TREM2 agonists

Abstract

The present invention provides compounds having the general formula (I) wherein A1, A2, X1, X2, R1, R2, R3, R4 and R7 are as described herein, compositions comprising the compounds, methods of making the compounds, and methods of using the compounds in the treatment or prevention of diseases associated with TREM2.

Description

Technical Field

[0001] This invention relates to organic compounds that can be used for the treatment or prevention of diseases in mammals, and 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 residing in the central nervous system (CNS) that play a crucial role in CNS development and the maintenance of 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 are also key factors in response to neurodegenerative symptoms and neuropathological lesions, in which they transition 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 a variety of receptors on their surface, which play a crucial role in sensing complex crosstalk between environmental changes and regulating their physiological functions.

[0004] TREM2 (Trigger Receptor 2 expressed on myeloid cells) is one of these cell surface receptors that is expressed on microglia in the brain and plays a key role in microglia survival and activation (Colonna, M. et al., Nat Rev Immunol 3, 445-453 (2003). https: / / doi.org / 10.1038 / nri1106). TREM2 is a single-transmembrane receptor belonging to the immunoglobulin superfamily (Ig-SF). It consists of a ligand-binding extracellular immunoglobulin variable-like domain (IgV) followed by a long-stalked domain, a single transmembrane helix, and a short cytoplasmic tail without signal transduction motifs. Downstream signal transduction is mediated by its interaction with the effector protein DAP12, a transmembrane disulfide-linked adaptor dimer whose expression and cellular localization on the plasma membrane depend on TREM2. DAP12 is associated with TREM2 via a lysine-aspartate interaction (K156-D50) to form a signal transduction complex (Zhong L. et al., J Biol Chem. 2015;290(25):15866–77). Due to its short extracellular domain, DAP12 lacks ligand-binding capacity. Endogenous ligands for TREM2 include a variety of molecules, including phospholipids, glycolipids, lipoproteins, cell debris, myelin, and Aβ oligomers. Stimulation of the TREM2 / DAP12 complex induces phosphorylation of two tyrosine residues within the immune receptor-based tyrosine activation motif (ITAM) in the cytoplasmic domain of DAP12, which leads to the recruitment of Syk kinase to activate downstream signaling molecules.

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

[0006] Genetic variants of TREM2 are associated with many neurodegenerative diseases (Hou J. et al. Molecular Neurodegeneration (2022) 17:84; doi: org / 10.1186 / s13024-022-00588-y). TREM2 variants resulting in the loss of TREM2 expression have been identified as a cause of Nasu-Hakola disease (NHD) or polycystic fat membrane osteodysplasia with sclerotic leukoencephalopathy (PLOSL), a fatal disease characterized by progressive premature dementia and myelin loss and skeletal abnormalities, 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). Several of these TREM2 variants are associated with impaired microglial function and a reduced response to neurodegenerative diseases. (Kleinberger, G. et al., Sci. Transl. Med. 2014, 6, 243ra86).

[0007] Furthermore, genome-wide association studies (GWAS) have shown a strong association between some 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 them, the R47H variant is a LoF mutation associated with structural changes within the extracellular domain of TREM2, which leads to impaired binding of endogenous ligands and is associated with an approximately 3-fold increase in the risk of LOAD (Sudom, A. et al., JBiol Chem. 2018 10;293(32):12634-12646; doi: 10.1074 / jbc.RA118.002352). Ongoing research aims to elucidate the mechanisms by which TREM2 LoF mutations lead to Alzheimer's disease (AD). Patients carrying these mutations may exhibit impaired microglial function, including reduced clearance of extracellular aggregates (e.g., amyloid and myelin debris) and apoptotic neurons, ultimately resulting in a decreased ability to fight the disease and increased susceptibility to neurodegeneration. Indeed, reduced microglial activation and failure to aggregate around amyloid plaques have been observed in mouse models with TREM2 or DAP12 deficiencies, confirming the central role of TREM2 signaling in microglial function and the response to pathological markers of Alzheimer's disease.

[0008] Given all this evidence, pharmacological activation of TREM2 appears to be a viable therapeutic intervention. The small molecule disclosed in this article is a potent, selective agonist of TREM2. Summary of the Invention

[0009] In a first aspect, the present invention provides a compound of formula (I).

[0010] (I)

[0011] Where A 1 A 2 X 1 X 2 R 1 R 2 R 3 R 4 and R 7 As defined in this article.

[0012] In another aspect, the present invention provides compositions comprising formula (I), methods for manufacturing formula (I), and methods for using formula (I). Detailed Implementation

[0013] Definitions

[0014] Features, integers, properties, compounds, chemical parts, or groups described in connection with specific aspects, embodiments, or examples of the invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless incompatible therewith. All features disclosed in this specification (including any appended claims, abstract, and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for at least some mutually exclusive combinations of these features and / or steps. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any appended claims, abstract, and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0015] The term "alkyl" refers to 1 to 6 carbon atoms ("C6H ...7H6H6H6H6H7H6H6H6H7H6H6H6H7H6H6H7H6H6H7H6H6H7H6H6H7H6H6H7H6H 1-6 Alkyl groups are monovalent or polyvalent (e.g., monovalent or divalent) straight-chain or branched saturated hydrocarbon groups ("-alkyl"). In some embodiments, the alkyl group contains 1 to 4 carbon atoms, such as 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.

[0016] The term "alkoxy group" refers to an alkyl group as defined above, attached to the parent molecule via an oxygen atom. Unless otherwise stated, an alkoxy group contains 1 to 6 carbon atoms ("C"). 1-6 (-alkoxy group). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, such as 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of an alkoxy group is methoxy.

[0017] The term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferably, the term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), or bromine (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halogenated" are fluorine (F) and chlorine (Cl).

[0018] As used herein, the term "cycloalkyl" refers to a ring of 3 to 10 carbon atoms ("C10") 3-10 A saturated monocyclic or bicyclic hydrocarbon group of the form "-cycloalkyl". In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group with 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms (i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms) and a spirocyclic moiety (i.e., the two rings are connected by a common ring atom). Preferably, the cycloalkyl group is a monocyclic hydrocarbon group with 3 to 6 ring carbon atoms (e.g., 3, 4, 5 or 6 carbon atoms). Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, norbornelalkyl and 1-bicyclo[2.2.2]octyl. Particularly preferred but non-limiting examples of cycloalkyl are cyclopropyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl and cyclohexyl.

[0019] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbon ring system ("C6-C") having a total of 6 to 10 ring members. 10 "-aryl", wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred but non-limiting example of aryl is phenyl.

[0020] The term "heteroaryl" refers to a monovalent or polyvalent monocyclic ring system having a total of 5 to 6 ring members, wherein the ring system is aromatic and contains one or more heteroatoms. Preferably, the heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, the heteroaryl contains 1 to 2 heteroatoms independently selected from O, S, and N. Some preferred but non-limiting examples of heteroaryl include thiazolyl (e.g., thiazolyl-2-yl); oxazolyl (e.g., oxazol-2-yl); oxadiazolyl; 1,2,4-oxadiazol-5-yl; pyridinyl (e.g., 2-pyridinyl); pyrazolyl (e.g., pyrazol-1-yl); triazolyl; tetrazolyl; pyrazinyl; and imidazoleyl (e.g., imidazole-1-yl). Some preferred but non-limiting examples of heteroaryl include pyridinyl and pyrazolyl.

[0021] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic system having 3 to 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. Some non-limiting examples of heterocyclic groups include azirrobutyl, piperidinyl, pyrrolyl, oxadienobutyl, piperidinyl, 1,2-dihydropyridinyl, piperidinyl, pyrrolyl, tetrahydrothiophene, and thioheterobutyl. Preferred but non-limiting examples of heterocyclic groups include 1,2-dihydropyridinyl and oxadienobutyl.

[0022] The term "haloalkyl" refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom (preferably fluorine). Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluorine. Particularly preferred but non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.

[0023] The term "alkoxyalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom of the alkyl group has been replaced by an alkoxy group (preferably methoxy). Preferably, "alkoxyalkyl" refers to an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by an alkoxy group (most preferably methoxy). A particularly preferred, but non-limiting, example of an alkoxyalkyl group is 2-methoxyethyl.

[0024] The term "cycloalkylalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom of the alkyl group has been replaced by a cycloalkyl group (preferably cyclopropyl). Preferably, "cycloalkylalkyl" refers to an alkyl group wherein one of the hydrogen atoms of the alkyl group has been replaced by a cycloalkyl group (most preferably cyclopropyl). A particularly preferred, but non-limiting, example of cycloalkylalkyl is cyclopropylmethyl.

[0025] The term "cycloalkylalkoxy" refers to an alkoxy group as defined herein, wherein at least one hydrogen atom of the alkoxy group has been replaced by a cycloalkyl group (preferably cyclopropyl). Preferably, "cycloalkylalkoxy" refers to an alkoxy group wherein one of the hydrogen atoms of the alkoxy group has been replaced by a cycloalkyl group (most preferably cyclopropyl). A particularly preferred but non-limiting example of a cycloalkylalkoxy group is cyclopropylmethoxy.

[0026] The term "cycloalkoxy" refers to a cycloalkyl group as defined herein, wherein the cycloalkyl group is bonded to the parent molecule via an oxygen atom. A particularly preferred, but not limiting, example of a cycloalkoxy group is a cyclobutoxy group.

