Pyrido[3,4-D]pyrimidine-4-one and pyrimido[5,4-D]pyrimidine-4-one derivatives as TREM2 agonists for the treatment of Parkinson's disease

Abstract

The present invention relates to compounds having general formula (I). TIFF2026519581000186.tif45165 (In the formula, A, B, R 1 , R 2 , R 3 , R 5 , and R 6 The present invention provides compositions containing the compound (as described herein), methods for producing the compound, and the compound for use in methods for treating or preventing diseases associated with TREM2, such as Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion diseases, and stroke.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to organic compounds useful for the treatment or prevention of mammals, and more particularly to trigger receptor 2 (TREM2) agonists expressed on myeloid cells 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 responses 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. These receptors play a crucial role in sensing environmental changes and enabling complex interactions that regulate 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 a ligand-binding extracellular immunoglobulin variable-like domain (IgV), followed by a long stalk domain, a single transmembrane helix, and a short cytosolic end lacking a signaling motif. Downstream signaling is mediated through interaction with the effector protein DAP12. DAP12 is a transmembrane disulfide bond adapter dimer whose expression and cellular localization on the cell membrane are TREM2-dependent. It binds to the TREM2 transmembrane helix via lysine-aspartate interactions (K156-D50) to form a signaling complex (Zhong L. et al., J Biol Chem. 2015;290(25):15866-77). Due to its short extracellular domain, DAP12 lacks ligand-binding ability. Endogenous ligands for TREM2 include a wide range of molecules, including phospholipids, glycolipids, lipoproteins, cell debris, myelin, and Aβ oligomers. Stimulation of the TREM2 / DAP12 complex induces phosphorylation of two tyrosine residues within the immune receptor tyrosine-based activation motif (ITAM) of the cytoplasmic domain of DAP12, thereby recruiting 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, β-amyloid phagocytosis, myelin debris removal, and transition from homeostasis to disease-associated microglia (DAM) 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., Cell, 2017 Jun 15;169(7):1276-1290.e17.doi:10.1016 / j.cell.2017.05.018).

[0006] TREM2 gene variants have been suggested to be involved in 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), a fatal condition characterized by progressive juvenile dementia, myelin loss, and bone abnormalities, or polycystic lipomegaly dysplasia (PLOSL) with sclerosing leukoencephalopathy, and are 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 suggested to be involved in impaired microglial function and reduced response to neurodegenerative diseases. (Kleinberger, G. et al., Sci. Transl. Med. 2014, 6, 243ra86).

[0007] Furthermore, genome-wide association studies (GWAS) have shown 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 mutation, a LoF mutation associated with structural changes within the extracellular domain of TREM2, was linked to impaired binding ability to endogenous ligands and 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 ongoing to elucidate the mechanisms by which TREM2 LoF mutations contribute to AD. Patients with these mutations may have microglial dysfunction, including reduced clearance of extracellular aggregates (e.g., amyloid and myelin debris) and apoptotic neurons, ultimately leading to a reduced ability to fight the disease and increased susceptibility to neurodegeneration. Indeed, mouse models lacking TREM2 or DAP12 showed reduced microglial activation and impaired cluster formation around amyloid plaques, confirming that TREM2 signaling plays a central role in the response to microglial function and the pathological features of Alzheimer's disease.

[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 a compound of formula (I). [ka] (In the formula, A, B, R 1, R 2 , R 3 , R 5 and R 6 It provides (as defined herein).

[0010] In further embodiments, the present invention provides a composition comprising a compound of formula (I), a method 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, components, 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, for example, 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, alkyl groups contain 1 to 4 carbon atoms, for example, 1, 2, 3, or 4 carbon atoms. In other embodiments, alkoxy groups contain 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 the previously defined alkyl group 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 through 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 cycloalkyl"). 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., the two rings are joined through 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 10The term "aryl" 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 non-limiting 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-dihydrobenzofuranyl; 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 =O group.

[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 as defined 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, as well as 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, N-acetylcysteine, and others. 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 in 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 at least one condition, disorder or symptom, or its clinical or asymptomatic symptom). 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 is not always 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 a compound of formula (I). [ka] or provides a pharmaceutically acceptable salt thereof, in the formula, X 1 , X 2and 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 as follows: [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 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 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. R 5 These include C1-C6 alkyl, halo-C1-C6 alkyl, 3-10 member heterocyclyl and C3-C 10 Selected from cycloalkyl groups, the C3-C 10 The cycloalkyl group is optionally substituted with a halogen and one substituent selected from C1-C6 alkyl groups. R 6 It is selected from hydrogen and fluoro, R 7 and R 8These 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 heterocyclyls, C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H-triazole, 2H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl.

[0030] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, 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 as follows: [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 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 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. R 5 These include C1-C6 alkyl, halo-C1-C6 alkyl, 3-10 member heterocyclyl and C3-C 10 Selected from cycloalkyl groups, the C3-C 10 The cycloalkyl group is optionally substituted with a halogen and one substituent selected from C1-C6 alkyl groups. R 6 It is selected from hydrogen and fluoro, R 7 and R 8 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 heterocyclyls, 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.

[0031] In one embodiment, the present invention provides 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 it CH, or (ii)X 1 , X 2 , X 3 All are N, or (iii)X 1 and X 2 is N, and X 3Is it CH, or?

[0032] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, (i)X 1 and X 3 is N, and X 2 Is it CH, or (ii)X 1 , X 2 , X 3 All of them are N.

[0033] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, A is C6-C 10 Aryl and C3-C 10 Selected from cycloalkyl groups, R 1 These are selected from C1-C6 alkyl and halogens. R 2 It is selected from hydrogen and halogens. R 3 The element is selected from hydrogen and halogens.

[0034] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, A is C6-C 10 Aryl and C3-C 10 Selected from cycloalkyl groups, R 1 These are selected from C1-C6 alkyl and halogens. R 2 It is selected from hydrogen and halogens. R 3 It is hydrogen.

[0035] In a more preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, A is C6-C 10It is Ariel, R 1 It is a halogen, R 2 It is a halogen, R 3 It is hydrogen.

[0036] 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 phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R 1 These are selected from CF3, CHF2, fluoro and chloro. R 2 It is selected from hydrogen and fluoro, R 3 The element is selected from hydrogen and fluorocarbon.

[0037] In particularly preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R 1 These are selected from CF3, CHF2, fluoro and chloro. R 2 It is selected from hydrogen and fluoro, R 3 It is hydrogen.

[0038] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, A is phenyl, R 1 It is Chlorophyll, R 2 is fluoro and R 3 It is hydrogen.

[0039] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, and [ka] The following [ka] Selected from.

[0040] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, and [ka] The following [ka] Selected from.

[0041] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, and [ka] teeth [ka] That is the case.

[0042] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein, B is [ka] and [ka] selected from R 4a is a group [Chem.] and is R 4b is selected from hydrogen and C1-C6 alkyl, R 4c is hydrogen, C is selected from pyridyl, pyrazolyl and 2H-triazole, R 7 is selected from C1-C6 alkyl, C1-C6 alkoxy and C3-C 10 cycloalkyl, R 8 is hydrogen.

[0043] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein B is [Chem.] and [Chem.] selected from R 4a is a group [Chem.] and is R 4b is selected from hydrogen and C1-C6 alkyl, R 4c is hydrogen, C is selected from pyridyl and pyrazolyl, R 7 is selected from C1-C6 alkyl and C3-C 10 cycloalkyl, R8 It is hydrogen.

[0044] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is as follows: [ka] Selected from.

[0045] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is as follows: [ka] Selected from.

[0046] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, B is [ka] and [ka] Selected from, R 4a is, [ka] And, R 4b It is hydrogen, R 4c It is hydrogen, C is selected from pyridyl and pyrazolyl. R 7 These are selected from C1-C6 alkyl and C1-C6 alkoxy, R 8 It is hydrogen.

[0047] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, B is [ka] and [ka] Selected from, R 4a is, [ka] And, R 4b It is hydrogen, R 4c It is hydrogen, C is selected from pyridyl and pyrazolyl. R 7 is a C1-C6 alkyl group, and R 8 It is hydrogen.

[0048] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, B is [ka] and [ka] Selected from, R 4a is, [ka] And, R 4b It is hydrogen, R 4c It is hydrogen, C is selected from pyridyl and pyrazolyl. R 7 It is selected from methyl and methoxy, R 8 It is hydrogen.

[0049] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein B is as follows [ka] Selected from.

[0050] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein B is as follows [ka] Selected from.

[0051] In a preferred embodiment, the present invention is R 5 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein the compound is a C1-C6 alkyl group.

[0052] In a particularly preferred embodiment, the present invention is R 5 This specification provides compounds of formula (I) described herein, wherein the compound is methyl, or pharmaceutically acceptable salts thereof.

[0053] In one embodiment, the present invention is R 6 This specification provides compounds of formula (I) described herein, wherein the compound is hydrogen, or pharmaceutically acceptable salts thereof.

[0054] In one embodiment, the present invention is R 6 This specification provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein is a halogen.

[0055] In one embodiment, the present invention provides 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 it CH, or (ii)X 1 , X 2 , X 3 All are N, or (iii)X 1 and X 2 N is X 3 CH is, A is C6-C 10 Aryl and C3-C 10 Selected from cycloalkyl groups, R 1 These are selected from C1-C6 alkyl and halogens. R 2 It is selected from hydrogen and halogens. R 3 It is selected from hydrogen and halogens. B, [ka] and [ka] Selected from, R 4a is, [ka] And, R 4b These are selected from hydrogen and C1-C6 alkyl groups. R 4c It is hydrogen, R 5 It is a C1-C6 alkyl group, C is selected from pyridyl, pyrazolyl, and 2H-triazole. R 6 It is selected from hydrogen and fluoro, R 7 These are C1-C6 alkyl, C1-C6 alkoxy and C3-C 10 Selected from cycloalkyl groups, R 8 It is hydrogen.

