TREM2 Modulator

Abstract

The present invention relates to compounds useful for regulating Triggering Receptor Expressed on Myeloid Cells 2 ("TREM2"), which is expressed on myeloid cells. The present invention also relates to compounds for use in the treatment of conditions associated with loss of TREM2 function, such as neurodegenerative diseases, and pharmaceutical compositions containing such compounds. JPEG2026524663000460.jpg33159

Description

[Technical Field]

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

[0002] Trigger receptor-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 external domain, a single transmembrane helix, and a short cytosolic tail (Colonna, M. et al. (2016)).

[0003] Insights into the role of TREM2 can be gained from its restricted expression pattern. It is expressed only on myeloid cells such as macrophages, microglia, dendritic cells, and osteoclasts. In tissue maintenance, it plays a role as a pathological sensor and an inducer of innate immune signaling in specific tissues. In the brain, TREM2 is expressed only on microglia and is functionally required, for example, in the phagocytosis of cell debris, but it is also assigned a role 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, TR (2019)).

[0005] TREM2-mediated signaling is well described through its co-receptor, DAP12. The adapter molecule DAP12 is expressed as a homodimer on the surface of various cells involved in the innate immune response, including microglia, macrophages, granulocytes, NK cells, and dendritic cells. Following TREM2 ligation, phosphorylation of the ITAM (immune receptor tyrosine 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, as well as the regulation of the actin cytoskeleton, have been described.

[0006] Shedding of soluble TREM2 (sTREM2) can occur in human cerebrospinal fluid (CSF) through proteolytic cleavage of the external domain of TREM2 by metalloproteinases, including ADAM10 and ADAM17, and possibly by matrix metalloproteinases. sTREM2 has been suggested as a potential biomarker of microglial activity in early Alzheimer's disease (Suarez-Calvet, M. et al. (2016)).

[0007] Deficiencies in either TREM2 or DAP12 lead to a blunted microglial response to pathogens. The effects of TREM2 deficiency in vitro have been demonstrated in association with stimulation with typical TLR ligands such as LPS. Loss-of-function variants of TREM2 are associated with neurodegenerative diseases and support the central role of microglial function in 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. Det. al. (2017)), while heterozygous loss-of-function TREM2 variants are associated with an increased risk of several neurological and neurodegenerative disorders, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD), Parkinson's disease, FTLD-like syndromes, and amyotrophic lateral sclerosis (ALS). The most widely observed 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 modulation of TREM2 activity and / or signaling 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. [Overview of the Initiative]

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

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

Chemical formula

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

[0012] definition As used herein, the singular forms "a," "an," and "the" include plural referents unless explicitly indicated otherwise by the context.

[0013] The terms “approximately” and “about” as used herein are synonymous. In some embodiments, “about” refers to a listed quantity, value, or duration of ±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 illustrated structure unless otherwise specified.

[0015] The term "C" used herein 1-3 Alkyl," "C 1-5 "Alkyl" and "C 1-6 The term "alkyl" refers to a straight or branched hydrocarbon chain containing 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. 1-3 Alkyl, C 1-5 Alkyl and C 1-6 Typical examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, and hexyl.

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

[0017] The term "C" used herein 3-6 The term "cycloalkyl" refers to saturated carbocyclic molecules whose cyclic framework has 3 to 6 carbon atoms. 3-6 Typical examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0018] The term "DiC" used herein 1-3 The term "alkylamino" refers to -NR*R**, where R* and R** are independently C as defined herein. 1-3 Represents alkyl. DiC 1-3 Typical examples of alkylaminos 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] The term "C" used herein 1-3 "alkoxy" and "C 1-6 The term "alkoxy" is -OR # This refers to R # C as defined herein 1-3 Alkyl and C 1-6 Each represents an alkyl group. C 1-3 Alkoxy and C 1-6 Typical examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, 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 other terms representing chemical groups, the term "halo" refers to a modification of a 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, "C 1-6 The term "haloalkyl" refers to a C14 alkyl group as defined herein, in which one or more hydrogen atoms are substituted with halogens. 1-6 Refers to alkyl. 1-6 Typical examples of haloalkyls include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCl, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and -CH(CH2F)(CF3). Furthermore, for example, "C 1-6 The term "haloalkoxy" refers to a C as defined herein, in which one or more hydrogen atoms are substituted with halogens. 1-6 Refers to alkoxy. 1-6Typical examples of haloalkoxys 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" in this specification refers to the cyano group [ka] It is used to point to something.

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

[0024] The term "C" used herein 3-6 The term "heterocycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic framework has 3 to 6 carbon atoms, and one or more carbon atoms are substituted with heteroatoms selected from N, O, and S. In some embodiments, "C 3-6 A "heterocycloalkyl" refers to a saturated carbocyclic molecule in which the cyclic framework has 3 to 6 carbon atoms, and one carbon atom is substituted with a heteroatom selected from N, O, and S. 3-6 If the heterocycloalkyl group is a C6 heterocycloalkyl group, then one or two carbon atoms are substituted with a heteroatom independently selected from N, O, and S. 3-6Typical examples of heterocycloalkyls include, but are not limited to, azilidinyl, 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 sole common member of two rings. 5-8 A "spiroalkyl" refers to a bicyclic system containing 5 to 8 carbon atoms, where two rings are linked by a single shared carbon atom. 5-8 Typical examples of spiroalkyls 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] The term "C" used herein 5-8 The term "tricycloalkyl" refers to a tricyclic system in which all three cycloalkyl rings share two identical ring atoms. 5-8 Typical examples of tricycloalkyls include tricyclo[1.1.1.0 1,3 ]Pentanyl, tricyclo[2.1.1.0 1,4 ]Hexanyl, tricyclo[3.1.1.0 1,5 ]Hexanyl and tricyclo[3.2.1.0 1,5 Octanil is one example, but it is not limited to these.

[0027] The term "C" used herein 5-8 The term "bicycloalkyl" refers to a bicyclic system in which both cycloalkyl rings share two identical ring atoms. 5-8 The term "bicycloalkyl" includes crosslinked bicyclic compounds, that is, compounds in which two rings share three or more atoms, and two of these rings are separated by a bridge containing at least one atom. For example, "C 5-8 The term “bicycloalkyl” includes bicyclo[1.1.1]pentyl. For example, “C 5-8The term "bicycloalkyl" means [ka] Includes.

[0028] The term "aryl," used alone or as part of a larger phrase such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic, and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present 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. Groups in which an aromatic ring is condensed with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthoimidyl, phenantridinyl, or tetrahydronaphthyl, are also included within the scope of the term "aryl" as used herein.

[0029] The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger phrase, such as “heteroaryl” or “heteroarcoxy”, refer to 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 relation to “heteroaryl” includes, but is not limited to, nitrogen, oxygen, or sulfur, 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, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-” as used herein also include groups in which a heteroaromatic ring is condensed to one or more aryl, cyclic aliphatic, or heterocyclyl rings, and the radical or bond site is located on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, synnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. Heteroaryl rings may contain one or more oxo (=O) or thioxo (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which may include optionally substituted rings.The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl portions are substituted independently and at will.

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

[0031] In some embodiments, the chemical group is a "bond," which is sometimes referred to as the absence of the chemical group. For example, CH3-R a -R during OH a If it is a "bond," then it refers to CH3OH.

[0032] In some embodiments, two R groups are linked together to form a ring, i.e., the ring is formed by two R groups and one intervening atom.

[0033] As used herein, the term “stable” means a compound that remains substantially unchanged when subjected to conditions that enable their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0034] As used herein, the term “medically acceptable salt” refers to a salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that has a reasonable benefit-risk ratio. Medicinally acceptable salts are well known in the art. [Modes for carrying out the invention]

[0035] In one embodiment, the present invention relates to a compound of formula IA or formula IB: [ka] During the ceremony, X A However, N or C(R 5 ) and R 5 However, H is, R 1 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 6 Replaced by choice, R 2 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl, halogen, and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 9 Replaced by choice, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8Bicycloalkylcyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexane-3-yl, piperidine-1-yl, and -OCH2-(C 3-6 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl, the C 3-6 Cycloalkyl, the C 5-8 Spiroalkyl, the C 5-8 Bicycloalkyl, the C 5-8 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 a halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 The C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN. 3-6 One methylene group of the cycloalkyl group is -O- or -N(R 10 )- Replaced by any choice, R 10 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, The azetidine-1-yl, the pyrrolidine-1-yl, the 3-azabicyclo[3.1.0]hexane-3-yl, the piperidine-1-yl, or the -OCH2-(C 3-6 Cycloalkyl) is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. R 6 Each of them, -OC 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyls and halogens, R 9 However, -OC 1-6Alkyl, C 3-6 Cycloalkyl, C 1-6 Selected from the group consisting of haloalkyl and phenyl, wherein the phenyl is -OC 1-6 They are optionally substituted with 1 to 5 substituents individually selected from alkyl groups. R 4 However, it is from Equation II: [ka] During the ceremony, X B However, N or C(R 11 ) and R 11 However, H, C 1-3 alkyl, -OH, -OC 1-3 Selected from the group consisting of alkyl and halogen, X C However, C(R 12 )(R 13 ) and R 12 H, C 1-3 Alkyl, or bonded, Here, R 12 If R is a bond, 11 However, C 1-3 It is alkyl, R 11 and R 12 They connect together to form a 3-5 membered ring. R 13 Each of them is H or C 1-3 It is alkyl, X D However, C(R 14 ) or N, R 14 However, H or C1-3 It is alkyl, R 23 However, a bond, -O-, or one methylene group can be optionally replaced by -O- in C 1-6 It is a hydrocarbon chain, R 15 However, C 1-6 Alkyl, C 1-6 Haloalkyl, diC 1-3 Alkylamino, -C(O)-O-(C1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) Applicable C 3-6 Cycloalkyl or the C 3-6 Heterocycloalkyl groups are oxo (=O) and C 1-3 Optionally substituted with 1 to 3 substituents independently selected from alkoxys and halogens, (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 a halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 Alkyl), -CN, C 2-4 Alkenil, C 3-6 Cycloalkyl, and C 3-6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of heterocycloalkyl groups. C of the lower category (b) 1-6 Alkyl or the C 1-6 The haloalkyl group is optionally substituted with -OH. C of the lower category (b) 3-6 Heterocycloalkyls are halogens, C 1-3 Alkyl and -C(O)O(C 1-6 They are optionally substituted with 1 to 3 substituents individually selected from the group consisting of alkyl groups. (c) Applicable C 1-6 Alkyl is -N(H)C(O)R 24 -Oxo (=O), -OC 1-3 Alkyl, and -N(R 25 )(R 26) is optionally substituted by 1 to 3 substituents independently selected from the original, R 24 However, C 1-6 The C is alkyl or aryl, 1-6 Alkyl is C 1-3 Optionally substituted with alkoxy or halogen, R 25 However, H or C 1-3 It is alkyl, R 26 However, H or C 1-3 It is alkyl, X E However, C(R 16 )(R 17 ), O, NR 18 , or a combination, R 16 However, it is H or F, R 17 However, it is H or F, R 18 However, H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl, the -C(O)-C 1-6 Alkyl, or the -C(O)-C 3-6 Cycloalkyls, halogens and C 1-3 It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, X F However, C(R 19 )(R 20 ) and R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl, Here, R 19 and R 20 However, C 1-3 If it is alkyl, R 19 and R 20They can optionally be linked together to form a 3-6 member ring, and / or Here, R 19 and R 20 However, C 1-3 If it is alkyl, one methylene group is -O- or -N(R 27 )- is optionally replaced by, where R 27 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, X G Each of them, C(R 21 )(R 22 ) or C(O), R 21 H, C 1-3 Alkyl, or bonded, Here, R 21 If R is a bond, 19 However, C 1-3 It is alkyl, n is 1, R 21 and R 19 They connect together to form a 3-5 membered ring. R 22 Each of them is H or C 1-3 It is alkyl, m is 0, 1, or 2, n is 0, 1, or 2. Or relating to salts that are permissible as medicine.

[0036] In one embodiment, the present invention relates to a compound of formula IA or formula IB: [ka] During the ceremony, X A However, N or C(R 5 ) and R 5 However, H is, R 1 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl and H, the C 1-6Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 6 Replaced by choice, R 2 However, C 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyl, halogen, and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 9 Replaced by choice, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8 Bicycloalkylcyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexane-3-yl, piperidine-1-yl, and -OCH2-(C 3-6 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl, the C 3-6 Cycloalkyl, the C 5-8 Spiroalkyl, the C 5-8 Bicycloalkyl, the C 5-8 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 a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxys and CN. C 3-6 One methylene group of the cycloalkyl group is -O- or -N(R 10 )- can be optionally replaced by, R 10 However, H, C1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, The azetidine-1-yl, the pyrrolidine-1-yl, the 3-azabicyclo[3.1.0]hexane-3-yl, the piperidine-1-yl, or the -OCH2-(C 3-6 Cycloalkyl) is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. R 6 Each of them, -OC 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyls and halogens, R 9 However, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Selected from the group consisting of haloalkyl and phenyl, wherein the phenyl is -OC 1-6 They are optionally substituted with 1 to 5 substituents individually selected from alkyl groups. R 4 However, it is from Equation II: [ka] During the ceremony, X B However, N or C(R 11 ) and R 11 However, H, C 1-3 alkyl, -OH, -OC 1-3 Selected from the group consisting of alkyl and halogen, X C However, C(R 12 )(R 13 ) and R 12 H, C 1-3 Alkyl, or bonded, Here, R 12 If R is a bond, 11 However, C1-3 It is alkyl, R 11 and R 12 They connect together to form a 3-5 membered ring. R 13 Each of them is H or C 1-3 It is alkyl, X D However, C(R 14 ) or N, R 14 However, H or C 1-3 It is alkyl, R 23 However, a bond, -O-, or one methylene group can be optionally replaced by -O- in C 1-6 It is a hydrocarbon chain, R 15 However, C 1-6 Alkyl, C 1-6 Haloalkyl, diC 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) Applicable C 3-6 Cycloalkyl or the C 3-6 Heterocycloalkyl groups are oxo (=O) and C 1-3 Optionally substituted with 1 to 3 substituents independently selected from alkoxys and halogens, (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 a halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 Alkyl), -CN, C 2-4 Alkenil, C 3-6 Cycloalkyl, and C3-6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of heterocycloalkyl groups. C of the lower category (b) 1-6 Alkyl or the C 1-6 The haloalkyl group is optionally substituted with -OH. C of the lower category (b) 3-6 Heterocycloalkyls are halogens, C 1-3 Alkyl and -C(O)O(C 1-6 They are optionally substituted with 1 to 3 substituents individually selected from the group consisting of alkyl groups. (c) Applicable C 1-6 Alkyl is -N(H)C(O)R 24 -Oxo (=O), -OC 1-3 Alkyl, and -N(R 25 )(R 26 ) is optionally substituted by 1 to 3 substituents independently selected from the original, R 24 However, C 1-6 The C is alkyl or aryl, 1-6 Alkyl is C 1-3 Optionally substituted with alkoxy or halogen, R 25 However, H or C 1-3 It is alkyl, R 26 However, H or C 1-3 It is alkyl, X E However, C(R 16 )(R 17 ), O, NR 18 , or a combination, R 16 However, it is H or F, R 17 However, it is H or F, R 18 However, H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl, the -C(O)-C 1-6Alkyl, or the -C(O)-C 3-6 Cycloalkyls, halogens and C 1-3 It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, X F However, C(R 19 )(R 20 ) and R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl, Here, R 19 and R 20 However, C 1-3 If it is alkyl, R 19 and R 20 They can optionally be linked together to form a 3-6 member ring, and / or Here, R 19 and R 20 However, C 1-3 If it is alkyl, one methylene group is -O- or -N(R 27 )- is optionally replaced by, where R 27 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, X G Each of them, C(R 21 )(R 22 ) or C(O), R 21 H, C 1-3 Alkyl, or bonded, Here, R 21 If R is a bond, 19 However, C 1-3 It is alkyl, n is 1, R 21 and R 19 They connect together to form a 3-5 membered ring. R 22 Each of them is H or C 1-3 It is alkyl, m is 0, 1, or 2, n is 0, 1, or 2. Or relating to salts that are permissible as medicine.

[0037] In one embodiment, the present invention relates to a compound of formula IA or formula IB: [ka] During the ceremony, X A However, N or C(R 5 ) and R 5 However, H is, R 1 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 6 Replaced by choice, R 2 However, C 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyl and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 9 Replaced by choice, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8 Bicycloalkylcyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexane-3-yl, piperidine-1-yl, and -OCH2-(C 3-6 Selected from the group consisting of cycloalkyls, C 1-6 Alkyl, the C3-6 Cycloalkyl, the C 5-8 Spiroalkyl, the C 5-8 Bicycloalkyl, the C 5-8 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 a halogen, C 1-3 Alkyl, C 1-3 Optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN, C 3-6 One methylene group of the cycloalkyl group is -O- or -N(R 10 )- can be optionally replaced by, R 10 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, The azetidine-1-yl, the pyrrolidine-1-yl, the 3-azabicyclo[3.1.0]hexane-3-yl, the piperidine-1-yl, or the -OCH2-(C 3-6 Cycloalkyl) is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. R 6 Each of them, -OC 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyls and halogens, R 9 However, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Selected from the group consisting of haloalkyl and phenyl, wherein the phenyl is -OC 1-6 They are optionally substituted with 1 to 5 substituents individually selected from alkyl groups. R 4 However, it is from Equation II: [ka] During the ceremony, X B However, N or C(R 11 ) and R 11 However, H, C 1-3 alkyl, -OH, -OC 1-3 Selected from the group consisting of alkyl and halogen, X C However, C(R 12 )(R 13 ) and R 12 H, C 1-3 Alkyl, or bonded, Here, R 12 If R is a bond, 11 However, C 1-3 It is alkyl, R 11 and R 12 They connect together to form a 3-5 membered ring. R 13 Each of them is H or C 1-3 It is alkyl, X D However, C(R 14 ) or N, R 14 However, H or C 1-3 It is alkyl, R 23 However, a bond, -O-, or one methylene group can be optionally replaced by -O- in C 1-6 It is a hydrocarbon chain, R 15 However, C 1-6 Alkyl, C 1-6 Haloalkyl, diC 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) Applicable C 3-6 Cycloalkyl or the C 3-6Heterocycloalkyl groups are oxo (=O) and C 1-3 Optionally substituted with 1 to 3 substituents independently selected from alkoxys and halogens, (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 a halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 Alkyl), -CN, C 2-4 Alkenil, C 3-6 Cycloalkyl, and C 3-6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of heterocycloalkyl groups. C of the lower category (b) 1-6 Alkyl or the C 1-6 The haloalkyl group is optionally substituted with -OH. C of the lower category (b) 3-6 Heterocycloalkyls are halogens, C 1-3 Alkyl and -C(O)O(C 1-6 They are optionally substituted with 1 to 3 substituents individually selected from the group consisting of alkyl groups. (c) Applicable C 1-6 Alkyl is -N(H)C(O)R 24 -Oxo (=O), -OC 1-3 Alkyl, and -N(R 25 )(R 26 ) is optionally substituted by 1 to 3 substituents independently selected from the original, R 24 However, C 1-6 The C is alkyl or aryl, 1-6 Alkyl is C 1-3 Optionally substituted with alkoxy or halogen, R 25 However, H or C 1-3 It is alkyl, R26 However, H or C 1-3 It is alkyl, X E However, C(R 16 )(R 17 ), O, NR 18 , or a combination, R 16 However, it is H or F, R 17 However, it is H or F, R 18 However, H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl, the -C(O)-C 1-6 Alkyl, or the -C(O)-C 3-6 Cycloalkyls, halogens and C 1-3 It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, X F However, C(R 19 )(R 20 ) and R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl, Here, R 19 and R 20 However, C 1-3 If it is alkyl, R 19 and R 20 They can optionally be linked together to form a 3-6 member ring, and / or Here, R 19 and R 20 However, C 1-3 If it is alkyl, one methylene group is -O- or -N(R 27 )- is optionally replaced by, where R 27 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, X G Each of them, C(R 21 )(R 22 ) or C(O), R 21 H, C 1-3 Alkyl, or bonded, Here, R 21 If R is a bond, 19 However, C 1-3 It is alkyl, n is 1, R 21 and R 19 They connect together to form a 3-5 membered ring. R 22 Each of them is H or C 1-3 It is alkyl, m is 0, 1, or 2, n is 0, 1, or 2. Or relating to salts that are permissible as medicine.

[0038] In some embodiments, the compound is a compound of formula IA. In some embodiments, the compound is a compound of formula IB.

[0039] In one embodiment, the present invention relates to a compound of formula IA: [ka] During the ceremony, R 1 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 2 However, halogen, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 3 However, halogen, C 1-3 Alkyl and C 1-3 A phenyl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups. X A However, it is N or C(H), R4 However, it is of formula XXVI: [ka] During the ceremony, X B However, it is N or C(H), R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and C 3-6 A 5-membered heteroaryl or 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups. R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl. Or relating to salts that are permissible as medicine.

[0040] In some embodiments, X A In some embodiments, X A C(R 5 ) and R 5 H is H.

[0041] In some embodiments, the compound is a compound of formula IA, and X A is N. In some embodiments, the compound is a compound of formula IA, and X Aは , C(R 5 ) and R 5 is H. In some embodiments, the compound is a compound of formula IB, and X A is C(R 5 ) and R 5 H is H.

[0042] In some embodiments, R 1 R is a substituent selected from 1 to 3 individuals. 6 C is optionally replaced by 1-6It is alkyl. In some embodiments, R 1 C 1-3 It is alkyl. In some embodiments, R 1 is -CH3. In some embodiments, R 1 R is a substituent selected from 1 to 3 individuals. 6 C is replaced by 1-6 It is alkyl. In some embodiments, R 1 R is a substituent selected from 1 to 3 individuals. 6 C is replaced by 1-3 It is alkyl. In some embodiments, R 6 is a halogen. In some embodiments, R 6 F is F. In some embodiments, R 1 C 1-6 In some embodiments, R 1 C 1-3 In some embodiments, R 1 It is -CF3.

[0043] In some embodiments, R 2 R is a substituent selected from 1 to 3 individuals. 9 C is optionally replaced by 1-6 It is alkyl. In some embodiments, R 2 R is a substituent selected from 1 to 3 individuals. 9 C is optionally replaced by 1-3 It is alkyl. In some embodiments, R 2 is -CH3. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is Cl. In some embodiments, R 2 It is F.

