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

257. R5 is a C3-6 heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from oxo(=O), C1-3 alkoxy, and halogen, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

258. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5 is C4 heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from C1-3 alkoxy and halogen.

259. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5 is C3-6 heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen.

260. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5 is C4 heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from C1-3 alkoxy and halogen.

261. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5 is azetidine optionally substituted with 1 to 3 substituents independently selected from C1-3 alkoxy and halogen.

262. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5 is optionally substituted with one or two substituents independently selected from C1-3 alkoxy such as C1 alkoxy and halogen such as F. 【Chemical Formula 103】

263. R5 is 【Chemical 104】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

264. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R5 is C6 heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from oxo (=O), C1-3 alkoxy, and halogen.

265. R5 is 【Chemical 105】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

266. The C3-6 heterocycloalkyl is 【Chemical 106】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

267. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 is H.

268. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 is C1-3 alkyl such as C1 alkyl.

269. The compound according to any one of the preceding claims, wherein R6 is halogen.

270. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6b is H.

271. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6b is C1-3 alkyl such as C1 alkyl.

272. The compound according to any one of the preceding claims, wherein R6b is halogen.

273. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 and R6b are H.

274. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 and R6b are C1-3 alkyl such as C1 alkyl.

275. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 and R6b are C1-3 alkyl and R6 and R6b are linked together to form a 3- to 6-membered ring such as a 4-membered ring or a 3-membered ring.

276. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 and R6b are C1-3 alkyl and R6 and R6b are linked together to form a 3- to 6-membered ring, and one methylene group is replaced by -O-.

277. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6 and R6b are C1-3 alkyl and R6 and R6b are linked together to form a 3- to 6-membered ring, and one methylene group is replaced by -N(R35)-, where R35 is selected from the group consisting of H, C1-3 alkyl, and -C(O)C1-3 alkyl.

278. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X10 is C(H)(R7).

279. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7 is H.

280. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R37 is H.

281. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7 is H and R37 is H.

282. The compound according to any one of the preceding claims, wherein X10 is C(H)2, or a pharmaceutically acceptable salt thereof.

283. R23 is 【Chemical 107】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

284. R23 is 【Chemical 108】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

285. R23 is 【Chemical 109】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

286. R23 is 【Chemical 110】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

287. R23 is 【Chemical 111】 【Chem.】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

288. R23 is 【Chemical 112】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

289. R23 is 【Chemical 113】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein it is

290. R23 is 【Chemical 114】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

291. R23 is 【Chemical 115】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

292. R23 is 【Chemical 116】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

293. R23 is 【Chemical 117】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

294. R23 is 【Chemical 118】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

295. R23 is 【Chemical 119】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

296. R23 is 【Chemical 120】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

297. R23 is 【Chemical 121】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

298. R23 is 【Chemical 122】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

299. R23 is 【Chemical 123】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

300. R23 is 【Chemical 124】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

301. X3 is N, X4 is O, R4 is H, R6 is H, X10 is C(H)(R7), R7 is H, and n is 1, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

302. X3 is CH, X4 is O, R4 is H, R6 is H, X10 is C(H)(R7), R7 is H, and n is 1, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

303. X3 is N, X4 is a bond, R4 is H, R6 is H, and n is 0, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

304. R23 is of formula XI: 【Chemical 125】 wherein R25 is individually selected from the group consisting of C1-6 alkyl, -O-C1-6 alkyl, halogen, C1-6 haloalkyl, and -CN, t is 0, 1, 2, or 3, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

305. R23 is of formula XIX: 【Chemical 126】 wherein R26 is a 5- or 6-membered heteroaryl optionally substituted by 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, said C1-6 alkyl or said C1-6 haloalkyl is optionally substituted by -OH, said C3-6 heterocycloalkyl is optionally substituted by 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), R29 is a bond, -O-, or a C1-6 hydrocarbon chain in which one methylene group is optionally replaced by -O-. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

