TREM2 Agonist

Abstract

The present invention relates to general formula (I) TIFF2026519580000291.tif45165 (In the formula, A, B, R 1 , R 2 , R 3 , R 7 , and R 8 The present invention provides a compound having (as described herein), a composition comprising the compound, a method for producing the compound, and a method for using the compound in the treatment or prevention of diseases related to TREM2.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to organic compounds useful for the treatment or prevention in mammals, and more particularly to trigger receptor agonists expressed on myeloid cells 2 (TREM2) for the treatment or prevention of Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion diseases, and stroke. [Background technology]

[0002] Background of the Invention Microglia are immune cells commensal to the central nervous system (CNS) and play a crucial role in CNS development and maintaining brain homeostasis through synaptic pruning and the removal of apoptotic neurons (Paolicelli RC et al., Science 2011, 9;333(6048):1456-8 doi:10.1126 / science.1202529). Microglia also play an important role in response to neurodegenerative states and neuropathological lesions, thereby transitioning to an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to lesion sites, and phagocytosis of dead cells and debris (Lue LF et al., Mol. Neurobiol. 2010, 41(2-3):115-28, doi:10.1007 / s12035-010-8106-8).

[0003] Microglia express numerous receptors on their surface, which play a crucial role in sensing environmental changes and enabling complex crosstalk that modulates their physiological functions.

[0004] TREM2 (trigger receptor 2 expressed on myeloid cells) is one of these cell surface receptors, selectively expressed on microglia in the brain, and plays a crucial role in their survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445-453 (2003). https: / / doi.org / 10.1038 / nri1106). TREM2 is a single-pass transmembrane receptor belonging to the immunoglobulin superfamily (Ig-SF). It consists of an extracellular immunoglobulin variable-like domain (IgV) that binds to a ligand, followed by a long stalk domain, a single transmembrane helix, and a short cytosolic tail that lacks a signaling motif. Downstream signaling is mediated via interaction with the effector protein DAP12, which is a transmembrane disulfide adapter dimer whose expression and cellular localization in the plasma membrane are TREM2-dependent and which associates with the TREM2 transmembrane helix via a lysine-aspartate interaction (K156-D50) that forms a signaling complex (Zhong L. et al., J Biol Chem. 2015;290(25):15866-77). Given its short extracellular domain, DAP12 lacks ligand-binding ability. Endogenous ligands for TREM2 include a wide range of molecules such as phospholipids, glycolipids, lipoproteins, cellular debris, myelin, and Aβ oligomers. Stimulation of the TREM2 / DAP12 complex induces phosphorylation of two tyrosine residues within the immune receptor tyrosine activation motif (ITAM) of the cytoplasmic domain of DAP12, resulting in the recruitment of Syk kinase to activate downstream signaling molecules.

[0005] TREM2 activation plays a crucial role in microglial signaling and function, including survival, migration, amyloid plaque insulation, beta-amyloid phagocytosis, myelin debris removal, and transition from homeostasis to disease-associated microglia (DAM) state in relation to neurodegenerative environments (Condello, C. et al., Nat Commun 6, 6176, 2015, doi:org / 10.1038 / ncomms7176, Poliani et al., J Clin Invest, 2015 May;125(5):2161-70, doi:10.1172 / JCI77983, Zhao et al., Neuron, 2018 Mar 7;97(5):1023-1031.e7, doi:10.1016 / j.neuron.2018.01.031, Keren-Shaul H. et al. al.,Cell,2017 Jun 15;169(7):1276-1290.e17.doi:10.1016 / j.cell.2017.05.018).

[0006] TREM2 gene variants are associated with numerous neurodegenerative diseases (Hou J. et al. Molecular Neurodegeneration (2022) 17:84; doi:org / 10.1186 / s13024-022-00588-y). TREM2 variants resulting in a lack of TREM2 expression have been identified as the cause of Nasu-Hakola disease (NHD) or polycystic lipomegaly dysplasia (PLOSL) with sclerosing leukoencephalopathy, a fatal condition characterized by progressive senile dementia, loss of myelin and bone abnormalities, and consistent with TREM2 expression in myeloid cells (microglia and osteoclasts) (Paloneva, J. et al., Am J Hum Genet. 2002, 71(3):656-62, doi:10.1086 / 342259). Similarly, missense mutations in TREM2 are associated with an increased risk of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Some of these TREM2 variants have been associated with microglial dysfunction and reduced responses to neurodegenerative diseases. (Kleinberger, G. et al., Sci. Transl. Med. 2014, 6, 243ra86).

[0007] Furthermore, genome-wide association studies (GWAS) showed a strong association between several rare loss-of-function (LoF) variants of TREM2 and an increased risk of late-onset Alzheimer's disease (LOAD) (Guerreiro R. et al., N Engl J Med. 2013, 368(2):117-27, Jonsson T. et al., N Engl J Med. 2013, 368(2):107-16). Among these, the R47H variant, a LoF variant associated with structural changes in the extracellular domain of TREM2 that impairs its ability to bind to endogenous ligands, was associated with an approximately threefold increase in the risk of LOAD (Sudom, A. et al., J Biol Chem. 2018:10;293(32):12634-12646;doi:10.1074 / jbc.RA118.002352). Research is underway to elucidate the mechanisms by which TREM2 LoF mutations contribute to Alzheimer's disease (AD). Patients with these mutations exhibit microglial dysfunction, such as reduced clearance of extracellular aggregates (e.g., amyloid and myelin debris) and apoptotic neurons, which may ultimately reduce their ability to fight the disease and increase their susceptibility to neurodegeneration. Indeed, mouse models lacking TREM2 or DAP12 have shown decreased microglial activation and impaired clustering around amyloid plaques, confirming the central role of TREM2 signaling in responses to microglial function and the pathological features of Alzheimer's.

[0008] In light of all this evidence, pharmacological activation of TREM2 appears to be a viable therapeutic intervention. The small molecules disclosed herein are potent and selective agonists of TREM2. [Overview of the project]

[0009] Summary of the Invention In the first aspect, the present invention relates to formula (I) [ka] The compound (wherein A, B, R in the formula) 1 , R2 , R 3 , R 7 and R 8 (This is defined herein.) To provide.

[0010] In further embodiments, the present invention provides compositions comprising a compound of formula (I), a process for producing a compound of formula (I), and a method for using a compound of formula (I). [Modes for carrying out the invention]

[0011] Detailed description of the invention definition Features, integers, characteristics, compounds, chemical parts, or groups described in relation to specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, unless they are incompatible. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process so so disclosed may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the embodiments described above. The present invention extends to any novel one or any novel combination of features disclosed herein (including any appended claims, abstract, and drawings), or any novel one or any novel combination of steps of any method or process so so disclosed.

[0012] The term "alkyl" refers to a group of 1 to 6 carbon atoms ("C"). 1~6"-alkyl" refers to a monovalent or polyvalent, for example, monovalent or divalent linear or branched saturated hydrocarbon group comprising 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, for example, 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, but non-limiting, examples of alkyl groups are methyl, tert-butyl, and 2,2-dimethylpropyl.

[0013] The term "alkoxy" refers to an alkyl group, as previously defined, that is bonded to the parent molecule via an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C"). 1~6 (Alkoxy). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, for example, 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting, example of an alkoxy is methoxy.

[0014] The term "halogen" or "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I). Preferably, the term "halogen" or "halo" refers to fluoro(F), chloro(Cl), or bromo(Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluoro(F) and chloro(Cl).

[0015] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C"). 3~10-Cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spiro ring moiety, i.e., a cycloalkyl moiety in which the two rings are joined via one common ring atom. Preferably, the cycloalkyl group is a monocyclic hydrocarbon group having 3 to 6 ring carbon atoms, for example, a monocyclic hydrocarbon group having 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. A particularly preferred but non-limiting example of cycloalkyl is cyclopropyl.

[0016] As used herein, the term "cycloalkenyl" refers to a partially unsaturated monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3~10 Cycloalkenyl"). In some preferred embodiments, the cycloalkenyl group is a monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. "Bicyclic cycloalkenyl" refers to a cycloalkenyl moiety consisting of two saturated carbon rings having two common carbon atoms, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spiro ring moiety, i.e., a cycloalkenyl moiety in which the two rings are joined via one common ring atom. Preferably, the cycloalkenyl group is a monocyclic hydrocarbon group having 3 to 6 ring carbon atoms, for example, a monocyclic hydrocarbon group having 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

[0017] The term "aryl" refers to a total of 6 to 10 ring members ("C6-C 10This refers to a monocyclic, bicyclic, or tricyclic carbocyclic system having an "aryl" ring, where at least one ring in the system is aromatic. Some non-limiting examples of aryls include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred, but non-limiting, example of an aryl is phenyl.

[0018] The terms “heterocyclyl” and “heterocycloalkyl” are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system consisting of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, preferably 3 to 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. A “bicyclic heterocyclyl” refers to a heterocyclic portion consisting of two rings sharing two ring atoms (i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms) and a spirocyclic portion (i.e., the two rings are connected via one common ring atom). Some non-limiting examples of heterocyclyl groups include azetidine-3-yl, azetidine-2-yl, oxetan-3-yl, oxetan-2-yl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, piperazinyl, pyrrolidinyl, oxazolidinyl, dihydropyradinyl (e.g., 1,2-dihydropyrazine-6-yl), morpholinyl, 2-azaspiro[3.3]heptan-2-yl, 7-azaspiro[3.5]nonane-7-yl, 8-azabicyclo[3.2.1]octane-8-yl, 8-oxa-3-azabicyclo[3.2.1]octane, and 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-yl.

[0019] The term "heteroaryl" refers to a monovalent or polyvalent monocyclic or bicyclic ring system having a total of 5 to 10 ring members, preferably 5 to 8 ring members, more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O, S and N. Some preferred, but not limited, examples of heteroaryls include thiazolyl (e.g., thiazolyl-2-yl), oxazolyl (e.g., oxazol-2-yl), oxadiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl-2-yl, 1,2,4-oxadiazolyl-5-yl, pyridyl (e.g., 2-pyridyl), pyrazolyl (e.g., pyrazol-1-yl), triazolyl, tetrazolyl, pyrazinyl, imidazolyl (e.g., imidazole-1-yl), benzoxazolyl (e.g., benzoxazol-2-yl), 2,3-dihydrobenzofuranil, and oxazolo[5,4-c]pyridine-2-yl.

[0020] The term "cyano" refers to the -CN (nitrile) group.

[0021] The term "oxo" refers to the base = O.

[0022] The term “haloalkyl” refers to an alkyl group as defined herein, in which at least one of the hydrogen atoms of the alkyl group is substituted with a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group in which one, two, or three of the hydrogen atoms of the alkyl group are substituted with a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting, examples of haloalkyls are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0023] The term "haloalkoxy" refers to an alkoxy group described herein in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably a fluoro atom. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by a halogen atom, most preferably a fluoro atom. Particularly preferred, but non-limiting, examples of haloalkoxys are trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoro-1,1-dimethylethoxy, (1,1,1-trifluoropropan-2-yl)oxy, and 2,2,2-trifluoroethoxy.

[0024] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed from inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and especially hydrochloric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyimine resins.

[0025] The compound of formula (I) may contain several chiral centers and may exist as an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereoisomer, a mixture of diastereoisomers, a racemate of diastereoisomers, or a mixture of racemates of diastereoisomers.

[0026] The abbreviation "TREM2" refers to trigger receptor 2, which is expressed on myeloid cells.

[0027] As used herein, the term “treatment” includes (1) suppressing a condition, disorder, or symptom (e.g., stopping, reducing, or delaying the onset of a disease, or the recurrence of a disease, or the onset of at least one clinical or asymptomatic symptom of a disease, in the case of disease onset or maintenance treatment), and / or (2) alleviating a symptom (i.e., causing the regression of a condition, disorder, or symptom, or at least one clinical or asymptomatic symptom thereof). The benefit to the patient to be treated is either statistically significant or at least recognizable to the patient or physician. However, it will be understood that when a medicine is administered to a patient to treat a disease, the outcome may not always be an effective treatment.

[0028] As used herein, the term “prevention” includes preventing or delaying the onset of clinical symptoms of a condition, disorder, or symptom in mammals, particularly humans, who may be susceptible to or prone to such conditions, disorders, or symptoms but have not yet experienced or shown any clinical or asymptomatic symptoms of such conditions, disorders, or symptoms.

[0029] The compound of the present invention In the first aspect, the present invention relates to formula (I) [ka] A compound of or a pharmaceutically acceptable salt thereof (in the formula, X 1 , X 2 and X 3These are independently selected from N and CH, A is C3~C 10 -Cycloalkyl, C3~C 10 -Cycloalkenyl, C6~C 10 - Selected from aryls, 5-10 membered heteroaryls, and 3-10 membered heterocyclines, B is [ka] Selected from, R 1 , R 2 and R 3 Each of these is independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and halo-C1-C6-alkoxy. R 4a and R 5a These include hydrogen, halogens, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and groups [ka] Selected from, R 6a These include hydrogen, halogens, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and groups [ka] Selected from, R 4b , R 4c , R 5b , R 5c , R 6b and R 6c Each of these is independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and oxo. C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl. D is selected from cyclopropyl, phenyl, pyrazolyl, 1H-1,2,4-triazole, 1H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl. R 7 These include C1-C6 alkyl, halo-C1-C6 alkyl, 3-10 member heterocyclyl and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group is optionally substituted with a halogen and one substituent selected from C1-C6 alkyl groups. R 8 These include hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, 3-10 member heterocyclyl, and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group is optionally substituted with a halogen and one substituent selected from C1-C6-alkyl groups, or R 7 and R 8 However, together with the atoms to which they are bonded, they form a heterocycle of 3 to 10 members. R 9 and R 10 These are, independently, hydrogen, halogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and C3-C 10 -Cycloalkyl, Halo-C3~C 10 - Selected from cycloalkyl and 3-10 membered heterocyclyl, R 11 and R 12Each of these is independently selected from hydrogen, halogens, C1-C6 alkyl groups, halo-C1-C6 alkyl groups, C1-C6 alkoxy groups, halo-C1-C6 alkoxy groups, and 3-10 member heterocyclines. To provide.

[0030] In a further embodiment, the present invention relates to formula (I) [ka] A compound of or a pharmaceutically acceptable salt thereof (in the formula, X 1 , X 2 and X 3 These are independently selected from N and CH, A is C3~C 10 -Cycloalkyl, C3~C 10 -Cycloalkenyl, C6~C 10 - Selected from aryls, 5-10 membered heteroaryls, and 3-10 membered heterocyclines, B is [ka] Selected from, R 1 , R 2 and R 3 Each of these is independently selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and halo-C1-C6-alkoxy. R 7 These include C1-C6 alkyl, halo-C1-C6 alkyl, 3-10 member heterocyclyl and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group is optionally substituted with a halogen and one substituent selected from C1-C6 alkyl groups. R 8 These include hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, 3-10 member heterocyclyl, and C3-C 10- Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group is optionally substituted with a halogen and one substituent selected from C1-C6-alkyl groups, or R 7 and R 8 However, together with the atoms to which they are bonded, they form a heterocycle of 3 to 10 members. To provide.

[0031] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 2 and X 3 is N, and X 1 Is CH or (iii)X 1 , X 2 and X 3 All are N, or (iv)X 2 and X 3 CH is X 1 is N, or (v)X 1 and X 2 is N, and X 3 (is CH) To provide.

[0032] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 1 , X 2 and X 3 All are N, or (iii)X 2 and X 3 CH is X 1 (is N) To provide.

[0033] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein A is selected from C3-C 10 -cycloalkyl, C3-C 10 -cycloalkenyl, C6-C 10 -aryl, and 5- to 10-membered heteroaryl, R 1 is selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy, R 2 is selected from hydrogen, halogen and C1-C6-alkyl, R 3 is selected from hydrogen and halogen) To provide.

[0034] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl, R 1 is selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy, R 2 is selected from hydrogen, fluoro, and methyl, R 3 is selected from hydrogen and fluoro) To provide.

[0035] In a preferred embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein A is selected from C3-C 10 -cycloalkyl and C6-C 10 -aryl, R 1is selected from halogen and halo-C1-C6-alkyl, R 2 is selected from hydrogen and halogen, R 3 is selected from hydrogen and halogen) is provided.

[0036] In a particularly preferred embodiment, the present invention relates to a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl, R 1 is selected from fluoro, chloro, CHF2 and CF3, R 2 is selected from hydrogen and fluoro, R 3 is selected from hydrogen and fluoro) is provided.

[0037] In one embodiment, the present invention relates to a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein B is

Chemical formula

Chemical formula

Chemical formula

[0038] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] TIFF2026519580000013.tif89165 (selected from) is provided.

[0039] In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein B is

Chemical formula

Chemical formula

Chemical formula

[0040] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] (Selected from) To provide.

[0041] In more particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] It provides (that is).

[0042] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, R 7 These are C1-C6-alkyl, halo-C1-C6-alkyl and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group is optionally substituted with one C1-C6 alkyl substituent. R 8 These are hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group may optionally be substituted with one C1-C6 alkyl substituent, or R 7 and R 8 However, together with the atoms to which they are bonded, they form a heterocycle of 3 to 10 members. To provide.

[0043] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, R 7It is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl. R 8 is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1-difluoroethyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane, or R 7 and R 8 However, they form a pyrrolidine ring together with the atoms to which they are bonded. To provide.

[0044] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, R 7 These are C1-C6 alkyl groups, R 8 (Selected from C1-C6-alkyl and halo-C1-C6-alkyl) To provide.

[0045] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 7 and R 8 (All of these are methyl)

[0046] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 2 and X 3 is N, and X 1 Is CH or (iii)X 1 , X 2 and X 3 All are N, or (iv)X 2 and X 3CH is X 1 is N, or (v)X 1 and X 2 is N, and X 3 CH is, A is C3~C 10 -Cycloalkyl, C3~C 10 -Cycloalkenyl, C6~C 10 - Selected from aryls and 5-10 member heteroaryls, B is [ka] Selected from, R 1 These are selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy. R 2 These are selected from hydrogen, halogens, and C1-C6 alkyl groups. R 3 It is selected from hydrogen and halogens. R 4a and R 5a These are hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, and group [ka] Selected from, R 6a These are hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, and group [ka] Selected from, R 4b and R 6b These are selected from hydrogen, halogen, cyano, C1-C6 alkyl, and oxo. R 4c and R 6c These are selected from hydrogen, halogens, and C1-C6 alkyl groups. R 5b and R5c Both are hydrogen, C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl. D is selected from cyclopropyl, phenyl, pyrazolyl, 1H-1,2,4-triazole, 1H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl. R 7 These are C1-C6-alkyl, halo-C1-C6-alkyl and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group is optionally substituted with one C1-C6 alkyl substituent. R 8 These are hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group may optionally be substituted with one C1-C6 alkyl substituent, or R 7 and R 8 However, together with the atoms to which they are bonded, they form a heterocycle of 3 to 10 members. R 9 These are hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, and C3-C 10 -Cycloalkyl, Halo-C3~C 10 - Selected from cycloalkyl and 3-10 membered heterocyclyl, R 11 These are selected from hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and 3-10 membered heterocyclines. R 10 and R 12 (Selected from hydrogen and C1-C6 alkyl groups) To provide.

[0047] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 2 and X 3 is N, and X 1 Is CH or (iii)X 1 , X 2 and X 3 All are N, or (iv)X 2 and X 3 CH is X 1 is N, or (v)X 1 and X 2 is N, and X 3 CH is, A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl. B is [ka] TIFF2026519580000023.tif86165 Selected from, R 1 These are selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy. R 2 It is selected from hydrogen, fluoro, and methyl, R 3 It is selected from hydrogen and fluoro, R 7 It is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl. R 8is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1-difluoroethyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane, or R 7 and R 8 However, they form a pyrrolidine ring together with the atoms to which they are bonded. To provide.

[0048] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 1 , X 2 and X 3 All are N, or (iii)X 2 and X 3 CH is X 1 is N, A is C3~C 10 -Cycloalkyl and C6~C 10 - Selected from the alphabet, B is [ka] Selected from, R 1 These are selected from halogens and halo-C1~C6-alkyls. R 2 It is selected from hydrogen and halogens. R 3 It is selected from hydrogen and halogens. R 4a and R 5a is, [ka] And, R 6a is, [ka] And, R 4b , R 5b , and R 6b These are selected from hydrogen, halogens, and C1-C6 alkyl groups. R 4c , R 5c , and R 6c It is selected from hydrogen and halogens. R 7 These are C1-C6 alkyl groups, R 8 These are selected from C1-C6-alkyl and halo-C1-C6 alkyl. R 9 These are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 - Selected from cycloalkyl groups, R 11 These are selected from hydrogen, C1-C6 alkyl, and C1-C6 alkoxy. R 10 and R 12 Both are hydrogen, C is selected from cyclopropyl, pyridyl, and pyrazolyl. D is selected from cyclopropyl and pyrazolyl. To provide.

[0049] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 1 , X 2 and X 3 All are N, or (iii)X 2 and X 3 CH is X 1 is N, A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl. B is [ka] Selected from, R 1 These are selected from fluoro, chloro, CHF2, and CF3. R 2 It is selected from hydrogen and fluoro, R 3 It is selected from hydrogen and fluoro, R 7 and R 8 (All of them are methyl) To provide.