[0044] In some embodiments, R 3 is halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Phenyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of alkoxy and CN. In some embodiments, R 3 is halogen, C 1-3 Alkyl, C 1-3 Phenyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN. In some embodiments, R 3 is halogen, C 1-3 Alkyl, C 1-3 It is a 6-membered heteroaryl that is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN. In some embodiments, R 3 This is from Equation III: [ka] During the ceremony, X H However, C(R 31 ) or N, X I However, C(R 32 ) or N, R 28 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 30 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 32 However, H, halogen, C 1-3 Alkyl, C1-3 Haloalkyl, C 1-3 It is an alkoxy or CN.

[0045] In some embodiments, R 3 This is from equation III: in the equation, X H However, C(R 31 ) or N, X I However, C(R 32 ) or N, R 28 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 30 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 32 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN.

[0046] In some embodiments, X H C(R 31 ) is. In some embodiments, X H In some embodiments, X I C(R 32 ), or a pharmaceutically acceptable salt thereof. In some embodiments, X I In some embodiments, X H C(R 31 ) and X I C(R 32 ) or a pharmaceutically acceptable salt thereof. In some embodiments, XH is N and X I C(R 32 ) is. In some embodiments, X H C(R 31 ) and X I is N. In some embodiments, R 31 H is H.

[0047] In some embodiments, R 3 This is from equation IV: [ka] During the ceremony, R 28 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 30 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN.

[0048] In some embodiments, R 3 This is from equation IV: in the equation, R 28 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 30However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN.

[0049] In some embodiments, R 28 H is H. In some embodiments, R 28 is a halogen. In some embodiments, R 28 is F or Cl. In some embodiments, R 28 C such as -CH3 1-3 It is alkyl. In some embodiments, R 28 is CN. In some embodiments, R 29 H is H. In some embodiments, R 29 is a halogen. In some embodiments, R 29 F is F. In some embodiments, R 30 is a halogen. In some embodiments, R 30 is F or Cl. In some embodiments, R 30 C such as -CH3 1-3 It is alkyl. In some embodiments, R 30 C such as -CF3 1-3 In some embodiments, R 30 C such as -CHF2 1-3 In some embodiments, R 30 is CN. In some embodiments, R 30 C such as -OCH3 1-3 It is an alkoxy. In some embodiments, R 31 H is H. In some embodiments, R 31 is a halogen. In some embodiments, R 31 F is F. In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] In some embodiments, R 3 teeth, [ka] is. In some embodiments, R 3 is [Chemical formula] is.

[0050] In some embodiments, R 3 is halogen, C 1-3 alkyl, and C 1-3 haloalkyl independently selected from the group consisting of 1 to 4 substituents optionally substituted by, C 5-8 bicycloalkyl. In some embodiments, R 3 is bicyclo[1.1.1]pentyl optionally substituted by CF3 or C1 alkyl. In some embodiments, R 3 is [Chemical formula] is.

[0051] In some embodiments, R 3 is halogen, C 1-3 alkyl, and C1-3 haloalkyl independently selected from the group consisting of 1 to 4 substituents optionally substituted by, C 3-6 cycloalkyl. In some embodiments, R 3 is of formula XXV: [Chemical formula] wherein R 33 is H, halogen, C 1-3 alkyl, and C 1-3 haloalkyl, R 34 is H, halogen, C 1-3 alkyl, and C 1-3 haloalkyl, q is 1, 2, or 3,<0003!65>p is 1, 2, or 3.

[0052] In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, R 33 is H. In some embodiments, R 33 is a halogen such as F. In some embodiments, R 33 is a C 1-3 alkyl such as -CH3. In some embodiments, R 33 is a C 1-3 haloalkyl such as -CF3 or -CHF2. In some embodiments, R 34 is H. In some embodiments, R 34 is a halogen such as F. In some embodiments, R 34 is a C 1-3 alkyl such as -CH3. In some embodiments, R 34 is a C 1-3 haloalkyl such as -CF3 or -CHF2. In some embodiments, R 3 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0053] In some embodiments, X D C(R 14 ) is. In some embodiments, R4 This is from formula IIA. In some embodiments, R 4 This is from equation IIB. [ka]

[0054] In some embodiments, X B C(R 11 ) is. In some embodiments, R 4 This is of formula IIC. In some embodiments, R 4 This is from formula IID. [ka]

[0055] In some embodiments, X B C(R 11 ) and X D C(R 14 ) is. In some embodiments, R 4 This is from formula IIE. In some embodiments, R 4 This is of formula IIF. In some embodiments, R 4 This is of formula IIG. In some embodiments, R 4 This is from equation IIH. [ka] JPEG2026524663000057.jpg32159

[0056] In some embodiments, R 4 It is a 6-membered ring. In some embodiments, X E O, C(R 16 )(R 17 ), or NR 18 And m is 1 and n is 1. In some embodiments, X B is N and X C C(R 12 )(R 13) and X D is C(R 14 ) and X E is O and X F is C(R 19 )(R 20 ) and X G is C(R 21 )(R 22 ) and m is 1 and n is 1. In some embodiments, X B is C(R 11 ) and X C is C(R 12 )(R 13 ) and X D is C(R 14 ) and X E is O and X F is C(R 19 )(R 20 0) and X G [[ID=is C(R 21 )(R 22 ) and m is 1 and n is 1. In some embodiments, X B is N and X C is C(R 12 )(R 13 ) and X D is C(R 14 ) and X E is NR 18 and X F is C(R 19 )(R 20 ) and X G is C(R 21 )(R 22 ) and m is 1 and n is 1. In some embodiments, X B is N and X C is C(R 12 )(R 13 ) and X D is C(R 14 ) and X E is C(R 16 )(R 17 ) and X<[ F is C(R 19 )(R 20 ) and X G is C(R21 )(R 22 ) and m is 1 and n is 1.

[0057] In some embodiments, X B In some embodiments, X B C(R 11 ) is. In some embodiments, R 11 H is H. In some embodiments, R 11 C 1-3 It is alkyl.

[0058] In some embodiments, X C C(R 12 )(R 13 ) is. In some embodiments, R 12 In some embodiments, R 12 C 1-3 It is alkyl. In some embodiments, R 12 It is a bond, R 11 C 1-3 It is alkyl, R 11 and R 12 These are linked together to form a 3-5 membered ring. In some embodiments, R 13 In some embodiments, R 13 C 1-3 It is alkyl.

[0059] In some embodiments, X D C(R 14 ) is. In some embodiments, X D is N. In some embodiments, R 14 H is H. In some embodiments, R 14 C 1-3 It is alkyl.

[0060] In some embodiments, X B If X is N, D C(R 14 )

[0061] In some embodiments, R 23 It is a combination.

[0062] In some embodiments, R 4 This is from formula XXVI: [ka] During the ceremony, X B However, it is N or C(H), R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and C 3-6 A 5-membered heteroaryl or 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups. R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl.

[0063] In some embodiments, R 15 C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 It is a 5-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, -CN, and halogens. In some embodiments, R 15 The formula is selected from the group consisting of formulas V, VI, VII, VIII, IX, X, XI, and XII: [ka] In the formula, R 37 C 1-6Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, H, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 Selected from the group consisting of alkyl, -CN, and halogen. In some embodiments, R 15 This is of formula V. In some embodiments, R 15 This is the one in formula VI. In some embodiments, R 15 This is of formula VII. In some embodiments, R 15 This is of formula VIII. In some embodiments, R 15 This is from formula IX. In some embodiments, R 15は , of formula X. In some embodiments, R 15 This is from formula XI. In some embodiments, R 15 This is from equation XII.

[0064] In some embodiments, R 15 The formula is selected from the group consisting of formulas XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII: [ka] In the formula, R 37 and R 38 C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, H, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 In some embodiments, R is independently selected from the group consisting of alkyl, -CN, and halogen. 15 This is equation XIII. In some embodiments, R 15This is equation XIV. In some embodiments, R 15 This is given by equation XV. In some embodiments, R 15 This is equation XVI. In some embodiments, R 15 This is equation XVII. In some embodiments, R 15 This is equation XVIII. In some embodiments, R 15 This is equation XIX. In some embodiments, R 15 This is given by formula XX. In some embodiments, R 15 This is given by equation XXI. In some embodiments, R 15 This is given by formula XXII. In some embodiments, R 15 This is equation XXIII.

[0065] In some embodiments, R 37 C 1-3 It is alkyl. In some embodiments, R 37 is CH3. In some embodiments, R 37 C 3-6 It is cycloalkyl. In some embodiments, R 37 It is a C3 cycloalkyl group.

[0066] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] That is the case.

[0067] In some embodiments, R 15 C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, H, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 It is a 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, -CN, and halogens.

[0068] In some embodiments, R 15 This is from formula XXIV: [ka] During the ceremony, X J However, it is N or CH, X K However, N or C(R 7 ) and X L However, N or C(R 8 ) and R 7 However, C 1-3 It is alkyl, R 8 However, C 1-3 It is alkyl, R 36 However, H, or C 1-3 It is alkyl.

[0069] In some embodiments, X J is CH. In some embodiments, X K In some embodiments, X K C(R 7 ) is. In some embodiments, R 7 is -CH3. In some embodiments, X L In some embodiments, X L C(R 8 ) is. In some embodiments, R 8 is -CH3. In some embodiments, R 36 H is H. In some embodiments, R 36 C 1-3 It is alkyl. In some embodiments, R 36 is -CH3. In some embodiments, X J , X K , and X L At least one of them is N. In some embodiments, X J , X K , and X L One of them is N. In some embodiments, X J , X K , and X L Two of them are N.

[0070] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] In some embodiments, R 15 teeth, [ka] That is the case.

[0071] In some embodiments, X E C(R 16 )(R 17 ) is. In some embodiments, X E In some embodiments, X E , NR 18 In some embodiments, X E It is a combination.

[0072] In some embodiments, R 19 H is H. In some embodiments, R 19 is a halogen. In some embodiments, R 19 F is F. In some embodiments, R 19 C 1-3 It is alkyl. In some embodiments, R 19 is CH3. In some embodiments, R 20 H is H. In some embodiments, R 20 is a halogen. In some embodiments, R 20F is F. In some embodiments, R 20 C 1-3 It is alkyl. In some embodiments, R 20 is CH3. In some embodiments, R 19 and R 20 C 1-3 It is alkyl, R 19 and R 20 These elements can be optionally linked together to form a 3- to 6-membered ring.

[0073] In some embodiments, X G C(R 21 )(R 22 ) is. In some embodiments, X G is C(O). In some embodiments, R 21 H is H. In some embodiments, R 22 H is H.

[0074] In some embodiments, m is 1. In some embodiments, m is 0. In some embodiments, m is 2.

[0075] In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, n is 2.

[0076] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0077] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0078] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0079] In some embodiments, R 4 teeth, [ka] In some embodiments, R4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0080] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0081] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0082] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0083] In some embodiments, R 4 teeth, [ka] That is the case.

[0084] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0085] In some embodiments, R 4 It is a 5-membered ring. In some embodiments, m is 1 and XE This is a combination, and n is 1.

[0086] In some embodiments, X B is N and X C It is CH2, m is 1, and X D is C(H) and X E It is a combination, X F is C(H2) and X G is C(H2) and n is 1. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0087] In some embodiments, R 4 It is a 4-membered ring. In some embodiments, m is 1 and X E This is a combination, and n is 0.

[0088] In some embodiments, X B is N and X C It is CH2, m is 1, and X D is C(H) and X E It is a combination, X F is C(H2) and n is 0. In some embodiments, X B is N and X C It is CH2, m is 1, and XD is C(H) and X E It is a combination, X F is C(H2), n is 0, and R 15 teeth, [ka] That is the case.

[0089] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0090] In some embodiments, R 4 It is a three-membered ring. In some embodiments, m is 0 and X E is a combination, and n is 0. In some embodiments, X B is C(H), m is 0, and X D is C(H) and X E It is a combination, X F is C(H2) and n is 0. In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] In some embodiments, R 4 teeth, [ka] That is the case.

[0091] In some embodiments, the compound is of formula IA or a pharmaceutically acceptable salt thereof, where: R 1 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 2 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyls, halogens, and H, R 3 However, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 A phenyl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and CN, wherein the C 1-3 One methylene group of the alkyl group is optionally replaced by -O-. X A However, it is N or CH, X B However, it is N or CH, X C However, it is C(H)2, X D However, C(H), X E However, it is O, X F However, C(R 19 )(R 20 ) and here, each R 19 and R 20 However, each is individually selected as either H or CH3. X G However, it is C(H)2, m is 1, n is 1, R23 However, it is a combination, R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -CN, and C 3-6 It is a 5-membered heteroaryl or 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups.

[0092] In some embodiments, the compound is of formula IA or a pharmaceutically acceptable salt thereof, where: R 1 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 2 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 3 However, halogen, C 1-3 Alkyl and C 1-3 A phenyl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups. X A However, it is CH, X B However, N is, X C However, it is C(H)2, X D However, C(H), X E However, it is O, X F However, it is C(H)2, X G However, it is C(H)2, m is 1, n is 1, R 23 However, it is a combination, R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6Alkoxy, -CN, and C 3-6 It is a 5-membered heteroaryl or 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups.

[0093] In some embodiments, the compound is of formula IA, where: R 1 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 2 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 3 However, halogen, C 1-3 Alkyl and C 1-3 A phenyl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups. X A However, N is, X B However, C(H), X C However, it is C(H)2, X D However, C(H), X E However, it is O, X F However, it is C(H)2, X G However, it is C(H)2, m is 1, n is 1, R 23 However, it is a combination, R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and C 3-6 It is a 5-membered heteroaryl or 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups.

[0094] In some embodiments, the compound is selected from the group consisting of: [ka] JPEG2026524663000248.jpg190159JPEG2026524663000249.jpg193159JPEG2026524663000250.jpg198159JPEG2026524663000251.jpg212159JPEG2026524663000252.jpg184159JPEG2026524663000253.jp g210159JPEG2026524663000254.jpg196159JPEG2026524663000255.jpg199159JPEG2026524663000256.jpg209159JPEG2026524663000257.jpg192159JPEG2026524663000258.jpg126159 or its pharmaceutically acceptable salt.

[0095] In some embodiments, the compound is 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazole-4-yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is (S)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazole-4-yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)-6-methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,6S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)-6-methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,6R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)-6-methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-7-((2S,6R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)-6-methylmorpholino)-9-(2,4-difluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-7-((2S,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-7-((2R,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2-fluoro-4-methoxyphenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-((2S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-((2S,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9. -(2,4-difluorophenyl)-3-fluoro-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-(2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-(2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2S,4R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2S,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-difluorophenyl)-3-fluoro-7-(2-(2-methoxypyridine-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-difluorophenyl)-3-fluoro-7-((2S)-2-(2-methoxypyridine-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-difluorophenyl)-3-fluoro-7-((2S,4R)-2-(2-methoxypyridine-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-difluorophenyl)-3-fluoro-7-((2S,4S)-2-(2-methoxypyridine-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 9-(2,4-difluorophenyl)-3-fluoro-7-((2R,4S)-2-(2-methoxypyridine-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-3-fluoro-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-3-fluoro-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(7-((2S,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-3-fluoro-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-7-((2R,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-2-methyl-7-((2S,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyra. The compound is 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-7-((2S,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-2-methyl-7-((2R,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2S,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chlorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(4-chlorophenyl)-7-((2S,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chlorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2S,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl). 9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2S,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-2-methyl-7-((2S,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-2-methyl-7-((2R,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2S,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2R,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-(2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9 -(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2S,6S)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2R,6S)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2. ,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluor Ro-2-methyl-7-((2S,4R,6S)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2R,4R,6S)-2-methyl-6-(1-methyl-1H -pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2S,4R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazi The compound is no[1,2-a]pyrimidine-4-one or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2R,4R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2S,4S,6S)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2R,4S,6S)-2-methyl-6-(1- The compound is methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2S,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. The compound is a salt of which. In some embodiments, the compound is 9-(2,4-(difluorophenyl)-3-fluoro-2-methyl-7-((2R,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(3-fluoro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl) The compound is tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(3-fluoro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-fluoro-4-(3-fluoro-2-methyl-7-((2R,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-fluoro-4-(3-fluoro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (S)-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is (R)-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chlorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-methyl-6-(2-methyl-4-pyridyl)morpholine-4-yl]pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2,2-difluoro-6-(2-methyl-4-pyridyl)morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-methyl-6-(2-methyl-4-pyridyl)morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[(2R,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2,2-difluoro-6-(2-methyl-4-pyridyl)morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methylmorpholine-4-yl]-9-(2,4-difluorophenyl)-2-methylpyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-(trifluoromethyl)pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2,3-dimethyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2,2-difluoro-6-(1-methylpyrazole-4-yl)morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methylmorpholine-4-yl]-9-(2,4-difluorophenyl)pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-4-oxo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2-methyl-4-oxo-pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2-methyl-4-oxo-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2-methyl-4-oxo-pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 9-(3-methoxycyclobutyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(4-chlorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is 3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a pharmaceutically acceptable salt thereof.

[0097] The compounds of the present invention also include tautomerized forms. Tautomerized forms result from the exchange of a single bond with an adjacent double bond and the associated transfer of protons. Tautomerized forms include prototropic tautomers, which are isomerized protonated states having the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions in the heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomerized forms may exist in equilibrium or may be sterically fixed into one form by appropriate substitution. Tautomers may also include methyltropic tautomers, which result from the exchange of adjacent double bonds and the associated movement of methyl groups.

[0098] The compounds of the present invention also include all isotopes of atoms present in the intermediate or final compound. Isotopes include atoms with the same atomic number but different mass numbers. In some embodiments, the compounds of the present invention contain one or more isotopes of an atom in amounts 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 contain at least one deuterium atom in amounts exceeding the natural abundance of deuterium (for example, the compound is deuterium-enriched).

[0099] All compounds described herein, and their pharmaceutically acceptable salts, may be found together with other substances such as water and solvents (for example, in the form of hydrates and solvates).

[0100] In one embodiment, the present invention relates to intermediate compounds, or pharmaceutically acceptable salts thereof, which can be used in the synthesis of the compounds of the present invention. For example, the intermediate compound is, in some embodiments, one of the intermediate compounds from any one of the examples herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of the present invention is selected from any one of the intermediate compounds from the intermediates shown herein as I-1 to I-13, or a pharmaceutically acceptable salt thereof.

[0101] The compounds of the present invention may, for example, contain one or more chiral carbon atoms and therefore may exist as stereoisomers, enantiomers, and diastereomers. Therefore, it should be understood that the scope of the present invention encompasses all possible stereoisomers of the exemplary compounds, including stereoisomerically pure forms and mixtures of stereoisomers of any chemical structure disclosed herein, unless the stereochemical structure is explicitly specified. If the stereochemical structure of a structure or part of a structure is not specified, for example, in bold or dashed, that structure or part of a structure should be interpreted as encompassing all of its stereoisomers. If the stereochemical structure of a structure or part of a structure is specified, for example, in bold or dashed, that structure or part of a structure should be interpreted as encompassing only the specified stereoisomer.

[0102] As used herein, the terms “stereoisomer” or “stereoisomerically pure” compound refer to one stereoisomer of a compound that substantially contains no other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center substantially contains no enantiomers of that compound, and a stereoisomerically pure compound having two chiral centers substantially contains the other enantiomer and diastereomer of that compound. Typical stereoisomerically pure compounds contain about 80% by weight of one stereoisomer and about 20% by weight or less of the other stereoisomer of that compound, about 90% by weight of one stereoisomer and about 10% by weight or less of the other stereoisomer of that compound, about 95% by weight of one stereoisomer and about 5% by weight or less of the other stereoisomer of that compound, or about 97% by weight of one stereoisomer and about 3% by weight or less of the other stereoisomer of that compound.

[0103] In some embodiments, the compounds defined herein are stereoisomerically pure.

[0104] The mixture of stereoisomers can be separated using standard techniques such as chiral columns or chiral resolving agents, as outlined in the Examples section.

[0105] Pharmaceutical composition The present invention also relates to pharmaceutical compositions comprising, for example, a pharmaceutically effective amount of a compound disclosed herein as an active ingredient. In some embodiments, the pharmaceutical composition comprises 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.

[0106] The compounds disclosed herein for use in therapy may be administered in the form of raw chemical compounds, but it is often preferred that the active ingredient be introduced into a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other conventional pharmaceutical adjuvants, optionally in the form of a pharmaceutically acceptable salt.

[0107] In some embodiments, the present invention provides pharmaceutical compositions 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 components known and used in the art. The carrier(s) must be compatible with the other components of the formulation and “acceptable” in the sense that they are not harmful to the recipient. Examples of excipients and their uses can be found in Remington's Pharmaceutical Sciences 20th Edition (Lippincott Williams & Wilkins, 2000).

[0108] Therapeutic dose or therapeutically effective dose or size refers to the amount of the active ingredient, i.e., the compound or composition disclosed herein, that treats, alleviates, reduces or lessens the symptoms of a disease in a subject, for example, improving one or more symptoms of a condition or the condition itself. Therapeutic doses of the compounds described herein may improve a patient's survival rate, increase survival time or survival rate, reduce symptoms, make an injury, disease, or condition (e.g., neurodegenerative disease) more tolerable, slow the rate of degeneration or decay, or improve a patient's physical or mental health.

[0109] Therapeutic efficacy and toxicity, e.g., ED 50 This can be determined by standard pharmacological procedures in cell culture or experimental animals. The dose-to-toxicity ratio is the therapeutic index, which can be expressed as the ratio between the plasma level that produces the therapeutic effect and the plasma ratio that produces the toxic effect. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. In some embodiments, the therapeutically effective dose of the compounds disclosed herein is in the range of about 0.01 mg / kg to about 100 mg / kg body weight / day.

[0110] The dosage administered must, of course, be carefully adjusted to the age, weight, and condition of the individual being treated, as well as the route of administration, dosage form, and regimen, and the desired outcome. The exact dosage should, of course, be determined by a specialist.

[0111] Administration refers to a method of delivering a drug, compound, or composition to the desired 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.