[0056] In one embodiment, the present invention provides 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 it CH, or (ii)X 1 , X 2 , X 3 All are N, or (iii)X 1 and X 2 N is X 3 CH is, A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R 1 These are selected from CF3, CHF2, fluoro and chloro. R 2 It is selected from hydrogen and fluoro, R 3 It is selected from hydrogen and fluoro, B is as follows: [ka] Selected from, R 5 It is methyl, R 6 The element is selected from hydrogen and fluorocarbon.

[0057] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, (i)X 1 and X3 is N, and X 2 is CH, or (ii) X 1 , X 2 , X 3 are all N, A is selected from C6-C 10 aryl and C3-C 10 cycloalkyl, R 1 is selected from halo C1-C6 alkyl and halogen, R 2 is selected from hydrogen and halogen, R 3 is hydrogen, B is

Chemical formula

Chemical formula

Chemical formula

[0058] In particularly preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, (i)X 1 and X 3 is N, and X 2 Is it CH, or (ii)X 1 , X 2 , X 3 All are N, A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R 1 These are selected from CF3, CHF2, fluoro and chloro. R 2 It is selected from hydrogen and fluoro, R 3 It is hydrogen, B is [ka] and [ka] Selected from, R 4a is, [ka] And, R 4b It is hydrogen, R 4c It is hydrogen, C is selected from pyridyl and pyrazolyl. R 5 It is methyl; R 6 It is selected from hydrogen and fluoro, R 7 It is selected from methyl and methoxy, R 8 It is hydrogen.

[0059] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as 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 , X 3 are all N, A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R 1 is selected from CF3, CHF2, fluoro, and chloro, R 2 is selected from hydrogen and fluoro, R 3 is hydrogen, B is the following

Chemical formula

[0060] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein (i) X 1 and X 3 are N, and X 2 is CH, or (ii) X 1 , X 2 , X 3 are all N, A is selected from C6-C 10 aryl and C3-C 10 cycloalkyl, R<​​​​It is selected from hydrogen and halogens. R 3 It is selected from hydrogen and halogens. B is [ka] and [ka] Selected from, R 4a is, [ka] And, R 4b These are selected from hydrogen and C1-C6 alkyl groups. R 4c It is hydrogen, R 5 It is a C1-C6 alkyl group, C is selected from pyridyl and pyrazolyl. R 7 These are C1-C6 alkyl and C3-C 10 Selected from cycloalkyl groups, R 8 It is hydrogen.

[0061] In one embodiment, the present invention provides 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 it CH, or (ii)X 1 , X 2 , X 3 All are N, A is phenyl, R 1 It is selected from CF3, fluoro and chloro, R 2 It is fluoro, R3 It is hydrogen, B is as follows: [ka] Selected from, R 5 It is a C1-C6 alkyl group, R 7 These are C1-C6 alkyl and C3-C 10 Selected from cycloalkyl groups, R 8 It is hydrogen.

[0062] In preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, (i)X 1 and X 3 is N, and X 2 Is it CH, or (ii)X 1 , X 2 , X 3 All are N, A is C6-C 10 It is Ariel, R 1 It is a halogen, R 2 It is a halogen, R 3 It is hydrogen, B is [ka] and [ka] Selected from, R 4a is, [ka] And, R 4bIt is hydrogen, R 4c It is hydrogen, C is selected from pyridyl and pyrazolyl. R 7 is a C1-C6 alkyl group, and R 8 It is hydrogen.

[0063] In particularly preferred embodiments, the present invention provides compounds of formula (I) described herein or pharmaceutically acceptable salts thereof, wherein, (i)X 1 and X 3 is N, and X 2 Is it CH, or (ii)X 1 , X 2 , X 3 All are N, A is phenyl, R 1 It is Chlorophyll, R 2 It is fluoro, R 3 It is hydrogen, B is as follows: [ka] Selected from, R 7 is a C1-C6 alkyl group, and R 8 It is hydrogen.

[0064] 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 as follows: 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one; 2-(difluoromethyl)-3-methyl-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-(difluoromethyl)-3-methyl-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; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; and 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-8-one Selected from.

[0065] 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 as follows: 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; and 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one Selected from.

[0066] 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.

[0067] In some embodiments, compounds of formula (I) are isotope-labeled by substituting one or more atoms in them 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 compounds 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 the ease of their incorporation and the readily detectable 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.

[0068] 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 dose.

[0069] 11 C, 18 F, 15 O and 13 Substitution 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 manner similar to those described in the examples below.

[0070] Manufacturing method The compounds of formula (I) of the present invention may be prepared by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The techniques required to carry out the reactions and purify the resulting products are known to those skilled in the art. Substituents and indices used in the following description of the method have the meanings given herein unless otherwise indicated.

[0071] 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 a later stage of synthesis using standard methods described in the literature.

[0072] 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 enriched starting material and intermediate. When such diastereomerically / enantiomerically enriched starting material and intermediate are used in the synthesis of the compound of formula (I), the respective diastereomerically / enantiomerically enriched compounds of formula (I) are generally obtained.

[0073] Those skilled in the art will recognize that, in the synthesis of compounds of formula (I) (unless otherwise desired), the “orthogonal protecting 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 protection is well known in the art and has been documented 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).

[0074] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and properties of the intermediates.

[0075] 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. The described reaction is conveniently carried out in a temperature range from -78°C to reflux. The time required for the reaction can also vary considerably, 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.

[0076] If the starting material or intermediate is not commercially available, or if its synthesis is not documented in the literature, it can be prepared in the same manner as the existing procedures for closely related analogues, or as outlined in the experimental section.

[0077] 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 Hexadeuterodimethylsulfoxide 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 (Hexafluorophosphate Benzotriazole Tetramethyluronium) HCOOH Formic Acid HEK (Human Fetal Kidney) HPLC (High-Performance Liquid Chromatography) J coupling constant kg (kilogram) 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 ion mode NH4Cl (Ammonium Chloride) nm (nanometer) NMR nuclear magnetic resonance spectroscopy pH (Hydrogen Potential) pos. Cation mode POY3 phosphorus oxytrihalide psi (pounds per square inch) R-type according to the Kahn-Ingold Prelogue ranking rules. RP inverse phase RPM (revolutions per minute) s seconds S-body according to the Kahn-Ingold prelogue ranking rules 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) Specific rotation of αD at 589 nm δ chemical shift (ppm)

[0078] 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.

[0079] Scheme 1 [ka] Compounds of general formula Ia can be prepared by first reacting intermediate II with a boronic acid (or boronic acid derivative) III under palladium catalytic conditions (a palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(O) and a base such as cesium carbonate or sodium carbonate) to form compound IV, as described in Scheme 1. This intermediate is reacted with amine R in a dipolar aprotic solvent such as N,N-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 (tris(dibenzylideneacetone)dipalladium(0)), a suitable ligand such as xanthophos, and a base such as cesium carbonate or tert-butoxide sodium. B It can react with -H(V) to form compound Ia (metal-catalyzed coupling).

[0080] Scheme 2 [ka] Intermediate IIa can be prepared by coupling compound VI with amine VII using an amide coupling reagent such as HATU, HBTU, or EDC, and then reacting the formed intermediate VIII with orthoester IX at high temperature. Alternatively, compound VIII can be reacted with an acid chloride X (or acid anhydride) and a base such as N,N-diisopropylethylamine, triethylamine, or pyridine to form intermediate XI, which can then be cyclized by heating in the presence of a base, trimethylsilyl chloride, or a suitable solvent free of additives such as acetic acid (Scheme 2).

[0081] Scheme 3 [ka] Intermediate IIb can be prepared by coupling compound XII with amine VII 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 XV. This compound can be reacted with an acid anhydride or orthoester IX at high temperature to form intermediate IIb (Scheme 3).

[0082] Scheme 4 [ka] Intermediate IIc can be prepared by coupling compound XVI with amine VII using an amide coupling reagent such as HATU, HBTU, or EDC, and then reacting it with orthoester IX to form compound XVIII. Reacting this compound with an inorganic halogenating reagent such as phosphorus oxychloride or phosphorus oxybromide XIX yields intermediate IIc, with or without additional base (Scheme 4).

[0083] Scheme 5 [ka] Compounds of general formula Ib can be prepared as described in Scheme 5 by reacting intermediate IV with a boronic acid derivative XIX using a palladium catalyst and a base to form intermediate XX, which is then reduced by treatment with hydrogen and a suitable agent such as a catalyst to form compound Ib. Preferred catalysts are charcoal-supported palladium or platinum oxide in ethyl acetate, ethanol, or methanol, with or without the addition of further reagents such as magnesium oxide or triethylamine.

[0084] Scheme 6 [ka] Intermediate IVa(R A The compound XXIV (preferably an alicyclic group) can be prepared by reacting compound XXII (obtainable from XXI by amide coupling) with carboxylic acid XXIII under oxidative coupling conditions (e.g., using ammonium persulfate in dimethyl sulfoxide at a temperature of 0°C to 50°C, Miniski reaction, additional blue LED irradiation may be applied) to form compound XXIV. This intermediate can be reacted with an anhydride or orthoester IX at high temperatures to produce intermediate IVa. Furthermore, compound XXII can be cyclized first using an anhydride or orthoester IX to form intermediate XXV, which can then be reacted with carboxylic acid XXIII under oxidative coupling conditions (e.g., using ammonium persulfate in dimethyl sulfoxide at a temperature of 0°C to 50°C, Miniski reaction, additional blue LED irradiation may be applied) to form intermediate IVa (Scheme 6).

