TREM2 Agonist

Abstract

TIFF2026521750000301.tif38165 The present invention provides a compound having the general formula (I) (wherein A 1 , A 2 , X 1 , X 2 , R 1 , R 2 , R 3 , R 4 and R 7 are as described herein), a composition comprising the compound, a process for producing the compound, and a method of using the compound in the treatment or prevention of a disease associated with TREM2.

Description

[Technical Field]

[0001] 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] Microglia are immune cells commensal to the central nervous system (CNS) and play a crucial role in CNS development and maintaining brain homeostasis through synaptic pruning and the removal of apoptotic neurons (Paolicelli RC et al., Science 2011, 9;333(6048):1456-8 doi:10.1126 / science.1202529). Microglia also play an important role in response to neurodegenerative symptoms and neuropathological lesions, thereby transitioning to an activated state characterized by cell proliferation, expression and secretion of cytokines and neuroprotective factors, migration to lesion sites, and phagocytosis of dead cells and debris (Lue LF et al., Mol. Neurobiol. 2010, 41(2-3):115-28, doi:10.1007 / s12035-010-8106-8).

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

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

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

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

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

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

[0009] In the first aspect, the present invention relates to formula (I): [ka] (In the formula, A 1 , A 2 , X1 、 X 2 、 R 1 、 R 2 、 R 3 、 R 4 、 and R 7 provides compounds as defined herein.)

[0010] In a further aspect, the present invention provides a composition comprising a compound of formula (I), a process for producing a compound of formula (I), and a method of using a compound of formula (I).

Mode for Carrying Out the Invention

[0011] Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the present invention are to be understood as applicable to any other aspect, embodiment or example described herein, unless incompatible with them. All features disclosed in this specification (including any appended claims, abstract and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations where 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 foregoing embodiments. The present invention extends to any novel one or any novel combination of features disclosed in this specification (including any appended claims, abstract and drawings), or any novel one or any novel combination of steps of any method or process so disclosed. [[ID=2⑧]]

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

[0013] The term "alkoxy" refers to 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 with 3 to 10 ring carbon atoms ("C"). 3-101-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 sharing two carbon atoms (i.e., the bridging separating the two rings is either a single bond or a chain of one or two ring atoms) and a spirocyclic moiety (i.e., the two rings are connected via one common ring atom). Preferably, the cycloalkyl group is a monocyclic hydrocarbon group having 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. Particularly preferred but non-limiting examples of cycloalkyls are cyclopropyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, and cyclohexyl.

[0016] The term "aryl" refers to a total of 6-10 ring members ("C6-C6"). 10 This refers to a monocyclic, bicyclic, or tricyclic carbocyclic system having an aryl group, 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.

[0017] The term "heteroaryl" refers to a monovalent or polyvalent monocyclic ring system having a total of 5 to 6 ring members, the ring system being aromatic, and containing one or more heteroatoms. Preferably, a heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, a heteroaryl contains 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; 1,2,4-oxadiazolyl-5-yl; pyridyl (e.g., 2-pyridyl); pyrazolyl (e.g., pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; and imidazolyl (e.g., imidazole-1-yl). Some preferred but non-limiting examples of heteroaryls include pyridyl and pyrazolyl.

[0018] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic system of 3 to 6 ring atoms, where 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. Some non-limiting examples of heterocyclyl groups include azetidinyl, piperidyl, pyrrolidinyl, oxetanyl, piperidyl, 1,2-dihydropyridinyl, piperidyl, pyrrolidinyl, tetrahydrothiophenyl, and thietanyl. Preferred but non-limiting examples of heterocyclyl groups include 1,2-dihydropyridinyl and oxetanyl.

[0019] 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 replaced by a halogen atom, preferably a fluoro. Preferably, “haloalkyl” refers to an alkyl group in which one, two, or three of the hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably a fluoro. Particularly preferred but non-limiting examples of haloalkyls are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0020] The term "alkoxyalkyl" refers to an alkyl group as defined herein in which at least one hydrogen atom of the alkyl group is replaced by an alkoxy group, preferably methoxy. Preferably, "alkoxyalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group is replaced by an alkoxy group, most preferably methoxy. A particularly preferred but non-limiting example of an alkoxyalkyl is 2-methoxyethyl.

[0021] The term "cycloalkylalkyl" refers to an alkyl group as defined herein, in which at least one hydrogen atom of the alkyl group is replaced by a cycloalkyl group, preferably cyclopropyl. Preferably, "cycloalkylalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group is replaced by a cycloalkyl group, most preferably cyclopropyl. A particularly preferred but non-limiting example of a cycloalkylalkyl is cyclopropylmethyl.

[0022] The term "cycloalkylalkoxy" refers to an alkoxy group as defined herein, in which at least one hydrogen atom of the alkoxy group is replaced by a cycloalkyl group, preferably cyclopropyl. Preferably, "cycloalkylalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group is replaced by a cycloalkyl group, most preferably cyclopropyl. A particularly preferred but non-limiting example of a cycloalkylalkoxy is cyclopropylmethoxy.

[0023] The term "cycloalkyloxy" refers to a cycloalkyl group as defined herein, in which the cycloalkyl group is bonded to the parent molecule via an oxygen atom. A particularly preferred but non-limiting example of a cycloalkyloxy is cyclobutyloxy.

[0024] The term “heterocyclylalkyl” refers to an alkyl group as defined herein, in which at least one hydrogen atom of the alkyl group is replaced by a heterocyclyl group, preferably oxetanyl. Preferably, “heterocyclylalkyl” refers to an alkyl group in which one hydrogen atom of the alkyl group is replaced by a heterocyclyl group, most preferably oxetanyl. A particularly preferred but non-limiting example of a heterocyclylalkyl is oxetanylmethyl.

[0025] The term “heterocyclylalkoxy” refers to an alkoxy group as defined herein, in which at least one hydrogen atom of the alkoxy group is replaced by a heterocyclyl group, preferably oxetanyl. Preferably, “heterocyclylalkoxy” refers to an alkoxy group in which one hydrogen atom of the alkoxy group is replaced by a heterocyclyl group, most preferably oxetanyl. A particularly preferred but non-limiting example of a heterocyclylalkoxy is oxetanylmethoxy.

[0026] The term "heterocyclyloxy" refers to a heterocyclyl group, as defined herein, in which the heterocyclyl group is bonded to the parent molecule via an oxygen atom. A particularly preferred but non-limiting example of a heterocyclyloxy is oxetanyloxy.

[0027] 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, and phosphoric acid (especially hydrochloric acid), and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic base or an organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Examples of 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 isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyimine resins.

[0028] 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 diastereoisomer racemate, or a mixture of diastereoisomer racemates.

[0029] The abbreviation "TREM2" refers to trigger receptor 2, which is expressed in myeloid cells.

[0030] 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 result does not necessarily have to be an effective treatment.

[0031] 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.

[0032] The compound of the present invention In the first aspect, the present invention relates to formula (I): [ka] (In the formula, A 1 , X 1 and X 2 Each is independently selected from N and CH; A 2 O and CR 5 R 6 Selected from; R 1 These are selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 C6-C 10 -aryl, 5-6 member heteroaryl and C3-C 10 - Selected from cycloalkyl, the C6-C 10-aryl, 5-6 member heteroaryl and C3-C 10 - The cycloalkyl group is optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6-alkyl groups, and halo-C1-C6-alkyl groups; R 3 The 5-6 member heteroaryl and 3-6 member heterocyclyl compounds are selected from halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and C3-C 10 -Cycloalkyl, Halo-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -Cycloalkyl-C1-C6-alkoxy, C3-C 10 -Optionally substituted with 1 to 3 substituents independently selected from cycloalkyloxy, 3-6 member heterocyclyl, halo-3-6 member heterocyclyl, 3-6 member heterocyclyl-C1-C6-alkyl, 3-6 member heterocyclyl-C1-C6-alkoxy, and 3-6 member heterocyclyloxy; R 4 These are selected from hydrogen and C1-C6-alkyl; R 5 and R 6 Each is independently selected from hydrogen and halogen; and R 7 (Selected from hydrogen and C1-C6-alkyl) The present invention provides compounds of or pharmaceutically acceptable salts thereof.

[0033] In a further embodiment, the present invention is A 1 , X 1 and X 2 However, each is independently selected from N and CH; A 2 However, O and CR 5 R 6 Selected from; R 1 However, these are selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 However, C6-C 10 -Aryl and C3-C 10 - Selected from cycloalkyl, the C6-C 10 -Aryl and C3-C 10 - The cycloalkyl group is optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6-alkyl groups, and halo-C1-C6-alkyl groups; R 3 However, the 5-6 member heteroaryl and 3-6 member heterocyclil are selected from the halogen, cyano, amino, hydroxy, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and C3-C 10 -Optionally substituted with 1 to 3 substituents independently selected from cycloalkyl and 3- to 6-membered heterocyclyl groups; R 4 However, it is selected from hydrogen and C1-C6-alkyl; R 5 and R 6 However, each is independently selected from hydrogen and halogen; and R 7 However, selected from hydrogen and C1-C6-alkyl, This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0034] In a further embodiment, the present invention relates to a compound of formula (I) of formula (Ia): [ka] (In the formula, A 1 , X 1 and X 2 Each is independently selected from N and CH; A 2O and CR 5 R 6 Selected from; R 1 These are selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 C6-C 10 -Aryl and C3-C 10 - Selected from cycloalkyl, the C6-C 10 -Aryl and C3-C 10 - The cycloalkyl group is optionally substituted with 1 to 3 substituents independently selected from halogens, C1-C6-alkyl groups, and halo-C1-C6-alkyl groups; R 3 These are C1-C6-alkyl, C1-C6-alkoxy, and C3-C 10 -A 5-6 member heteroaryl that is optionally substituted with 1-3 substituents independently selected from the cycloalkyl group; R 4 is selected from hydrogen and C1-C6-alkyl; and R 5 and R 6 (Each is independently selected from hydrogen and halogen.) This specification provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0035] In one embodiment, the present invention is (i)X 1 and X 2 However, both are CH; or (ii)X 1 CH is, X 2 Is N; or (iii)X 1 N is X 2 CH is This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0036] In one embodiment, the present invention is (i)X 1 CH is, X2 is N; or (ii) X 1 is N and X 2 is CH, The present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0037] In one embodiment, the present invention relates to X 1 being CH and X 2 being N, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0038] In one embodiment, the present invention relates to X 1 being N and X 2 being CH, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0039] In a preferred embodiment, the present invention relates to X 1 and X 2 both being CH, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0040] In one embodiment, the present invention relates to A 1 being CH, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0041] In one embodiment, the present invention relates to A 1 being N, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the present invention relates to A 2 being selected from O and CR 5 R[[ID=​​​​​​​​​​​​​ Provided is a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, the present invention is A 2 is selected from O and CR 5 R 6 ; and R 5 and R 6 are both hydrogen, or R 5 and R 6 are both fluoro Provided is a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0044] In a preferred embodiment, the present invention is a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein A 2 is O.

[0045] In a preferred embodiment, the present invention is A 2 is CR 5 R 6 ; R 5 and R 6 are both hydrogen, or [[ID=5​​​​​​​​​​​​​​​​​​​​​

[0047] In one embodiment, the present invention relates to a compound of formula (I) of formula (II): [ka] (In the formula, the variables are as defined herein.) This specification provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, the present invention relates to a compound of formula (I) of formula (III): [ka] (In the formula, the variables are as defined herein.) This specification provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0049] In one embodiment, the present invention is R 1 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein is a C1-C6 alkyl group.

[0050] In one embodiment, the present invention is R 1 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein the compound is methyl.

[0051] In a particularly preferred embodiment, the present invention is R 1 This specification provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein is selected from methyl and CHF2.

[0052] In one embodiment, the present invention is R 2 However, C6-C 10 -Aryl, C3-C 10 -Selected from cycloalkyl and 5-6 membered heteroaryls containing 1-2 heteroatoms independently selected from N, O, and S, the C6-C10 -Aryl, C3-C 10 The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein a cycloalkyl and a 5-6 membered heteroaryl are optionally substituted with 1-3 substituents independently selected from halogens and halo-C1-C6-alkyl groups.

[0053] In one embodiment, the present invention is R 2 The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, selected from phenyl, pyridyl, cyclohexyl, bicyclo[3.1.0]hexane, and bicyclo[1.1.1]pentane, wherein the phenyl, cyclohexyl, bicyclo[3.1.0]hexane, and bicyclo[1.1.1]pentane are optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro, CHF2, and CF3.

[0054] In a preferred embodiment, the present invention is R 2 However, C6-C 10 -Aryl and C3-C 10 - Selected from cycloalkyl, the C6-C 10 -Aryl and C3-C 10 The following provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein the cycloalkyl group is substituted with 1 to 3 substituents independently selected from halogens and halo-C1-C6-alkyl groups.

[0055] In a particularly preferred embodiment, the present invention is R 2 The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane, substituted with 1 to 3 substituents independently selected from fluoro, chloro, and CHF2.

[0056] In a further particularly preferred embodiment, the present invention is R 2The following compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, are provided, selected from the following: [Table 1]

[0057] In one embodiment, the present invention is R 2 The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane, wherein the phenyl, cyclohexyl, and bicyclo[1.1.1]pentane are optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro, CHF2, and CF3.

[0058] In a preferred embodiment, the present invention is R 2 The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, which are phenyls substituted with 1 to 3 halogen substituents.

[0059] In a preferred embodiment, the present invention is R 2 The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, which are phenyl substituted with 1 to 3 substituents selected from fluoro and chloro.

[0060] In a particularly preferred embodiment, the present invention is R 2 The following compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, are provided, selected from the following: [Table 2]

[0061] In a particularly preferred embodiment, the present invention is R 2 but [ka] This specification provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0062] In one embodiment, the present invention is R 3 However, the 5-6 member heteroaryl is selected from a 5-6 member heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, and a 3-6 member heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, wherein the 5-6 member heteroaryl is C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, Halo-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -Cycloalkyl-C1-C6-alkoxy, C3-C 10 -Cycloalkyloxy, 3-6 member heterocyclyl, 3-6 member heterocyclyl-C1-C6-alkyl, and 3-6 member heterocyclyl-C1-C6-alkoxy are optionally substituted with 1-2 substituents independently selected from these, wherein the 3-6 member heterocyclyl is C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, Halo-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -Cycloalkyl-C1-C6-alkoxy, C3-C 10 The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, which are optionally substituted with one or two substituents independently selected from cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C1-C6-alkyl, 3-6 membered heterocyclyl-C1-C6-alkoxy, and oxo.

[0063] In one embodiment, the present invention is R 3The selected element is chosen from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, where the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are independently selected from methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, and oxetanylmethoxy. The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein the 1,2-dihydropyridine is optionally substituted with one or two substituents, wherein the 1,2-dihydropyridine is optionally substituted with one or two substituents independently selected from methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, oxetanylmethoxy, and oxo.

[0064] In a preferred embodiment, the present invention is R 3 However, the selection is made from a 5-6 membered heteroaryl having 1-3 heteroatoms independently selected from N, O, and S, with the remaining atoms being carbon, and a 3-6 membered heterocyclyl having 1-2 heteroatoms independently selected from N, O, and S, with the remaining atoms being carbon, wherein the 5-6 membered heteroaryl is C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 - Substituted with one substituent selected from cycloalkyl and 3- to 6-membered heterocyclyl, wherein the 3- to 6-membered heterocyclyl is oxo, and optionally C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C 10 - Provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, which are substituted with one further substituent selected from cycloalkyl groups.

[0065] In a particularly preferred embodiment, the present invention is R 3 The present invention provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are substituted with one substituent selected from methyl, methoxy, cyclopropyl, and oxetanyl, and the 1,2-dihydropyridine is substituted with oxo and optionally one further substituent selected from methyl, isopropyl, 2,2,2-trifluoroethyl, and cyclopropyl.

[0066] In a further particularly preferred embodiment, the present invention is R 3 The following compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, are provided, selected from the following: [Table 3]

[0067] In one embodiment, the present invention is R 3 The present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein is selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally substituted with one or two substituents independently selected from methyl, CF3, methoxy, cyclopropyl, and oxetanyl, and the 1,2-dihydropyridine is optionally substituted with one or two substituents independently selected from methyl, CF3, methoxy, cyclopropyl, oxetanyl, and oxo.

[0068] In one embodiment, the present invention is R 3is selected from pyridyl and pyrazolyl, and the pyridyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof is provided.

[0069] In a preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the following. [Table 4]

[0070] In a preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the following. [Table 5]

[0071] In a preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen and methyl.

[0072] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

[0073] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.

[0074] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen and methyl.

[0075] In a preferred embodiment, the present invention is R 7 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein is a C1-C6 alkyl group.

[0076] In a particularly preferred embodiment, the present invention is R 7 This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, wherein the compound is methyl.

[0077] In one embodiment, the present invention is (i)X 1 and X 2 However, both are CH; or (ii)X 1 CH is, X 2 Is N; or (iii)X 1 N is X 2 CH is; A 1 However, it is selected from N and CH; A 2 However, O and CR 5 R 6 Selected from; R 1 However, these are selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 However, C6-C 10 -Aryl, C3-C 10 -Selected from cycloalkyl and 5-6 membered heteroaryls containing 1-2 heteroatoms independently selected from N, O, and S, the C6-C 10 -Aryl, C3-C 10 -Cycloalkyl and 5-6 membered heteroaryl groups are optionally substituted with 1-3 substituents independently selected from halogens and halo-C1-C6-alkyl groups; R 3However, the 5-6 member heteroaryl is selected from a 5-6 member heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, and a 3-6 member heterocyclyl containing 1-2 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, wherein the 5-6 member heteroaryl is C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, Halo-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -Cycloalkyl-C1-C6-alkoxy, C3-C 10 - The substituent is optionally substituted with one or two substituents independently selected from cycloalkyloxy, 3-6 member heterocyclyl, 3-6 member heterocyclyl-C1-C6-alkyl, and 3-6 member heterocyclyl-C1-C6-alkoxy, wherein the 3-6 member heterocyclyl is C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, Halo-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -Cycloalkyl-C1-C6-alkoxy, C3-C 10 -Optionally substituted with one or two substituents independently selected from cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C1-C6-alkyl, 3-6 membered heterocyclyl-C1-C6-alkoxy, and oxo; R 4 However, it is selected from hydrogen and C1-C6-alkyl; R 5 and R 6 However, both are hydrogen, or R 5 and R 6 However, both are halogens; and R 7However, selected from hydrogen and C1-C6-alkyl, This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0078] In one embodiment, the present invention is (i)X 1 and X 2 However, both are CH; or (ii)X 1 CH is, X 2 Is N; or (iii)X 1 N is X 2 CH is; A 1 However, it is selected from N and CH; A 2 However, O and CR 5 R 6 Selected from; R 1 However, it is selected from methyl and CHF2; R 2 The substituents are selected from phenyl, pyridyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane, wherein the phenyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane are optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro, CHF2 and CF3; R 3However, the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl and 1,2-dihydropyridine are selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl, and the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl are methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl and The 1,2-dihydropyridine is optionally substituted with one or two substituents independently selected from methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, oxetanylmethoxy, and oxo; R 4 However, hydrogen and methyl are selected; R 5 and R 6 However, both are hydrogen, or R 5 and R 6 However, both are fluoro; and R 7 However, selected from hydrogen and methyl, This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0079] In a preferred embodiment, the present invention is (i)X 1 CH is, X 2 Is N; or (ii)X 1 N is X 2 CH is; A 1 However, it is CH; A 2 However, O is; R 1 is selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 is selected from C6-C 10 -aryl and C3-C 10 -cycloalkyl, said C6-C 10 -aryl and C3-C 10 -cycloalkyl being substituted with 1 to 3 substituents independently selected from halogen and halo-C1-C6-alkyl; R 3 is selected from 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O and S and the remaining atoms being carbon, and 3- to 6-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O and S and the remaining atoms being carbon, said 5- to 6-membered heteroaryl being substituted with 1 substituent selected from C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -cycloalkyl, and 3- to 6-membered heterocyclyl, said 3- to 6-membered heterocyclyl being substituted with 1 further substituent selected from oxo and optionally C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C 10 -cycloalkyl; R 4 is hydrogen; and R 7 is C1-C6-alkyl, There is provided a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0080] In a particularly preferred embodiment, the present invention relates to (i) X 1 is CH and X 2 is N; or (ii) X 1 is N and X 2 is CH; A 1 is CH; A 2 is O; R1 However, it is selected from methyl and CHF2; R 2 However, these are selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane substituted with 1 to 3 substituents independently selected from fluoro, chloro, and CHF2; R 3 The substituents are selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are substituted with one substituent selected from methyl, methoxy, cyclopropyl, and oxetanyl, and the 1,2-dihydropyridine is substituted with oxo and optionally one further substituent selected from methyl, isopropyl, 2,2,2-trifluoroethyl, and cyclopropyl; R 4 However, it is hydrogen; and R 7 However, it is methyl. This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0081] In one embodiment, the present invention is (i)X 1 and X 2 However, both are CH; or (ii)X 1 CH is, X 2 Is N; or (iii)X 1 N is X 2 CH is; A 1 However, it is selected from N and CH; A 2 However, O and CR 5 R 6 Selected from; R 1 However, it is a C1-C6 alkyl group; R 2However, selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane, the phenyl, cyclohexyl, and bicyclo[1.1.1]pentane are optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro, CHF2, and CF3; R 3 The compounds are selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally substituted with one or two substituents independently selected from methyl, CF3, methoxy, cyclopropyl, and oxetanyl, and the 1,2-dihydropyridine is optionally substituted with one or two substituents independently selected from methyl, CF3, methoxy, cyclopropyl, oxetanyl, and oxo; R 4 However, it is selected from hydrogen and C1-C6-alkyl; R 5 and R 6 However, both are hydrogen, or R 5 and R 6 However, both are halogens; and R 7 However, selected from hydrogen and C1-C6-alkyl, This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0082] In a preferred embodiment, the present invention is (i)X 1 and X 2 However, both are CH; or (ii)X 1 CH is, X 2 Is N; or (iii)X 1 N is X 2 CH is; A 1 However, it is selected from N and CH; A 2 However, O and CR5 R 6 Selected from; R 1 However, it is a C1-C6 alkyl group; R 2 However, it is a phenyl compound substituted with 1 to 3 halogen substituents; R 3 However, selected from pyridyl and pyrazolyl, the pyridyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl; R 4 However, hydrogen and methyl are selected; R 5 and R 6 However, both are hydrogen, or R 5 and R 6 However, both are halogens; and R 7 However, it is C1-C6-alkyl. This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0083] In a particularly preferred embodiment, the present invention is A 1 , X 1 and X 2 However, they are all CH; A 2 However, O is; R 1 However, it is methyl; R 2 However, it is a phenyl compound substituted with 1 to 3 substituents selected from fluoro and chloro compounds; R 3 However, selected from pyridyl and pyrazolyl, the pyridyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl; R 4 However, it is hydrogen; and R 7 However, it is methyl. This specification provides compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof.