[0112] biological activity As demonstrated in Example 32, the compounds of the present invention can modulate TREM2. Therefore, in some embodiments, the compounds of the present invention are TREM2 modulators, such as TREM2 agonists. The ability of the compounds to act as TREM2 agonists may be evaluated and characterized using the assay described in Example 32. In some embodiments, the compounds of the present invention are useful for TREM2 activation. 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, such as Syk, ZAP70, PI3K, Erk, AKT, and GSK3b, but are not limited to these. 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-inducible phosphorylation level of Syk kinase. In some embodiments, the compounds of the present invention induce or enhance the phosphorylation of Syk if the level of Syk phosphorylation in a sample treated with the compound increases 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, by at least 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, or more compared to a control value.

[0113] The efficacy of the compounds of the present invention, in some embodiments, corresponds to an EC of a concentration of the compound that can activate the AlphaScreen signal of phosphoSyk up to 50% of the maximum response. 50 It is expressed as follows. In some embodiments, the compounds of the present invention have an EC50 value of less than 1000 nM, for example an EC50 value of 100 nM to 1000 nM, for example an EC50 value of 10 nM to 100 nM, for example an EC50 value of 1 nM to 10 nM, for example an EC50 value of less than 1 nM.

[0114] In some embodiments, the compounds of the present invention can increase the expression of one or more genes regulated by TREM2. In some embodiments, the compounds of the present invention can increase the expression of 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 can increase the expression level, for example, the brain expression level, of one or more genes regulated by TREM2, selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119.

[0115] In some embodiments, the compounds of the present invention increase the expression level, for example, brain expression level, such as an increase in the gene expression level in a sample treated with the compound 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, by at least 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 5 times, or more compared to a control value (e.g., untreated control / vehicle).

[0116] Medical use As TREM2 modulators, the compounds of the present invention are useful for treating diseases and disorders in living organisms, including humans. As used herein, the term “treatment” includes the treatment, prevention, and / or alleviation or improvement of one or more diseases and disorders, or one or more symptoms of a disease or disorder. In one embodiment, the compounds described herein are intended for use as pharmaceuticals.

[0117] 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.

[0118] In one embodiment, the present invention relates to a compound as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of neurodegenerative diseases.

[0119] In some embodiments, the compounds described herein are used to treat neurodegenerative diseases characterized by loss of TREM2 function. In some embodiments, the compounds described herein are used to treat neurodegenerative diseases characterized by mutations in TREM2.

[0120] In one embodiment, the present invention relates to a method for enhancing or increasing TREM2 activity in subjects requiring enhancement or increase of TREM2 activity, for example, subjects with neurodegenerative diseases, the method comprising administering to the subject a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0121] In one embodiment, the present invention relates to a method for performing one or more of the following in a subject in need, for example in a subject with a neurodegenerative disease: i) enhancing or activating TREM2 signaling via DAP12; ii) inducing phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, such as 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 TREM2-regulated genes, e.g., in the brain; and / or v) increasing the expression level of one or more TREM2-regulated genes, e.g., in the brain, selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119, the method comprising administering to the subject a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the neurodegenerative disease is a tauopathy. Tauopathy represents several neurodegenerative disorders characterized by tau deposition in the brain, accompanied by dementia and parkinsonistic symptoms. In some embodiments, the neurodegenerative disease is a tauopathy selected from the group consisting of primary age-related tauopathy (PART), spheroid glial tauopathy, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy, corticobasal degeneration, diffuse neurofibrillary tangle disease with calcification (DNTC), frontotemporal dementia (FTD), and FTD-17 with parkinsonism (FTD-17 with parkinsonism linked to chromosome 17).

[0123] In some embodiments, the neurodegenerative disease is a neurodegenerative disorder associated with TDP-43 (TDP-43 proteinosis or TDP-43 opathy). Pathogenic deposition inclusions containing TAR DNA-binding protein 43 (TDP-43) are clearly present in the brain and spinal cord of patients, and this is observed across a wide variety of neurodegenerative diseases.

[0124] In some embodiments, neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), sporadic amyotrophic lateral sclerosis (sALS), familial amyotrophic lateral sclerosis (fALS), frontotemporal lobar degeneration / disease (FTLD), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), FTLD-tau, FTLD-FUS (bvFTLD), FTLD-TDP-43, or FTLD-U (types a, b, and c), facial-onset sensorimotor neuropathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), and cerebral age-related TDP-43 with sclerosis. This is a TDP-43 proteinosis selected from a group of disorders that coexist with TDP-43 pathology, including amyotrophic lateral sclerosis (CARTS), Guam parkinson's disease-dementia complex (G-PDC) and ALS (G-ALS), Kii ALS / PDC, Guam amyotrophic lateral sclerosis / parkinsonism-dementia complex (ALS-PDC), multiple system proteinosis (MSP; also known as inclusion body myopathy (IBM) with early-onset Paget's disease of bone and frontotemporal dementia), Perry's disease, and Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE).

[0125] In some embodiments, the neurodegenerative disease is a multiple system proteinosis (MSP). MSP is a dominantly inherited, multifaceted degenerative disorder in humans that can affect the muscles, bones, and / or the central nervous system. MSP can manifest clinically as classic amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myositis (IBM), Paget's disease of bone (PDB), or a combination of these disorders (IBMPFD, IBMPFD / ALS).

[0126] In some embodiments, neurodegenerative diseases are synucleinopathies.

[0127] Synucleinopathy (also known as α-synucleinopathy) is a neurodegenerative disease characterized by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibers, or glial cells.

[0128] In some embodiments, the neurodegenerative disease is a synucleinopathy selected from the group consisting of Parkinson's disease (PD), Lewy body dementia (DLB), multiple system atrophy (MSA), axonal dystrophy, and Alzheimer's disease with amygdalar-restricted Lewy Bodies (AD / ALB).

[0129] In some embodiments, neurodegenerative disease is cognitive impairment and / or memory loss. In some embodiments, neurodegenerative disease is dementia. In some embodiments, neurodegenerative disease is dementia selected from the group consisting of 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, dementia with Guadeloupe parkinsonism, neurofibrillary tangle-dominant dementia, neurofibrillary tangle-type senile dementia, Down syndrome, semantic dementia, familial British dementia, familial Danish dementia, as well as other dementias caused by brain tumors, subdural hematomas, endocrine disorders, malnutrition, infections, immune disorders, hepatic or renal failure, metabolic disorders such as Kufus disease, certain leukodystrophys, certain neurological disorders such as epilepsy, and other dementias caused by other medical conditions such as multiple sclerosis.

[0130] Peripheral nerve damage (peripheral neuropathy) is the most common neurological complication of systemic amyloidosis. In some embodiments, the neurodegenerative disease is peripheral amyloidosis (peripheral neuropathy in systemic amyloidosis).

[0131] In some embodiments, neurodegenerative diseases are demyelinating disorders. In some embodiments, neurodegenerative diseases are demyelinating disorders of the central nervous system (CNS). In some embodiments, demyelinating disorders are myelin-destroying or demyelinating disorders, selected from the group consisting of, for example, multiple sclerosis, neuromyelitis optica (Devic's disease), and idiopathic inflammatory demyelinating diseases. In some embodiments, demyelinating disorders are leukodystrophy or myelin-dysplasia, selected from the group consisting of, for example, CNS neuropathy such as vitamin B12 deficiency, myelopathy such as central pontine myelostomy and tabes dorsalis (syphilitic myelopathy), leukoencephalopathy, and leukodystrophy.

[0132] In some embodiments, neurodegenerative diseases are demyelinating disorders of the peripheral nervous system (PNS). In some embodiments, demyelinating disorders are selected from the group consisting of Guillain-Barré syndrome and its chronic equivalents, chronic inflammatory demyelinating polyneuropathy; anti-MAG peripheral neuropathy; Charcot-Marie-Tooth disease and its equivalents, hereditary pressure-fragile neuropathy; copper deficiency-related conditions (peripheral neuropathy, myelopathy, and rarely optic neuropathy); and progressive inflammatory neuropathy.

[0133] 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 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 Harrellforden-Spats disease. In some embodiments, the neurodegenerative disease is pallido-ponto-nigral degeneration. In some embodiments, the neurodegenerative disease is post-encephalitis parkinsonism.In some embodiments, the neurodegenerative disease is subacute sclerosing panencephalitis (SSPE). In some embodiments, the neurodegenerative disease is retinal degeneration (e.g., macular degeneration).

[0134] In some embodiments, the neurodegenerative disease is leukoencephalopathy.

[0135] Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all white matter diseases of the brain, regardless of whether their molecular causes are known or unknown. In some embodiments, neurodegenerative diseases are leukoencephalopathy selected from the group consisting of progressive multifocal leukoencephalopathy, toxic leukoencephalopathy, leukoencephalopathy with white matter loss, leukoencephalopathy with diffuse axonal spheroids, reversible posterior leukoencephalopathy syndrome, macrocephalic leukoencephalopathy with subcortical cysts, and hypertensive leukoencephalopathy. In some embodiments, neurodegenerative diseases are ALSP (Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; ALSP).

[0136] In some embodiments, neurodegenerative diseases are selected from the group consisting of autosomal dominant cerebral arteriovenous disease with subcortical infarction or leukoencephalopathy; autosomal recessive cerebral arteriovenous disease with subcortical infarction and leukoencephalopathy; and retinal vasculopathy with cerebral leukoencephalopathy (or cerebroretinal vasculopathy).

[0137] In some embodiments, the neurodegenerative disease is a leukodystrophy. In some embodiments, the neurodegenerative disease is a vanishing white matter disease (VWM). Leukodystrophy is a group of rare genetic disorders 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, cerebral white matter hypoplasia type 7 (4H syndrome), Peritheus-Merzbacher disease, cerebral tenosynovitis xanthomatosis, and leukoencephalopathy 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 lipomegaly dysplasia with sclerosing leukoencephalopathy (PLOSL)).

[0138] In some embodiments, neurodegenerative diseases include transmissible spongiform encephalopathy (TSE), such as Creutzfeldt-Jakob disease, Gerstmann-Streussler-Scheinker disease (GSS), Kuru disease, and fatal familial insomnia.

[0139] In one embodiment, the present invention relates to a method for treating neurodegenerative diseases, the method comprising administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0140] In one embodiment, the present invention relates to a method for treating neurodegenerative diseases, the method comprising one or more steps of administering a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0141] In some embodiments, the subject is a mammal such as a human.

[0142] In one aspect, the present invention relates to the use of compounds described herein, or pharmaceutically acceptable salts thereof, for the manufacture of pharmaceuticals for the treatment of neurodegenerative diseases.

[0143] In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders associated with dysfunction of the colony-stimulating factor 1 receptor (CSF1R, also known as macrophage colony-stimulating factor receptor / M-CSFR, or differentiation antigen group 115 / CD115). In some embodiments, the diseases or disorders associated with CSF1R dysfunction are neurodegenerative diseases associated with CSF1R dysfunction.

[0144] In some embodiments, the disease or disorder is caused by heterozygous CSF1R mutations, homozygous CSF1R mutations, splice mutations in the csf1r gene, missense mutations in the csf1r gene, mutations in the catalytic kinase domain of CSF1R, mutations in the immunoglobulin domain of CSF1R, mutations in the extradomain of CSF1R, or loss-of-function mutations in CSF1R. In some embodiments, the disease or disorder results from changes in CSF1R activity (e.g., increased, decreased, or stopped) and / or decreased or stopped CSF1R activity.

[0145] In some embodiments, the neurodegenerative disease associated with CSF1R dysfunction is leukoencephalopathy.

[0146] In some embodiments, neurodegenerative diseases associated with CSF1R dysfunction are Adult-onset leukoencephalopathy (ALSP) with axonal spheroids and pigmented glial cells, CSF1R-associated leukoencephalopathy, Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), Pigmented orthochromatic leukodystrophy (POLD), Childhood-onset leukoencephalopathy, Congenital absence of microglia, Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS), and The group is selected from those with autosomal dominant cerebral arterial disease (CADASIL) accompanied by subcortical infarction and leukoencephalopathy.

[0147] In some embodiments, neurodegenerative diseases are conditions associated with dysfunction of ATP-binding cassette transporter 1 (ABCD1).

[0148] In one aspect, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts thereof, for use in the treatment of lysosomal storage disorders (LSDs). Most lysosomal storage disorders cause progressive neurodegeneration and lead to premature death.

[0149] In some embodiments, LSD is a lipidosis selected from the group consisting of, for example, cholesteryl ester storage disease, fucosidosis, Schindler's disease, and Wolmann's disease.

[0150] In some embodiments, LSD is a sphingolipidosis selected from the group consisting of Fabry disease, Gaucher disease, Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (types A, B, and C), Sandhoff disease, Farmer's disease, multiple sulfatase deficiencies, and Tay-Sachs disease.

[0151] In some embodiments, LSD is a mucopolysaccharidosis selected from the group consisting of Hunter syndrome, Haller syndrome, Haller-Schaye syndrome, Schaye syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maloto-Lamy syndrome, Sly syndrome, and Natowicz syndrome.

[0152] In some embodiments, LSD is selected from the group consisting of Batten disease, cystinosis, Danon disease, and Pompe disease.

[0153] In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts thereof, for use in the treatment of diseases or disorders of bone and / or joints. In some embodiments, the disease or disorder is selected from the group consisting of arthritis, rheumatoid arthritis, Pyle's disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, and osteodysplasia.

[0154] In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts thereof, for use in the treatment of autism spectrum disorder, autism, and Asperger's syndrome.

[0155] In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts 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 disease. In some embodiments, TBI is chronic traumatic encephalopathy (CTE).

[0156] In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts thereof, for use in the treatment of muscular dystrophy, including myotonic dystrophy (DM) (including type 1 DM (DM1) and type 2 DM (DM2)).

[0157] In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts thereof, for use in the treatment of inflammation. In some embodiments, the inflammation is selected from a group consisting of certain intestinal conditions, including inclusion body myositis, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), gout, and inflammatory bowel disease (IBD).

[0158] A decrease in functional TREM2 levels leads to dysregulation of lipid metabolism. In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts thereof, for use in the treatment of dysregulation of lipid metabolism. In certain embodiments, 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.

[0159] In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts thereof, for use in the treatment of metabolic syndromes and related conditions, such as obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, and alcoholic and non-alcoholic steatohepatitis.

[0160] In one embodiment, the present invention relates to compounds as defined herein, or pharmaceutically acceptable salts 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 topical amyloidosis.

[0161] 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 comprises administering to a subject a compound described herein, or a pharmaceutical composition comprising a compound described herein.

[0162] The compounds of the present invention may be used to treat animal patients belonging to any classification. Examples of such animals include mammals such as humans, rodents, dogs, cats, zoo animals, and livestock. In one embodiment, the subject referred to herein is a mammal such as a human.

[0163] As used herein, the term “compound” is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the illustrated structure unless otherwise specified. Therefore, the methods and uses described herein should be understood to encompass all methods and uses involving such forms.

[0164] Depending on the specific condition or disease being treated, additional therapeutic agents typically administered to treat that condition may be administered in combination with the compounds and compositions of the present invention. When used herein, additional therapeutic agents typically administered to treat a particular disease or condition are known as “appropriate for the disease or condition being treated.” In some embodiments, the combinations or compositions provided are administered in combination with another therapeutic agent. In some embodiments, the present invention provides a method for treating the disclosed disease or condition, comprising administering to a patient in need of treatment of the disclosed disease or condition an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering an effective amount of one or more additional therapeutic agents simultaneously or sequentially. In some embodiments, the method comprises co-administering one or more additional therapeutic agents. Examples of therapeutic agents that may be further combined with the combinations of the present invention include, but are not limited to, therapeutic agents for Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion diseases, or stroke. In some embodiments, therapeutic agents to 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 tauopathies, TDP-43 protein disorders, synucleinopathy, dementia, amyloidosis, demyelinating disorders of the central nervous system (CNS), demyelinating disorders of the primary nervous system (PNS), leukoencephalopathy, leukodystrophy, transmissible spongiform encephalopathy (TSE), and lysosomal storage disorders (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, in separate unit dosage forms or in a single unit dosage form, together with another therapeutic agent.

[0165] Manufacturing method In general, the compounds of formulas IA and IB described herein may be synthesized according to the following scheme.

[0166] All starting materials are either commercially available or known in the art and may be synthesized using known procedures. Starting materials may also be synthesized using procedures disclosed herein. Reaction conditions, such as reaction temperature, solvent, and reagents, for the schemes in this section can be found in the experimental section herein.

[0167] As shown in Scheme 1, preferably substituted pyridines or pyrazines can be functionalized in many ways to deliver the desired compound. For example, R 3 The group can first be introduced via a cross-coupling reaction, and then the ketoester R 1 C(O)CHR 2 Cyclization by CO2R (where Q=NH2 in the formula) is followed by further substitution or cross-coupling reactions. Alternatively, R 4 It is first introduced via nucleophilic substitution or cross-coupling, followed by cyclization, and then finally cross-coupling to R 3 This can be introduced. In a further alternative form, cyclization occurs first, followed by R via cross-coupling. 3 Then, via a second cross-coupling reaction, or via nucleophilic substitution, finally R 4 We will implement this.

[0168] [ka] Scheme 1. Example of a synthesis route for the compound of formula IA. Q is NH2 or NO2, X is a halogen, Y is a halogen, R is an alkyl, X A , R 1 , R 2 , R 3 and R 4 This is as defined herein.

[0169] Other examples can be prepared as shown in Scheme 2. In some cases, cyclization is performed at R2=H, and this is then converted to a halogen using a suitable halogenating agent, such as NIS or Selectfluor.

[0170] [ka] Scheme 2. Example of a synthesis route for the compound of formula IA. Q is NH2, X is a halogen, Y is a halogen, R is an alkyl, X A , R 1 , R 2 , R 3 and R 4 This is as defined herein.

[0171] Further examples can be prepared as shown in Scheme 3. Amino-pyridone or pyrimidonone is converted to ketoester R 1 C(O)CHR 2 It cyclizes with CO2R. For example, following activation using POCl3, it undergoes a metal-catalyzed cross-coupling reaction with R. 3 We introduced R 4 This is incorporated using a second cross-coupling reaction or nucleophilic substitution.

[0172] [ka] Scheme 3. Example of a synthesis route for the compound of formula IB. X is a halogen, Y is a halogen, R is an alkyl, and X A , R 1 , R 2 , R 3 and R 4 This is as defined herein.

[0173] In schemes 1 and 2, R 4 If W in W is NH, then the N atom is R 4 It is part of the base, that is, X B It is N.

[0174] item 1. Compounds of formula IA or formula IB: [ka] During the ceremony, X A However, N or C(R 5 ) and R 5 However, H is, R 1 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl and H, the C 1-6 Alkyl or the C 3-6 Cycloalkyl groups have 1 to 3 individually selected substituents R 6 Replaced by choice, R 2 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl, halogen, and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 9 Replaced by choice, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8 Bicycloalkylcyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexane-3-yl, piperidine-1-yl, and -OCH2-(C 3-6 Selected from the group consisting of cycloalkyls, Said C 1-6 Alkyl, the C 3-6Cycloalkyl, the C 5-8 Spiroalkyl, the C 5-8 bicycloalkyl, the C 5-8 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 a halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 The C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN. 3-6 One methylene group of the cycloalkyl group is -O- or -N(R 10 )- can be optionally replaced by, R 10 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, The aforementioned azetidine-1-yl, the aforementioned pyrrolidine-1-yl, the aforementioned 3-azabicyclo[3.1.0]hexane-3-yl, the aforementioned piperidine-1-yl, or the aforementioned -OCH2-(C 3-6 Cycloalkyl) is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. R 6 Each of them, -OC 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyls and halogens, R 9 However, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Selected from the group consisting of haloalkyl and phenyl, wherein the phenyl is -OC 1-6 They are optionally substituted with 1 to 5 substituents individually selected from alkyl groups. R 4 However, it is from Equation II: [ka] During the ceremony, X B However, N or C(R 11 ) and R 11 However, H, C 1-3 alkyl, -OH, -OC 1-3 Selected from the group consisting of alkyl and halogen, X C However, C(R 12 )(R 13 ) and R 12 H, C 1-3 Alkyl, or bonded, Here, R 12 If R is a bond, 11 However, C 1-3 It is alkyl, R 11 and R 12 They connect together to form a 3-5 membered ring. R 13 Each of them is H or C 1-3 It is alkyl, X D However, C(R 14 ) or N, R 14 However, H or C 1-3 It is alkyl, R 23 However, a bond, -O-, or one methylene group can be optionally replaced by -O- in C 1-6 It is a hydrocarbon chain, R 15 However, C 1-6 Alkyl, C 1-6 Haloalkyl, diC 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) C 3-6 Cycloalkyl or the C 3-6Heterocycloalkyl groups are oxo (=O) and C 1-3 Optionally substituted with 1 to 3 substituents independently selected from alkoxys and halogens, (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 a halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 Alkyl), -CN, C 2-4 Alkenil, C 3-6 Cycloalkyl, and C 3-6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of heterocycloalkyl groups. C of the lower category (b) 1-6 Alkyl or the C 1-6 The haloalkyl group is optionally substituted with -OH. C of the lower category (b) 3-6 Heterocycloalkyls are halogens, C 1-3 Alkyl and -C(O)O(C 1-6 They are optionally substituted with 1 to 3 substituents individually selected from the group consisting of alkyl groups. (c)C above 1-6 Alkyl is -N(H)C(O)R 24 -Oxo (=O), -OC 1-3 Alkyl, and -N(R 25 )(R 26 ) is optionally substituted by 1 to 3 substituents independently selected from the original, R 24 However, C 1-6 Alkyl or aryl, and the C 1-6 Alkyl is C 1-3 Optionally substituted with alkoxy or halogen, R 25 However, H or C 1-3 It is alkyl, R 26 However, H or C 1-3 It is alkyl, X E However, C(R 16 )(R 17 ), O, NR 18 , or a combination, R 16 However, it is H or F, R 17 However, it is H or F, R 18 However, H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl, the -C(O)-C 1-6 Alkyl, or the aforementioned -C(O)-C 3-6 Cycloalkyls, halogens and C 1-3 It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, X F However, C(R 19 )(R 20 ) and R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl, Here, R 19 and R 20 However, C 1-3 If it is alkyl, R 19 and R 20 They can optionally be linked together to form a 3-6 member ring, and / or Here, R 19 and R 20 However, C 1-3 If it is alkyl, one methylene group is -O- or -N(R 27 )- is optionally replaced by, where R 27 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, X G Each of them, C(R 21 )(R 22 ) or C(O), R 21 H, C 1-3 Alkyl, or bonded, Here, R 21 If R is a bond, 19 However, C 1-3 It is alkyl, n is 1, R 21 and R 19 They connect together to form a 3-5 membered ring. R 22 Each of them is H or C 1-3 It is alkyl, m is 0, 1, or 2, n is 0, 1, or 2. Or, a salt that is permitted as a medicine.