[0085] Scheme 7 [ka] Compound Ic can be prepared according to Scheme 7. Compound XXVI is reacted with boronic acid III under palladium-catalyzed conditions to obtain compound XXVII. This intermediate is further reacted with amine V in a dipolar aprotic solvent such as N,N-dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, in the presence of a base such as N,N-diisopropylethylamine or triethylamine, to form XXVIII. This compound is reacted with N-bromosuccinimide in a suitable solvent to form XXIX, which is converted to compound XXXI by a palladium-catalyzed reaction with the tin derivative XXX. Aminolysis of ester XXXI and amine IX in a solvent such as ethanol or methanol yields compound XXXII, which is treated with a base such as sodium methoxide to achieve cyclization to compound XXXIII. Oxidation with a suitable reagent such as selenium dioxide yields aldehyde XXXVI, which can then be finally converted to compound Ic using a fluorinating reagent such as DAST or Deoxo-fluor.

[0086] In one embodiment, the present invention provides a method for producing a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, the method described in any one of schemes 1 to 7.

[0087] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, which is prepared according to any one of the methods described herein.

[0088] 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 in subjects that require the restoration of human TREM2 function.

[0089] In a further embodiment, the present invention provides a compound of formula (I) described herein for use in a method for restoring the function of human TREM2 in a subject requiring restoration of human TREM2 function.

[0090] 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 subjects requiring restoration of human TREM2 function.

[0091] In a further embodiment, the present invention provides a method for restoring the function of human TREM2 in a subject requiring restoration of human TREM2 function, the method comprising administering an effective amount of the compound of formula (I) described herein to the subject.

[0092] The TREM2 agonist efficacy of the compound of formula (I) according to the present invention was measured using HEK cell lines expressing human TREM2 and DAP12. When the small molecule ligand binds to the TREM2 receptor, DAP12 recruits and activates the Syk kinase. The resulting increase in phosphorylated Syk levels was measured in lysed cells using a commercially available AlphaLisa reagent kit.

[0093] To perform the assay, frozen HEK293-TREM2 / DAP12 cells were thawed, prepared, and seeded at a rate of 20,000 cells per well in 10 μL of phenol red-free DMEM medium supplemented with 5% FBS using Certus in a 384-well plate.

[0094] The dose-response (1:3) compounds were diluted with DMSO (maximum concentration 10 mM) and added to cells from low-dead-volume plates using ECHO (0-20 μM) at a 500-fold dilution (20 nL in 10 μl cell suspension; maximum concentration 20 μM in all wells, DMSO concentration 0.2%). Neutral (DMSO) and irritant (1 μM tool compound) controls were also added.

[0095] Cells were incubated at 37°C, 5% CO2, and 95% humidity for 30 minutes. After compound addition and incubation, 2.5 μL of lysis buffer was added using Certus. After rapid rotation, the plate was shaken at 450 RPM for 30 minutes at room temperature in the dark. 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 Geneda Screener and normalized to 100% activity for DMSO and the tool compound.

[0096] Table 1 shows the TREM2 agonist efficacy of the compound of formula (I) according to the present invention as measured by the above assay. Table 2 shows the TREM2 agonist efficacy of the reference compound as measured by the above assay. [Table 1] TIFF2026519581000062.tif237170 [Table 2]

[0097] 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.

[0098] In a further embodiment, the present invention relates to a method for treating or preventing symptoms associated with human TREM2 loss of function in a subject requiring treatment or prevention of such symptoms, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0099] 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 a subject requiring treatment or prevention of symptoms associated with human TREM2 loss of function.

[0100] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein, 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 such symptoms.

[0101] 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.

[0102] 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.

[0103] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is Parkinson's disease.

[0104] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is rheumatoid arthritis.

[0105] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is Alzheimer's disease.

[0106] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is amyotrophic lateral sclerosis (ALS).

[0107] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is Nasu-Hakola disease.

[0108] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is frontotemporal dementia.

[0109] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is multiple sclerosis.

[0110] In a preferred embodiment, the symptoms associated with loss of function of human TREM2 are prion diseases.

[0111] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is stroke.

[0112] 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 inactive carrier.

[0113] In one embodiment, the pharmaceutical composition described in Example 60 or Example 61 is provided.

[0114] Compounds of formula (I) and their pharmaceutically acceptable salts can be used as pharmaceuticals (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration can also be parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0115] Compounds of formula (I) and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert inorganic or organic adjuvants to manufacture 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.

[0116] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0117] Suitable adjuvants for the manufacture of liquid and syrup formulations include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0118] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0119] Suitable adjuvants for suppositories include, for example, natural oils or hydrogenated oils, waxes, fats, semi-solid or liquid polyols, etc.

[0120] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. These may also contain other therapeutically beneficial substances.

[0121] Dosages can vary widely and, of course, are adjusted to the individual requirements of each specific case. Generally, for oral administration, a daily dose of approximately 0.1 mg to 20 mg per kg of body weight, preferably approximately 0.5 mg to 4 mg per kg of body weight (e.g., approximately 300 mg per person), is appropriate, preferably administered in 1 to 3 divided doses, and these doses may consist of, for example, equal amounts. However, it will be clear that, where indicated, the upper limits described herein may be exceeded. [Examples]

[0122] 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.

[0123] 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.

[0124] 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 Caen-Ingold-Prelogue order rule, the chiral carbon atom may be in an "R" or "S" configuration. For the compounds described in the patent, the absolute configuration was arbitrarily assigned.

[0125] Unless otherwise specified, all reaction examples and intermediates were prepared under an argon atmosphere.

[0126] The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1.

[0127] 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.

[0128] Intermediate A1: 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 of 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, dichloromethane / methanol gradient 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.

[0129] Step 2: 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide [ka] To a solution of 5-amino-2-chloro-N-methyl-isonicotinamide (700 mg, 3.77 mmol) in N,N-dimethylformamide (7.5 ml), N-bromosuccinimide (806 mg, 4.53 mmol) was added, 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, heptane / ethyl acetate 100 / 0~50 / 50 gradient) 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.

[0130] Step 3: 8-Bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one [ka] To a solution of 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), acetic acid (218 mg, 208 μl, 3.63 mmol) was added, 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 vacuum evaporation of the excess, the crude mixture was purified by flash chromatography (silica gel, heptane / ethyl acetate 100 / 0~60 / 40 gradient) 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.

[0131] Intermediate A2: 8-bromo-6-chloro-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 2-Bromo-6-chloro-3-[(2,2-difluoroacetyl)amino]-N-methyl-isonicotinamide [ka] To a solution of 3-amino-2-bromo-6-chloro-N-methyl-isonicotinamide (see intermediate A1, 0.600 g, 2.27 mmol) in anhydrous tetrahydrofuran (15 ml), 2,2-difluoroacetic anhydride (395 mg, 282 μl, 2.27 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated and polished in diethyl ether to obtain 2-bromo-6-chloro-3-[(2,2-difluoroacetyl)amino]-N-methyl-isonicotinamide (678 mg, yield 88%) as a white solid, MS m / z: 344.0 [M+H]. + ESI pos.

[0132] Step 2: 8-Bromo-6-chloro-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] A solution of 2-bromo-6-chloro-3-[(2,2-difluoroacetyl)amino]-N-methyl-isonicotinamide (678 mg, 1.98 mmol) in acetic acid (8 ml) was heated at 110°C for 3 hours. The reaction mixture was concentrated under vacuum and polished in diethyl ether to obtain 8-bromo-6-chloro-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (510 mg, yield 79%) as a white solid. MS m / z: 326.0 [M+H] + ESI pos.

[0133] Intermediate A3: 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate A1, using trifluoroacetic anhydride instead of 2,2-difluoroacetic anhydride in step 1. Yellow solid, MS m / z: 344.0 [M+H] + ESI pos.

[0134] Intermediate A4: 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 of 5-amino-2,4-diketo-1H-pyrimidine-6-carboxylic acid (CAS 7164-43-4, 5 g, 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 in small amounts, 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 vacuum-dried to yield 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.

[0135] 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 vacuum-dried 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.

[0136] Step 3: 6,8-Dichloro-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one [ka] To a solution of 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 N,N-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, 0-100% ethyl acetate) 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.

[0137] Intermediate A5: 6-chloro-8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] 8-bromo-6-chloro-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 500 mg, 1.54 mmol) and (4-chloro-2-fluorophenyl)boronic acid (269 mg, 1.54 mmol) were dissolved in 1,4-dioxane (9 ml) and water (3 ml), to which cesium carbonate (1.51 g, 4.62 mmol) was added. The reaction mixture was purged and refilled three times with argon, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (63 mg, 0.077 mmol, 0.050 equivalents) was added. After purging and refilling again with argon, the 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, 0-30% ethyl acetate), and then polished in diethyl ether to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (235 mg, yield 41%) as a grayish-white solid. MS m / z: 374.1 [M+H] + ESI pos.

[0138] Intermediate A6: 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one [ka] To a solution of 8-bromo-6-chloro-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one (intermediate A3, 250 mg, 0.73 mmol) in 1,4-dioxane (3 ml) and water (1 ml), 4-chloro-2-fluorophenylboronic acid (127 mg, 0.73 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (30 mg, 0.04 mmol, 0.05 equivalents), and cesium carbonate (713 mg, 2.19 mmol) were added. The mixture was then degassed three times with nitrogen and stirred at 30°C under a nitrogen atmosphere for 16 hours. The reaction mixture was added to water (20 ml) and extracted with dichloromethane (20 ml x 3). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0~1:1) to obtain a pale yellow solid of 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one (60 mg, yield 21%), MS m / z: 392.0 [M+H]. + ESI pos.