[0084] In one embodiment, the present invention is (i)X 1 and X 2 However, both are CH; or (ii)X 1 CH is, X 2 Is N; or (iii)X 1 N is X 2 CH is; A 1 However, it is selected from N and CH; A 2 However, O and CR 5 R 6 Selected from; R 1 However, it is a C1-C6 alkyl group; R 2 However, selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane, the phenyl, cyclohexyl, and bicyclo[1.1.1]pentane are optionally substituted with 1 to 3 substituents independently selected from fluoro, chloro, CHF2, and CF3; R 3 However, selected from pyridyl and pyrazolyl, the pyridyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl; R 4 but selected from hydrogen and C1-C6-alkyl; and R 5 and R 6 However, both are hydrogen, or R 5 and R 6 However, both are halogens. This specification provides compounds of formula (Ia) as described herein, or pharmaceutically acceptable salts thereof.

[0085] In a preferred embodiment, the present invention is (i)X 1 and X 2 However, both are CH; or (ii)X1 CH is, X 2 Is N; or (iii)X 1 N is X 2 CH is; A 1 However, it is selected from N and CH; A 2 However, O and CR 5 R 6 Selected from; R 1 However, it is a C1-C6 alkyl group; R 2 However, it is a phenyl compound substituted with 1 to 3 halogen substituents; R 3 However, selected from pyridyl and pyrazolyl, the pyridyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl; R 4 but selected from hydrogen and methyl; and R 5 and R 6 However, both are hydrogen, or R 5 and R 6 However, both are halogens. This specification provides compounds of formula (Ia) as described herein, or pharmaceutically acceptable salts thereof.

[0086] In a particularly preferred embodiment, the present invention is A 1 , X 1 and X 2 However, they are all CH; A 2 However, O is; R 1 However, it is methyl; R 2 However, it is a phenyl compound substituted with 1 to 3 substituents selected from fluoro and chloro compounds; R 3However, selected from pyridyl and pyrazolyl, wherein the pyridyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl; and R 4 However, it is hydrogen. This specification provides compounds of formula (Ia) as described herein, or pharmaceutically acceptable salts thereof.

[0087] In one embodiment, the present invention relates to a compound of formula (I) that 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(3S)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridine-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methylpyridine-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methylpyridine-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-onformeate; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxypyridine-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxypyridine-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methyl-6-oxopyridine-3-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[rac-(2R,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[rac-(2R,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyltetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyltetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazine-4-one; 7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(difluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(difluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclobutylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclobutylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclobutylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclobutylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]-9-[6-(trifluoromethyl)pyridine-3-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(2-methoxyethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(2-methoxyethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazine-4-one; 7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[rac-(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(2-fluorophenyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[rac-(2R,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 2,3-dimethyl-7-[rac-(2R,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1,5-dimethylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1,5-dimethylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1,3-dimethylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1,3-dimethylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 7-[(2S,4R)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[2-(cyclobutoxy)-4-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-[2-(oxetan-3-ylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[(1R,5S)-6,6-difluoro-3-bicyclo[3.1.0]hexanyl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[6-keto-1-(trifluoromethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; and 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one The present specification provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, selected from the above.

[0088] In one embodiment, the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(3S)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridine-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methylpyridine-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methylpyridine-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-onformeate; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxypyridine-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxypyridine-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methyl-6-oxopyridine-3-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; and 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one The present specification provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, selected from the above.

[0089] In a preferred embodiment, the present invention relates to a compound of formula (I) and 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; and 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one The present specification provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, selected from the above.

[0090] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0091] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one.

[0092] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0093] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one.

[0094] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one.

[0095] In particularly preferred embodiments, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one.

[0096] In particularly preferred embodiments, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazin-4-one.

[0097] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0098] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one.

[0099] In particularly preferred embodiments, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one.

[0100] In particularly preferred embodiments, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0101] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0102] In particularly preferred embodiments, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one.

[0103] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0104] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one.

[0105] In particularly preferred embodiments, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one.

[0106] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one.

[0107] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0108] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, wherein the compound of formula (I) is 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one.

[0109] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0110] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0111] In particularly preferred embodiments, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one.

[0112] 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 or free acids.

[0113] In some embodiments, compounds of formula (I) are isotope-labeled by replacing one or more atoms 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, 14C is particularly useful for this purpose, given its ease of incorporation and simple detection methods. For example, the compound of formula (I) can be concentrated at 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0114] Heavier isotopes, such as deuterium, 2 Substitution with H, for example, can increase metabolic stability, leading to a longer in vivo half-life or a reduction in the required dosage, potentially resulting in specific therapeutic benefits. Therefore, deuterated versions of the compounds disclosed herein should be understood to fall within the scope of the present invention.

[0115] 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 the receptor occupancy of a substrate. Compounds of formula (I) with isotope labeling can generally be prepared by conventional techniques known to those skilled in the art, or by using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent, in a process similar to those described in the examples below.

[0116] Manufacturing process The compounds of formula (I) of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The techniques required to react and purify the obtained products are known to those skilled in the art. Substituents and indicators used in the following process description have the meaning given herein unless otherwise indicated.

[0117] 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 (such as those described in "Protective Groups in Organic Chemistry," TW Greene and PGMWutts, 5th edition (2014), John Wiley & Sons, New York) 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.

[0118] 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), typically the respective diastereomerically / enantiomerically enriched compound of formula (I) is obtained.

[0119] Those skilled in the art will recognize that, in the synthesis of compounds of formula (I) (unless another method is desired), the “orthogonal protection group strategy” can be applied to cleave several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and is also described in the literature (e.g., Barany and RBMerrifield, J.Am.Chem.Soc. (1977), Vol. 99, p. 7363; H.Waldmann et al., Angew.Chem.Int.Ed.Engl. (1996), Vol. 35, p. 2056).

[0120] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and properties of the intermediates.

[0121] 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 was favorable with or without a solvent. There are no particular restrictions on the properties of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and can dissolve the reagents to at least some extent. The described reaction can occur over a wide range of temperatures, and the exact reaction temperature is not important to the present invention. It is favorable to carry out the described reaction 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 produce 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.

[0122] If the starting materials or intermediates are not commercially available, or if their synthesis is not documented in the literature, they may be prepared in the same manner as existing procedures for similar analogs, or as outlined in the experimental section.

[0123] The following abbreviations are used in this specification: Celsius (℃) 1 H Proton Å Angstrom Alk (Alkyl) c concentration CAS Chemical Abstracts Service Registration 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 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 MPLC (Medium Pressure Liquid Chromatography) MS mass spectrometry Sodium sulfite (Na2SO3) Sodium sulfate (Na2SO4) NaHCO3 (sodium bicarbonate) neg. NH4Cl (Ammonium Chloride) nm (nanometer) NMR nuclear magnetic resonance spectroscopy pH (hydrogen ion concentration) pos. positive psi (pounds per square inch) Rectus using the R Cahn-Ingold-Prelog priority rules RP inverse phase RPM (revolutions per minute) s seconds Sinister by Cahn-Ingold-Prelog priority rules SFC Supercritical Fluid Chromatography 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 (parts per million)

[0124] Scheme 1 [ka] Compounds of general formulas Ia and Ib can be prepared by first reacting intermediate II with a boronic acid (or boronic acid derivative) III under palladium-catalyzed 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 can then be reacted with amine V in a dipolar aproton solvent such as dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone, in the presence of a base such as N,N-diisopropylethylamine or triethylamine, to form Ia (nucleophilic substitution). Furthermore, compound IV can be reacted with amine V to form compound Ia under palladium-catalyzed coupling conditions (using a palladium source such as tris(dibenzylideneacetone)dipalladium(0), a suitable ligand such as xanthophos, and a base such as cesium carbonate or sodium tert.-butoxide) (metal-catalyzed coupling). For the synthesis of the C-bonded derivative Ib, intermediate IV can be reacted directly with organozinc reagent VI under palladium-catalyzed conditions, or intermediate VIII can be formed by first reacting it with boronic acid derivative VII using a palladium catalyst and a base, and then reducing this intermediate with suitable agents such as hydrogen and a catalyst to form compound Ib. Preferred catalysts are carbon-supported palladium (palladium on charcoal) or platinum oxide in ethyl acetate, ethanol, or methanol, with or without the addition of further reagents such as magnesium oxide or triethylamine.

[0125] Scheme 2 [ka] Compounds of general formula II can be prepared, as described in scheme 2, by reacting heterocyclic compound IX with ketoester X at high temperature in the presence of an acid such as polyphosphate or a Lewis acid such as bismuth trichloride.

[0126] Scheme 3 [ka] Furthermore, the compound of general formula IV is converted to heterocyclic compound IX under palladium-catalyzed coupling conditions as described in Scheme 3, using 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 with a boronic acid (or a boronic acid derivative, R 2 Compound XI can be prepared by first reacting compound III (which is preferably aromatic or heteroaromatic) with compound XI. This intermediate can then be reacted with ketoester X at high temperature in the presence of an acid such as polyphosphate or a Lewis acid such as bismuth trichloride to form compound IV.

[0127] Scheme 4 [ka] Furthermore, compounds of general formula Ib can be prepared by first reacting intermediate IV with bis(pinacolato)diborone under palladium-catalyzed conditions (using 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 XII, as described in Scheme 4. This intermediate can be reacted with triflate XIII using a palladium catalyst and a base to form intermediate VIII, which can then be reduced to form compound Ib by treatment with hydrogen and a suitable agent such as a catalyst.

[0128] Scheme 5 [ka] Furthermore, the general formula IVa(R 2 Compounds (preferably alicyclic) can be prepared by first reacting heterocyclic compound XIV with carboxylic acid XV under oxidative coupling conditions (e.g., a Minisci reaction using ammonium persulfate in dimethyl sulfoxide at a temperature of 0°C to 50°C) to form compound XIa, as described in Scheme 5. This intermediate can then be reacted with ketoester X at high temperature in the presence of an acid such as polyphosphate or a Lewis acid such as bismuth trichloride to form compound IVa.

[0129] Scheme 6 [ka] Furthermore, compounds of general formula Ib can be prepared as described in Scheme 6. Intermediate XII is first reacted with triflate XVI under palladium-catalyzed 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 XVII. Similarly, intermediate IV can also be reacted with borate ester derivative XVIII under palladium-catalyzed 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 XVII. In the next step, this intermediate is reduced by treatment with hydrogen and appropriate agents such as a catalyst to form compound XIX. Next, the ester functional group is obtained by various heterocyclic residues R through multi-step reactions, which are known to those skilled in the art and have been published in various literature reviews such as J.Chem.Rev.,2022,4(3),255-271. 3 It can be converted to [this].

[0130] Scheme 7 [ka] Furthermore, compounds of general formula Ib can be prepared as described in Scheme 7 by late-stage modifications of compound XX. Such conversions of residue R3' to residue R3 include removal of protecting groups, halogen-carbon exchange reactions (e.g., bromine to methyl), or alkylation reactions (e.g., NH-pyrazole or NH-pyridone), and can be carried out according to known conditions for the relevant compounds published in the literature.

[0131] In one embodiment, the present invention provides a process for producing a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, the process being described in any one of schemes 1 to 7.

[0132] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when produced according to any one of the processes described herein.

[0133] TREM2 agonist activity The compounds of the present invention are TREM2 agonists. Accordingly, in one embodiment, the present invention provides the use of the compounds of formula (I) described herein for restoring the function of human TREM2 in subjects requiring such restoration.

[0134] In a further embodiment, the present invention provides compounds of formula (I) described herein for use in a method for restoring the function of human TREM2 in subjects requiring such restoration.

[0135] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein for the preparation of a pharmaceutical for restoring the function of human TREM2 in a subject that requires such restoration.

[0136] In a further embodiment, the present invention provides a method for restoring the function of human TREM2 in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) described herein to the subject.

[0137] 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, Syk kinase is recruited and activated by DAP12. The increased levels of phosphorylated Syk obtained were measured in lysed cells using a commercially available AlphaLisa reagent kit.

[0138] To perform the assay, frozen HEK293-TREM2 / DAP12 cells were thawed, prepared, and plated in 10 μL of DMEM medium supplemented with 5% FBS and without Phenolred, in 384-well plates at a rate of 20,000 cells per well using Certus.

[0139] The dose-response (1:3) compound was diluted with DMSO (maximum concentration 10 mM) and then diluted 500-fold (20 nL in 10 μl cell suspension; maximum concentration 20 μM in all wells, DMSO concentration 0.2%) using ECHO (0-20 μM) and added to cells from a low-dead-volume plate. Neutral (DMSO) and stimulant (1 μM tool compound) controls were also added.

[0140] 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 at room temperature in the dark for 30 minutes. After complete lysis, AlphaLisa reagent was added to the lysate using Certus, and fluorescence intensity was measured using a Pherastar plate reader (excitation: 680 nm / emission: 615 nm). EC 50The values ​​were calculated using Geneda Screener and normalized to 100% activity for DMSO and the tool compound.

[0141] 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 6] TIFF2026521750000022.tif254170 TIFF2026521750000023.tif249170

[0142] 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.

[0143] In a further embodiment, the present invention provides a method for treating or preventing symptoms associated with loss of function of human TREM2 in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, to the subject.

[0144] In a further embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in a method of treating or preventing symptoms associated with loss of function of human TREM2 in a subject that requires such treatment.

[0145] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in a method for treating or preventing symptoms associated with loss of function of human TREM2 in a subject that requires such treatment.

[0146] 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 pharmaceutically acceptable compound for use in a method of treating or preventing symptoms associated with loss of function of human TREM2 in a subject in need thereof.

[0147] In one embodiment, the symptoms associated with the 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.

[0148] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is Parkinson's disease.

[0149] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is rheumatoid arthritis.

[0150] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is Alzheimer's disease.

[0151] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is amyotrophic lateral sclerosis (ALS).

[0152] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is Nasu-Hakola disease.

[0153] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is frontotemporal dementia.

[0154] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is multiple sclerosis.

[0155] In a preferred embodiment, the symptoms associated with the loss of function of human TREM2 are prion diseases.

[0156] In a preferred embodiment, the symptom associated with the loss of function of the human TREM2 is stroke.

[0157] 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.

[0158] In one embodiment, a pharmaceutical composition according to Example 288 or 289 is provided.

[0159] Compounds of formula (I) and their pharmaceutically acceptable salts may be used as medicines (e.g., in the form of pharmaceutical formulations). Pharmaceutical formulations may be administered into the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may also be parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0160] Compounds of formula (I) and pharmaceutically acceptable salts thereof can be treated with pharmaceutically inert inorganic or organic adjuvants for the manufacture of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid, or salts thereof can be used, for example, as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules.

[0161] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0162] Suitable adjuvants for the production of solutions and syrups include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0163] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0164] Suitable adjuvants for suppositories include, for example, natural or hydrogenated oils, waxes, fats, and semi-solid or liquid polyols.

[0165] Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances of therapeutic value.

[0166] Dosage can vary widely and, naturally, be adapted to the individual requirements of each specific case. Generally, for oral administration, a daily dose of approximately 0.1 mg to 20 mg / kg body weight, preferably approximately 0.5 mg to 4 mg / kg body weight (e.g., approximately 300 mg / person), may be appropriately divided into 1 to 3 individual doses, each consisting of, for example, the same amount. However, it is clear that the upper limits given herein can be exceeded where indicated. [Examples]

[0167] 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.

[0168] 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.

[0169] The compounds of formula I may contain several chiral centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, or mixtures of diastereoisomers. According to the Cahn-Ingold-Prelog rule, the chiral carbon atom may have an "R" or "S" stereoconfiguration. Absolute stereochemistry has been arbitrarily assigned to the compounds described in this patent.

[0170] Unless otherwise specified, all reaction examples and intermediates were prepared under an argon atmosphere.

[0171] The compounds disclosed and described herein are named using the IUPAC naming function of Biovia Draw 22.1. In the event of any discrepancy between a depicted structure and the name assigned to that structure, the depicted structure shall prevail.

[0172] The following intermediates can be prepared by following the procedures provided herein, are commercially available, or can be prepared by following the procedures in the literature.

[0173] Intermediate A1: 7-bromo-9-iodo-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one [ka] A mixture of 5-bromo-3-iodopyridine-2-amine (CAS 381233-96-1, 2.0 g, 6.69 mmol), ethyl 2-methyl acetacetate (CAS 609-14-3, 965 mg, 0.97 ml, 6.69 mmol), and polyphosphate (1.0 g, 6.69 mmol) was stirred at 120°C for 90 minutes. The reaction mixture was taken to water, basicized with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain the title compound (1.07 g, yield 40%) as a grayish-white solid, MS m / z: 378.8 [M+H]. + ,ESI pos.

[0174] Intermediate A2: 9-bromo-7-chloro-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared using 3-bromo-5-chloropyrazine-2-amine (CAS 76537-18-3) instead of 5-bromo-3-iodopyridine-2-amine, similar to the preparation of intermediate A1. Yellow solid, MS m / z: 290.0 [M+H] + ,ESI pos.

[0175] Intermediate A3: 7-bromo-2-(difluoromethyl)-9-iodo-3-methylpyrido[1,2-a]pyrimidine-4-one [ka] Polyphosphate (31.8 g, 132 mmol) was added to a mixture of ethyl 4,4-difluoro-2-methyl-3-oxo-butanoate (5.3 g, 26.5 mmol) and 2-amino-5-bromo-3-iodopyridine (3.17 g, 10.6 mmol, 0.4 equivalents). After stirring at 120°C for 1.5 hours, the mixture was cooled to room temperature, quenched with saturated NaHCO3 aqueous solution (300 ml), and extracted with ethyl acetate (2 × 250 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum. The crude product was purified by flash chromatography (silica gel, chloroform with 0-50% acetonitrile) to obtain 7-bromo-2-(difluoromethyl)-9-iodo-3-methylpyrido[1,2-a]pyrimidine-4-one (0.34 g, yield 3%). MS m / z:414.8 [M+H] + ,ESI pos.

[0176] Intermediate A4: 9-bromo-7-chloro-2-methylpyrido[1,2-a]pyrimidine-4-one [ka] Similar to intermediate A1, the title compound was prepared using 3-bromo-5-chloropyridine-2-amine instead of 5-bromo-3-iodopyridine-2-amine and ethyl 3-ketobutyrate (CAS 141-97-9) instead of ethyl 2-methylacetate. Yellow solid, MS m / z: 273.0 [M+H] + ,ESI pos.

[0177] Intermediate B1: 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one [ka] To a solution of 7-bromo-9-iodo-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one (intermediate A1, 260 mg, 0.68 mmol) in dioxane (7 ml), (4-chloro-2-fluorophenyl)boronic acid (179 mg, 1.03 mmol) and 2 M aqueous cesium carbonate solution (1.03 ml, 2.06 mmol) were added at room temperature. After degassing the mixture with argon, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (56 mg, 0.069 mmol, 0.100 equivalents) was added. The mixture was stirred overnight at 60°C, then diluted with water and extracted twice with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (on silica, 0-50% ethyl acetate in heptane) to obtain the title compound (221 mg, 81% yield) as a white solid. MS m / z: 383.0 [M+H] + ,ESI pos.