[0175] 2. Compounds of formula IA or formula IB: [ka] During the ceremony, X A However, N or C(R 5 ) and R 5 However, H is, R 1 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 6 Replaced by choice, R 2 However, C 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyl, halogen, and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 9Replaced by choice, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8 Bicycloalkylcyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexane-3-yl, piperidine-1-yl, and -OCH2-(C 3-6 Selected from the group consisting of cycloalkyls, Said C 1-6 Alkyl, the C 3-6 Cycloalkyl, the C 5-8 Spiroalkyl, the C 5-8 bicycloalkyl, the C 5-8 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 a halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 The C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN. 3-6 One methylene group of the cycloalkyl group is -O- or -N(R 10 )- can be optionally replaced by, R 10 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, The aforementioned azetidine-1-yl, the aforementioned pyrrolidine-1-yl, the aforementioned 3-azabicyclo[3.1.0]hexane-3-yl, the aforementioned piperidine-1-yl, or the aforementioned -OCH2-(C 3-6 Cycloalkyl) is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. R 6 Each of them, -OC 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyls and halogens, R 9 However, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Selected from the group consisting of haloalkyl and phenyl, wherein the phenyl is -OC 1-6 They are optionally substituted with 1 to 5 substituents individually selected from alkyl groups. R 4 However, it is from Equation II: [ka] During the ceremony, X B However, N or C(R 11 ) and R 11 However, H, C 1-3 alkyl, -OH, -OC 1-3 Selected from the group consisting of alkyl and halogen, X C However, C(R 12 )(R 13 ) and R 12 H, C 1-3 Alkyl, or bonded, Here, R 12 If R is a bond, 11 However, C 1-3 It is alkyl, R 11 and R 12 They connect together to form a 3-5 membered ring. R 13 Each of them is H or C 1-3 It is alkyl, X D However, C(R 14 ) or N, R 14 However, H or C 1-3 It is alkyl, R 23 However, a bond, -O-, or one methylene group can be optionally replaced by -O- in C 1-6 It is a hydrocarbon chain, R 15 However, C 1-6 Alkyl, C 1-6 Haloalkyl, diC 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) C 3-6 Cycloalkyl or the C 3-6 Heterocycloalkyl groups are oxo (=O) and C 1-3 Optionally substituted with 1 to 3 substituents independently selected from alkoxys and halogens, (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 a halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 Alkyl), -CN, C 2-4 Alkenil, C 3-6 Cycloalkyl, and C 3-6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of heterocycloalkyl groups. C of the lower category (b) 1-6 Alkyl or the C 1-6 The haloalkyl group is optionally substituted with -OH. C of the lower category (b) 3-6 Heterocycloalkyls are halogens, C 1-3 Alkyl and -C(O)O(C 1-6They are optionally substituted with 1 to 3 substituents individually selected from the group consisting of alkyl groups. (c)C above 1-6 Alkyl is -N(H)C(O)R 24 -Oxo (=O), -OC 1-3 Alkyl, and -N(R 25 )(R 26 ) is optionally substituted by 1 to 3 substituents independently selected from the original, R 24 However, C 1-6 Alkyl or aryl, and the C 1-6 Alkyl is C 1-3 Optionally substituted with alkoxy or halogen, R 25 However, H or C 1-3 It is alkyl, R 26 However, H or C 1-3 It is alkyl, X E However, C(R 16 )(R 17 ), O, NR 18 , or a combination, R 16 However, it is H or F, R 17 However, it is H or F, R 18 However, H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl, the -C(O)-C 1-6 Alkyl, or the aforementioned -C(O)-C 3-6 Cycloalkyls, halogens and C 1-3 It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, X F However, C(R 19 )(R 20 ) and R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl, Here, R 19 and R 20 However, C 1-3 If it is alkyl, R 19 and R 20 They can optionally be linked together to form a 3-6 member ring, and / or Here, R 19 and R 20 However, C 1-3 If it is alkyl, one methylene group is -O- or -N(R 27 )- is optionally replaced by, where R 27 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, X G Each of them, C(R 21 )(R 22 ) or C(O), R 21 H, C 1-3 Alkyl, or bonded, Here, R 21 If R is a bond, 19 However, C 1-3 It is alkyl, n is 1, R 21 and R 19 They connect together to form a 3-5 membered ring. R 22 Each of them is H or C 1-3 It is alkyl, m is 0, 1, or 2, n is 0, 1, or 2. Or, a salt that is permitted as a medicine.

[0176] 3. Compounds of formula IA or formula IB: [ka] During the ceremony, X A However, N or C(R 5 ) and R 5 However, H is, R 1 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from the group consisting of cycloalkyl and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 6 Replaced by choice, R 2 However, C 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyl and H, the C 1-6 Alkyl or the C 3-6 The cycloalkyl group has 1 to 3 individually selected substituents R 9 Replaced by choice, R 3 However, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-8 Spiroalkyl, C 5-8 Tricycloalkyl, C 5-8 Bicycloalkylcyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexane-3-yl, piperidine-1-yl, and -OCH2-(C 3-6 Selected from the group consisting of cycloalkyls, Said C 1-6 Alkyl, the C 3-6 Cycloalkyl, the C 5-8 Spiroalkyl, the C 5-8 bicycloalkyl, the C 5-8 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 a halogen, C 1-3 Alkyl, C 1-3Optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN, Said C 3-6 One methylene group of the cycloalkyl group is -O- or -N(R 10 )- can be optionally replaced by, R 10 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, The aforementioned azetidine-1-yl, the aforementioned pyrrolidine-1-yl, the aforementioned 3-azabicyclo[3.1.0]hexane-3-yl, the aforementioned piperidine-1-yl, or the aforementioned -OCH2-(C 3-6 Cycloalkyl) is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, and C 1-3 It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. R 6 Each of them, -OC 1-6 Alkyl, C 3-6 Selected from the group consisting of cycloalkyls and halogens, R 9 However, -OC 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 Selected from the group consisting of haloalkyl and phenyl, wherein the phenyl is -OC 1-6 They are optionally substituted with 1 to 5 substituents individually selected from alkyl groups. R 4 However, it is from Equation II: [ka] During the ceremony, X B However, N or C(R 11 ) and R 11 However, H, C 1-3 alkyl, -OH, -OC 1-3 Selected from the group consisting of alkyl and halogen, XC However, C(R 12 )(R 13 ) and R 12 H, C 1-3 Alkyl, or bonded, Here, R 12 If R is a bond, 11 However, C 1-3 It is alkyl, R 11 and R 12 They connect together to form a 3-5 membered ring. R 13 Each of them is H or C 1-3 It is alkyl, X D However, C(R 14 ) or N, R 14 However, H or C 1-3 It is alkyl, R 23 However, a bond, -O-, or one methylene group can be optionally replaced by -O- in C 1-6 It is a hydrocarbon chain, R 15 However, C 1-6 Alkyl, C 1-6 Haloalkyl, diC 1-3 Alkylamino, -C(O)-O-(C 1-6 Alkyl), C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) C 3-6 Cycloalkyl or the C 3-6 Heterocycloalkyl groups are oxo (=O) and C 1-3 Optionally substituted with 1 to 3 substituents independently selected from alkoxys and halogens, (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 a halogen, C 1-6 Alkyl, -OC1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 Alkyl), -CN, C 2-4 Alkenil, C 3-6 Cycloalkyl, and C 3-6 It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of heterocycloalkyl groups. C of the lower category (b) 1-6 Alkyl or the C 1-6 The haloalkyl group is optionally substituted with -OH. C of the lower category (b) 3-6 Heterocycloalkyls are halogens, C 1-3 Alkyl and -C(O)O(C 1-6 They are optionally substituted with 1 to 3 substituents individually selected from the group consisting of alkyl groups. (c)C above 1-6 Alkyl is -N(H)C(O)R 24 -Oxo (=O), -OC 1-3 Alkyl, and -N(R 25 )(R 26 ) is optionally substituted by 1 to 3 substituents independently selected from the original, R 24 However, C 1-6 Alkyl or aryl, and the C 1-6 Alkyl is C 1-3 Optionally substituted with alkoxy or halogen, R 25 However, H or C 1-3 It is alkyl, R 26 However, H or C 1-3 It is alkyl, X E However, C(R 16 )(R 17 ), O, NR 18 , or a combination, R 16 However, it is H or F, R 17However, it is H or F, R 18 However, H, C 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -C(O)-C 3-6 Cycloalkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl, the -C(O)-C 1-6 Alkyl, or the aforementioned -C(O)-C 3-6 Cycloalkyls, halogens and C 1-3 It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, X F However, C(R 19 )(R 20 ) and R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl, Here, R 19 and R 20 However, C 1-3 If it is alkyl, R 19 and R 20 They can optionally be linked together to form a 3-6 member ring, and / or Here, R 19 and R 20 However, C 1-3 If it is alkyl, one methylene group is -O- or -N(R 27 )- is optionally replaced by, where R 27 However, H, C 1-3 Alkyl and -C(O)C 1-3 Selected from the group consisting of alkyl groups, X G Each of them, C(R 21 )(R 22 ) or C(O), R 21 H, C 1-3 Alkyl, or bonded, Here, R 21 If R is a bond, 19 However, C1-3 It is alkyl, n is 1, R 21 and R 19 They connect together to form a 3-5 membered ring. R 22 Each of them is H or C 1-3 It is alkyl, m is 0, 1, or 2, n is 0, 1, or 2. Or, a salt that is permitted as a medicine.

[0177] 4. The compound described in item 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IA.

[0178] 5. The compound described in item 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IB.

[0179] 6. Compounds of formula IA: [ka] During the ceremony, R 1 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 2 However, halogen, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 3 However, halogen, C 1-3 Alkyl and C 1-3 A phenyl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups. X A However, it is N or C(H), R 4 However, it is of formula XXVI: [ka] During the ceremony, X B However, it is N or C(H), R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and C 3-6 A 5-membered heteroaryl or 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups. R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl. Or, a salt that is permitted as a medicine.

[0180] 7.X A A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0181] 8.X A However, C(R 5 ) and R 5 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0182] 9. The compound is a compound of formula IA, and X A The compound listed in item 1, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0183] 10. The compound is a compound of formula IA, and X A However, C(R 5 ) and R 5 A compound listed in item 1, or a pharmaceutically acceptable salt thereof, which is H.

[0184] 11. The compound is a compound of formula IB, and X A However, C(R 5 ) and R 5 A compound listed in item 1, or a pharmaceutically acceptable salt thereof, which is H.

[0185] 12.R1 However, one to three individually selected substituents R 6 C is optionally replaced by 1-6 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0186] 13.R 1 However, C 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0187] 14.R 1 However, a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is -CH3.

[0188] 15.R 1 However, one to three individually selected substituents R 6 C is replaced by 1-6 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0189] 16.R 1 However, one to three individually selected substituents R 6 C is replaced by 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0190] 17.R 6 However, a halogen compound, one of the compounds listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0191] 18.R 6 However, F is a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0192] 19.R 1 However, C 1-6 A compound that is a haloalkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0193] 20.R 1 However, C 1-3 A compound that is a haloalkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0194] 21.R 1 However, a compound described in any one of the preceding items, which is -CF3, or a pharmaceutically acceptable salt thereof.

[0195] 22.R 2 However, one to three individually selected substituents R 9 C is optionally replaced by 1-6 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0196] 23.R 2 However, one to three individually selected substituents R 9 C is optionally replaced by 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0197] 24.R 2 However, a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is -CH3.

[0198] 25.R 2 However, a halogen compound, one of the compounds listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0199] 26.R 2 However, the compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, is Cl.

[0200] 27.R 2 However, F is a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0201] 28.R 3 However, halogen, C 1-3 Alkyl, C 1-3Alkoxy, C 1-3 A phenyl compound as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN.

[0202] 29.R 3 However, halogen, C 1-3 Alkyl, C 1-3 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is a six-membered heteroaryl compound optionally substituted with one to four substituents independently selected from the group consisting of haloalkyl and CN.

[0203] 30.R 3 However, this is the one in Equation III: [ka] During the ceremony, X H However, C(R 31 ) or N, X I However, C(R 32 ) or N, R 28 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 30 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 32However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN. A compound listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0204] 31.R 3 However, this is the one in Equation III: [ka] During the ceremony, X H However, C(R 31 ) or N, X I However, C(R 32 ) or N, R 28 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 30 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 32 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN. A compound listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0205] 32.X H However, C(R 31 ) a compound as described in any one of items 30 to 31, or a pharmaceutically acceptable salt thereof.

[0206] 33.X H A compound described in any one of items 30 to 31, or a pharmaceutically acceptable salt thereof, wherein N is N.

[0207] 34.X I However, C(R 32 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0208] 35.X I A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0209] 36.X H However, C(R 31 ) and X I However, C(R 32 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0210] 37.X H However, N is X I However, C(R 32 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0211] 38.X H However, C(R 31 ) and X I A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0212] 39.R 31 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0213] 40.R 3 However, this is the one in equation IV: [ka] During the ceremony, R 28 However, H, halogen, C 1-3Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 30 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0214] 41.R 3 However, this is the one in equation IV: [ka] During the ceremony, R 28 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 30 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 It is a haloalkyl or CN. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0215] 42.R 3However, this is the one in equation IV: [ka] During the ceremony, R 28 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, or C 1-3 It is an alkoxy, R 29 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 30 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN, R 31 However, H, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 It is an alkoxy or CN. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0216] 43.R 28 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0217] 44.R 28 However, a halogen compound, one of the compounds listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0218] 45.R 28 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is F or Cl.

[0219] 46.R 28 However, F is a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0220] 47.R28 However, the compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, is Cl.

[0221] 48.R 28 However, C such as -CH3 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0222] 49.R 28 However, the compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, is CN.

[0223] 50.R 29 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0224] 51.R 29 However, a halogen compound, one of the compounds listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0225] 52.R 29 However, F is a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0226] 53.R 30 However, a halogen compound, one of the compounds listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0227] 54.R 30 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is F or Cl.

[0228] 55.R 30 However, C such as -CH3 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0229] 56.R 30 However, C such as -OCH3 1-3A compound that is an alkoxy, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0230] 57.R 30 However, C such as -CF3 1-3 A compound that is a haloalkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0231] 58.R 30 However, C such as -CHF2 1-3 A compound that is a haloalkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0232] 59.R 30 However, the compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, is CN.

[0233] 60.R 31 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0234] 61.R 31 However, a halogen compound, one of the compounds listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0235] 62.R 31 However, F is a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0236] 63.R 3 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] JPEG2026524663000276.jpg44159 or a pharmaceutically acceptable salt thereof.

[0237] 64.R 3 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0238] 65.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0239] 66.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0240] 67.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0241] 68.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0242] 69.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0243] 70.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0244] 71.R 3 However, a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: [ka]

[0245] 72.R 3 However, halogen, C 1-3 Alkyl and C 1-3 C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyls. 5-8 A compound that is bicycloalkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0246] 73.R 3 The compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, is a bicyclo[1.1.1]pentyl optionally substituted with CF3 or a C1 alkyl group.

[0247] 74.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0248] 75.R 3 However, halogen, C 1-3 Alkyl and C 1-3 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is a C3-6 cycloalkyl compound optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyls.

[0249] 76.R3 However, it belongs to equation XXV: [ka] During the ceremony, R 33 However, H, halogen, C 1-3 Alkyl and C 1-3 It is a haloalkyl, R 34 However, H, halogen, C 1-3 Alkyl and C 1-3 It is a haloalkyl, q is 1, 2, or 3, p is 1, 2, or 3. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0250] 77. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein q is 1.

[0251] 78. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein q is 2.

[0252] 79. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0253] 80. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein p is 2.

[0254] 81.R 33 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0255] 82.R 33 However, a halogen such as F, a compound listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0256] 83.R 33 However, C such as -CH3 1-3A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0257] 84.R 33 However, C such as -CF3 or -CHF2 1-3 A compound that is a haloalkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0258] 85.R 34 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0259] 86.R 34 However, a halogen such as F, a compound listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0260] 87.R 34 However, C such as -CH3 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0261] 88.R 34 However, C such as -CF3 or -CHF2 1-3 A compound that is a haloalkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0262] 89.R 3 However, a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following: [ka]

[0263] 90.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0264] 91.R 3 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0265] 92.R 4 However, the compound of formula XXVI, as described in any one of the preceding items: [ka] During the ceremony, X B However, it is N or C(H), R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and C 3-6 A 5-membered heteroaryl or 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups. R 19 However, H, halogen, or C 1-3 It is alkyl, R 20 However, H, halogen, or C 1-3 It is alkyl. or a salt of which is permitted as a medicine.

[0266] 93.X D but, C(R 14 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0267] 94.R 4 However, the compound of formula IIA, as described in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0268] 95.R 4 However, the compound of formula IIB, as described in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0269] 96.X B but, C(R 11 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0270] 97.R 4 However, the compound of formula IIC, as described in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0271] 98.R 4 However, the compound of formula IID, as described in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0272] 99.X B However, C(R 11 ) and X D However, C(R 14 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0273] 100.R 4 However, the compound is of formula IIE, as described in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0274] 101.R 4However, the compound is of formula IIF and is one of the compounds listed in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0275] 102.R 4 However, the compound of formula IIG, as described in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0276] 103.R 4 However, the compound of formula IIH, as described in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0277] 104.R 4 However, a compound described in any one of the preceding items, which is a six-membered ring, or a pharmaceutically acceptable salt thereof.

[0278] 105.X E However, O, C(R 16 )(R 17 ), or NR 18 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

[0279] 106.X B However, N is X C However, C(R 12 )(R 13 ) and X D However, C(R 14 ) and X E However, O and X F However, C(R 19 )(R 20 ) and X G However, C(R 21 )(R22 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

[0280] 107.X B However, C(R 11 ) and X C However, C(R 12 )(R 13 ) and X D However, C(R 14 ) and X E However, O and X F However, C(R 19 )(R 20 ) and X G However, C(R 21 )(R 22 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

[0281] 108.X B However, N is X C However, C(R 12 )(R 13 ) and X D However, C(R 14 ) and X E However, NR 18 X F However, C(R 19 )(R 20 ) and X G However, C(R 21 )(R 22 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

[0282] 109.X B However, N is X C However, C(R 12 )(R 13 ) and X D However, C(R 14 ) and X E However, C(R 16 )(R 17 ) and X F However, C(R 19)(R 20 ) and X G However, C(R 21 )(R 22 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

[0283] 110.X B A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0284] 111.X B However, C(R 11 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0285] 112.R 11 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0286] 113.R 11 However, C 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0287] 114.X C However, C(R 12 )(R 13 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0288] 115.R 12 However, each compound is H, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0289] 116.R 12 However, C 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0290] 117.R 12 However, it is a bond, R 11 However, C1-3 It is alkyl, R 11 and R 12 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compounds are linked together to form a 3- to 5-membered ring.

[0291] 118.R 13 However, each compound is H, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0292] 119.R 13 However, C 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0293] 120.X D However, C(R 14 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0294] 121.X D A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0295] 122.R 14 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0296] 123.R 14 However, C 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0297] 124.X B If X is N, D However, C(R 14 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0298] 125.R 23 However, the compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, is a bond.

[0299] 126.R 15 However, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is a five-membered heteroaryl compound optionally substituted with one to three substituents independently selected from the group consisting of alkyl, -CN, and halogen.

[0300] 127.R 15 However, a compound selected from the group consisting of formulas V, VI, VII, VIII, IX, X, XI, and XII, as described in any one of the preceding items: [ka] In the formula, R 37 However, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, H, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 A salt selected from the group consisting of alkyl, -CN, and halogen, or a pharmaceutically acceptable salt thereof.

[0301] 128.R 15 However, a compound selected from the group consisting of formulas XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, and XXIII, as described in any one of the preceding items: [ka] JPEG2026524663000301.jpg48159In formula, R37 and R 38 However, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, H, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 A salt selected from the group consisting of alkyl, -CN, and halogen, or a pharmaceutically acceptable salt thereof.

[0302] 129.R 37 However, C 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0303] 130.R 37 However, a compound described in any one of the preceding items, which is CH3, or a pharmaceutically acceptable salt thereof.

[0304] 131.R 37 However, C 3-6 A cycloalkyl compound, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0305] 132.R 37 However, a compound described in any one of the preceding items, which is a C3 cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

[0306] 133.R 15 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] JPEG2026524663000303.jpg24159 or a pharmaceutically acceptable salt thereof.

[0307] 134.R 15 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0308] 135.R 15 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0309] 136.R 15 However, C 1-6 Alkyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, H, C 1-6 Haloalkyl, -C 1-6 Alkoxy, C 1-6 Haloalkoxy, -(C 1-3 Alkyl)O(C 1-3 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is a six-membered heteroaryl compound optionally substituted with one to three substituents independently selected from the group consisting of alkyl, -CN, and halogen.

[0310] 137.R 15 However, the compound of formula XXV, as described in any one of the preceding items: [ka] During the ceremony, X J However, it is N or CH, X K However, N or C(R 7 ) and X L However, N or C(R 8 ) and R 7 However, C 1-3 It is alkyl, R 8 However, C 1-3 It is alkyl, R 36However, H, or C 1-3 It is alkyl. or a salt of which is permitted as a medicine.

[0311] 138.X J However, a compound described in any one of the preceding items, which is CH, or a pharmaceutically acceptable salt thereof.

[0312] 139.X K A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0313] 140.X K However, C(R 7 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0314] 141.R 7 However, a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is -CH3.

[0315] 142.X L A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein N is present.

[0316] 143.X L However, C(R 8 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0317] 144.R 8 However, a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is -CH3.

[0318] 145.R 36 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0319] 146.R 36 However, C 1-3A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0320] 147.R 36 However, a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is -CH3.

[0321] 148.X J , X K , and X L A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein at least one of the compounds is N.

[0322] 149.X J , X K , and X L A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein one of the compounds is N.

[0323] 150.X J , X K , and X L A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein two of the compounds are N.

[0324] 151.R 15 but: [ka] A compound selected from the group consisting of any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0325] 152.R 15 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0326] 153.X E However, C(R 16 )(R 17A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0327] 154.X E A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is O.