[0050] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 2 and X 3 is N, and X 1 Is CH or (iii)X 1 , X 2 and X 3 All are N, or (iv)X 2 and X 3 CH is X 1 is N, or (v)X 1 and X 2 is N, and X 3 CH is, A is C3~C 10 -Cycloalkyl, C3~C 10 -Cycloalkenyl, C6~C 10 - Selected from aryls and 5-10 member heteroaryls, B is [ka] Selected from, R 1 These are selected from hydrogen, halogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, and C1-C6-alkoxy. R 2 These are selected from hydrogen, halogens, and C1-C6 alkyl groups. R 3 It is selected from hydrogen and halogens. R 7 These are C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group is optionally substituted with one C1-C6 alkyl substituent. R 8 These are hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - The cycloalkyl group may optionally be substituted with one C1-C6 alkyl substituent, or R 7 and R 8 However, together with the atoms to which they are bonded, they form a heterocycle of 3 to 10 members. To provide.

[0051] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 2 and X 3 is N, and X 1 Is CH or (iii)X 1 , X 2 and X 3 All are N, or (iv)X 2 and X 3 CH is X1 is N, or (v)X 1 and X 2 is N, and X 3 CH is, A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl. B is [ka] Selected from, R 1 These are selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy. R 2 It is selected from hydrogen, fluoro, and methyl, R 3 It is selected from hydrogen and fluoro, R 7 It is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl. R 8 is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1-difluoroethyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane, or R 7 and R 8 However, they form a pyrrolidine ring together with the atoms to which they are bonded. To provide.

[0052] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 1 , X 2 and X3 All are N, or (iii)X 2 and X 3 CH is X 1 is N, A is C3~C 10 -Cycloalkyl and C6~C 10 - Selected from the alphabet, B is [ka] Selected from, R 1 These are selected from halogens and halo-C1~C6-alkyls. R 2 It is selected from hydrogen and halogens. R 3 It is selected from hydrogen and halogens. R 4a and R 5a is, [ka] And, R 6a is, [ka] And, R 4b , R 5b , and R 6b These are selected from hydrogen, halogens, and C1-C6 alkyl groups. R 4c , R 5c , and R 6c It is selected from hydrogen and halogens. R 7 These are C1-C6 alkyl groups, R 8 These are selected from C1-C6-alkyl and halo-C1-C6 alkyl. R 9 These are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10- Selected from cycloalkyl groups, R 11 These are selected from hydrogen, C1-C6 alkyl, and C1-C6 alkoxy. R 10 and R 12 Both are hydrogen, C is selected from cyclopropyl, pyridyl, and pyrazolyl. D is selected from cyclopropyl and pyrazolyl. To provide.

[0053] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 1 , X 2 and X 3 All are N, or (iii)X 2 and X 3 CH is X 1 is N, A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl. B is [ka] Selected from, R 1 These are selected from fluoro, chloro, CHF2, and CF3. R 2 It is selected from hydrogen and fluoro, R 3 It is selected from hydrogen and fluoro, R 7 and R 8 (All of them are methyl) To provide.

[0054] In more particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 1 , X 2 and X 3 All are N, or (iii)X 2 and X 3 CH is X 1 is N, A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl. B is [ka] And, R 1 These are selected from fluoro, chloro, CHF2, and CF3. R 2 It is selected from hydrogen and fluoro, R 3 It is selected from hydrogen and fluoro, R 7 and R 8 (All of them are methyl) To provide.

[0055] In a preferred embodiment, the present invention is X 1 and X 3 N is X 2 This specification provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein CH is present.

[0056] In one embodiment, the present invention is X 2 and X 3 N is X 1 This specification provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein CH is present.

[0057] In a preferred embodiment, the present invention is X 1 , X 2 and X 3 This specification provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein all atoms are N.

[0058] In one embodiment, the present invention is X 2 and X 3 CH is, X 1 The present specification provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein the compound is N.

[0059] In one embodiment, the present invention is X 1 and X 2 N is X 3 This specification provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein CH is present.

[0060] In one embodiment, the present invention is that A is C3~C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6~C 10 The present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, selected from aryls and 5- to 10-membered heteroaryls.

[0061] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] Selected from, In the formula, R 4a , R 4b , R 4c , R 5a , R 5b and R 5c (This is defined herein.) To provide.

[0062] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R1 The solution provides hydrogen, halogen, cyano, C1-C6 alkyl, halo-C1-C6 alkyl, and C1-C6 alkoxy elements.

[0063] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 2 The material provides hydrogen, halogens, and C1-C6 alkyl groups.

[0064] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 3 It provides (which is selected from hydrogen and halogens).

[0065] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 4a is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and group [ka] Selected from, R 9 , R 10 The invention provides (where C is as defined herein).

[0066] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 5a is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and group [ka] Selected from, R 9 , R 10 The invention provides (where C is as defined herein).

[0067] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 6ais hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and group [ka] Selected from, R 11 , R 12 The invention provides (where D is as defined herein).

[0068] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 4b The product provides hydrogen, halogen, cyano, C1-C6 alkyl, and oxo elements.

[0069] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 6b The product provides hydrogen, halogen, cyano, C1-C6 alkyl, and oxo elements.

[0070] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 4c The material provides hydrogen, halogens, and C1-C6 alkyl groups.

[0071] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 6c The material provides hydrogen, halogens, and C1-C6 alkyl groups.

[0072] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 5b It provides (which is hydrogen).

[0073] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 5c It provides (which is hydrogen).

[0074] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 7 C1~C6-alkyl, halo-C1~C6-alkyl, and C3~C 10 - Selected from cycloalkyl, the C3~C 10 - Provides a cycloalkyl group (in which case the cycloalkyl group is optionally substituted with one C1-C6 alkyl substituent).

[0075] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 8 is hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C 10 - Selected from cycloalkyl, the C3~C 10 - Provides a cycloalkyl group (in which case the cycloalkyl group is optionally substituted with one C1-C6 alkyl substituent).

[0076] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 7 and R 8 However, together with the atoms to which they are bonded, they provide a heterocycle with 3 to 10 members.

[0077] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 9 is hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, Halo-C3~C 10 - Provides cycloalkyls and heterocyclines selected from 3- to 10-membered heterocyclines.

[0078] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 10 The material provides hydrogen and C1-C6 alkyl (selected from C1-C6 alkyl).

[0079] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 11 The material provides hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and 3-10 member heterocyclines.

[0080] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 12 The material provides hydrogen and C1-C6 alkyl (selected from C1-C6 alkyl).

[0081] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanil, phenyl, and pyridyl).

[0082] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] TIFF2026519580000040.tif89165 (Selected from) To provide.

[0083] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] TIFF2026519580000042.tif79165 (Selected from) To provide.

[0084] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 1 The components provided are selected from hydrogen, fluoro, chloro, cyano, CHF2, CF3, methyl, and methoxy.

[0085] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 2 The solution provides (selected from hydrogen, fluoro, and methyl).

[0086] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 3 It provides (which is selected from hydrogen and fluoro).

[0087] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 7 The available options are selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl.

[0088] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 8 The present invention provides hydrogen (selected from methyl, ethyl, 2-propyl, tert-butyl, 1,1-difluoroethyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane).

[0089] In one embodiment, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 7 and R 8 However, together with the atoms to which they are bonded, they provide a pyrrolidine ring.

[0090] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein, (i)X 1 and X 3 is N, and X 2 Is CH or (ii)X 1 , X 2 and X 3 All are N, or (iii)X 2 and X 3 CH is X 1 (is N) To provide.

[0091] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein A is C3-C3). 10 -Cycloalkyl and C6~C 10 - Provides (selected from the alphabet)

[0092] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] Selected from, In the formula, R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 6a , R 6b , R 6c (As described herein) To provide.

[0093] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] And R 4a , R 4b and R 4c Provides (as described herein).

[0094] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] And R 5a , R 5b and R 5c Provides (as described herein).

[0095] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] And R 6a , R 6b and R 6c Provides (as described herein).

[0096] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] And R 6a , R 6b and R 6c Provides (as described herein).

[0097] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 1 The product provides halogens and halos (selected from C1-C6 alkyl groups).

[0098] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 2 It provides (which is selected from hydrogen and halogens).

[0099] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 3 It provides (which is selected from hydrogen and halogens).

[0100] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 4a is the basis [ka] And R 9 , R 10 It provides, and C as defined herein.

[0101] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 5a is the basis [ka] And R 9 , R 10 It provides, and C as defined herein.

[0102] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 6a is the basis [ka] And R 11 , R 12 It provides, and D as defined herein.

[0103] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 4bIt provides hydrogen, halogens, and C1-C6 alkyl groups.

[0104] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 5b It provides hydrogen, halogens, and C1-C6 alkyl groups.

[0105] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 6b It provides hydrogen, halogens, and C1-C6 alkyl groups.

[0106] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 4c It provides (which is selected from hydrogen and halogens).

[0107] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 5c It provides (which is selected from hydrogen and halogens).

[0108] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 6c It provides (which is selected from hydrogen and halogens).

[0109] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 7 Provides (where C1-C6 alkyl).

[0110] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 8 The present invention provides a C1-C6 alkyl group (selected from C1-C6 alkyl groups and halo-C1-C6 alkyl groups).

[0111] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 9 is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 - Provides (selected from cycloalkyl)

[0112] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 10 It provides (which is hydrogen).

[0113] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 11 The material provides hydrogen, C1-C6 alkyl, and C1-C6 alkoxy (selected from hydrogen).

[0114] In preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R 12 It provides (which is hydrogen).

[0115] In particularly preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof (wherein A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl).

[0116] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein B is [ka] (Selected from) To provide.

[0117] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein B is [ka] That is the case.

[0118] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein B is [ka] That is the case.

[0119] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein B is [ka] That is the case.

[0120] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein B is [ka] That is the case.

[0121] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 1 The present invention provides a compound selected from fluoro, chloro, CHF2, and CF3.

[0122] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 2 It provides (which is selected from hydrogen and fluoro).

[0123] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 3 It provides (which is selected from hydrogen and fluoro).

[0124] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, wherein C is selected from cyclopropyl, pyridyl, and pyrazolyl.

[0125] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, wherein C is selected from cyclopropyl and pyridyl.

[0126] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein R 4b , R 5b , and R 6b The element is selected from hydrogen, fluoro, and methyl.

[0127] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 4c , R 5c , and R 6c It provides (which is selected from hydrogen and fluoro).

[0128] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 7 It provides (where is methyl).

[0129] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 8 It provides (where is methyl).

[0130] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 9 The provided element is selected from hydrogen, methyl, methoxy, and cyclopropyl.

[0131] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof (wherein R, R 11 It provides (which is selected from hydrogen, methyl, and methoxy).

[0132] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(3R)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(trifluoromethyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3S)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3R)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 3-Fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-8-yl]benzonitrile, 8-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(2-fluoro-4-methylphenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-methylphenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-spiro[2.5]octan-6-ylpyrido[3,4-d]pyrimidine-4-one, 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-dimethylcyclohexyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-ethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-cyclobutyl-2-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-cyclobutyl-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2-(1-bicyclo[1.1.1]pentanyl)-8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-cyclopentyl-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2-tert-butyl-8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-2-(1-methylcyclopropyl)-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-methyl-3-(1-methylcyclopropyl)-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1,2,4-triazol-1-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(2-methylpyrazole-3-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3,3-dimethyl-4-(1-methylpyrazole-4-yl)pyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(5-methyl-1,2,4-oxadiazole-3-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-(3-methoxyphenyl)-3-methylpyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 6-[(3aR,6aR)-3a-phenyl-3,4,6,6a-tetrahydro-1H-fluoro[3,4-c]pyrrole-5-yl]-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-(3,5-dimethylpyrazole-1-yl)piperidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[6-(3-pyridyl)-3-azabicyclo[4.1.0]heptan-3-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(2-cyclopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(triazol-1-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(3-methyl-1,2,4-oxadiazole-5-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 6-(2-tert-butyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-yl)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1-methylpyrazole-4-yl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(7,8-dihydro-5H-1,6-naphthyridine-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(3-methyl-1,2,4-oxadiazole-5-yl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-keto-4-(p-tolyl)piperazino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1,2,4-triazol-1-yl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-(4-cyclopropyltriazol-1-yl)pyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(7-methyl-2,6-dioxa-9-azaspiro[4.5]decane-9-yl)pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-methyl-3-(p-tolyl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 4-[8-(4-chloro-2-fluorophenyl)-4-keto-2,3-dimethylpyrimido[5,4-d]pyrimidine-6-yl]-1-cyclopropyl-piperazine-2-carbonitrile, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-methyl-6-phenyl-tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)cyclobutyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-8-(3-methyl-1-bicyclo[1.1.1]pentanyl)-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 3-[2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-4-oxopyrido[3,4-d]pyrimidine-8-yl]bicyclo[1.1.1]pentan-1-carbonitride, 8-(3-methoxy-1-bicyclo[1.1.1]pentanyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one, 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one, 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one, 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one, 8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-isopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-(1,1-difluoroethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)phenyl]pyrimido[5,4-d]pyrimidine-4-one, 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)-3-pyridyl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 13-(4-chloro-2-fluorophenyl)-11-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2,7,10,12-tetrazatricyclo[7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(5-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-[2-fluoro-5-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-(difluoromethyl)pyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one, 8-(6,6-difluoro-3-bicyclo[3.1.0]hexanyl)-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-[4-(difluoromethyl)cyclohexyl]-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(2-methylpyrazole-3-yl)-6-azaspiro[3,4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(1-methylpyrazole-3-yl)-6-azaspiro[3,4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-8-one, 8-(4-chloro-2-fluorophenyl)-6-[2-[1-(2,2-difluoroethyl)pyrazole-4-yl]morpholino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]morpholino]pyrimido[5,4-d]pyrimidine-4-one, and Selected from 8-(4-chloro-2-fluorophenyl)-6-[2-[1-(2,2-difluorocyclopropyl)pyrazole-4-yl]morpholino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one.

[0133] In certain embodiments, the present invention provides pharmaceutically acceptable salts of compounds according to formula (I) described herein. In even more specific embodiments, the present invention provides compounds according to formula (I) described herein as free bases.

[0134] In some embodiments, the compound of formula (I) is isotope-labeled by substituting one or more atoms in it with atoms having different atomic masses or mass numbers. Such isotope-labeled (i.e., radioactively labeled) compounds of formula (I) are considered to be within the scope of this disclosure. Exemplary isotopes that can be incorporated into the compound of formula (I) are the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, for example. 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Examples include, but are not limited to, formula (I). Certain isotope-labeled compounds of formula (I), for example, those incorporating radioactive isotopes, are useful for studying the tissue distribution of drugs and / or substrates. Radioactive isotope tritium, i.e., 3 H and carbon-14, that is, 14 C is particularly useful for this purpose, considering its ease of incorporation and readily available detection means. For example, the compound of formula (I) can be concentrated at 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0135] Heavier isotopes, such as deuterium, 2 Substitution with H, etc., can improve metabolic stability, potentially leading to certain therapeutic benefits, such as a longer in vivo half-life or a reduced required dosage.

[0136] 11 C, 18 F, 15 O and 13Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Compounds of formula (I) labeled with isotopes can generally be prepared by conventional techniques known to those skilled in the art, or by using appropriate isotope-labeled reagents instead of previously used unlabeled reagents, in a process similar to those described in the examples below.

[0137] Manufacturing process The compounds of formula (I) of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to react and purify the resulting products are known to those skilled in the art. Substituents and subscripts used in the following process description have the meanings given herein unless otherwise indicated.

[0138] If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (e.g., as described in "Protective Groups in Organic Chemistry" by TW Greene and PGMWutts, 5th Ed., 2014, John Wiley & Sons, NY) can be introduced before a critical step by applying methods well known in the art. Such protecting groups can be removed at later stages of synthesis using standard methods described in the literature.

[0139] If the starting material or intermediate contains a stereocenter, the compound of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemic compounds can be separated into their counterparts via diastereomer salts, for example, by crystallization with an optically pure acid, or by separating the counterparts by a specific chromatographic method using either a chiral adsorbent or a chiral eluent. It is also possible to separate the starting material and intermediate containing a stereocenter to obtain diastereomerically / enantiomerically concentrated starting material and intermediate. When such diastereomerically / enantiomerically concentrated starting material and intermediate are used in the synthesis of the compound of formula (I), the respective diastereomerically / enantiomerically concentrated compounds of formula (I) are generally obtained.

[0140] Those skilled in the art will recognize that, in the synthesis of compounds of formula (I), unless otherwise desired, the “orthogonal protecting group strategy” can be applied to cleave several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protecting groups is well known in the art and has been described in the literature (e.g., Barany and RBMerrifield, J.Am.Chem.Soc. 1977, 99, 7363; H.Waldmann et al., Angew.Chem.Int.Ed.Engl. 1996, 35, 2056).

[0141] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and properties of the intermediates.

[0142] More specifically, the compound of formula (I) can be prepared by the method shown below, the method shown in the examples, or a similar method. Suitable reaction conditions for each reaction step are known to those skilled in the art. For reaction conditions described in the literature that may affect the described reaction, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999. The reaction could be carried out readily with or without a solvent. There are no particular restrictions on the properties of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and can dissolve the reagents to at least some extent. The described reaction can occur over a wide range of temperatures, and the exact reaction temperature is not important to the present invention. It is convenient to carry out the described reaction in the temperature range from -78°C to reflux. The time required for the reaction can also vary greatly depending on many factors, particularly the reaction temperature and the properties of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the described intermediates and compounds. The reaction sequence is not limited to the order shown in the scheme; the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity.

[0143] If the starting materials or intermediates are not commercially available, or if their synthesis is not documented in the literature, they may be prepared in the same manner as existing procedures for similar analogs, or as outlined in the experimental section.

[0144] The following abbreviations are used in this specification. Celsius (℃) 1 H proton Å Angstrom Alk (Alkyl) c concentration CAS Chemical Abstracts Service Registry Number CH3CN Acetonitrile CO2 (carbon dioxide) DIPEA N,N-diisopropylethylamine DMEM Dulbecco's Modified Eagle Medium DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) DMSO-d6 Hexaduterodimethylsulfoxide EC 50 Maximum half-dose effective concentration EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq equivalent ESI Electron Spray Ionization Example FBS Fetal Bovine Serum g grams g / L (grams / liter) h time HATU Azabenzotriazole Tetramethyluronium Hexafluorophosphate HBTU Benzotriazole tetramethyluronium hexafluorophosphate HCOOH Formic Acid HEK Human Embryonic Kidney HPLC (High-Performance Liquid Chromatography) i-PrMgCl·LiCl Isopropylmagnesium chloride-lithium chloride complex J coupling constant kg (kilogram) LED Light Emitting Diode M molar concentration m / z mass-to-charge ratio MeOH methanol mg milligrams MgSO4 Magnesium Sulfate MHz (megahertz) min ml (milliliter) mm (millimeters) mmol millimol MS mass spectrometry Sodium sulfite (Na2SO3) Sodium sulfate (Na2SO4) NaHCO3 (sodium bicarbonate) NBS N-bromosuccinimide NCS N-chlorosuccinimide neg.negative NH4Cl (Ammonium Chloride) nm (nanometer) NMR nuclear magnetic resonance spectroscopy Pd / C Palladium Charcoal pH (hydrogen ion concentration) pos. positive POY3 phosphorus oxytrihalide psi (pounds per square inch) R. Kahn-Ingold Prelogue Rule of Rectus RP inverse phase RPM (revolutions per minute) s seconds S. Sinister by the Khan-Ingold Prelogue Rule SFC Supercritical Fluid Chromatography TFA (Trifluoroacetic Acid) TLC (Thin-Layer Chromatography) μl (microliter) μm micrometer μmol (micromol) Xantphos (9,9-dimethyl-9H-xanthen-4,5-diyl)bis(diphenylphosphan) XantPhos Pd G3 [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate XPhos Pd G3 (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Specific rotation at αD 589nm δ chemical shift (ppm)

[0145] In the following scheme, R A is the base [ka] It refers to R B is the base [ka] It refers to A, B, R 1 , R 2 and R 3 This is defined herein.

[0146] Scheme 1 [ka] Compounds of general formulas Ia and Ib can be prepared by first reacting intermediate II with a boronic acid (or boronic acid derivative) III under palladium catalytic conditions ((1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(O) as a palladium source and a base such as cesium carbonate or sodium carbonate) to form compound IV. N-bonded residue R B In the case of compounds containing amine R, this intermediate is prepared in a dipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, in the presence of a base such as N,N-diisopropylethylamine or triethylamine. B Compound IV can react with -H(V) to form Ia (nucleophilic substitution). Furthermore, compound IV can be coupled with amine R using palladium-catalyzed coupling conditions (palladium source such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand such as Xantphos, and a base such as cesium carbonate or sodium tert-butoxide). B -It can be reacted with H(V) to form compound Ia (metal-catalyzed coupling). In the case of the C-bonded derivative Ib, the corresponding halogen derivative R B -X 3 (VI) is reacted with zinc under anhydrous conditions to first produce organozinc compound RB -Zn-X 3 This can be converted to (VII). Then, this organometallic reagent can be reacted with intermediate IV under palladium catalytic conditions to produce the compound of formula 1b using metal-catalyzed coupling (Scheme 1).