[0178] Intermediate B2: 7-Chloro-9-(4-Chloro-2-fluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of 9-bromo-7-chloro-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (intermediate A2, 290 mg, 1.01 mmol) in 1,4-dioxane (6 ml), (4-chloro-2-fluorophenyl)boronic acid (263 mg, 1.51 mmol) and aqueous cesium carbonate (1.51 ml, 3.02 mmol) were added at room temperature. After degassing the mixture with argon, 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (82 mg, 0.10 mmol, 0.10 equivalents) was added. The mixture was stirred at 60°C for 3 hours, then 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, 0-100% ethyl acetate), and the resulting substance was polished with methyl tert-butyl ether to obtain the title compound (177 mg, yield 49%) as a yellow solid. MS m / z: 338.0 [M+H] + ,ESI pos.

[0179] Intermediate B3: 7-Chloro-9-(4-Chloro-2-fluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] Step 1: 6-Chloro-4-(4-Chloro-2-fluorophenyl)pyridazine-3-amine [ka] To a solution of 4-bromo-6-chloropyridazine-3-amine (CAS 446273-59-2, 1.00 g, 4.8 mmol) in 1,4-dioxane (20 ml), (4-chloro-2-fluorophenyl)boronic acid (836 mg, 4.8 mmol) and cesium carbonate (4.69 g, 14.4 mmol) were added. The mixture was degassed with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (392 mg, 0.48 mmol, 0.10 equivalents) was added. The reaction mixture was stirred at room temperature for 2 hours. The 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 flash chromatography (silica gel, dichloromethane / methanol 0-10%), yielding 6-chloro-4-(4-chloro-2-fluorophenyl)pyridazine-3-amine as a dark brown solid (852 mg, yield 69%). MS m / z: 258.0 [M+H] + ,ESI pos.

[0180] Step 2: 7-Chloro-9-(4-Chloro-2-fluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] To a suspension of 6-chloro-4-(4-chloro-2-fluorophenyl)pyridazine-3-amine (100 mg, 0.388 mmol) in ethyl 2-methyl acetate (559 mg, 564 μl, 3.87 mmol), bismuth trichloride (12 mg, 0.038 μmol, 0.10 equivalents) was added at room temperature, and the mixture was stirred at 120°C for 16 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, 0-50% ethyl acetate) to obtain the title compound as a pale yellow solid (62 mg, yield 43%), MS m / z: 338.1 [M+H]. +,ESI pos.

[0181] Intermediate B4: 7-bromo-9-(4-chlorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one [ka] The title compound was prepared using (4-chlorophenyl)boronic acid instead of (4-chloro-2-fluorophenyl)boronic acid, similar to intermediate B1. White solid, MS m / z: 365.1 [M+H] + ,ESI pos.

[0182] Intermediate B5: 7-bromo-9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrido[1,2-a]pyrimidine-4-one [ka] Cesium carbonate (603 mg, 1.85 mmol) was added to a stirred solution of a mixture of 4-chloro-2-fluorophenylboronic acid (75 mg, 0.43 mmol) and 7-bromo-2-(difluoromethyl)-9-iodo-3-methylpyrido[1,2-a]pyrimidine-4-one (intermediate A3, 320 mg, 0.62 mmol) in 1,4-dioxane (17 ml) and water (1.7 ml). The mixture was degassed, argon was added, and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (50 mg, 0.06 mmol, 0.1 equivalent) was added. After stirring at 60°C for 18 hours, the mixture was evaporated under vacuum. The residue was diluted with water (100 ml) and extracted with ethyl acetate (2 × 100 ml). The combined organic layer was then filtered with anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by preparative HPLC (XBridge column 19 × 100 mm, 60% water-acetonitrile, 4 ml / min acetonitrile) to obtain the title compound (103 mg, 40% yield) as a light brown solid. MS m / z: 417.0 [M+H] +,ESI pos.

[0183] Intermediate B6: 7-Chloro-9-(4-Chloro-2,6-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] Step 1: 5-Chloro-3-(4-Chloro-2,6-difluorophenyl)pyrazine-2-amine [ka] In a glove box, (3-bromo-5-chloropyrazine-2-yl)amine (500 mg, 2.4 mmol) was dissolved in toluene (7.5 ml), to which (4-chloro-2,6-difluorophenyl)boronic acid (600 mg, 3.12 mmol) and diisopropylethylamine (930 mg, 7.2 mmol) were added. After degassing the mixture with argon, chloro(clotyl)(tri-tert-butylphosphine)palladium(II) (CAS 1334497-00-5, 48 mg, 0.12 mmol) was added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate, followed by five extractions with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. Purification of the crude substance by flash chromatography (C18, 10-100% acetonitrile in water) yielded 5-chloro-3-(4-chloro-2,6-difluorophenyl)pyrazine-2-amine as a yellow solid (193 mg, 29% yield). MS m / z: 276.0 [M+H] + ,ESI pos.

[0184] Step 2: 7-Chloro-9-(4-Chloro-2,6-difluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] 5-Chloro-3-(4-chloro-2,6-difluorophenyl)pyrazine-2-amine (170 mg, 0.616 mmol), ethyl 2-methyl acetate (888 mg, 897 μl, 6.16 mmol), and polyphosphate (85 mg) were mixed at room temperature and stirred at 120°C for 6 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated to dryness. The crude substance was purified by flash chromatography (silica gel, heptane, 0-50% ethyl acetate). The obtained substance was suspended in tert-butyl methyl ether, stirred for 5 minutes, and then filtered off. The solid was washed with tert-butyl methyl ether and then dried under vacuum to obtain the title compound (156 mg, yield 71%) as a yellow solid. MS m / z: 356.1 [M+H] + ,ESI pos.

[0185] Intermediate B7: 7-Chloro-9-(4-Chloro-2,6-difluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] Step 1: 6-Chloro-4-(4-Chloro-2,6-difluorophenyl)pyridazine-3-amine [ka] (4-bromo-6-chloropyridazine-3-yl)amine (491 mg, 2.36 mmol) was dissolved in t-amyl alcohol (7.5 ml), to which (4-chloro-2,6-difluorophenyl)boronic acid (680 mg, 3.53 mmol) and diisopropylethylamine (913 mg, 7.07 mmol) were added. The mixture was degassed with argon, and PdCl2(amphos) (CAS 887919-35-9, 250 mg, 0.15 mmol) was added. The mixture was stirred at 50°C for 2.5 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate, followed by five extractions with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. Purification of the crude substance by flash chromatography (C18, 10-70% acetonitrile in water) yielded 6-chloro-4-(4-chloro-2,6-difluorophenyl)pyridazine-3-amine as a light brown solid (214 mg, yield 33%). MS m / z: 276.1 [M+H] + ,ESI pos.

[0186] Step 2: 7-Chloro-9-(4-Chloro-2,6-difluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] A mixture of 6-chloro-4-(4-chloro-2,6-difluorophenyl)pyridazine-3-amine (210 mg, 0.76 mmol) and ethyl 2-methyl acetate (1.1 g, 1.11 ml, 7.61 mmol) was mixed with bismuth trichloride (24 mg, 0.076 mmol, 0.10 equivalents) at room temperature, and the mixture was stirred overnight at 120°C. The reaction mixture was diluted with saturated NaHCO3 solution and extracted twice with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude material was purified by flash chromatography (silica gel, heptane, 0-40% ethyl acetate) to obtain the title compound (152 mg, yield 55%) as a brown solid, MS m / z: 356.1 [M+H]. + ,ESI pos.

[0187] Intermediate B8: 7-Chloro-9-(4-Chloro-2-fluorophenyl)-2-methylpyrido[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate B1, using intermediate A4 instead of intermediate A1. White solid, MS m / z: 323.1 [M+H] + ,ESI pos.

[0188] Intermediate B9: 7-Chloro-9-(4-chlorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] Similar to intermediate B3, the title compound was prepared in step a) by using 3-bromo-5-chloropyrazine-2-amine instead of 4-bromo-6-chloropyridazine-3-amine and (4-chlorophenyl)boronic acid instead of (4-chloro-2-fluorophenyl)boronic acid. Yellow solid, MS m / z: 320.0 [M+H] + ,ESI pos.

[0189] Intermediate B10: 7-Chloro-9-(4-Chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrazino[1,2-a]pyrimidine-4-one [ka] Step 1: 5-Chloro-3-(4-Chloro-2-fluorophenyl)pyrazine-2-amine [ka] (3-bromo-5-chloropyrazine-2-yl)amine (2.5 g, 12.0 mmol) was dissolved in 1,4-dioxane (50 ml), to which (4-chloro-2-fluorophenyl)boronic acid (2.51 g, 14.4 mmol) and 3M cesium carbonate solution (12 ml, 36 mmol) were added at room temperature. The mixture was degassed with argon, and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (980 mg, 1.2 mmol, 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 Na2SO4, and concentrated to dryness. When the crude substance was polished with tert-butyl methyl ether, 5-chloro-3-(4-chloro-2-fluorophenyl)pyrazine-2-amine was obtained as a light brown solid (2.2 g, yield 64%, purity 90%), MS m / z: 258.1 [M+H]. + ,ESI pos.

[0190] Step 2: 7-Chloro-9-(4-Chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrazino[1,2-a]pyrimidine-4-one [ka] In a vial, 4,4-difluoro-3-keto-2-methylbutyrate ethyl ester (CAS 425394-84-9, 3.49 g, 19.4 mmol), polyphosphate (250 mg), and 5-chloro-3-(4-chloro-2-fluorophenyl)pyrazine-2-amine (500 mg, 1.94 mmol) were mixed. The vial was sealed and the reaction mixture was heated to 140°C overnight. Another portion of 4,4-difluoro-3-keto-2-methylbutyrate ethyl ester (3.49 g, 19.37 mmol) and polyphosphate (250 mg) was added. The reaction was sealed and stirred at 140°C for a further 6 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and volatile substances were evaporated. The residue was purified by flash column chromatography (silica, heptane, ethyl acetate 0-50%), yielding the title compound (197 mg, yield 26%) as a yellow solid. MS m / z: 374.2 [M+H] + ,ESI pos. 1 H NMR(300 MHz,DMSO-d6):δ=8.86(s,1H),7.77-7.70(m,1H),7.68(dd,J=2.0,10.1 Hz,1H),7.51(td,J=1.0,8.3 Hz,1H),7.30-6.82(m,1H),2.31(t,J=1.9 Hz,3H).

[0191] Intermediate B11: 7-Chloro-9-(4-Chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared using ethyl 4,4-difluoro-3-keto-2-methylbutyrate ethyl ester instead of ethyl 2-methylacetoacetate, similar to intermediate B3. It was a light brown solid, MS m / z: 374.0 [M+H]. + ,ESI pos.

[0192] Intermediate B12: 7-bromo-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one [ka] Step 1: 5-Bromo-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazine-2-amine [ka] To a solution of (5-bromopyrazine-2-yl)amine (300 mg, 1.72 mmol) in dimethyl sulfoxide / water (600 / 1), 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (3.11 g, 17.2 mmol) was added. The reaction mixture was degassed by bubbling with argon. A freshly prepared solution of ammonium persulfate (2.36 g, 10.3 mmol) in purged dimethyl sulfoxide / water (600 / 1) was added under argon, and the mixture was stirred at 40°C for 20 hours. The reaction mixture was quenched with a saturated solution of NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, heptane, ethyl acetate 0-35%) to obtain 5-bromo-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazine-2-amine (190 mg, yield 31%) as a yellow solid. MS m / z: 308.2 / 310.2 [M+H] + ,ESI pos.

[0193] Step 2: 7-Bromo-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one [ka] A mixture of 5-bromo-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazine-2-amine (170 mg, 0.55 mmol) and ethyl 2-methyl acetate (796 mg, 805 μl, 5.52 mmol) was mixed with bismuth trichloride (17 mg, 0.055 mmol, 0.10 equivalents) at room temperature, and the mixture was stirred at 100°C for 18 hours. The reaction mixture was diluted with saturated NaHCO3 solution and extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, dichloromethane with 0-10% methanol) to obtain the title compound (111 mg, yield 52%) as a pale yellow solid, MS m / z: 388.2 / 390.2 [M+H] + ,ESI pos.

[0194] Intermediate B13: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (intermediate B2, 1.5 g, 4.44 mmol) in 1,4-dioxane (27 ml), bis(pinacorato)diborone (1.35 g, 5.32 mmol), potassium acetate (1.31 g, 13.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (367 mg, 0.445 mmol, 0.10 equivalents) were added under argon. The reaction mixture was heated to 80°C and stirred for 20 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated and purified by flash chromatography (silica gel, heptane, ethyl acetate 0%-100%) to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazino[1,2-a]pyrimidine-4-one (1.8 g, yield 85%) as an orange oily substance.

[0195] Intermediate B14: 7-Chloro-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] Step 1: 6-Chloro-4-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyridazine-3-amine [ka] 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (7.5 g, 46.3 mmol) was added to a solution of 3-amino-6-chloropyridazine (600 mg, 4.63 mmol) in 9-dimethyl sulfoxide / water (600 / 1; 9 ml). The reaction mixture was degassed by bubbling nitrogen. A freshly prepared solution of ammonium persulfate (6.34 g, 27.79 mmol) in purged dimethyl sulfoxide / water (600 / 1) was added under nitrogen, and the mixture was stirred at 40°C for 20 hours. The reaction mixture was quenched with a saturated solution of NaHCO3 to adjust the pH to 8-9, and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was first purified by preparative HPLC (column: Phenomenex Luna C18 150×25mm×10μm, mobile phase: water + 0.25% formic acid / acetonitrile 10-15%, flow rate 25 ml / min) to obtain the crude product. This was further purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100:1-1:1) to obtain 6-chloro-4-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyridazine-3-amine (190 mg, yield 17%) as a pale yellow solid. MS m / z: 246.1 [M+H] + ,ESI pos.

[0196] Step 2: 7-Chloro-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] To a solution of 6-chloro-4-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyridazine-3-amine (190 mg, 0.77 mmol) in toluene (5 ml), ethyl 2-methyl acetate (556 mg, 3.87 mmol) and p-toluenesulfonic acid (27 mg, 0.15 mmol) were added, and the mixture was stirred at 110°C for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (150 ml), neutralized to pH=8 with saturated sodium bicarbonate aqueous solution, and then extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (silica, petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (200 mg, yield 79%) as a pale yellow solid. MS m / z: 326.1 [M+H] + ,ESI pos.

[0197] Intermediate B15: 7-bromo-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] Similar to intermediate B12, the title compound was prepared by using 4,4-difluorocyclohexanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1). Pale yellow solid, MS m / z: 372.1 / 374.1 [M+H] + ,ESI pos.

[0198] Intermediate B16: 7-Chloro-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one [ka] Similar to intermediate B14, the title compound was prepared by using 4,4-difluorocyclohexanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1). Yellow solid, MS m / z: 328.1 [M+H] + ,ESI pos.

[0199] Intermediate B17: 7-bromo-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] Similar to intermediate B12, the title compound was prepared by using 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1). Pale yellow solid, MS m / z: 370.1 [M+H] + ,ESI pos.

[0200] Intermediate B18: 7-Chloro-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one [ka] Similar to intermediate B14, the title compound was prepared by using 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1). It was a pale yellow solid, MS m / z: 344.1 [M+H]. + ,ESI pos.

[0201] Intermediate B19: 7-Chloro-2,3-dimethyl-9-[6-(trifluoromethyl)-3-pyridyl]pyrazino[1,2-a]pyrimidine-4-one [ka] Similar to intermediate B2, the title compound was prepared in step 1 using [6-(trifluoromethyl)-3-pyridyl]boronic acid instead of (2,4-difluorophenyl)boronic acid. Yellow solid, MS m / z: 355.1 [M+H] + ,ESI pos.

[0202] Intermediate B20: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as intermediate B13, using intermediate B6 instead of intermediate B2. Orange oily substance, MS m / z: 366.0 [M+H] + (Equivalent to boronic acid), ESI pos.

[0203] Intermediate B21: 7-Chloro-2,3-dimethyl-9-[rac-(1R,5S)-6,6-difluoro-3-bicyclo[3.1.0]hexanyl]pyrimido[1,2-b]pyridazin-4-one [ka] Similar to intermediate B14, the title compound was prepared by using 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid in step 1). Yellow oily substance, MS m / z: 326.0 [M+H] + ,ESI pos. [Table 7]

[0204] Chiral separation of intermediate C1: 2-(1-methylpyrazole-4-yl)morpholine (intermediate C1) was separated by chiral SFC (column AD-H, 5 μm, 100 × 4.6 mm, 20-40% MeOH + 0.2% diethylamine) to obtain (+)-2-(1-methylpyrazole-4-yl)morpholine(+)-C1 as the first eluted enantiomer and (-)-2-(1-methylpyrazole-4-yl)morpholine(-)-C1 as the second eluted enantiomer. (+)-2-(1-methylpyrazole-4-yl)morpholine: yellow oily substance, αD (589 nm) 20℃ = +13.36° (c = 0.1 g / l, MeOH).

[0205] Intermediate C8: 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, ethyl acetate 0-100%) 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.

[0206] 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, packed with argon three times, and then stirred at 90°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. The residue was purified by flash chromatography (silica gel, heptane, ethyl acetate 0-80%) 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. [Table 8]

[0207] Intermediate C13: 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]-2-(trifluoromethyl)pyridine [ka] The title compound was prepared using 2-(trifluoromethyl)isonicotinaldehyde instead of 2-methoxyisonicotinaldehyde, similar to the preparation of intermediate C8. It was a pale yellow oily substance, MS m / z: 356.3 [M+H]. + ,ESI pos.

[0208] Intermediate C14: 2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine [ka] Step 1: 2-Chloro-1-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethanone [ka] To a solution of 4-iodo-1-tetrahydropyran-2-ylpyrazole (CAS 938066-17-2, 32.0 g, 115 mmol) in tetrahydrofuran (350 ml), isopropyl magnesium chloride lithium chloride complex (1.3 M in tetrahydrofuran, 133 ml, 173 mmol) was added under a nitrogen atmosphere at -70°C, and the mixture was stirred at -70°C for 0.5 hours. Then, a solution of 2-chloro-N-methoxy-N-methylacetamide (CAS 67442-07-3, 19 g, 138 mmol) in tetrahydrofuran (100 ml) was added dropwise under a nitrogen atmosphere at -70°C, and the mixture was stirred at 0°C for 1.5 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (500 ml), and the aqueous phase was extracted with ethyl acetate (300 ml x 3). The combined organic layers were washed with brine (300 ml x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100:1~2:1) to obtain 2-chloro-1-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethanone (25.0 g, 95% yield) as a pale yellow oily substance. MS m / z: 145.0 [M+H] + ,ESI pos.

[0209] Step 2: 2-[Benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethanone [ka] To a pale yellow solution of 2-chloro-1-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethanone (25.0 g, 109.32 mmol) in dimethyl sulfoxide (250 ml), potassium carbonate (30.2 g, 219 mmol), potassium iodide (18.15 g, 109.3 mmol), and 1-(benzylamino)propan-2-ol (CAS 27159-32-6, 18.06 g, 109.32 mmol) were added, and the mixture was stirred at 20°C for 2 hours. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (300 ml x 3). The combined organic layers were washed with brine (300 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative MPLC (column: Spherical C18, 20-45 μm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile 10-15%, flow rate 200 ml / min). The eluent was adjusted to pH 8 with ammonium hydroxide, extracted with ethyl acetate (500 ml x 3), washed with brine (500 ml), dried over Na2SO4, and concentrated under vacuum to obtain 2-[benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethanone (26.0 g, yield 66%) as a pale yellow oil. MS m / z: 358.2 [M+H] + ,ESI pos.

[0210] Step 3: 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethyl]amino]propan-2-ol [ka] To a solution of 2-[benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethanone (26.0 g, 72.7 mmol) in methanol (260 ml), sodium borohydride (8.26 g, 218 mmol, multiple batches) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The mixture was slowly poured into a saturated aqueous solution of ammonium chloride (1000 ml) at 0-5°C, stirred for 0.5 hours, and the aqueous layer was extracted with dichloromethane (300 ml x 3). The combined organic layers were washed with brine (300 ml), dried over Na2SO4, and concentrated under vacuum to obtain 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethyl]amino]propan-2-ol (24.0 g, yield 92%) as a pale yellow oil. The product was used directly in the next step without further purification. MS m / z: 360.2 [M+H] + ,ESI pos.