[0328] 155.X E However, NR 18 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0329] 156.X E However, the compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, is a bond.

[0330] 157.R 19 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0331] 158.R 19 However, a halogen compound, one of the compounds listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0332] 159.R 19 However, F is a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0333] 160.R 19 However, C 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0334] 161.R 19 However, a compound described in any one of the preceding items, which is CH3, or a pharmaceutically acceptable salt thereof.

[0335] 162.R 20 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0336] 163.R 20 However, a halogen compound, one of the compounds listed in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0337] 164.R 20 However, F is a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0338] 165.R 20 However, C 1-3 A compound that is alkyl, as described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0339] 166.R 20 However, a compound described in any one of the preceding items, which is CH3, or a pharmaceutically acceptable salt thereof.

[0340] 167.R 19 and R 20 However, C 1-3 It is alkyl, R 19 and R 20 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compounds are linked together to form a 3-6 membered ring.

[0341] 168.X G However, C(R 21 )(R 22 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0342] 169.X G However, a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, which is C(O).

[0343] 170.R 21 A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0344] 171.R 22A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is H.

[0345] 172. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0346] 173. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0347] 174. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0348] 175. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0349] 176. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0350] 177. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0351] 178.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] JPEG2026524663000310.jpg79159 or a pharmaceutically acceptable salt thereof.

[0352] 179.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] JPEG2026524663000312.jpg198159JPEG2026524663000313.jpg72159 or a pharmaceutically acceptable salt thereof.

[0353] 180.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0354] 181.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] JPEG2026524663000316.jpg21159 or a pharmaceutically acceptable salt thereof.

[0355] 182.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0356] 183.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] JPEG2026524663000319.jpg29159 or its pharmaceutically acceptable salt.

[0357] 184.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] JPEG2026524663000321.jpg117159 or a pharmaceutically acceptable salt thereof.

[0358] 185.R 4 However, a compound described in any one of the preceding items, which is a five-membered ring, or a pharmaceutically acceptable salt thereof.

[0359] 186.m is 1, X E A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein n is a bond and n is 1.

[0360] 187.X B However, N is X C However, it is CH2, m is 1, and X D However, C(H) and X E However, it is a combination, X F However, C(H2) and X G A compound described in any one of the preceding items, wherein n is C(H2) and n is 1, or a pharmaceutically acceptable salt thereof.

[0361] 188.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] JPEG2026524663000323.jpg17159 or its pharmaceutically acceptable salt.

[0362] 189.R 4 However, a compound described in any one of the preceding items, which is a four-membered ring, or a pharmaceutically acceptable salt thereof.

[0363] 190.m is 1, X E A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein n is a bond and n is 0.

[0364] 191.X BHowever, N is X C However, it is CH2, m is 1, and X D However, C(H) and X E However, it is a combination, X F A compound described in any one of the preceding items, wherein n is C(H2) and n is 0, or a pharmaceutically acceptable salt thereof.

[0365] 192.X B However, N is X C However, it is CH2, m is 1, and X D However, C(H) and X E However, it is a combination, X F However, C(H2), n is 0, and R 15 but, [ka] A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0366] 193.R 4 However, the following compounds are selected from the group consisting of the following, and are listed in any one of the preceding items: [ka] or a salt of which is permitted as a medicine.

[0367] 194.R 4 However, a compound described in any one of the preceding items, which is a three-membered ring, or a pharmaceutically acceptable salt thereof.

[0368] 195.m is 0, X E A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein n is a bond and n is 0.

[0369] 196.X B However, C(H) is 0, and X D However, C(H) and X E However, it is a combination, X FA compound described in any one of the preceding items, wherein n is C(H2) and n is 0, or a pharmaceutically acceptable salt thereof.

[0370] 197.R 4 but, [ka] The compound described in any one of the preceding items, or a salt of which is permitted as a medicine.

[0371] 198. The compound is a compound of formula IA, in which, R 1 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 2 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyls, halogens, and H, R 3 However, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 A phenyl molecule optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl and CN, wherein the C 1-3 One methylene group of the alkyl group is optionally replaced by -O-. X A However, it is N or CH, X B However, it is N or CH, X C However, it is C(H)2, X D However, C(H), X E However, it is O, X F However, C(R 19 )(R 20 ) and here, each R 19 and R 20 However, each is individually selected as either H or CH3. X GHowever, it is C(H)2, m is 1, n is 1, R 23 However, it is a combination, R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -CN, and C 3-6 It is a 5-membered heteroaryl or 6-membered heteroaryl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof.

[0372] 199. The compound is a compound of formula IA, in which, R 1 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 2 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 3 However, halogen, C 1-3 Alkyl and C 1-3 A phenyl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups. X A However, it is CH, X B However, N is, X C However, it is C(H)2, X D However, C(H), X E However, it is O, X F However, it is C(H)2, X G However, it is C(H)2, m is 1, n is 1, R 23However, it is a combination, R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and C 3-6 A compound according to any one of the preceding items, which is a 5-membered heteroaryl or 6-membered heteroaryl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups.

[0373] 200. The compound is a compound of formula IA, in which, R 1 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 2 However, C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl and H, R 3 However, halogen, C 1-3 Alkyl and C 1-3 A phenyl molecule that is optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups. X A However, N is, X B However, C(H), X C However, it is C(H)2, X D However, C(H), X E However, it is O, X F However, it is C(H)2, X G However, it is C(H)2, m is 1, n is 1, R 23 However, it is a combination, R 15 However, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and C 3-6A compound according to any one of the preceding items, which is a 5-membered heteroaryl or 6-membered heteroaryl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of cycloalkyl groups.

[0374] 201. The compound is selected from the group consisting of the following, and is a compound described in any one of the preceding items: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, (R)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, 9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, 9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one, (R)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazole-4-yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, (S)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazole-4-yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one, 6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chlorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chlorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(3,4-difluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, 3-Chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-methyl-6-(2-methyl-4-pyridyl)morpholin-4-yl)pyrazino[1,2-a]pyrimidine-4-one, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl)pyrido[1,2-a]pyrimidine-4-one, 7-[2,2-difluoro-6-(2-methyl-4-pyridyl)morpholin-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-methyl-6-(2-methyl-4-pyridyl)morpholin-4-yl)pyrido[1,2-a]pyrimidine-4-one, 7-[(2R,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyltetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 7-[2,2-difluoro-6-(2-methyl-4-pyridyl)morpholin-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-pyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-pyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-(trifluoromethyl)pyrazino[1,2-a]pyrimidine-4-one, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrazino[1,2-a]pyrimidine-4-one, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2,3-dimethyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 7-[2,2-difluoro-6-(1-methylpyrazole-4-yl)morpholin-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-pyrido[1,2-a]pyrimidine-4-one, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-4-oxo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 3-Chloro-7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2-methyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2-methyl-4-oxo-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-4-oxo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2-methyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-4-oxo-2-(trifluoromethyl)pyrazino[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 9-(3-methoxycyclobutyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one, 9-(3-methoxycyclobutyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-Chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chlorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chlorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-chlorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, 3-Chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 3-Chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, and 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a salt of which is permitted as a medicine.

[0375] 202. A compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, e.g., a TREM2 activator, e.g., a TREM2 agonist.

[0376] 203. A compound described in any one of the preceding items, 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, such as Syk, ZAP70, PI3K, Erk, AKT, and GSK3b, and / or the compound enhances the TREM2-inducible phosphorylation level of the Syk kinase.

[0377] 204. A compound described in any one of the preceding items, 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 selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119 that are regulated by TREM2.

[0378] 205. A pharmaceutical composition comprising a compound described in any one of the preceding items, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

[0379] 206. A compound described in any one of items 1 to 204, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 205, for use as a pharmaceutical.

[0380] 207. A compound described in any one of items 1 to 204, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 205, for use in the treatment of conditions associated with loss of function of TREM2, for example, for use in the treatment of conditions associated with mutations in TREM2.

[0381] 208. A compound described in any one of items 1 to 204, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 205, for use in the treatment of neurodegenerative diseases.

[0382] 209. A compound or composition for use as described in item 208, wherein the neurodegenerative disease is selected from the group consisting of tauopathy, TDP-43 proteinopathy, synucleinopathy, dementia, amyloidosis, demyelinating disorders of the central nervous system (CNS), demyelinating disorders of the primary nervous system (PNS), leukoencephalopathy, leukodystrophy, transmissible spongiform encephalopathy (TSE), and lysosomal storage disorders (LSD).

[0383] 210. A compound described in any one of items 1 to 204, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 205, 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.

[0384] 211. A compound described in any one of items 1 to 204, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 205, for use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, Pyle's disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, osteodysplasia, 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 disorders, inflammatory bowel disease (IBD), metabolic syndromes, obesity, type 2 diabetes mellitus, atherosclerosis, alcoholic and non-alcoholic fatty liver, alcoholic and non-alcoholic steatohepatitis, and amyloidosis.

[0385] 212. A compound or composition for use as described in any one of items 206 to 211, wherein the compound is administered in an amount of about 0.01 mg / kg to about 100 mg / kg body weight / day.

[0386] 213. A compound or composition for use as described in any one of items 206 to 211, wherein the compound is administered by enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

[0387] 214. A method for treating a condition related to loss of TREM2 function, such as neurodegenerative diseases, comprising administering a therapeutically effective amount of a compound described in any one of items 1 to 204, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 205, to a subject requiring such treatment.

[0388] 215. Use of any one of the compounds described in items 1 to 204, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in item 205, for the manufacture of a pharmaceutical for the treatment of conditions associated with loss of TREM2 function, such as neurodegenerative diseases.

[0389] 216. A method for enhancing or increasing TREM2 activity in a subject requiring enhancement or increase of TREM2 activity, for example in a subject with a neurodegenerative disease, for example, one or more of the following: i) enhancing or activating TREM2 signaling via DAP12; ii) inducing phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, such as Syk, ZAP70, PI3K, Erk, AKT, and GSK3b; iii) enhancing the TREM2-induced phosphorylation level of the Syk kinase; iv) increasing the expression level of one or more TREM2-regulated genes, for example, in the brain; and / or v) increasing the expression level of one or more TREM2-regulated genes selected from the group consisting of CXCL10, CCL2, CST7, and TMEM119, for example, in the brain, the method comprising administering to the subject a compound described in any one of items 1 to 204, or a pharmaceutically acceptable salt thereof.

[0390] Abbreviation DCM Dichloromethane PIDA Phenyliodin(III) Diacetate HPLC (High-Performance Liquid Chromatography) MeCN acetonitrile MeOH methanol EtOH Ethanol THF (Tetrahydrofuran) DMF Dimethylformamide TFA (Trifluoroacetic Acid) DIPEA Diisopropylethylamine HCl ethyl acetate NBS N-bromosuccinimide NCS N-chlorosuccinimide Pd / C Palladium Carbon NaOAc sodium acetate Acetic acid (ACOH) NaHCO3 (sodium bicarbonate) NH4OAc (Ammonium acetate) NiCl2·6H2O Nickel chloride hexahydrate DMAP 4-dimethylaminopyridine Pd2(dba)3 Tris(dibenzylideneacetone) Dipalladium(0) Pd(tBu3P)2 bis(tri-tert-butylphosphine)palladium(0) PdCl2(dppf) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl Xanthophos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Me2NH2,HCl methylamine hydrochloride HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate NH4OAc (Ammonium acetate) RuPhos-Pd-G3 (2-dicyclohexylphosphin-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate rt room temperature Rt retention time SFC Supercritical Fluid Chromatography Preparative HPLC (Preparative High-Performance Liquid Chromatography) NP normal phase mL (milliliter) mg milligrams g grams mmol millimol mole

[0391] LCMS conditions: Condition A LCMS column - Acquity BEH C18 (50 × 2.1 mm, 1.7 u). Initially, (90% [0.05% HCOOH aqueous solution] and 10% [0.05% HCOOH in CH3CN:water (90:10)] were maintained for 0.75 minutes, then by 1.00 minutes, to 50% [0.05% HCOOH aqueous solution] and 50% [0.05% HCOOH in CH3CN:water (90:10)], then by 2.00 minutes, to 2% [0.05% HCOOH aqueous solution] and 98% [0.05% HCOOH in CH3CN:water (90:10)]. This mobile phase composition was maintained for 2.25 minutes, and finally, by 2.60 minutes, it was returned to the initial conditions and maintained for 3.00 minutes). Flow rate: 0.60 ml / min.

[0392] Condition B Column: Xbridge C18 (4.6 × 50 mm, 5 u). Mobile phase: 90% [10 mM ammonium acetate aqueous solution] and 10% [CH3CN]. This was changed to 70% [10 mM ammonium acetate aqueous solution] and 30% [CH3CN] by 1.5 minutes, and then to 10% [10 mM ammonium acetate aqueous solution] and 90% [CH3CN] by 3.00 minutes. This mobile phase composition was maintained until 4.00 minutes, and finally returned to the initial conditions by 5.00 minutes. Flow rate = 1.20 ml / min

[0393] Condition C LCMS column - Acquity BEH C8 (50 × 2.1 mm, 1.7 u). Initially, a 95% [0.05% HCOOH aqueous solution] and 5% [0.05% HCOOH in CH3CN:water (90:10)] were maintained for 0.75 minutes, then changed to 75% [0.05% HCOOH aqueous solution] and 25% [0.05% HCOOH in CH3CN:water (90:10)] by 1.50 minutes, then changed to 5% [0.05% HCOOH aqueous solution] and 95% [0.05% HCOOH in CH3CN:water (90:10)] by 3.00 minutes. This mobile phase composition was maintained for 4.00 minutes, and finally returned to the initial conditions by 4.50 minutes and maintained for 5.10 minutes. Flow rate: 0.80 ml / min.

[0394] Condition D Column: Xbridge C18 column (3.5 μm, 50 × 3 mm), (Initially, 95% [5 mM NH4OAc aqueous solution] and 5% [5 mM NH4OAc:water in ACN (90:10)] were maintained for 0.75 minutes, then 70% [5 mM NH4OAc aqueous solution] and 30% [5 mM NH4OAc:water in ACN (90:10)] by 1.00 minutes, and finally 2% [5 mM NH4OAc aqueous solution] and 98% [5 mM NH4OAc:water in ACN (90:10)] by 2.00 minutes, this mobile phase composition was maintained until 2.50 minutes, and finally returned to the initial conditions by 2.75 minutes, and this composition was maintained until 3.0 minutes). Flow rate: 1.20 ml / min.

[0395] Condition E Column: YMC Triart C18 (33 × 2.1 mm, 3u), (Initially, 98% [0.05% HCOOH aqueous solution] and 2% [0.05% HCOOH in ACN:water (90:10)] were maintained for 0.75 minutes, then by 1.0 minute, 90% [0.05% HCOOH aqueous solution] and 10% [0.05% HCOOH in ACN:water (90:10)], and further by 2.00 minutes, 2% [0.05% HCOOH aqueous solution] and 98% [0.05% HCOOH in ACN:water (90:10)], this mobile phase composition was maintained for 2.50 minutes, and finally by 4.90 minutes, it was returned to the initial conditions, and this composition was maintained for 3.0 minutes). Flow rate: 1.0 ml / min.

[0396] Reverse-phase preparative purification method: Unless otherwise specified, preparative HPLC was performed using a Waters automated purifier operating at ambient temperature and a flow rate of 16 mL / min.

[0397] Preparative A Column name: YMC-Actus C18 (250 × 20 mm, 5 μm). Mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile; Gradient profile: The initial composition of the mobile phase was 60% A and 40% B, then 40% A and 60% B by 3 minutes, then 20% A and 80% B by 20 minutes, then 5% A and 95% B by 21 minutes. This composition was held for 22 minutes for column washing, then returned to the initial composition by 23 minutes and held for 25 minutes.

[0398] Preparative B Column name: Chromcore C18 (250 × 21.2 mm, 5 μm). Mobile phase: A = 20 mM ammonium bicarbonate aqueous solution, B = acetonitrile:methanol (50:50); Gradient profile: The initial composition of the mobile phase was 60% A and 40% B, then by 3 minutes, 35% A and 65% B, then by 20 minutes, 5% A and 95% B, then by 21 minutes, this composition was held for 22 minutes for column washing, then returned to the initial composition by 23 minutes and held for 25 minutes.

[0399] Preparative C Column name: Hydrosphere C18 (250 × 20 mm, 5 μm). Mobile phase: A = 10 mM ammonium acetate aqueous solution, B = acetonitrile; Gradient profile: The initial composition of the mobile phase was 60% A and 40% B, then by 3 minutes, 45% A and 55% B, then by 20 minutes, 30% A and 70% B, then by 21 minutes, 5% A and 95% B. This composition was held for 22 minutes for column washing, then returned to the initial composition by 23 minutes and held for 25 minutes.

[0400] Preparative D Column name: CHROMCORE 120 C18.5μm (21.2×250mm). Mobile phase: A = acetonitrile, B = 20mM ammonium bicarbonate aqueous solution; gradient profile: The initial composition of the mobile phase was 30% A and 70% B, then 50% A and 50% B by 3 minutes, then 61.6% A and 38.4% B by 14 minutes, then 100% A and 0% B by 14.1 minutes. This composition was held for 18 minutes for column washing, then returned to the initial composition by 18.1 minutes and held for 21 minutes.

[0401] SFC method: SFC Condition 1: Chiral separation was performed using a Waters TharSFC-80 instrument equipped with a UV detector 40D, a CHIRALPAK-IG (30.0 mm × 250 mm), 5 μm column, at a temperature of 35°C, maintaining a flow rate of 70 ml / min, and delivering the sample using supercritical 60% CO2 and 40% (100% MeOH) as the mobile phase. This homogeneous mixture was delivered for 10.0 minutes, and an isobaric condition of 110 bar was maintained (wavelength 220 nm).

[0402] SFC Condition 2: Preparative SFC purification of CR635-22308-31-P (TN-86) was performed using a PIC SOLUTIONS-175 instrument equipped with a Knauer 40D detector, an I CELLULOSE J (30.0 mm × 250 mm) and a 5 μm column, at a temperature of 35°C, maintaining a flow rate of 80 ml / min, and using supercritical 60% CO2 and 40% [100% MeOH] as the mobile phase. This homogeneous mixture was delivered for 14.0 minutes, and an isobaric condition of 100 bar was maintained (wavelength 275 nm).

[0403] Normal-phase chiral separation method: NP Chiral Method 1: Chiral separation was performed using an Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 × 4.6 mm) 5u. The operation was performed at ambient temperature with a flow rate of 1.0 mL / min. The mobile phase was a mixture of 50% hexane, 25% ethyl alcohol, 25% dichloromethane, and 0.1% IP amine. This homogeneous mixture was maintained for 25 minutes, and a wavelength of 296 nm was used.

[0404] NP Chiral Method 2: Chiral separation was performed using an Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 × 21 mm) 5 μm. Operation was performed at ambient temperature, with a flow rate of 21.0 mL / min. The mobile phase was a mixture of 60% hexane, 20% dichloromethane, and 20% ethyl alcohol. This homogeneous mixture was maintained for 25 minutes, and a wavelength of 260 nm was used.

[0405] NP Chiral Method 3: Chiral separation was performed using an Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 × 21 mm) 5 μm. Operation was performed at ambient temperature with a flow rate of 21.0 mL / min. The mobile phase was a mixture of 70% hexane, 15% DCM, and 15% EtOH. This homogeneous mixture was maintained for up to 20 minutes, and a wavelength of 308 nm was used.

[0406] NP Chiral Method 4: Chiral separation was performed using an Agilent 1200 series instrument. Column name: CHIRALPAK IC (250 × 20 mm) 5u. The operation was performed at ambient temperature with a flow rate of 18.0 mL / min. The mobile phase was a mixture of 50% hexane, 25% dichloromethane, and 25% ethyl alcohol. This homogeneous mixture was maintained for 25 minutes, and a wavelength of 328 nm was used.

[0407] Synthesis of intermediates Synthesis of 2-(1-methyl-1H-pyrazole-4-yl)morpholine (intermediate I-1) Step 1-2: Preparation of chloro-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one: [ka] In a furnace-dried two-necked round-bottom flask, 10 g of 4-bromo-1-methyl-1H-pyrazole (62.2 mmol) was dissolved in 100 mL of anhydrous THF and cooled to -78°C. 40 mL of n-BuLi (93.2 mmol; 2.3 M in hexane) was slowly added under an argon atmosphere, and the reaction was continued at -78°C for 1 hour. Next, a solution of 2-chloro-N-methoxy-N-methylacetamide (13 g of 2-chloro-N-methoxy-N-methylacetamide) in 40 mL of THF was slowly added, and the reaction was extended at 78°C for another hour. After completion, the reaction mixture was stopped with a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated under vacuum. The crude substance was purified by column chromatography (100-200 mesh size) using silica gel with 20-50% ethyl acetate in hexane to obtain 2-chloro-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (3.5 g, yield 35.5%) as an off-white solid.

[0408] 1H NMR (400 MHz, DMSO D6) δ8.46(s,1H),7.99(s,1H),4.81(s,2H),3.88(s,3H). LCMS condition A: Rt=1.48 min. m / z 159.02[M+H] + .

[0409] Step 2-2: Preparation of (benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one: [ka] To a suspension of 2-chloro-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (5.0 g, 31.6 mmol) in acetonitrile (50 mL), 2-(benzylamino)ethen-1-ol (5.7 g, 38.3 mmol) and potassium carbonate (8.8 g, 63.2 mmol) were added, and the reaction mixture was heated at 60 °C for 16 hours. After completion, excess solvent was removed under reduced pressure, the residue was washed with cold water, and then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain the crude product. The crude product was purified by silica gel column chromatography (100-200 mesh size) using 40-60% ethyl acetate in hexane to obtain 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (6 g, yield 69.5%) as a yellow oil.

[0410] 1H NMR(400MHz,DMSO D6)δ8.38(s,1H),7.92(s,1H),7.56-7.27(m,5H),4.44(t,J=5.04Hz,1H),3.85(s,3H) ),3.76(s,1H),3.71(s,3H),3.67(s,3H),3.51-3.48(m,2H),2.61(t,J=6.32Hz,2H), LCMS condition A: Rt=0.46 min. m / z 274.3[M+H] + .