[0027] The term "heterocyclic alkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom of the alkyl group has been replaced by a heterocyclic group (preferably oxetane). Preferably, "heterocyclic alkyl" refers to an alkyl group, wherein one of the hydrogen atoms of the alkyl group has been replaced by a heterocyclic group (most preferably oxetane). A particularly preferred, but non-limiting, example of a heterocyclic alkyl group is oxetanemethyl.

[0028] The term "heterocyclic alkoxy" refers to an alkoxy group as defined herein, wherein at least one hydrogen atom of the alkoxy group has been replaced by a heterocyclic group (preferably oxetane). Preferably, "heterocyclic alkoxy" refers to an alkoxy group wherein one of the hydrogen atoms of the alkoxy group has been replaced by a heterocyclic group (most preferably oxetane). A particularly preferred, but non-limiting, example of a heterocyclic alkoxy group is an oxetane methoxy group.

[0029] The term "heterocyclic group" refers to a heterocyclic group as defined herein, wherein the heterocyclic group is bonded to the parent molecule via an oxygen atom. A particularly preferred, but not limiting, example of a heterocyclic group is an oxocyclic butyloxy group.

[0030] The term "pharmaceutically acceptable salt" refers to those salts that retain the biological effects and properties of a free base or free acid, and are not undesirable in biological or other respects. These salts are formed using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. (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, ethylsulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Additionally, these salts can be prepared by adding an inorganic or 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. Salts derived from organic bases include, but are not limited to, salts of the following: primary amines, secondary amines 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, polyimide resin, etc.).

[0031] Compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (e.g., racemates), optically pure diastereomers, mixtures of diastereomers, diastereomers, or mixtures of diastereomers.

[0032] The abbreviation "TREM2" refers to trigger receptor 2 expressed on myeloid cells.

[0033] As used herein, the term "treatment" includes: (1) a state, ailment, or condition that suppresses at least one clinical or subclinical symptom of a disease (e.g.,, in the case of maintenance therapy, preventing, alleviating, or delaying the progression or recurrence of the disease); and / or (2) a symptom relief (i.e., the resolution of a state, symptom, or condition of the disease or at least one clinical or subclinical symptom). The benefit of treatment to a patient is statistically significant or at least perceptible to the patient or physician. However, it should be understood that when a patient is given medication to treat a disease, the outcome may not always be an effective treatment.

[0034] As used herein, the term “prevention” includes: prevention or delay of the development of clinical symptoms of a state, disease, or symptom in mammals, particularly in humans, that may have or be susceptible to the state, disease, or symptom but have not yet experienced or displayed clinical or subclinical symptoms of the state, disease, or symptom.

[0035] Compounds of the invention

[0036] In a first aspect, the present invention provides a compound of formula (I).

[0037] (I)

[0038] Or its pharmaceutically acceptable salt, wherein:

[0039] A 1 X 1 and X 2 Each is independently selected from N and CH;

[0040] A 2 Selected from O and CR 5 R 6 ;

[0041] R 1 Selected from C1-C6-alkyl and halo-C1-C6-alkyl;

[0042] R 2 Selected from C6-C 10 -Aryl, 5- to 6-membered heteroaryl and C3-C 10 -cycloalkyl, wherein the C6-C 10 -Aryl, 5- to 6-membered heteroaryl and C3-C 10-The cycloalkyl group is optionally substituted by one to three substituents independently selected from the following: halogen, C1-C6-alkyl and halo-C1-C6-alkyl;

[0043] R 3 Selected from 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic groups, wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic groups are optionally derived from 1 to 3 independently selected from halogen, cyano, amino, hydroxyl, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 Substitution of -cycloalkoxy, 3- to 6-membered heterocyclic, halo-3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic-C1-C6-alkyl, 3- to 6-membered heterocyclic-C1-C6-alkoxy and 3- to 6-membered heterocyclic groups;

[0044] R 4 Selected from hydrogen and C1-C6-alkyl;

[0045] R 5 and R 6 Each is independently selected from hydrogen and halogen; and

[0046] R 7 Selected from hydrogen and C1-C6-alkyl.

[0047] In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0048] A 1 X 1 and X 2 Each is independently selected from N and CH;

[0049] A 2 Selected from O and CR 5 R 6 ;

[0050] R 1 Selected from C1-C6-alkyl and halo-C1-C6-alkyl;

[0051] R 2 Selected from C6-C10 -Aryl and C3-C 10 -cycloalkyl, wherein the C6-C 10 -Aryl and C3-C 10 -The cycloalkyl group is optionally substituted by one to three substituents independently selected from the following: halogen, C1-C6-alkyl and halo-C1-C6-alkyl;

[0052] R 3 Selected from 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic groups, wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from: halogen, cyano, amino, hydroxyl, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C 10 -Cycloalkyl and 3- to 6-membered heterocyclic groups;

[0053] R 4 Selected from hydrogen and C1-C6-alkyl;

[0054] R 5 and R 6 Each is independently selected from hydrogen and halogen; and

[0055] R 7 Selected from hydrogen and C1-C6-alkyl.

[0056] On the other hand, 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 a compound of formula (Ia).

[0057] (Ia)

[0058] in:

[0059] A 1 X 1 and X 2 Each is independently selected from N and CH;

[0060] A 2 Selected from O and CR 5 R 6 ;

[0061] R 1 Selected from C1-C6-alkyl and halo-C1-C6-alkyl;

[0062] R 2 Selected from C6-C 10 -Aryl and C3-C10 -cycloalkyl, wherein the C6-C 10 -Aryl and C3-C 10 -The cycloalkyl group is optionally substituted by one to three substituents independently selected from the following: halogen, C1-C6-alkyl and halo-C1-C6-alkyl;

[0063] R 3 It is a 5- to 6-membered heteroaryl group, optionally independently selected from C1-C6-alkyl, C1-C6-alkoxy, and C3-C 10 -One to three substituents of the cycloalkyl group;

[0064] R 4 Selected from hydrogen and C1-C6-alkyl; and

[0065] R 5 and R 6 Each is independently selected from hydrogen and halogens.

[0066] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0067] (i)X 1 and X 2 Both are CH; or

[0068] (ii)X 1 For CH and X 2 For N; or

[0069] (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH.

[0070] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0071] (i)X 1 For CH and X 2 For N; or

[0072] (ii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH.

[0073] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 For CH and X 2 Let N be the number of elements in the array.

[0074] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 Let N be the number of elements and X be the number of elements. 2 For CH.

[0075] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein X 1 and X 2 Both are CH.

[0076] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A 1 For CH.

[0077] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A 1 Let N be the number of elements in the array.

[0078] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0079] A 2 Selected from O and CR 5 R 6 ;

[0080] R 5 and R 6 Both are hydrogen, or

[0081] R 5 and R 6 Both are halogens.

[0082] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0083] A 2 Selected from O and CR 5 R 6 ;

[0084] R 5 and R 6 Both are hydrogen, or

[0085] R 5 and R 6 Both are fluorine.

[0086] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A2 It is O.

[0087] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0088] A 2 For CR 5 R 6 ;

[0089] R 5 and R 6 Both are hydrogen, or

[0090] R 5 and R 6 Both are fluorine.

[0091] In one embodiment, 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 a compound of formula (II) or (III):

[0092] (II) (III)

[0093] The variables are as defined in this article.

[0094] In one embodiment, 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 a compound of formula (II):

[0095] (II)

[0096] The variables are as defined in this article.

[0097] In one embodiment, 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 a compound of formula (III):

[0098] (III)

[0099] The variables are as defined in this article.

[0100] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a C1-C6-alkyl group.

[0101] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1 It is a methyl group.

[0102] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from methyl and CHF2.

[0103] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C6-C 10 -Aryl, C3-C 10 -Cycloalkyl, and a 5- to 6-membered heteroaryl group comprising 1 to 2 heteroatoms independently selected from N, O, and S, wherein the C6-C 10 -Aryl, C3-C 10 -The cycloalkyl group and the 5- to 6-membered heteroaryl group are optionally substituted by 1 to 3 substituents independently selected from halogens and halogenated -C1-C6-alkyl groups.

[0104] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 The molecule is 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 by 1 to 3 substituents independently selected from fluorine, chlorine, CHF2 and CF3.

[0105] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C6-C 10 -Aryl and C3-C 10 -cycloalkyl, wherein the C6-C 10 -Aryl and C3-C 10 -The cycloalkyl group is substituted with 1 to 3 substituents independently selected from halogens and halogenated -C1-C6-alkyl groups.

[0106] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from phenyl, cyclohexyl, and bicyclo[1.1.1]pentane, which are substituted by 1 to 3 substituents independently selected from fluorine, chlorine, and CHF2.

[0107] In another particularly preferred embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:

[0108]

[0109] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 The molecule is selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentane, wherein the phenyl, cyclohexyl and bicyclo[1.1.1]pentane are optionally substituted by 1 to 3 substituents independently selected from fluorine, chlorine, CHF2 and CF3.

[0110] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a phenyl group substituted with 1 to 3 halogen substituents.

[0111] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a phenyl group substituted with 1 to 3 substituents selected from fluorine and chlorine.

[0112] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:

[0113]

[0114] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 for .