[0211] Step 4: 4-Benzyl-2-methyl-6-(1H-pyrazole-4-yl)morpholine [ka] To a solution of 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazole-4-yl)ethyl]amino]propan-2-ol (24.0 g, 66.8 mmol) in 1,4-dioxane (96 ml) at 20°C, water (48 ml) and hydrochloric acid (37% in water, 48 ml, 576 mmol) were slowly added. The reaction mixture was stirred at 110°C for 2 hours, then cooled to room temperature, and the pH was adjusted to 8 with saturated NaHCO3 aqueous solution. The aqueous layer (1000 ml) was extracted with dichloromethane (300 ml x 3). The combined organic layers were washed with brine (500 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative MPLC (column: Spherical C18, 20-45 μm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile 10-15%, flow rate 150 ml / min) to obtain product 4-benzyl-2-methyl-6-(1H-pyrazole-4-yl)morpholine (14.0 g, yield 82%) as a pale yellow oily substance. MS m / z: 258.2 [M+H] + ESI pos., 1 H NMR(400 MHz, CDCl3):δ=7.68(s,1H),7.56(s,1H),7.40-7.27(m,5H),4.99-4.64(m,1H),3.95-3.76(m,1H),3. 55(s,1H),3.48(s,1H),2.94-2.79(m,1H),2.72-2.54(m,1H),2.21-1.80(m,2H),1.17(dd,J=6.4,15.8 Hz,3H).

[0212] Step 5: 4-Benzyl-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine [ka] To a solution of 4-benzyl-2-methyl-6-(1H-pyrazole-4-yl)morpholine (1.0 mg, 3.89 mmol) in dimethylformamide (20 ml), cesium carbonate (3.17 g, 9.71 mmol) and 3-iodooxetane (1.07 g, 5.83 mmol) were added, and the mixture was stirred at 50°C for 16 hours. The reaction mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative MPLC (column: Spherical C18, 20-45 μm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile 40-60%, flow rate 70 ml / min) to obtain 4-benzyl-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine (850 mg, yield 70%) as a pale yellow oil. MS m / z: 314.2 [M+H] + ,ESI pos.

[0213] Step 6: 2-Methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine [ka] A suspension of 4-benzyl-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine (1.0 g, 3.19 mmol) in methanol (20 ml) was degassed three times with argon. Then, carbon-supported palladium (10%, 340 mg) was added to the reaction mixture, and the gas phase was exchanged with hydrogen three times. The reaction mixture was stirred under a hydrogen atmosphere (15 Psi) at 50 °C for 12 hours, then cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under vacuum to obtain 2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine (680 mg, yield 96%) as a pale yellow oil. MS m / z: 224.2 [M+H] + ,ESI pos.

[0214] Intermediate C15: 2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine [ka] The title compound was prepared in step 2) using 2-(benzylamino)ethanol instead of 1-(benzylamino)propan-2-ol, similar to intermediate C14. It was a pale yellow oily substance, MS m / z: 210.1 [M+H]. + ,ESI pos.

[0215] Intermediate C16: 1-methyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine-2-one [ka] The title compound was prepared using 1-methyl-6-oxopyridine-3-carbaldehyde (CAS 98279-50-6) instead of 2-methoxyisonicotinaldehyde, similar to the preparation of intermediate C8. It was a brown oily substance, MS m / z: 318.2 [M+H]. + ,ESI pos.

[0216] Intermediate C17: [6-(2-bromo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] In a 100 ml three-necked flask, 2-bromoisonicotinaldehyde (2.0 g, 10.75 mmol), 3-buty-1-ol (1.13 g, 1.23 ml, 40.87 mmol), and dichloromethane (23 ml) were introduced under argon at 25°C. The reaction mixture was cooled to 0°C, and trifluoromethanesulfonic acid (4.84 g, 2.86 ml, 32.26 mmol) was added in portions. The mixture was stirred at 0°C for 30 minutes, then at room temperature for 4 hours. The reaction mixture was poured into a saturated NaHCO3 solution and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, heptane with 0%-40% ethyl acetate) to obtain the title compound (1.2 g, yield 23%) as a colorless liquid.

[0217] Intermediate C18: 1-Cyclopropyl-4-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole [ka] The title compound was prepared in the same manner as intermediate C8, using 1-cyclopropylpyrazole-4-carbaldehyde (CAS 1082066-00-9) instead of 2-methoxyisonicotinaldehyde and 4-pentin-2-ol instead of 3-butin-1-ol. Brown oily substance MS m / z: 331.2 [M+H] + ,ESI pos.

[0218] Intermediate C19: 1-(oxetan-3-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole [ka] Step 1: [6-(1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] 1H-pyrazole-4-carbaldehyde (20.0 g, 208 mmol) was charged into a 500 mL three-necked flask, and 3-buty-1-ol (21.9 g, 312 mmol) was added at 25°C under a nitrogen stream. While stirring, trifluoromethanesulfonic acid (55.2 ml, 624 mmol) was added in installments at -10°C, and the mixture was stirred at -10°C for 2 hours. The reaction mixture was poured into an aqueous solution of NaHCO3 (400 ml) and extracted with dichloromethane (200 ml x 3). The combined layers were washed with brine (200 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification of the residue by preparative HPLC (Unisil C18, 250 × 100 mm × 10 μm, water + 0.1% formic acid / acetonitrile, flow rate 350 ml / min) yielded [6-(1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (24.0 g, yield 39%). MS m / z: 299.1 [M+H] + ,ESI pos.

[0219] Step 2: [6-[1-(oxetan-3-yl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] To a solution of [6-(1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (4.0 g, 13.41 mmol) in dimethylformamide (32 ml), 3-iodooxetane (12.3 g, 67.1 mmol) and cesium carbonate (8.74 g, 26.8 mmol) were added, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was added to water (160 ml) and extracted with ethyl acetate (160 ml x 3). The combined organic layers were washed with brine (160 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Luna C18, 150 × 40 mm × 15 μm, water + 0.225% formic acid / acetonitrile, flow rate 60 ml / min) to obtain [6-[1-(oxetan-3-yl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (440 mg, yield 9%) as a yellow oil. MS m / z: 355.0 [M+H] + ,ESI pos.

[0220] Step 3: 1-(oxetan-3-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole [ka] [6-[1-(oxetan-3-yl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (325 mg, 0.81 mmol) and bis(pinacorato)diborone (246 mg, 0.97 mmol) were suspended in 1,4-dioxane (5 ml) to which potassium acetate (965 mg, 2.42 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (66 mg, 0.08 mmol, 0.1 equivalent) were added. After degassing three times with nitrogen, the resulting mixture was stirred under nitrogen at 90°C for 1 hour. The reaction mixture was added to water (20 ml) and extracted with ethyl acetate (10 ml x 3). The combined organic layer was washed with brine (10 ml), dried over Na2SO4, and concentrated under vacuum. The residue was purified by chromatography (silica, petroleum ether, ether = 1:1) to obtain the title compound (108 mg, yield 36%) as a pale yellow oil. MS m / z: 333.1 [M+H] + ,ESI pos.

[0221] Intermediate C20: Trimethyl-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole-1-yl]methoxy]ethyl]silane [ka] Step 1: [6-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] [6-(1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (see intermediate C19 step 1, 2.0 g, 6.71 mmol) was dissolved in tetrahydrofuran (20 ml), to which lithium tert-butoxide (1.075 g, 13.4 mmol) was added at 0°C, and the solution was stirred at 0°C for 0.5 hours. Then, 2-(trimethylsilyl)ethoxymethyl chloride (1.78 ml, 10.06 mmol) was added dropwise, and the mixture was stirred under a nitrogen atmosphere at 20°C for 2 hours. The reaction mixture was poured into water (500 ml), the aqueous layer was separated, and extracted with ethyl acetate (300 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 = 3:1 to 1:1) to obtain [6-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (2.0 g, yield 70%) as a yellow oily substance, MS m / z: 429.3 [M+H] + ,ESI pos.

[0222] Step 2: Trimethyl-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole-1-yl]methoxy]ethyl]silane [ka] To a solution of [6-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (2.1 g, 4.9 mmol) in 1,4-dioxane (20 ml), bis(pinacorato)diborone (1.49 g, 5.88 mmol), potassium acetate (1.44 g, 14.7 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (200 mg, 0.25 mmol, 0.05 equivalents) were added. The mixture was degassed three times with nitrogen and stirred at 90°C for 2 hours. After cooling to room temperature, the mixture was poured into water (200 ml) and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine (200 ml), dried over Na2SO4, and concentrated under vacuum to obtain the title compound (2.1 g, 63% yield) as a brown oily substance. This was used directly without further purification. MS m / z: 407.3 [M+H] + ,ESI pos.

[0223] Intermediate C21: 4-(4-bromotetrahydropyran-2-yl)-1-(trifluoromethyl)pyrazole [ka] 1-(trifluoromethyl)pyrazole-4-carbaldehyde (870 mg, 5.3 mmol) was combined with 3-buten-1-ol (401 mg, 0.48 ml, 5.57 mmol) in dichloromethane (7.5 ml) under an argon atmosphere. Hydrobromic acid (33% in acetic acid, 1.29 g, 0.91 ml, 15.91 mmol) was then added dropwise at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was carefully poured into a saturated NaHCO3 solution (100 ml), and the resulting solution was extracted with dichloromethane (3 × 100 ml), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica, heptane, 0-25% ethyl acetate) to obtain 4-(4-bromotetrahydropyran-2-yl)-1-(trifluoromethyl)pyrazole (1.25 g, 79%) as a pale yellow oily substance. MS m / z:299.0 [M+H] + ,ESI pos.

[0224] Intermediate C22: Trimethyl-[2-[(4-morpholine-2-ylpyrazole-1-yl)methoxyethyl]silane [ka] Step 1: 2-[[4-(4-benzylmorpholin-2-yl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane [ka] To a solution of 4-benzyl-2-(1H-pyrazole-4-yl)morpholine (CAS 2228909-51-9, 930 mg, 3.82 mmol) in tetrahydrofuran (10 ml), lithium tert-butoxide (1.02 g, 7.64 mmol) was added at 0°C, and the solution was stirred at 0°C for 1 hour. Then, 2-(trimethylsilyl)ethoxymethyl chloride (1.01 ml, 5.73 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an aqueous solution of ammonium chloride (50 ml) and extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with saturated sodium chloride solution (10 ml x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by reverse-phase chromatography (column: spherical C18, 20-45 mm, 100 Å; mobile phase: water / 0.1% formate-acetonitrile, 0-100%, flow rate 80 ml / min) to obtain 2-[[4-(4-benzylmorpholine-2-yl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane (1.2 g, yield 84%) as a colorless oil. MS m / z: 374.2 [M+H] + ,ESI pos.

[0225] Step 2: Trimethyl-[2-[(4-morpholine-2-ylpyrazole-1-yl)methoxyethyl]silane [ka] 820 mg, 2.2 mmol of 2-[[4-(4-benzylmorpholine-2-yl)pyrazole-1-yl]methoxy]ethyl-trimethyl-silane (820 mg, 2.2 mmol) was dissolved in methanol (5 ml), to which carbon-supported palladium (10%, 233 mg) was added under a nitrogen atmosphere. The reaction mixture was then degassed under vacuum, and hydrogen was added (three times). The mixture was stirred at 50°C for 12 hours under a hydrogen atmosphere of 45 Psi. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and the filtrate was concentrated under vacuum to obtain trimethyl-[2-[(4-morpholine-2-ylpyrazole-1-yl)methoxy]ethyl]silane (610 mg, yield 98%) as a colorless oil. 1H NMR(400 MHz,CDCl3)δ=7.55(s,1H),7.52(s,1H),5.39(s,2H),4.51(dd,J=2.4,10.1 Hz,1H),3.96(dd,J=1.8,11.4 Hz,1H),3.74(dt,J=2.8,11.3 Hz,1H),3.60-3.50(m,2H),3.07(dd,J=2.1,12.2 Hz,1H),3.01-2.93(m,1H),2.92-2.84(m,2H),1.87(s,1H),0.94-0.87(m,2H),0.00-0.04(m,9H).

[0226] Intermediate C23: Trimethyl-[2-[[4-(6-methylmorpholine-2-yl)pyrazole-1-yl]methoxyethyl]silane [ka] Similar to intermediate C22, the title compound was prepared by using 4-benzyl-2-methyl-6-(1H-pyrazole-4-yl)morpholine (see intermediate C14) instead of 4-benzyl-2-(1H-pyrazole-4-yl)morpholine in step 1). It was a pale yellow oily substance, MS m / z: 298.2 [M+H]. + ,ESI pos.

[0227] Intermediate C24: 4-(4-bromotetrahydropyran-2-yl)-1-(difluoromethyl)pyrazole [ka] Step 1: 4-(4-bromotetrahydropyran-2-yl)-1H-pyrazole [ka] To a solution of 1H-pyrazole-4-carbaldehyde (3.0 g, 31.2 mmol) in dichloromethane (43 ml), 3-buten-1-ol (2.46 g, 2.94 ml, 32.8 mmol) was added under argon. The mixture was sonicated at 40°C for 5 minutes, and then hydrobromic acid (33% in acetic acid, 23.0 g, 16.2 ml, 93.6 mmol) was added dropwise at 0°C. The reaction mixture was stirred at room temperature for 3 hours. A saturated aqueous solution of NaHCO3 was carefully added until the pH became neutral, and the mixture was extracted several times with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography (silica gel, heptane, 0-50% ethyl acetate / ethanol 3:1) to obtain 4-(4-bromotetrahydropyran-2-yl)-1H-pyrazole (4.6 g, yield 64%) as a white solid. MS m / z:231.1 / 233.0 [M+H] + ,ESI pos.

[0228] Step 2: 4-(4-bromotetrahydropyran-2-yl)-1-(difluoromethyl)pyrazole [ka] To a solution of diethyl(bromodifluoromethyl)phosphonate (CAS 65094-22-6, 1.73 g, 1.15 ml, 6.49 mmol) in acetonitrile (40 ml), potassium fluoride (754 mg, 13 mmol) and 4-(4-bromotetrahydropyran-2-yl)-1H-pyrazole (1.0 g, 4.33 mmol) were added under argon at room temperature. The reaction mixture was sonicated for 5 minutes and then stirred at 40°C for 8 hours. After cooling to room temperature, the mixture was filtered and the liquid was concentrated to dryness. The crude substance was purified by flash chromatography (silica gel, heptane, 0-50% ethyl acetate) to obtain 4-(4-bromotetrahydropyran-2-yl)-1-(difluoromethyl)pyrazole (1.3 g, yield 98%) as a yellow oil. MS m / z: 281.1 / 283.1 [M+H] + ,ESI pos.

[0229] Intermediate C25: 2-(1-cyclobutylpyrazole-4-yl)morpholine [ka] Step 1: 4-Benzyl-2-(1-cyclobutylpyrazole-4-yl)morpholine [ka] To a solution of 4-benzyl-2-(1H-pyrazole-4-yl)morpholine (CAS 2228909-51-9, 500 mg, 2.05 mmol) in dimethylformamide (5 ml), bromocyclobutane (832 mg, 6.16 mmol) and potassium carbonate (568 mg, 4.11 mmol) were added, and the mixture was stirred at 120°C for 48 hours. The mixture was filtered and evaporated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 × 25 mm × 10 μm, water + 0.1% formic acid / acetonitrile, flow rate 60 ml / min) to obtain 4-benzyl-2-(1-cyclobutylpyrazole-4-yl)morpholine (400 mg, yield 65%) as a yellow oil. MS m / z: 298.2 [M+H] + ,ESI pos.

[0230] Step 2: 2-(1-cyclobutylpyrazole-4-yl)morpholine [ka] To a solution of 4-benzyl-2-(1-cyclobutylpyrazole-4-yl)morpholine (400 mg, 1.34 mmol) in methanol (5 ml), carbon-supported palladium (10%, 143 mg) was added under nitrogen. The reaction mixture was degassed three times with hydrogen and stirred at 50°C for 12 hours under a hydrogen atmosphere of 45 Psi. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The filtrate was concentrated under vacuum to obtain the title compound (260 mg, yield 93%) as a colorless oil. 1H NMR(400 MHz,CDCl3)δ=7.51-7.48(m,1H),7.47-7.44(m,1H),4.77-4.68(m,1H),4.48(dd,J=2.6,10.1 Hz,1H),3.98-3.92(m,1H),3.78-3.70(m,1H),3.12-3.02(m,1H),3.00-2.93(m, 1H),2.92-2.84(m,2H),2.58-2.50(m,1H),2.49-2.42(m,2H),1.95-1.76(m,3H).

[0231] Intermediate C26: 1-Cyclobutyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole [ka] Step 1: [6-(1-cyclobutylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] To a solution of [6-(1H-pyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (see intermediate C19 step 1, 1.0 g, 3.35 mmol) in dimethylformamide (15 ml), iodocyclobutane (3.05 g, 16.77 mmol) and cesium carbonate (2.18 g, 6.71 mmol) were added, and the reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was added to water (40 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml x 3), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 × 40 mm × 15 μm, water + 0.225% formic acid / acetonitrile, flow rate 60 ml / min) to obtain [6-(1-cyclobutylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (0.35 g, yield 30%) as a pale yellow oil. MS m / z: 353.1 [M+H] + ,ESI pos.

[0232] Step 2: 1-Cyclobutyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole [ka] To a solution of [6-(1-cyclobutylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (350 mg, 0.99 mmol) in 1,4-dioxane (10 ml), bis(pinacorato)diborone (303 mg, 1.19 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (40 mg, 0.05 mmol, 0.05 equivalents), and potassium acetate (292 mg, 2.98 mmol) were added. The mixture was degassed three times with nitrogen, and the reaction was stirred under nitrogen at 90°C for 2 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml x 3), dried over Na2SO4, and concentrated under vacuum to obtain the title compound (328 mg, 99% yield) as a pale yellow oil. MS m / z: 331.1 [M+H] + ,ESI pos.

[0233] Intermediate C27: [6-[1-(cyclopropylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] Step 1: [6-(6-oxo-1H-pyridine-3-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] Under an inert atmosphere, 6-keto-1H-pyridine-3-carbaldehyde (3 g, 24.4 mmol) and 3-buty-1-ol (2.56 g, 2.78 ml, 36.6 mmol) were dissolved in dichloromethane (65 ml) at room temperature. The resulting solution was cooled to -10°C, and trifluoromethanesulfonic acid (11.0 g, 6.5 ml, 73.1 mmol) was carefully added dropwise. The reaction mixture was stirred at -10°C for 30 minutes, then at room temperature for 4 hours. The reaction mixture was quenched with saturated NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, dichloromethane, 0-10% methanol) to obtain [6-(6-oxo-1H-pyridine-3-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (4.85 g, yield 60%) as a pale yellow rubber, MS m / z: 326.0 [M+H]. + ,ESI pos.

[0234] Step 2: [6-[1-(cyclopropylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] To a solution of [6-(6-oxo-1H-pyridine-3-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (1.5 g, 4.61 mmol) in acetonitrile (20 ml), bromomethylcyclopropane (934 mg, 671 μl, 6.92 mmol) and potassium carbonate (1.27 g, 9.22 mmol) were added at room temperature, and the mixture was stirred at 90°C for 18 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, dichloromethane with 0-4% methanol) to obtain the title compound (1.24 g, yield 67%) as a pale yellow solid, MS m / z: 380.1 [M+H]. + ,ESI pos.

[0235] Intermediate C28: 1-(cyclopropylmethyl)-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine-2-one [ka] [6-[1-(cyclopropylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (intermediate C27, 800 mg, 2.11 mmol) was dissolved in 1,4-dioxane (12 ml), to which potassium acetate (828 mg, 8.44 mmol) and bis(pinacorato)diborone (803 mg, 3.16 mmol) were added at room temperature. After degassing the mixture with argon, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (172 mg, 0.211 mmol, 0.10 equivalents) was added. The reaction mixture was stirred at 90°C for 2 hours, then 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, dichloromethane, methanol 0-3%), yielding the product shown in the title (585 mg, yield 58%) as a brown liquid. MS m / z: 358.2 [M+H] + ,ESI pos.

[0236] Intermediate C29: [6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] To a solution of [6-(6-oxo-1H-pyridine-3-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (see intermediate C27 step 1, 1.75 g, 5.38 mmol) in 1,2-dichloroethane (30 ml), cyclopropylboronic acid (1.02 g, 11.84 mmol), 2,2'-bipyridine (924 mg, 5.92 mmol), copper(II) acetate monohydrate (1.18 g, 5.92 mmol), and sodium carbonate (1.31 g, 12.4 mmol) were added at room temperature, and air was bubbled through for 3 minutes. The mixture was stirred overnight at 70°C under an air atmosphere. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by flash chromatography (silica gel, dichloromethane, methanol 0-40%), yielding [6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (1.37 g, yield 61%) as a pale yellow oily substance. MS m / z: 366.0 [M+H] + ,ESI pos.

[0237] Intermediate C30: 1-Cyclopropyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine-2-one [ka] [6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (intermediate C29, 950 mg, 2.6 mmol) was dissolved in 1,4-dioxane (13 ml), to which potassium acetate (1.02 g, 10.4 mmol) and bis(pinacorato)diborone (991 mg, 3.9 mmol) were added at room temperature. After degassing the mixture with argon, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (212 mg, 0.26 mmol, 0.10 equivalents) was added. The mixture was stirred at 90°C for 1 hour, then 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, dichloromethane, methanol 0-40%), yielding the title compound (775 mg, yield 61%, purity 705) as a brown oily substance. MS m / z: 344.2 [M+H] + ,ESI pos.