[0139] Intermediate A7: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: Ethyl 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate [ka] A solution of (4-chloro-2-fluorophenyl)-boronic acid (1.33 g, 7.63 mmol) and 5-amino-2,6-dichloropyrimidine-4-carboxylate ethyl ester (1.5 g, 6.35 mmol) in 1,4-dioxane (28.85 ml) was purged with argon. Next, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (525 mg, 0.635 mmol, 0.10 equivalents) and 3M cesium carbonate aqueous solution (6.35 ml, 19.1 mmol) were added, and the reaction mixture was heated overnight at 60°C with stirring under argon. The reaction mixture was filtered through Celite, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The product was purified by flash chromatography (silica gel, heptane, 10-50% ethyl acetate) to obtain ethyl 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate (1.64 g, yield 74%) as a yellow powder. MS m / z: 330.0 [M+H] + ESI pos.

[0140] Step 2: 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid [ka] To a solution of ethyl 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate (1.64 g, 4.97 mmol) in tetrahydrofuran (20 ml) and water (20 ml), an aqueous lithium hydroxide solution (0.5 M, 14.9 ml, 7.45 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Next, hydrochloric acid (2 M, 8 ml) was added, the volatile substances were evaporated, the formed precipitate was filtered, washed with water, and dried under high vacuum to obtain 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid (1.49 g, yield 95%) as a yellow solid. MS m / z: 302.0 [M+H] + ESI pos.

[0141] Step 3: 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)-N-methylpyrimidine-4-carboxamide [ka] 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylic acid (1.0 g, 3.18 mmol) was dissolved in N,N-dimethylformamide (15 ml). N,N-diisopropylethylamine (1.64 g, 2.2 ml, 12.7 mmol) and methylamine hydrochloride (429 mg, 6.36 mmol) were added, and then HATU (1.57 g, 4.13 mmol) was added in small amounts, and the mixture was stirred overnight. The reaction product was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with NH4Cl solution and brine, dried over Na2SO4, and evaporated. The residue was purified by flash column chromatography (silica gel, heptane, 50% ethyl acetate) to obtain 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)-N-methylpyrimidine-4-carboxamide (429 mg, yield 42%) as a yellow solid. MS m / z: 315.0 [M+H] + ESI pos.

[0142] Step 4: 2-Chloro-6-(4-Chloro-2-fluorophenyl)-5-[(2,2-difluoroacetyl)amino]-N-methylpyrimidine-4-carboxamide [ka] 2,2-difluoroacetic anhydride (147 mg, 105 μl, 0.846 mmol) was added at 0°C to a solution of 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)-N-methylpyrimidine-4-carboxamide (272 mg, 0.846 mmol) in tetrahydrofuran (5 ml). The reaction mixture was stirred overnight at room temperature. After evaporating the volatile substances, 2-chloro-6-(4-chloro-2-fluorophenyl)-5-[(2,2-difluoroacetyl)amino]-N-methylpyrimidine-4-carboxamide (332 mg, 97% yield) was obtained as a yellow solid. MS m / z: 393.1 [M+H] + ESI pos.

[0143] Step 5: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] A solution of 2-chloro-6-(4-chloro-2-fluorophenyl)-5-[(2,2-difluoroacetyl)amino]-N-methylpyrimidine-4-carboxamide (332 mg, 0.819 mmol) in acetic acid (4.1 ml) was stirred at 110°C for 1 hour. After evaporating volatile substances, the product was purified by flash column chromatography (silica gel, heptane, 5-50% ethyl acetate) to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrimido[5,4-d]pyrimidine-4-one (98 mg, yield 32%) as a grayish-white solid. MS m / z: 375.1 [M+H] + ESI pos.

[0144] Intermediate A8: 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 2-Chloro-6-(4-Chloro-2-fluorophenyl)-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide [ka] 5-amino-2-chloro-6-(4-chloro-2-fluorophenyl)-N-methylpyrimidine-4-carboxamide (see intermediate A7, 2.2 g, 6.98 mmol) was dissolved in tetrahydrofuran (30 ml), to which 4-dimethylaminopyridine (85 mg, 0.7 mmol) and trifluoroacetic anhydride (1.48 ml, 10.5 mmol) were added at 0°C. The reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0~5:1) to obtain 2-chloro-6-(4-chloro-2-fluorophenyl)-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (2.2 g, yield 75%) as a pale yellow rubber.

[0145] Step 2: 6-Chloro-8-(4-Chloro-2-fluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimidine[5,4-d]pyrimidine-4-one [ka] To a solution of 2-chloro-6-(4-chloro-2-fluorophenyl)-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (1.4 g, 3.41 mmol) in dichloromethane (20 ml), triethylamine (14.2 ml, 102.15 mmol) and trimethylsilyl chloride (4.33 ml, 34.1 mmol) were added at 0°C, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (1.34 g, yield 100%) as a pale yellow solid. MS m / z:393.0[M+H] + ESI pos.

[0146] Intermediate A9: 6-Chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 5-amino-2-chloro-N-methylpyrimidine-4-carboxamide [ka] To a solution of 5-amino-2-chloropyrimidine-4-carboxylic acid (3 g, 17.3 mmol) in N,N-dimethylformamide (50 ml), methylamine hydrochloride (1.75 g, 25.9 mmol) and N,N-diisopropylethylamine (6.7 g, 9.06 ml, 51.9 mmol) were added at room temperature. Next, HATU (7.89 g, 20.74 mmol) was added, and the mixture was stirred at room temperature for 3 days. The solvent was evaporated, and water and ethyl acetate were added to the residue. The layers were separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain 5-amino-2-chloro-N-methylpyrimidine-4-carboxamide (2.6 g, yield 81%) as a pink solid. MS m / z: 187.0 [M+H] + ESI pos.

[0147] Step 2: 2-Chloro-5-[(2,2-difluoroacetyl)amino]-N-methylpyrimidine-4-carboxamide [ka] 2,2-difluoroacetic anhydride (1.03 g, 0.73 μl, 5.89 mmol) was added at 0°C to a solution of 5-amino-2-chloro-N-methylpyrimidine-4-carboxamide (1.1 g, 5.89 mmol) in tetrahydrofuran (33 ml). The reaction mixture was stirred at 0°C for 30 minutes, then the cooling bath was removed, and the reaction mixture was heated to room temperature for 1 hour. Volatile substances were evaporated under vacuum, and the crude product was purified by flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methylpyrimidine-4-carboxamide (1.12 g, yield 72%) as a colorless oil. MS m / z: 265.1 [M+H] + ESI pos.

[0148] Step 3: 2-Chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide [ka] 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (2.19 g, 12.17 mmol) was added to a solution of 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methylpyrimidine-4-carboxamide (322 mg, 1.22 mmol) in dimethyl sulfoxide / water (600:1). The reaction mixture was spurged with argon. A freshly prepared solution of ammonium persulfate (1.67 g, 7.3 mmol) in spurged dimethyl sulfoxide / water (600:1) was added under argon, and the reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide (240 mg, yield 44%) as a pale yellow solid. MS m / z: 397.1 [MH] - ESI neg.

[0149] Step 4: 6-Chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution of 2-chloro-5-[(2,2-difluoroacetyl)amino]-N-methyl-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimidine-4-carboxamide (230 mg, 0.49 mmol) in toluene (5 ml), p-toluenesulfonic acid monohydrate (9 mg, 49 μmol) was added, and the mixture was heated at 110°C for 1 hour. 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 flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain the title compound (120 mg, yield 61%) as a white foamy substance. MS m / z: 381.1 [M+H] + ESI pos.

[0150] Intermediate A10: 6-Chloro-8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in step 3 using 4,4-difluorocyclohexanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid, similar to intermediate A9. White foamy substance, MS m / z: 365.1 [M+H] + ESI pos.

[0151] Intermediate A11: 6-Chloro-2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in step 3 using 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid, similar to intermediate A9. White solid, MS m / z: 363.2 [M+H] + ESI pos.

[0152] Intermediate A12: 6-Chloro-2-(difluoromethyl)-8-(2,4-difluorophenyl)-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in step 1 using (2,4-difluorophenyl)boronic acid instead of (4-chloro-2-fluorophenyl)boronic acid, similar to intermediate A7. It was a yellow foamy substance, MS m / z: 359.1 [M+H]. + ESI pos.

[0153] Intermediate A13: 6-Chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 6-Chloro-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one [ka] 8-bromo-6-chloro-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A2, 1 g, 3.08 mmol) and charcoal-supported palladium (10%, 100 mg) were added to a flask, and the flask was purged with argon. Ethyl acetate (15 ml) and triethylamine (468 mg, 644 μl, 4.62 mmol) were added, and the argon balloon was replaced with hydrogen. The reaction mixture was stirred for 3 hours. The product was purified by flash column chromatography (silica gel, heptane, 2-10% ethyl acetate) to obtain 6-chloro-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (283 mg, yield 37%) as a white solid. MS m / z: 246.0 [M+H] + ESI pos.

[0154] Step 2: 6-Chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] To a degassed solution of 6-chloro-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (450 mg, 1.83 mmol) in 12 ml of dimethyl sulfoxide / water (600:1), a solution of ammonium persulfate (2.51 g, 11 mmol) in the same dimethyl sulfoxide / water mixture (24 ml) was added, and the reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water, then brine. The product was purified by flash column chromatography (silica gel, heptane / ethyl acetate) to obtain the title compound (130 mg, yield 16%) as a white solid. MS m / z: 380.2 [M+H] + ESI pos.

[0155] Intermediate A14: 6-Chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 2-Chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide [ka] 5-amino-2-chloro-N-methylpyrimidine-4-carboxamide (see intermediate A9 step 1, 6.0 g, 32.2 mmol) and 4-dimethylaminopyridine (393 mg, 3.22 mmol) were dissolved in tetrahydrofuran (60 ml) and trifluoroacetic anhydride (5.35 ml, 38.6 mmol) at 0°C. The mixture was then stirred at 25°C for 12 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine (100 ml), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 1:0~2:1) to obtain 2-chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (8.0 g, yield 88%) as a grayish-white solid. MS m / z:283.1[M+H] + ESI pos.