[0115] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from 1 to 3 heteroatoms independently selected from N, O, and S, with the remaining atoms being 5- to 6-membered heteroaryls of carbon; or 1 to 2 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon, wherein the 5- to 6-membered heteroaryls are optionally independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10-Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 -cycloalkoxy, 3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic-C1-C6-alkyl, and 3- to 6-membered heterocyclic-C1-C6-alkoxy, wherein the 3- to 6-membered heterocyclic group is optionally substituted with one or two substituents independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 -Cycloalkoxy, 3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic-C1-C6-alkyl, 3- to 6-membered heterocyclic-C1-C6-alkoxy, and 1 to 2 oxo-substituted groups.

[0116] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally independently selected from 1 to 2 of methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutoxy, oxetyl, oxetylmethyl, and oxetylmethoxy. 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, cyclobutoxy, oxetyl, oxetylmethyl, oxetylmethoxy, and oxo.

[0117] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3Selected from 5- to 6-membered heteroaryl groups comprising 1 to 3 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon; or 1 to 2 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon, wherein the 5- to 6-membered heteroaryl groups are selected from C1-C6-alkyl, C1-C6-alkoxy, C3-C6-alkyl, C4-C6-alkyl, C5-C6-alkyl, C6 ... 10 The cycloalkyl group is substituted with one of the three- to six-membered heterocyclic groups, wherein the three- to six-membered heterocyclic group is oxidized and optionally selected from C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C6-alkyl groups. 10 -Other substituents of cycloalkyl groups.

[0118] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are substituted with one substituent selected from methyl, methoxy, cyclopropyl, and oxetane, and wherein the 1,2-dihydropyridine is substituted with an oxo group and optionally with another substituent selected from methyl, isopropyl, 2,2,2-trifluoroethyl, and cyclopropyl.

[0119] In another particularly preferred embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

[0120]

[0121] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally substituted with one or two substituents selected from methyl, CF3, methoxy, cyclopropyl, and oxetane, and wherein the 1,2-dihydropyridine is optionally substituted with one or two substituents independently selected from methyl, CF3, methoxy, cyclopropyl, oxetane, and oxo.

[0122] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3The group is selected from pyridyl and pyrazolyl, wherein the pyridyl and pyrazolyl groups are substituted with one substituent selected from methyl, methoxy, and cyclopropyl.

[0123] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

[0124]

[0125] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

[0126]

[0127] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen and methyl.

[0128] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 It is hydrogen.

[0129] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 It is a methyl group.

[0130] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 Selected from hydrogen and methyl.

[0131] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 It is a C1-C6-alkyl group.

[0132] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 It is a methyl group.

[0133] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0134] (i)X 1 and X 2 Both are CH; or

[0135] (ii)X 1 For CH and X 2 For N; or

[0136] (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH;

[0137] A 1 Selected from N and CH;

[0138] A 2 Selected from O and CR 5 R 6 ;

[0139] R 1 Selected from C1-C6-alkyl and halo-C1-C6-alkyl;

[0140] R 2 Selected from C6-C 10 -Aryl, C3-C 10 -Cycloalkyl and a 5- to 6-membered heteroaryl group comprising 1 to 2 heteroatoms independently selected from N, O, and S, wherein the C6-C 10 -Aryl, C3-C 10 -Cycloalkyl and 5- to 6-membered heteroaryl groups are optionally substituted by 1 to 3 independent substituents selected from halogens and halogenated -C1- to -C6-alkyl groups;

[0141] R 3 The atom is selected from 1 to 3 heteroatoms independently selected from N, O, and S, with the remaining atoms being 5- to 6-membered heteroaryl groups of carbon, and 1 to 2 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon, wherein the 5- to 6-membered heteroaryl groups are optionally derived from 1 to 2 heteroatoms independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10-cycloalkoxy, 3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic-C1-C6-alkyl, and 3- to 6-membered heterocyclic-C1-C6-alkoxy, wherein the 3- to 6-membered heterocyclic group is optionally substituted with 1 to 2 substituents independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 -Cycloalkoxy, 3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic -C1-C6-alkyl, 3- to 6-membered heterocyclic -C1-C6-alkoxy and oxo substituents;

[0142] R 4 Selected from hydrogen and C1-C6-alkyl;

[0143] R 5 and R 6 Both are hydrogen, or

[0144] R 5 and R 6 Both are halogens; and

[0145] R 7 Selected from hydrogen and C1-C6-alkyl.

[0146] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0147] (i)X 1 and X 2 Both are CH; or

[0148] (ii)X 1 For CH and X 2 For N; or

[0149] (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH;

[0150] A 1 Selected from N and CH;

[0151] A 2 Selected from O and CR 5 R6 ;

[0152] R 1 Selected from methyl and CHF2;

[0153] R 2 The molecule is 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 fluorine, chlorine, CHF2 and CF3;

[0154] R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally substituted with 1 to 2 substituents independently selected from methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutoxy, oxetyl, oxetylmethyl, and oxetylmethoxy, and wherein the 1,2-dihydropyridine is optionally substituted with 1 to 2 substituents. The substituents are independently selected from methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutoxy, oxetane, oxetanemethyl, oxetanemethoxy, and oxo.

[0155] R 4 Selected from hydrogen and methyl;

[0156] R 5 and R 6 Both are hydrogen, or

[0157] R 5 and R 6 Both are fluorine; and

[0158] R 7 Selected from hydrogen and methyl.

[0159] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0160] (i)X 1 For CH and X 2 For N; or

[0161] (ii)X1 Let N be the number of elements and X be the number of elements. 2 For CH;

[0162] A 1 For CH;

[0163] A 2 It is O;

[0164] R 1 Selected from C1-C6-alkyl and halo-C1-C6-alkyl;

[0165] R 2 Selected from C6-C 10 -Aryl and C3-C 10 -cycloalkyl, wherein the C6-C 10 -Aryl and C3-C 10 -The cycloalkyl group is substituted with 1 to 3 independent substituents selected from halogens and halo-C1-C6-alkyl groups;

[0166] R 3 The atom is selected from 1 to 3 heteroatoms independently selected from N, O, and S, with the remaining atoms being 5- to 6-membered heteroaryls of carbon, and 1 to 2 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon, wherein the 5- to 6-membered heteroaryl group is derived from 1 C1-C6-alkyl, C1-C6-alkoxy, C3-C... 10 The cyclic alkyl group is substituted with a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is oxidized and optionally selected from C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C6-alkyl groups. 10 -Other substituents of cycloalkyl groups;

[0167] R 4 It is hydrogen; and

[0168] R 7 It is a C1-C6-alkyl group.

[0169] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0170] (i)X 1 For CH and X 2 For N; or

[0171] (ii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH;

[0172] A 1 For CH;

[0173] A 2 It is O;

[0174] R 1 Selected from methyl and CHF2;

[0175] R 2 Selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentanes substituted with 1 to 3 substituents independently selected from fluorine, chlorine and CHF2;

[0176] R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl and 1,2-dihydropyridine, wherein the pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl are substituted with one of the substituents selected from methyl, methoxy, cyclopropyl and oxetane, and wherein the 1,2-dihydropyridine is oxidized and optionally substituted with another substituent selected from methyl, isopropyl, 2,2,2-trifluoroethyl and cyclopropyl;

[0177] R 4 It is hydrogen; and

[0178] R 7 It is a methyl group.

[0179] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0180] (i)X 1 and X 2 Both are CH; or

[0181] (ii)X 1 For CH and X 2 For N; or

[0182] (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH;

[0183] A 1 Selected from N and CH;

[0184] A 2 Selected from O and CR 5 R 6 ;

[0185] R 1 It is a C1-C6-alkyl group;

[0186] R2 The molecule is selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentane, wherein the phenyl, cyclohexyl and bicyclo[1.1.1]pentane are optionally substituted by 1 to 3 substituents independently selected from fluorine, chlorine, CHF2 and CF3;

[0187] R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally substituted with one or two substituents selected from methyl, CF3, methoxy, cyclopropyl, and oxetane, and wherein the 1,2-dihydropyridine is optionally substituted with one or two substituents independently selected from methyl, CF3, methoxy, cyclopropyl, oxetane, and oxo.

[0188] R 4 Selected from hydrogen and C1-C6-alkyl;

[0189] R 5 and R 6 Both are hydrogen, or

[0190] R 5 and R 6 Both are halogens; and

[0191] R 7 Selected from hydrogen and C1-C6-alkyl.

[0192] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0193] (i)X 1 and X 2 Both are CH; or

[0194] (ii)X 1 For CH and X 2 For N; or

[0195] (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH;

[0196] A 1 Selected from N and CH;

[0197] A 2 Selected from O and CR 5 R 6 ;

[0198] R1 It is a C1-C6-alkyl group;

[0199] R 2 It is a phenyl group substituted with 1 to 3 halogen substituents;

[0200] R 3 The group is selected from pyridinyl and pyrazolyl, wherein the pyridinyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl;

[0201] R 4 Selected from hydrogen and methyl;

[0202] R 5 and R 6 Both are hydrogen, or

[0203] R 5 and R 6 Both are halogens; and

[0204] R 7 It is a C1-C6-alkyl group.