[0238] Intermediate C31: 4-(4-bromotetrahydropyran-2-yl)-1-methylpyrazole [ka] To a solution of 1-methylpyrazole-4-carbaldehyde (2 g, 18.2 mmol) in dichloromethane (25 ml), 3-buten-1-ol (1.38 g, 1.64 ml, 19.1 mmol) was added under argon. Hydrobromic acid (33% solution in acetic acid (13.4 g, 9.9 mL, 54.5 mmol)) was added all at once at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was carefully quenched with saturated NaHCO3 solution and washed with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, heptane, 0-50% ethyl acetate / ethanol = 3:1) to obtain 4-(4-bromotetrahydropyran-2-yl)-1-methylpyrazole (2.87 g, yield 62%) as a pale yellow oily substance, 245.1 [M+H] +,ESI pos.

[0239] Intermediate C32: 1-(2-methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole [ka] Similar to intermediate C26, the title compound was prepared in step 1 using 2-bromoethyl methyl ether instead of iodocyclobutane. Yellow solid, MS m / z: 335.1 [M+H] + ,ESI pos.

[0240] Intermediate C33: [6-[1-(oxetan-3-ylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] [6-(6-oxo-1H-pyridine-3-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (see intermediate C27 step 1, 1.25 g, 3.84 mmol) was dissolved in acetonitrile (17 ml), to which 3-(bromomethyl)oxetane (871 mg, 625 µl, 5.76 mmol) and potassium carbonate (1.06 g, 7.69 mmol) were added at room temperature, and the mixture was stirred at 90°C for 4 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, dichloromethane with 0-10% methanol) to obtain the title compound (1.06 g, yield 66%) as a pale yellow oily substance, MS m / z: 396.1 [M+H] + ,ESI pos.

[0241] Intermediate C34: 2-Chloro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine [ka] The title compound was prepared using 2-chloroisonicotinaldehyde instead of 2-methoxyisonicotinaldehyde, similar to the preparation of intermediate C8. It was a pale yellow oily substance, MS m / z: 322.2 [M+H]. + ,ESI pos.

[0242] Intermediate C35: 2-Methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine [ka] The title compound was prepared using 6-methoxynicotinaldehyde instead of 2-methoxyisonicotinaldehyde, similar to intermediate C8. It was a yellow oily substance, MS m / z: 318.3 [M+H]. + ,ESI pos.

[0243] Intermediate C36: [6-(6-oxo-1H-pyridine-3-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] The title compound was prepared using 6-keto-1H-pyridine-3-carbaldehyde instead of 2-methoxyisonicotinaldehyde, in the same manner as intermediate C8 (step 1). The result was a brown oily substance, MS m / z: 326.1 [M+H]. + ,ESI pos.

[0244] Intermediate C37: [6-(1,5-dimethylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] The title compound was prepared using 1,5-dimethylpyrazole-4-carbaldehyde instead of 2-methoxyisonicotinaldehyde, in the same manner as in intermediate C8 (step 1). Pale yellow liquid, MS m / z: 327.4 [M+H] + ,ESI pos.

[0245] Intermediate C38: [6-(1,3-dimethylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] The title compound was prepared using 1,3-dimethylpyrazole-4-carbaldehyde instead of 2-methoxyisonicotinaldehyde, in the same manner as in intermediate C8 (step 1). Pale yellow liquid, MS m / z: 327.5 [M+H] + ,ESI pos.

[0246] Intermediate C39: [6-(1-methyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] The title compound was prepared using 2-keto-1-methyl-isonicotinaldehyde instead of 2-methoxyisonicotinaldehyde, in the same manner as in intermediate C8 (step 1). It was a pale yellow oily substance, MS m / z: 340.1 [M+H]. + ,ESI pos.

[0247] Intermediate C40: [6-(1-cyclobutyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] The title compound was prepared using 1-cyclobutyl-6-keto-nicotinaldehyde instead of 2-methoxyisonicotinaldehyde, in the same manner as intermediate C8 (step 1). It was a pale yellow oily substance, MS m / z: 358.3 [M+H]. + ,ESI pos.

[0248] Intermediate C41: 1-Cyclobutyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine-2-one [ka] The title compound was prepared using 1-cyclobutyl-6-keto-nicotinaldehyde instead of 2-methoxyisonicotinaldehyde, similar to intermediate C8. It was a pale yellow oily substance, MS m / z: 358.3 [M+H]. + ,ESI pos.

[0249] Intermediate C42: [6-(1-isopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] The title compound was prepared using 1-isopropyl-6-keto-nicotinaldehyde instead of 2-methoxyisonicotinaldehyde, in the same manner as intermediate C8 (step 1). Brown oily substance, MS m / z: 368.1 [M+H] + ,ESI pos.

[0250] Intermediate C43: [6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] The title compound was prepared using 2-methyl-isonicotinaldehyde instead of 2-methoxyisonicotinaldehyde, in the same manner as in intermediate C8 (step 1). Orange oily substance, MS m / z: 324.1 [M+H] + ,ESI pos.

[0251] Intermediate C44: [6-(2-cyclopropyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] The title compound was prepared using 2-cyclopropylpyridine-4-carbaldehyde instead of 2-methoxyisonicotinaldehyde, in the same manner as intermediate C8 (step 1). Yellow oily substance, MS m / z: 350.0 [M+H] + ,ESI pos.

[0252] Intermediate C45: [6-[1-(3,3-difluorocyclobutyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] Step 1: Methyl 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carboxylate [ka] To a solution of 6-ketopyran-3-carboxylate methyl ester (CAS 6018-41-3, 3.3 g, 21.4 mmol) in N,N-dimethylformamide (30 ml), (3,3-difluorocyclobutyl)amine hydrochloride (CAS 637031-93-7, 3.38 g, 23.6 mmol) and N,N-diisopropylethylamine (3.04 g, 4.1 ml, 23.6 mmol) were added at 0°C. After stirring at 0°C for 30 minutes, the mixture was warmed to room temperature, and 4-(dimethylamino)pyridine (523 mg, 4.28 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.34 g, 27.8 mmol) were added, and stirring at room temperature was continued overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, heptane, 10-100% ethyl acetate) to obtain methyl 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carboxylate (1.44 g, yield 28%) as a yellow solid. MS m / z: 244.1 [M+H] + ,ESI pos.

[0253] Step 2: 1-(3,3-difluorocyclobutyl)-5-(hydroxymethyl)pyridine-2-one [ka] To a solution of methyl 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carboxylate (1 g, 4.11 mmol) in toluene (30 ml), a 1.2 M solution of diisobutylaluminum hydride (10.28 ml, 12.34 mmol) in toluene was added dropwise under argon at -78°C, and the mixture was stirred at -78°C for 3 hours. Diethyl ether was then added, and the mixture was warmed to 0°C. Water (10 μl), 1 M sodium hydroxide solution (0.5 ml), and water again (20 μl) were added, and the resulting mixture was stirred at room temperature for 10 minutes. Na2SO4 was added, and the mixture was stirred at room temperature for another 10 minutes. The suspension was filtered, the solid was rinsed with dichloromethane / methanol, and the resulting solution was concentrated to dryness and used in the next step without further purification. Orange solid, MS m / z: 216.1 [M+H] + ,ESI pos.

[0254] Step 3: 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carbaldehyde [ka] To a solution of 1-(3,3-difluorocyclobutyl)-5-(hydroxymethyl)pyridine-2-one (880 mg, 4.09 mmol) in dichloromethane (25 ml), manganese dioxide (3.56 g, 40.9 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a dikalyte filter, and the solvent was evaporated under reduced pressure to obtain 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carbaldehyde as an orange solid, which was used in subsequent reactions without further purification. MS m / z: 214.1 [M+H] + ,ESI pos.

[0255] Step 4: [6-[1-(3,3-difluorocyclobutyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] To a solution of 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carbaldehyde (590 mg, 1.38 mmol) in dichloromethane (8 ml), 3-buty-1-ol (146 mg, 158 μl, 2.08 mmol) was added under an argon atmosphere at room temperature. The reaction mixture was cooled to -10°C, and trifluoromethanesulfonic acid (623 mg, 366 μl, 4.15 mmol) was added dropwise. The mixture was stirred at -10°C for 1 hour, then stirred at room temperature for 3.5 hours. The reaction mixture was diluted with saturated NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The crude product was used in subsequent reactions without further purification (662 mg, yield 35%, purity 30%), red rubber, MS m / z: 416.1 [M+H] + ,ESI pos.

[0256] Intermediate C46: 1-(3,3-difluorocyclobutyl)-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine-2-one [ka] The title compound was prepared using intermediate C45 instead of intermediate C27, similar to the preparation of intermediate C28. It was a red solid, MS m / z: 394.3 [M+H]. + ,ESI pos.

[0257] Intermediate C47: 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]-1-(trifluoromethyl)pyridine-2-one [ka] Step 1: Methyl 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carboxylate [ka] In a 185 ml carbonylation reactor, 5-bromo-1-(trifluoromethyl)-2-pyridone (1.5 g, 6.2 mmol) was dissolved in methanol (50 ml). Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (177 mg, 0.217 mmol) and triethylamine (1.78 g, 2.45 ml, 17.85 mmol) were added. The reactor was flushed three times with 7 bar argon and five times with 10 bar carbon monoxide. Then, the reactor was filled with 8 bar carbon monoxide, heated to 70°C, and stirred overnight for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica, heptane, 0-50% ethyl acetate). Methyl 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carboxylate (1.23 g, 90% yield) was obtained as a white solid. MS m / z: 222.1 [M+H] + ,ESI pos.

[0258] Step 2: 5-(hydroxymethyl)-1-(trifluoromethyl)pyridine-2-one [ka] To a solution of methyl 1-(3,3-difluorocyclobutyl)-6-oxopyridine-3-carboxylate (750 mg, 3.39 mmol) in toluene (22 ml), a solution of diisobutylaluminum hydride (1.2 M in toluene, 8.5 ml, 10.2 mmol) was added at -78°C under argon. The reaction mixture was stirred at -78°C for 1.5 hours and then diluted with diethyl ether. At 0°C, water (7 mg, 7 μl, 386 μmol), sodium hydroxide (1 M, 386 μL, 386 μmol), and water again (17 mg, 17 μl, 956 μmol) were added, and the resulting mixture was stirred for 10 minutes while warming to room temperature. Na2SO4 was added and the mixture was dried. The suspension was stirred for another 10 minutes at room temperature and then filtered. The filter residue was rinsed with dichloromethane and methanol, and the filtrate was concentrated to dryness to obtain the crude product, which was used in the next step without further purification. Red solid, MS m / z:194.1 [M+H] + ,ESI pos.

[0259] Step 3: 6-Oxo-1-(trifluoromethyl)pyridine-3-carbaldehyde [ka] To a solution of 5-(hydroxymethyl)-1-(trifluoromethyl)pyridine-2-one (520 mg, 2.69 mmol) in dichloromethane (20 ml), manganese dioxide (2.34 g, 26.9 mmol) was added, and the reaction mixture was stirred at room temperature for 96 hours. The mixture was filtered through dikalyte, and the resulting filtrate was concentrated under reduced pressure to obtain 6-oxo-1-(trifluoromethyl)pyridine-3-carbaldehyde as a red oily substance (175 mg, 14%, purity 40%), which was used in the next reaction without further purification. MS m / z: 192.1 [M+H] + ,ESI pos.

[0260] Step 4: [6-[6-oxo-1-(trifluoromethyl)-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate [ka] To a solution of 6-oxo-1-(trifluoromethyl)pyridine-3-carbaldehyde (175 mg, 0.458 mmol) in dichloromethane (3 ml), 3-buty-1-ol (48 mg, 52 μl, 0.688 μmol) was added at room temperature under an argon atmosphere. The reaction mixture was cooled to -10°C, and trifluoromethanesulfonic acid (206 mg, 121 μl, 1.37 mmol) was added dropwise by syringe. The mixture was stirred at -10°C for 60 minutes, then brought to room temperature and stirred at ambient temperature for 3 hours. Upon completion, the reaction mixture was diluted with saturated NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by flash chromatography (silica gel, dichloromethane, 0-5% methanol) to obtain [6-[6-oxo-1-(trifluoromethyl)-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate as a pale yellow liquid (35 mg, 14%, purity 70%), MS m / z: 394.1 [M+H]. + ,ESI pos.

[0261] Step 5: 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]-1-(trifluoromethyl)pyridine-2-one [ka] [6-[6-oxo-1-(trifluoromethyl)-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (35 mg, 89 μmol) was dissolved in 1,4-dioxane (1 ml), to which potassium acetate (35 mg, 0.356 mmol) and bis(pinacorato)diborone (29 mg, 0.116 mmol) were added. After degassing the mixture with argon, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (7.3 mg, 8.9 μmol, 0.100 equivalents) was added, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness, yielding the title compound as a brown liquid (59 mg, 89% yield, 50% purity). This liquid was used in the next step without further purification. MS m / z: 372.3 [M+H] + ,ESI pos.

[0262] Intermediate D1: 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylic acid [ka] Step 1: Ethyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate [ka] A mixture of 4-ketotetrahydropyran-2-carboxylate ethyl ester (CAS 287193-07-1, 2.32 g, 2 ml, 13.5 mmol) and 2,6-di-tert-butyl-4-methylpyridine (3.33 g, 16.2 mmol) in dichloromethane (46 ml) was mixed with trifluoromethanesulfonic anhydride (7.62 g, 4.56 ml, 27.0 mmol) at 0°C. After addition, the ice bath was removed and the mixture was stirred overnight at 35°C. The reaction mixture was poured into ice-cold sodium bicarbonate solution (60 ml) while stirring, and then diluted with water. The aqueous layer was separated and back-extracted with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. When the crude substance was purified by flash chromatography (silica gel, heptane, 0% to 50% ethyl acetate), ethyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate (1.67 g, 41%) was obtained as a colorless liquid.

[0263] Step 2: Ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate [ka] To a solution of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazino[1,2-a]pyrimidine-4-one (intermediate B13, 2.33 g, 5.42 mmol) in 1,4-dioxane (108 ml) and water (18 ml), ethyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate (1.65 g, 5.42 mmol), potassium carbonate (2.25 g, 16.3 mmol), and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride (402 mg, 0.542 mmol, 0.10 equivalents) were added under an argon stream, and the reaction mixture was stirred at 60°C for 2.5 hours. The reaction mixture was filtered with dikalyte. The filtrate was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, dichloromethane, 0%-10% methanol). The product was suspended in ethyl acetate and then filtered to obtain ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.07 g, 79%) as a yellow solid. MS m / z: 458.2 [M+H] + ,ESI pos.

[0264] Step 3: Ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylate [ka] To a solution of 4-[9-(4-chloro-2-fluorophenyl)-4-keto-2,3-dimethylpyrazino[1,2-a]pyrimidine-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate ethyl ester (400 mg, 0.874 mmol) in ethyl acetate (60 ml), triethylamine (106 mg, 146 μl, 1.05 mmol), magnesium oxide (352 mg, 8.74 mmol), and carbon-supported palladium (10%, 186 mg) were added under argon. The mixture was degassed several times with argon and then stirred at room temperature for 40 minutes under a hydrogen gas atmosphere (balloon pressure). The reaction mixture was filtered through dikalyte and washed with ethyl acetate. The filtrate was concentrated, and the crude substance was purified by flash chromatography (HP C18 RediSep Gold, 0%~70% acetonitrile in water) to obtain ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylate (230 mg, 52%) as a yellow foam. MS m / z: 460.2 [M+H] + ,ESI pos.

[0265] Step 4: 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylic acid [ka] To a solution of ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylate (246 mg, 0.535 mmol) in tetrahydrofuran (2 ml) and ethanol (1 ml), an aqueous lithium hydroxide solution (1 M, 1.6 ml, 1.6 mmol) was added, and the reaction mixture was stirred at room temperature. Then, an aqueous hydrochloric acid solution (1 M, 1.6 ml, 1.6 mmol) was added, and the mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to obtain the title compound (248 mg, 97%) as a yellow foam. MS m / z: 432.2 [M+H] + ,ESI pos.

[0266] Intermediate D2: 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid [ka] Step 1: Ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-carboxylate [ka] To a solution of ethyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate (see intermediate D1 step 1, 24.3 g, 79.87 mmol) in 1,4-dioxane (240 ml), bis(pinacorato)diborone (21.3 g, 83.9 mmol), potassium acetate (23.52 g, 240 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.96 g, 2.4 mmol, 0.03 equivalents) were added. The mixture was then degassed three times with nitrogen, and the reaction was stirred at 90°C for 2 hours under a nitrogen atmosphere. The mixture was poured into water (500 ml) and extracted with ethyl acetate (300 ml x 3). The combined organic layers were washed with brine (300 ml), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100:1~3:1) to obtain ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-carboxylate (14.0 g, yield 62%) as a pale yellow oil. MS m / z: 283.2 [M+H] + ,ESI pos.

[0267] Step 2: Ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate [ka] To a solution of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (intermediate B3, 2.1 g, 6.21 mmol) in 1,4-dioxane (50 ml) and water (5 ml), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-2-carboxylate (2.45 g, 8.69 mmol), cesium carbonate (6.07 g, 18.63 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (254 mg, 0.31 mmol, 0.05 equivalents) were added. The reaction mixture was then degassed three times with nitrogen and stirred under a nitrogen atmosphere at 25°C for 2 hours. The mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100:1~1:3) to obtain ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.6 g, yield 91%) as a pale yellow solid. MS m / z: 458.1 [M+H] + ,ESI pos.

[0268] Step 3: Ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylate [ka] Under nitrogen, a suspension of platinum oxide (198 mg, 0.87 mmol, 0.2 equivalents) in ethyl acetate (25 ml) was to be mixed with a solution of ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.0 g, 4.37 mmol), magnesium oxide (1.76 g, 43.7 mmol), and triethylamine (530 mg, 5.24 mmol) in ethyl acetate (25 ml) and dimethylformamide (10 mL). The reaction mixture was degassed three times with hydrogen, and then stirred under hydrogen (15 Psi) at 25°C for 4 hours. The reaction mixture was filtered through a diatomaceous earth pad, then poured into water (150 ml), and extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (50 ml x 3), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Luna C18, 250 x 70 mm x 10 μm, water + 0.225% formic acid / acetonitrile, flow rate 140 ml / min) to obtain ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylate (1.3 g, yield 65%) as a pale yellow solid. MS m / z: 460.2 [M+H] + ,ESI pos.

[0269] Step 4: 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid [ka] To a solution of ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylate (1.3 g, 2.83 mmol) in tetrahydrofuran (12 ml) and water (4 ml), lithium hydroxide monohydrate (178 mg, 4.24 mmol) was added, and the reaction mixture was stirred at 20°C for 1 hour. The mixture was poured into water (100 ml), the pH was adjusted to 6 with 1 M hydrochloric acid, and then extracted with ethyl acetate (80 ml x 3). The combined organic layers were washed with brine (80 ml), dried over Na2SO4, and then concentrated under vacuum to obtain the title compound (1.2 g, yield 98%) as a yellow solid. MS m / z: 432.1 [M+H] + ,ESI pos.

[0270] Intermediate D3: 4-[9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylic acid [ka] The title compound was prepared in the same manner as intermediate D2, using intermediate B17 instead of intermediate B3 in step 2. Pale yellow solid, MS m / z: 420.2 [M+H] + ,ESI pos.

[0271] Intermediate D4: 4-[9-(4,4-difluorocyclohexyl)-2,3-dimethyl-4-oxopyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid [ka] The title compound was prepared in the same manner as intermediate D2, using intermediate B16 instead of intermediate B3 in step 2. White solid, MS m / z: 422.1 [M+H] + ,ESI pos.

[0272] Example 1: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one [ka] To a suspension of 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one (intermediate B1, 75 mg, 0.196 mmol) in 1,4-dioxane (2 ml), (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-C1, 39 mg, 0.235 mmol) and cesium carbonate (192 mg, 0.589 mmol) were added at room temperature. After degassing the mixture with argon, tris(dibenzylideneacetone)dipalladium (9 mg, 0.0098 mmol, 0.05 equivalents) and xanthophos (11 mg, 0.0196 mmol, 0.10 equivalents) were added. The reaction mixture was stirred overnight at 100°C, then 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, dichloromethane, methanol 0-5%) to obtain the title compound (38 mg, yield 41%) as a pale yellow solid. MS m / z: 468.1 [M+H] + ESI pos., arbitrarily assigned absolute stereochemistry.

[0273] Example 2: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 1, starting from intermediate (-)-C1 instead of intermediate (+)-C1. It was a light brown solid, MS m / z: 468.2 [M+H]. +ESI pos., arbitrarily assigned absolute stereochemistry.