[0147] Scheme 2 [ka] Intermediate IIa can be prepared from compound VIII by coupling it with amine IX using an amide coupling reagent such as HATU, HBTU, or EDC, and then reacting the formed intermediate X with orthoester XI at high temperature. Alternatively, compound X can be reacted with an acid chloride XII (or acid anhydride) and a base such as N,N-diisopropylethylamine, triethylamine, or pyridine to form intermediate XIII, which can then be cyclized by heating in the presence of a base or a suitable solvent such as acetic acid (Scheme 2).

[0148] Scheme 3 [ka] Intermediate IIb can be prepared from compound XIV by coupling it with amine IX using an amide coupling reagent such as HATU, HBTU, or EDC, followed by halogenation with N-bromosuccinimide or N-chlorosuccinimide in a suitable solvent to obtain compound XVI. This compound can then be reacted with orthoester XI at high temperature to form intermediate IIb and intermediate IIc (Scheme 3).

[0149] Scheme 4 [ka] Intermediate IIc can be prepared from compound XVII by coupling it with amine IX using an amide coupling reagent such as HATU, HBTU, or EDC, followed by reaction with orthoester XI to form compound XIX. Intermediate IIc can be obtained by reaction of this compound with an inorganic halogenating reagent such as phosphorus oxychloride or phosphorus oxybromide XX, with or without the use of an additional base (Scheme 4).

[0150] Scheme 5 [ka] Compound Ic can be prepared from compound XV by reacting compound XV with an orthoester to form intermediate XXI, which can then be converted to compound XXII by nucleophilic substitution or metal-catalyzed coupling with reactants V or VII (see also the explanation in Scheme 1 for details). Either intermediate XXI or intermediate XXII can then be reacted with carboxylic acid XXIII under oxidative coupling conditions (Minisci reaction) to form compound XXIV or Ic, respectively. Compound Ic can be produced from compound XXIV using the aforementioned nucleophilic substitution or metal-catalyzed coupling reaction with reagents V or VII (Scheme 5).

[0151] Scheme 6 [ka] Compound Id can be prepared according to Scheme 6. Compound XXV is reacted with amine V in a bipolar aprotic solvent such as dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone in the presence of a base such as N,N-diisopropylethylamine or triethylamine to form XXVI, which is then further reacted with boronic acid III to obtain compound XXVII. This compound is reacted with N-bromosuccinimide in a suitable solvent to form XXVIII, which is converted to compound XXX by a palladium-catalyzed reaction with the tin derivative XXIX. Aminolysis of ester XXX with amine IX in a solvent such as ethanol or methanol yields compound XXXI, which is treated with a base such as sodium methoxide to achieve cyclization to compound Id.

[0152] Scheme 7 [ka] Furthermore, compounds of formula If or Ig can be obtained by late functionalization or related transformation of existing compounds Ie. Such processes include hydrogenation of compounds having a partially unsaturated carbon ring at position R A Formation of saturated carbon rings, or appropriate substituent R using alkylating agents and bases B Alkylation is one example (Scheme 7).

[0153] In one embodiment, the present invention provides a process for producing a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, the process described in any one of schemes 1 to 7.

[0154] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, which is produced according to any one of the processes described herein.

[0155] TREM2 agonist activity The compounds of the present invention are TREM2 agonists. Accordingly, in one embodiment, the present invention provides the use of the compounds of formula (I) described herein for the restoration of human TREM2 function in subjects requiring it.

[0156] In a further embodiment, the present invention provides compounds of formula (I) described herein for use in a method for restoring the function of human TREM2 in subjects requiring such restoration.

[0157] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein for preparing a pharmacopoeia for restoring the function of human TREM2 in a subject requiring it.

[0158] In a further embodiment, the present invention provides a method for restoring the function of human TREM2 in a subject requiring such restoration, comprising administering an effective amount of a compound of formula (I) described herein to the subject.

[0159] The TREM2 agonist efficacy of the compound of formula (I) according to the present invention was measured using a HEK cell line expressing human TREM2 and DAP12. When the small molecule ligand binds to the TREM2 receptor, Syk kinase is recruited and activated by DAP12. The elevated levels of phosphorylated Syk obtained were measured in lysed cells using a commercially available AlphaLisa reagent kit.

[0160] To perform this assay, frozen HEK293-TREM2 / DAP12 cells were thawed, prepared, and plated in 10 μL of DMEM medium supplemented with 5% FBS and without Phenolred, using Certus at a rate of 20,000 cells per well in a 384-well plate.

[0161] The dose-response (1:3) compound was diluted with DMSO (maximum concentration 10 mM), added to cells from a low-dead-volume plate using ECHO (0-20 μM), and diluted 500-fold (20 nL in 10 μl cell suspension, maximum concentration 20 μM in all wells, DMSO concentration 0.2%). A neutral control (DMSO) and a stimulating control (1 μM tool compound) were also added.

[0162] Cells were incubated at 37°C, 5% CO2, and 95% humidity for 30 minutes. After compound addition and incubation, 2.5 μL of cell lysis buffer was added using Certus. After short centrifugation, the plate was shaken at 450 RPM at room temperature in the dark for 30 minutes. After complete lysis, AlphaLisa reagent was added to the lysate using Certus, and fluorescence intensity was measured using a Pherastar plate reader (excitation: 680 nm / emission: 615 nm). EC 50 The values ​​were calculated using Genedata Screener and normalized to 100% activity for DMSO and the tool compound.

[0163] The TREM2 agonist efficacy of the compound of formula (I) according to the present invention, as measured by the above assay, is shown in the table below. [Table 1] TIFF2026519580000066.tif252170 TIFF2026519580000067.tif252170

[0164] Use of the compound of the present invention In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

[0165] In a further embodiment, the present invention provides a method for treating or preventing symptoms associated with human TREM2 loss of function in a subject requiring treatment or prevention of such symptoms, comprising administering a therapeutically effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein to the subject.

[0166] In a further embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein for use in a method of treating or preventing symptoms associated with human TREM2 loss of function in subjects requiring treatment or prevention of symptoms associated with human TREM2 loss of function.

[0167] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein in a method for treating or preventing symptoms associated with human TREM2 loss of function in subjects requiring treatment or prevention of symptoms associated with human TREM2 loss of function.

[0168] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical for use in a method for treating or preventing symptoms associated with human TREM2 loss of function in subjects requiring treatment or prevention of symptoms associated with human TREM2 loss of function.

[0169] In one embodiment, the symptoms associated with loss of function of human TREM2 are selected from Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

[0170] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is Parkinson's disease.

[0171] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is rheumatoid arthritis.

[0172] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is Alzheimer's disease.

[0173] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is amyotrophic lateral sclerosis (ALS).

[0174] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is Nasu-Hakola disease.

[0175] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is frontotemporal dementia.

[0176] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is multiple sclerosis.

[0177] In a preferred embodiment, the symptoms associated with loss of function of human TREM2 are prion diseases.

[0178] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is stroke.

[0179] Pharmaceutical composition and administration In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein and a therapeutic inactivating carrier.

[0180] In one embodiment, a pharmaceutical composition according to Example 168 or Example 169 is provided.

[0181] Compounds of formula (I) and pharmaceutically acceptable salts thereof may be used as pharmaceuticals (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations may be administered into the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may also be parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0182] Compounds of formula (I) and pharmaceutically acceptable salts thereof may be treated with pharmaceutically inert inorganic or organic adjuvants for the manufacture of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid, or their salts can be used, for example, as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules.

[0183] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0184] Suitable adjuvants for the manufacture of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0185] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0186] Suitable adjuvants for suppositories include, for example, natural or hydrogenated oils, waxes, fats, semi-solid or liquid polyols.

[0187] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts, buffers, masking agents, or antioxidants to alter osmotic pressure. They may also contain other therapeutically valuable substances.

[0188] Dosage can vary widely and, of course, to suit the individual requirements of each specific case. Generally, for oral administration, a daily dose of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (e.g., about 300 mg per person), is preferably divided into 1 to 3 individual doses, which, if appropriate, may consist of, for example, the same amount. However, it is clear that the upper limits given herein can be exceeded where indicated. [Examples]

[0189] The present invention will be better understood by referring to the following embodiments. However, the claims should not be construed as being limited to the scope of these embodiments.

[0190] If the preparation is obtained as a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0191] The compounds of formula I may contain several chiral centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, or mixtures of diastereoisomers. According to the Cahn-Ingold-Prelog rule, the chiral carbon atom may have an "R" or "S" stereoconfiguration. For the compounds described in this patent, absolute stereochemistry has been arbitrarily assigned.

[0192] Unless otherwise specified, all reaction examples and intermediates were prepared under an argon atmosphere.

[0193] The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1.

[0194] The following intermediates can be prepared according to the procedures provided herein, are commercially available, or can be prepared according to the procedures in the literature.

[0195] Intermediate A1: 6,8-dichloro-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 3-amino-2,6-dichloro-isonicotinic acid [ka] A suspension of methyl 3-amino-2,6-dichloro-isonicotinate (1000 mg, 4.52 mmol) was prepared by suspending it in tetrahydrofuran (12 ml) and water (4 ml). Lithium hydroxide (325 mg, 13.57 mmol) was added at 0°C, and the mixture was stirred at 0°C for 1 hour, followed by stirring overnight at room temperature. After adding water, the mixture was extracted once with ethyl acetate. The aqueous phase was acidified (pH 4) by adding 3 M hydrochloric acid. The resulting precipitate was dried under vacuum to obtain the title compound (592 mg, 60% yield) as a yellow solid. MS m / z: 205.1 [MH] - ESI pos.

[0196] Step 2: 3-amino-2,6-dichloro-N-methylpyridine-4-carboxamide [ka] To a solution prepared by dissolving 3-amino-2,6-dichloropyridine-4-carboxylic acid (1000 mg, 4.83 mmol) and methylamine hydrochloride (489 mg, 7.25 mmol) in anhydrous dimethylformamide (10 ml), N,N-diisopropylethylamine (1873 mg, 14.5 mmol) was added, and the mixture was stirred at 25°C for 10 minutes. Then, HATU (2.76 g, 7.25 mmol) was added, and the reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was extracted with ethyl acetate (3 times with 50 ml), the combined organic layer was washed twice with saturated brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:1) to obtain 3-amino-2,6-dichloro-N-methylpyridine-4-carboxamide (864 mg, 3.93 mmol, yield 81%) as a white solid. MS m / z:220.1[M+H] + ESI pos.

[0197] Step 3: 6,8-Dichloro-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] Trimethyl orthoformic acid (2.08 g, 19.6 mmol) was added to 3-amino-2,6-dichloro-N-methylpyridine-4-carboxamide (864.0 mg, 3.93 mmol) in 1,4-dioxane (5 ml). Toluene-4-sulfonic acid (676 mg, 3.93 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated, followed by the addition of saturated NaHCO3 solution. The resulting solid was collected by vacuum filtration, washed with water, and dried to obtain the title compound 6,8-dichloro-3-methylpyrido[3,4-d]pyrimidine-4-one (800 mg, yield 88%) as a white solid. MS m / z: 230.1 [M+H] + ESI pos.

[0198] Intermediate A2: 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 5-amino-2-chloro-N-methyl-isonicotinamide [ka] To a solution prepared by dissolving 5-amino-2-chloroisonicotinic acid (800 mg, 4.64 mmol) in dichloromethane (10 ml), methylamine hydrochloride (438 mg, 6.49 mmol), N,N-diisopropylethylamine (1.8 g, 2.43 ml, 13.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.07 g, 5.56 mmol), and 1-hydroxybenzotriazole hydrate (710 mg, 4.64 mmol) were added at room temperature, and the mixture was stirred for 42 hours. The solvent was evaporated. Water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude mixture was purified by flash chromatography (silica gel, gradient dichloromethane / methanol 100:0 to 92:8) to obtain 5-amino-2-chloro-N-methyl-isonicotinamide (724 mg, yield 84%) as a pale yellow solid. MS m / z: 186.0 [M+H] + ESI pos.

[0199] Step 2: 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide [ka] N,N-dimethylformamide (7.5 ml) was dissolved in 5-amino-2-chloro-N-methyl-isonicotinamide (700 mg, 3.77 mmol). N-bromosuccinimide (806 mg, 4.53 mmol) was added to this solution, and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude mixture was purified by flash chromatography (silica gel, gradient heptane / ethyl acetate 100 / 0~50 / 50) to obtain 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (961 mg, yield 96%) as a pale yellow solid. MS m / z: 264.0 [M+H] + ESI pos.

[0200] Step 3: 8-Bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] A solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (961 mg, 3.63 mmol) was prepared by dissolving 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (961 mg, 3.63 mmol) in 1,1,1-trimethoxyethane (3.2 g, 3.35 ml, 26.6 mmol). This solution was then added to acetic acid (218 mg, 208 μl, 3.63 mmol), and the reaction mixture was stirred at 135°C for 20 hours. Since the reaction was not yet complete, 1,1,1-trimethoxyethane (1.31 g, 1.37 ml, 10.9 mmol) and acetic acid (109 mg, 104 μl, 1.82 mmol) were added, and stirring was continued overnight at 135°C. After evaporating the excess under vacuum, the crude mixture was purified by flash chromatography (silica gel, gradient heptane / ethyl acetate 100 / 0~60 / 40) to obtain 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (789 mg, 75%) as a pale yellow solid. MS m / z: 290.0[M+H] + ESI pos.

[0201] Intermediate A3: 8-bromo-6-chloro-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see intermediate A2, 870 mg, 3.29 mmol) was mixed with trimethyl orthoformic acid (6.63 g, 6.9 ml, 62.49 mmol) at room temperature, followed by the addition of 25% hydrochloric acid in water (dropwise, 480 mg, 400 μl, 3.29 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction was concentrated under vacuum to obtain 8-bromo-6-chloro-3-methylpyrido[3,4-d]pyrimidine-4-one (892 mg, 91% yield) as a white solid. MS m / z: 276.0 [M+H] + ESI pos.

[0202] Intermediate A4: 6-Chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 5-amino-2-chloro-N-methyl-isonicotinamide (see intermediate A2, 350 mg, 1.89 mmol) in 1,1,1-trimethoxyethane (1.66 g, 1.74 ml, 13.83 mmol), acetic acid (113 mg, 108 μl, 1.89 mmol) was added, and the reaction mixture was stirred overnight at 135°C. Excess reagent was evaporated under vacuum to obtain 6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (392 mg, 99% yield) as a pale yellow solid. MS m / z: 210.1 [M+H] + ESI pos.

[0203] Intermediate A5: 6,8-dichloro-3-ethyl-pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A1, using ethylamine hydrochloride instead of methylamine hydrochloride in step 2. White solid, MS m / z: 244.1 [M+H] + ESI pos.

[0204] Intermediate A6: 6,8-dichloro-3-cyclopropyl-pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A1 in step 2, using cyclopropylamine instead of methylamine hydrochloride. White solid, MS m / z: 256.1 [M+H] + ESI pos.

[0205] Intermediate A7: 6,8-dichloro-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A1 in step 2, using 2,2,2-trifluoroethylamine instead of methylamine hydrochloride. Pale yellow rubber, MS m / z: 297.9 [M+H] + ESI pos.

[0206] Intermediate A8: 8-bromo-6-chloro-2-ethyl-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see intermediate A2, 0.600 g, 2.27 mmol) in dried 1,4-dioxane (12 ml), 1,1,1-trimethoxypropane (1.52 g, 1.61 ml, 11.3 mmol) was added at room temperature, followed by the addition of p-toluenesulfonic acid monohydrate (432 mg, 2.27 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated to dryness and then triturated with methanol (2 ml). The pale yellow solid was filtered, washed with methanol (2 ml), and dried under vacuum to obtain 8-bromo-6-chloro-2-ethyl-3-methylpyrido[3,4-d]pyrimidine-4-one (475 mg, 67% yield) as a white solid. MS m / z: 304.0 [M+H] + ESI pos.

[0207] Intermediate A9: 2-(1-bicyclo[1.1.1]pentanyl)-8-bromo-6-chloro-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 3-(bicyclo[1.1.1]pentane-1-carbonylamino)-2-bromo-6-chloro-N-methylpyridine-4-carboxamide [ka] To a solution prepared by dissolving 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see intermediate A2, 500 mg, 1.89 mmol) in dichloromethane (8 ml), bicyclo[1.1.1]pentane-1-carboxylic acid (212 mg, 1.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (544 mg, 2.84 mmol), and 4-dimethylaminopyridine (462 mg, 3.78 mmol) were added, and the mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (silica gel, petroleum ether, ethyl acetate = 1:1) to obtain 3-(bicyclo[1.1.1]pentane-1-carbonylamino)-2-bromo-6-chloro-N-methylpyridine-4-carboxamide (230 mg, 0.64 mmol, yield 34%) as a pale yellow solid. MS m / z: 330.0 [M+H] + ESI pos.

[0208] Step 2: 2-(1-bicyclo[1.1.1]pentanyl)-8-bromo-6-chloro-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] A solution of 3-(bicyclo[1.1.1]pentan-1-carbonylamino)-2-bromo-6-chloro-N-methylpyridine-4-carboxamide (230 mg, 0.64 mmol) dissolved in acetic acid (3.0 ml) was stirred at 110°C for 16 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic extract was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate) to obtain 2-(1-bicyclo[1.1.1]pentanyl)-8-bromo-6-chloro-3-methylpyrido[3,4-d]pyrimidine-4-one (200 mg, yield 92%) as a pale yellow solid. MS m / z: 342.0 [M+H] +ESI pos.

[0209] Intermediate A10: 8-bromo-6-chloro-3-cyclopropyl-2-methylpyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 3-amino-2-bromo-6-chloro-N-cyclopropyl-isonicotinamide [ka] To a solution prepared by dissolving 3-amino-2-bromo-6-chloro-isonicotinic acid (2 g, 7.56 mmol) in dried N,N-dimethylformamide (60 ml), cyclopropylamine (1.29 g, 1.6 ml, 22.6 mmol) and N-ethyldiisopropylamine (5.86 g, 7.84 ml, 45.4 mmol) were added. The reaction mixture was cooled to 0°C, HATU (4.9 g, 12.9 mmol) was added, and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with saturated NaHCO3 solution and water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain 3-amino-2-bromo-6-chloro-N-cyclopropyl-isonicotinamide (464 mg, yield 21%) as a white solid. MS m / z:292.0[M+H] + ESI pos.

[0210] Step 2: 8-bromo-6-chloro-3-cyclopropyl-2-methylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 3-amino-2-bromo-6-chloro-N-cyclopropyl-isonicotinamide (460 mg, 1.58 mmol) in dried 1,4-dioxane (9 ml), 1,1,1-trimethoxyethane (951 mg, 1.01 ml, 7.92 mmol) was added at room temperature, followed by the addition of p-toluenesulfonic acid monohydrate (301 mg, 1.58 mmol). The reaction mixture was stirred overnight at room temperature. The mixture was concentrated to dryness and then triturated with methanol (3 ml). The solid was filtered, washed with methanol (3 ml), and dried under vacuum to obtain 8-bromo-6-chloro-3-cyclopropyl-2-methylpyrido[3,4-d]pyrimidine-4-one (440 mg, yield 88%) as a white solid. MS m / z: 316.0 [M+H] + ESI pos.

[0211] Intermediate A11: 8-bromo-6-chloro-2-methyl-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide [ka] To a solution prepared by dissolving 5-amino-2-chloropyridine-4-carboxylic acid (300 mg, 1.74 mmol) in dichloromethane (9 ml), 2,2,2-trifluoroethylamine (258 mg, 2.61 mmol) and N-ethyldiisopropylamine (0.91 mL, 5.22 mmol) were added at room temperature. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (400 mg, 2.09 mmol) and 1-hydroxybenzotriazole hydrate (235 mg, 1.74 mmol) were added at room temperature. The mixture was stirred at 30°C for 12 hours. The solvent was evaporated. Then, water (100 ml) and ethyl acetate (50 ml) were added, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate (50 ml). The combined organic layers were dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative TLC (silica, petroleum ether / ethyl acetate = 3:2) to obtain 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (350 mg, 1.38 mmol, yield 79%) as a pale yellow solid. MS m / z: 254.1 [M+H] + ESI pos.

[0212] Step 2: 3-amino-2-bromo-6-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide [ka] To a solution prepared by dissolving 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (130 mg, 0.51 mmol) in dimethylformamide (3 ml), N-bromosuccinimide (110 mg, 0.62 mmol) was added, and the reaction mixture was stirred at 30°C for 12 hours. The mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (50 ml x 3), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: spherical C18, 20-45 μm, 100 A, mobile phase: water / 0.1% TFA / acetonitrile, flow rate: 40 ml / min) to obtain 3-amino-2-bromo-6-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (150 mg, yield 88%) as a light brown solid. MS m / z: 333.9 [M+H] + ESI pos.