[0205] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0206] A 1 X 1 and X 2 All are CH;

[0207] A 2 It is O;

[0208] R 1 It is methyl;

[0209] R 2 It is a phenyl group substituted with 1 to 3 substituents selected from fluorine and chlorine;

[0210] R 3 The group is selected from pyridinyl and pyrazolyl, wherein the pyridinyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl;

[0211] R 4 It is hydrogen; and

[0212] R 7 It is a methyl group.

[0213] In one embodiment, the present invention provides a compound of formula (Ia) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0214] (i)X 1 and X2 Both are CH; or

[0215] (ii)X 1 For CH and X 2 For N; or

[0216] (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH;

[0217] A 1 Selected from N and CH;

[0218] A 2 Selected from O and CR 5 R 6 ;

[0219] R 1 It is a C1-C6-alkyl group;

[0220] R 2 The molecule is selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentane, wherein the phenyl, cyclohexyl and bicyclo[1.1.1]pentane are optionally substituted by 1 to 3 substituents independently selected from fluorine, chlorine, CHF2 and CF3;

[0221] R 3 The group is selected from pyridinyl and pyrazolyl, wherein the pyridinyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl;

[0222] R 4 Selected from hydrogen and C1-C6-alkyl; and

[0223] R 5 and R 6 Both are hydrogen, or

[0224] R 5 and R 6 Both are halogens.

[0225] In a preferred embodiment, the present invention provides a compound of formula (Ia) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0226] (i)X 1 and X 2 Both are CH; or

[0227] (ii)X 1 For CH and X 2 For N; or

[0228] (iii)X1 Let N be the number of elements and X be the number of elements. 2 For CH;

[0229] A 1 Selected from N and CH;

[0230] A 2 Selected from O and CR 5 R 6 ;

[0231] R 1 It is a C1-C6-alkyl group;

[0232] R 2 It is a phenyl group substituted with 1 to 3 halogen substituents;

[0233] R 3 The group is selected from pyridinyl and pyrazolyl, wherein the pyridinyl and pyrazolyl are substituted with one substituent selected from methyl, methoxy, and cyclopropyl;

[0234] R 4 Selected from hydrogen and methyl; and

[0235] R 5 and R 6 Both are hydrogen, or

[0236] R 5 and R 6 Both are halogens.

[0237] In a particularly preferred embodiment, the present invention provides a compound of formula (Ia) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0238] A 1 X 1 and X 2 All are CH;

[0239] A 2 It is O;

[0240] R 1 It is methyl;

[0241] R 2 It is a phenyl group substituted with 1 to 3 substituents selected from fluorine and chlorine;

[0242] R 3 The group is selected from pyridyl and pyrazolyl, wherein the pyridyl and pyrazolyl groups are substituted with one substituent selected from methyl, methoxy, and cyclopropyl; and

[0243] R 4 It is hydrogen.

[0244] In one embodiment, 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 selected from:

[0245] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0246] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0247] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0248] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0249] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0250] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(3S)-3-(1-methylpyrazol-4-yl)-1-piperidinyl]pyrido[1,2-a]pyrimidin-4-one;

[0251] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0252] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0253] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0254] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0255] 9-(4-chloro-2-fluoro-phenyl)-7-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidinyl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0256] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0257] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0258] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0259] 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0260] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0261] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0262] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0263] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0264] 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[1,2-a]pyrimidin-4-one;

[0265] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0266] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0267] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0268] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0269] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0270] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0271] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0272] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0273] 9-(4-Chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0274] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0275] 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0276] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0277] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0278] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0279] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0280] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0281] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0282] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0283] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0284] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one carboxylate;

[0285] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0286] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0287] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0288] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0289] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0290] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0291] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0292] 9-(4-chloro-2-fluoro-phenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[1,2-a]pyrimidin-4-one;

[0293] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0294] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0295] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0296] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0297] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0298] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0299] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0300] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0301] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0302] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1H-pyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0303] 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0304] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0305] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0306] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0307] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0308] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0309] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0310] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0311] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0312] 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one;

[0313] 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one;

[0314] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0315] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0316] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0317] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0318] 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrazino[1,2-a]pyrimidin-4-one;

[0319] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0320] 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0321] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0322] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0323] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0324] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0325] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0326] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0327] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-methyl-6-oxopyridin-3-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0328] 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one;

[0329] 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one;

[0330] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0331] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0332] 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0333] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0334] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0335] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0336] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0337] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0338] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0339] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0340] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0341] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0342] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0343] 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0344] 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0345] 7-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0346] 7-[(2R,4S)-2-(1-Cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0347] 7-[(2R,4S)-2-(1-Cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0348] 7-[racemic-(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one;

[0349] 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazin[1,2-a]pyrimidin-4-one;

[0350] 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazin[1,2-a]pyrimidin-4-one;

[0351] 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0352] 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0353] 7-[racemic-(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0354] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0355] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0356] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0357] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0358] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0359] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0360] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0361] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0362] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0363] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0364] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0365] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0366] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0367] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0368] 7-[(2S)-2-(1-Cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0369] 7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0370] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0371] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0372] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0373] 2,3-Dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one;

[0374] 2,3-Dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one;

[0375] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0376] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0377] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0378] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0379] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one;

[0380] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one;

[0381] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one;

[0382] 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0383] 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0384] 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0385] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0386] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0387] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0388] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0389] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0390] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0391] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0392] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0393] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0394] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0395] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0396] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclobutylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0397] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclobutylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0398] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methyl-pyrazino[1,2-a]pyrimidin-4-one;

[0399] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methyl-pyrazino[1,2-a]pyrimidin-4-one;

[0400] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclobutylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0401] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclobutylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0402] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0403] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0404] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0405] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0406] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one;

[0407] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0408] 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0409] 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0410] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0411] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0412] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0413] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0414] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0415] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0416] 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0417] 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0418] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0419] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0420] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0421] 2,3-Dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]-9-[6-(trifluoromethyl)pyridin-3-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0422] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0423] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0424] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(2-methoxyethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0425] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(2-methoxyethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0426] 7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0427] 7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0428] 7-[racemic-(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0429] 7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0430] 7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0431] 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0432] 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0433] 7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one;

[0434] 7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one;

[0435] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0436] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0437] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0438] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0439] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0440] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0441] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0442] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0443] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0444] 9-(2-fluorophenyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0445] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0446] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0447] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0448] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0449] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0450] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0451] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one;

[0452] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0453] 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0454] 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0455] 9-(4,4-difluorocyclohexyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0456] 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0457] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0458] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0459] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0460] 9-(4-chloro-2,6-difluoro-phenyl)-7-[racemic-(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0461] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0462] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0463] 2,3-Dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0464] 2,3-Dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0465] 2,3-Dimethyl-7-[racemic-(2R,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one;

[0466] 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0467] 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0468] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0469] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0470] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0471] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0472] 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0473] 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimidino[1,2-b]pyridazin-4-one;

[0474] 9-(4-chloro-2-fluoro-phenyl)-7-[2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one;

[0475] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0476] 7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0477] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0478] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0479] 7-[(2R,4S)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0480] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1,5-dimethylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0481] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1,5-dimethylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0482] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1,3-dimethylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0483] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1,3-dimethylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0484] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0485] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0486] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0487] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0488] 7-[(2S,4R)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0489] 7-[(2R,4S)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0490] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0491] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[2-(cyclobutoxy)-4-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one;

[0492] 7-[2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0493] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-[2-(oxecyclobutane-3-ylmethoxy)-4-pyridinyl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0494] 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[(1R,5S)-6,6-difluoro-3-bicyclo[3.1.0]hexyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0495] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0496] 9-(4-chloro-2-fluoro-phenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0497] 9-(4-chloro-2-fluoro-phenyl)-7-[2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0498] 9-(4-chloro-2-fluoro-phenyl)-7-[2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0499] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0500] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0501] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0502] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0503] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0504] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one;

[0505] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one;

[0506] 7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0507] 7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0508] 9-(4,4-difluorocyclohexyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0509] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0510] 9-(4-chloro-2-fluoro-phenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0511] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0512] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0513] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0514] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0515] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0516] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0517] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0518] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0519] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0520] 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0521] 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0522] 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0523] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0524] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0525] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[6-keto-1-(trifluoromethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0526] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0527] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0528] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0529] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0530] 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; and

[0531] 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0532] In one embodiment, 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 selected from:

[0533] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0534] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0535] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0536] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0537] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0538] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(3S)-3-(1-methylpyrazol-4-yl)-1-piperidinyl]pyrido[1,2-a]pyrimidin-4-one;

[0539] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0540] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0541] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0542] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0543] 9-(4-chloro-2-fluoro-phenyl)-7-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidinyl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0544] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0545] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0546] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0547] 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0548] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0549] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0550] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0551] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0552] 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[1,2-a]pyrimidin-4-one;

[0553] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0554] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0555] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0556] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0557] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0558] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0559] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0560] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0561] 9-(4-Chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0562] 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0563] 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0564] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one;

[0565] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0566] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0567] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0568] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0569] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0570] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0571] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0572] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one carboxylate;

[0573] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0574] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0575] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0576] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0577] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0578] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0579] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0580] 9-(4-chloro-2-fluoro-phenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[1,2-a]pyrimidin-4-one;

[0581] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0582] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0583] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0584] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0585] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0586] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0587] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0588] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0589] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0590] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1H-pyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0591] 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0592] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0593] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0594] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0595] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0596] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0597] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one;

[0598] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0599] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0600] 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one;

[0601] 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one;

[0602] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0603] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0604] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0605] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0606] 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrazino[1,2-a]pyrimidin-4-one;

[0607] 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one;

[0608] 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one;

[0609] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0610] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0611] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0612] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0613] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0614] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one;

[0615] 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-methyl-6-oxopyridin-3-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one; and

[0616] 7-[(2R,4S)-2-(1-Cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one.