[0274] Example 3: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 1, starting from intermediate B2 instead of intermediate B1. Orange solid, MS m / z: 469.1 [M+H] + ESI pos., arbitrarily assigned absolute stereochemistry.

[0275] Examples 4 and 5: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one [ka] To a suspension of 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one (intermediate B1, 50 mg, 0.13 mmol) in 1,4-dioxane (3 ml), 2-(2-methyl-4-pyridyl)morpholine (intermediate C2, 28 mg, 0.16 mmol), cesium carbonate (128 mg, 0.39 mmol), tris(dibenzylideneacetone)dipalladium (6.0 mg, 0.01 mmol, 0.05 equivalents) and xanthophos (7.5 mg, 0.01 mmol, 0.1 equivalents) were added, and the mixture was stirred under nitrogen at 100°C for 16 hours. The reaction mixture was poured into water (40 ml) and extracted with ethyl acetate (20 ml x 2). The combined original layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative MPLC (column: Spherical C18, 20-45 μm, 100 Å; water containing 0.1% formic acid / acetonitrile, flow rate 50 ml / min) to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one (40 mg). When this racemic mixture was separated by chiral SFC (Daicel Chiralpak AD column, 250mm x 30mm, 10μm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 70ml / min), 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one was eluted as the first enantiomer, with a retention time of 0.848 min, a white solid, and MS m / z: 479.2 [M+H]. + ESI pos. and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one were obtained as a white solid with a retention time of 1.289 min, MS m / z: 479.1 [M+H]. + ESI pos., arbitrarily assigned absolute stereochemistry.

[0276] Examples 6-13 below were prepared in the same manner as in Examples 4 and 5, starting from the intermediate shown instead of intermediate C2. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 9] TIFF2026521750000148.tif142170

[0277] Example 14: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] To a solution of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (intermediate B3, 100 mg, 0.30 mmol) in acetonitrile (3 ml), 2-(1-methylpyrazole-4-yl)morpholine (intermediate C1, 49 mg, 0.30 mmol) and potassium carbonate (191 mg, 0.90 mmol) were added, and the mixture was stirred at 80°C for 4 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 flash chromatography (silica gel, dichloromethane with 0-10% methanol) to obtain the title compound (19 mg, yield 14%) as a light brown solid, MS m / z: 469.2 [M+H]. + ,ESI pos.

[0278] Example 15: 9-(4-chloro-2-fluorophenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one [ka] Step 1: 9-(4-chloro-2-fluorophenyl)-7-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one [ka] To a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one (intermediate B1, 50 mg, 0.131 mmol) in 1,4-dioxane (1.5 ml), 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (intermediate C8, 54 mg, 0.170 mmol) was added, followed by the addition of a solution of potassium carbonate (54 mg, 0.393 mmol) in water (0.30 ml). The mixture was flushed with argon for 5 minutes, after which 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (11 mg, 0.013 mmol, 0.10 equivalents) was added. Flushing with argon was continued for 5 minutes, then the tube was sealed and heated at 60°C for 1 hour. Saturated NaHCO3 solution (10 ml) was added, and the mixture was extracted with ethyl acetate (2 × 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. Purification of the residue by flash column chromatography (silica gel, heptane, 0-70% ethyl acetate) yielded 9-(4-chloro-2-fluorophenyl)-7-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one (51 mg, yield 79%) as a light brown solid. MS m / z: 492.3 [M+H] + ,ESI pos.

[0279] Step 2: 9-(4-chloro-2-fluorophenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one [ka] A solution of 9-(4-chloro-2-fluorophenyl)-7-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one (47 mg, 0.096 mmol) in ethyl acetate (2 ml) was purged and nitrogen was packed (3 ×). Then, palladium (10% on activated carbon, 10 mg, 0.0096 mmol, 0.10 equivalents) was added. The mixture was purged, hydrogen was packed, and the mixture was stirred overnight at 22°C with a hydrogen-filled balloon attached. The catalyst was filtered off, washed with ethyl acetate (3 × 5 ml), and the filtrate was concentrated under vacuum. The residue was purified by flash column chromatography (silica gel, heptane, 0-100% ethyl acetate) to obtain the title compound (44 mg, 93% yield) as a pale yellow oily substance. MS m / z: 494.3 [M+H] + ,ESI pos.

[0280] Example 16: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one [ka] When the racemic mixture of 9-(4-chloro-2-fluorophenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one was separated by chiral SFC (column IB, 250 mm × 20 mm, 5 μm, 30% methanol), 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one was obtained as the first eluted enantiomer with a retention time of 2.582 minutes, as a white powder. MS m / z: 494.4 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0281] Example 17: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] When the racemic mixture of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one was separated by chiral SFC (column OD-H, 250 mm × 20 mm, 5 μm, 25% methanol + 0.2% diethylamine), 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one was obtained as a second eluted enantiomer with a retention time of 4.033 minutes, as a pale yellow solid. MS m / z: 469.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0282] Example 18: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 15, starting from intermediate C9 instead of intermediate C8. Pale yellow powder, MS m / z: 467.3 [M+H] + ,ESI pos.

[0283] Example 19: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridine-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared in the same manner as in Example 14, starting from intermediate C2 instead of intermediate C1. It was a light brown solid, MS m / z: 480.2 [M+H]. + ,ESI pos.

[0284] Example 20: 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 1, starting from intermediate B4 instead of intermediate B1. Pale yellow powder, MS m / z: 450.4 [M+H] + ,ESI pos.

[0285] Examples 21 and 22: 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 15, starting from intermediate B2 instead of intermediate B1. The resulting racemic 9-(4-chloro-2-fluorophenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one was separated by chiral SFC (Chiralpak Cel-SZ column, 250 mm × 20 mm, 5 μm, 40% methanol). The first eluted enantiomer was 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, obtained as a white powder with a retention time of 3.63 minutes. MS m / z: 495.4 [M+H] + ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one were obtained as a white powder with a retention time of 4.04 minutes, MS m / z: 495.4 [M+H]. + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0286] Examples 23-26 below were prepared in the same manner as in Examples 4 and 5, starting from the indicated intermediates. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 10]

[0287] Examples 27 and 28: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 15, starting from intermediate C11 instead of intermediate C8. Separation of the racemic mixture by chiral SFC (Chiral IJ column, 250 mm × 20 mm, 5 μm, 20% methanol) yielded 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one as the first eluted enantiomer, with a retention time of 1.921 minutes and obtained as a white powder. MS m / z: 493.4 [M+H] + ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one were obtained as a white powder with a retention time of 2.398 mins, MS m / z: 493.4 [M+H]. + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0288] Example 29: 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 15, using intermediate B4 instead of intermediate B1 and intermediate C9 instead of intermediate C8. Separation of the racemic mixture by chiral SFC (Chiralpak Cel-SZ, 250 mm × 20 mm, 5 μm, 53% methanol) yielded 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one as the first eluted enantiomer, with a retention time of 2.809 minutes and obtained as a white powder. MS m / z: 449.4 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0289] Example 30: 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 15, using intermediate B2 instead of intermediate B1 and intermediate C11 instead of intermediate C8. Pale yellow powder, MS m / z: 494.4 [M+H] + The ESI compound is a racemic mixture.

[0290] Examples 31-33 below were prepared in the same manner as in Examples 4 and 5, starting from the indicated intermediates. Example 32 was a racemic mixture, and its relative stereochemistry was determined by NMR. [Table 11]

[0291] Examples 34 and 35: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] Similar to Example 15, the title compound was prepared using intermediate B2 instead of intermediate B1 and intermediate C13 instead of intermediate C8. The resulting racemic mixture was separated by chiral SFC (Chiral IB column, 250 mm × 20 mm, 5 μm, 25% methanol). The first eluted enantiomer was 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one, obtained as a pale yellow oily substance with a retention time of 1.875 minutes. MS m / z: 533.4 [M+H] + ESI pos. and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one as a second eluted enantiomer were obtained as a pale yellow oily substance with a retention time of 2.094 minutes, MS m / z: 533.4 [M+H]. + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0292] Examples 36 and 37: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] When the racemic mixture of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholine-4-yl]pyrazino[1,2-a]pyrimidine-4-one was separated by chiral SFC (Chiral AD-H column, 250 mm × 20 mm, 5 μm, 40% methanol), 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholine-4-yl]pyrazino[1,2-a]pyrimidine-4-one was obtained as the first eluted enantiomer, with a retention time of 3.25 minutes, as a light brown solid. MS m / z: 471.4 [M+H] + ESI pos. and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one were obtained as a light brown solid with a retention time of 3.82 minutes, MS m / z: 471.3 [M+H]. + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0293] Example 38: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 15, using intermediate B2 instead of intermediate B1 and intermediate C9 instead of intermediate C8. It was a pale yellow solid, MS m / z: 468.3 [M+H]. + ,ESI pos.

[0294] Examples 39 and 40: 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimide[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimide[1,2-b]pyridazin-4-one formate [ka] To a solution of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (intermediate B3, 97 mg, 0.29 mmol) in dimethyl sulfoxide (10 mL), diisopropylethylamine (0.15 ml, 0.86 mmol) and 2-(1-cyclopropylpyrazole-4-yl)morpholine (intermediate C5, 166 mg, 0.86 mmol) were added, and the mixture was stirred at 120 °C for 16 hours. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 2). The combined organic layers were washed with brine (20 ml x 2), dried over Na2SO4, and then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 × 25 mm × 10 μm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min), and extracted with ethyl acetate to obtain 9-(4-chloro-2-fluorophenyl)-7-[2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (100 mg) as a yellow oily substance. When this racemic mixture was separated by chiral SFC (Chiralpak AD column, 250 mm × 30 mm, 10 μm, 30% ethanol), 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one was obtained as the first eluted enantiomer (37 mg, yield 37%) as a grayish-white solid. MS m / z: 495.1 [M+H] + ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimide[1,2-b]pyridazine-4-onformate were obtained as a second eluted enantiomer (34 mg, yield 34%) as a grayish-white solid, MS m / z: 495.1 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0295] Example 41: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 15, using intermediate B6 instead of intermediate B1 and intermediate C9 instead of intermediate C8. It was a pale yellow solid, MS m / z: 486.3 [M+H]. + ,ESI pos.

[0296] Example 42: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] To a solution of 7-chloro-9-(4-chloro-2,6-difluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (intermediate B7, 50 mg, 0.14 mmol) in acetonitrile (1.4 ml), (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-C1, 23.5 mg, 0.140 mmol) and a 3 M aqueous solution of tripotassium phosphate (3.25 M, 0.140 mL, 0.421 mmol) were added. The mixture was stirred at 80°C for 6 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to dryness. The crude substance was purified by flash chromatography (silica gel, heptane with 0-100% ethyl acetate, followed by dichloromethane with 0-6% methanol) to obtain the title compound (38 mg, 56% yield) as a light brown solid. MS m / z: 487.3 [M+H] + ,ESI pos.

[0297] Examples 43-46 below were prepared in the same manner as in Examples 39 and 40, starting from the indicated intermediates. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 12]

[0298] Example 47: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared in the same manner as in Example 15, using intermediate B3 instead of intermediate B1 and intermediate C9 instead of intermediate C8. Yellow solid, MS m / z: 468.3 [M+H] + ,ESI pos.

[0299] Example 48: 9-(4-chloro-2-fluorophenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 1, using intermediate B8 instead of intermediate B1. Yellow solid, MS m / z: 454.4 [M+H] + ,ESI pos.

[0300] Examples 49-56 below were prepared in the same manner as in Example 42, starting from the indicated intermediates. Chiral separation was performed as described for Examples 4 and 5. Absolute stereochemistry was arbitrarily assigned. [Table 13] TIFF2026521750000174.tif133170

[0301] Example 57: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] The racemic mixture 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one (Example 47) was separated by chiral SFC (Chiral NR, 250 mm × 20 mm, 5 μm, 50% methanol), and the title compound was obtained as the second eluted enantiomer with a retention time of 5.406 minutes as a light brown solid. MS m / z: 468.4 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0302] Example 58: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one [ka] Step 1: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one [ka] To a solution of 7-bromo-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one (intermediate B1, 400 mg, 1.05 mmol) in t-amyl alcohol (4.0 ml), trimethyl-[2-[(4-morpholine-2-ylpyrazole-1-yl)methoxyethyl]silane (intermediate C22, 356 mg, 1.26 mmol), cesium carbonate (1.024 g, 3.14 mmol), and Xphos Pd G4 (90 mg, 0.1 mmol, 0.1 equivalent) were added. The mixture was then degassed three times with nitrogen and stirred at 90°C under a nitrogen atmosphere for 16 hours. The reactive dimethylsin mixture was added to water (40 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were washed with brine (20 ml x 3), dried over Na2SO4, and the residue was purified by column chromatography (silica, ethyl acetate / petroleum ether = 1:1) to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one (220 mg, yield 36%) as a pale yellow oily substance. MS m / z: 584.4 [M+H] + ,ESI pos.

[0303] Step 2: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one [ka] To a solution of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one (210 mg, 0.36 mmol) in dichloromethane (10 ml), trifluoroacetic acid (5.0 ml, 67 mmol) was added, and the mixture was stirred at 20°C for 1 hour. Water (40 ml) was added to the reaction mixture, and an aqueous sodium carbonate solution was added to the reactants to adjust the pH to 7-8. This was extracted three times with ethyl acetate, the combined extract was washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by reverse-phase chromatography (column: spherical C18, 20-45 mm, 100 Å; mobile phase: water / 0.1% formate-acetonitrile, 0-100%, flow rate 80 ml / min) to obtain the title compound (120 mg, yield 74%) as a pale yellow solid. MS m / z: 454.2 [M+H] + ,ESI pos.

[0304] Examples 59-61 below were prepared in the same manner as in Examples 4 and 5, starting from the indicated intermediates, and their relative stereochemistry was determined by NMR. [Table 14]

[0305] Examples 62, 63, 64, and 659-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2 -b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared in the same manner as in Examples 39 and 40, using intermediate C14 instead of intermediate C5. All white solids were MS m / z: 525.2 [M+H] + Absolute stereochemistry was arbitrarily assigned to ESI pos., and relative stereochemistry was determined by NMR.

[0306] Examples 66 and 679: 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (intermediate B2, 150 mg, 0.44 mmol) in 1,4-dioxane (5 ml), 2-(1-cyclopropylpyrazole-4-yl)morpholine (intermediate C5, 86 mg, 0.44 mmol), cesium carbonate (433 mg, 1.33 mmol), and xanthophos-Pd-G4 (43 mg, 0.04 mmol, 0.1 equivalent) were added in a glove box, and the mixture was stirred at 90°C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 ml x 3). The combined layers were washed with brine (20 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25mm×10μm, mobile phase: water / 0.25% formate-acetonitrile, 0-100%, flow rate 25ml / min) to obtain the racemic mixture 9-(4-chloro-2-fluorophenyl)-7-[2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one. When this substance was separated into enantiomers by chiral SFC (Daicel Chiralpak AD, 250 mm × 30 mm, 10 μm, CO2 / ethanol containing 0.1% ammonium hydroxide), 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (20 mg, yield 30%) and 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (22 mg, yield 32%) were obtained as yellow solids. MS m / z: 495.1 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0307] Examples 68 and 699: -(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxypyridine-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxypyridine-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Examples 66 and 67, using intermediate C4 instead of intermediate C5. Yellow solid, MS m / z: 496.1 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0308] Examples 70-73 below were prepared in the same manner as in Example 15, starting from the indicated intermediates. Chiral separation was performed as described for Examples 34 and 35. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 15]

[0309] Example 74: 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of (2S)-2-(1-methylpyrazole-4-yl)morpholine (intermediate (+)-C1, 76 mg, 0.45 mmol) in ethanol (4.5 ml), 7-chloro-9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methylpyrazino[1,2-a]pyrimidine-4-one (intermediate B10, 75 mg, 0.16 mmol) was added, and the mixture was left in a microwave at 150°C for 5 hours. After evaporating the volatile substances and purifying the residue by chromatography (silica gel, heptane, 0-100% ethyl acetate), 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrazino[1,2-a]pyrimidine-4-one (9 mg, yield 9%) was obtained as a yellow powder. MS m / z: 505.4 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0310] Example 75: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Example 15, using intermediate B6 instead of intermediate B1 and intermediate C11 instead of intermediate C8. Yellow solid, MS m / z: 512.3 [M+H] + ,ESI pos.

[0311] Example 76: 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared in the same manner as in Example 42, using intermediate B11 instead of intermediate B7. White solid, MS m / z: 505.4 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0312] Example 77: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared in the same manner as in Example 15, using intermediate B3 instead of intermediate B1 and intermediate C11 instead of intermediate C8. Yellow solid, MS m / z: 494.3 [M+H] + ,ESI pos.

[0313] Example 78: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one [ka] The racemic mixture 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one (Example 77) was separated by chiral SFC (column chiral OD-H, 5 μm, 250 × 20 mm, 33% methanol), and the title compound was obtained as the first eluted enantiomer with a retention time of 3.184 mins as a yellow solid. MS m / z: 494.1 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0314] Examples 79-82 below were prepared in the same manner as in Examples 39 and 40, starting from the indicated intermediates. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 16]

[0315] Example 83: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methyl-6-oxopyridine-3-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] Similar to Example 15, the title compound was prepared using intermediate B3 instead of intermediate B1 and intermediate C16 instead of C8. Pale yellow solid, MS m / z: 495.3 [M+H] + ,ESI pos.

[0316] Examples 84 and 85: 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one and 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one [ka] Similar to Example 15, the title compound was prepared from intermediate B12 instead of intermediate B1 and from intermediate C11 instead of C8. Chiral separation was performed as described for Examples 34 and 35. Absolute stereochemistry was arbitrarily assigned. Pale yellow solid, MS m / z: 500.2 [M+H] +,ESI pos.

[0317] Examples 86-87 below were prepared in the same manner as in Examples 4 and 5, starting from the indicated intermediates. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 17]

[0318] Example 88: 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] The racemic mixture 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one (Example 77) was separated by chiral SFC (column chiral OD-H, 5 μm, 250 × 20 mm, 33% methanol), and the title compound was obtained as the second eluted enantiomer with a retention time of 4.030 minutes as a yellow solid. MS m / z: 494.1 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0319] Examples 89-91 below were prepared in the same manner as in Example 15, starting from the indicated intermediates. Chiral separation was performed as described for Examples 34 and 35. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 18]

[0320] Example 92: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] Step 1: 7-[6-(2-bromo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] A solution of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazino[1,2-a]pyrimidine-4-one (intermediate B13, 1.8 g, 4.2 mmol) in 1,4-dioxane (60 ml) and water (10 ml) was prepared under argon light by adding [6-(2-bromo-4-pyridyl)-3,6-dihy [Dro-2H-pyran-4-yl]trifluoromethanesulfonate (intermediate C17, 1.63 g, 4.2 mmol), potassium carbonate (1.74 g, 12.6 mmol), and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (347 mg, 0.420 mmol, 0.10 equivalents) were added, and the mixture was heated to 60°C and stirred for 3 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. Purification of the residue by flash chromatography (silica gel, heptane, 0-50% ethyl acetate) yielded 7-[6-(2-bromo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (710 mg, yield 30%) as a pale yellow solid. MS m / z: 541.2 [MH] + ,ESI neg.

[0321] Step 2: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of 7-[6-(2-bromo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (710 mg, 1.31 mmol) in 1,4-dioxane (12 ml), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinan (3.5 M solution in tetrahydrofuran, 0.450 ml, 1.58 mmol), potassium carbonate (543 mg, 3.93 mmol), and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (108 mg, 0.131 mmol, 0.10 equivalents) were added under argon, and the mixture was heated to 90°C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, ethyl acetate + ethanol 3 / 1-heptane 0-50%) to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (482 mg, yield 73%) as an orange foam, MS m / z: 477.2 [M+H]. + ,ESI pos.

[0322] Step 3: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] In a 100 ml round-bottom flask, 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (482 mg, 1.01 mmol) was dissolved in methanol (25 ml). The mixture was degassed with argon, and then carbon-supported palladium (10%, 108 mg) was added. The reaction mixture was stirred at room temperature for 2 hours under a hydrogen gas atmosphere (balloon). The reaction mixture was filtered through dikalyte, washed with ethyl acetate, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, ethyl acetate + ethanol 3 / 1-heptane 0-50%), followed by a second chromatography (HP C18 RediSep Gold, water 0-70% acetonitrile). The title compound (210 mg, 43%) was obtained as a yellow foamy substance. MS m / z: 479.2 [M+H] + ,ESI pos.