306. R23 is of formula XII: 【Chemical 127】 wherein, R26 is a 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-6 alkyl, -O-C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -(C1-3 alkyl)O(C1-3 alkyl), -CN, C2-4 alkenyl, C3-6 cycloalkyl, and C3-6 heterocycloalkyl, said C1-6 alkyl or said C1-6 haloalkyl is optionally substituted with -OH, said C3-6 heterocycloalkyl is optionally substituted with 1 to 3 substituents individually selected from the group consisting of halogen, C1-3 alkyl, and -C(O)O(C1-6 alkyl), the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

307. R26 is R5, the compound according to any one of the preceding claims.

308. R23 is 【Chemical 128】 the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

309. R23 is of formula XIV: 【Chemical 129】 wherein, R27 is C1-6 alkyl, u is 1, 2, or 3, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

310. R23 is a 3-membered ring, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

311. X3 is C(R8), X4 is a bond, n is 0, X11 is C(R4), X12 is C(R6)(R6b), v is 0, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

312. X3 is C(H), X12 is C(H)2, X4 is a bond, X11 is C(H), n is 0, v is 0, the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

313. R23 is of formula LXII: 【Chemical 130】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

314. R23 is of formula LXIIa or formula LXIIb: 【Chemical 131】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

315. R23 is 【Chemical 132】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

316. R23 is of formula XVII: 【Chemical 133】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

317. R23 is of formula XVIII: 【Chemical 134】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

318. R23 is of formula X: 【Chemical 135】 The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.

319. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R29 is a bond.

320. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R29 is C1-3 alkoxy.

321. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R29 is -O-C1-3 alkyl.

322. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X11 is C(R4).

323. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X11 is N.

324. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X13 is CH2.

325. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R40 is H.

326. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R41 is H.

327. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R40 is H and R41 is H.

328. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein v is 1.

329. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein v is 0.

330. The compound according to any one of the preceding claims, wherein v is 2, or a pharmaceutically acceptable salt thereof.

331. The compound according to any one of the preceding claims, wherein R5 is C3-6 cycloalkyl or C3-6 heterocycloalkyl, and the C3-6 cycloalkyl or the C3-6 heterocycloalkyl is optionally substituted by oxo (=O), or a pharmaceutically acceptable salt thereof.

332. The compound according to any one of the preceding claims, wherein R5 is C1-6 alkyl, and the C1-6 alkyl is optionally substituted by -N(H)C(O)R24.

333. The compound according to any one of the preceding claims, wherein R9 is C1-6 alkyl, -C(O)-C1-6 alkyl, or -C(O)-C3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

334. The compound according to any one of the preceding claims, wherein R29 is a bond, or a pharmaceutically acceptable salt thereof.

335. The compound according to any one of the preceding claims, wherein R29 is O, or a pharmaceutically acceptable salt thereof.

336. The compound according to any one of the preceding claims, wherein R30 is H, or a pharmaceutically acceptable salt thereof.

337. The compound according to any one of the preceding claims, wherein R30 is C1-3 alkyl such as C1 alkyl, or a pharmaceutically acceptable salt thereof.

338. The compound according to any one of the preceding claims, wherein R31 is H, or a pharmaceutically acceptable salt thereof.

339. The compound according to any one of the preceding claims, wherein R31 is C1-3 alkyl such as C1 alkyl, or a pharmaceutically acceptable salt thereof.

340. The compound according to any one of the preceding claims, wherein R30 is C1-3 alkyl such as C1 alkyl and R31 is H, or a pharmaceutically acceptable salt thereof.

341. The compound according to any one of the preceding claims, wherein R30 is C1-3 alkyl such as C1 alkyl and R31 is C1-3 alkyl such as C1 alkyl, or a pharmaceutically acceptable salt thereof.

342. The compound according to any one of the preceding claims, wherein v is 1, or a pharmaceutically acceptable salt thereof.

343. The compound according to any one of the preceding claims, wherein v is 2, or a pharmaceutically acceptable salt thereof.

344. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0.

345. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1.

346. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X12 is CH2, R29 is a bond, and R5 is pyrazolyl optionally substituted by C1-6 alkyl or C3-6 cycloalkyl.

347. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X12 is CH2, R29 is a bond, and R5 is pyrazolyl substituted by C3-6 cycloalkyl such as cyclopropyl.

348. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the halogen is F.

349. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the halogen is Cl.

350. The compound is of formula LXI, wherein X1 is N, X2 is N, X14 is N, R1 is -CF3, R2 is C1-6 alkyl such as CH3, R3 is of formula IV: 【Chemical 136】 wherein R12 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R13 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R14 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R15 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

351. The compound according to claim 350, or a pharmaceutically acceptable salt thereof, wherein R12 is halogen, R13 is H, R14 is halogen, and R15 is H.

352. The compound according to claim 351, or a pharmaceutically acceptable salt thereof, wherein R12 is F and R14 is Cl.

353. R23 is of formula XXXIV: 【Chemical 137】 wherein R6 is H, halogen, or C1-3 alkyl, R6b is H, halogen, or C1-3 alkyl, R29 is a bond. The compound according to any one of claims 350 to 352, or a pharmaceutically acceptable salt thereof.

354. The compound according to claim 353, wherein R6 is H and R6b is H.

355. R5 is of formula XXII: 【Chemical 138】 wherein R20 is C1-3 alkyl or C3-6 cycloalkyl, the compound according to any one of claims 350 to 354, or a pharmaceutically acceptable salt thereof.

356. R5 is of formula VII: 【Chemical 139】 wherein R20 is C1-3 alkyl or C3-6 cycloalkyl, the compound according to any one of claims 350 to 355, or a pharmaceutically acceptable salt thereof.

357. R23 is 【Chemical 140】 the compound according to any one of claims 350 to 356, or a pharmaceutically acceptable salt thereof.

358. R23 is 【Chemical 141】 the compound according to any one of claims 350 to 356, or a pharmaceutically acceptable salt thereof.

359. The compound is of formula LXI, wherein X1 is N, X2 is N, X14 is N, R1 is -CH3, R2 is C1-6 alkyl such as CH3, R3 is of formula IV: 【Chemical 142】 wherein R12 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R13 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R14 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, R15 is H, halogen, C1-3 alkyl, or C1-3 haloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

360. The compound according to claim 359, wherein R12 is halogen, R13 is H, R14 is haloalkyl, and R15 is H, or a pharmaceutically acceptable salt thereof.

361. The compound according to claim 360, wherein R12 is F and R14 is CF3, or a pharmaceutically acceptable salt thereof.

362. R23 is of formula XXXIV: 【Chemical 143】 wherein R6 is H, halogen, or C1-3 alkyl, R6b is H, halogen, or C1-3 alkyl, R29 is a bond, the compound according to any one of claims 359 to 361, or a pharmaceutically acceptable salt thereof.

363. The compound according to claim 362, wherein R6 is H and R6b is H.

364. R5 is of formula VIII: 【Chemical 144】 wherein X7 is N or CH; X8 is N or C(R21); X9 is N or C(R22); R21 is C1-3 alkyl such as -CH3; R22 is C1-3 alkyl such as -CH3, The compound according to any one of claims 359 to 363, or a pharmaceutically acceptable salt thereof.

365. R5 is 【Chemical 145】 The compound according to any one of claims 359 to 364, or a pharmaceutically acceptable salt thereof.

366. R23 is 【Chemical 146】 The compound according to any one of claims 359 to 365, or a pharmaceutically acceptable salt thereof.

367. R23 is 【Chemical 147】 The compound according to any one of claims 359 to 366, or a pharmaceutically acceptable salt thereof.