[0411] Step 3-2-Preparation of (benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-ol: [ka] The reaction mixture was cooled to 0°C to a stirred solution of 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (5 g, 18.3 mmol) in anhydrous methanol. NaBH4 (1.4 g, 3.7 mmol) was added in small amounts over 10 minutes, and the reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was then warmed to room temperature for 2 hours. The reaction mixture was stopped with cold water and subsequently extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under vacuum, and purified by silica gel column chromatography (100-200 mesh size) using 5% methanol in dichloromethane to obtain 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-ol (3.0 g, yield 59.5%) as a yellow, viscous oil.

[0412] 1H NMR(400MHz,DMSO D6)δ7.47(s,1H),7.35-7.29(m,5H),7.26(s,1H).4.76(d,J=3.52Hz,1H),4.62-4.58(M,1H),4. 38(t,J=5.36Hz,1H),3.75(s,3H),3.69(d,J=9.08Hz,2H),3.48-3.4(m,2H),2.63-2.54(m,3H). LCMS condition A: Rt=0.39 min. m / z 276.3[M+H] + .

[0413] Step 4 - Preparation of 4-benzyl-2-(1-methyl-1H-pyrazole-4-yl)morpholine (as HCl salt): [ka] The mixture of the obtained 2-(benzyl(2-hydroxyethyl)amino)-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-ol (2 g, 7.27 mmol) and an aqueous HCl solution (6 N, 20.0 mL) was heated under reflux for 2 hours. The reaction mixture was evaporated under reduced pressure, the residue was washed with ether, and the mixture was vacuum-dried to obtain 4-benzyl-2-(1-methyl-1H-pyrazole-4-yl)morpholine HCl salt (1.7 g, yield 90.8%) as a yellow, sticky solid.

[0414] We were able to proceed to the next step without further refining this substance.

[0415] 1H NMR(400MHz,DMSO D6)δ12.05(bs,1H),7.76(s,1H),7.68-7.63(m,2H),7.46-7.43(m,3H),7.41(s,1H),4.95(d,J=10.0Hz,1H),4 .34(s,2H),4.08-4.0(m,2H),3.78(s,3H),3.32(d,J=11.8Hz,1H),3.21(d,J=12.12Hz,1H),3.15-3.07(m,2H). LCMS condition A: Rt=0.40 min. m / z 258.3[M+H] + .

[0416] Step 5-2: Preparation of (1-methyl-1H-pyrazole-4-yl)morpholine HCl salt (intermediate I-1): [ka] A 50 mL ethanol solution of 4-benzyl-2-(1-methyl-1H-pyrazole-4-yl)morpholine (2 g, 7.8 mmol) was placed in a 100 mL par-autoclave container and purged with argon. Pd(OH)2 (0.5 g; 10 w / w%) was added, and the reaction mixture was hydrogenated at room temperature for 18 hours (30 psi). The reaction mixture was filtered through a Celite pad and washed with ethanol. By evaporation of the solvent under reduced pressure, 2-(1-methyl-1H-pyrazole-4-yl)morpholine HCl salt (1.2 g, yield 92.2%) was obtained as a sticky solid.

[0417] 1H NMR(400MHz,DMSO D6)δ9.82(bs,1H),9.64(bs,1H),7.77(s,1H),7.45(s,1H),4.75(d,J=9.68Hz,1H),3 .98-3.86(m,2H),3.78(s,3H),3.31(d,J=11.32Hz,1H),3.31(d,J=11.32Hz,1H),3.18 3.31(d,J=11.36Hz,1H),3.15-2.85(m,2H). LCMS condition A: Rt=0.70 min. m / z 168.1[M+H] + .

[0418] Intermediates I-2 and I-14 were synthesized using the same procedure as steps 1-5 described for intermediate I-1. [Table 1]

[0419] Synthesis of (S)-2-(1-methyl-1H-pyrazole-4-yl)morpholine HCl salt (intermediate I-3) Step 1: Chiral separation of (S)-2-(1-methyl-1H-pyrazole-4-yl)morpholine, HCl salt (intermediate I-3), and (R)-2-(1-methyl-1H-pyrazole-4-yl)morpholine: [ka] Chiral separation of 2-(1-methyl-1H-pyrazole-4-yl)morpholine (3 g, 0.086 mmol) was performed by SFC (SFC condition 1) to obtain (S)-2-(1-methyl-1H-pyrazole-4-yl)morpholine (730.2 mg, yield 24.3%; eluted first and assigned as intermediate I-3 (peak 1) as pale yellow rubber) and (R)-2-(1-methyl-1H-pyrazole-4-yl)morpholine (762.3 mg, yield 25.4%, eluted later and assigned as peak 2 as pale yellow rubber). The stereochemistry of both peaks was assigned based on the report in WO2021226135.

[0420] Intermediate I-3 (peak 1): 1H NMR(400MHz,DMSO-d6)δ9.82(brs,1H),9.64(brs,1H),7.77(s,1H),7.45(s,1H),4.75(d,J=9.6 8Hz,1H),3.98-3.86(m,2H),3.78(s,3H),3.31(d,J=11.32Hz,1H),3.31(d,J=11.32Hz,1H),3.18 3.31(d,J=11.36Hz,1H),3.15-2.85(m,2H). LCMS condition A: Rt=0.70 min. m / z 168.1[M+H] + .

[0421] Peak 2:1H NMR(400MHz,DMSO-d6)δ9.82(brs,1H),9.64(brs,1H),7.77(s,1H),7.45(s,1H),4.75(d,J=9.6 8Hz,1H),3.98-3.86(m,2H),3.78(s,3H),3.31(d,J=11.32Hz,1H),3.31(d,J=11.32Hz,1H),3.18 3.31(d,J=11.36Hz,1H),3.15-2.85(m,2H). LCMS condition A: Rt=0.70 min. m / z 168.1[M+H] + .

[0422] Analytical chiral HPLC: CHIRALPAK AD-H (4.6 x 250 mm), 5 μl mobile phase: 0.5% DEA in EtOH; flow rate: 4.0 ml / min. Solubility: MeOH, Rt = 2.4 min (for peak 1) and Rt = 3.02 min (for peak 2).

[0423] Synthesis of 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (intermediate I-4) Step 1 - Preparation of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde: [ka] To a stirred solution of 1H-pyrazole-4-carbaldehyde (5 g, 52.1 mmol) in DCE (200 mL), cyclopropylboronic acid (8.9 g, 104.2 mmol), 2,2-bipyridyl (8.9 g, 57.3 mmol), and sodium carbonate (15.8 g, 114.6 mmol) were added under an oxygen atmosphere. Copper acetate (10.4 g, 57.3 mmol) was added to the reaction mixture. The resulting mixture was heated to 70°C for 16 hours. The reaction mixture was filtered through a Celite short pad, washed with methanol, and concentrated under reduced pressure. The crude residue was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (10% ethyl acetate-hexane) to obtain 1-cyclopropyl-1H-pyrazole-4-carbaldehyde (6 g, yield 84.1%) as a colorless liquid.

[0424] LCMS condition A: Rt=0.93 min. m / z 137.2[M+H] + .

[0425] Step 2-6 Preparation of (1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate [ka] To a solution of 1-cyclopropyl-1H-pyrazole-4-carbaldehyde (3.5 g, 25.7 mmol) in DCM (80 mL) stirred at 0°C, buta-3-in-1-ol (3.2 mL, 38.6 mmol) was added, followed by triflic acid (5.7 mL, 64.3 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction was stopped with a saturated aqueous solution of sodium bicarbonate, extracted with DCM, and concentrated under reduced pressure. The crude product was purified by column chromatography (20-40% ethyl acetate in hexane) to obtain 6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (3 g, yield 34.2%) as brown rubber.

[0426] 1H NMR (400MHz, DMSO-d6) δ7.74(s,1H),7.36(s,1H),6.20(s,1H),5.32(s,1H),3.91-3.64(m,3H),2.49-2.42(m,2H),1.11-0.88(m,4H). LCMS condition B: Rt=3.35 minutes. m / z 339[M+H] +

[0427] Step 3-1 Preparation of cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (intermediate I-4) [ka] To a stirred solution of 6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (1 g, 2.96 mmol) and bis(pinacolate)diborone (1.2 g, 4.4 mmol) in 1,4-dioxane (15 mL), potassium acetate (1.2 mg, 11.8 mmol) was added and the mixture was degassed with argon. PdCl2 (dppf).DCM (0.2 g, 0.3 mmol) was added under an inert atmosphere. The resulting mixture was heated at 80°C for 2 hours. The reaction mixture was diluted with ethyl acetate, filtered through a Celite short pad, and washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure, and the crude product was purified by column chromatography (30% ethyl acetate in hexane) to obtain 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole (0.5 g, yield 53%) as a solid.

[0428] LCMS condition B: Rt=3.19 minutes. m / z 317[M+H] + .

[0429] The following intermediates I-5 and I-6 were synthesized using the corresponding commercially available aldehydes and alkynes, following the same procedure as described for intermediate I-4 in two steps (steps 2 and 3). [Table 2]

[0430] The following table contains information on the analysis and yield of intermediates I-5 and I-6: [Table 3]

[0431] Synthesis of 7-bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one (intermediate I-7): Step 1-5 Preparation of bromo-3-(2,4-difluorophenyl)pyrazine-2-amine: [ka] To a stirred suspension of 3,5-dibromopyrazine-2-amine (10 g, 39.5 mmol) and (2,4-difluorophenyl)boronic acid (6.2 g, 39.5 mmol) in toluene (225 mL), ethanol (50 mL), and water (40 mL), K3PO4 (16.8 g, 17.1 mmol) was added and the mixture was purged with argon. Pd(PPh3)4 (2.1 g, 1.9 mmol) was added under an inert atmosphere. The resulting mixture was heated at 100 °C for 16 hours. The reaction mixture was then passed through a Celite short pad and washed with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (5-15% ethyl acetate-hexane) to obtain 5-bromo-3-(2,4-difluorophenyl)pyrazine-2-amine (8 g, yield 70.7%) as a yellow solid.

[0432] LCMS condition A: Rt=2.04 min. m / z 286.01[M+H]+ .

[0433] Step 2-7 Preparation of bromo-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one: [ka] To a stirred solution of 5-bromo-3-(2,4-difluorophenyl)pyrazine-2-amine (1.0 g, 3.5 mmol) and methyl 3-oxobutanoate (2.0 g, 17.5 mmol) in diphenyl ether (6 mL), BiCl3 (662 mg, 2.1 mmol) was gradually added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 150 °C for 4 hours. The reaction mixture was diluted with DCM (30 mL) and the reaction was stopped with cold saturated sodium bicarbonate solution (25 mL). The reaction mixture was filtered through a Celite pad, the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous Na2SO4, and then evaporated under reduced pressure to obtain the crude product. The crude product was purified by combiflush (2-10% ethyl acetate in hexane) to obtain 7-bromo-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one (300 mg, yield 24.3%) as an off-white solid.

[0434] LCMS condition A: Rt=2.32 minutes. m / z 352.3[M+H] + .

[0435] Step 3-7 Preparation of bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one (intermediate I-7): [ka] 7-Bromo-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one (700 mg, 2 mmol) was mixed in 10 mL of DMF with NCS (398.2 mg, 3 mmol) added at room temperature. The resulting mixture was heated at 90°C for 16 hours. The reaction mixture was poured into cold water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (5% ethyl acetate-hexane) to obtain 7-bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one (450 mg, yield 58.6%) as a yellow solid.

[0436] LCMS condition A: Rt=2.33 minutes. m / z 386.04[M+H]+.

[0437] The following intermediates I-8 to I-12 were synthesized using the same procedure as described for intermediate I-7. [Table 4] JPEG2026524663000343.jpg13159

[0438] The following table contains information on the analysis and yield of intermediates I-8 to I-12: [Table 5]

[0439] Synthesis of 4-((2R,6R)-4-iodo-6-methyltetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (intermediate I-13): Step 1-4: Preparation of ((2R,6R)-4-iodo-6-methyltetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (intermediate I-13): [ka] To a stirred solution of 1-methyl-1H-pyrazole-4-carbaldehyde (1 g, 9.1 mmol), (2R)-penta-4-en-2-ol (0.93 g, 10.8 mmol), and tetrabutylammonium iodide (2.1 g, 10.9 mmol) in DCM (20 mL), trimethylsilyltrifluoromethanesulfonate (2 mL, 10.8 mmol) was added dropwise at room temperature and the mixture was stirred for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure, diluted with saturated Na2S2O3 solution, and extracted with siRNA. The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography eluting with (50% EA in hexane) to obtain 4-((2R,6R)-4-iodo-6-methyltetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole (0.7 g, yield 25%) as a pale yellow liquid.

[0440] LCMS condition A: Rt=2.01 min. m / z 307.13[M+H] + .

[0441] Synthesis of the Examples Examples 1-8 Example 1: 3-Chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Step 1-3 Preparation of chloro-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one [ka] 7-Bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one[I-7] (500 mg, 1.3 mmol) and 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole[I-4] (817.9 mg, 2.6 mmol) were mixed in 1,4-dioxane (10 mL) and water (2.5 mL). K3PO4 (822.6 mg, 3.9 mmol) was added to the mixed solution, and the mixture was purged with argon. Pd-118 (42.1 mg, 0.06 mmol) was added under an inert atmosphere. The resulting mixture was heated at 90°C for 0.5 hours. The reaction mixture was then passed through a Celite short pad and washed with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (40-60% ethyl acetate-hexane) to obtain 3-chloro-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one (300 mg, yield 46.7%) as a pale yellow solid. LCMS conditions A: Rt = 3.33 min. m / z 496.13 [M+H] + .

[0442] Step 2-3 Preparation of chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one [ka] To a degassed solution of 3-chloro-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one (200 mg, 0.4 mmol) in THF (20 mL), NaOAc (66 mg, 0.8 mmol) and acetic acid (0.05 mL, 0.8 mmol) were added, and the mixture was stirred for 10 minutes under an inert atmosphere. Pd(OH)2 carbon (20%, 84.7 mg) was added, and the mixture was degassed again. The resulting mixture was stirred at room temperature for 3 hours under balloon pressure hydrogen. The reaction mixture was filtered through a Celite short pad and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (preparative B) to obtain 3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one (104 mg, yield 51.2%) as an off-white solid.

[0443] 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),7.75-7.72(m,2H),7.43(t,J=10.0Hz,1H),7.37(s,1H),7.27(t,J=8.4Hz,1H),4.45(d,J=11.2Hz,1H),4.09- 4.06(m,1H),3.69-3.63(m,2H),3.28-3.27(m,1H),2.45(s,3H),2.11(d, J=11.6Hz,1H),1.87-1.77(m,3H),1.00-0.98(m,2H),0.91-0.89(m,2H). LCMS condition C: Rt=3.02 min. m / z 498.39[M+H] + .

[0444] Examples 2-8 were synthesized using the same procedure as described for Example 1. [Table 6] JPEG2026524663000349.jpg207159JPEG2026524663000350.jpg22159

[0445] The following table contains information on the analysis and yield of the analytical data for Examples 2-8. [Table 7] JPEG2026524663000352.jpg210159JPEG2026524663000353.jpg177159

[0446] Example 9 9-(4-chloro-2-fluorophenyl)-7-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one: Step 1-7 Preparation of bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one: [ka] In a sealed tube, 5-bromo-3-chloropyridine-2-amine (1 gm, 4.8 mmol), methyl 2-methyl-3-oxobutanoate (0.6 ml, 4.8 mmol), and BiCl3 (76 mg, 0.2 mmol) were mixed. The resulting mixture was heated at 130°C for 16 hours. The reaction mixture was then diluted with DCM, washed with NaHCO3 solution and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (5% methanol-DCM) to obtain 7-bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (1.4 g, yield 57.7%) as an orange solid.

[0447] LCMS condition A: Rt=1.96 min. m / z 288.98[M+H] + .

[0448] Step 2-9 Preparation of chloro-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one [ka] 7-bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (650 mg, 2.3 mmol) and 1-cyclopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-2H-pyran-2-yl)-1H-pyrazole[I-4] (2.1 gm, 6.8 mmol) were suspended in 1,4-dioxane (30 mL) and water (8 mL). K3PO4 (958.5 mg, 4.5 mmol) was added to the suspension, and the reaction mixture was purged with argon for 5 minutes. Then, Pd118 (73.7 mg, 0.11 mmol) was added under an inert atmosphere. The resulting mixture was heated at 90°C for 4 hours. The reaction mixture was passed through a short bed of Celite, washed with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (50-95% ethyl acetate-hexane) to obtain 9-chloro-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (700 mg, yield 78.1%) as a yellowish solid.

[0449] LCMS condition A: Rt=1.87 min. m / z 397.28[M+H] + .

[0450] Step 3-9 Preparation of (4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4one [ka] 9-Chloro-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (400 mg, 1 mmol) and (4-chloro-2-fluorophenyl)boronic acid (263 mg, 1.5 mmol) were stirred in 1,4-dioxane (16 mL) and water (4 mL). K3PO4 (428 mg, 2 mmol) was added to the mixture, and the reaction mixture was purged with argon for 5 minutes. Pd118 (32.9 mg, 0.05 mmol) was then added under an inert atmosphere. The resulting mixture was heated at 90°C for 2 hours. The reaction mixture was then passed through a short bed of Celite, washed with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography (50-95% ethyl acetate-hexane) to obtain 9-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (250 mg, yield 50.4%) as a gray solid.

[0451] LCMS condition A: Rt=2.01 min. m / z 491.4[M+H] + .

[0452] Step 4-9 Preparation of (4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (Example 9) [ka] 9-(4-chloro-2-fluorophenyl)-7-(6-(1-cyclopropyl-1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (100 mg, 0.2 mmol) was dissolved in 1,4-dioxane (20 mL). Sodium acetate (60 mg) and acetic acid (0.05 mL) were added to the degassed solution and the mixture was stirred for 10 minutes under an inert atmosphere. Pd(OH)2 carbon (20%, 40 mg) was added and the mixture was degassed again. The resulting mixture was stirred at room temperature for 3 hours under balloon pressure hydrogen. The reaction mixture was filtered through a Celite short pad and washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure. The crude substance was purified by reverse-phase preparative HPLC to obtain 9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (55 mg, yield 54.7%) as a white solid.

[0453] 1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.72(s,1H),7.57-7.55(m,2H),7.41-7.39(m,2H),4.45-4.42(m,1H),4.08-4.0 5(m,1H),3.67-3.64(m,2H),3.19-3.11(m,1H),2.28(s,3H),2.13-2.09(m,4H),1.87-1.74(m,3H),0.97-0.91(m,4H). LCMS condition A: Rt=2.20 minutes. m / z 493.23[M+H] + .

[0454] The following table provides information regarding the separation of enantiomers 1A / 1B to 9A / 9B. [Table 8] JPEG2026524663000359.jpg197159JPEG2026524663000360.jpg195159JPEG2026524663000361.jpg119159

[0455] The following table contains information on the analysis and yield of the analytical data for Examples 1A / 1B through 9A / 9B: [Table 9] JPEG2026524663000363.jpg211159JPEG2026524663000364.jpg212159JPEG2026524663000365.jpg206159JPEG2026524663000366.jpg207159 JPEG2026524663000367.jpg211159JPEG2026524663000368.jpg211159JPEG2026524663000369.jpg212159JPEG2026524663000370.jpg119159

[0456] Examples 10A and 10B: Synthesis of 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one and 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one Step 1 - Preparation of 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one (Example 10A) and 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one (Example 10B) [ka] 7-Bromo-3-chloro-9-(2,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one[I-7] (180 mg, 0.47 mmol) and 4-((2R,6R)-4-iodo-6-methyltetrahydro-2H-pyran-2-yl)-1-methyl-1H-pyrazole[I-13] (239.4 mg, 0.8 mmol) were mixed in DMA (6 mL) and TBAI (257 mg, 0.7 mmol) and zinc (60 mg, 0.9 mmol) were added. The reaction mixture was degassed with argon for 10 minutes. Next, nickel(II) chloride ethylene glycol dimethyl ether complex (102 mg, 0.47 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridyl (187 mg, 0.7 mmol) were added to the reaction mixture. The resulting mixture was heated at 100°C for 16 hours. The reaction mixture was diluted with ethyl acetate, filtered through a Celite short pad, and washed with ethyl acetate. The combined organic portion was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by diastereomer separation by combiflash chromatography (40% ethyl acetate in hexane) and subsequent reverse-phase preparative HPLC (preparative method A). 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4R,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyridyl Midine-4-one [Example 10A] (4.2 mg, yield 2%) and 3-chloro-9-(2,4-difluorophenyl)-2-methyl-7-((2R,4S,6R)-2-methyl-6-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one (Example 10B) (13.2 mg, yield 6%) were both obtained as off-white solids. The stereochemistry of both peaks was arbitrarily assigned.

[0457] Example 10A: 1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.80-7.74(m,1H),7.58(s,1H),7.47-7.42(m,1H),7.31-7.26(m,2H),4.65(d,J=10.8Hz,1H),3.93-3.89(m, 1H),3.77(s.3H),3.59-3.58(m,1H),2.47(s,3H),2.37-2.32(m,1H),2.2 3-2.20(m,1H),2.07-2.06(m,1H),1.78-1.72(m,1H),1.12-1.11(m,3H). Condition C: Rt=2.97 minutes. m / z 486.33[M+H] + .

[0458] Example 10B: 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.74-7.73(m,1H),7.64(s,1H),7.39- 7.43(m,1H),7.37(s,1H),7.31-7.26(m,1H),4.52(d,J=10.0Hz,1H),3.77(s .3H),3.76-3.75(m,1H),3.35-3.34(m,1H),2.47(s,3H),2.07-2.06(m,1H), 1.98-1.97(m,1H),1.77-1.75(m,1H),1.50-1.49(m,1H),1.23-1.22(m,3H). Condition C: Rt=2.99 minutes. m / z 486.33[M+H] + .

[0459] Example 11 Examples 11A and 11B were synthesized in one step using the same procedure as described for Examples 10A and 10B, and the stereochemistry of both peaks was assigned in the same manner as for Examples 10A and 10B. [Table 10]

[0460] The following table contains information on the analysis and yield of the analytical data for Examples 11A and 11B: [Table 11]

[0461] Example 12 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one Step 1-3: Preparation of bromo-5-fluoro-2-nitropyridine: [ka] Potassium persulfate (10.2 g, 37.7 mmol) was added to sulfuric acid (10.7 mL), and the resulting mixture was stirred at room temperature for 10 minutes. It was cooled to 0°C, and 3-bromo-5-fluoropyridine-2-amine (1.8 g, 9.4 mmol) was added. The reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was slowly poured onto crushed ice, neutralized with aqueous NH3 solution, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by combiflash chromatography (30-40% ethyl acetate-hexane) to obtain 3-bromo-5-fluoro-2-nitropyridine (1 g, yield 48.1%) as a brown solid.