[0213] Step 3: 8-Bromo-6-chloro-2-methyl-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 3-amino-2-bromo-6-chloro-N-(2,2,2-trifluoroethyl)pyridine-4-carboxamide (150 mg, 0.45 mmol) in 1,4-dioxane (5 ml), trimethyl orthoacetate (271 mg, 2.26 mmol) and p-toluenesulfonic acid (155 mg, 0.9 mmol) were added, and the reaction mixture was stirred at 110°C for 12 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (column: spherical C18, 20-45 μm, 100 A, mobile phase: water / 0.1% TFA / acetonitrile, flow rate: 50 ml / min) to obtain 8-bromo-6-chloro-2-methyl-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one (100 mg, 0.28 mmol, yield 62%) as an off-white solid. MS m / z: 358.0 [M+H] + ESI pos.

[0214] Intermediate A12: 8-bromo-6-chloro-3-cyclobutyl-2-methylpyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A11, using cyclobutylamine instead of 2,2,2-trifluoroethylamine in step 1. It was a pale yellow solid, MS m / z: 328.0 [M+H]. + ESI pos.

[0215] Intermediate A13: 8-bromo-6-chloro-2-cyclobutyl-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 2-Bromo-6-chloro-3-(cyclobutanecarbonylamino)-N-methylpyridine-4-carboxamide [ka] To a solution prepared by dissolving 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see intermediate A2, 300 mg, 1.13 mmol) in pyridine (3 ml), 4-dimethylaminopyridine (28 mg, 0.23 mmol) and cyclobutane carbonyl chloride (208 mg, 1.7 mmol) were added at 0°C, and the reaction mixture was stirred at 0°C to 20°C for 12 hours. Next, the reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (column: spherical C18, 20-45 μm, 100 A, mobile phase: water containing 0.1% TFA, acetonitrile, flow rate: 80 ml / min) to obtain 2-bromo-6-chloro-3-(cyclobutanecarbonylamino)-N-methylpyridine-4-carboxamide (120 mg, yield 31%) as a white solid. MS m / z: 346.0 [M+H] + ESI pos.

[0216] Step 2: 8-Bromo-6-chloro-2-cyclobutyl-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] The reaction mixture was stirred at 110°C for 12 hours in a solution of 2-bromo-6-chloro-3-(cyclobutanecarbonylamino)-N-methylpyridine-4-carboxamide (120 mg, 0.35 mmol) dissolved in acetic acid (4 ml). The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (column: spherical C18, 20-45 μm, 100 A, mobile phase: water containing 0.1% TFA, acetonitrile, flow rate 60 ml / min) to obtain 8-bromo-6-chloro-2-cyclobutyl-3-methylpyrido[3,4-d]pyrimidine-4-one (45 mg, 0.14 mmol, yield 40%) as an off-white solid. MS m / z: 330.0 [M+H] + ESI pos.

[0217] Intermediate A14: 8-bromo-6-chloro-2-methyl-3-(1-methylcyclopropyl)pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A11, using 1-methylcyclopropanamine instead of 2,2,2-trifluoroethylamine in step 1. It was a pale yellow solid, MS m / z: 329.9 [M+H]. + ESI pos.

[0218] Intermediate A15: 8-bromo-6-chloro-2-cyclopentyl-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see intermediate A2, 300 mg, 1.13 mmol) in pyridine (5 ml), 4-dimethylaminopyridine (28 mg, 0.23 mmol) was added. Then, cyclopentane carbonyl chloride (301 mg, 2.27 mmol) was added dropwise to the mixture while maintaining the temperature between 0 and 5°C. After the addition, the mixture was stirred at 0°C for 2 hours, then heated to 50°C and stirred for 12 hours. The mixture was poured into water (50 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 1:2) to obtain 8-bromo-6-chloro-2-cyclopentyl-3-methylpyrido[3,4-d]pyrimidine-4-one (210 mg, yield 54%) as a white solid.

[0219] Intermediate A16: 8-bromo-6-chloro-2-cyclopropyl-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] In step 1, the title compound was prepared using cyclopropane carbonyl chloride instead of cyclobutane carbonyl chloride, similar to intermediate A13. It was a light brown solid, MS m / z: 315.9 [M+H]. + ESI pos.

[0220] Intermediate A17: 8-bromo-2-tert-butyl-6-chloro-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A13, using pivaloyl chloride instead of cyclobutane carbonyl chloride in step 1. White solid, MS m / z: 330.0, 332.0 [M+H] +ESI pos.

[0221] Intermediate A18: 8-bromo-6-chloro-2-(1,1-difluoroethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] In step 1, the title compound was prepared using 2,2-difluoropropionyl chloride instead of cyclobutane carbonyl chloride, similar to intermediate A13. It was a light brown solid, MS m / z: 339.9 [M+H]. + ESI pos.

[0222] Intermediate A19: 8-bromo-6-chloro-3-ethyl-2-methylpyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A11, using ethylamine instead of 2,2,2-trifluoroethylamine in step 1. It was a pale yellow solid, MS m / z: 304.0 [M+H]. + ESI pos.

[0223] Intermediate A20: 8-bromo-6-chloro-2-isopropyl-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A13, using 2-methylpropionyl chloride instead of cyclobutanecarbonyl chloride in step 1. It was a pale yellow solid, MS m / z: 318.0 [M+H]. + ESI pos.

[0224] Intermediate A21: 8-bromo-6-chloro-3-methyl-2-(1-methylcyclopropyl)pyrido[3,4-d]pyrimidine-4-one [ka] In step 1, the title compound was prepared in the same manner as intermediate A13, using 1-methylcyclopropanecarbonyl chloride instead of cyclobutanecarbonyl chloride. Off-white solid, MS m / z: 328.1 [M+H] + ESI pos.

[0225] Intermediate B1: 8-bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-4-one [ka] Step 1: 8-Bromo-6-chloro-3H-pyrido[3,2-d]pyrimidine-4-one [ka] Bromine (2.0 g, 650 μl, 12.6 mmol) was added dropwise to 3-amino-6-chloropicolinamide (CAS 175358-01-7, 540 mg, 3.15 mmol) in acetic acid (13.5 ml) at 0°C. After 30 minutes, the reaction mixture was warmed to room temperature. The reaction was quenched by adding aqueous Na2SO3 solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and evaporated. The crude product was dissolved in diethoxymethyl acetate (CAS 14036-06-7, 10.2 g, 10.3 ml, 63 mmol) and stirred overnight at 150°C. After cooling to room temperature, the formed crystalline substance was washed with water and dichloromethane to obtain the title compound (589 mg, yield 65%, purity 90%) as a pale yellow solid, which was used directly in the next step. MS m / z: 260.0, 262.0 [M+H] + ESI pos.

[0226] Step 2: 8-Bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-4-one [ka] A solution of 8-bromo-6-chloro-3H-pyrido[3,2-d]pyrimidine-4-one (589 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (8 ml). Sodium hydride (98 mg, 2.44 mmol) was added at 0°C, and the mixture was stirred for 30 minutes. Iodomethane (433 mg, 191 μl, 3.05 mmol) was added at room temperature, and the reaction mixture was stirred for 60 minutes. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to dryness to obtain the title compound (341 mg, yield 61%) as a pale yellow solid. MS m / z: 274.0, 276.0 [M+H] + ESI pos.

[0227] Intermediate B2: 8-bromo-6-chloro-2,3-dimethylpyrido[3,2-d]pyrimidine-4-one [ka] Step 1: 3-amino-4-bromo-6-chloropicolinic acid [ka] To a solution prepared by dissolving methyl 3-amino-4-bromo-6-chloropicolinate (CAS 1073182-89-4, 1.3 g, 4.65 mmol) in tetrahydrofuran (17 ml) and methanol (8.5 ml), 1 M lithium hydroxide aqueous solution (7.0 ml, 7.0 mmol) was added. After stirring for 4 hours, 3 M hydrochloric acid aqueous solution (2.33 ml, 7.0 mmol) was added, and the solvent was removed under vacuum. The resulting solid was filtered and rinsed with cold water. After drying under high vacuum, 3-amino-4-bromo-6-chloropicolinate (1.1 g, yield 89%) was isolated as a light brown powder, MS m / z: 251.0, 253.0 [M+H]. + ESI pos.

[0228] Step 2: 3-amino-4-bromo-6-chloro-N-methylpicolinamide [ka] 3-amino-4-bromo-6-chloropicolinic acid (500 mg, 1.79 mmol) and methylamine hydrochloride (181 mg, 2.68 mmol) were dissolved in N,N-dimethylformamide (14 ml), and N,N-diisopropylethylamine (694 mg, 920 μl, 5.37 mmol) was added. After cooling the mixture to 0°C, HATU (817 mg, 2.15 mmol) was added. The reaction mixture was stirred overnight at room temperature, then diluted with water and ethyl acetate and extracted. The combined organic layers were washed with saturated NaHCO3 and brine, dried over dry Na2SO4, and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, heptane, 0-20% ethyl acetate) to obtain 3-amino-4-bromo-6-chloro-N-methylpicolinamide (371 mg, yield 75%) as a pale yellow powder, MS m / z: 264.0, 266.0 [M+H] + ESI pos.

[0229] Step 3: 8-Bromo-6-chloro-2,3-dimethylpyrido[3,2-d]pyrimidine-4-one [ka] A solution of 3-amino-4-bromo-6-chloro-N-methylpicolinamide (371 mg, 1.4 mmol) was prepared by dissolving it in 1,1-trimethoxyethane (1.24 g, 1.31 ml, 10.3 mmol). Acetic acid (84 mg, 80 μl, 1.4 mmol) was added to this solution, and the reaction mixture was stirred at 135°C for two nights. The reaction mixture was concentrated to dryness, and the crude product was purified by flash chromatography (silica gel, 100% dichloromethane) to obtain a product still containing some of the starting material. Further trituration with diethyl ether yielded 8-bromo-6-chloro-2,3-dimethylpyrido[3,2-d]pyrimidine-4-one (250 mg, yield 59%) as a pale yellow powder. MS m / z: 288.0, 290.0 [M+H] + ESI pos.

[0230] Intermediate C1: 6,8-dichloro-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylate methyl ester [ka] Sodium bicarbonate (5 g, 59.5 mmol) and 2,4-diketo-5-nitro-1H-pyrimidine-6-carboxylate methyl ester (CAS 6311-73-5, 1 g, 4.65 mmol) were suspended in water (50 ml). Sodium dithionite (5 g, 24.3 mmol) was added gradually at room temperature, and the mixture was stirred for 1 hour. The solid was filtered off, washed with water, and dried in a vacuum to obtain 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylate methyl ester (443 mg, yield 50%) as a yellow solid, which was used directly in the next step.

[0231] Step 2: 5-(ethoxymethyleneamino)-2,4-diketo-1H-pyrimidine-6-carboxylate methyl ester [ka] A suspension of methyl 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylate (440 mg, 2.38 mmol) in diethoxymethyl acetate (4.0 g, 4 ml, 24.5 mmol) was stirred at 80°C for 2 hours. The mixture was cooled to room temperature, and methyl tert-butyl ether was added. After stirring the suspension for 5 minutes, the solid was filtered off and washed with methyl tert-butyl ether. The solid was dried in vacuum to obtain the crude title compound (512 mg, yield 85%) as a white solid, which was used directly in the next step.

[0232] Step 3: 3-methyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione [ka] A suspension of 5-(ethoxymethyleneamino)-2,4-diketo-1H-pyrimidine-6-carboxylate methyl ester (400 mg, 1.66 mmol) in a 33% methylamine solution in ethanol (4 ml, 32.1 mmol) was stirred overnight at 80°C. The solid was filtered off, washed with ethanol, and then dried under vacuum to obtain the crude title compound 3-methyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (350 mg, 100%) as a pale yellow solid. MS m / z: 195.1[M+H] + ESI pos.

[0233] Step 4: 6,8-Dichloro-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] To a suspension prepared by suspending 3-methyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (375 mg, 1.93 mmol) in phosphorus oxychloride (8.23 g, 5 ml, 53.6 mmol), a mixture of N,N-diisopropylethylamine (250 mg, 337 μl, 1.93 mmol) and dimethylformamide (23 mg, 24 μl, 311 μmol) was added dropwise at room temperature. The mixture was stirred overnight at 130 °C. The reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane, quenched with water, and extracted twice with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, methanol-containing dichloromethane 0-5%) to obtain the title compound (128 mg, yield 24%, purity 85%) as a brown solid. MS m / z:231.0,233.0[M+H] + ESI pos.

[0234] Intermediate C2: 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 5-amino-2,4-diketo-N-methyl-1H-pyrimidine-6-carboxamide [ka] To a solution prepared by dissolving 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylic acid (CAS 7164-43-4, 5g, 29.2 mmol) in N,N-dimethylformamide (120 ml), N,N-diisopropylethylamine (15.1 g, 20.4 ml, 117 mmol) and methylamine hydrochloride (3.95 g, 58.4 mmol) were added at room temperature. HATU (14.4 g, 38 mmol) was added gradually, and the mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum to remove most of the solvent, and the residue was suspended in 150 ml of methanol / methyl tert-butyl ether = 1:1. After stirring the suspension for 10 minutes, it was filtered and washed with methanol / methyl tert-butyl ether. The obtained solid was dried in vacuum to obtain 5-amino-2,4-diketo-N-methyl-1H-pyrimidine-6-carboxamide (4.0 g, yield 67%) as a yellow solid. MS m / z: 185.0 [M+H] + ESI pos.

[0235] Step 2: 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione [ka] A suspension of 5-amino-2,4-diketo-N-methyl-1H-pyrimidine-6-carboxamide (3 g, 16.3 mmol) in triethyl orthoacetate (13.2 g, 15 ml, 81.5 mmol) and acetic acid (980 mg, 933 μl, 16.3 mmol) was stirred at 130°C for 5 hours. The reaction mixture was diluted with methyl tert-butyl ether and stirred for a further 5 minutes. The solid was filtered off and washed with methyl tert-butyl ether. The solid was dried under vacuum to obtain the title compound 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (3.26 g, yield 86.5%) as a yellow solid. MS m / z: 209.0 [M+H] + ESI pos.

[0236] Step 3: 6,8-Dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 2,3-dimethyl-5H-pyrimido[5,4-d]pyrimidine-4,6,8-trione (3.2 g, 15.4 mmol) in phosphorus oxychloride (49.35 g, 30 ml, 322 mmol), a mixture of N,N-diisopropylethylamine (2.0 g, 2.68 ml, 15.4 mmol) and dimethylformamide (181 mg, 192 μl, 2.48 mmol) was added dropwise at room temperature. The mixture was stirred overnight at 130°C and then concentrated to dryness. The residue was dissolved in dichloromethane. Water was added, and the mixture was extracted twice with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The crude substance was purified by flash chromatography (silica gel, heptane, ethyl acetate 0-100%) to obtain the title compound 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (1.44 g, yield 38%) as a brown solid. MS m / z: 245.0 [M+H] + ESI pos.

[0237] Intermediate C3: 11,13-dichloro-2,7,10,12-tetrazatricyclo[7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one [ka] A suspension of methyl 5-amino-2,6-dichloropyrimidine-4-carboxylate (CAS 502184-51-2, 1.5 g, 6.76 mmol) in dry toluene (45 ml) was prepared, to which 5-methoxy-3,4-dihydro-2H-pyrrole (CAS 5264-35-7, 4.18 ml, 40.5 mmol) and phosphorus oxychloride (3.78 ml, 40.5 mmol) were added. After stirring at 100°C for 18 hours, the mixture was concentrated under vacuum, quenched with cold saturated NaHCO3 aqueous solution (300 ml), and extracted with ethyl acetate (2 × 250 ml). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by flash chromatography (silica gel, chloroform, 0-95% acetonitrile) to obtain the title compound (436 mg, yield 25%) as a yellow solid. MS m / z:257.2[M+H] + ESI pos.

[0238] Intermediate C4: 6-Chloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 5-amino-2-chloro-N-methylpyrimidine-4-carboxamide [ka] To a solution prepared by dissolving 5-amino-2-chloropyrimidine-4-carboxylate ethyl ester (500 mg, 2.48 mmol) in ethanol (1.65 ml), methylamine aqueous solution (40%, 2.7 ml, 31 mmol) was added, and the reaction mixture was stirred at 70°C for 2 hours. The solvent was evaporated to obtain 5-amino-2-chloro-N-methylpyrimidine-4-carboxamide (455 mg, 98% yield) as an orange solid. MS m / z: 187.0 [M+H] + ESI pos.

[0239] Step 2: 6-Chloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] A solution of 5-amino-2-chloro-N-methylpyrimidine-4-carboxamide (455 mg, 2.44 mmol) was prepared by dissolving it in 1,1,1-trimethoxyethane (2.15 g, 2.25 ml, 17.88 mmol). Acetic acid (146 mg, 140 μl, 2.44 mmol) was added to this solution, and the reaction mixture was stirred at 135°C for 16 hours. After evaporating the volatile substances, 6-chloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (531 mg, 94% yield) was obtained as an orange solid. MS m / z: 211.0 [M+H] + ESI pos.

[0240] Intermediate D1: 4-(4-bromotetrahydropyran-2-yl)-1-methylpyrazole [ka] To a solution of 1-methylpyrazole-4-carbaldehyde (2 g, 18.2 mmol) dissolved in dichloromethane (25 ml), 3-buten-1-ol (1.38 g, 1.64 ml, 19.1 mmol) was added under argon. Hydrobromic acid (33% acetic acid solution (13.4 g, 9.9 mL, 54.5 mmol)) was added all at once at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was carefully quenched with saturated NaHCO3 solution and washed with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude substance was purified by flash chromatography (silica gel, heptane with 0-50% ethyl acetate / ethanol = 3:1) to obtain 4-(4-bromotetrahydropyran-2-yl)-1-methylpyrazole (2.87 g, yield 62%) as a pale yellow oil. 245.1[M+H] + ESI pos.

[0241] Intermediate D2: (2S)-4-bromo-2-methyl-6-phenyltetrahydropyran [ka] A pale yellow oily substance prepared in the same manner as intermediate D1, using (2S)-penta-4-en-2-ol instead of 3-buten-1-ol. [Table 2] TIFF2026519580000127.tif233170 TIFF2026519580000128.tif232170 TIFF2026519580000129.tif230170 TIFF2026519580000130.tif157170

[0242] Intermediate E39: 2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine [ka] Step 1: 2-Chloro-1-[1-(oxetan-3-yl)pyrazole-4-yl]ethanone [ka] To a solution of 4-iodo-1-(oxetan-3-yl)pyrazole (CAS 1314393-99-1, 600 mg, 2.4 mmol) dissolved in tetrahydrofuran (6 ml), i-PrMgCl·LiCl (1.3 M, 2.8 ml, 3.6 mmol, 1.5 equivalents) was added under a nitrogen atmosphere at -70°C. After stirring the mixture at -70°C for 0.5 hours, a solution of 2-chloro-N-methoxy-N-methylacetamide (396 mg, 2.88 mmol, 1.2 equivalents) dissolved in tetrahydrofuran (4 ml) was added dropwise to the mixture at -70°C. Stirring was then continued at 0°C for 1 hour. The reaction mixture was poured into a saturated ammonium chloride solution (50 ml), and the aqueous phase was extracted with dichloromethane (50 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 1:1) and concentrated under reduced pressure to obtain 2-chloro-1-[1-(oxetan-3-yl)pyrazole-4-yl]etanone (300 mg, 1.5 mmol, yield 62%) as a pale yellow solid. MS m / z: 201.3[M+H] + ESI pos.

[0243] Step 2: 2-[Benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazole-4-yl]ethanone [ka] To a solution prepared by dissolving 2-chloro-1-[1-(oxetan-3-yl)pyrazole-4-yl]ethanone (3.60 g, 17.9 mmol) in dimethyl sulfoxide (60 ml), N-benzylethanolamine (2.71 g, 17.9 mmol), potassium carbonate (4.96 g, 35.9 mmol), and potassium iodide (2.98 g, 17.9 mmol) were added. The mixture was then stirred at 20°C for 2 hours. The reaction mixture was poured into water (500 ml) and extracted with dichloromethane (200 ml x 3). The combined organic phase was washed with brine (500 ml), dried over Na2SO4, and concentrated under vacuum to obtain 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazole-4-yl]ethanone (5.0 mg, yield 88%) as a pale yellow oil. MS m / z:316.4[M+H] + ESI pos.

[0244] Step 3: 2-[Benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazole-4-yl]ethanol [ka] 5.0 g, 13.6 mmol of 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazole-4-yl]ethanone (5.0 g, 13.6 mmol) was dissolved in methanol (80 ml), and sodium borohydride (2.06 g, 54.5 mmol) was added at 0°C. The mixture was stirred at 0°C for 1 hour. The reaction mixture was poured into saturated NH4Cl aqueous solution (300 ml), and the aqueous layer was extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine (200 ml x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: UniSil 10-120, C18 70 x 250 mm, water + 0.1% formic acid / acetonitrile, flow rate 140 ml / min). The pH of the eluent was adjusted to 8-9 with ammonium hydroxide, and the mixture was extracted with ethyl acetate (200 ml x 3). The combined organic layer was dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazole-4-yl]ethanol (3.6 g, yield 83%) as a colorless oil. MS m / z: 318.2[M+H] + ESI pos.