368. The compound is 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methylpyridin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methylpyridin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methylpyrimidin-5-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methylpyrimidin-5-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(6-methylpyridazin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(6-methylpyridazin-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methyl-1H-pyrazol-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(2R,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(2S,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)oxan-4-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(2-methylpyridin-4-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4S)-2-(2-methylpyrimidin-5-yl)oxan-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-{6,6-Difluorospiro[3.3]heptan-2-yl}-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-{6,6-Difluorospiro[3.3]heptan-2-yl}-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,3r)-3-(trifluoromethyl)cyclobutyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)pyridin-3-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)pyridin-3-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4,4-Difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4,4-Difluorocyclohexyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(2,4-Difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(2,4-Difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,3,4-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,3,4-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(2,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(3,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(3,4,5-trifluorophenyl)-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(3,4-Difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(3,4-Difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,4r)-4-methylcyclohexyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-[(1r,4r)-4-methylcyclohexyl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-[2-Fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-[2-Fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 2,3-Dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(oxan-4-yl)-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, 2,3-Dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-8-(oxan-4-yl)-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, 8-(4,4-Difluoropiperidin-1-yl)-2,3-dimethyl-6-[(2R)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, 8-(4,4-Difluoropiperidin-1-yl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazol-4-yl)morpholin-4-yl]-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-{3-[(1-methyl-1H-pyrazol-4-yl)oxy]azetidin-1-yl}-3H,4H,4aH,8aH-[1,3]diazino[5,4-d]pyrimidin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3R)-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3S)-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(3R)-4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4-Chloro-2-fluorophenyl)-6-[(3S)-4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl]-2,3-dimethyl-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, 8-(4,4-Difluorocyclohexyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1s,4s)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4r)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(4,4-difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)methoxy)azetidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (S)--6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-methyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(4-(2-fluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(4-(2,2-difluoroethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-(1-methyl-1H-pyrazol-4-yl)-4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(4-(2-methoxyethyl)-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyrimidin-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-3-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-Dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-Dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-(2-(1H-Pyrazol-4-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-(2-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(4-methylthiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(3-methyl-1H-1,2,4-triazol-5-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-(2-(1H-Pyrazol-3-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(thiazol-2-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 4-(4-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-2-yl)-N-methylmorpholine-2-carboxamide, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 4-(4-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-8-oxo-7,8-dihydropyrimido[5,4-d]pyrimidin-2-yl)-N,N-dimethylmorpholine-2-carboxamide, 8-(4-Chloro-2-fluorophenyl)-6-(2-(methoxymethyl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(2-((dimethylamino)methyl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-oxa-9-azaspiro[4.5]decan-9-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-methyl-2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(9-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-(2-(1,2,4-Oxadiazol-3-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-3-(4-methoxybenzyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-3-(2-methoxyethyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl]-3H,4H-pyrimido[5,4-d][1,3]diazin-4-one, (R)-8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-chloro-2-fluorophenyl)-6-(2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(2-chloro-4-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-dimethyl-6-((R)-2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4R)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-dimethyl-6-((S)-2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-((1r,4S)-4-methylcyclohexyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(6,6-Difluorospiro[3.3]heptan-2-yl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-1,2,3-triazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(3-morpholinopiperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(3-(3-methoxyazetidin-1-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(3-(3,3-difluoroazetidin-1-yl)piperidin-1-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-(2-(1H-Imidazol-2-yl)morpholino)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-imidazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(4-((3-methylpyridin-4-yl)oxy)piperidin-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(2,3-dihydrospiro[indene-1,2'-morpholine]-4'-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(5,6,7,9-tetrahydro-8H-pyrido[3,4-c]azepin-8-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(piperidin-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-Dimethyl-6-((2S,4R)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-Dimethyl-6-((2R,4S)-2-(1-methyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro(3,5)nonan-8-yl)pyrimido(5,4-d)pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(4,4-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-6-(4,4-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)piperidin-1-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2S,4R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-(trifluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro(2,5)octan-7-yl)pyrimido(5,4-d)pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-4-(4-Chloro-2-fluorophenyl)-6,7-dimethyl-2-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-8(7H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]heptan-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((1S,2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]heptan-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((1R,2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-3-oxabicyclo[4.1.0]heptan-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylquinazolin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylquinazolin-4(3H)-one, 