[0156] Step 2: 6-Chloro-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution of 2-chloro-N-methyl-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (7.0 g, 24.77 mmol, 1.0 equivalent) in dichloromethane (100 ml), triethylamine (34.4 ml, 248 mmol) was added dropwise, followed by trimethylsilyl chloride (15.8 ml, 124 mmol) under nitrogen at 0°C. The mixture was then stirred under nitrogen at 25°C for 2 hours. 1 M hydrochloric acid solution was added dropwise to the mixture until the pH reached 3-4, and then extracted with dichloromethane (100 ml x 2). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, and 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-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (3.8 g, yield 58%) as a pale yellow solid. MS m / z: 265.2 [M+H] + ESI pos.

[0157] Step 3: 6-Chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution of 6-chloro-3-methyl-2-(trifluoromethyl)pyrimidine[5,4-d]pyrimidine-4-one (1.0 g, 3.78 mmol) in dimethyl sulfoxide (75 ml), 4,4-difluorocyclohexanecarboxylic acid (1.86 mg, 11.3 mmol), ammonium persulfate (3.45 g, 15.12 mmol), and [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (CAS 870987-63-6, 42 mg, 0.04 mmol, 0.01 equivalents) were added. The mixture was degassed, purged with nitrogen, stirred at 25°C for 16 hours, and irradiated with a 455 nm blue LED. The reaction mixture was purified by preparative MPLC (column: spherical C18, 20-45 μm, 100 A, water + 0.1% formic acid / acetonitrile, flow rate 100 ml / min), and the eluate was freeze-dried to obtain the product 6-chloro-8-(4,4-difluorocyclohexyl)-3-methyl-2-(trifluoromethyl)pyrimidine[5,4-d]pyrimidine-4-one (1.0 g, yield 69%) as a light brown solid. MS m / z: 383.1 [M+H] + ESI pos.

[0158] Intermediate A15: 6-Chloro-8-(4-chlorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one [ka] The title compound was prepared in step 1 using 4-chlorophenylboronic acid instead of 4-chloro-2-fluorophenylboronic acid, similar to intermediate A6. Yellow solid, MS m / z: 374.0 [M+H] + ESI pos.

[0159] Intermediate A16: 6-chloro-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in step 3 using 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 4,4-difluorocyclohexanecarboxylic acid, similar to intermediate A14. Yellow solid, MS m / z: 374.0 [M+H] + ESI pos.

[0160] Intermediate A17: 6-Chloro-8-(4-chlorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound, like intermediate A7, was prepared by using 4-chlorophenylboronic acid instead of (4-chloro-2-fluorophenyl)boronic acid in step 1 and trifluoroacetic anhydride instead of 2,2-difluoroacetic anhydride in step 4. It is a pale yellow rubber with an MS m / z of 375.0 [M+H]. + ESI pos. [Table 3]

[0161] Chiral separation of intermediate B1: 2-(1-methylpyrazole-4-yl)morpholine (intermediate B1) was separated by chiral SFC (column AD-H, 5 μm, 100 × 4.6 mm, 20-40% MeOH + 0, 2% diethylamine), yielding (+)-2-(1-methylpyrazole-4-yl)morpholine(+)-B1 as the first enantiomer to elute and (-)-2-(1-methylpyrazole-4-yl)morpholine(-)-B1 as the second enantiomer to elute. (+)-2-(1-methylpyrazole-4-yl)morpholine: yellow oil, αD (589 nm) 20℃ = +13.36° (c = 0.1 g / L, MeOH).

[0162] Intermediate B6: 2-Methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine [ka] Step 1: [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] To a solution of 2-methoxyisonicotinaldehyde (1.0 g, 7.29 mmol) in dichloromethane (10 ml), 3-buty-1-ol (767 mg, 0.833 ml, 10.94 mmol) was added under argon. The mixture was then cooled to -10°C, and trifluoromethanesulfonic acid (3.28 g, 1.92 ml, 21.9 mmol) was added. After stirring at -10°C for 30 minutes, the mixture was warmed to room temperature and stirred overnight. 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. The residue was purified by flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (870 mg, yield 32%) as a colorless oil. MS m / z: 340.1 [M+H] + ESI pos.

[0163] Step 2: 2-Methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine [ka] To a solution of [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (870 mg, 2.31 mmol) in 1,4-dioxane (15 ml), bis(pinacorato)diborone (1.17 g, 4.62 mmol), potassium acetate (906 mg, 9.23 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (189 mg, 0.231 mmol, 0.10 equivalents) were added. The mixture was purged and refilled three times with argon, then stirred at 90°C for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (silica gel, heptane, 0-80% ethyl acetate) to obtain 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (656 mg, yield 81%) as a colorless oil. MS m / z: 318.3[M+H] + ESI pos.

[0164] Intermediate B7: 2-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]triazole [ka] The title compound was prepared using 2-methyl-2H-1,2,3-triazole-4-carboxyaldehyde (CAS 1104078-88-7) instead of 2-methoxyisonicotinaldehyde, similar to intermediate B6. Pale yellow oil, MS m / z: 292.1 [M+H] + ESI pos.

[0165] Example 1: 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] A solution of 2-(2-methyl-4-pyridyl)morpholine (intermediate B2, 48 mg, 0.267 mmol), 6-chloro-8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrido[3,4-d]pyrimidine-4-one (intermediate A5, 50 mg, 0.134 mmol), and N,N-diisopropylethylamine (52 mg, 70 μl, 401 μmol) in dimethyl sulfoxide (1 ml) 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 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 (47 mg, yield 66%) as a yellow powder. MS m / z: 516.2 [M + H] + ESI pos.

[0166] Examples 2 and 3: 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one [ka] The enantiomer of 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one (Example 1) was separated by chiral SFC (Daicel IH column, 5 μm, 250 × 20 mm, 20% methanol + 0, 2% diethylamine). After evaporation of the solvent, the second isomer of 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one (15 mg, yield 36%) was obtained as a yellow solid (t=1.64 min), MS m / z: 516.1 [M+H]. + Furthermore, ESI pos. was performed, and the first isomer (t=1.22 min) of 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one (15 mg, 36%) was obtained as a yellow solid, MS m / z: 516.1 [M+H]. + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0167] Example 4: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one [ka] To a solution of 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methyl-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one (intermediate A6, 50 mg, 0.13 mmol) in 1,4-dioxane (2 ml), tris(dibenzylideneacetone)dipalladium (6 mg, 0.01 mmol, 0.05 equivalent), xanthophos (7.5 mg, 0.01 mmol, 0.1 equivalent), and (2R)-2-(1-methylpyrazole-4-yl)morpholine (32 mg, 0.19 mmol) were added. The mixture was degassed three times with nitrogen and stirred at 100°C under nitrogen for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (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 (4.5 mg, yield 7%) as a pale yellow solid. MS m / z: 523.1 [M + H] + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0168] Examples 5 and 6 below were prepared, similarly to Example 1, by starting with the intermediate shown instead of intermediate B2. The absolute configuration was assigned arbitrarily. [Table 4]

[0169] Example 7: 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution of 6-chloro-8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrimido[5,4-d]pyrimidine-4-one (intermediate A7, 62 mg, 0.15 mmol) and 2-(2-methyl-4-pyridyl)morpholine (intermediate B2, 54 mg, 0.30 mmol) in N,N-dimethylformamide (1 ml), N,N-diisopropylethylamine (97 mg, 131 μl, 0.75 mmol) was added, and the mixture was heated at 120°C for 90 minutes. The solution was subjected to direct preparative HPLC (Gemini NX, 12 nm, 5 μm, 100 × 30 mm, acetonitrile / water + 0.1% triethylamine) to obtain the title compound (27 mg, yield 35%) as a yellow solid. MS m / z: 517.2 [M + H] + ESI pos.

[0170] Examples 8 and 9: 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one [ka] The enantiomer of 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one (Example 7, 23 mg) was separated by chiral SFC (column: chiral IC, 5 μm, 250 × 20 mm, 40% methanol + 0.2% diethylamine). After evaporation of the solvent, the first eluted isomer (t=4.19 min) of 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one (9 mg, yield 39%) was obtained as a yellow solid. MS m / z: 517.2 [M+H]+ Furthermore, ESI pos. was performed, and the second isomer (t=5.25 min) of 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one (9 mg, 39%) was obtained as a yellow solid, MS m / z: 517.2 [M+H]. + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0171] Example 10: 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 7, using intermediate (+)-B1 instead of intermediate B2. It was a yellow solid with an MS m / z of 506.2 [M+H]. + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0172] Example 11: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] To a solution of 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (intermediate A8, 60 mg, 0.15 mmol) in dimethyl sulfoxide (2 ml), N,N-diisopropylethylamine (0.08 ml, 0.46 mmol) and (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-B1, 38 mg, 0.23 mmol) were added, and the resulting mixture was stirred at 25°C for 2 hours. The reaction mixture was filtered, and the filtrate was acidified with formic acid until the pH was 5-7. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18, 150 × 25 mm × 10 μm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min) to obtain the title compound (14 mg, yield 17%) as a pale yellow solid. MS m / z: 524.1 [M + H] + ESI pos.