[0617] In a preferred embodiment, 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 selected from:

[0618] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0619] 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0620] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0621] 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0622] 7-[(2R,4S)-2-(1-Cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0623] 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0624] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one;

[0625] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0626] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0627] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one;

[0628] 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0629] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0630] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0631] 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0632] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0633] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one;

[0634] 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one;

[0635] 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0636] 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one;

[0637] 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one;

[0638] 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; and

[0639] 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0640] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0641] In a particularly preferred embodiment, 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-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one.

[0642] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0643] In a particularly preferred embodiment, 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 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one.

[0644] In a particularly preferred embodiment, 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 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one.

[0645] In a particularly preferred embodiment, 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-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one.

[0646] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one.

[0647] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0648] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one.

[0649] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one.

[0650] In a particularly preferred embodiment, 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]pentyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0651] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0652] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one.

[0653] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0654] In a particularly preferred embodiment, 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-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one.

[0655] In a particularly preferred embodiment, 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-dimethyl-pyrimidino[1,2-b]pyridazin-4-one.

[0656] In a particularly preferred embodiment, 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-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one.

[0657] In a particularly preferred embodiment, 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-fluoro-phenyl)-7-[(2S,4R)-2-(1-isopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0658] In a particularly preferred embodiment, 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)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one.

[0659] In a particularly preferred embodiment, 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-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0660] In a particularly preferred embodiment, 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 7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0661] In a particularly preferred embodiment, 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 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

[0662] In one particular embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of formula (I) as described herein. In another particular embodiment, the present invention provides a compound of formula (I) as described herein as a free base or acid.

[0663] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radioactively labeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, isotopes of these elements. 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 I. Certain isotope-labeled compounds of formula (I) (e.g., those containing a radioactive isotope) can be used for drug and / or matrix tissue distribution studies. Radioactive isotope tritium (i.e....) 3 H) and carbon-14 (i.e. 14 C) This is particularly useful because they are easy to incorporate and detection methods are readily available. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95 or 99% of a given isotope.

[0664] Using, for example, deuterium (i.e.) 2 Substitution of heavier isotopes with H) can yield certain therapeutic advantages resulting from greater metabolic stability, such as prolonged in vivo half-life or reduced dose requirements. Therefore, the deuterated forms of the compounds disclosed herein should be understood as being within the scope of this invention.

[0665] Using positron emission isotopes (such as 11 C 18 F, 15 O and 13 N) substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the examples set forth below, using an appropriate isotopically labeled reagent instead of the previously used unlabeled reagent.

[0666] Preparation processes

[0667] The preparation of compounds of formula (I) of the present invention can be carried out via sequential or concurrent synthetic routes. The synthesis of the present invention is illustrated in the following general scheme. The skills required to perform the reactions and purify the resulting products are known to those skilled in the art. Unless otherwise specified, the substituents and indices used in the following description of the methods have the meanings provided herein.

[0668] If any of the starting material, intermediate, or compound 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 may be introduced prior to the critical steps of a process well known in the art (as described, for example, in TW Greene and PGM Wutts, “Protective Groups in Organic Chemistry,” 5th edition, 2014, John Wiley & Sons, NY). Such protecting groups may be removed later in the synthesis using standard methods described in the literature.

[0669] If the starting material or intermediate contains a stereoisomeric center, the compound of formula (I) can be obtained as a diastereomer or a mixture of 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 corresponding counterparts, for example, by diastereomeric salts, which are obtained by crystallization with optically pure acids, or by specific chromatographic methods using chiral adsorbents or chiral eluents. Similarly, starting materials and intermediates containing stereoisomeric centers can be separated to provide diastereomer / enantiomer-enriched starting materials and intermediates. The use of such diastereomer / enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally yield diastereomer / enantiomer-enriched compounds of the corresponding formula (I).

[0670] Those skilled in the art will recognize that, if not desired, an "orthogonal protecting group strategy" will be applied in the synthesis of compounds of formula (I), which allows multiple protecting groups to be cleaved at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been reported in the literature (e.g., Barany and R.B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0671] Those skilled in the art will recognize that the reaction sequence can vary depending on the reactivity and properties of the intermediate.

[0672] More specifically, the compound of formula (I) can be prepared by the methods given below, by the methods given in the examples, or by similar methods. Appropriate reaction conditions for each reaction step are known to those skilled in the art. Similarly, for information on reaction conditions affecting the reactions reported in the literature, 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 can be carried out with or without a solvent. There are no particular limitations on the nature of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and is at least partially capable of dissolving the reagents. The described reaction can occur over a wide temperature range, and precise reaction temperatures are not critical to the invention. The above reactions can be conveniently carried out in the temperature range from -78°C to reflux. The reaction time can also vary considerably depending on many factors, particularly the reaction temperature and the nature of the reagents. However, it typically takes from 0.5 hours to several days to obtain the intermediates and compounds described. The reaction sequence is not limited to the order shown in the scheme; however, the order of reaction steps can be freely changed depending on the starting materials and their corresponding reactivity.

[0673] If the starting materials or intermediates are not commercially available, or their synthesis has not been reported in the literature, existing preparation methods similar to or close analogues can be used, or preparation can be carried out according to the overview in the experimental section.

[0674] The following abbreviations are used in this text:

[0675] ℃ Celsius

[0676] 1 H protons

[0677] Å

[0678] Alkalkyl

[0679] c concentration

[0680] CAS (Chemical Abstracts Service Registry Number)

[0681] CH3CN Acetonitrile

[0682] CO2 carbon dioxide

[0683] DIPEAN, N-diisopropylethylamine

[0684] DMEM Dubec Modified Eagle Medium

[0685] DMFN, N-dimethylformamide

[0686] DMSO dimethyl sulfoxide

[0687] DMSO-d6 hexadecimalized dimethyl sulfoxide

[0688] EC 50 Half-maximum effective concentration

[0689] eq equivalent

[0690] ESI Electrospray Ionization

[0691] Example Example

[0692] FBS fetal bovine serum

[0693] g grams

[0694] g / L g / L

[0695] h hours

[0696] HATU hexafluorophosphate aziridinetriazole tetramethylurea

[0697] HBTU Benzotriazole hexafluorophosphate tetramethylurea

[0698] HCOOH formic acid

[0699] HEK human embryonic kidney

[0700] HPLC (High Performance Liquid Chromatography)

[0701] J coupling constant

[0702] kg

[0703] M Moore

[0704] m / z mass-to-charge ratio

[0705] MeOH Methanol

[0706] mg Milligram

[0707] MgSO4 Magnesium Sulfate

[0708] MHz Megahertz

[0709] min Minute

[0710] ml Milliliter

[0711] mm Millimeter

[0712] mmol Millimole

[0713] MPLC Medium Pressure Liquid Chromatography

[0714] MS Mass Spectrometry

[0715] Na2SO3 Sodium Sulfite

[0716] Na2SO4 Sodium Sulfate

[0717] NaHCO3 Sodium Bicarbonate

[0718] neg. Negative

[0719] NH4Cl Ammonium Chloride

[0720] nm Nanometer

[0721] NMR Nuclear Magnetic Resonance Spectroscopy

[0722] pH pH value

[0723] pos. Positive

[0724] psi Pounds per Square Inch

[0725] R Dextrorotatory according to the Cahn–Ingold–Prelog priority rules

[0726] RP Reverse Phase

[0727] RPM Revolutions Per Minute

[0728] s Second

[0729] S Levorotatory according to the Cahn–Ingold–Prelog priority rules

[0730] SFC Supercritical Fluid Chromatography

[0731] TLC Thin Layer Chromatography

[0732] µl Microliter

[0733] µm Micrometer

[0734] µmol

[0735] Xantphos (9,9-dimethyl-9H-oxanthracene-4,5-diyl)bis(diphenylphosphine)

[0736] Specific curl at αD589 nm

[0737] δ chemical shift (ppm)

[0738] Scheme 1

[0739]

[0740] Compounds having general formulas Ia and Ib can be prepared as described in Scheme 1, wherein intermediate II is first reacted with boric acid (or a boric acid derivative) III under palladium-catalyzed conditions (palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) or tetra(triphenylphosphine)palladium(O) and base such as cesium carbonate or sodium carbonate) to form compound IV. This intermediate can be reacted with amine V in a dipolar aprotic solvent (such as dimethylformamide, dimethyl sulfoxide, or N-methylpyrrolidone) in the presence of a base (such as N,N-diisopropylethylamine, triethylamine, etc.) to form Ia (nucleophilic substitution). Alternatively, compound IV can be reacted with amine V using palladium-catalyzed coupling conditions (palladium source such as tris(dibenzylacetone)dipalladium(O), suitable ligand such as Xantphos, and base such as cesium carbonate or sodium tert-butoxide) to form compound Ia (metal-catalyzed coupling). For the synthesis of C-linked derivative Ib, intermediate IV can be reacted directly with organozinc reagent VI under palladium-catalyzed conditions, or first reacted with boric acid derivative VII using a palladium catalyst and a base to form intermediate VIII, which can then be reduced by treatment with a suitable agent such as hydrogen and a catalyst to form compound Ib. Preferred catalysts are palladium on carbon or platinum oxide in ethyl acetate, ethanol, or methanol, with or without additional reagents (such as magnesium oxide or triethylamine).