[0462] 1H NMR(400MHz,DMSO D6)δ8.72(m,2H)

[0463] Step 2-4 Preparation of (5-bromo-6-nitropyridine-3-yl)-2-(1-methyl-1H-pyrazole-4-yl)morpholine: [ka] To a stirred solution of 2-(1-methyl-1H-pyrazole-4-yl)morpholine[I-1] (HCl salt, 113.4 mg, 0.7 mmol) in DMSO (2 mL), DIPEA (0.3 mL, 1.8 mmol) was added at room temperature and the mixture was stirred for 15 minutes. 3-bromo-5-fluoro-2-nitropyridine (100 mg, 0.5 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was slowly poured into ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by combiflash chromatography (80-90% ethyl acetate-hexane) to obtain 4-(5-bromo-6-nitropyridine-3-yl)-2-(1-methyl-1H-pyrazole-4-yl)morpholine (140 mg, yield 84.1%) as a yellow solid.

[0464] LCMS condition B: Rt=1.86 min. m / z 368.3[M+H] + .

[0465] Step 3-Preparation of 3-bromo-5-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)pyridine-2-amine: [ka] To a stirred solution of 4-(5-bromo-6-nitropyridine-3-yl)-2-(1-methyl-1H-pyrazole-4-yl)morpholine (166 mg, 0.5 mmol) in ethanol (2 mL), SnCl2.2H2O (1 g, 4.5 mmol) was added at room temperature. The resulting mixture was heated at 80°C for 2 hours. The reaction was stopped with water and extracted by DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by combiflash chromatography (5% methanol-DCM) to obtain 3-bromo-5-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)pyridine-2-amine (100 mg, yield 65.4%) as a brown solid.

[0466] LCMS condition A: Rt=1.56 min. m / z 338.3[M+H] + .

[0467] Step 4-9 Preparation of bromo-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4one [ka] In a sealed tube, 3-bromo-5-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)pyridine-2-amine (70 mg, 0.2 mmol), methyl 2-methyl-3-oxobutanoate (53.9 mg, 0.4 mmol), and BiCl3 (6.5 mg, 0.02 mmol) were mixed. The resulting mixture was heated at 130°C for 16 hours. The reaction mixture was then diluted with DCM, washed with NaHCO3 solution and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by combiflash chromatography (5% methanol-DCM) to obtain 9-bromo-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)4H-pyrido[1,2-a]pyrimidine-4-one (40 mg, yield 46.2%) as a yellow solid.

[0468] LCMS condition A: Rt=1.89 min. m / z 418.3[M+H] + .

[0469] Step 5-9 Preparation of (4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one [Example 12]: [ka] 9-bromo-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one (160 mg, 0.4 mmol) and (4-chloro-2-fluorophenyl)boronic acid (80.1 mg, 0.5 mmol) were stirred in 1,4-dioxane (6 mL) and water (2 mL). Sodium carbonate (81.1 mg, 0.8 mmol) was added, and the mixture was degassed with argon. PdCl2 (dppf) (27.9 mg, 0.04 mmol) was added under an inert atmosphere. The resulting mixture was heated at 60°C for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered through a Celite short pad, and washed with ethyl acetate. The combined organic portion was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude aggregate was purified by reverse-phase preparative HPLC (preparative method A) to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one (38 mg, yield 21.3%) as a yellow solid.

[0470] 1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.72(s,1H),7.57-7.53(m,2H),7.45(s,1H), 7.42-7.39(m,1H),4.63-4.61(m,1H),4.05-4.03(m,1H),3.85-3.79(m,5H),3.5 9-3.56(m,1H),2.89-2.84(m,1H),2.79-2.67(m,1H),2.26(s,3H),2.12(s,3H). LCMS condition C: Rt=2.84 min. m / z 468.2[M+H] + .

[0471] Examples 13 and 14 Examples 13 and 14 were synthesized using the same procedure as described for Example 12. [Table 12]

[0472] The following table provides information on the analysis and yield of the analytical data for Examples 13 and 14: [Table 13]

[0473] The details of the chiral separation from Examples 12A-12B to 13A-13B are recorded in the table below: [Table 14] JPEG2026524663000382.jpg18159

[0474] The following table contains information on the analysis and yield of the analytical data for Examples 12A / 12B and 13A / 13B: [Table 15] JPEG2026524663000384.jpg202159JPEG2026524663000385.jpg24159

[0475] Example 15 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one: Step 1: Preparation of 5-chloro-3-(4-chloro-2-fluorophenyl)pyrazine-2-amine: [ka] 3-bromo-5-chloropyrazine-2-amine (1 g, 4.8 mmol) and (4-chloro-2-fluorophenyl)boronic acid (752.8 mg, 4.3 mmol) were stirred in 1,4-dioxane (100 mL) and water (20 mL). Sodium carbonate (762.6 mg, 7.2 mmol) was added, and the mixture was degassed with argon. PdCl2 (dppf) (350.7 mg, 0.5 mmol) was added under an inert atmosphere. The resulting mixture was heated at 60°C for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered through a Celite short pad, and washed with ethyl acetate. The combined organic portion was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude mass was purified by combiflash chromatography (45% ethyl acetate in hexane) to obtain 5-chloro-3-(4-chloro-2-fluorophenyl)pyrazine-2-amine (691 mg, yield 56.2%) as a yellow solid.

[0476] LCMS condition A: Rt=2.07 min. m / z 302.3[M+H] + .

[0477] Step 2-7 Preparation of chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidine-4-one [ka] BiCl3 (30.2 mg, 1.9 mmol) was added to a stirred mixture of 3-bromo-5-chloropyrazine-2-amine (247.9 mg, 0.9 mmol) and methyl 2-methyl-3-oxobutanoate (250 mg, 1.9 mmol). The resulting mixture was heated at 170°C for 6 hours. The reaction was stopped with ice-cold aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude mass was purified by combi-flash chromatography on silica gel using 10%-20% ethyl acetate in hexane to obtain 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidine-4-one (70 mg, yield 20.7%) as a brown solid.

[0478] LCMS condition C: Rt=2.44 min. m / z 338.3[M+H] + .

[0479] Step 3-9 Preparation of (4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one [Example 15]: [ka] A stirred solution of 2-(1-methyl-1H-pyrazole-4-yl)morpholine[I-1] (HCl salt, 148.3 mg, 0.9 mmol) in DMSO (3 mL) was mixed with DIPEA (0.6 mL, 3.5 mmol) at room temperature and stirred for 15 minutes. 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrazino[1,2-a]pyrimidine-4-one (150 mg, 0.4 mmol) was added at room temperature. The resulting mixture was heated to 110 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude aggregate was purified by reverse-phase preparative HPLC (preparative method A) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)pyrimido[5,4-d]pyrimidine-4(3H)-one (10 mg, yield 4.9%) as a yellow solid.

[0480] 1H NMR(400MHz,DMSOD6)δ8.01(s,1H),7.75(s,1H),7.73-7.69(m,1H),7.63-7.61(m,1H),7.46-7.44(m,2H ),4.63-4.61(m,1H),4.06-4.03(m,2H),3.81-3.74(m,4H),2.99-2.89(m,3H),2.32(s,3H),2.17(s,3H). LCMS condition C: Rt=2.91 min. m / z 469.3[M+H] + .

[0481] Example 16 (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one Step 1-7 Preparation of bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one: [ka] BiCl3 (75 mg, 0.24 mmol) was added to a stirred mixture of 3-bromo-5-chloropyrazine-2-amine (500 mg, 2.39 mmol) and methyl 2-methyl-3-oxobutanoate (624 mg, 4.8 mmol). The resulting mixture was heated at 130°C for 16 hours. The reaction was stopped with ice-cold aqueous sodium bicarbonate solution, extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The crude mass was purified by combi-flash chromatography on silica gel using 30%-40% ethyl acetate in hexane to obtain 7-bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (250 mg, yield 36.2%) as a yellow rubbery mass.

[0482] LCMS condition C: Rt=1.98 min. m / z 288.1[M+H] + .

[0483] Step 2-7 Preparation of bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4one: [ka] To a stirred solution of 7-bromo-9-chloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (100 mg, 0.3 mmol) in 1,4-dioxane-water (10 mL, 9:1), (4-chloro-2-fluorophenyl)boronic acid (54 mg, 0.3 mmol) and Na2CO3 (55 mg, 0.5 mmol) were added. The resulting mixture was degassed with argon, and Pd(dppf)Cl2 (25 mg, 0.04 mmol) was added. The resulting mixture was heated at 60°C for 2 hours. After completion, the reaction mixture was passed through a Celite pad, washed with ethyl acetate, and concentrated. The crude product was purified by combi-flash chromatography using silica gel with 10%-20% ethyl acetate in hexane to obtain 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (50 mg, yield 37.2%) as a yellow, rubbery mass.

[0484] LCMS condition C: Rt=2.29 min. m / z 382.0[M+H] + .

[0485] Step 3-(S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one (Example 16): [ka] To a stirred solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (100 mg, 0.3 mmol) in toluene (10 mL), (S)-2-(1-methyl-1H-pyrazole-4-yl)morpholine[I-3] (35 mg, 0.21 mmol), tert-butoxide sodium (75 mg, 0.8 mmol), and Ru-Phos (6 mg, 0.01 mmol) were added. The resulting mixture was degassed with argon, and Ru-Phos-Pd-G3 (11 mg, 0.06 mmol) was added. The resulting mixture was heated at 80°C for 1 hour. After completion, the reaction mixture was passed through a Celite bed, washed with DCM, and concentrated. The crude product was purified by reverse-phase preparative HPLC (preparative method B) to obtain (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one (17 mg, yield 14.2%) as a yellow solid.

[0486] 1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),7.75(s,1H),7.71(t,J=8.0Hz,1H),7.62-7.59(dd,J=9.6 Hz,J=1.6Hz,1H),7.46(s,1H),7.44(d,J=2.0Hz,1H),4.63-4.60(dd,J=10.4Hz,J=2.4Hz,1H), 4.03(d,J=12.0Hz,2H),3.86(d,J=12.0Hz,1H),3.80(s,3H),3.76-3.74(m,1H),3.01-2.89(m,2H),2.32(s,3H),2.16(s,3H). LCMS conditions K: Rt=2.90 minutes. m / z 469.3[M+H] + .

[0487] Example 17 6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one Step 1-6 Preparation of amino-4-bromopyridine-2(1H)-one: [ka] A stirred solution of 4-bromopyridine-2,6-diamine (2 g, 10.6 mmol) in 50% aqueous sulfuric acid (20 mL) was heated at 100°C for 5 hours. The reaction was stopped with crushed ice and neutralized with sodium bicarbonate. The solid was precipitated, filtered, washed with water, and dried to obtain 6-amino-4-bromopyridine-2(1H)-one (1.7 g, yield 84.1%) as a brown solid.

[0488] LCMS condition C: Rt=0.78 min. m / z 189.1[M+H] + .

[0489] Step 2-8 Preparation of 8-bromo-6-hydroxy-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one: [ka] BiCl3 (41 mg, 0.13 mmol) was added to a stirred mixture of 6-amino-4-bromopyridine-2(1H)-one (250 mg, 1.32 mmol) and methyl 2-methyl-3-oxobutanoate (343 mg, 2.6 mmol). The resulting mixture was heated at 130°C for 16 hours. The reaction was stopped with ice-cold aqueous sodium bicarbonate solution, extracted with DCM, dried over sodium sulfate, and concentrated. The crude mass was purified by combiflash chromatography on silica gel using 30%-50% DCM in ethyl acetate to obtain 8-bromo-6-hydroxy-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (250 mg, yield 70%) as a yellow rubbery mass.

[0490] LCMS condition C: Rt=1.55 min. m / z 269.1[M+H] + .

[0491] Step 3 - Preparation of 6,8-dichloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one [ka] 8-bromo-6-hydroxy-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (350 mg, 1.3 mmol) was mixed in POCl3 (12 mL) and DIPEA (1.2 mL, 6.5 mmol) was added at 0°C. The resulting mixture was stirred at 100°C for 16 hours. The crude reaction mixture was evaporated and purified by combiflash chromatography on silica gel using 10%-30% ethyl acetate in hexane to obtain 6,8-dichloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (200 mg, yield 63.2%) as a brown solid.

[0492] LCMS condition C: Rt=2.00 min. m / z 243.2[M+H] + .

[0493] Step 4-8 Preparation of chloro-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one: [ka] To a stirred solution of 6,8-dichloro-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (100 mg, 0.41 mmol) in 1,4-dioxane-water (10 mL, 9:1), (4-chloro-2-fluorophenyl)boronic acid (64 mg, 0.4 mmol) and Na2CO3 (87 mg, 0.82 mmol) were added. The resulting mixture was degassed with argon, and Pd(dppf)Cl2 (30 mg, 0.04 mmol) was added. The resulting mixture was heated at 80°C for 16 hours. After completion, the reaction mixture was passed through a Celite pad and washed with ethyl acetate. The crude reaction mixture was extracted with ethyl acetate, dried over sodium sulfate, concentrated, and purified by combi-flash chromatography on silica gel using 20%-30% ethyl acetate in hexane to obtain 8-chloro-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (40 mg, yield 28.7%) as a brown solid. [Structure confirmed by 2D NMR].

[0494] LCMS condition C: Rt=2.35 minutes. m / z 337.2[M+H] + .

[0495] Step 5-6 Preparation of (4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one (Example 72): [ka] To a stirred solution of 8-chloro-6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one (80 mg, 0.24 mmol) in toluene (10 mL), 2-(1-methyl-1H-pyrazole-4-yl)morpholine[I-1] (40 mg, 0.24 mmol), tert-butoxide sodium (75 mg, 0.8 mmol), and RuPhos (6 mg, 0.01 mmol) were added. The resulting mixture was degassed with argon, and Ru-Phos-Pd-G3 (10 mg, 0.01 mmol) was added. The resulting mixture was heated at 80°C for 16 hours. After completion, the reaction mixture was passed through a Celite bed, washed with DCM, and concentrated. The crude product was purified by reverse-phase preparative HPLC to obtain 6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one (8 mg, yield 7%) as a white solid.

[0496] 1H NMR(400MHz,DMSO-d6)δ7.32(s,1H),7.50-7.46(m,2H),7.37-7.30(m,2H),7.02(s,1H),6.70(d,J=1.6Hz,1H),4.51(d,J=10.0Hz,1H) ),4.14(brs,1H),3.99-3.91(m,2H),3.80(s,3H),3.69(t,J=11.6Hz,1H),3.08(m,1H),2.99-2.94(m,1H),2.26(s,3H),1.87(s,3H). LCMS conditions K: Rt=2.38 min. m / z 468.3[M+H] + .

[0497] Examples 18-31 Examples 18-31 were synthesized in two steps using the same procedure as described for Example 1. [Table 16] JPEG2026524663000398.jpg197159JPEG2026524663000399.jpg197159JPEG2026524663000400.jpg95159

[0498] The following table contains information on the analysis and yield of the analytical data for Examples 18-29. [Table 17] JPEG2026524663000402.jpg206159JPEG2026524663000403.jpg207159JPEG2026524663000404.jpg207159JPEG2026524663000405.jpg168159

[0499] The following table provides information regarding the separation of enantiomer examples 18A / 18B to 29A / 29B. [Table 18] JPEG2026524663000407.jpg193159JPEG2026524663000408.jpg183159JPEG202 6524663000409.jpg192159JPEG2026524663000410.jpg193159JPEG2026524663 000411.jpg204159JPEG2026524663000412.jpg192159JPEG2026524663000413. jpg193159JPEG2026524663000414.jpg188159JPEG2026524663000415.jpg63159

[0500] The following table contains information on the analysis and yield of the analytical data from Examples 18A / 18B to 29A / 29B: [Table 19] JPEG2026524663000417.jpg210159JPEG2026524663000418.jpg214159JPEG2026524663000419.jpg216159JPEG202 6524663000420.jpg213159JPEG2026524663000421.jpg204159JPEG2026524663000422.jpg213159JPEG20265246630 00423.jpg213159JPEG2026524663000424.jpg208159JPEG2026524663000425.jpg212159JPEG2026524663000426.j pg203159JPEG2026524663000427.jpg214159JPEG2026524663000428.jpg213159JPEG2026524663000429.jpg132159

[0501] Example 32 - Biological Assay In vitro measurement of the activity of human TREM2, trigger receptor 2 expressed in myeloid cells, using an intracellular phosphorylation assay of spleen tyrosine kinase ("Syk"). Cell line: To generate stable cell lines, HEK-293 cells were cotransfected with separate plasmids encoding TREM2 and DAP12. After antibiotic selection, analysis of the functional clone pool, and two serial limiting dilutions, the final clone "HEK293 / DAP12+TREM2" was subjected to qPCR analysis and pharmacological validation.

[0502] Assay In the HEK293 / DAP12+TREM2 stable cell line, DAP12-mediated TREM2 signaling was monitored by measuring the phosphorylation level of Syk kinase using the commercially available AlphaLISA SureFire Ultra p-SYK (Tyr525 / 526) assay kit (PerkinElmer number ALSU-PSYK) based on Perkin Elmer AlphaScreen / AlphaLISA technology.

[0503] The compounds were transferred to test plates and tested at eight concentrations using a four-point data set for the total dose-response. Serial dilutions of the compounds were performed in 100% DMSO using a Cybi-Felix instrument, and dose-response curves were constructed in an automated manner using a Hamilton STARlet instrument with a 384MPT. All stock solutions were prepared at 20 mM in 100% DMSO. For the compound tests, the starting concentration was 100 μM, and the dilution step was 1:6. Based on preliminary results, different concentration ranges were adapted to the compound's activity. Finally, using a 384MPT reformatted for all compounds at eight concentrations in a four-point set as a "mother-to-child" process, 1 μL of each compound was transferred using a CyBi®-Well dispenser to a target plate filled with 65.6 μL of EMEM cell culture medium (BIOWHITTAKER catalog BE12-125F), thus obtaining a 3-fold concentrated standard solution of the compound. Control wells were added to columns 1-2 and 23-24. Specifically, dose-response curves of reference control agonists were included in columns 1 and 24 as reference control agonists (the reference control agonists used included human TREM2 polyclonal antibody AF1828: R&D Systems and human TREM2 monoclonal antibody MAB1828: R&D Systems). Dose-response curve testing was started at 30 μM with a dilution step of 1:6. Both the "source" compound plate and the "target" compound plate were barcoded to generate the relationship between the two plates.

[0504] HEK293 / DAP12+TREM2 cells were cultured in EMEM medium (referred to as "HEK293 culture medium") supplemented with IX penicillin / streptomycin (BIOWHITTAKER catalog DE17-602E), ULTRAGLUTAMINE I 200 mM, and 10% fetal bovine serum + antibiotics. The day before the experiment, the cells were detached by gently washing with DPBS and then incubated with trypsin solution at 37°C for 5 minutes. The cells were then diluted in antibiotic-free HEK293 culture medium, counted, and seeded at a density of 10,000 cells / well in 25 μL / well of poly-D-lysine coated 384-well black / clear-bottom microplate (GREINER 781946) using a MATRIX WellMate dispenser. The plates were placed in a humidified cell culture incubator at 37°C with 5% CO2 until the day of the experiment. Twenty-four hours after seeding, the matured medium was removed using a CyBi®-Well instrument and replaced with 10 μL / well EMEM cell medium (referred to as “assay buffer”) supplemented with 0.1% Pluronic F-68 nonionic surfactant (Thermofisher, 24040032). Next, 5 μL / well of assay buffer containing a 3-fold concentrated test compound or reference control agonist (at a final DMSO concentration of 0.5%) was added to the cells using a CyBi®-Well instrument. The cell plate was incubated for 30 minutes in a humidified cell culture incubator at 37°C with 5% CO2, and then the medium was removed by manual discarding. Using a CyBi®-Well instrument, 20 μL / well of lysis buffer was dispensed, and the plate was placed on a plate shaker (350 rpm) and incubated at room temperature for 10 minutes. Then, 10 μL / well of the lysate was transferred to an Alpha plate. Using a CyBi®-Well instrument, 5 μL / well of AlphaLISA acceptor bead solution in 1X immunoassay buffer (Perkin Elmer AL000F) was dispensed. The plate was then sealed with heat-sealing foil, shaken for 2 minutes (350 rpm), and incubated at room temperature for 1 hour.Following incubation with AlphaLISA acceptor bead solution, 5 μL / well of AlphaLISA donor bead solution in 1X immunoassay buffer was dispensed using a CyBi®-Well instrument. The plate was sealed with heat-sealing foil, shaken for 2 minutes (350 rpm), and then incubated at room temperature for 1 hour. At the end of incubation, AlphaLISA signals were acquired from the donor and acceptor beads using a 384-well mode, excitation wavelength of 680–615 nanometers, with an AlphaLISA mirror and filter set, calibrated for the plate type using a Pherastar FSX instrument, a high-throughput multimode microplate reader. The total integration time was 0.60 seconds, the excitation time was 0.30 seconds, and the gain was 3600.

[0505] Data analysis was performed using Genedata Screener® software, and the compound activity was reported as an effect percentage relative to the normalization standard. To obtain the activity [%] for each well, the AlphaScreen signal was measured against a neutral control (assay buffer + DMSO final concentration 0.5%) and a stimulator control (assay buffer + DMSO final concentration 0.5%), with EC2 being the second to last. 100 The values ​​were normalized in comparison to a reference control agonist. Normalization places the activity values ​​of the compounds on an equivalence scale, making them comparable across plates or batches of different compounds. Thus, the activity values ​​of the compounds were scaled (two-point normalization) to fit a common range (based on two criteria). The following equation was used by the software to normalize the signal values ​​to the desired signal range: N(x) = CR + [((x- <cr> ) / ( <sr> - <cr>))·(SR-CR)] [In the formula, x is the signal value of the well, <cr>This is the median signal value for the central reference well of the plate (median of the neutral control), <sr>is the median signal value for the scale criterion well of the plate (median of the stimulator control), CR is the normalized value of the desired median for the median criterion (0), and SR is the normalized value of the desired median for the scale criterion (100).