[0323] Examples 93 and 94: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] When the racemic mixture 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (Example 92) was separated by chiral SFC (column chiral IH, 5 μm, 250 × 20 mm, 22% methanol + 0.2% diethylamine), the first eluted enantiomer was 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (Example 92), the first eluted enantiomer was 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one. Tyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one was obtained as a pale yellow solid with a retention time of 1.571 minutes, and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one as a second eluted enantiomer with a retention time of 2.185 minutes. MS m / z: 479.3 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0324] Examples 95 and 96: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one (Example 38) was processed into chiral SFC (Column Daicel Separation was performed using Chiralpak (250 × 30 mm, 10 μm, ethanol + 0.1% ammonium hydroxide) to obtain a white solid with 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one as the first eluted enantiomer and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one as the second eluted enantiomer. MS m / z: 468.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0325] Example 97: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was isolated as a small amount of diastereomer during the final step of the synthesis in Example 38; it was a white solid, MS m / z: 468.2 [M+H]. + ,ESI pos.

[0326] Example 98: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] Similar to Example 15, the title compound was prepared using intermediate B7 instead of intermediate B1 and intermediate C9 instead of intermediate C8. Chiral separation was performed by chiral SFC (Chiral IK column, 250 mm × 20 mm, 5 μm, 37% methanol) to obtain the second eluted enantiomer. Yellow solid, MS m / z: 486.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0327] Examples 99-109 below were prepared in the same manner as in Example 15, starting from the indicated intermediates. Chiral separation was performed as described for Examples 95 and 96. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 19] TIFF2026521750000204.tif218170 TIFF2026521750000205.tif47170

[0328] Examples 110 and 111: 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2,6-difluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] Racemic 9-(4-chloro-2,6-difluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (Example 75) is converted to chiral SFC (Column Chiral Separation was performed using Cellulose-SZ (250×20mm, 5μm, 45% methanol) to obtain 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one as the first eluted enantiomer and 9-(4-chloro-2,6-difluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one as the second eluted enantiomer, yielding a pale yellow solid. MS m / z: 512.3 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0329] Examples 112-123 below were prepared in the same manner as in Example 15, starting from the indicated intermediates. Diastereomer separation was performed by preparative HPLC (Waters Xbridge C18 column, 150 × 25 mm × 10 μm, 50-80% water-acetonitrile, 60 ml / min acetonitrile), and chiral separation was performed by chiral SFC (Daicel Chiralpak IC 250 mm × 30 mm, 10 μm, acetonitrile / methanol / 0.1% ammonium hydroxide, flow rate 80 ml / min). Relative stereochemistry was performed. 1 The assignment was based on evaluation of H-NMR measurements, and absolute stereochemistry was assigned arbitrarily. [Table 20] TIFF2026521750000208.tif214170 TIFF2026521750000209.tif90170

[0330] Examples 124 and 1257-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one and 7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared in the same manner as in Examples 39 and 40, using intermediate B18 instead of B3. Pale yellow solid, MS m / z: 501.3 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0331] Examples 126-130 below were prepared in the same manner as in Example 15, starting from the indicated intermediates. Chiral separation was performed as described for Examples 95 and 96. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 21]

[0332] Examples 131 and 1329-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] Step 1: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of trimethyl-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole-1-yl]methoxy]ethyl]silane (intermediate C20, 600 mg, 1.48 mmol) in 1,4-dioxane (10 ml) and water (2 ml), 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (intermediate B2, 1.25 g, 2.21 mmol), sodium carbonate (469 mg, 4.43 mmol), and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (120 mg, 0.15 mmol, 0.1 equivalent) were added. The reaction mixture was degassed three times with nitrogen, and the reaction mixture was stirred under a nitrogen atmosphere at 90°C for 2 hours. After cooling to room temperature, 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 = 3:1~1:1) to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (400 mg, yield 46%) as a yellow oil, MS m / z: 582.2 [M+H] + ,ESI pos.

[0333] Step 2: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] Under nitrogen, a suspension of carbon-supported palladium (10%, 73 mg) in ethyl acetate (1 ml) was mixed with a solution of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (400 mg, 0.69 mmol) in ethyl acetate (40 ml), magnesium oxide (277 mg, 6.87 mmol), and triethylamine (0.11 ml, 0.82 mmol). The mixture was degassed three times with hydrogen and then stirred at 30°C for 1.5 hours under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a diatomaceous earth pad to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (330 mg, yield 28%) as a yellow oily substance, MS m / z: 584.2 [M+H] + ,ESI pos.

[0334] Step 3: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (700 mg, 0.72 mmol) in dichloromethane (8 ml), trifluoroacetic acid (4.0 ml, 0.72 mmol) was added at room temperature, and the mixture was stirred at 25°C for 2 hours. The reaction mixture was carefully poured into an aqueous sodium bicarbonate solution (20 ml) and extracted with dichloromethane (50 ml x 3). The combined layers were washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150×25mm×10μm, mobile phase: water / 0.25% formate-acetonitrile, 0-100%, flow rate 25ml / min) to obtain a racemic compound (220mg, yield 67%). From this, 60mg was separated by chiral SFC (Daicel Chiralpak OD 250mm×30mm, 10μm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 75ml / min), and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (first eluted enantiomer, 13mg, yield 22%) was detected as a yellow solid by MS. m / z:454.1 [M+H] + ESI pos. and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (second eluted enantiomer, 18 mg, yield 30%) were obtained as a yellow solid. MS m / z: 454.1 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0335] Examples 133 and 1349 - (4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one and 9 - (4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] First, Rieke zinc was prepared by reducing zinc chloride with lithium using stoichiometric amounts of naphthalene: Naphthalene (179 mg, 1.4 mmol) and lithium (102 mg, 14.7 mmol) were placed in a pear-shaped flask. The flask was degassed three times with argon. Zinc chloride (1.9 M in 2-methyltetrahydrofuran, 3.7 ml, 7 mmol) was added to this mixture, and the mixture was sonicated for 20 minutes and further stirred overnight at room temperature to obtain a black suspension of highly reactive Rieke zinc.

[0336] 4-(4-bromotetrahydropyran-2-yl)-1-(trifluoromethyl)pyrazole (intermediate C21, 600 mg, 2.01 mmol) was dissolved in tetrahydrofuran (super-dehydrated, 2 ml), and argon was passed through the solution for 2-5 minutes by bubbling. This solution was added dropwise to a Rieke zinc suspension at room temperature, and the reaction mixture was stirred at room temperature for 3 hours to obtain a 0.23 M bromo-[2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]zinc solution (6.8 ml).

[0337] To a solution of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (intermediate B2, 250 mg, 0.74 mmol) in tetrahydrofuran (super-dehydrated, 2 ml), xanthophos paradacycle G3 (80 mg, 74 μmol, 0.10 equivalents) was added. The flask was degassed three times with argon, and then bromo-[2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]zinc solution (0.23 M, 5.1 ml, 1.18 mmol) was added. The mixture was stirred at room temperature for 30 minutes, then at 45°C for 1.5 hours. The reaction mixture was filtered through a decalite and concentrated under reduced pressure. Saturated ammonium chloride solution was added to the residue, and the resulting solution was extracted with ethyl acetate (3 × 50 ml). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse-phase chromatography (column: YMC Triart C18, 100 mm × 30 mm, 5 μm, mobile phase: water / 0.1% formate-acetonitrile, 0-100%) to obtain 50 mg of racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one. Separation by chiral SFC (Chiral OD column, 5 μm, 250 × 20 mm, 20% methanol) yielded 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (first eluted enantiomer, 12 mg, 24%) as a pale yellow powder. MS m / z: 522.1 [M+H] + ESI pos. and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one (second eluted enantiomer, 12 mg, 24%) were obtained as a pale yellow powder, MS m / z: 522.1 [M+H] +The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0338] Examples 135-140 below were prepared in the same manner as in Example 15, starting from the indicated intermediates. Chiral separation was performed as described for Examples 95 and 96. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 22] TIFF2026521750000218.tif45170

[0339] Examples 141, 142 and 1439-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1 [rac-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] Step 1: 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]-N'-(cyclopropanecarbonyl)tetrahydropyran-2-carbhydrazide [ka] To a solution of 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylic acid (intermediate D1, 100 mg, 0.23 mmol) in dimethylformamide (3 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (89 mg, 0.46 mmol), N,N-diisopropylethylamine (120 mg, 0.93 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol), and cyclopropanecarbohydrazide (46 mg, 0.46 mmol) were added, and the mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (30 ml x 3). The combined organic layers were washed with brine (30 ml x 3), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative MPLC (column: Spherical C18, 20-45 μm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile, flow rate 50 ml / min) to obtain 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]-N'-(cyclopropanecarbonyl)tetrahydropyran-2-carbohydrazide (110 mg, yield 92%) as a pale yellow solid. MS m / z: 514.2 [M+H] + ,ESI pos.

[0340] Step 2: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadi [Azole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]-N'-(cyclopropanecarbonyl)tetrahydropyran-2-carbohydrazide (90 mg, 0.18 mmol) in tetrahydrofuran (3 ml), Burgess reagent (CAS 29684-56-8, 417 mg, 1.75 mmol) was added, and the mixture was stirred at 130°C for 0.5 hours under microwave irradiation. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried over Na2SO4 and then concentrated under vacuum. The residue was purified by preparative HPLC (Phenomenex Luna, C18, 150×25mm×10μm, mobile phase: water / 0.25% formate-acetonitrile, 0-82%, flow rate 25ml / min) to obtain a racemic compound. This was then separated by chiral SFC (Daicel Chiralpak AS, 250mm×30mm, 10μm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 75ml / min) to obtain 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (18mg, yield 28%) as the first eluted enantiomer. It was a pale yellow solid, MS m / z: 496.2 [M+H]. + ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (17 mg, yield 26%) were eluted as the second enantiomer, a pale yellow solid, MS m / z: 496.2 [M+H] +ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (10 mg, yield 15%) were prepared as a racemic mixture, pale yellow solid, MS m / z: 496.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0341] Examples 144-149 below were prepared in the same manner as in Example 58, starting from the indicated intermediates. Diastereomer separation was performed by preparative HPLC (Phenomenex Luna column, C18, 150 × 25 mm × 10 μm, mobile phase: water / 0.25% formate-acetonitrile, 0-73%, flow rate 25 ml / min), and chiral separation was performed by chiral SFC (Daicel Chiralpak IC 250 mm × 30 mm, 10 μm, acetonitrile / methanol / 0.1% ammonium hydroxide, flow rate 80 ml / min). Relative stereochemistry was performed. 1 The assignment was based on evaluation of H-NMR measurements, and absolute stereochemistry was assigned arbitrarily. [Table 23] TIFF2026521750000223.tif90170

[0342] Examples 150 and 1519-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(difluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(difluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Examples 133 and 134, using intermediate C24 instead of intermediate C21. Yellow solid, MS m / z: 504.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0343] Examples 152 and 1539-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclobutylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclobutylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] The title compound was prepared in the same manner as in Examples 66 and 67, using intermediate C25 instead of intermediate C5. Yellow solid, MS m / z: 509.1 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0344] Examples 154-165 below were prepared in the same manner as in Example 15, starting from the indicated intermediates. The reduction in step 2 was carried out by adding magnesium oxide and triethylamine, as described in Examples 131 and 132. Chiral separation was performed as described in Examples 95 and 96. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 24] TIFF2026521750000227.tif241170 TIFF2026521750000228.tif42170

[0345] Examples 166, 167 and 1689-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1 [2,4-Oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] Step 1: 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxamide [ka] Ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylate (see intermediate D1 step 3, 150 mg, 0.33 mmol) was reacted in a methanol-ammonia solution (7 M, 5.0 ml, 35.0 mmol) in a sealed tube at 60°C for 16 hours. The reaction mixture was then concentrated under vacuum to obtain 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxamide (140 mg, 99% yield) as a pale yellow solid. MS m / z: 431.1 [M+H] + ,ESI pos.

[0346] Step 2: 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carbonitrile [ka] To a solution of 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxamide (140 mg, 0.32 mmol) in tetrahydrofuran (4 ml), pyridine (0.08 ml, 0.97 mmol) was added at 25°C, followed by the dropwise addition of trifluoroacetic anhydride (0.14 ml, 0.97 mmol) at 0°C. The reaction mixture was stirred at 20°C for 16 hours. The reaction mixture was poured into a saturated aqueous solution of NaHCO3 (30 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layer was washed with saturated brine (50 ml), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC (silica gel, ethyl acetate) to obtain 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carbonitrile (100 mg, yield 74%) as a pale yellow solid. MS m / z: 413.1 [M+H] + ,ESI pos.

[0347] Step 3: 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]-N-hydroxytetrahydropyran-2-carboxamidine [ka] To a well-mixed solution of hydroxylamine hydrochloride (50 mg, 0.73 mmol) and triethylamine (98 mg, 0.97 mmol) in 1,4-dioxane (1 ml), a solution of 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxopyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carbonitrile (100 mg, 0.24 mmol) in 1,4-dioxane (2 ml) was added, and the reaction mixture was then heated at 100°C for 3 hours. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (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 preparative MPLC (column: Spherical C18, 20-45 μm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile 54-62%, flow rate 50 ml / min). The eluent was adjusted to 8 with saturated NaHCO3 aqueous solution, and then extracted to obtain 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]-N-hydroxytetrahydropyran-2-carboxamidine (80 mg, yield 74%) as a pale yellow solid. MS m / z: 446.1 [M+H] + ,ESI pos.

[0348] Step 4: N-[C-[4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-yl]-N-hydroxy-carbonimidoyl]cyclopropanecarboxamide [ka] To a solution of 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]-N-hydroxytetrahydropyran-2-carboxamidine (80 mg, 0.18 mmol) in dimethylformamide (3 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol), N,N-diisopropylethylamine (93 mg, 0.72 mmol), 1-hydroxybenzotriazole (24 mg, 0.18 mmol), and cyclopropanecarboxylic acid (15.5 mg, 0.18 mmol) were added. The reaction mixture was stirred at 20°C for 16 hours, then poured into water (30 ml) and extracted with ethyl acetate (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 preparative TLC (silica gel, ethyl acetate) to obtain N-[C-[4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-yl]-N-hydroxy-carbonimidoyl]cyclopropanecarboxamide (80 mg, yield 87%) as a pale yellow solid. MS m / z: 514.1 [M+H] + ,ESI pos.

[0349] Step 5: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadi [Azole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] N-[C-[4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-yl]-N-hydroxy-carbonimidoyl]cyclopropanecarboxamide (70 mg, 0.14 mmol) was dissolved in ethanol (1 ml) and water (0.8 ml), to which sodium acetate (22 mg, 0.27 mmol) was added, and the reaction mixture was stirred at 80°C for 48 hours. The mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml x 3). The combined organic layers were dried over Na2SO4 and then concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether / ether = 1:1) to obtain 9-(4-chloro-2-fluorophenyl)-7-[2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one, which was then used as a chiral SFC (Daicel Chiralpak AS). Separation was performed using a 250mm x 30mm, 10μm filter (ethanol / 0.1% ammonium hydroxide, flow rate 80ml / min) to obtain 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (13mg, yield 18%) as the first eluted enantiomer, a pale yellow solid, MS m / z: 496.2 [M+H]. + ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (10 mg, yield 14%) were eluted as the second enantiomer, a pale yellow solid, MS m / z: 496.2 [M+H] +ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (6 mg, yield 8%) were prepared as a racemic mixture, pale yellow solid, MS m / z: 496.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0350] Examples 169, 170 and 1719-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl [-1,2,4-Oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] In step 1, the title compound was prepared in the same manner as in Examples 166-168, using ethyl 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7-yl]tetrahydropyran-2-carboxylate (see intermediate D2) instead of 4-[9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (see intermediate D2). Pale yellow solid, MS m / z: 496.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0351] Examples 172-176 were prepared in the same manner as Examples 141-143, starting from the intermediate shown instead of intermediate D1. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 25]

[0352] Example 177 2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]-9-[6-(trifluoromethyl)pyridine-3-yl]pyrazino[1,2-a]pyrimidine-4-one [ka] Similar to Example 133, the title compound was prepared using intermediate C31 instead of intermediate C21 and intermediate B19 instead of intermediate B2. Yellow solid, MS m / z: 485.4 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0353] Examples 178 and 179: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared by chiral separation of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methyl-6-oxopyridine-3-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one (Example 83) using chiral SFC (Chiral AD-H column, 250 mm × 30 mm, 5 μm, 55% methanol + 0.2% diethylamine). Absolute stereochemistry was arbitrarily assigned. Yellow solid, MS m / z: 495.2 [M+H] + ,ESI pos.

[0354] Examples 180-190 were prepared in the same manner as in Example 15, starting from the indicated intermediates. The reduction in step 2 was carried out by adding magnesium oxide and triethylamine, as described in Examples 131 and 132. Chiral separation was performed as described in Examples 178 and 179. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 26] TIFF2026521750000240.tif249170

[0355] Examples 191 and 192: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] Step 1: 9-(4-chloro-2-fluorophenyl)-7-[6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of [6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (intermediate C29, 400 mg, 1.09 mmol) in 1,4-dioxane (12 ml) and water (2.5 ml), 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazino[1,2-a]pyrimidine-4-one (intermediate B13, 470 mg, 1.09 mmol), potassium carbonate (454 mg, 3.28 mmol), and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride (81 mg, 0.11 mmol, 0.10 equivalents) were added under argon flow. The reaction mixture was heated to 60°C, stirred for 2.5 hours, filtered through dikalyte, and washed with ethyl acetate. The filtrate was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (silica gel, dichloromethane, 0-10% methanol) to obtain 9-(4-chloro-2-fluorophenyl)-7-[6-(1-cyclopropyl-6-keto-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (566 mg, yield 90%) as a pale brown foam, MS m / z: 519.2 [M+H]. + ,ESI pos.

[0356] Step 2: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] To a solution of 9-(4-chloro-2-fluorophenyl)-7-[6-(1-cyclopropyl-6-keto-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (250 mg, 0.482 mmol) in ethyl acetate (11 ml), triethylamine (58 mg, 80 μl, 0.578 mmol), magnesium oxide (194 mg, 4.82 mmol), and carbon-supported palladium (10%, 102 mg) were added under argon. The mixture was degassed several times with argon, and then stirred at room temperature under a hydrogen gas atmosphere (balloon pressure) for 4 hours. The reaction mixture was filtered through a dikalyte, and the mother liquor was concentrated under vacuum. The residue was purified by reverse-phase chromatography (column C18, 10-70% acetonitrile in water) to obtain 9-(4-chloro-2-fluorophenyl)-7-[2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one. When the enantiomer was separated by chiral SFC (Chiralpak SZ column, 250 mm × 20 mm, 5 μm, 55% methanol), the first eluted enantiomer was 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (19 mg, yield 8%), yellow solid, MS m / z: 521.2 [M+H]. +ESI pos. and a second eluted enantiomer, 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one (15 mg, yield 6%), were obtained as a yellow solid. MS m / z: 521.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0357] Examples 193–196 below were prepared in the same manner as in Examples 191 and 192, starting from the intermediate shown instead of intermediate C29. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 27]

[0358] Example 197: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] Step 1: 9-(4-chloro-2-fluorophenyl)-7-[6-(2-chloro-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one [ka] Potassium carbonate (1.23 g, 8.87 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (219 mg, 0.296 mmol, 0.10 equivalents) were added to a solution of 2-chloro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (intermediate C34, 1.05 g, 3.25 mmol) and 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (intermediate B3, 1 g, 2.96 mmol) in 1,4-dioxane (48 ml) and water (8 ml). The mixture was purged, argon was added three times, and then heated to 60°C and stirred for 1.5 hours. The reaction mixture was filtered through dikalyte and washed twice with ethyl acetate. The filtrate was poured into water and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (silica gel, heptane, 0%-70% ethyl acetate) to obtain 9-(4-chloro-2-fluorophenyl)-7-[6-(2-chloro-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (930 mg, yield 51%) as a grayish-white solid, MS m / z: 495.2 [MH]. + ,ESI neg.

[0359] Step 2: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] To a solution of 9-(4-chloro-2-fluorophenyl)-7-[6-(2-chloro-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (720 mg, 1.45 mmol) in 1,4-dioxane (12 ml), solutions of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatrivolinane (3.5 M in tetrahydrofuran, 538 μl, 1.88 mmol), potassium carbonate (600 mg, 4.34 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride) (107.39 mg, 0.145 mmol, 0.10 equivalents) were added under an argon stream. The reaction mixture was heated to 90°C and stirred for 2 hours. After cooling to room temperature, the mixture was filtered through Celite and washed with ethyl acetate. The filtrate was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (Si-amine, heptane, 0%-70% ethyl acetate) to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,4-dihydro-2H-pyran-4-yl]pyrimido[1,2-b]pyridazin-4-one (380 mg, yield 52%) as a yellow foam, MS m / z: 477.2 [M+H]. + ,ESI pos.

[0360] Step 3: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrimido[1,2-b]pyridazin-4-one (380 mg, 0.757 mmol) was dissolved in ethanol (15 ml), to which carbon-supported palladium (10%, 84 mg) was added under argon. The mixture was stirred at room temperature for 10 hours under a hydrogen gas atmosphere (balloon pressure). The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated under vacuum and purified by flash chromatography (column C18, 0-50% acetonitrile in water). The fractions containing the product were combined, and acetonitrile was removed by evaporation. The residue was poured into ethyl acetate and extracted. The combined organic layers were dried with Na2SO4 and concentrated under vacuum to obtain the title compound (205 mg, 54% yield) as a yellow foamy substance. MS m / z: 479.2 [M+H] + ,ESI pos.