6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylquinazolin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylquinazolin-4(3H)-one, 6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylquinazolin-4(3H)-one, 8-(2,4-Difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(2,4-Difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (R)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one (S)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one 6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (R)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (S)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one 8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(2-methylpyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(2-methylpyridin-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2S,4R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((2S,4R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(2-(2-methylpyridin-4-yl)morpholino)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,2-d]pyrimidin-4(3H)-one, (S)8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[3,2-d]pyrimidin-4(3H)-one, (R)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methyl-2H-1,2,3-triazol-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-((1R,2S)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-((1R,2R)-2-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-2,3-Dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-2,3-Dimethyl-6-(6-(1-methyl-1H-pyrazol-4-yl)-5-oxa-8-azaspiro[3.5]nonan-8-yl)-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2S,4R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-3-Methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-3-Methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-5-fluoro-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(2,4,5-trifluorophenyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-3-Methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-3-Methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-8-(2-fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-3-methyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Difluoro-6-(1-methyl-1H-pyrazol-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-5-fluoro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,4R)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, 8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,4S)-2-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(4-Chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(4-Chloro-2-fluorophenyl)-5-fluoro-2,3-dimethyl-6-(5-(1-methyl-1H-pyrazol-4-yl)-4-oxa-7-azaspiro[2.5]octan-7-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (R)-8-(2,4-Difluorophenyl)-5-fluoro-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(2,4-Difluorophenyl)-5-fluoro-3-methyl-6-(2-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 8-(2,4-Difluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (8-(2,4-Difluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2R,6S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2S,6R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-(2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one (trans-racemate), 8-(4-Chloro-2-fluorophenyl)-6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, (R)-8-(6-(Difluoromethyl)pyridin-3-yl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-8-(6-(Difluoromethyl)pyridin-3-yl)-6-(2,2-dimethyl-6-(2-methylpyridin-4-yl)morpholino)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (R)-6-(2,2-Difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, (S)-6-(2,2-Difluoro-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 8-(2,4-Difluorophenyl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, 8-(2,4-Difluorophenyl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2R,6S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2S,6R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2R,6S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2S,6R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, (8-(2,4-Difluorophenyl)-2,3-dimethyl-6-((2R,4S,6R)-2-methyl-6-(2-methylpyridin-4-yl)tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2S,4R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-3-methyl-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-3-methyl-2-(trifluoromethyl)-8-(2,4,5-trifluorophenyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-3-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(4-Chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(2,4-Difluorophenyl)-3-methyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 8-(2,4-Difluorophenyl)-3-methyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2R,6S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2S,6R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 8-(2,4-Difluorophenyl)-3-methyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 8-(6-(Difluoromethyl)pyridin-3-yl)-2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, 8-(6-(Difluoromethyl)pyridin-3-yl)-2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2R,6S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2S,6R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2R,6S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2S,6R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(6-(difluoromethyl)pyridin-3-yl)-2,3-dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2R,6S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2S,6R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-8-(2-Fluoro-4-(trifluoromethyl)phenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2S,4R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidin-4(3H)-one, 6-((2S,4R)-2-(1-Cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one, 6-((2R,4S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)tetrahydro-2H-pyran-4-yl)-8-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4(3H)-one dimethylpyrido[3,4-d]pyrimidin-4(3H)-one, 5-chloro-2-(6-(2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)benzonitrile, 2,3-dimethyl-6-((2S,6R)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, 2,3-dimethyl-6-((2R,6S)-2-methyl-6-(2-methylpyridin-4-yl)morpholino)-8-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, 4-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile, 4-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-3-fluorobenzonitrile, 2-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-fluorobenzonitrile, 2-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-fluorobenzonitrile, 2-(6-((2R,6S)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-(trifluoromethyl)benzonitrile, 2-(6-((2S,6R)-2-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methylmorpholino)-2,3-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)-5-(trifluoromethyl)benzonitrile, (R)-8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, and (S)-8-(4-chloro-2-fluorophenyl)-2-methyl-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)pyrimido[5,4-d]pyrimidin-4(3H)-one, A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

369. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, such as a TREM2 activator, such as a TREM2 agonist.

370. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound enhances or activates TREM2 signaling via DAP12, and / or the compound induces phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, including but not limited to Syk, ZAP70, PI3K, Erk, AKT, and GSK3b, and / or the compound enhances the TREM2-induced phosphorylation level of the Syk kinase.

371. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound increases the expression of one or more genes regulated by TREM2, for example, the compound increases the expression of one or more genes regulated by TREM2 selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119.

372. A pharmaceutical composition comprising the compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

373. The compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 372, for use as a medicament.

374. The compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 372, for use in the treatment of a condition associated with loss of function of TREM2, for example, for use in the treatment of a condition associated with a mutation in TREM2.

375. The compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 372, for use in the treatment of a neurodegenerative disease.

376. The compound according to any one of claims 1 to 371368, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 372, for use as claimed, wherein the neurodegenerative disease is selected from the group consisting of tauopathy, TDP-43 proteinopathy, synucleinopathy, dementia, amyloidosis, demyelinating disorders of the CNS, demyelinating disorders of the PNS, leukodystrophy, leukodystrophy, transmissible spongiform encephalopathy (TSE), and lysosomal storage disease (LSD).

377. The compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 372, for use in the treatment of a neurodegenerative disease selected from the group consisting of Alzheimer's disease, frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson's disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, prion disease, and stroke.

378. A compound according to any one of claims 1 to 371 for use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, hemorrhoids, osteoporosis, marble bone disease, osteopetrosis, skeletal dysplasia, bone dysplasia, autism spectrum disorder, autism and Asperger's syndrome, traumatic brain injury (TBI), spinal cord injury, muscular dystrophy, myotonic dystrophy, inclusion body myositis, systemic lupus erythematosus (SLE), RA, gout, intestinal pathology, inflammatory bowel disease (IBD), metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver, alcoholic and non-alcoholic steatohepatitis, amyloidosis, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372.

379. A compound according to any one of claims 1 to 371 for use, wherein the compound is administered in an amount of about 0.01 mg / kg to about 100 mg / kg body weight / day, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372.

380. A compound according to any one of claims 1 to 371 for use, wherein the compound is administered via enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372.

381. A method for the treatment of a condition associated with loss of function of TREM2, such as a neurodegenerative disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372.

382. Use of a compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 372, for the manufacture of a medicament for the treatment of a condition associated with loss of function of TREM2, such as a neurodegenerative disease.

383. In a subject in need of enhancing or increasing TREM2 activity, such as a subject having a neurodegenerative disease, a method of enhancing or increasing the TREM2 activity, for example, i) enhancing or activating TREM2 signaling via DAP12; ii) inducing phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, including but not limited to Syk, ZAP70, PI3K, Erk, AKT, and GSK3b; iii) enhancing the TREM2-inducible phosphorylation level of the Syk kinase; iv) increasing the expression level of one or more genes regulated by TREM2, such as the expression level in the brain; and / or v) increasing the expression level of one or more genes regulated by TREM2 selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119, such as the expression level in the brain, the method comprising performing one or more of the above, and administering to the subject a compound according to any one of claims 1 to 371, or a pharmaceutically acceptable salt thereof.