[0173] Examples 12–14 below were prepared by starting from the indicated intermediates, similar to Example 7. The absolute configurations were arbitrarily assigned. [Table 5]

[0174] Examples 15 and 16: 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka]

[0175] The title compound was prepared from intermediate B3 instead of intermediate (+)-B1, similar to Example 11. The enantiomers were then separated by chiral SFC (Daicel Chiralpak AD column 250 mm × 30 mm, 10 μm, isopropanol / 0.1% ammonium hydroxide, flow rate 70 ml / min), and 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one was obtained as the first enantiomer to elute, as a pale yellow solid. MS m / z: 551.1 [M+H] + Furthermore, ESI pos. was performed, and 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one was obtained as a pale yellow solid as the second eluted enantiomer, MS m / z: 551.1[M+H] + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0176] Examples 17 and 18 and Examples 19 and 20: 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[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]-3-methyl-2-(trifluoromethyl)pyrimido[5, 4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimide[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimide[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 11, starting from intermediate B4 instead of intermediate (+)-B1, followed by preparative HPLC of the diastereomer (column: Phenomenex Synergi C18, 150 × 25 mm × 10 μm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min), and then the enantiomer was subjected to chiral SFC (column: Daicel Chiralpak AD Separation was performed using ethanol / 0.1% ammonium hydroxide (250mm x 30mm, 10μm, flow rate 70ml / min) to obtain 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[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]-3-methyl-2-(trifluoromethyl)pyrimido [5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimide[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimide[5,4-d]pyrimidine-4-one were obtained as pale yellow rubber, MS m / z: 564.3 [M+H] + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0177] Examples 21, 22, and 23: 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] 6-Chloro-2-(difluoromethyl)-8-(2,4-difluorophenyl)-3-methylpyrimido[5,4-d]pyrimidine-4-one (intermediate A12, 110 mg, 0.245 mmol), 2-Methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (intermediate A mixture of B6 (117 mg, 0.368 mmol), potassium carbonate (102 mg, 0.74 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (20 mg, 24 μmol, 0.10 equivalents) in 1,4-dioxane (2.5 ml) and water (0.5 ml) was passed through with argon and stirred at 60°C for 2 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 flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one (111 mg, yield 86%) as a pale yellow foamy substance. MS m / z: 514.3 [M+H] + ESI pos.

[0178] Step 2: 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one and 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one [ka] To a solution of 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one (105 mg, 0.204 mmol) in ethyl acetate (2 ml), charcoal-supported palladium (10%, 44 mg) was added under argon. The flask was evacuated, refilled with argon three times, and then filled with hydrogen. The reaction mixture was stirred under hydrogen at room temperature for 3 hours, then filtered through dikalyte and washed with ethyl acetate. The combined organic layer was concentrated. The residue was purified by preparative HPLC (column: YMC Triart, C18, 100 mm × 30 mm, 5 μm, mobile phase: water / 0.1% formate-acetonitrile, 0-100%) to obtain 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one (48 mg, yield 45%) as a white powder. MS m / z: 516.3 [M+H] + ESI pos. 44 mg of this compound was separated by chiral SFC (column chiral Lux C4, 5 μm, 250 × 20 mm, 40% methanol + 0, 2% diethylamine, flow rate 90 ml / min), and the first eluted enantiomer of 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one (17 mg, yield 39%) was obtained as a white powder, MS m / z: 516.3 [M+H]. + Furthermore, ESI pos. was obtained, along with the second-eluting enantiomer of 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one (18 mg, yield 41%), as a white powder, MS m / z: 516.3 [M+H]. +ESI pos., absolute spatial configuration was assigned arbitrarily.

[0179] Examples 24–31 below were prepared by starting from the indicated intermediates, similar to Examples 21–23. The absolute configurations were assigned arbitrarily. [Table 6] TIFF2026519581000125.tif136170

[0180] Examples 32 and 33: 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one and 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] Step 1: 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] To a flask containing 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (14 mg, 17 μmol, 0.10 equivalents), 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (intermediate B6, 71 mg, 222 μmol), 6-chloro-2-(difluoromethyl)-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (intermediate A13, 65 mg, 171 μmol), and potassium carbonate (71 mg, 514 μmol), toluene (1.43 ml) and water (0.28 ml) were added under argon. The reaction vessel was sealed and heated at 60°C for 1 hour. The reaction mixture was cooled and diluted with saturated sodium bicarbonate solution. The product was extracted with ethyl acetate, washed with water and brine, and concentrated under vacuum. The residue was purified by column chromatography to obtain 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (82.5 mg, yield 78%) as a light brown solid. MS m / z: 535.3[M+H] + ESI pos.

[0181] Step 2: 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one and 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one [ka] Ethanol (2 ml) was added to a vial containing 2-(difluoromethyl)-6-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (82 mg, 0.154 mmol) and charcoal-supported palladium (10%, 8 mg) under argon. The argon balloon was replaced with a hydrogen balloon, the reaction mixture was sparged and purged, and the mixture was stirred overnight. The reaction product was filtered through a silica pad and concentrated under vacuum. The residue was purified by column chromatography (silica gel, heptane, 20-40% ethyl acetate) to obtain 2-(difluoromethyl)-6-[(rac)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (70 mg, yield 84%) as a colorless oil. The cis-enantiomer was separated by chiral SFC, and 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (13 mg, yield 16%) was obtained as a pale yellow oil as the second eluted enantiomer, MS m / z: 537.2[M+H]. + Furthermore, ESI pos. was obtained as the first eluted enantiomer, 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one (13 mg, yield 16%), as a pale yellow oil, MS m / z: 537.2[M+H] + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0182] Examples 34–39 below were prepared by starting from the indicated intermediates, similar to Examples 21–23. The absolute configurations were assigned arbitrarily. [Table 7] TIFF2026519581000130.tif45170

[0183] Examples 40, 41, and 42: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[6-(2-methyltriazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] To a suspension of 6-chloro-8-(4-chloro-2-fluorophenyl)-3-methyl-2-(trifluoromethyl)-pyrimido[5,4-d]pyrimidine-4-one (intermediate A8, 250 mg, 0.64 mmol) and 2-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]triazole (intermediate B7, 444 mg, 0.76 mmol) in 1,4-dioxane (10 ml) and water (1 ml), cesium carbonate (518 mg, 1.59 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (26 mg, 0.03 mmol, 0.05 equivalents) were added. After degassing three times with nitrogen, the resulting mixture was stirred under a nitrogen atmosphere at 25°C for 2 hours. The reaction mixture was added to 0.1 M hydrochloric acid (150 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine (100 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100:1~1:2) to obtain 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[6-(2-methyltriazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (240 mg, yield 72%) as a pale yellow oil. MS m / z: 522.1[M+H] + ESI pos.

[0184] Step 2: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[6-(2-methyltriazol-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (150 mg, 0.29 mmol) was dissolved in ethyl acetate (8 ml), to which magnesium oxide (116 mg, 2.87 mmol), triethylamine (35 mg, 0.34 mmol), and charcoal-supported palladium (10%, 61 mg) were added. The mixture was degassed three times with hydrogen and then stirred at 25°C for 2 hours under a hydrogen atmosphere (15 Psi). The reaction mixture was passed through a Celite pad and filtered. The filtrate was diluted with ethyl acetate (100 ml), washed with 1 M hydrochloric acid (50 ml x 2) and brine (50 ml), then dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 × 25 mm × 10 μm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min) to obtain 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one. This diastereomar racemic mixture was separated by chiral SFC (Daicel Chiralpak AD column, 250mm x 30mm, 10μm, isopropanol / 0.1% ammonium hydroxide, flow rate 70ml / min). The first enantiomer to elute was 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (12mg, yield 4%), obtained as a white solid. MS m / z: 546.3[M+Na] +Furthermore, ESI pos. was obtained, and the second eluted enantiomer, 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (17 mg, yield 6%), was obtained as a white solid, MS m / z: 524.3 [M+H]. + Furthermore, ESI pos. was obtained as an off-white solid: 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (6 mg, yield 2%), MS m / z: 524.3 [M+H] + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0185] Examples 43–52 below were prepared by starting from the indicated intermediates, similar to Examples 21–23. The absolute configurations were arbitrarily assigned. [Table 8] TIFF2026519581000135.tif209170

[0186] Example 53: 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 21, using intermediate A7 instead of intermediate A12, and intermediates B6 and B5 instead, resulting in a light brown solid with an MS m / z of 505.3 [M+H]. + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0187] Examples 54 and 55: 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] Step 1: 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1-methylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1-methylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide [ka] 6-Chloro-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (intermediate A16, 200 mg, 0.53 mmol) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H- To a suspension of pyran-6-yl]pyrazole (intermediate B5, 366 mg, 0.63 mmol) in 1,4-dioxane (5 ml) and water (0.5 ml), cesium carbonate (513 mg, 1.58 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (21 mg, 0.03 mmol, 0.05 equivalents) were added. After degassing three times with nitrogen, the resulting mixture was stirred at 80°C under a nitrogen atmosphere for 2 hours. The mixture was poured into water (100 ml), the aqueous layer was separated and extracted with ethyl acetate (50 ml x 3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100:1 to 1:3) to obtain 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1-methylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1-methylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (210 mg, 51:44), which was used in the next step.

[0188] Step 2: 6-[3-(difluoromethyl)-1-bicyclo[1,1,1]pentanyl]-N-methyl-2-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide [ka] 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[6-(1-methylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[6-(1-methylpyramidyl] To a solution of 190 mg, 0.37 mmol of zole-4-yl)-3,6-dihydro-2H-pyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (190 mg, 0.37 mmol) in ethyl acetate (15 ml), magnesium oxide (150 mg, 3.74 mmol), triethylamine (45 mg, 0.45 mmol), and charcoal-supported palladium (10%, 60 mg) were added. The reaction mixture was degassed three times with hydrogen, and then stirred at 25°C for 2 hours under hydrogen (15 Psi). The mixture was passed through a Celite pad and filtered. The filtrate was diluted with ethyl acetate (100 ml), washed with hydrochloric acid (1 M, 30 ml) and brine (30 ml), dried over Na2SO4, and concentrated to obtain crude 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (190 mg, yield 96%) as a pale yellow oil. MS m / z: 529.2[M+H] + ESI pos.