[0245] Step 4: 4-Benzyl-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine [ka] A solution of 2-[benzyl(2-hydroxyethyl)amino]-1-[1-(oxetan-3-yl)pyrazole-4-yl]ethanol (2.5 g, 7.88 mmol) dissolved in toluene (40 ml) was stirred, purged with nitrogen, cooled to 0°C, and diisopropyl azodicarboxylate (1.66 ml, 9.45 mmol) and triphenylphosphine (2.48 g, 9.45 mmol) were added in fractions. The mixture was then stirred under a nitrogen atmosphere at 25°C for 12 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by reverse-phase HPLC (column: spherical C18, 20-45 μm, 100 A, water + 0.1% formic acid / acetonitrile, flow rate: 50 ml / min). The eluent was extracted with ethyl acetate (200 ml x 2), the combined organic layer was dried, and concentrated under vacuum to obtain 4-benzyl-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine (1.2 g, yield 51%) as a colorless oil. MS m / z: 300.2 [M+H] + ESI pos.

[0246] Step 5: 2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine [ka] 4-benzyl-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine (1.2 g, 4.01 mmol) was dissolved in methanol (15 ml). After degassing three times with nitrogen, Pd / C (10%, 213 mg) was added, and a hydrogen atmosphere was applied. The reaction mixture was stirred at 50°C for 12 hours under hydrogen (15 psi). The reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under vacuum, and the crude product was diluted with ethyl acetate (100 ml) and washed with water (100 ml) and brine (100 ml). The organic phase was then dried over Na2SO4, filtered, and concentrated under vacuum to obtain the title compound (800 mg, yield 95%) as a pale yellow oil. MS m / z: 210.1 [M+H] + ESI pos.

[0247] Intermediate (+)-E1:(+)-2-(1-methylpyrazole-4-yl)morpholine 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1) was separated by chiral SFC (column AD-H, 5 μm, 100 × 4.6 mm, 20-40% MeOH + 0, 2% diethylamine) to obtain (+)-2-(1-methylpyrazole-4-yl)morpholine as the first eluted enantiomer and (-)-2-(1-methylpyrazole-4-yl)morpholine as the second eluted enantiomer. (+)-2-(1-methylpyrazole-4-yl)morpholine: yellow oily substance, αD (589 nm) 20℃ = +13.36° (c = 0.1 g / L, MeOH).

[0248] Examples Example 1: 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-chlorophenyl)-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6,8-dichloro-3-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A1, 150 mg, 0.65 mmol) in a mixture of toluene (10 ml) and ethanol (5 ml), 4-chlorophenylboronic acid (102 mg, 0.65 mmol), sodium carbonate (276 mg, 2.61 mmol), and tetrakis(triphenylphosphine)-palladium(0) (60 mg, 0.05 mmol, 0.08 equivalents) were added. After degassing three times with nitrogen, the resulting mixture was stirred at 75°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (30 ml). The mixture was then filtered through a Celite pad, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC-A (column: Welch Ultimate XB-SiOH 250*50*10um, mobile phase: hexane-ethanol, flow rate 100 ml / min) to obtain 6-chloro-8-(4-chlorophenyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (120 mg, yield 45%) as a white solid. MS m / z: 306.1[M+H] + ESI pos.

[0249] Step 2: 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] N-methylpyrrolidone (3 ml) was dissolved in a solution containing 6-chloro-8-(4-chlorophenyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (90 mg, 0.29 mmol) and 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1, 74 mg, 0.44 mmol). N,N-diisopropylethylamine (152 mg, 1.18 mmol) was added to this solution, and the mixture was heated at 150°C for 12 hours under microwave irradiation. The mixture was poured into water (40 ml), extracted twice with ethyl acetate, washed with brine (3 × 30 ml), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Phenomenex luna L18 column, 150*25mm*10um, water + formic acid / acetonitrile, flow rate: 25 ml / min) to obtain 8-(4-chlorophenyl)-3-methyl-6-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one (28 mg). This racemic mixture was separated by SFC (Daicel Chiralcel OD column, 250mm*30mm, 10um, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 75ml / min) to obtain 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one as the first eluted enantiomer, with a retention time of 1.18 minutes (retention time for other enantiomers: 1.51 minutes), as a pale yellow solid. MS m / z: 437.2[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0250] Example 2: 8-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] In step 1, 2-fluoro-4-(trifluoromethyl)phenylboronic acid was used instead of 4-chlorophenylboronic acid, and in step 2, (+)-2-(1-methylpyrazole-4-yl)morpholine was used instead of 2-(1-methylpyrazole-4-yl)morpholine. Chiral SFC separation was omitted, and the title compound was prepared in the same manner as in Example 1. Yellow solid, MS m / z: 489.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0251] Example 3: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-3-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A3, 834 mg, 3.04 mmol) and (4-chloro-2-fluorophenyl)boronic acid (530 mg, 3.04 mmol) in 1,4-dioxane (15 ml) and water (5 ml), cesium carbonate (2.97 g, 9.11 mmol) was added. The reaction mixture was purged with argon and refilled with argon three times. Next, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (124 mg, 152 μmol, 0.05 equivalents) was added, and the mixture was purged with argon and refilled with argon three times. The reaction mixture was stirred at room temperature for 16 hours, then diluted with water and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The crude material was triturated with diethyl ether to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (870 mg, yield 87%) as a pale yellow solid. MS m / z: 324.1[M+H] + , ESI pos., 1H NMR(300MHz,DMSO-d6)δ=8.45(s,1H),8.12(s,1H),7.68-7.54(m,2H),7.46(dd,J=1.9,8.4Hz,1H),3.51(s,3H).

[0252] Step 2: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] N-methylpyrrolidone (3 ml) was dissolved in 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1, 134 mg, 0.8 mmol) and 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (130 mg, 0.4 mmol). N,N-diisopropylethylamine (0.21 ml, 1.2 mmol) was added to this solution, and the mixture was stirred at 150°C for 16 hours. The reaction mixture was added to water (50 ml) and extracted with ethyl acetate (2 × 30 ml). The combined organic layers were washed with brine (2 × 50 ml), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether / ethyl acetate) to obtain 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one (110 mg). This racemic mixture was separated by SFC (Daicel Chiralcel OD-3 column, 50 mm*4.6 mm, 3 μm, mobile phase 50% acetonitrile / isopropyl alcohol / 0.05% diethylamine, flow rate 3 ml / min) to obtain 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one as the first eluted enantiomer, with a retention time of 1.25 minutes (retention time for the other enantiomers was 0.85 minutes), as a yellow solid. MS m / z: 455.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0253] Examples 4-12 below were prepared in the same manner as in Example 3 by coupling the indicated intermediate instead of intermediate E1. For the chiral examples, absolute stereochemistry was assigned arbitrarily. [Table 3] TIFF2026519580000145.tif180170

[0254] Example 13: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 750 mg, 2.6 mmol) and (4-chloro-2-fluorophenyl)boronic acid (453 mg, 2.6 mmol) in 1,4-dioxane (12 ml) and water (4 ml), cesium carbonate (2.54 g, 7.8 mmol) was added. The reaction mixture was purged with argon and refilled with argon three times, and 1,1'-bis(diphenylphosphin)ferrocene-palladium(ii) dichloride dichloromethane complex (106 mg, 130 μmol, 0.05 equivalents) was added. The reaction mixture was purged with argon and refilled with argon three times, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, heptane, 0-60% ethyl acetate), and then triturated with diethyl ether to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (556 mg, yield 62%) as a pale yellow solid. MS m / z: 338.1[M+H] + , ESI pos., 1H NMR(300MHz,DMSO-d6)δ=8.06(s,1H),7.65-7.56(m,2H),7.48-7.43(m,1H),3.55(s,3H),2.52(br s,3H).

[0255] Step 2: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] N,N-diisopropylethylamine (138 mg, 1.06 mmol) was added to a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (120 mg, 0.35 mmol) and 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1, 89 mg, 0.53 mmol) in N-methylpyrrolidone (1 ml). The mixture was heated under microwave irradiation at 150°C for 12 hours, and then purified by preparative HPLC (Phenomenex Luna C18 column 150×25mm×10um, water (0.225% formic acid / acetonitrile, flow rate 25 ml / min) to obtain the product 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one (50 mg). This racemic mixture was then subjected to SFC (Daicel Chiralcel OD column). Separation was performed using a 250mm*30mm, 10um field with solvents: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 70 ml / min, to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one as the first eluted enantiomer, with a retention time of 2.06 min (retention time for the other enantiomers was 2.46 min), as a pale yellow solid. MS m / z: 469.3[M+H] +ESI pos., absolute stereochemistry was assigned arbitrarily. 1H NMR(400MHz,DMSO-d6)δ=7.74(s,1H),7.61-7.50(m,2H),7.46(s,1H),7.40(d,J=8.2Hz,1H),7.32(s,1H),4.55(br d,J=8.7Hz,1H),4.29(br d,J=12.6Hz,1H),4.12(br d,J=12.6Hz,1H),4.02(br d,J=10.4Hz,1H),3.81(s,3H),3.74-3.67(m,1H),3.52(s,3H),3.43(br d,J=3.8Hz,1H),3.05-2.89(m,2H),2.44(s,3H).

[0256] Example 14: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 13. The second eluted enantiomer had a retention time of 2.46 minutes, was a pale yellow solid, and was MS m / z: 469.3 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0257] Example 15: 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 13, using intermediate E5 instead of intermediate E1 in step 2. The first eluted enantiomer had a retention time of 1.58 minutes, was a pale yellow solid, and was MS m / z: 495.2 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0258] Example 16: 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 13, using intermediate E5 instead of intermediate E1 in step 2. The second eluted enantiomer had a retention time of 2.58 minutes, was a pale yellow solid, and was MS m / z: 495.2 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0259] Example 17: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[3,4-d]pyrimidine-4-one [ka] 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (see Example 13, 25 mg, 74 μmol), 1-methyl-4,5,6,7-tetrahydropyrazolo[3,4-c]pyridine dihydrochloride (intermediate E6, 16 mg, 74 μmol), tris(dibenzylideneacetone)dipalladium (3 mg, 3.7 μmol, 0.05 equivalents), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (2 mg, 3.7 μmol, 0.05 equivalents), and cesium carbonate (96 mg, 296 μmol) were stirred under argon at 100°C for 15 minutes. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The crude material was purified by preparative HPLC (Gemini NX column, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[3,4-d]pyrimidine-4-one (2 mg, yield 5%) as a yellow powder. MS m / z: 439.2 [M+H] + , ESI pos., 1H NMR(300MHz,DMSO-d6)δ=7.65-7.51(m,2H),7.47-7.36(m,2H),7.23(s,1H),4.71(s, 2H), 3.92(t,J=5.7Hz,2H),3.77(s,3H),3.53(s,3H),2.64-2.59(m,2H),2.44(s,3H).

[0260] Example 18: 8-(4-chloro-2-fluorophenyl)-6-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 17, using intermediate E8 instead of intermediate E6. Yellow powder, MS m / z 436.2 [M+H] + ESI pos.

[0261] Example 19: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (see Example 13, 30 mg, 0.09 mmol) in 1,4-dioxane (1.5 ml), 2-(2-methyl-4-pyridyl)morpholine (intermediate E3, 24 mg, 0.13 mmol), cesium carbonate (87 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (6.5 mg, 0.01 mmol, 0.08 equivalents), and Xantphos (10 mg, 0.02 mmol, 0.2 equivalents) were added, and the mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate (3 × 50 ml). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by chromatography (silica gel plate, dichloromethane / ethyl acetate = 10:1) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one (30 mg). This racemic mixture was separated by SFC (Daicel Chiralcel OD column, 250mm*30mm, 10um, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 80ml / min) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one as the first eluted enantiomer, with a retention time of 1.02 minutes (retention time for the other enantiomers was 2.08 minutes), as a yellow solid. MS m / z: 480.2[M+H] + ESI pos., arbitrarily assigned absolute stereochemistry.

[0262] Example 20: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 19. The second eluted enantiomer, with a retention time of 2.08 minutes, was a yellow solid, and the MS m / z was 480.2 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0263] Examples 21-30 below were prepared in the same manner as in Examples 19 and 20 by coupling the intermediates shown instead of intermediate E3. Absolute stereochemistry was assigned arbitrarily. [Table 4] TIFF2026519580000157.tif217170

[0264] Example 31: 3-Fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-8-yl]benzonitrile [ka] Step 1: 4-(6-chloro-2,3-dimethyl-4-oxopyrido[3,4-d]pyrimidine-8-yl)-3-fluorobenzonitrile [ka] 1,4-Dioxane (5 ml) and water (1.5 ml) were used to dissolve 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 300 mg, 1.04 mmol) and (4-chloro-2-fluorophenyl)boronic acid (181 mg, 1.04 mmol). Cesium carbonate (1.02 g, 3.12 mmol) was added to this solution. The reaction mixture was purged with argon and refilled with argon three times, and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (42 mg, 0.052 mmol, 0.050 equivalents) was added. The reaction mixture was purged with argon and refilled with argon three times. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane, 0-60% ethyl acetate), and then triturated with diethyl ether to obtain 4-(6-chloro-4-keto-2,3-dimethylpyrido[3,4-d]pyrimidine-8-yl)-3-fluorobenzonitrile (200 mg, yield 42%) as a pale yellow solid. MS m / z: 329.1 [M+H] + ESI pos.

[0265] Step 2: 3-Fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-8-yl]benzonitrile [ka] (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 73 mg, 58 μl, 438 μmol), 4-(6-chloro-4-keto-2,3-dimethylpyrido[3,4-d]pyrimidine-8-yl)-3-fluorobenzonitrile (100 mg, 219 μmol), N,N-diisopropylethylamine (85 mg, 115 μl, 657 μmol), and dimethyl sulfoxide (1.5 ml) were added to a flask. The reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain the title compound (24 mg, yield 24%) as a yellow solid. MS m / z: 460.3 [M + H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0266] Example 32: 8-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 31, using 2-(4-chloro-2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane at a reaction temperature of 80°C in step 1, instead of using (4-chloro-2-fluorophenyl)boronic acid at room temperature. Yellow solid, MS m / z: 487.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0267] Example 33: 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 300 mg, 1.04 mmol) in 1,4-dioxane (10 ml), 2,4-difluorobenzeneboronic acid (164 mg, 1.04 mmol), sodium carbonate (331 mg, 3.12 mmol), and tetrakis(triphenylphosphine)-palladium(0) (60 mg, 0.05 mmol, 0.05 equivalents) were added. After degassing three times with nitrogen, the resulting mixture was stirred at 100°C for 16 hours. The mixture was then poured into water (200 ml) and extracted with ethyl acetate (3 × 200 ml). The combined organic layers were dried over Na₂SO₄ and the solution was concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether: 30%) to obtain 6-chloro-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (110 mg, yield 33%) as a pale yellow solid. MS m / z: 322.0 [M+H] + ESI pos.

[0268] Step 2: 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(2,4-difluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (47 mg, 0.15 mmol) in N-methylpyrrolidone (2 ml), (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 37 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.12 ml, 0.73 mmol) were added, and the mixture was heated at 150°C for 12 hours under microwave irradiation. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by preparative HPLC (Phenomenex Luna L18 column, 150*25mm*10um, water + formic acid / acetonitrile, flow rate: 25 ml / min) to obtain the title compound (6 mg, yield 9%) as a yellow solid. MS m / z: 453.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0269] Example 34: 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 33, using (2R)-2-(1-methylpyrazole-4-yl)morpholine instead of (2S)-2-(1-methylpyrazole-4-yl)morpholine in step 2. Yellow solid, MS m / z: 453.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0270] Example 35: 8-(2-fluoro-4-methylphenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 33, using 2-fluoro-4-methylphenylboronic acid instead of 2,4-difluorobenzeneboronic acid in step 1, and (2R)-2-(1-methylpyrazole-4-yl)morpholine instead of (2S)-2-(1-methylpyrazole-4-yl)morpholine in step 2. Yellow solid, MS m / z: 449.3 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0271] Example 36: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-2,3-dimethyl-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 200 mg, 0.69 mmol) in 1,4-dioxane (6 ml), 4-methylphenylboronic acid (94 mg, 0.69 mmol), cesium carbonate (678 mg, 2.08 mmol), bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (28 mg, 0.03 mmol, 0.05 equivalents) and water (2 ml) were added. The reaction mixture was then degassed three times with nitrogen and stirred at 25°C under nitrogen for 12 hours. The reaction mixture was poured into water (50 ml) and extracted with dichloromethane (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na2SO4, and concentrated under vacuum. The solid was triturated with petroleum ether / ethyl acetate = 5:1 (20 ml), recovered by filtration, and 6-chloro-2,3-dimethyl-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one (180 mg, yield 86%) was obtained as a gray solid. MS m / z: 300.2 [M+H] + ESI pos.

[0272] Step 2: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-2,3-dimethyl-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one (60 mg, 0.2 mmol) in N-methylpyrrolidone (2 ml), (2R)-2-(1-methylpyrazole-4-yl)morpholine (50 mg, 0.3 mmol) and N,N-diisopropylethylamine (0.1 ml, 0.6 mmol) were added, and the reaction mixture was heated at 150°C for 16 hours under microwave irradiation. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge C18, 150 × 25 mm × 10 μm, acetonitrile / water + 0.225% formic acid, flow rate 25 ml / min) to obtain 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one (15 mg, yield 18%) as a yellow solid. MS m / z: 431.3 [M + H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0273] Example 37: 2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 36, using (2S)-2-(1-methylpyrazole-4-yl)morpholine instead of (2R)-2-(1-methylpyrazole-4-yl)morpholine in step 2. Yellow solid, MS m / z: 431.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0274] Example 38: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka]

[0275] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (see Example 13, 300 mg, 0.89 mmol) in N-methylpyrrolidone (4 ml), 2-(1H-pyrazole-4-yl)morpholine (intermediate E11, 204 mg, 1.33 mmol) and N,N-diisopropylethylamine (0.44 ml, 2.66 mmol) were added, and the mixture was heated at 150°C for 16 hours under microwave irradiation. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, and the residue was purified by column chromatography (silica gel, ethyl acetate / MeOH = 1:5-10:1) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one (70 mg, yield 14%) as a pale yellow solid. MS m / z: 455.2[M+H] + ESI pos.

[0276] Step 2: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Dimethylformamide (1 ml) was used to dissolve 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one (35 mg, 0.08 mmol) and 3-iodooxetane (28 mg, 0.15 mmol). Cesium carbonate (75 mg, 0.23 mmol) was added to this solution, and the mixture was stirred at 50°C for 16 hours. The reaction mixture was added to water (50 ml) and extracted with dichloromethane (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by preparative TLC (ethyl acetate / methanol = 10:1) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one (30 mg, yield 72%) as a green solid. The enantiomer was separated by SFC (Daicel Chiralpak AD column, 250 mm × 30 mm, 10 μm, solvent ethanol + 0.1% ammonium hydroxide, flow rate 70 ml / min), and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one (2.8 mg, 10%) was obtained as the first eluted compound (retention time 1.08 min) as a pale yellow rubber. MS m / z: 511.1[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0277] Example 39: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in step 2 of Example 38. The second eluted compound (retention time 1.62 mins), pale yellow rubber, MS m / z: 511.1 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0278] Example 40: 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 500 mg, 1.73 mmol) in ethanol (3 ml), toluene (6 ml), water (0.9 ml), 2-(4,4-dimethylcyclohexen-1-yl)-4, 4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 859217-67-7, 409 mg, 1.73 mmol), sodium carbonate (551 mg, 5.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol, 0.05 equivalents) were added. After degassing three times with nitrogen, the resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was poured into water (150 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:1) to obtain 6-chloro-8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (370 mg, yield 67%) as a white solid. MS m / z: 318.1[M+H] + ESI pos.

[0279] Step 2: 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (130 mg, 0.41 mmol) in 1,4-dioxane (3 ml), 2-(2-methyl-4-pyridyl)morpholine (intermediate E3, 109 mg, 0.615 mmol), cesium carbonate (400 mg, 1.23 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.03 mmol, 0.08 equivalents), and Xantphos (47 mg, 0.08 mmol, 0.2 equivalents) were added, and the mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (silica gel, dichloromethane / ethyl acetate = 10:1) to obtain 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one (130 mg). The enantiomer was separated by SFC (Daicel Chiralpak AD column, 250 mm × 30 mm, 10 μm, solvent ethanol + 0.1% ammonium hydroxide, flow rate 75 ml / min) to obtain the first eluted compound (retention time 2.1 min). MS m / z: 460.4 [M + H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0280] Example 41: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-2,3-dimethyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 500 mg, 1.73 mmol) in 1,4-dioxane (12 ml), 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane (CAS 683242-93-5, 478 mg, 1.73 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (71 mg, 0.09 mmol, 0.05 equivalents), cesium carbonate (1.69 g, 5.2 mmol), and water (4 ml) were added. After degassing three times with nitrogen, the reaction mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours. The reaction mixture was added to water (50 ml) and extracted with dichloromethane (40 ml x 3). The combined organic layer was washed with brine (100 ml x 3), dried over Na2SO4, and then concentrated under vacuum. The resulting precipitate was triturated with petroleum ether / ethyl acetate in a 5:1 ratio and recovered by filtration. Solid, MS m / z: 358.1 [M+H] + ESI pos.