384. A method for producing a compound of formula IX according to any one of claims 1 to 371, comprising: a. reacting a compound of formula (R1CO)2O with 5-amino-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid to produce a compound of formula A1; 【Chemical 148】 b. reacting the compound of formula A1 produced in a) with a compound of formula R2NH2 to produce a compound of formula A2; 【Chemical 149】 c. activating the compound of formula A2 produced in b) with POY3 (wherein Y is Cl or Br) to produce a compound of formula A3; 【Chemical 150】 d. reacting the compound of formula A3 produced in c) with R3W1 (wherein W is B(OH)2, OH, or NH) to produce a compound of formula A4; 【Chemical 151】 e. reacting the compound of formula A4 produced in d) with R23W2 (wherein W is B(OH)2, OH, or NH) to produce a compound of formula IX. The method as described above.

385. A method for producing a compound of formula B6, comprising: a. reacting R1COCl with a compound of formula B1 to form a compound of formula B2; 【Chemical 152】 b. hydrolyzing the ester of B2 to form a compound of formula B3. 【Chemical 153】 c. reacting the compound of formula B3 with R2NH2 to form a compound of formula B4; 【Chemical 154】 d. reacting the compound of formula B4 with R3W1 (wherein W1 is B(OH)2, OH, or NH) to produce a compound of formula B5; 【Chemical 155】 e. reacting the compound of formula B5 with R23W2 (wherein W2 is B(OH)2, OH, or NH) to produce a compound of formula B6, 【Chemical 156】 wherein R1, R2, R3, and R23 are as defined in any one of claims 1 to 371, R is alkyl such as C1-6 alkyl, A is N, CH, or CF, Q is N or CH, X is Cl or Br, and Y is Cl or Br, said method.

386. A method for producing a compound of formula C4, comprising: a. reacting a compound of formula C1 with an orthoacetate reagent (e.g., R1C(OEt)3) to form a compound of formula C2; 【Chemical 157】 b. reacting the compound of formula C2 with R3W1 (wherein W1 is B(OH)2, OH, or NH) to produce a compound of formula C3; 【Chemical 158】 c. reacting the compound of formula C3 with R23W2 (wherein W2 is B(OH)2, OH, or NH) to produce a compound of formula C4, 【Chemical Formula 159】 wherein R1, R2, R3, and R23 are as defined in any one of claims 1 to 371, A is CH, CF, or N, Q is N or CH, X is Cl or Br, and Y is Cl or Br, said method.

387. A method for producing a compound of formula D6, comprising: a. reacting a compound of formula D1 with R23W2 (wherein W2 is B(OH)2, OH, or NH) to produce a compound of formula D2; 【Chemical 160】 b. reacting the compound of formula D2 with R3W1 (wherein W1 is B(OH)2, OH, or NH) to produce a compound of formula D3; 【Chemical 161】 c. reducing and hydrolyzing the compound of formula D3 to produce a compound of formula D4; 【Chemical 162】 d. reacting the compound of formula D4 with (RCO)2O to produce a compound of formula D5; 【Chemical 163】 e. reacting the compound of formula D5 with R2NH2 to produce a compound of formula D6, 【Chemical 164】 In the formula, R1, R2, R3, and R23 are as defined in any one of claims 1 to 371, X is Cl or Br, Y is Cl or Br, and R is an alkyl such as C1-6 alkyl, said method.

388. A method for producing a compound of formula E7, comprising: a. reacting a compound of formula E1 with R1CCCH to produce a compound of formula E2; 【Chemical 165】 b. hydrolyzing the compound of formula E2 to produce a compound of formula E3; 【Chemical 166】 c. reacting the compound of formula E3 with R2NH2 to remove the R group and produce a compound of formula E4; 【Chemical 167】 d. reacting the compound of formula E4 with POCl3 or POBr3 to produce a compound of formula E5; 【Chemical 168】 e. reacting the compound of formula E5 with R3W1 (wherein W1 is B(OH)2, OH, or NH) to produce a compound of formula E6; 【Chemical 169】 f. reacting the compound of formula E6 with R23W2 (wherein W2 is B(OH)2, OH, or NH) to produce a compound of formula E7, 【Chemical 170】 In the formula, R1, R2, R3, and R23 are as defined in any one of claims 1 to 371, R is a suitable protecting group such as PMB, and X is I, Cl, or Br, said method.

Images