[0189] Step 3: 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] 6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-N-methyl-2-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-5-[(2,2,2-trifluoroacetyl)amino]pyrimidine-4-carboxamide (190 mg, 0.36 mmol) was dissolved in dichloromethane (8 ml), to which triethylamine (0.5 ml, 3.6 mmol) was added at 25°C. Next, trimethylsilyl chloride (0.23 ml, 1.8 mmol) was added dropwise under nitrogen at 0°C, and the reaction mixture was stirred at 25°C for 2 hours. Hydrochloric acid (1 M) was added to the reaction mixture to adjust the pH to 3-5, and the aqueous mixture was extracted with dichloromethane (50 ml x 3). The combined organic layers were washed with brine (50 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residues were combined and purified by preparative HPLC (Phenomenex Luna C18 column, 150×25mm×10μm, 0.225% formic acid aqueous solution / acetonitrile, flow rate 25ml / min) to obtain 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (105 mg, yield 57%) as a pale yellow solid. MS m / z: 511.3[M+H] + ESI pos.

[0190] Step 4: 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] Racemic 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (105 mg) is processed using chiral SFX (Daicel Chiralcel OX column). Separation was performed using a 250mm x 30mm, 10μm substrate (solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 70ml / min). The first enantiomer to elute was 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (41mg, yield 39%), obtained as a white solid. MS m / z: 511.2[M+H] + Furthermore, ESI pos. was performed, and 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one (35 mg, yield 33%) was obtained as a white solid as the second eluted enantiomer, MS m / z: 511.2 [M+H]. + ESI pos.

[0191] Examples 56, 57, and 58: 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one and 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one [ka] The title compound was prepared using intermediate A17 instead of intermediate A16, similar to Examples 54 and 55, as a pale yellow solid, MS m / z: 505.2 [M+H]. + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0192] Example 59: 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-8-one [ka] Step 1: Methyl 2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate [ka] To a solution of 2,6-dichloropyrimidine-4-carboxylate methyl ester (1.0 g, 4.83 mmol) in 1,4-dioxane (32 ml), (4-chloro-2-fluorophenyl)boronic acid (842 mg, 4.83 mmol) and cesium carbonate (4.72 g, 14.5 mmol) were added at room temperature. After degassing the mixture, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (395 mg, 0.483 μmol, 0.10 equivalents) was added, and 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 dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane, 0-50% ethyl acetate) to obtain methyl 2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate (983 mg, 60%) as a pale yellow solid. MS m / z: 301.0 [M+H] + ESI pos.

[0193] Step 2: Methyl 6-(4-chloro-2-fluorophenyl)-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxylate [ka] To a solution of 2-chloro-6-(4-chloro-2-fluorophenyl)pyrimidine-4-carboxylate methyl ester (235 mg, 0.780 mmol) in N,N-dimethylformamide (4 ml), (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-B1, 144 mg, 0.858 mmol) and N,N-diisopropylethylamine (202 mg, 272 μl, 1.56 mmol) were added at room temperature, and the mixture was stirred at 110°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, heptane, 0-100% ethyl acetate) to obtain methyl 6-(4-chloro-2-fluorophenyl)-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxylate (304 mg, yield 90%) as a yellow solid. MS m / z: 432.1[M+H] + ESI pos.

[0194] Step 3: Methyl 5-bromo-6-(4-chloro-2-fluorophenyl)-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxylate [ka] To a solution of methyl 6-(4-chloro-2-fluorophenyl)-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (275 mg, 0.637 mmol) in dichloromethane (6 ml), N-bromosuccinimide (125 mg, 0.70 mmol) was added at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain methyl 5-bromo-6-(4-chloro-2-fluorophenyl)-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxylate (225 mg, yield 65%) as a yellow solid. MS m / z: 512.1 [M+H] + ESI pos.

[0195] Step 4: Methyl 6-(4-chloro-2-fluorophenyl)-5-propa-1-inyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxylate [ka] To a solution of methyl 5-bromo-6-(4-chloro-2-fluorophenyl)-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimidine-4-carboxylate (190 mg, 0.372 mmol) in N,N-dimethylformamide (3 ml), tributyl(propa-1-inyl) stannane (184 mg, 170 μl, 0.558 mmol) was added at room temperature. After degassing the mixture with argon, tetrakis(triphenylphosphine)palladium (0) (43 mg, 37 μmol, 0.10 equivalents) was added. The mixture was stirred in a microwave at 110°C for 1 hour. 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, heptane, 0-100% ethyl acetate) to obtain methyl 6-(4-chloro-2-fluorophenyl)-5-propa-1-inyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxylate (182 mg, yield 97%) as a pale yellow solid. MS m / z: 470.2 [M+H] + ESI pos.

[0196] Step 5: 6-(4-chloro-2-fluorophenyl)-N-methyl-5-propa-1-inyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxamide [ka] Methyl 6-(4-chloro-2-fluorophenyl)-5-propa-1-inyl-2-([(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxylate (180 mg, 0.383 mmol) was dissolved in a solution of methylamine (40% in methanol, 4.77 ml, 38.3 mmol) at room temperature, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated to dryness. The crude product was purified by flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain 6-(4-chloro-2-fluorophenyl)-N-methyl-5-propa-1-inyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimidine-4-carboxamide (160 mg, yield 80%) as a yellow solid. m / z:469.2[M+H] + ESI pos.

[0197] Step 6: 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] To a solution of 6-(4-chloro-2-fluorophenyl)-N-methyl-5-propa-1-inyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimidine-4-carboxamide (160 mg, 0.341 mmol) in ethanol (2.5 ml), sodium ethoxide (232 mg, 3.41 mmol) was added at room temperature, and the mixture was stirred overnight at 80°C. The reaction mixture was diluted with water and extracted four times with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, methanol-containing dichloromethane 0-5%) to obtain 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 (71 mg, yield 42%) as a yellow solid. MS m / z: 469.1 [M+H] + ESI pos.

[0198] Step 7: 4-(4-chloro-2-fluorophenyl)-7-methyl-8-oxo-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde [ka] To a solution of 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 (20 mg, 43 μmol) in 1,4-dioxane (1 ml), selenium dioxide (9.5 mg, 85.3 μmol) was added at room temperature, and the mixture was stirred at 100 °C for 2 hours. The reaction mixture was concentrated to dryness, and the residue was purified by flash chromatography (silica gel, methanol-containing dichloromethane 0-8%) to obtain 4-(4-chloro-2-fluorophenyl)-7-methyl-8-oxo-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde (18 mg, yield 83%) as a yellow solid. MS m / z: 483.1 [M+H] + ESI pos.

[0199] Step 8: 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-8-one [ka] To a solution of 4-(4-chloro-2-fluorophenyl)-7-methyl-8-oxo-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-6-carbaldehyde (7 mg, 14.5 μmol) in dichloromethane (1 ml), [bis(2-methoxyethyl)amino]sulfur trifluoride (2.7 M in toluene, 54 μl, 145 μmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated NaHCO3 solution and extracted twice with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by preparative HPLC (Gemini NX C-18, 5 μm, 100 × 30 mm, acetonitrile / water) to obtain the title compound (2 mg, yield 26%) as a yellow solid, MS m / z: 505.1 [M+H]. + ESI pos.

[0200] Reference example Reference Example 1: 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] 8-bromo-6-chloro-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (intermediate A1, 750 mg, 2.6 mmol) and (4-chloro-2-fluorophenyl)boronic acid (453 mg, 2.6 mmol) were dissolved in 1,4-dioxane (12 ml) and water (4 ml), to which cesium carbonate (2.54 g, 7.8 mmol) was added. The reaction mixture was purged and packed three times with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (106 mg, 130 μmol, 0.05 equivalents) was added. The reaction mixture was purged and packed three times with argon, and 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 substance was purified by flash chromatography (silica gel, heptane, 0-60% ethyl acetate), and then polished in 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).

[0201] 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 of 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 B1, 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×10μm, water + 0.1% 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)morpholin-4-yl]pyrido[3,4-d]pyrimidine-4-one (50 mg). This racemic mixture was separated by SFC (Daicel Chiralcel OD column 250mm*30mm, 10μm, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 70ml / min). 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one was obtained as a pale yellow solid as the first enantiomer to elute at a retention time of 2.06 minutes (retention time for other enantiomers: 2.46 minutes). MS m / z: 469.3[M+H] +ESI pos., absolute configuration 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).

[0202] Reference example 2: 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 Reference Example 1, and the second enantiomer to elute after a retention time of 2.46 minutes was obtained as a pale yellow solid. MS m / z: 469.3 [M+H] + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0203] Reference Example 3: 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 of 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[3,4-d]pyrimidine-4-one (see Reference Example 1, 30 mg, 0.09 mmol) in 1,4-dioxane (1.5 ml), 2-(2-methyl-4-pyridyl)morpholine (intermediate B2, 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 xanthophos (10 mg, 0.02 mmol, 0.2 equivalents) were added, and the mixture was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3 × 50 mL). The combined extract was washed with brine, dried over Na₂SO₄, and evaporated. 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, 10μm, solvent: acetonitrile / isopropyl alcohol / 0.1% ammonium hydroxide, flow rate 80ml / min). 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrido[3,4-d]pyrimidine-4-one was obtained as a yellow solid, with a retention time of 1.02 minutes (retention time for other enantiomers: 2.08 minutes). MS m / z: 480.2[M+H] + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0204] Reference example 4: 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 Reference Example 3, and the second enantiomer to elute after a retention time of 2.08 minutes was obtained as a yellow solid. MS m / z: 480.2 [M+H] + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0205] Reference example 5: 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 A4, 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 (silica gel, heptane, 0-100% ethyl acetate) 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.

[0206] 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 (+)-B1, 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., absolute spatial configuration was assigned arbitrarily.