[0281] Step 2: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-2,3-dimethyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidine-4-one (170 mg, 0.48 mmol) in 1,4-dioxane (1 ml), (2R)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 119 mg, 0.71 mmol), cesium carbonate (387 mg, 1.19 mmol), tris(dibenzylideneacetone)dipalladium (22 mg, 0.02 mmol, 0.05 equivalent), and Xantphos (27.5 mg, 0.05 mmol, 0.1 equivalent) were added. The mixture was then degassed three times with nitrogen and heated at 100°C for 12 hours. The reaction mixture was added to water (50 ml) and extracted with ethyl acetate (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC (Waters Xbridge C18 column, 150 x 50 mm x 10 μm, water / acetonitrile / acetonitrile containing 10 mM ammonium carbonate, flow rate 60 ml / m) to obtain the title compound (80 mg, yield 34%) as a pale yellow solid. MS m / z: 489.2 [M+H] + ESI pos.

[0282] Examples 42-45 below were prepared in the same manner as in Example 41 by coupling the indicated boronic acid derivatives instead of 4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolane. Absolute stereochemistry was assigned arbitrarily. [Table 5]

[0283] Example 46: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-spiro[2.5]octan-6-ylpyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-2,3-dimethyl-8-spiro[2.5]octa-6-en-6-ylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 280 mg, 0.97 mmol) in 1,4-dioxane (6 ml), 4,4,5,5-tetramethyl-2-spiro[2.5]octa-6-en-6-yl-1,3,2-dioxaborolane (CAS 859219-46-8, 227 mg, 0.97 mmol), cesium carbonate (948 mg, 2.91 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (40 mg, 0.05 mmol, 0.05 equivalents), and water (2 ml) were added. The mixture was degassed three times with nitrogen and stirred at 30°C for 16 hours. After cooling to room temperature, the precipitate was washed with petroleum ether, and the solid was removed by filtration. The solution was evaporated to obtain the crude product, which was used directly in the next step. MS m / z: 316.2[M+H] + ESI pos.

[0284] Step 2: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-spiro[2.5]octa-6-en-6-ylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-2,3-dimethyl-8-spiro[2.5]octa-6-en-6-ylpyrido[3,4-d]pyrimidine-4-one (135 mg, 0.43 mmol) in 1,4-dioxane (3 ml), (2R)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 107 mg, 0.64 mmol), tris(dibenzylideneacetone)dipalladium (31 mg, 0.03 mmol, 0.08 equivalents), cesium carbonate (418 mg, 1.28 mmol), and Xantphos (49.5 mg, 0.09 mmol, 0.2 equivalents) were added, and the mixture was stirred under nitrogen at 100°C for 16 hours. The reaction mixture was poured into water (40 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (Phenomenex Luna C18 column, 150 × 25 mm × 10 μm, water + 0.1% formic acid / acetonitrile, flow rate 25 ml / min) to obtain 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-spiro[2.5]octa-6-en-6-ylpyrido[3,4-d]pyrimidine-4-one (58 mg, yield 29%) as a yellow solid. MS m / z: 447.2[M+H] + ESI pos.

[0285] Step 3: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-spiro[2.5]octan-6-ylpyrido[3,4-d]pyrimidine-4-one [ka] 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-spiro[2.5]octa-6-en-6-ylpyrido[3,4-d]pyrimidine-4-one (58 mg, 0.13 mmol) was dissolved in methanol (2 ml). Palladium carbon (10%, 10 mg) was added to the solution, and the mixture was hydrogenated at 50°C for 2 hours under a hydrogen atmosphere of 30 psi. The crude mixture was filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (column: Phenomenex luna C18, 150 × 25 mm × 10 μm, water + 0.1% formic acid / acetonitrile, flow rate 25 ml / min) to obtain the title compound (27 mg, yield 44%) as a pale yellow solid. MS m / z: 449.2 [M + H] + ESI pos.

[0286] Example 47: 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 46, by replacing 4,4,5,5-tetramethyl-2-spiro[2.5]octa-6-en-6-yl-1,3,2-dioxaborolane with 2-(4,4-difluorocyclohexa-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 1227068-84-9) in step 1, and by hydrogenation at 50°C and atmospheric pressure for 16 hours in step 3. The result was a pale yellow solid, MS m / z: 459.2 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0287] Example 48: 8-(4,4-dimethylcyclohexyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 46, using 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one (Example 40) instead of 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one (Example 40) in step 3, under atmospheric pressure at room temperature for 16 hours. The result was a pale yellow solid, MS m / z: 462.2 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0288] Example 49: 8-(4-chloro-2-fluorophenyl)-3-ethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-3-ethyl-pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6,8-dichloro-3-ethylpyrido[3,4-d]pyrimidine-4-one (intermediate A5, 240 mg, 0.98 mmol) in 1,4-dioxane (10 ml), 4-chloro-2-fluorophenylboronic acid (189 mg, 1.08 mmol), sodium carbonate (314 mg, 2.95 mmol), and tetrakis(triphenylphosphine)palladium (0) (91 mg, 0.08 mmol, 0.08 equivalents) were added. The reaction mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours. After cooling to room temperature, the reaction product was added to water (100 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layer was washed with brine (100 ml), dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:0 to 4:1) to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-3-ethyl-pyrido[3,4-d]pyrimidine-4-one (115 mg, yield 35%) as a white solid. MS m / z: 338.2 [M+H] + ESI pos.

[0289] Step 2: 8-(4-chloro-2-fluorophenyl)-3-ethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-3-ethylpyrido[3,4-d]pyrimidine-4-one (110 mg, 0.33 mmol) in N-methylpyrrolidone (2 ml), 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1, 82 mg, 0.49 mmol) and N,N-diisopropylethylamine (126 mg, 0.98 mmol) were added. The reaction mixture was then heated at 150°C for 16 hours under microwave irradiation. After cooling to room temperature, the reaction mixture was added to water (50 ml) and extracted with ethyl acetate (30 ml x 2). The combined organic layers were washed with brine (50 ml x 2), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by preparative HPLC (Waters Xbridge C18 column, 150 × 25 mm × 10 μm, water + 10 mM ammonium carbonate / acetonitrile, flow rate 25 ml / min) NH4HCO3) to obtain 8-(4-chloro-2-fluorophenyl)-3-ethyl-6-[2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one (65 mg). This racemic mixture was separated by SFC (Daicel Chiralpak OD column, 250 mm × 30 mm, 10 μm, solvent: acetonitrile / methanol / 0.1% ammonium hydroxide, flow rate 70 ml / min) to obtain the title compound (8 mg, yield 12%) as a yellow solid, second eluted enantiomer with a retention time of 0.99 min (retention time for other enantiomers: 0.71 min). MS m / z: 469.1 [M + H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0290] Example 50: 8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 49, using 6,8-dichloro-3-cyclopropyl-pyrido[3,4-d]pyrimidine-4-one (intermediate A6) instead of 6,8-dichloro-3-ethyl-pyrido[3,4-d]pyrimidine-4-one (intermediate A5) in step 1. Pale yellow solid, MS m / z: 481.1 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0291] Example 51: 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 49, except that in step 1, 6,8-dichloro-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one (intermediate A7) was used instead of 6,8-dichloro-3-ethyl-pyrido[3,4-d]pyrimidine-4-one (intermediate A5). Yellow solid, MS m / z: 523.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0292] Example 52: 8-(4-chloro-2-fluorophenyl)-3-cyclobutyl-2-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-3-cyclobutyl-2-methyl-pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-3-cyclobutyl-2-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A12, 200 mg, 0.61 mmol) in 1,4-dioxane (6 ml), 4-chloro-2-fluorophenylboronic acid (106 mg, 0.61 mmol), 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (25 mg, 0.03 mmol, 0.05 equivalents), cesium carbonate (595 mg, 1.83 mmol), and water (2 ml) were added. The mixture was then degassed three times with nitrogen and stirred under a nitrogen atmosphere at 30°C for 16 hours. The reaction mixture was added to water (20 ml) and extracted with dichloromethane (20 ml x 3). The combined organic layers were washed with brine (50 ml), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0 to 1:1) to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-3-cyclobutyl-2-methylpyrido[3,4-d]pyrimidine-4-one (160 mg, yield 69%) as a pale yellow solid. MS m / z: 378.1 [M+H] + ESI pos.

[0293] Step 2: 8-(4-chloro-2-fluorophenyl)-3-cyclobutyl-2-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-3-cyclobutyl-2-methylpyrido[3,4-d]pyrimidine-4-one (60 mg, 0.16 mmol) and (2R)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 32 mg, 0.19 mmol) in 1,4-dioxane (3 ml), cesium carbonate (65 mg, 0.48 mmol), XantPhos (9 mg, 0.02 mmol, 0.1 equivalent), and tris(dibenzylideneacetone)dipalladium (7 mg, 0.01 mmol, 0.05 equivalent) were added. The mixture was degassed three times with nitrogen and stirred under nitrogen at 100°C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Luna C18 column, 150 × 25 mm × 10 μm, water + 0.1% formic acid / acetonitrile, flow rate 60 ml / min) to obtain the title compound (13 mg, yield 16%) as a pale yellow solid. MS m / z: 509.1 [M + H] + ESI pos.

[0294] Examples 53-59 below were prepared in the same manner as Example 52 by coupling the intermediate shown in place of intermediate A12 in step 1. Absolute stereochemistry was assigned arbitrarily. [Table 6] TIFF2026519580000197.tif42170

[0295] Example 60: 8-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-2-cyclopropyl-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 8-bromo-6-chloro-2-cyclopropyl-3-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A16, 445 mg, 1.41 mmol) and (4-chloro-2-fluorophenyl)boronic acid (247 mg, 1.41 mmol) in 1,4-dioxane (7.5 ml) and water (2.5 ml), cesium carbonate (1.38 g, 4.24 mmol) was added. The reaction mixture was purged with argon and refilled with argon three times. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (58 mg, 0.071 mmol, 0.05 equivalents) was added. The mixture was purged with argon and refilled with argon three times, and stirred at 30°C for 1 hour. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane, 0-50% ethyl acetate) to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methylpyrido[3,4-d]pyrimidine-4-one (95 mg, yield 13%) as a white solid. MS m / z: 364.0 [M+H] + ESI pos.

[0296] Step 2: 8-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methylpyrido[3,4-d]pyrimidine-4-one (30 mg, 0.082 mmol) in 1,4-dioxane (3 ml), (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 18 mg, 0.107 mmol) was added at room temperature, followed by the addition of cesium carbonate in water (81 mg, 0.247 mmol) (1 ml). The mixture was degassed for 10 minutes by bubbling argon through it. Then, PdCl(clotyl)QPhos (CAS 1252598-33-6, 7.5 mg, 0.0082 mmol, 0.10 equivalents) was added, and degassing was continued for 5 minutes. The tube was sealed and heated at 60°C for 18 hours. The mixture was treated with saturated NaHCO3 aqueous solution (10 ml) and extracted with ethyl acetate (2 × 10 ml). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (Gemini NX column, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain the title compound (2.5 mg, yield 6%) as a yellow powder. MS m / z: 495.2 [M + H] + ESI pos.

[0297] Example 61: 8-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 60, using 8-bromo-6-chloro-3-ethyl-2-methyl-pyrido[3,4-d]pyrimidine-4-one (intermediate A19) instead of 6,8-dichloro-3-cyclopropyl-pyrido[3,4-d]pyrimidine-4-one (intermediate A16) in step 1. Yellow solid, MS m / z: 483.0 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0298] Example 62: 8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-3-cyclopropyl-2-methylpyrido[3,4-d]pyrimidine-4-one [ka] A solution was prepared by dissolving 8-bromo-6-chloro-3-cyclopropyl-2-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A10, 440 mg, 1.4 mmol) and (4-chloro-2-fluorophenyl)boronic acid (244 mg, 1.4 mmol) in 1,4-dioxane (6 ml) and water (2 ml). Cesium carbonate (1.37 g, 4.2 mmol) was then added to this solution. The reaction mixture was purged with argon and refilled with argon three times. Next, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (57 mg, 0.07 mmol, 0.050 equivalents) was added. The reaction mixture was purged with argon and refilled with argon, and then stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane, 0-60% ethyl acetate), and then triturated with diethyl ether to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methylpyrido[3,4-d]pyrimidine-4-one (178 mg, yield 33%) as a pale yellow solid. MS m / z: 364.1 [M+H] + ESI pos.

[0299] Step 2: 8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] In a flask, (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 46 mg, 36 μl, 0.275 mmol), 6-chloro-8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methylpyrido[3,4-d]pyrimidine-4-one (50 mg, 0.137 mmol), N,N-diisopropylethylamine (53 mg, 72 μl, 0.412 mmol), and dimethyl sulfoxide (1 ml) were added, and the mixture was stirred at 120°C for 16 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC (Gemini NX column, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain the title compound (14 mg, yield 21%) as a yellow powder. MS m / z: 495.3 [M + H] + ESI pos.

[0300] Example 63: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 66, using 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate B2) instead of 8-bromo-6-chloro-3-cyclopropyl-2-methylpyrido[3,2-d]pyrimidine-4-one (intermediate B2) in step 1, and 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1) instead of (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1) in step 2. The result was a light brown solid, MS m / z: 469.3 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0301] Examples 64 and 65: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one [ka] The enantiomer of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one (Example 63, 42 mg) was separated by chiral SFC (column chiral OD-H, 5 μm, 250 × 20 mm, 45% methanol + 0, 2% diethylamine). After evaporation of the solvent, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one (15 mg, yield 36%), the first eluted isomer (t=1.78 min), was obtained as a pale yellow solid, MS m / z: 469.1 [M+H]. +ESI pos., 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one (15 mg, 36%), the second eluted isomer (t=2.44 min) was obtained as a pale yellow solid. MS m / z: 469.1[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0302] Example 66: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-3-methylpyrido[3,2-d]pyrimidine-4-one [ka] A mixture of (4-chloro-2-fluorophenyl)boronic acid (19 mg, 0.11 mmol), 8-bromo-6-chloro-3-methylpyrido[3,2-d]pyrimidine-4-one (intermediate B1, 30 mg, 0.11 mmol), and cesium carbonate (105 mg, 0.321 mmol) was mixed with 1,4-dioxane (480 μl) and water (144 μl). The tube was placed under an argon atmosphere, and tetrakis(triphenylphosphine)palladium (6 mg, 0.0054 mmol, 0.050 equivalents) was added. The mixture was heated overnight at 55°C. The reaction mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane / 0-50% ethyl acetate) to obtain the title compound (14 mg, yield 40%) as a white solid. MS m / z:324.1[M+H] + ESI pos.

[0303] Step 2: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methylpyrido[3,2-d]pyrimidine-4-one (50 mg, 0.148 mmol) in toluene (2 ml), 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1, 30 mg, 0.178 mmol), sodium tert-butyrate (19 mg, 0.193 mmol), and XPhos-Pd-G3 (9 mg, 0.010 μmol, 0.070 equivalents) were added under argon, and the mixture was stirred at 100°C for 8 hours. The reaction mixture was diluted with saturated NaHCO3 solution and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by reverse-phase chromatography (column: YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one (19 mg). This racemic mixture was separated by chiral SFC (column chiral OD-H, 5 μm, 250 × 20 mm, 45% methanol + 0.2% diethylamine) to obtain 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one (7 mg, yield 10%) as the second eluted isomer (t=2.45 min), a pale yellow solid. MS m / z: 455.3[M+H] + ESI pos.

[0304] Example 67: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] 6,8-Dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (intermediate C2, 850 mg, 3.47 mmol) was dissolved in 1,4-dioxane (20 ml), and (4-chloro-2-fluorophenyl)boronic acid (605 mg, 3.47 mmol) and 2M cesium carbonate in water (5.2 ml, 10.41 mmol) were added at room temperature. After degassing the mixture, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (283 mg, 347 μmol, 0.10 equivalents) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (0-100% ethyl acetate in silica gel and heptane) to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (928 mg, yield 76%) as a light brown solid. MS m / z: 339.0[M+H] + ESI pos.

[0305] Step 2: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] 6-Chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (25 mg, 0.074 mmol) was dissolved in dimethyl sulfoxide (1 ml), and (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 25 mg, 0.174 mmol) and N,N-diisopropylethylamine (48 mg, 64 μl, 0.369 mmol) were added at room temperature. The mixture was stirred at 120 °C for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol-containing dichloromethane 0-4%) to obtain the title compound (30 mg, 85%) as a yellow solid. MS m / z: 470.2 [M+H] + ESI pos.

[0306] Example 68: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 67, except that in step 1, 6,8-dichloro-3-methylpyrimido[5,4-d]pyrimidine-4-one (intermediate C1) was used instead of 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (intermediate C2). Yellow solid, MS m / z: 456.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0307] Example 69: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 67, except that in step 2, (2R)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (-)-E1) was used instead of (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1). Yellow solid, MS m / z: 470.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0308] Example 70: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] 6-Chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (see Example 67, 25 mg, 0.074 mmol) was dissolved in N,N-dimethylformamide (0.5 ml). Then, 2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholine (intermediate E12, 19 mg, 0.111 mmol) and N,N-diisopropylethylamine (48 mg, 64 μl, 0.369 mmol) were added at room temperature. The mixture was stirred at 120 °C for 2 hours. A few drops of water were added. The reaction mixture was purified by preparative HPLC (Gemini NX-C18 column, 300 × 100 mm × 5 μm, water / acetonitrile) to obtain the title compound (24 mg, 70% yield) as a yellow solid. MS m / z:472.1[M+H] + ESI pos.

[0309] Examples 71 and 72: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] The enantiomer of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one (Example 70, 16 mg) was separated by chiral SFC (column YMC chiral SZ, 5 μm, 250 × 20 mm, 5 μm, 35% methanol + 0, 2% diethylamine). The solvent was evaporated to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one (6 mg, yield 37%), the first eluted isomer (t=3.00 min), as a pale yellow solid, MS m / z: 472.1 [M+H]. + ESI pos., 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one (6 mg, 37%) yielded a second eluted isomer (t=3.68 min) as a pale yellow solid. MS m / z: 472.1[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0310] Examples 73-98 below were prepared in the same manner as Example 70 by coupling the intermediate shown instead of intermediate E12 and, if necessary, separating the enantiomer as described in Examples 71 and 72. Absolute stereochemistry was assigned arbitrarily. [Table 7] TIFF2026519580000218.tif233170 TIFF2026519580000219.tif230170 TIFF2026519580000220.tif228170 TIFF2026519580000221.tif230170 TIFF2026519580000222.tif47170

[0311] Examples 99 and 100: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: Bromo-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]zinc [ka] Zinc powder (4.0 g, 61.2 mmol) was added to a flask dried in a drying oven, and the flask was then purged with argon and refilled with argon, repeating this process three times. After adding lithium chloride solution (0.5 M in tetrahydrofuran, 40.8 ml, 20.4 mmol), 1,2-dibromoethane (192 mg, 88 μl, 1.02 mmol) was added, and the reaction mixture was heated at 50°C for 20 minutes. The flask was removed from the heating block and cooled to room temperature. Trimethylsilyl chloride (111 mg, 130 μl, 1.02 mmol) was added, and the reaction mixture was heated at 50°C for 20 minutes. The flask was removed from the heating block and cooled to room temperature. Iodine (104 mg, 408 μmol) was added as a solution dissolved in tetrahydrofuran (1.5 ml), and the reaction mixture was heated at 50°C for 20 minutes. While still hot, a solution of 4-(4-bromotetrahydropyran-2-yl)-1-methylpyrazole (intermediate D1, 5.0 g, 20.4 mmol) dissolved in tetrahydrofuran (25 ml) was added, and the resulting mixture was stirred at 50°C for 18 hours. After cooling to room temperature, the reaction mixture was filtered to obtain a zinc reagent solution, which was used directly in the next step.

[0312] Step 2: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (see Step 13, 1,100 mg, 0.296 mmol) in dry tetrahydrofuran (0.50 ml), Xantphos Paradacycle G3 (31 mg, 0.030 mmol, 0.10 equivalents) was added, the reaction mixture was purged with argon, and then refilled with argon. To this solution, [2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]zinc bromide (2.0 ml, 0.44 mmol, 1.5 equivalents) was added, and the mixture was stirred at 50°C for 1.5 hours. The reaction mixture was diluted with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol-containing dichloromethane 0-10%) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one (140 mg) as an isomer mixture. Separation was performed using chiral SFC (Chiralcel OJ column, 50 mm × 250 mm, 5-20% methanol) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one as the first eluted enantiomer (t=3.41 min), a white solid (MS m / z: 466.2 [MH]). + The compound was obtained as ESI neg., and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one (t=3.51 min) was obtained as the second eluted enantiomer, a white solid. MS m / z: 468.3 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0313] Examples 101-105 below were prepared in the same manner as in Examples 99 / 100, starting with the intermediate shown in step 2 instead of intermediate A2. Absolute stereochemistry was assigned arbitrarily. [Table 8]

[0314] Example 106: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-methyl-6-phenyl-tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 99, using (2S)-4-bromo-2-methyl-6-phenyl-tetrahydropyran (intermediate D2) instead of 4-(4-bromotetrahydropyran-2-yl)-1-methylpyrazole (intermediate D1) in step 1. White solid, MS m / z: 479.4 [M+H] + ESI pos., a mixture of diastereomers.