[0741] Scheme 2

[0742]

[0743] Compounds having general formula II can be prepared as described in Scheme 2, wherein the heterocyclic compound IX is reacted with ketone ester X in the presence of an acid (such as polyphosphate or Lewis acid such as bismuth trichloride) at an elevated temperature.

[0744] Scheme 3

[0745]

[0746] Furthermore, compounds having general formula IV can be processed as described in Scheme 3 by first reacting heterocyclic compound IX with boric acid (or a boric acid derivative, R) 2 Preferably, (aromatic or heteroaromatic)III is prepared by reacting under palladium-catalyzed coupling conditions (palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) or tetra(triphenylphosphine)palladium(O) and base such as cesium carbonate or sodium carbonate) to form compound XI. This intermediate can then be reacted with ketone ester X in the presence of an acid (such as polyphosphate or Lewis acid such as bismuth trichloride) at elevated temperatures to form compound IV.

[0747] Scheme 4

[0748]

[0749] Furthermore, compounds having the general formula Ib can be prepared as described in Scheme 4, wherein intermediate IV is first reacted with bis(pinacol)diboron under palladium-catalyzed conditions (palladium source such as (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) or tetra(triphenylphosphine)palladium(O) and base such as cesium carbonate or sodium carbonate) to form compound XII. This intermediate can be reacted with trifluoromethanesulfonate XIII using a palladium catalyst and a base to form intermediate VIII, which can then be reduced by treatment with a suitable agent such as hydrogen and a catalyst to form compound Ib.

[0750] Scheme 5

[0751]

[0752] In addition, compounds having the general formula IVa (R 2 Preferably alicyclic compounds can be reacted as described in Scheme 5, first by reacting the heterocyclic compound XIV with the carboxylic acid XV under oxidative coupling conditions (using, for example, dimethyl sulfoxide containing ammonium persulfate at a temperature of 0°C to 50°C, a Minisci reaction) to form compound XIa. This intermediate can then be reacted with the ketone ester X in the presence of an acid (such as a polyphosphate or a Lewis acid such as bismuth trichloride) at an elevated temperature to form compound IVa.

[0753] Scheme 6

[0754]

[0755] Furthermore, compounds having the general formula Ib can be prepared as described in Scheme 6. First, intermediate XII is reacted with trifluoromethanesulfonate XVI under palladium-catalyzed conditions (palladium source such as (1,1'-bis(diphenylphosphine)ferrocene)palladium(II) or tetra(triphenylphosphine)palladium(O) and base such as cesium carbonate or sodium carbonate) to form compound XVII. Similarly, intermediate IV can be reacted with borate derivative XVIII under palladium-catalyzed conditions (palladium source such as (1,1'-bis(diphenylphosphine)ferrocene)palladium(II) or tetra(triphenylphosphine)palladium(O) and base such as cesium carbonate or sodium carbonate) to similarly form compound XVII. In a next step, this intermediate is reduced by treatment with a suitable agent such as hydrogen and a catalyst to form compound XIX. Then, through a multi-step reaction known to those skilled in the art and published in various literature reviews (such as J. Chem. Rev., 2022, 4(3), 255-271), the ester functional group can be converted into various heterocyclic substituents R. 3 .

[0756] Scheme 7

[0757]

[0758] Furthermore, compounds having the general formula Ib can be prepared by late modification of compound XX as described in Scheme 7. Such transformations from residue R3' to residue R3 include the removal of protecting groups, halogen-carbon exchange reactions (such as bromine to methyl), or alkylation reactions (e.g., on NH-pyrazole or NH-pyridone), and can be carried out according to known conditions published in the literature for the relevant compounds.

[0759] In one aspect, the present invention provides a method for producing a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein the method is as described in any one of schemes 1 to 7.

[0760] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, which is manufactured according to any of the methods described herein.

[0761] TREM2 agonistic activity

[0762] The compounds of the present invention are TREM2 agonists. Therefore, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for restoring human TREM2 function in subjects in need.

[0763] In another aspect, the present invention provides a compound of formula (I) as described herein for use in a method for restoring the function of TREM2 in a subject in need.

[0764] In another aspect, the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for restoring the function of TREM2 in a subject in need.

[0765] In another aspect, the present invention provides a method for restoring the function of a human TREM2 in a subject in need, the method comprising administering to the subject an effective amount of a compound of formula (I) as described herein.

[0766] The TREM2 agonist efficacy of the compound of formula (I) according to the invention was measured using HEK cell lines expressing human TREM2 and DAP12. Upon binding of the small molecule ligand to the TREM2 receptor, DAP12 recruits and activates Syk kinase. The resulting increase in phosphorylated Syk levels was measured in lysed cells using a commercial AlphaLisa kit.

[0767] For the assay, frozen HEK293-TREM2 / DAP12 cells were thawed, adjusted, and seeded at 20,000 cells per well in 10 μL of DMEM medium (excluding Phenolred but supplemented with 5% FBS) in 384-well plates using Certus.

[0768] The dose-response (1:3) compound was diluted in DMSO (maximum concentration 10 mM) and added to cells from low dead volume plates using ECHO (0 to 20 μM), diluted 500-fold (20 nL in 10 µL cell suspension; maximum concentration 20 μM, DMSO concentration in all wells 0.2%). Neutral (DMSO) and stimulant (1 µM tool compound) controls were also added.

[0769] 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 a Certus microplate reader. After rapid rotation, the plate was shaken at 450 RPM for 30 minutes at room temperature and in the dark. After complete lysis, AlphaLisa reagent was added to the lysate using a Certus microplate reader, and fluorescence intensity (excitation: 680 nm / emission: 615 nm) was measured using a Pherastar microplate reader. EC50 was calculated using Genedata Screener. 50The value was normalized to DMSO and the activity of the tool compound was 100%.

[0770] The TREM2 agonist efficacy of the compounds of formula (I) according to the invention, as measured in the above determinations, is presented in Table 1. The TREM2 agonist efficacy of the reference compounds, as measured in the above determinations, is presented in Table 2.

[0771] Table 1

[0772]

[0773] Use of compounds of the invention

[0774] In one aspect, the present invention provides compounds of formula (I) as described herein, or pharmaceutically acceptable salts thereof, which are used as therapeutically active substances.

[0775] In another aspect, the present invention provides a method for treating or preventing symptoms associated with loss of function of human TREM2 in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0776] In another aspect, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing symptoms associated with loss of function of human TREM2 in a subject in need of such treatment.

[0777] In another aspect, the present invention provides the use of the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, in a method of treating or preventing symptoms associated with loss of function of human TREM2 in a subject in need of such treatment.

[0778] In another aspect, the present invention provides the use of the compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, in the preparation of a medicament for use in a method of treating or preventing symptoms associated with loss of function of human TREM2 in a subject in need of such treatment.

[0779] In one embodiment, the symptoms associated with loss of function of human TREM2 are selected from Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prion diseases, and stroke.

[0780] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is Parkinson's disease.

[0781] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is rheumatoid arthritis.

[0782] In a preferred embodiment, the symptom associated with the loss of function of TREM2 in humans is Alzheimer's disease.

[0783] In a preferred embodiment, the symptom associated with the loss of function of human TREM2 is amyotrophic lateral sclerosis (ALS).

[0784] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is Nasu-Hakola disease.

[0785] In a preferred embodiment, the symptom associated with the loss of TREM2 function in humans is frontotemporal dementia.

[0786] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is multiple sclerosis.

[0787] In a preferred embodiment, the symptom associated with loss of function of human TREM2 is prion disease.

[0788] In a preferred embodiment, the symptom associated with the loss of TREM2 function in humans is stroke.

[0789] Pharmaceutical compositions and administration

[0790] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0791] In one embodiment, a pharmaceutical composition according to Example 288 or 289 is provided.

[0792] Compounds of formula (I) and their pharmaceutically acceptable salts may be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations may be administered orally, such as orally (e.g., in the form of tablets, coated tablets, sugar lozenges, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, they may also be administered parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0793] Compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic adjuvants to produce tablets, coated tablets, sugar tablets, and hard gelatin capsules. For example, lactose, corn starch, or derivatives thereof (talc, stearic acid, or their salts, etc.) can be used as such adjuvants for tablets, sugar-coated pills, and hard gelatin capsules.

[0794] Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0795] Suitable additives for preparing solutions and syrups include, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0796] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerin, and vegetable oil.

[0797] Suitable adjuvants for suppositories include, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols.

[0798] In addition, pharmaceutical preparations may contain preservatives, solubilizers, thickeners, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for altering osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other substances with therapeutic value.

[0799] Dosage can vary within a wide range to suit the various requirements of each specific situation. Generally, a daily oral dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person), should be appropriate, preferably divided into 1-3 individual doses (which may consist of, for example, the same amount). However, it will be apparent that, when indicated, the upper limits given herein may be exceeded.

[0800] Examples

[0801] The invention will be more fully understood by referring to the following examples. However, the claims should not be construed as limiting the scope of the examples.