[0361] Examples 198 and 199: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] When the racemic mixture 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one (Example 197) was separated by chiral SFC (column chiral SZ, 5 μm, 250 × 20 mm, 43% methanol), the first eluted enantiomer was 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[( [2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one was obtained as a yellow foam with a retention time of 3.595 minutes, and as a second eluted enantiomer, 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one was obtained as a yellow foam with a retention time of 4.843 minutes. MS m / z: 479.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0362] Example 200: 9-(2-fluorophenyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one [ka] This compound was formed as a byproduct during the hydrogenation step in the synthesis of Examples 89 and 90. It was isolated after this reaction by column chromatography (silica gel, dichloromethane, 10% methanol) (yield 18%), resulting in a yellow solid, MS m / z: 461.4 [M+H]. + ,ESI pos.

[0363] Examples 201 and 202: 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] Step 1: 9-(4-chloro-2-fluorophenyl)-7-[6-(6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one [ka] A solution of 2-methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (intermediate C35, 2.19 g, 6.92 mmol) in 1,4-dioxane (62 ml) and water (10 ml) was added to 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (intermediate B3, 1.8 g, 5.32 mmol). The mixture was degassed and refilled with nitrogen three times. Next, potassium carbonate (2.21 g, 16.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (395 mg, 0.532 mmol, 0.10 equivalents) were added, and the mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered through dikalyte and washed with ethyl acetate. The filtrate was poured into water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to dryness. Purification of the residue by flash chromatography (silica gel, heptane, 0-80% ethyl acetate) yielded 9-(4-chloro-2-fluorophenyl)-7-[6-(6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (1.95 g, yield 74%) as a pale yellow solid, MS m / z: 493.3 [M+H] + ,ESI pos..

[0364] Step 2: 9-(4-chloro-2-fluorophenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one [ka] To a solution of 9-(4-chloro-2-fluorophenyl)-7-[6-(6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (350 mg, 0.639 mmol), triethylamine (78 mg, 107 μl, 0.767 mmol), and magnesium oxide (257 mg, 6.39 mmol) in ethyl acetate (7 ml), platinum(IV) oxide (29 mg, 0.128 mmol, 0.20 equivalents) was added under argon. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through a dikalyte and evaporated. Purification of the crude substance by flash chromatography (ethyl acetate / ethanol in silica gel and heptane = 3:1, 0-20%) yielded 9-(4-chloro-2-fluorophenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one as a yellow solid (184 mg, yield 58%), MS m / z: 493.3 [M+H]. + ,ESI pos.

[0365] Step 3: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridine-3-yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one [ka] 9-(4-chloro-2-fluorophenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (134 mg, 0.27 mmol) and sodium iodide (40.5 mg, 0.27 mmol) were dissolved in acetonitrile (5.5 ml), to which trimethylsilyl chloride (29 mg, 34 μl, 0.27 mmol) was added, and the mixture was stirred at 65°C for 3 hours. The solvent was removed under vacuum, and the residue was purified by chromatography (ethyl acetate / ethanol in silica gel and heptane = 3:1, 0-90%) to obtain 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridine-3-yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one as a yellow powder (107 mg, yield 78%), MS m / z: 481.3 [M+H]. + ,ESI pos.

[0366] Step 4: 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] When the racemic mixture of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridine-3-yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one was separated by chiral SFC (Chiral NR column, 250 mm × 20 mm, 5 μm, 60% methanol), 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one was obtained. The first eluted enantiomer was an orange powder, MS m / z: 481.3 [M+H]. + ,ESI pos. and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one, second elution enantiomer, orange powder, MS m / z:481.3 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0367] Examples 203-206 below were prepared in the same manner as in Examples 191 and 192, starting from the intermediate shown instead of intermediate C29. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 28]

[0368] Examples 207 and 208: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] Step 1: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-[1-(oxetan-3-ylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]pyrimido[1,2-b]pyridazine-4-one [ka] To a suspension of 7-chloro-9-(4-chloro-2-fluorophenyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (intermediate B3, 300 mg, 0.887 mmol) in 1,4-dioxane (6 ml), bis(pinacorato)diborone (338 mg, 1.33 mmol) and potassium acetate (261 mg, 2.66 mmol) were added at room temperature. After degassing the mixture with argon, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (73 mg, 89 μmol, 0.10 equivalents) was added, and the mixture was stirred at 90°C for 90 minutes. Next, [6-[1-(oxetan-3-ylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]trifluoromethanesulfonate (intermediate C33, 421 mg, 1.06 mmol), cesium carbonate solution (3 M, 0.88 μl, 2.66 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (73 mg, 89 μmol, 0.10 equivalents) were added, and the reaction mixture was stirred at 90°C for a further 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 C18, 10-100% acetonitrile in water), followed by a second flash chromatography (silica gel, 0-4% methanol in dichloromethane), yielding 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-[1-(oxetan-3-ylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]pyrimido[1,2-b]pyridazin-4-one (47 mg, 9% yield) as a light brown solid. MS m / z: 549.2 [M+H] + ,ESI pos.

[0369] Step 2: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] To a solution of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[6-[1-(oxetan-3-ylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl]pyrimido[1,2-b]pyridazin-4-one (30 mg, 55 μmol) in ethyl acetate (1.5 ml) and triethylamine (6.6 mg, 9 μl, 66 μmol), magnesium oxide (22 mg, 546 μmol) and platinum(IV) oxide (2.5 mg, 11 μmol, 0.20 equivalents) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered, washed with dichloromethane / methanol in a 9:1 ratio, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography (silica C18, acetonitrile 10-100% in water) to obtain the racemic mixture 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one, which was then purified by chiral SFC (column). Further separation by (SZ, 5 μm, 250 × 20 mm, 55% methanol) yielded 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (5 mg, yield 15%), pale yellow solid, MS m / z: 551.2 [M+H] as the first eluted enantiomer. + ,ESI pos. and second eluted enantiomer: 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (5 mg, yield 15%), pale yellow solid, MS m / z: 551.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0370] Examples 209-221 below were prepared in the same manner as in Example 15, starting from the indicated intermediates. The reduction in step 2 was carried out by adding magnesium oxide and triethylamine, as described in Examples 131 and 132. Chiral separation was performed as described in Examples 178 and 179. Absolute stereochemistry was arbitrarily assigned, and relative stereochemistry was determined by NMR. [Table 29] TIFF2026521750000261.tif229170 TIFF2026521750000262.tif81170

[0371] Examples 222 and 223: 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] The title compound was prepared using intermediate D4 instead of intermediate D1, in the same manner as in Examples 141 and 142. Yellow solid, MS m / z: 486.2 [M+H] + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0372] Example 224: 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one [ka] The title compound was prepared in the same manner as in Example 201, using intermediate B16 instead of intermediate B3 in step 1. It was a grayish-white solid, MS m / z: 471.3 [M+H]. + The absolute stereochemistry of the ESI pos. was arbitrarily assigned.

[0373] Example 225: 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one [ka] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (Example 201, 15 mg, 31 μmol) was suspended in acetonitrile (2 ml) to which cesium carbonate (30.5 ...

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, A １ , X １ and X ２ Each is independently selected from N and CH; A ２ O and CR ５ R ６ Selected from; R １ is selected from C １ -C ６ -alkyl and halo-C １ -C ６ -alkyl; R ２ C ６ -C １０ - Aryl, 5-6 member heteroaryl and C ３ -C １０ - Selected from cycloalkyl, the C ６ -C １０ - Aryl, 5-6 member heteroaryl and C ３ -C １０ -Cycloalkyls are halogens, C １ -C ６ -Alkyl and halo-C １ -C ６ - It is optionally substituted with 1 to 3 substituents independently selected from the alkyl group; R ３ The 5-6 member heteroaryl and 3-6 member heterocyclil are selected from halogen, cyano, amino, hydroxy, oxo, and C. １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, C １ -C ６ -Alkoxy-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 - Cycloalkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyloxy, 3-6 membered heterocyclyl, halo-3-6 membered heterocyclyl, 3-6 membered heterocyclyl-C １ -C ６ -Alkyl, 3-6 member heterocyclyl-C １ -C ６ - Optionally substituted with 1 to 3 substituents independently selected from alkoxys and 3- to 6-membered heterocyclyloxys; R ４ is hydrogen and C １ -C ６ - Selected from alkyl groups; R ５ and R ６ Each is independently selected from hydrogen and halogen; and R ７ is hydrogen and C １ -C ６ (Selected from alkyl groups) Compounds thereof, or pharmaceutically acceptable salts thereof.

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

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

4. A １ A compound of formula (I) according to any one of claims 1 to 3, wherein is CH, or a pharmaceutically acceptable salt thereof.

5. A １ A compound of formula (I) according to any one of claims 1 to 3, wherein is N, or a pharmaceutically acceptable salt thereof.

6. A ２ However, O and CR ５ R ６ Selected from; R ５ and R ６ However, both are hydrogen, or R ５ and R ６ However, both are halogens. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. A ２ However, O and CR ５ R ６ Selected from; R ５ and R ６ However, both are hydrogen, or R ５ and R ６ However, both are fluoro. A compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof.

8. A ２ The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein A is O.

9. The compound of formula (I) is of formula (II) or (III): 【Chemistry 2】 (In the formula, the variables are as defined in any one of claims 1 to 3.) A compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

10. R １ is methyl and CHF ２ A compound of formula (I) according to any one of claims 1 to 9, selected from, or a pharmaceutically acceptable salt thereof.

11. R ２ is selected from C ６ -C １０ -aryl, C ３ -C １０ -cycloalkyl, and 5- to 6-membered heteroaryl containing 1 to 2 heteroatoms independently selected from N, O, and S, wherein the C ６ -C １０ -aryl, C ３ -C １０ -cycloalkyl and 5- to 6-membered heteroaryl are optionally substituted with 1 to 3 substituents independently selected from halogen and halo-C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

12. R ２ The phenyl, pyridyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane are selected from phenyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane, and the phenyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane are fluoro, chloro, CHF ２ and CF ３ A compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is optionally substituted with one to three substituents independently selected from the compound.

13. R ２ However, C ６ -C １０ - Aryl and C ３ -C １０ - Selected from cycloalkyl, the C ６ -C １０ - Aryl and C ３ -C １０ -Cycloalkyl is a halogen and halo-C １ -C ６ - A compound of formula (I) according to claim 11, or a pharmaceutically acceptable salt thereof, substituted with one to three substituents independently selected from alkyl.

14. R ２ However, fluoro, chloro and CHF ２ A compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane substituted with one to three substituents independently selected from the above.

15. R ２ A compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein is selected from the following. Table 1

16. R ３ However, the following are selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, and a 3-6 membered heterocycline containing 1-2 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, wherein the 5-6 membered heteroaryl is C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, C １ -C ６ -Alkoxy-C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyl, Halo-C ３ -C １０ - Cycloalkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyloxy, 3-6 member heterocyclyl, 3-6 member heterocyclyl-C １ -C ６ - Alkyl and 3-6 member heterocyclyl-C １ -C ６ - It is optionally substituted with one or two substituents independently selected from the alkoxy, and the 3-6 member heterocyclyl is C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, C １ -C ６ -Alkoxy-C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyl, Halo-C ３ -C １０ - Cycloalkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyloxy, 3-6 member heterocyclyl, 3-6 member heterocyclyl-C １ -C ６ -Alkyl, 3-6 member heterocyclyl-C １ -C ６ A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from alkoxy and oxo.

17. R ３ However, the following are selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl and 1,2-dihydropyridine, and the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl are methyl, ethyl, isopropyl, CHF ２ CF ３ , 1,2-dihydropyridine is optionally substituted with one or two substituents independently selected from 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl and oxetanylmethoxy, wherein the 1,2-dihydropyridine is methyl, ethyl, isopropyl, CHF ２ CF ３ A compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, optionally substituted with one or two substituents independently selected from 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, oxetanylmethoxy, and oxo.

18. R ３ However, the following are selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, and a 3-6 membered heterocycline containing 1-2 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, wherein the 5-6 membered heteroaryl is C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, C ３ -C １０ - Substituted with one substituent selected from cycloalkyl and 3- to 6-membered heterocyclines, wherein the 3- to 6-membered heterocycline is oxo and optionally C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, and C ３ -C １０ - A compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, substituted with one further substituent selected from cycloalkyl groups.

19. R ３ A compound of formula (I) according to claim 18, or a pharmaceutically acceptable salt thereof, wherein the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine are selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are substituted with one substituent selected from methyl, methoxy, cyclopropyl, and oxetanyl, and the 1,2-dihydropyridine is substituted with oxo and optionally one further substituent selected from methyl, isopropyl, 2,2,2-trifluoroethyl, and cyclopropyl.

20. R ３ A compound of formula (I) according to claim 19, or a pharmaceutically acceptable salt thereof, wherein is selected from the following. Table 2

21. R ４ A compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and methyl.

22. R ４ A compound of formula (I) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

23. R ７ A compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and methyl.

24. R ７ C １ -C ６ - A compound of formula (I) according to any one of claims 1 to 22, which is alkyl, or a pharmaceutically acceptable salt thereof.

25. R ７ A compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, wherein is methyl.

26. (i) X １ and X ２ However, both are CH; or (ii) X １ CH is, X ２ Is N; or (iii)X １ N is X ２ CH is; A １ However, selected from N and CH; A ２ However, O and CR ５ R ６ Selected from; R １ However, C １ -C ６ -Alkyl and halo-C １ -C ６ - Selected from alkyl groups; R ２ However, C ６ -C １０ - Aryl, C ３ -C １０ - Selected from cycloalkyls and 5-6 membered heteroaryls containing 1-2 heteroatoms independently selected from N, O, and S, and the C ６ -C １０ - Aryl, C ３ -C １０ -Cycloalkyl and 5-6 member heteroaryl compounds are halogens and halo-C １ -C ６ - It is optionally substituted with 1 to 3 substituents independently selected from the alkyl group; R ３ However, the following are selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, and a 3-6 membered heterocycline containing 1-2 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, wherein the 5-6 membered heteroaryl is C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, C １ -C ６ -Alkoxy-C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyl, Halo-C ３ -C １０ - Cycloalkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyloxy, 3-6 member heterocyclyl, 3-6 member heterocyclyl-C １ -C ６ - Alkyl and 3-6 member heterocyclyl-C １ -C ６ - It is optionally substituted with one or two substituents independently selected from the alkoxy, and the 3-6 member heterocyclyl is C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, C １ -C ６ -Alkoxy-C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyl, Halo-C ３ -C １０ - Cycloalkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkyl, C ３ -C １０ -Cycloalkyl-C １ -C ６ - Alkoxy, C ３ -C １０ -Cycloalkyloxy, 3-6 member heterocyclyl, 3-6 member heterocyclyl-C １ -C ６ -Alkyl, 3-6 member heterocyclyl-C １ -C ６ - Optionally substituted with one or two substituents independently selected from alkoxy and oxo; R ４ However, hydrogen and C １ -C ６ - Selected from alkyl groups; R ５ and R ６ However, both are hydrogen, or R ５ and R ６ However, both are halogens; and R ７ However, hydrogen and C １ -C ６ - Selected from alkyl groups, A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

27. (i) X １ and X ２ However, both are CH; or (ii) X １ CH is, X ２ Is it N; or (iii)X １ N is X ２ is CH; A １ However, selected from N and CH; A ２ However, O and CR ５ R ６ Selected from; R １ However, methyl and CHF ２ Selected from; R ２ The phenyl, pyridyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane are selected from phenyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane, and the phenyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane are fluoro, chloro, CHF ２ and CF ３ It is optionally substituted with 1 to 3 substituents independently selected from the original molecule; R ３ However, the following are selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl and 1,2-dihydropyridine, and the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl are methyl, ethyl, isopropyl, CHF ２ CF ３ , 1,2-dihydropyridine is optionally substituted with one or two substituents independently selected from 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl and oxetanylmethoxy, wherein the 1,2-dihydropyridine is methyl, ethyl, isopropyl, CHF ２ CF ３ , optionally substituted with one or two substituents independently selected from 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutyloxy, oxetanyl, oxetanylmethyl, oxetanylmethoxy and oxo; R ４ However, hydrogen and methyl are selected; R ５ and R ６ However, both are hydrogen, or R ５ and R ６ However, both are fluoro; and R ７ However, selected from hydrogen and methyl, A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

28. (i) X １ CH is, X ２ Is N; or (ii) X １ N is X ２ CH is; A １ However, it is CH; A ２ However, it is O; R １ However, C １ -C ６ -Alkyl and halo-C １ -C ６ - Selected from alkyl groups; R ２ However, C ６ -C １０ - Aryl and C ３ -C １０ - Selected from cycloalkyl, the C ６ -C １０ - Aryl and C ３ -C １０ -Cycloalkyl is a halogen and halo-C １ -C ６ - Substituted with 1 to 3 substituents independently selected from alkyl groups; R ３ However, the following are selected from a 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, and a 3-6 membered heterocycline containing 1-2 heteroatoms independently selected from N, O, and S, with the remaining atom being carbon, wherein the 5-6 membered heteroaryl is C １ -C ６ - Alkyl, C １ -C ６ - Alkoxy, C ３ -C １０ - Substituted with one substituent selected from cycloalkyl and 3- to 6-membered heterocyclines, wherein the 3- to 6-membered heterocycline is oxo and optionally C １ -C ６ -Alkyl, Halo-C １ -C ６ - Alkyl, and C ３ -C １０ - Substituted with one further substituent selected from cycloalkyl groups; R ４ but is hydrogen; and R ７ However, C １ -C ６ - It is alkyl, A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

29. (i) X １ CH is, X ２ Is N; or (ii) X １ N is X ２ CH is; A １ However, it is CH; A ２ However, it is O; R １ However, methyl and CHF ２ Selected from; R ２ However, fluoro, chloro and CHF ２ Selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane substituted with one to three substituents independently selected from; R ３ The substituents are selected from pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are substituted with one substituent selected from methyl, methoxy, cyclopropyl, and oxetanyl, and the 1,2-dihydropyridine is substituted with oxo and optionally one further substituent selected from methyl, isopropyl, 2,2,2-trifluoroethyl, and cyclopropyl; R ４ However, it is hydrogen; and R ７ However, it is methyl. A compound of formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

30. The compound of formula (I) above, 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(3S)-3-(1-methylpyrazole-4-yl)-1-piperidyl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholin-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(3S)-4,4-difluoro-3-(1-methylpyrazole-4-yl)-1-piperidyl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methylmorpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridine-4-yl)morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methylpyridine-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methylpyridine-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methylmorpholine-4-yl]-2,3-dimethylpyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-onformeate; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methylmorpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methylmorpholine-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,2,4-oxadiazole-3-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazole-2-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxypyridine-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxypyridine-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazole-4-yl)morpholino]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]morpholine-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxetan-3-yl)pyrazole-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(1-methyl-6-oxopyridine-3-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)oxan-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[rac-(2R,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[rac-(2R,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyltetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyltetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R,6S)-2-(1-cyclopropylpyrazole-4-yl)-6-methyltetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4S,6R)-2-(1-cyclopropylpyrazole-4-yl)-6-methyltetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2S)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2R)-2-(1-cyclopropylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(trifluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[rac-(2R,4R)-2-(1-methylpyrazole-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1H-pyrazole-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(difluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(difluoromethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclobutylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclobutylpyrazole-4-yl)morpholine-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclobutylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclobutylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazole-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazole-4-yl)oxan-4-yl]-9-[6-(trifluoromethyl)pyridine-3-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(2-methoxyethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(2-methoxyethyl)pyrazole-4-yl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[rac-(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[rac-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(2-fluorophenyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4R)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetan-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[rac-(2R,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 2,3-dimethyl-7-[rac-(2R,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1H-pyridine-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-2-(difluoromethyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1,5-dimethylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1,5-dimethylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1,3-dimethylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1,3-dimethylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[2-(cyclobutoxy)-4-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-[2-(oxetan-3-ylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-9-[(1R,5S)-6,6-difluoro-3-bicyclo[3.1.0]hexanyl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4,4-difluorocyclohexyl)-7-[rac-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxetan-3-yl)pyrazole-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[rac-(2R,4S)-2-[6-keto-1-(trifluoromethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one; 9-(4-chloro-2,6-difluorophenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one; and 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethylpyrazino[1,2-a]pyrimidine-4-one A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

31. A compound of formula (I) according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

32. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, and a therapeutically inactive carrier.

33. A method for treating or preventing symptoms associated with loss of function of human TREM2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32.

34. The method according to claim 33, wherein the symptoms associated with the 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.

35. A compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32, for use in the method according to claim 33 or 34.

36. The use of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 32, in the method according to claim 33 or 34.

37. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 30 in the preparation of a pharmaceutical for use in the method according to claim 33 or 34.

38. The invention is as described above.

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