[0315] Example 107: 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] Under a nitrogen atmosphere, 6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A4, 2.05 g, 9.78 mmol) was dissolved in super-dehydrated tetrahydrofuran (10 ml). To this solution, XantPhos Pd G3 (505 mg, 489 μmol, 0.05 equivalents) was added, followed by the addition of the above solution of bromide-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]zinc (see Example 99, 67 ml, 14.67 mmol, 1.5 equivalents). The mixture was stirred at 50°C for 3 hours. After evaporating the solvent, the residue was adsorbed onto isolute and purified by flash chromatography (silica gel, heptane / ethyl acetate = 50:50~0:100) to obtain 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one (2.71 g, 77%) as a yellow solid. MS m / z: 340.3 [M+H] + ESI pos.

[0316] Step 2: 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2 g, 11.1 mmol) was dissolved in 7.7 ml of a mixture of dimethyl sulfoxide and water (600 / 1), and 10 ml of a solution of 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one (500 mg, 1.38 mmol) dissolved in dimethyl sulfoxide / water (600 / 1) was added. The tube was placed under argon bubbling through the liquid. Next, 10 ml of a freshly prepared solution of ammonium persulfate (1.9 g, 8.31 mmol) in dimethyl sulfoxide / water (600 / 1, purged with argon) was added, and the tube was sealed. The reaction mixture was stirred at 40°C for 22 hours. Saturated solutions of ethyl acetate and NaHCO3 were added, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and evaporated. The crude mixture was purified by reverse-phase chromatography (column: YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain the title compound (70 mg, yield 11%) as a yellow solid. MS m / z: 474.2 [M + H] + ESI pos.

[0317] Examples 108 and 109: 2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one and 2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] The enantiomer of 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (see Example 107) was separated by SFC (column chiral Lux C4, 5 μm, 250 × 20 mm, 30% methanol + 0, 2% diethylamine). The solvent was evaporated to obtain 2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (26.5 mg, yield 4%) as a brown solid, the first eluted isomer, MS m / z: 474.2 [M+H]. + ESI pos., 2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (30 mg, 4.5%) was obtained as a brown solid, the second eluted isomer. MS m / z: 474.2[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0318] Example 110: 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)cyclobutyl]pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 107, using 3-(trifluoromethyl)cyclobutanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 2. Yellow solid, MS m / z: 462.2 [M+H] + ESI pos.

[0319] Examples 111, 112 and 113: 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one and 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one and 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one [ka] These compounds were prepared in the same manner as in Example 107, by using 4,4-difluorocyclohexanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 2, followed by chiral separation as described in Examples 108 and 109. 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one: second eluted isomer with retention time = 3.62 min, yellow solid, MS m / z: 458.2 [M+H] + ESI pos., and 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one: third eluted isomer with retention time = 3.98 min, yellow solid, MS m / z: 458.2 [M+H] + ESI pos., and 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one: fourth elution isomer, retention time = 4.60 min, yellow solid, MS m / z: 458.2 [M+H] +ESI pos., absolute stereochemistry was assigned arbitrarily.

[0320] Example 114: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] A mixture of dimethyl sulfoxide (3 ml), 6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A4, 260 mg, 1.24 mmol), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (670 mg, 3.72 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (CAS: 870987-63-6, 3.0 mg, 0.01 mmol, 0.01 equivalent), and ammonium peroxodisulfate (183 mg, 4.96 mmol) was degassed, purged with oxygen, and then stirred at 25°C for 16 hours while irradiated with a 455 nm blue LED. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine (15 ml x 3), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0-2:1) to obtain 6-chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (50 mg, 0.15 mmol, yield 12%) as a pale yellow solid. MS m / z: 344.1[M+H] + ESI pos.

[0321] Step 2: 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-2,3-dimethyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (40 mg, 0.12 mmol) in 1,4-dioxane (3 ml), (2R)-2-(1-methylpyrazole-4-yl)morpholine (23 mg, 0.14 mmol), cesium carbonate (95 mg, 0.29 mmol), tris(dibenzylideneacetone)dipalladium (5 mg, 0.01 mmol, 0.05 equivalent), and Xantphos (6.5 mg, 0.01 mmol, 0.1 equivalent) were added. The mixture was then degassed three times with nitrogen and stirred at 100°C under a nitrogen atmosphere for 12 hours. The reaction mixture was added to water (50 ml) and extracted with ethyl acetate (40 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna C18, 150 x 25 mm x 10 μm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min) to obtain 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (4 mg, yield 7%) as a pale green solid. MS m / z: 475.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0322] Examples 115-118 below were prepared in the same manner as Example 114, starting with the indicated carboxylic acid in step 1 instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. Absolute stereochemistry was assigned arbitrarily. [Table 9]

[0323] Example 119: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one [ka] Step 1: 2-Chloro-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate methyl ester [ka] A solution prepared by dissolving 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1, 2.5 g, 15 mmol), 2,6-dichloropyridine-4-carboxylate methyl (2.8 g, 13.6 mmol), and 7.1 ml, 40.8 mmol) in dried N-methylpyrrolidone (30 ml) was stirred overnight at 100°C. The mixture was poured into water (50 ml) and extracted with ethyl acetate (2 × 50 ml). The organic layer was washed with water (3 × 25 ml) and brine (30 ml), dried over Na₂SO₄, and evaporated under reduced pressure to obtain 2-chloro-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate methyl ester (2.5 g, yield 54%) as an orange solid. MS m / z: 337.2 [M + H] + ESI pos.

[0324] Step 2: 2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate methyl ester [ka] A suspension was prepared by suspending 2-chloro-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate methyl ester (675 mg, 2.0 mmol) in 1,4-dioxane (6.8 ml). 4-chloro-2-fluorobenzeneboronic acid (367 mg, 2.1 mmol) was added at room temperature, followed by the addition of a solution of cesium carbonate (2 M in water, 3.0 ml, 6.0 mmol). The mixture was degassed by bubbling argon over it for 10 minutes, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (49 mg, 60 μmol, 0.030 equivalents) was added, followed by degassing as described. The mixture was stirred at 22°C for 1.5 hours, then saturated NaHCO3 aqueous solution (50 ml) was added, and the mixture was extracted with ethyl acetate (2 × 50 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, heptane, 0-100% [ethyl acetate / ethanol 3:1]) to obtain 2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate methyl ester (850 mg, yield 98%) as a yellow solid. MS m / z: 431.2 [M+H] + ESI pos.

[0325] Step 3: 3-Bromo-2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate methyl ester [ka] To a solution of methyl 2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate (850 mg, 1.97 mmol) dissolved in dichloromethane (17 ml), N-bromosuccinimide (351 mg, 1.97 mmol) was added in three portions over 1.5 hours at 22°C. After the addition was complete, the mixture was stirred for a further 30 minutes at 22°C. Another dose of N-bromosuccinimide (35 mg, 0.197 μmol) was added, and stirring was continued for another 30 minutes. The mixture was quenched with saturated NaHCO3 aqueous solution (50 ml) and extracted with dichloromethane (2 × 50 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, heptane, 20-100% ethyl acetate) to obtain 3-bromo-2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate methyl ester (780 mg, yield 78%) as a yellow foam. MS m / z: 509.0 [M+H] + ESI pos.

[0326] Step 4: 2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]-3-propyne-1-inyl-isonicotinate methyl ester [ka] In a microwave tube, a solution of 3-bromo-2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]isonicotinate methyl ester (120 mg, 0.235 mmol) dissolved in N,N-dimethylformamide (1.2 ml) was prepared. Tributyl(propyne-1-inyl) stannan (93 mg, 86 μl, 0.283 mmol) was added at room temperature, followed by the addition of tetrakis(triphenylphosphine)palladium (0) (8 mg, 7.0 μmol, 0.03 equivalents). The tube was filled with argon, sealed, and irradiated with microwaves at 110°C for 60 minutes. Tributyl(propyne-1-inyl) stannan (78 mg, 72 μl, 0.235 μl mol) and tetrakis(triphenylphosphine) palladium (0) (5.5 mg, 4.7 μmol, 0.02 equivalents) were added to the mixture, and irradiation was continued at 110°C for a further 30 minutes. The mixture was concentrated under vacuum and directly purified by flash column chromatography (RP18, adsorbing the compound onto Isolute HM-N, 30-100% acetonitrile in water) to obtain 2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]-3-propyne-1-inyl isonicotinate methyl ester (56 mg, yield 51%) as a yellow oil. MS m / z: 469.0 [M+H] + ESI pos.

[0327] Step 5: 2-(4-chloro-2-fluorophenyl)-N-methyl-6-[2-(1-methylpyrazole-4-yl)morpholino]-3-propyne-1-inyl-isonicotinamide [ka] In a reaction tube, 2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]-3-propyne-1-inylisonicotinate methyl ester (55 mg, 117 μmol) was dissolved in methylamine (40% solution in MeOH, 1.82 g, 2.39 ml, 23.5 mmol). The tube was sealed and heated at 50°C for 2 hours, then concentrated under vacuum. The residue was purified by flash column chromatography (RP18, compound adsorbed on Isolute HM-N, 10-100% acetonitrile in water) to obtain 2-(4-chloro-2-fluorophenyl)-6-[2-(1-methylpyrazole-4-yl)morpholino]-3-propyne-1-inylisonicotinate methyl ester (36 mg, yield 66%) as a pale yellow solid. MS m / z: 468.2 [M+H] + ESI pos.

[0328] Step 6: 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one [ka] In a reaction tube, 2-(4-chloro-2-fluorophenyl)-N-methyl-6-[2-(1-methylpyrazole-4-yl)morpholino]-3-propyne-1-inylisonicotinamide (15 mg, 32 μmol) was dissolved at room temperature in ethanol (3 ml) containing sodium ethoxide (22 mg, 320 μmol). The tube was sealed, and the turbid mixture was heated at 80°C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by flash column chromatography (RP18, adsorbing the compound onto isolute HM-N in 30-100% acetonitrile water containing 0.1% HCOOH) to obtain 14 mg of solid. This was further purified by flash column chromatography (silica gel, 10-80% [ethyl acetate / ethanol = 3:1] in heptane) to obtain 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthirizine-1-one (8.8 mg, yield 59%) as a yellow solid. MS m / z: 468.2 [M+H] + ESI pos.

[0329] Example 120: 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one [ka] The title compound was prepared in the same manner as in Example 119, using 4-chlorobenzeneboronic acid instead of 4-chloro-2-fluorobenzeneboronic acid in step 2. Yellow solid, MS m / z: 450.2 [M+H] + ESI pos.

[0330] Examples 121 and 122: 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one and 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one [ka] The enantiomer of 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one (Example 120, 44 mg) was separated by SFC (column chiral IK, 5 μm, 150 × 4.6 mm, 40-60% methanol + 0, 2% diethylamine). The solvent was evaporated to obtain 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one (20 mg, yield 46%) as the first eluted isomer, a yellow solid with a retention time of 5.09 minutes, MS m / z: 450.2 [M+H]. + ESI pos., 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthirizine-1-one (18 mg, 42%) was obtained as a second eluted isomer, a yellow solid with a retention time of 5.92 minutes. MS m / z: 450.2[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0331] Example 123: 8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-2-ethyl-3-methyl-pyrido[3,4-d]pyrimidine-4-one [ka] 8-bromo-6-chloro-2-ethyl-3-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A8, 468 mg, 1.55 mmol) and (4-chloro-2-fluorophenyl)boronic acid (270 mg, 1.55 mmol) were dissolved in 1,4-dioxane (8.1 ml) and water (2.7 ml), to which cesium carbonate (1.51 g, 4.64 mmol) was added. The reaction mixture was purged with argon and refilled with argon three times. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (63 mg, 0.077 mmol, 0.050 equivalents) was added. The mixture was purged with argon and refilled with argon three times, and stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane, 0-60% ethyl acetate), and then triturated with diethyl ether to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methylpyrido[3,4-d]pyrimidine-4-one (385 mg, yield 62%) as a pale yellow solid. MS m / z: 352.1[M+H] + ESI pos.

[0332] Step 2: 8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] In a flask, (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-E1, 47.5 mg, 38 μl, 0.284 mmol), 6-chloro-8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methylpyrido[3,4-d]pyrimidine-4-one (50 mg, 0.142 mmol), N,N-diisopropylethylamine (55 mg, 74 μl, 0.426 mmol), and dimethyl sulfoxide (1 ml) were added, and the mixture was stirred at 120°C for 16 hours. The reaction mixture was filtered and directly separated by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain the title compound (22 mg, yield 32%) as a yellow powder. MS m / z:483.3[M+H] + ESI pos.

[0333] Examples 124-126 below were prepared in the same manner as Example 127, starting with the indicated intermediates instead of intermediate A8 in step 1 and intermediate (+)-E1 in step 2. Absolute stereochemistry was assigned arbitrarily. [Table 10]

[0334] Examples 127, 128, 129 and 130: 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d] Pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (see Example 67, 100 mg, 0.29 mmol) in dimethyl sulfoxide (2 ml), N,N-diisopropylethylamine (0.15 ml, 0.88 mmol) and 2-(1-cyclopropylpyrazole-4-yl)-6-methylmorpholine (intermediate E10, 73 mg, 0.35 mmol) were added, and the mixture was stirred at 30°C for 16 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (50 ml x 2), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by chromatography (column: Phenomenex Luna C18, 150*25mm*10um, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min) to obtain 8-(4-chloro-2-fluorophenyl)-6-[2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (130 mg). The isomers were separated by chiral SFC (Daicel Chiralpak AD column, 250 mm x 30 mm, 10 μm, ethanol + 0.1% ammonium hydroxide, flow rate 70 ml / min) to obtain 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (21 mg, yield 30%) as the first eluted isomer with a retention time of 0.75 minutes, as a pale yellow solid, MS m / z: 510.2 [M+H]. + ESI pos., 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (23 mg, yield 14%) was obtained as a second eluted isomer, a pale yellow solid, with a retention time of 1.03 minutes, MS m / z: 510.1 [M+H]. +ESI pos., 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (38 mg, yield 54%) was obtained as a third eluted isomer, pale yellow solid, with a retention time of 1.28 minutes, MS m / z: 510.1 [M+H]. + ESI pos., 8-(4-chloro-2-fluorophenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (36 mg, yield 21%) was obtained as a fourth eluted isomer, a pale yellow solid, with a retention time of 1.47 minutes. MS m / z: 510.1[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0335] Examples 131 and 132: 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka]

[0336] The title compound was prepared in the same manner as in Examples 127-130, using intermediate E9 instead of intermediate E10. Pale yellow rubber, MS m / z: 504.1 [M+H] + , ESI pos., and MS m / z:504.2[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0337] Example 133: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 127, using intermediate E39 instead of intermediate E10. The first eluted enantiomer was a pale yellow rubber, MS m / z: 512.1 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0338] Example 134: 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6,8-dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (intermediate C2, 50 mg, 0.2 mmol) in 1,4-dioxane (1.5 ml) and water (0.5 ml), 2-[2-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 1073353-68-0, 59 mg, 0.2 mmol) was added. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (17 mg, 0.02 mmol, 0.1 equivalent) and cesium carbonate (199 mg, 0.61 mmol) were added, and the mixture was degassed three times with nitrogen and stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into water (50 ml), the aqueous layer was separated, and extracted with ethyl acetate (30 ml x 3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate = 1:1) to obtain 6-chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (65 mg, yield 85%) as an off-white solid. MS m / z: 373.0 [M+H] + ESI pos.

[0339] Step 2: 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (55 mg, 0.15 mmol) in dimethyl sulfoxide (1 ml), N,N-diisopropylethylamine (0.08 ml, 0.44 mmol) and (2R)-2-(1-methylpyrazole-4-yl)morpholine (30 mg, 0.18 mmol) were added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 ml x 2), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Luna C18 column, 150 × 25 mm × 10 μm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min) to obtain the title compound (50 mg, yield 67%) as a yellow solid. MS m / z: 504.2 [M + H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0340] Examples 135-137 below were prepared in the same manner as in Example 134 by coupling the boronic acid derivatives shown instead of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Absolute stereochemistry was assigned arbitrarily. [Table 11]

[0341] Examples 138 and 139: 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (see Example 67, 50 mg, 0.15 mmol) in dimethyl sulfoxide (1.5 ml), N,N-diisopropylethylamine (0.13 ml, 0.74 mmol) and 2-(2-methoxy-4-pyridyl)morpholine hydrochloride (intermediate E4, 41 mg, 0.18 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 2). The organic phase was washed with brine (50 ml x 2), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography (column: spherical C18, 20-45 μm, 100 A, water + 0.1% formic acid / acetonitrile, flow rate 40 ml / min). The eluent was extracted with ethyl acetate (50 ml x 2), and the combined organic layers were dried over Na2SO4 and concentrated to obtain 8-(4-chloro-2-fluorophenyl)-6-[2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (65 mg). The enantiomer was separated by chiral SFC (Daicel Chiralpak AD column, 250 mm x 30 mm, 10 μm, ethanol + 0.1% ammonium hydroxide, flow rate 70 ml / min) to obtain 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (25 mg, yield 42%) as the first eluted enantiomer with a retention time of 1.21 minutes, as a yellow solid, MS m / z: 497.2 [M+H]. + ESI pos., 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (26 mg, yield 40%), second eluted enantiomer, obtained as a yellow solid with a retention time of 1.48 minutes. MS m / z: 497.1[M+H] + ESI pos.

[0342] Examples 140 and 141: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Examples 144 and 145, using intermediate E3 instead of intermediate E4. It was a pale yellow solid, MS m / z 481.2 [M+H]. + , ESI pos., and MS m / z:481.2[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0343] Example 142: 13-(4-chloro-2-fluorophenyl)-11-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2,7,10,12-tetrazatricyclo[7.4.0.0 3,7 Trideca-1(9),2,10,12-tetraen-8-one [ka] Step 1: 11-Chloro-13-(4-Chloro-2-fluorophenyl)-2,7,10,12-tetrazatricyclo[7.4.0.0 3,7 Trideca-1(9),2,10,12-tetraen-8-one [ka] 11,13-dichloro-2,7,10,12-tetrazatricyclo[7.4.0.0] in toluene (12 ml) and water (1.2 ml). 3,7Trideca-1(9),2,10,12-tetraen-8-one (intermediate C3, 200 mg, 0.74 mmol) and 4-chloro-2-fluorophenylboronic acid (129 mg, 0.74 mmol) were stirred to a mixed solution to which K3PO4 (471 mg, 2.22 mmol) was added. The mixture was degassed, argon was packed in, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (52 mg, 0.07 mmol, 0.1 equivalent) was added. After stirring at 20°C for 18 hours, the mixture was diluted with water (60 ml) and extracted with ethyl acetate (3 × 60 ml). The combined organic layers were dried (with sodium sulfate) and evaporated to obtain crude 11-chloro-13-(4-chloro-2-fluorophenyl)-2,7,10,12-tetrazatricyclo[7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one (187 mg, yield 25%), which was used in the next step without further purification. Brown rubber, MS m / z: 351.0 [M+H] + ESI pos.

[0344] Step 2: 13-(4-chloro-2-fluorophenyl)-11-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2,7,10,12-tetrazatricyclo[7.4.0.0 3,7 Trideca-1(9),2,10,12-tetraen-8-one [ka]

[0345] To a solution prepared by dissolving 11-chloro-13-(4-chloro-2-fluorophenyl)-2,7,10,12-tetrazatricyclo[7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one (187 mg, 0.2 mmol) and 2-(1-methylpyrazole-4-yl)morpholine (intermediate E1, 66 mg, 0.39 mmol) in dried dimethyl sulfoxide (6 ml), N,N-diisopropylethylamine (0.17 ml, 0.99 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by preparative HPLC using DMSO solution (column: XBridge 19*100 mm, 30 ml / min water / acetonitrile + ammonia) to obtain the title compound (42 mg, yield 41%) as a yellow solid. MS m / z: 482.2 [M+H] + ESI pos.