[0207] Reference Examples 6 and 7: 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] To a solution of 2-(2-methyl-4-pyridyl)morpholine (intermediate B2, 43 mg, 0.24 mmol) in dimethyl sulfoxide (1 ml), 6-chloro-8-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[5,4-d]pyrimidine-4-one (see Reference Example 5, 55 mg, 0.16 mmol) and N,N-diisopropylethylamine (23 mg, 0.18 mmol) were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (40 ml x 2). The organic phase was washed with brine (100 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether / ether = 1:0) to obtain 8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6-[2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrimido[5,4-d]pyrimidine-4-one (44 mg). The enantiomer was separated by chiral SFC (Daicel Chiralpak AD column, 250 mm × 30 mm, 10 μm, ethanol + 0.1% ammonium hydroxide, flow rate 70 ml / min). At a retention time of 1.05 minutes, 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 (19 mg, yield 42%) was obtained as a pale yellow solid as the first enantiomer to elute. MS m / z: 481.2 [M+H] + Furthermore, ESI pos. was performed, 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 (21 mg, yield 47%) was obtained as a pale yellow solid as the second enantiomer to elute at a retention time of 1.44 minutes, MS m / z: 481.2 [M+H]. + ESI pos., absolute spatial configuration was assigned arbitrarily.

[0208] Example 60 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

[0209] Example 61 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. Compound of formula (I) 【Chemistry 1】 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 as follows: 【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 ４ａ is hydrogen, halogen, cyano, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, Halo C １ -C ６ Alkyl, Halo C １ -C ６ Alkoxy, and groups 【Transformation 3】 Selected from, R ４ｂ and R ４ｃ These are, independently, hydrogen, halogen, cyano, and C. １ -C ６ Alkyl, C １ -C ６ Alkoxy, Halo C １ -C ６ Alkyl, Halo C １ -C ６ Selected from alkoxy and oxo, R ５ 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 Cycloalkyls are halogens and C １ -C ６ It is optionally substituted with one substituent selected from alkyl groups. R ６ It is selected from hydrogen and fluoro, R ７ and R ８ These are, independently, hydrogen, halogen, and C. １ -C ６ Alkyl, Halo C １ -C ６ Alkyl, C １ -C ６ Alkoxy, Halo C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, Halo C ３ -C １０ Selected from cycloalkyl and 3- to 10-membered heterocyclines, C is selected from cyclopropyl, phenyl, pyridyl, pyrazolyl, 1H-1,2,4-triazole, 1H-triazole, 2H-triazole, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine, 1,2,4-oxadiazolyl, and 1,3,4-oxadiazolyl).

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

3. (i) X １ and X ３ N is X ２ Is CH or (ii) X １ , X ２ , X ３ All are N. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

4. A is C ６ -C １０ Aryl and C ３ -C １０ Selected from cycloalkyl groups, R １ However, Hello C １ -C ６ Selected from alkyl and halogen, R ２ However, hydrogen and halogens are selected, R ３ However, selected from hydrogen and halogens, A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. A is C ６ -C １０ aryl and C ３ -C １０ selected from cycloalkyl, R １ However, Hello C １ -C ６ Selected from alkyl and halogen, R ２ is selected from hydrogen and halogen, R ３ However, it is hydrogen. A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

6. A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R １ However, CF ３ CHF ２ Selected from fluoro and chloro, R ２ However, selected from hydrogen and fluoro, R ３ However, selected from hydrogen and fluoro, A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

7. A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R １ However, CF ３ CHF ２ Selected from fluoro and chloro, R ２ However, selected from hydrogen and fluoro, R ３ However, it is hydrogen. A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

8. basis 【Chemistry 4】 The following 【Transformation 5】 A compound of formula (I) according to any one of claims 1 to 3, selected from, or a pharmaceutically acceptable salt thereof.

9. B, 【Transformation 6】 and 【Transformation 7】 Selected from, R ４ａ However, 【Transformation 8】 And, R ４ｂ However, hydrogen and C １ -C ６ Selected from alkyl groups, R ４ｃ That is hydrogen, C is selected from pyridyl, pyrazolyl, and 2H-triazole. R ７ However, C １ -C ６ Alkyl, C １ -C ６ Alkoxy and C ３ -C １０ Selected from cycloalkyl groups, R ８ That is hydrogen. A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. B is below 【Chemistry 9】 A compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, selected from the above.

11. B, 【Chemistry 10】 and 【Chemistry 11】 Selected from, R ４ａ However, 【Chemistry 12】 And, R ４ｂ However, it is hydrogen, R ４ｃ That is hydrogen, C is selected from pyridyl and pyrazolyl, R ７ However, C １ -C ６ Alkyl and C １ -C ６ Selected from alkoxy, R ８ That is hydrogen. A compound of formula (I) as described in claim 9, or a pharmaceutically acceptable salt thereof.

12. B, 【Chemistry 13】 and 【Chemistry 14】 Selected from, R ４ａ However, 【Chemistry 15】 And, R ４ｂ However, it is hydrogen, R ４ｃ However, it is hydrogen, C is selected from pyridyl and pyrazolyl, R ７ However, selected from methyl and methoxy, R ８ However, it is hydrogen. A compound of formula (I) as described in claim 9, or a pharmaceutically acceptable salt thereof.

13. B is below 【Chemistry 16】 A compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, selected from the above.

14. R ５ However, C １ -C ６ A compound of formula (I) according to any one of claims 1 to 13, which is alkyl, or a pharmaceutically acceptable salt thereof.

15. R ５ A compound of formula (I) according to claim 14 or a pharmaceutically acceptable salt thereof, wherein is methyl.

16. (i) X １ and X ３ N is X ２ Is CH or (ii) X １ , X ２ , X ３ All are N, or (iii)X １ and X ２ N is X ３ CH is, A is C ６ -C １０ Aryl and C ３ -C １０ Selected from cycloalkyl groups, R １ However, Hello C １ -C ６ Selected from alkyl and halogen, R ２ However, hydrogen and halogens are selected, R ３ However, hydrogen and halogens are selected, B, 【Chemistry 17】 and [Chemistry 18] Selected from, R ４ａ However, 【Chemistry 19】 And, R ４ｂ However, hydrogen and C １ -C ６ Selected from alkyl groups, R ４ｃ However, it is hydrogen, R ５ However, C １ -C ６ It is alkyl, C is selected from pyridyl, pyrazolyl, and 2H-triazole. R ６ However, selected from hydrogen and fluoro, R ７ However, C １ -C ６ Alkyl, C １ -C ６ Alkoxy and C ３ -C １０ Selected from cycloalkyl groups, R ８ However, it is hydrogen. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

17. (i) X １ and X ３ N is X ２ Is CH or (ii) X １ , X ２ , X ３ All are N, or (iii)X １ and X ２ N is X ３ CH is, A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R １ However, CF ３ CHF ２ Selected from fluoro and chloro, R ２ However, selected from hydrogen and fluoro, R ３ However, selected from hydrogen and fluoro, B, the following 【Chemistry 20】 Selected from, R ５ However, it is methyl, R ６ However, selected from hydrogen and fluoro, A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

18. (i) X １ and X ３ N is X ２ Is CH or (ii) X １ , X ２ , X ３ All are N, A is C ６ -C １０ Aryl and C ３ -C １０ Selected from cycloalkyl groups, R １ However, Hello C １ -C ６ Selected from alkyl and halogen, R ２ However, hydrogen and halogens are selected, R ３ However, it is hydrogen, B, 【Chemistry 21】 and 【Chemistry 22】 Selected from, R ４ａ However, 【Chemistry 23】 And, R ４ｂ However, it is hydrogen, R ４ｃ However, it is hydrogen, C is selected from pyridyl and pyrazolyl, R ５ However, C １ -C ６ It is alkyl, R ６ However, hydrogen and halogens are selected, R ７ However, C １ -C ６ Alkyl and C １ -C ６ Selected from alkoxy, R ８ However, it is hydrogen. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

19. (i) X １ and X ３ N is X ２ Is CH or (ii) X １ , X ２ , X ３ All are N, A is selected from phenyl, cyclohexyl, and 1-bicyclo[1.1.1]pentanyl, R １ However, CF ３ CHF ２ Selected from fluoro and chloro, R ２ However, selected from hydrogen and fluoro, R ３ However, it is hydrogen, B, the following 【Chemistry 24】 Selected from, R ５ However, it is methyl, R ６ However, selected from hydrogen and fluoro, A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

20. The compound of formula (I) above, 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R)-2-(2-methyl-4-pyridyl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-(2,4-difluorophenyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[5,4-d]pyrimidine-4-one; 2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one; 2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-8-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrido[3,4-d]pyrimidine-4-one; 2-(difluoromethyl)-3-methyl-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-(difluoromethyl)-3-methyl-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; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-6-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-6-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-3-methylpyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(2-methyltriazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4,4-difluorocyclohexyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrido[3,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2S,4R)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-6-[(2R,4S)-2-(2-methoxypyridine-4-yl)oxan-4-yl]-3-methyl-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-6-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[5,4-d]pyrimidine-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; 8-(4-chlorophenyl)-3-methyl-6-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(trifluoromethyl)pyrimido[5,4-d]pyrimidine-4-one; and 4-(4-chloro-2-fluorophenyl)-6-(difluoromethyl)-7-methyl-2-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[3,4-d]pyrimidine-8-one A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

21. A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

23. A method for treating or preventing symptoms associated with human TREM2 loss of function in a subject requiring treatment or prevention of such symptoms, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22.

24. The method according to claim 23, 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.

25. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23, for use in the method according to claim 23 or 24.

26. The use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22, in the method according to claim 23 or 24.

27. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in the preparation of a pharmaceutical for use in the method according to claim 23 or 24.

28. The invention as previously described herein.

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