[0802] In the case of preparation examples obtained as mixtures of enantiomers, pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art (e.g., chiral chromatography (e.g., chiral SFC) or crystallization).

[0803] Compounds of Formula I may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (such as, for example, racemates), optically pure diastereomers, or mixtures of diastereomers. According to the Cahn-Ingold-Prelog specification, the asymmetric carbon atom may have an "R" or "S" configuration. For the compounds described in this patent, the absolute stereochemical structure is arbitrarily specified.

[0804] Unless otherwise specified, all reaction examples and intermediates are prepared under an argon atmosphere.

[0805] The compounds disclosed and described herein have been named using the IUPAC nomenclature function of Biovia Draw 22.1. In the event of a discrepancy between the described structure and the name given to that structure, the described structure shall prevail.

[0806] The following intermediates are prepared according to the procedures provided herein, or are commercially available, or can be prepared according to literature procedures.

[0807] Intermediate Al: 7-Bromo-9-iodo-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one

[0808]

[0809] A mixture of 5-bromo-3-iodopyridin-2-amine (CAS 381233-96-1, 2.0 g, 6.69 mmol), ethyl 2-methylacetoacetate (CAS 609-14-3, 965 mg, 0.97 ml, 6.69 mmol), and polyphosphoric acid (1.0 g, 6.69 mmol) was stirred at 120 °C for 90 min. The reaction mixture was absorbed with water, alkalized with saturated sodium bicarbonate solution, and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to dryness. The residue was purified by rapid chromatography (silica gel, ethyl acetate in heptane, 0% to 100%) to give the title compound (1.07 g, 40% yield) as a grayish-white solid, MS m / z: 378.8 [M+H] + , ESI pos.

[0810] Intermediate A2:9-Bromo-7-chloro-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[0811]

[0812] Similar to intermediate A1, the title compound was prepared by replacing 5-bromo-3-iodopyridin-2-amine with 3-bromo-5-chloro-pyrazin-2-amine (CAS 76537-18-3). Yellow solid, MS m / z: 290.0 [M+H] + , ESI pos.

[0813] Intermediate A3: 7-Bromo-2-(difluoromethyl)-9-iodo-3-methylpyrido[1,2-a]pyrimidin-4-one

[0814]

[0815] Polyphosphate (31.8 g, 132 mmol) was added to a mixture of ethyl 4,4-difluoro-2-methyl-3-oxo-butyrate (5.3 g, 26.5 mmol) and 2-amino-5-bromo-3-iodopyridine (3.17 g, 10.6 mmol, 0.4 eq). After stirring at 120 °C for 1.5 hours, the mixture was cooled to room temperature, quenched with a saturated aqueous solution of NaHCO3 (300 mL), and extracted with ethyl acetate (2 x 250 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under vacuum. The crude material was purified by rapid chromatography (silica gel, acetonitrile in chloroform, 0% to 50%) to obtain 7-bromo-2-(difluoromethyl)-9-iodo-3-methylpyridano[1,2-a]pyrimidin-4-one (0.34 g, 3% yield). MS m / z: 414.8 [M+H] + , ESI pos.

[0816] Intermediate A4: 9-Bromo-7-chloro-2-methylpyrido[1,2-a]pyrimidin-4-one

[0817]

[0818] Similar to intermediate A1, the title compound was prepared by replacing 5-bromo-3-iodopyridine-2-amine with 3-bromo-5-chloro-pyridine-2-amine and ethyl 3-butanone (CAS 141-97-9) with ethyl 2-methylacetoacetate. Yellow solid, MS m / z: 273.0 [M+H] + , ESI pos.

[0819] Intermediate Bl: 7-Bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one

[0820]

[0821] At room temperature, a solution of 7-bromo-9-iodo-2,3-dimethylpyrido[1,2-a]pyrimidin-4-one (intermediate A1, 260 mg, 0.68 mmol) in dioxane (7 ml) was supplemented with 179 mg (4-chloro-2-fluoro-phenyl)boronic acid (1.03 mmol) and 2 M cesium carbonate aqueous solution (1.03 ml, 2.06 mmol). The mixture was degassed with argon, and then a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (56 mg, 0.069 mmol, 0.100 eq) 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 rapid chromatography (on silica gel, ethyl acetate in heptane, 0% to 50%) to obtain the title compound as a white solid (221 mg, 81% yield), MS m / z: 383.0 [M+H] + , ESIpos.

[0822] Intermediate B2: 7-Chloro-9-(4-Chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[0823]

[0824] At room temperature, (4-chloro-2-fluoro-phenyl)boronic acid (263 mg, 1.51 mmol) and an aqueous solution of cesium carbonate (1.51 ml, 3.02 mmol) were added to a solution of 9-bromo-7-chloro-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (intermediate A2, 290 mg, 1.01 mmol) in 1,4-dioxane (6 ml). The mixture was degassed with argon, and then a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (82 mg, 0.10 mmol, 0.10 eq) was added. The mixture was stirred at 60 °C for 3 h, 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 rapid chromatography (silica gel, ethyl acetate in heptane, 0% to 100%), and the obtained material was ground with methyl tert-butyl ether to obtain the title compound as a yellow solid (177 mg, 49% yield), MS m / z: 338.0 [M+H]. + , ESI pos.

[0825] Intermediate B3: 7-Chloro-9-(4-Chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one

[0826]

[0827] Step 1: 6-chloro-4-(4-chloro-2-fluoro-phenyl)pyridazin-3-amine

[0828]

[0829] To a solution of 4-bromo-6-chloro-pyridazine-3-amine (CAS 446273-59-2, 1.00 g, 4.8 mmol) in 1,4-dioxane (20 ml), (4-chloro-2-fluoro-phenyl)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) dichloromethane (392 mg, 0.48 mmol, 0.10 eq) 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 rapid chromatography (silica gel, dichloromethane / methanol, 0% to 10%) to give a dark brown solid, 6-chloro-4-(4-chloro-2-fluoro-phenyl)pyridazin-3-amine (852 mg, 69% yield), MS m / z: 258.0 [M+H]. + , ESI pos.

[0830] Step 2: 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4- one

[0831]

[0832] Bismuth trichloride (12 mg, 0.0388 mmol) was added to a suspension of 6-chloro-4-(4-chloro-2-fluoro-phenyl)pyridazin-3-amine (100 mg, 0.388 mmol) in ethyl 2-methylacetoacetate (559 mg, 564 µl, 3.87 mmol) at room temperature, and the mixture was stirred at 120 °C for 16 h. 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 rapid chromatography (silica gel, ethyl acetate in heptane, 0% to 50%) to give the title compound (62 mg, 43% yield) as a pale yellow solid, MS m / z: 338.1 [M+H] + , ESI pos.

[0833] Intermediate B4: 7-Bromo-9-(4-chlorophenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one

[0834]

[0835] Similar to intermediate B1, the title compound was prepared using (4-chlorophenyl)boronic acid instead of (4-chloro-2-fluorophenyl)boronic acid. White solid, MS m / z: 365.1 [M+H] + , ESI pos.

[0836] Intermediate B5: 7-Bromo-9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methylpyrido[1,2-a]pyrimidin-4-one

[0837]

[0838] Cesium carbonate (603 mg, 1.85 mmol) was added to a stirred solution of 4-chloro-2-fluorophenylboronic acid (75 mg, 0.43 mmol) and 7-bromo-2-(difluoromethyl)-9-iodo-3-methyl-pyrido[1,2-a]pyrimidin-4-one (intermediate A3, 320 mg, 0.62 mmol) in a mixture of 1,4-dioxane (17 ml) and water (1.7 ml). The mixture was degassed, filled with argon, and a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (50 mg, 0.06 mmol, 0.1 eq) 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 x 100 ml). The combined organic layers were then filtered through anhydrous sodium sulfate and evaporated under vacuum. The residue was purified by preparative HPLC (XBridge column 19 x 100 mm, 60% water-acetonitrile, 4 ml / min acetonitrile) to obtain the title compound as a light brown solid (103 mg, 40% yield). MS m / z: 417.0 [M+H] + , ESI pos.

[0839] Intermediate B6: 7-Chloro-9-(4-Chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[0840]

[0841] Step 1: 5-chloro-3-(4-chloro-2,6-difluoro-phenyl)pyrazin-2-amine

[0842]

[0843] In a glove box, (4-chloro-2,6-difluorophenyl)boronic acid (600 mg, 3.12 mmol) and diisopropylethylamine (930 mg, 7.2 mmol) were added to a solution of (3-bromo-5-chloro-pyrazin-2-yl)amine (500 mg, 2.4 mmol) in toluene (7.5 mL). The mixture was degassed with argon, and then chloro(crotonyl)(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. The crude material was purified by rapid chromatography (C18, acetonitrile in water, 10% to 100%) to give a yellow solid, 5-chloro-3-(4-chloro-2,6-difluorophenyl)pyrazin-2-amine (193 mg, 29% yield). MS m / z: 276.0 [M+H] + , ESI pos.