[0506] The final equation for calculating the activity percentage can be simplified as follows: Activity % = 100·(x - <neutral control>) / (<stimulator control> - <neutral control>) (In the formula, complete activation corresponds to an activity percentage of 100).

[0507] The analyzer module of the screener software fitted the dose-response curves of each test compound to normalized values, applying the "Smart Fit" strategy. This strategy allowed for automatic selection between the "Constant Fit" and "Hill Fit" models, calculating which fit model best matched the experimental data. If no change in activity was detected across the measured concentrations, the Constant Fit was applied, and the corresponding compound was further classified as "Inactive." If the observed activity changed significantly with compound concentration, the Hill Fit was applied. In the case of the Hill Fit, Hill's equation was used to determine the concentration at which the activity reached 50% of its maximum level, i.e., AC. 50 We made that decision.

[0508] Y=S0+((S inf -S0) / (1+(10 LogAC50 / 10 X ) n )) (In the formula, X is the Log10 of the compound concentration).

[0509] This equation has the following four parameters: • Zero activity (S0) - Activity level of the test compound at zero concentration. · Infinite activity (S inf )-Activity level at infinite concentration of test compound, AC 50 - The concentration at which the activity reaches 50% of the maximum level. This term refers to the EC in this assay. 50 Corresponding to, • Hill coefficient (n) - AC 50 A measure of the slope.

[0510] The potency of the test compound corresponds to the concentration of the test compound that can activate the phospho-Syk AlphaScreen signal up to 50% of the maximum response, in terms of EC. 50 It was expressed as follows.

[0511] EC for representative compounds measured in this assay 50 The values ​​are shown in the table below. [Table 20] JPEG2026524663000431.jpg139159

[0512] In the table, "A" represents EC <10nM 50 The values ​​are shown, and "B" represents an EC of 10nM to 100nM. 50 The values ​​are shown, and "C" represents an EC of 100-1000 nM. 50 The values ​​are shown, and 'D' indicates an EC of over 1000 nM. 50 Shows the value. E max Regarding the values, "+" indicates <75% of the maximum response of the reference agonist (8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methyl-1H-pyrazole-4-yl)morpholin-4-yl]-3H,4H-[1,3]diazino[5,4-d]pyrimidine-4-one), "++" indicates 75-110%, and "+++" indicates a maximum response of >110%.

[0513] Examples 33-71 The following additional examples were prepared using the same method as described for the previous examples and evaluated using the biological assay described in Example 32. [Table 22] JPEG2026524663000433.jpg188159JPEG2026524663000434.jpg209159JPEG2026524663000435.jpg191159JPEG2026524663000436.jpg208159JPEG2026524663000437.jpg190159JPEG2026524663000438.jpg193159JPEG2026524663000439.jpg198159JPEG2026524663000440.jpg187159JPEG2026524663000441.jpg201159JPEG2026524663000442.jpg213159JPEG2026524663000443.jpg196159JPEG2026524663000444.jpg186159JPEG2026524663000445.jpg189159JPEG2026524663000446.jpg136159

[0514] References Colonna,M.et al.(2016)Nat Rev Neurosci17,201-207 Deczkowska,A. et al.(2020)Perspective,181,6,1207-1217 Hammond,T.R.(2019)Immunity,50,4 5955-974<见 Suarez-Calvet,M.et al.(2016)EMBO Mol Med,8,466-476 Yamazaki,K.et al.(2015)Clinical psychopharmacology and neuroscience:the official scientific journal of the Korean College of Neuropsychopharmacology,13(3),324-326 Paloneva BM,J.et al.(2001)Neurology,56(11)1552-1558; It should be noted that there seems to be a formatting issue in the original text where " " is likely to be " " which is not a standard tag format. I've translated it as "见0006678" for the purpose of maintaining the integrity of the translation based on the existing content. You may want to double-check the original text for accuracy.Ulrich JDet al.(2017)Neuron.,19;94(2):237-248) Atagi,Y.et al.(2015)J Biol Chem.,290(43),26043-50 Kleinberger,G.et al(2014)Sci Transl Med.,2,6(243):243< / sr> < / cr> < / cr> < / sr> < / cr>

Claims

1. A compound of formula IA or formula IB, 【Chemistry 1】 During the ceremony, X Ａ However, N or C (R ５ ) and R ５ However, it is H, R １ is selected from the group consisting of C １－６ alkyl, C １－６ haloalkyl, C ３－６ cycloalkyl, and H, wherein the C １－６ alkyl or the C ３－６ cycloalkyl is optionally substituted by one to three individually selected substituents R ６ , R ２ However, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Selected from the group consisting of cycloalkyl, halogen, and H, the C １－６ Alkyl or the C ３－６ The cycloalkyl group has one to three individually selected substituents R ９ Replaced by choice, R ３ However, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C ５－８ Spiroalkyl, C ５－８ Tricycloalkyl, C ５－８ Bicycloalkylcyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, phenyl, 6-membered heteroaryl, 5-membered heteroaryl, azetidine-1-yl, pyrrolidine-1-yl, 3-azabicyclo[3.1.0]hexane-3-yl, piperidine-1-yl, and -OCH ２ - (C ３－６ Selected from the group consisting of cycloalkyl, Said C １－６ alkyl, the C ３－６ Cycloalkyl, the C ５－８ Spiroalkyl, the C ５－８ bicycloalkyl, the C ５－８ 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 a halogen, C １－３ Alkyl, C １－３ Alkoxy, C １－３ The C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN. ３－６ One methylene group of the cycloalkyl group is -O- or -N(R １０ ) - can be optionally replaced by, R １０ However, H, C １－３ Alkyl and -C(O)C １－３ Selected from the group consisting of alkyl groups, The aforementioned azetidine-1-yl, the aforementioned pyrrolidine-1-yl, the aforementioned 3-azabicyclo[3.1.0]hexane-3-yl, the aforementioned piperidine-1-yl, or the aforementioned -OCH ２ - (C ３－６ Cycloalkyl) is a halogen, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy and C １－３ It is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkoxys. R ６ Each of them is -O-C １－６ Alkyl, C ３－６ Selected from the group consisting of cycloalkyls and halogens, R ９ However, -O-C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ A compound selected from the group consisting of haloalkyls and phenyl, wherein the phenyl is -O-C １－６ They are optionally substituted with 1 to 5 substituents individually selected from alkyl groups. R ４ However, it is from equation II: 【Chemistry 2】 During the ceremony, X Ｂ However, N or C (R １１ ) and R １１ However, H, C １－３ Alkyl, -OH, -O-C １－３ Selected from the group consisting of alkyl and halogen, X Ｃ However, C(R １２ ) (Caution １３ ) and R １２ H, C １－３ Alkyl, or bonded, Here, R １２ If R is a bond, １１ However, C １－３ It is alkyl, R １１ and R １２ They connect together to form a 3-5 membered ring. R １３ Each of them is H or C １－３ It is alkyl, X Ｄ However, C(R １４ ) or N, R １４ However, H or C １－３ It is alkyl, R ２３ However, C is a bond, -O-, or one methylene group that can be optionally replaced by -O-. １－６ It is a hydrocarbon chain, R １５ However, C １－６ Alkyl, C １－６ Haloalkyl, diC １－３ Alkylamino, -C(O)-O-(C １－６ Alkyl), C ３－６ Cycloalkyl, C ３－６ Selected from the group consisting of heterocycloalkyl, phenyl, -O-phenyl, 5-membered heteroaryl, -O-(5-membered heteroaryl), 6-membered heteroaryl, and -O-(6-membered heteroaryl), (a) C ３－６ Cycloalkyl or the C ３－６ Heterocycloalkyl groups are oxo (=O) and C １－３ Optionally substituted with one to three substituents independently selected from alkoxys and halogens, (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 independently selected from the group consisting of halogen, C １－６ alkyl, -O-C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C １－６ haloalkoxy, -(C １－３ alkyl)O(C １－３ alkyl), -CN, C ２－４ alkenyl, C ３－６ cycloalkyl, and C ３－６ heterocycloalkyl, and is optionally substituted by 1 to 3 substituents independently selected from the group consisting of: C of the lower category (b) １－６ Alkyl or the C １－６ The haloalkyl group is optionally substituted with -OH. C of the lower category (b) ３－６ Heterocycloalkyls are halogens, C １－３ Alkyl and -C(O)O(C １－６ They are optionally substituted with one to three substituents individually selected from the group consisting of alkyl groups. (c) C above １－６ Alkyl is -N(H)C(O)R ２４ , -oxo (=O), -O-C １－３ Alkyl and -N(R ２５ ) (Caution ２６ ) is optionally substituted by one to three substituents independently selected from the original, R ２４ However, C １－６ Alkyl or aryl, and the C １－６ Alkyl is C １－３ Optionally substituted with alkoxy or halogen, R ２５ However, H or C １－３ It is alkyl, R ２６ However, H or C １－３ It is alkyl, X Ｅ However, C(R １６ ) (Caution １７ ), O, NR １８ , or a combination, R １６ However, it is H or F, R １７ However, it is H or F, R １８ However, H, C １－６ Alkyl, -C(O)-C １－６ Alkyl, -C(O)-C ３－６ Cycloalkyl, or C １－６ It is a haloalkyl, and the C １－６ Alkyl, the aforementioned -C(O)-C １－６ Alkyl, or the aforementioned -C(O)-C ３－６ Cycloalkyls, halogens and C １－３ It is optionally substituted with one to three substituents independently selected from the alkoxy, X Ｆ However, C(R １９ ) (Caution ２０ ) and R １９ However, H, halogen, or C １－３ It is alkyl, R ２０ However, H, halogen, or C １－３ It is alkyl, Here, R １９ and R ２０ However, C １－３ If it is alkyl, R １９ and R ２０ They can optionally be linked together to form a 3-6 member ring, and / or Here, R １９ and R ２０ However, C １－３ If it is an alkyl group, one methylene group is -O- or -N(R) ２７ ) - which can be optionally replaced, where R ２７ However, H, C １－３ Alkyl and -C(O)C １－３ Selected from the group consisting of alkyl groups, X Ｇ Each of them, C(R ２１ ) (Caution ２２ ) or C(O), R ２１ H, C １－３ Alkyl, or bonded, Here, R ２１ If R is a bond, １９ However, C １－３ It is an alkyl group, n is 1, R ２１ and R １９ They connect together to form a 3-5 membered ring. R ２２ Each of them is H or C １－３ It is alkyl, m is 0, 1, or 2, The compound, where n is 0, 1, or 2. Or, a salt that is permitted as a medicine.

2. R ３ However, it is of formula IV, 【Transformation 3】 During the ceremony, R ２８ However, H, halogen, C １－３ Alkyl, C １－３ It is a haloalkyl or CN. R ２９ However, H, halogen, C １－３ Alkyl, C １－３ It is a haloalkyl or CN. R ３０ However, H, halogen, C １－３ Alkyl, C １－３ It is a haloalkyl or CN. R ３１ However, H, halogen, C １－３ Alkyl, C １－３ It is a haloalkyl or CN. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R ３ However, halogen, C １－３ Alkyl, C １－３ Alkoxy, C １－３ C is optionally substituted with 1 to 4 substituents independently selected from the group consisting of haloalkyl and CN. ３－６ A compound according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

4. R ３ but, 【Chemistry 4】 or 【Transformation 5】 The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. X Ｂ However, C(R １１ ) and X Ｃ However, C(R １２ ) (Caution １３ ) and X Ｄ However, C(R １４ ) and X Ｅ However, O and X Ｆ However, C(R １９ ) (Caution ２０ ) and X Ｇ However, C(R ２１ ) (Caution ２２ A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

6. X Ｂ However, N is X Ｃ However, C(R １２ ) (Caution １３ ) and X Ｄ However, C(R １４ ) and X Ｅ However, O and X Ｆ However, C(R １９ ) (Caution ２０ ) and X Ｇ However, C(R ２１ ) (Caution ２２ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

7. R １５ However, C １－６ Alkyl, C ３－６ Cycloalkyl, -O-C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -(C) １－３ Alkyl)O(C １－３ A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, which is a five-membered heteroaryl compound optionally substituted with one to three substituents independently selected from the group consisting of alkyl, -CN, and halogen.

8. R １５ However, selected from the group consisting of formulas V, VI, VII, VIII, IX, X, XI, and XII, 【Transformation 6】 In the formula, R ３７ However, C １－６ Alkyl, C ３－６ Cycloalkyl, -O-C １－６ Alkyl, H, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -(C) １－３ Alkyl)O(C １－３ A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl, -CN, and halogen.

9. R １５ However, it is of formula XIII, 【Transformation 7】 In the formula, R ３７ However, C １－６ Alkyl, C ３－６ Cycloalkyl, -O-C １－６ Alkyl, H, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -(C) １－３ Alkyl)O(C １－３ A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, selected from the group consisting of alkyl, -CN, and halogen.

10. R ３７ However, CH ３ C etc. １－３ Alkyl, or C ３ Cycloalkyl and other C ３－６ A cycloalkyl compound according to claim 9, or a pharmaceutically acceptable salt thereof.

11. R １５ but, 【Transformation 8】 A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

12. The aforementioned compound is a compound of formula IA, 【Chemistry 9】 During the ceremony, R １ However, C １－６ Alkyl, C １－６ Selected from the group consisting of haloalkyl and H, R ２ However, halogen, C １－６ Alkyl, C １－６ Selected from the group consisting of haloalkyl and H, R ３ However, halogen, C １－３ Alkyl and C １－３ A phenyl molecule that is optionally substituted with one to three substituents independently selected from the group consisting of haloalkyl groups. X Ａ However, it is N or C(H), R ４ However, it is of formula XXVI, 【Chemistry 10】 During the ceremony, X Ｂ However, it is N or C(H), R １５ However, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -CN, and C ３－６ A five-membered heteroaryl or six-membered heteroaryl molecule that is optionally substituted with one to three substituents independently selected from the group consisting of cycloalkyl groups. R １９ However, H, halogen, or C １－３ It is alkyl, R ２０ However, H, halogen, or C １－３ It is alkyl. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. X Ａ A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, wherein N is present.

14. X Ａ A compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, wherein the compound is C(H).

15. X Ｂ A compound according to any one of claims 1 to 4 or 7 to 14, wherein N is present, or a pharmaceutically acceptable salt thereof.

16. X Ｂ A compound according to any one of claims 1 to 4 or 7 to 14, wherein the compound is C(H), or a pharmaceutically acceptable salt thereof.

17. R １ However, C １－３ A compound according to any one of the prior claims, which is alkyl, or a pharmaceutically acceptable salt thereof.

18. R ２ However, C １－３ A compound according to any one of the prior claims, which is alkyl, or a pharmaceutically acceptable salt thereof.

19. R ２ However, the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, is a halogen such as Cl.

20. R ３ but, 【Chemistry 11】 A compound according to any one of claims 1, 2 to 5 to 19, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

21. R ４ but, 【Chemistry 12】 A compound according to any one of claims 1 to 4, 12 to 14, or 17 to 20, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

22. R ４ but, 【Chemistry 13】 A compound according to any one of claims 1 to 4, 12 to 14, or 17 to 20, selected from the group consisting of the above, or a pharmaceutically acceptable salt thereof.

23. The aforementioned compound is a compound of formula IA, wherein, R １ However, C １－６ Alkyl, C １－６ Selected from the group consisting of haloalkyl and H, R ２ However, C １－６ Alkyl, C １－６ Selected from the group consisting of haloalkyl and H, R ３ However, halogen, C １－３ Alkyl and C １－３ A phenyl molecule that is optionally substituted with one to three substituents independently selected from the group consisting of haloalkyl groups. X Ａ However, it is CH, X Ｂ However, N is, X Ｃ However, C(H) ２ And, X Ｄ However, C(H), X Ｅ However, it is O, X Ｆ However, C(H) ２ And, X Ｇ However, C(H) ２ And, m is 1, n is 1, R ２３ However, it is a combination, R １５ However, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -CN, and C ３－６ It is a five-membered heteroaryl or six-membered heteroaryl molecule that is optionally substituted with one to three substituents independently selected from the group consisting of cycloalkyl groups. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

24. The aforementioned compound is a compound of formula IA, wherein, R １ However, C １－６ Alkyl, C １－６ Selected from the group consisting of haloalkyl and H, R ２ However, C １－６ Alkyl, C １－６ Selected from the group consisting of haloalkyl and H, R ３ However, halogen, C １－３ Alkyl and C １－３ A phenyl molecule that is optionally substituted with one to three substituents independently selected from the group consisting of haloalkyl groups. X Ａ However, N is, X Ｂ However, C(H), X Ｃ However, C(H) ２ And, X Ｄ However, C(H), X Ｅ However, it is O, X Ｆ However, C(H) ２ And, X Ｇ However, C(H) ２ And, m is 1, n is 1, R ２３ However, it is a combination, R １５ However, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -CN, and C ３－６ It is a five-membered heteroaryl or six-membered heteroaryl molecule that is optionally substituted with one to three substituents independently selected from the group consisting of cycloalkyl groups. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 1, wherein the compound is selected from the group consisting of the following: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, (R)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, 9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, 9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one, (R)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazole-4-yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, (S)-9-(4-chloro-2-fluorophenyl)-7-(2,2-dimethyl-6-(1-methyl-1H-pyrazole-4-yl)morpholino)-2,3-dimethyl-4H-pyrido[1,2-a]pyrimidine-4-one, (S)-9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrazino[1,2-a]pyrimidine-4-one, 6-(4-chloro-2-fluorophenyl)-2,3-dimethyl-8-(2-(1-methyl-1H-pyrazole-4-yl)morpholino)-4H-pyrido[1,2-a]pyrimidine-4-one, Chloro-9-(4-chloro-2-fluorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chlorophenyl)-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chlorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one Chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(3,4-difluorophenyl)-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, Chloro-7-(2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-2-methyl-7-(2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-methyl-6-(2-methyl-4-pyridyl)morpholin-4-yl)pyrazino[1,2-a]pyrimidine-4-one, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl)pyrido[1,2-a]pyrimidine-4-one, 7-[2,2-difluoro-6-(2-methyl-4-pyridyl)morpholin-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 9-(2,4-difluorophenyl)-2,3-dimethyl-7-[2-methyl-6-(2-methyl-4-pyridyl)morpholin-4-yl)pyrido[1,2-a]pyrimidine-4-one, 7-[(2R,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyltetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 7-[2,2-difluoro-6-(2-methyl-4-pyridyl)morpholin-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-pyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-pyrazino[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-(trifluoromethyl)pyrazino[1,2-a]pyrimidine-4-one, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-3-methyl-2-(trifluoromethyl)pyrazino[1,2-a]pyrimidine-4-one, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2,3-dimethyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 7-[2,2-difluoro-6-(1-methylpyrazole-4-yl)morpholin-4-yl]-9-(2,4-difluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one, 7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-pyrido[1,2-a]pyrimidine-4-one, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-4-oxo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, Chloro-7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-9-(2,4-difluorophenyl)-2-methyl-pyrido[1,2-a]pyrimidine-4-one, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2-methyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2-methyl-4-oxo-3-(trifluoromethyl)pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-4-oxo-2-(trifluoromethyl)pyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-2-methyl-4-oxopyrido[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 4-[7-[2-(1-cyclopropylpyrazole-4-yl)-tetrahydropyran-4-yl]-4-oxo-2-(trifluoromethyl)pyrazino[1,2-a]pyrimidine-9-yl]-3-fluorobenzonitrile, 9-(3-methoxycyclobutyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one, 9-(3-methoxycyclobutyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one, Chloro-9-(4-chloro-2-fluorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chloro-2-fluorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chloro-2-fluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one Chloro-9-(4-chlorophenyl)-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chlorophenyl)-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chlorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-chlorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(4-(trifluoromethyl)phenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(4-(difluoromethyl)phenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(3,4-difluorophenyl)-2-methyl-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-9-(3,4-difluorophenyl)-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, 4-(3-chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, Chloro-7-((2R,4S)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-7-((2S,4R)-2-(1-cyclopropyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-2-methyl-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, Chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-9-(2,4,5-trifluorophenyl)-4H-pyrazino[1,2-a]pyrimidine-4-one, 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)-3-fluorobenzonitrile, 4-(3-chloro-2-methyl-7-((2R,4S)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, and 4-(3-chloro-2-methyl-7-((2S,4R)-2-(1-methyl-1H-pyrazole-4-yl)tetrahydro-2H-pyran-4-yl)-4-oxo-4H-pyrazino[1,2-a]pyrimidine-9-yl)benzonitrile, or a salt of which is permitted as a medicine.

26. The compound according to any one of the prior claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, for example, a TREM2 activator, for example, a TREM2 agonist.

27. A pharmaceutical composition comprising a compound described in any one of the prior claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients, and / or diluents.

28. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use as a pharmaceutical.

29. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in the treatment of conditions related to loss of function of TREM2, for example, for use in the treatment of conditions related to mutations of TREM2.

30. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in the treatment of neurodegenerative diseases.

31. The compound or composition for use according to claim 30, 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, leukoencephalopathy, leukodystrophy, transmissible spongiform encephalopathy (TSE), and lysosomal storage disease (LSD).

32. A compound for use according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in the treatment of neurodegenerative diseases 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.

33. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, Pyle's disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, osteodysplasia, 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 disorders, inflammatory bowel disease (IBD), metabolic syndromes, obesity, type 2 diabetes mellitus, atherosclerosis, alcoholic and non-alcoholic fatty liver, alcoholic and non-alcoholic steatohepatitis, and amyloidosis.

34. A method for treating a pathological condition related to loss of function of TREM2, such as neurodegenerative diseases, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, to a subject requiring such treatment.

35. Use of a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 27, for the manufacture of a pharmaceutical for treating conditions related to loss of TREM2 function, such as neurodegenerative diseases.

36. In subjects requiring enhancement or increase of TREM2 activity, for example, in subjects with neurodegenerative diseases, methods for enhancing or increasing TREM2 activity include, for example, i) enhancing or activating TREM2 signaling via DAP12; ii) inducing phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, such as Syk, ZAP70, PI3K, Erk, AKT, and GSK3b, and iii) enhancing the TREM2-inducible phosphorylation level of the Syk kinase. The method comprising: IV) increasing the expression level of one or more genes regulated by TREM2, for example, the brain expression level; 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, for example, the brain expression level, wherein the subject is administered a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof.

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