[0346] Examples 143-146 below were prepared using boronic acid derivatives in the same manner as in Example 140, and in the same manner as in Examples 146 / 147, and are shown in the table below. Absolute stereochemistry was assigned arbitrarily. [Table 12]

[0347] Examples 147-150 below were prepared in the same manner as in Examples 127-130, using 6-chloro-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (same as in Example 142) instead of 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one. Absolute stereochemistry was assigned arbitrarily. [Table 13]

[0348] Example 151: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 127, using intermediate E39 instead of intermediate E10. The second eluted enantiomer was a pale yellow rubber, MS m / z: 512.1 [M+H]. + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0349] Examples 152-153 were prepared in the same manner as in Example 134 by coupling the boronic acid derivatives shown instead of 2-[2-fluoro-4-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Absolute stereochemistry was assigned arbitrarily. [Table 14]

[0350] Example 154: 8-(4-chloro-2-fluorophenyl)-6-[3-(difluoromethyl)pyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (see Example 67, 40 mg, 0.10 mmol) in N,N-dimethylformamide (1.5 ml), 3-(difluoromethyl)pyrrolidine hydrochloride (intermediate E37, 32 mg, 0.20 mmol) and N,N-diisopropylethylamine (65 mg, 88 μl, 0.50 mmol) were added at room temperature, and the mixture was stirred at 120 °C for 2 hours. The reaction mixture was subjected directly to preparative HPLC (column: YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain the title compound (28 mg, yield 66%) as a yellow solid. MS m / z: 424.2 [M + H] +ESI pos.

[0351] Example 155: 8-(4-chloro-2-fluorophenyl)-6-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 154, using intermediate E8 instead of intermediate E37. Yellow solid, MS m / z: 437.2 [M+H] + ESI pos.

[0352] Example 156: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 154, using intermediate E11 instead of intermediate E37. Yellow solid, MS m / z: 456.2 [M+H] + ESI pos.

[0353] Examples 157 and 158: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one [ka] The enantiomer of 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one (Example 156, 49 mg) was separated by chiral SFC (column: chiral IJ, 5 μm, 250 × 20 mm, 20% methanol). After evaporation of the solvent, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one (21 mg, yield 43%), the first eluted isomer (t=1.64 min), was obtained as a yellow solid, MS m / z: 456.2 [M+H]. + ESI pos., 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one (19 mg, yield 38%), second eluted isomer (t=1.82 min), obtained as a yellow solid. MS m / z: 456.2[M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0354] Examples 159-160 below were prepared in the same manner as Example 107, by starting in step 1 using the indicated carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. [Table 15]

[0355] Example 161: 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (intermediate C4, 530 mg, 2.52 mmol) in dimethyl sulfoxide (33 ml), 2-(1-methylpyrazole-4-yl)morpholine (842 mg, 5.03 mmol) and N,N-diisopropylethylamine (1.63 g, 2.2 ml, 12.58 mmol) were added at room temperature. The reaction mixture was stirred at 120 °C for 3 hours. Water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. Since the residue contained dimethyl sulfoxide, a complete conversion was assumed for volume calculation purposes, and the solution was used directly in the next step.

[0356] Step 2: 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one (an aliquot of a dimethyl sulfoxide solution prepared assuming 50 mg, 0.146 μmol) in DMSO / water (600 / 1), 264 mg, 1.46 mmol, was added. The reaction mixture was degassed by bubbling with argon. A freshly prepared solution of ammonium persulfate (200 mg, 0.88 μmol) in purged DMSO / water (600 / 1) was added under argon. The reaction mixture was stirred at 40°C for 21 hours. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase HPLC (Gemini NX, 12 nm, 5 μm, 100 × 30 mm) using water + 0.1% formic acid with a 20% to 98% acetonitrile gradient to obtain the title compound (4.5 mg, 5% yield) as a yellow solid. MS m / z: 476.2 [M + H] + ESI pos.

[0357] Examples 162 and 163: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(2-methylpyrazole-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(1-methylpyrazole-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(1H-pyrazole-3-yl)-6-azaspiro[3,4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution prepared by dissolving 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (see Example 67, 45 mg, 0.118 mmol) in N,N-dimethylformamide (1.63 ml), 8-(1H-pyrazole-3-yl)-6-azaspiro[3.4]octane dihydrochloride (intermediate E38, 59 mg, 0.235 mmol) and N,N-diisopropylethylamine (106 mg, 144 μl, 0.824 mmol) were added at room temperature, and the mixture was stirred at 120°C for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol-containing dichloromethane 0-10%) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(1H-pyrazole-3-yl)-6-azaspiro[3,4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one (55 mg, yield 97%) as a yellow oil. MS m / z: 480.2[M+H] + ESI pos.

[0358] Step 2: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(2-methylpyrazole-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(1-methylpyrazole-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] In a solution prepared by dissolving 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(1H-pyrazole-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one (55 mg, 0.115 mmol) in N,N-dimethylformamide (1 ml) under argon at 0°C, sodium hydride (60% in mineral oil, 5.5 mg, 0.137 mmol) was added, and the mixture was stirred at 0°C for 20 minutes. Iodomethane (19 mg, 8.6 μl, 0.137 mmol) was added, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by preparative HPLC (column: YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% formic acid) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(2-methylpyrazole-3-yl)-6-azaspiro[3,4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one (10 mg, yield 17%) as a yellow solid, MS m / z: 494.2 [M+H]. + ESI pos., 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(1-methylpyrazole-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one (12 mg, yield 20%) was obtained as a yellow solid. MS m / z: 494.2[M+H] + ESI pos.

[0359] Example 164: 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-8-one [ka] In step 1, the title compound was prepared in the same manner as in Example 119, using methyl 2,6-dichloropyrimidine-4-carboxylate instead of methyl 2,6-dichloropyridine-4-carboxylate, and using intermediate (+)-E1 instead of intermediate E1. Yellow solid, MS m / z: 469.2 [M+H] + ESI pos., absolute stereochemistry was assigned arbitrarily.

[0360] Example 165: 8-(4-chloro-2-fluorophenyl)-6-[2-[1-(2,2-difluoroethyl)pyrazole-4-yl]morpholino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] A solution of 2,2-difluoroethyl trifluoromethanesulfonic acid (37 mg, 0.175 mmol) dissolved in N,N-dimethylformamide (0.8 mL) was added to 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one (see Example 156, 40 mg, 0.0877 mmol) and cesium carbonate (114 mg, 0.351 mmol). The vial was sealed and the reaction mixture was stirred at 90°C for 4 hours. The mixture was diluted with saturated ammonium chloride and ethyl acetate. The product was extracted with ethyl acetate, the combined organic layers were washed with water and brine, dried over Na2SO4, and evaporated. The residue was purified by flash column chromatography (silica gel, heptane, 50-100% ethyl acetate) to obtain the title compound (23 mg, yield 48%) as a yellow solid. MS m / z:520.2[M+H] + ESI pos.

[0361] Example 166: 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]morpholino]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 165, using 2,2,2-trifluoroethyl trifluoromethanesulfonic acid instead of 2,2-difluoroethyl trifluoromethanesulfonic acid. Yellow oily substance, MS m / z: 538.2 [M+H] + ESI pos.

[0362] Example 167: 8-(4-chloro-2-fluorophenyl)-6-[2-[1-(2,2-difluorocyclopropyl)pyrazole-4-yl]morpholino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka]

[0363] The title compound was prepared in the same manner as in Example 165, using 2-bromo-1,1-difluorocyclopropane instead of 2,2-difluoroethyl trifluoromethanesulfonic acid. Yellow oily substance, MS m / z: 532.2 [M+H] + ESI pos.

[0364] Example 168 The compound of formula (I) can be used as an active ingredient in a manner known to itself to manufacture tablets of the following composition: Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

[0365] Example 169 The compound of formula (I) can be used as an active ingredient in a manner known to itself to produce capsules of the following composition: Per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg 220.0 mg

Claims

1. Equation (I) 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof (in the formula, X １ , X ２ and X ３ These are independently selected from N and CH, A is C ３ ~C １０ -cycloalkyl, C ３ ~C １０ -cycloalkenyl, C ６ ~C １０ selected from -aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl B is, 【Chemistry 2】 Selected from, R １ , R ２ and R ３ These are, independently, hydrogen, halogen, cyano, and C. １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl, C １ ~C ６ - Alkoxy and Halo-C １ ~C ６ - Selected from alkoxy, R ７ C １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl, 3-10 membered heterocyclyl and C ３ ~C １０ - Selected from cycloalkyl, the C ３ ~C １０ - Cycloalkyl groups may optionally include halogens and C １ ~C ６ - Substituted with one substituent selected from alkyl groups, R ８ is hydrogen, C １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl, 3-10 membered heterocyclyl, and C ３ ~C １０ - Selected from cycloalkyl, the C ３ ~C １０ - Cycloalkyl groups may optionally include halogens and C １ ~C ６ - Substituted with one substituent selected from alkyl groups, or R ７ and R ８ However, together with the atoms to which they are bonded, they form a heterocycle of 3 to 10 members.

2. (i) X １ and X ３ is N, X ２ is CH or (ii) X ２ and X ３ is N, X １ is CH or (iii)X １ , X ２ and X ３ All are N, or (iv) X ２ and X ３ CH is X １ Is N, or (v) X １ and X ２ is N, X ３ A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is CH.

3. (i) X １ and X ３ is N, X ２ is CH or (ii) X １ , X ２ and X ３ All are N, or (iii)X ２ and X ３ CH is X １ A compound of formula (I) according to claim 2 or a pharmaceutically acceptable salt thereof, wherein is N.

4. A is C ３ ~C １０ - Cycloalkyl, C ３ ~C １０ -Cycloalkenyl, C ６ ~C １０ - Selected from aryls and 5- to 10-membered heteroaryls, R １ These are hydrogen, halogen, cyano, and C １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl and C １ ~C ６ - Selected from alkoxy, R ２ These are hydrogen, halogens and C １ ~C ６ - Selected from alkyl groups, R ３ a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, selected from hydrogen and halogens.

5. A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl. R １ These are hydrogen, fluoro, chloro, cyano, CHF ２ CF ３ Selected from methyl and methoxy, R ２ It is selected from hydrogen, fluoro, and methyl, R ３ is a compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt thereof, selected from hydrogen and fluorine.

6. A is C ３ ~C １０ - Cycloalkyl and C ６ ~C １０ - Selected from the alphabet, R １ is selected from halogen and halo-C １ ~C ６ -alkyl, R ２ It is selected from hydrogen and halogens. R ３ a compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, selected from hydrogen and halogens.

7. A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl. R １ Fluorochloro, CHF ２ and CF ３ Selected from, R ２ It is selected from hydrogen and fluoro, R ３ is a compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, selected from hydrogen and fluoro.

8. B, 【Transformation 3】 A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. R ７ C １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl and C ３ ~C １０ - Selected from cycloalkyl, the C ３ ~C １０ - Cycloalkyl groups optionally contain one C １ ~C ６ - Substituted with alkyl substituents, R ８ is hydrogen, C １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl and C ３ ~C １０ - Selected from cycloalkyl, the C ３ ~C １０ - Cycloalkyl groups optionally contain one C １ ~C ６ - Substituted with an alkyl substituent, or R ７ and R ８ A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein these atoms, together with the atoms to which they are bonded, form a 3- to 10-membered heterocycle.

10. R ７ It is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl. R ８ is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1-difluoroethyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane, or R ７ and R ８ A compound of formula (I) according to claim 9 or a pharmaceutically acceptable salt thereof, wherein they form a pyrrolidine ring together with the atoms to which they are bonded.

11. R ７ C １ ~C ６ -It is alkyl, R ８ C １ ~C ６ -Alkyl and Halo-C １ ~C ６ - A compound of formula (I) according to claim 9, selected from alkyl groups, or a pharmaceutically acceptable salt thereof.

12. R ７ and R ８ A compound of formula (I) according to claim 11 or a pharmaceutically acceptable salt thereof, wherein all of the members are methyl.

13. (i) X １ and X ３ is N, X ２ is CH or (ii) X ２ and X ３ is N, X １ is CH or (iii)X １ , X ２ and X ３ All are N, or (iv) X ２ and X ３ CH is X １ Is N, or (v) X １ and X ２ is N, X ３ is CH, A is C ３ ~C １０ - Cycloalkyl, C ３ ~C １０ -Cycloalkenyl, C ６ ~C １０ - Selected from aryls and 5- to 10-membered heteroaryls, B is, 【Chemistry 4】 Selected from, R １ These are hydrogen, halogen, cyano, and C １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl and C １ ~C ６ - Selected from alkoxy, R ２ These are hydrogen, halogens, and C １ ~C ６ - Selected from alkyl groups, R ３ It is selected from hydrogen and halogens. R ７ C １ ~C ６ Alkyl, Halo-C １ ~C ６ Alkyl and C ３ ~C １０ Selected from cycloalkyl, the C ３ ~C １０ A cycloalkyl group may optionally contain one C １ ~C ６ - Substituted with alkyl substituents, R ８ is hydrogen, C １ ~C ６ -Alkyl, Halo-C １ ~C ６ - Alkyl and C ３ ~C １０ - Selected from cycloalkyl, the C ３ ~C １０ - Cycloalkyl groups optionally contain one C １ ~C ６ - Substituted with an alkyl substituent, or R ７ and R ８ A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, together with the atoms to which they are bonded, they form a 3- to 10-membered heterocycle.

14. (i) X １ and X ３ is N, X ２ is CH or (ii) X ２ and X ３ is N, X １ is CH or (iii)X １ , X ２ and X ３ All are N, or (iv) X ２ and X ３ CH is X １ Is N, or (v) X １ and X ２ is N, X ３ is CH, A is selected from cyclobutyl, cyclohexyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, spiro[2.5]octanyl, phenyl, and pyridyl. B is, 【Transformation 5】 Selected from, R １ These are hydrogen, fluoro, chloro, cyano, CHF ２ CF ３ Selected from methyl and methoxy, R ２ It is selected from hydrogen, fluoro, and methyl, R ３ It is selected from hydrogen and fluoro, R ７ It is selected from methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropyl, 1-methylcyclopropyl, and cyclobutyl. R ８ is selected from hydrogen, methyl, ethyl, 2-propyl, tert-butyl, 1,1-difluoroethyl, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, and bicyclo[1.1.1]pentane, or R ７ and R ８ A compound of formula (I) according to claim 13 or a pharmaceutically acceptable salt thereof, wherein they form a pyrrolidine ring together with the atoms to which they are bonded.

15. (i) X １ and X ３ is N, X ２ is CH or (ii) X １ , X ２ and X ３ All are N, or (iii)X ２ and X ３ CH is X １ is N, A is C ３ ~C １０ - Cycloalkyl and C ６ ~C １０ - Selected from the alphabet, B is, 【Transformation 6】 Selected from, R １ This includes halogens and halo-C １ ~C ６ - Selected from alkyl groups, R ２ It is selected from hydrogen and halogens. R ３ It is selected from hydrogen and halogens. R ４ａ and R ５ａ is, 【Transformation 7】 And, R ６ａ is, 【Transformation 8】 And, R ４ｂ , R ５ｂ , and R ６ｂ These are hydrogen, halogens and C １ ~C ６ - Selected from alkyl groups, R ４ｃ , R ５ｃ , and R ６ｃ It is selected from hydrogen and halogens. R ７ C １ ~C ６ -It is alkyl, R ８ C １ ~C ６ -Alkyl and Halo-C １ -C ６ - Selected from alkyl groups, R ９ is hydrogen, C １ ~C ６ - Alkyl, C １ ~C ６ - Alkoxy, and C ３ ~C １０ - Selected from cycloalkyl groups, R １１ is hydrogen, C １ ~C ６ - Alkyl and C １ ~C ６ - Selected from alkoxy, R １０ and R １２ Both are hydrogen, C is selected from cyclopropyl, pyridyl, and pyrazolyl. D is a compound of formula (I) according to claim 13 or a pharmaceutically acceptable salt thereof, selected from cyclopropyl and pyrazolyl.

16. (i) X １ and X ３ is N, X ２ is CH or (ii) X １ , X ２ and X ３ All are N, or (iii)X ２ and X ３ CH is X １ is N, A is selected from cyclohexyl, bicyclo[1.1.1]pentanyl, and phenyl. B is, 【Chemistry 9】 Selected from, R １ Fluorochloro, CHF ２ and CF ３ Selected from, R ２ It is selected from hydrogen and fluoro, R ３ It is selected from hydrogen and fluoro, R ７ and R ８ The compound of formula (I) according to claim 15 or a pharmaceutically acceptable salt thereof, wherein all of the members are methyl.

17. The compound of formula (I) above, 8-(4-chlorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(3R)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(trifluoromethyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-3-methylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(1-methyl-5,7-dihydro-4H-pyrazolo[3,4-c]pyridin-6-yl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3S)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(3R)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one, 3-Fluoro-4-[4-keto-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-8-yl]benzonitrile, 8-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(2-fluoro-4-methylphenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-(p-tolyl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-dimethylcyclohexen-1-yl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)cyclohexen-1-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)phenyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chlorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-methylphenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-spiro[2.5]octan-6-ylpyrido[3,4-d]pyrimidine-4-one, 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-dimethylcyclohexyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-ethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-cyclobutyl-2-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-3-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-cyclobutyl-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2-(1-bicyclo[1.1.1]pentanyl)-8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-cyclopentyl-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2-tert-butyl-8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-2-(1-methylcyclopropyl)-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-methyl-3-(1-methylcyclopropyl)-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-cyclopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-ethyl-2-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-cyclopropyl-2-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,2-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(3-methyl-1,2,4-oxadiazole-5-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1,2,4-triazole-1-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(2-methylpyrazole-3-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3,3-dimethyl-4-(1-methylpyrazole-4-yl)pyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(5-methyl-1,2,4-oxadiazole-3-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-(3-methoxyphenyl)-3-methylpyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 6-[(3aR,6aR)-3a-phenyl-3,4,6,6a-tetrahydro-1H-fluoro[3,4-c]pyrrole-5-yl]-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-(3,5-dimethylpyrazole-1-yl)piperidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[6-(3-pyridyl)-3-azabicyclo[4.1.0]heptan-3-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(2-cyclopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(triazole-1-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(3-methyl-1,2,4-oxadiazole-5-yl)piperidino]pyrimido[5,4-d]pyrimidine-4-one, 6-(2-tert-butyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-yl)-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1-methylpyrazole-4-yl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(7,8-dihydro-5H-1,6-naphthyridine-6-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(3-methyl-1,2,4-oxadiazole-5-yl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-keto-4-(p-tolyl)piperazino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(1,2,4-triazole-1-yl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-(4-cyclopropyltriazole-1-yl)pyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-(7-methyl-2,6-dioxa-9-azaspiro[4.5]decane-9-yl)pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-methyl-3-(p-tolyl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 4-[8-(4-chloro-2-fluorophenyl)-4-keto-2,3-dimethylpyrimido[5,4-d]pyrimidine-6-yl]-1-cyclopropyl-piperazine-2-carbonitrile, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)pyrrolidino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-methyl-6-phenyl-tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-8-[3-(trifluoromethyl)cyclobutyl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-(4,4-difluorocyclohexyl)-2,3-dimethyl-6-[(2S,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-8-(3-methyl-1-bicyclo[1.1.1]pentanyl)-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 3-[2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-4-oxopyrido[3,4-d]pyrimidine-8-yl]bicyclo[1.1.1]pentan-1-carbonitrile, 8-(3-methoxy-1-bicyclo[1.1.1]pentanyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one, 5-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one, 5-(4-chlorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one, 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one, 5-(4-chlorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]-2,6-naphthyridine-1-one, 8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-ethyl-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-isopropyl-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2-(1,1-difluoroethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(3R)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[4-(trifluoromethyl)phenyl]pyrimido[5,4-d]pyrimidine-4-one, 8-(2,4-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-8-[6-(trifluoromethyl)-3-pyridyl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 13-(4-chloro-2-fluorophenyl)-11-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2,7,10,12-tetrazatricyclo[7.4.0.03,7]trideca-1(9),2,10,12-tetraen-8-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-[2-fluoro-4-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-8-(2,4-difluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(5-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-[2-fluoro-5-(trifluoromethyl)phenyl]-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-[3-(difluoromethyl)pyrrolidino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-6-(3,4-dihydro-1H-2,7-naphthyridine-2-yl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1H-pyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one, 8-(6,6-difluoro-3-bicyclo[3.1.0]hexanyl)-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 8-[4-(difluoromethyl)cyclohexyl]-2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[3,4-d]pyrimidine-4-one, 2,3-dimethyl-6-[2-(1-methylpyrazole-4-yl)morpholino]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(2-methylpyrazole-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[8-(1-methylpyrazole-3-yl)-6-azaspiro[3.4]octan-6-yl]pyrimido[5,4-d]pyrimidine-4-one, 4-(4-chloro-2-fluorophenyl)-6,7-dimethyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-8-one, 8-(4-chloro-2-fluorophenyl)-6-[2-[1-(2,2-difluoroethyl)pyrazole-4-yl]morpholino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one, 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-[1-(2,2,2-trifluoroethyl)pyrazole-4-yl]morpholino]pyrimido[5,4-d]pyrimidine-4-one, and 8-(4-chloro-2-fluorophenyl)-6-[2-[1-(2,2-difluorocyclopropyl)pyrazole-4-yl]morpholino]-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

18. A compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

19. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a therapeutically inactive carrier.

20. A method for treating or preventing symptoms associated with loss of function of human TREM2 in a subject requiring treatment or prevention of such symptoms, comprising the step of administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19.

21. The method according to claim 20, wherein the symptoms associated with loss of function of human TREM2 are selected from Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, and stroke.

22. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, for use in the method according to claim 20 or 21.

23. The use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the method according to claim 20 or 21.

24. Use of a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical for use in the method according to claim 20 or 21.

25. The invention is as described above.

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