[0844] Step 2: 7-chloro-9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin- 4-one

[0845]

[0846] 5-Chloro-3-(4-chloro-2,6-difluoro-phenyl)pyrazin-2-amine (170 mg, 0.616 mmol), ethyl 2-methylacetoacetate (888 mg, 897 µl, 6.16 mmol), and polyphosphoric acid (85 mg) were mixed at room temperature and stirred at 120 °C for 6 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to dryness. The crude material was purified by rapid chromatography (silica gel, ethyl acetate in heptane, 0% to 50%). The obtained material was suspended in methyl tert-butyl ether and stirred for 5 min, then filtered off. The solid was washed with methyl tert-butyl ether and then dried under vacuum to obtain the title compound as a yellow solid (156 mg, 71% yield). MS m / z: 356.1 [M+H] + , ESI pos.

[0847] Intermediate B7: 7-Chloro-9-(4-Chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one

[0848]

[0849] Step 1: 6-chloro-4-(4-chloro-2,6-difluoro-phenyl)pyridazin-3-amine

[0850]

[0851] To a solution of (4-bromo-6-chloro-pyridazin-3-yl)amine (491 mg, 2.36 mmol) in tert-amyl alcohol (7.5 ml), (4-chloro-2,6-difluoro-phenyl)boronic acid (680 mg, 3.53 mmol) and diisopropylethylamine (913 mg, 7.07 mmol) were added. The mixture was degassed with argon, and then PdCl2 (amphos) (CAS 887919-35-9, 250 mg, 0.15 mmol) was added, and the mixture was stirred at 50 °C for 2.5 h. 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. The crude material was purified by rapid chromatography (C18, acetonitrile in water, 10% to 70%) to give a light brown solid, 6-chloro-4-(4-chloro-2,6-difluorophenyl)pyridazine-3-amine (214 mg, 33% yield). MS m / z: 276.1 [M+H] + , ESIpos.

[0852] Step 2: 7-chloro-9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin- 4-one

[0853]

[0854] Bismuth trichloride (24 mg, 0.076 mmol, 0.10 eq) was added to a mixture of 6-chloro-4-(4-chloro-2,6-difluoro-phenyl)pyridazin-3-amine (210 mg, 0.76 mmol) and ethyl 2-methylacetoacetate (1.1 g, 1.11 ml, 7.61 mmol) 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 rapid chromatography (silica gel, ethyl acetate in heptane, 0% to 40%) to obtain the title compound as a brown solid (152 mg, 55% yield), MS m / z: 356.1 [M+H] + , ESI pos.

[0855] Intermediate B8: 7-Chloro-9-(4-chloro-2-fluoro-phenyl)-2-methyl-pyrido[1,2-a]pyrimidin-4-one

[0856]

[0857] Similar to intermediate B1, intermediate A4 was used instead of intermediate A1 to prepare the title compound. White solid, MS m / z: 323.1 [M+H] + , ESI pos.

[0858] Intermediate B9: 7-Chloro-9-(4-chlorophenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[0859]

[0860] Similar to intermediate B3, the title compound was prepared in step a) by replacing 4-bromo-6-chloro-pyridazin-3-amine with 3-bromo-5-chloro-pyridazin-2-amine and (4-chlorophenyl)boronic acid with (4-chloro-2-fluorophenyl)boronic acid. Yellow solid, MS m / z: 320.0 [M+H] + , ESI pos.

[0861] Intermediate B10: 7-Chloro-9-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrazino[1,2-a]pyrimidin-4-one

[0862]

[0863] Step 1: 5-chloro-3-(4-chloro-2-fluoro-phenyl)pyrazin-2-amine

[0864]

[0865] (4-Chloro-2-fluorophenyl)boronic acid (2.51 g, 14.4 mmol) and 3 M cesium carbonate solution (12 ml, 36 mmol) were added to a solution of (3-bromo-5-chloro-pyrazin-2-yl)amine (2.5 g, 12.0 mmol) in 1,4-dioxane (50 ml) at room temperature. The mixture was degassed with argon, and a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (980 mg, 1.2 mmol, 0.10 eq) 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. The crude material was ground with methyl tert-butyl ether to obtain a light brown solid, 5-chloro-3-(4-chloro-2-fluoro-phenyl)pyrazin-2-amine (2.2 g, yield 64%, purity 90%), MS m / z: 258.1 [M+H]. +, ESI pos.

[0866] Step 2: 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrazino[1,2- a]pyrimidin-4-one Intermediate Bl l:

[0867]

[0868] In a vial, ethyl 4,4-difluoro-3-keto-2-methyl-butyrate (CAS 425394-84-9, 3.49 g, 19.4 mmol), polyphosphate (250 mg), and 5-chloro-3-(4-chloro-2-fluoro-phenyl)pyrazine-2-amine (500 mg, 1.94 mmol) were mixed. The vial was sealed, and the reaction was heated to 140 °C overnight. Another portion of ethyl 4,4-difluoro-3-keto-2-methyl-butyrate (3.49 g, 19.37 mmol) and polyphosphate (250 mg) were added. The reaction was sealed again, and stirred at 140 °C for another 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 the volatiles were evaporated. The residue was purified by rapid column chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give the title compound as a yellow solid (197 mg, 26% yield). 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).

[0869] Intermediate B12: 7-Chloro-9-(4-Chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one

[0870]

[0871] Similar to intermediate B3, the title compound was prepared using ethyl 4,4-difluoro-3-keto-2-methyl-butyrate instead of ethyl 2-methylacetoacetate. Light brown solid, MS m / z: 374.0 [M+H] + , ESI pos.

[0872] Step 1: 5-bromo-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyrazin-2-amine7-Bromo-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one

[0873]

[0874] Step 2: 7-bromo-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1,1.1]pentanyl]pyrazino[1, 2-a]pyrimidin-4-one

[0875]

[0876] Add 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (3.11 g, 17.2 mmol) to a solution of (5-bromopyrazin-2-yl)amine (300 mg, 1.72 mmol) in dimethyl sulfoxide / water (600 / 1). Degas the reaction mixture by bubbling it through argon. Under argon, add a freshly prepared solution of ammonium persulfate (2.36 g, 10.3 mmol) in purged dimethyl sulfoxide / water (600 / 1), and stir the mixture at 40 °C for 20 h. Quench the reaction mixture with a saturated solution of NaHCO3 and extract with ethyl acetate. Dry the combined organic layers with Na2SO4, filter, and concentrate to dryness. The residue was purified by column chromatography (silica gel, 0% to 35% ethyl acetate in heptane) to give a yellow solid 5-bromo-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazin-2-amine (190 mg, 31% yield), MS m / z: 308.2 / 310.2 [M+H] + , ESI pos.

[0877] Intermediate B13: Intermediate B14:

[0878]

[0879] Bismuth trichloride (17 mg, 0.055 mmol) was added to a mixture of 5-bromo-3-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazine-2-amine (170 mg, 0.55 mmol) and ethyl 2-methylacetoacetate (796 mg, 805 µl, 5.52 mmol) at room temperature, and the mixture was stirred at 100 °C for 18 h. 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 10%) to give the title compound (111 mg, 52% yield) as a pale yellow solid, MS m / z: 388.2 / 390.2 [M+H] + , ESI pos.

[0880] Step 1: 6-chloro-4-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]pyridazin-3-amine 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazino[1,2-a]pyrimidin-4-one

[0881]

[0882] Under argon atmosphere, a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (intermediate B2, 1.5 g, 4.44 mmol) in 1,4-dioxane (27 ml) was added to bis(pinacol)diboron (1.35 g, 5.32 mmol), potassium acetate (1.31 g, 13.3 mmol), and a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (367 mg, 0.445 mmol, 0.10 eq). The reaction mixture was heated to 80 °C and stirred for 20 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated and purified by rapid chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give an orange oily 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyrazino[1,2-a]pyrimidin-4-one (1.8 g, 85% yield).

[0883] Step 2: 7-chloro-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-2,3-dimethyl- pyrimido[1,2-b]pyridazin-4-one7-Chloro-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one

[0884]

[0885] Intermediate B15:

[0886]

[0887] Add 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (7.5 g, 46.3 mmol) to a solution of 3-amino-6-chloropyridazine (600 mg, 4.63 mmol) in 9-dimethyl sulfoxide / water (600 / 1; 9 ml). Degas the reaction mixture by bubbling it through nitrogen. Under nitrogen, add a freshly prepared solution of ammonium persulfate (6.34 g, 27.79 mmol) in purged dimethyl sulfoxide / water (600 / 1), and stir the mixture at 40 °C for 20 h. Quench the reaction mixture with a saturated solution of NaHCO3, adjust the pH to 8 to 9, and extract with ethyl acetate (200 ml x 3). Wash the combined organic layers with brine, dry with Na2SO4, filter, and concentrate to dryness. The residue was first purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 µm, mobile phase: water + 0.25% formic acid / acetonitrile 10% to 15%, flow rate 25 ml / min) to obtain a crude product. This crude product was further purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100:1 to 1:1) to obtain a pale yellow solid, 6-chloro-4-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]pyridazine-3-amine (190 mg, yield 17%), MS m / z: 246.1 [M+H]. + , ESI pos.

[0888] Intermediate B16: Intermediate B17:

[0889]

[0890] To a solution of 6-chloro-4-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]pyridazine-3-amine (190 mg, 0.77 mmol) in toluene (5 ml), ethyl 2-methylacetoacetate (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 h under nitrogen atmosphere. The reaction mixture was poured into water (150 ml), neutralized to pH 8 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, petroleum ether / ethyl acetate = 1 / 1) to give the title compound (200 mg, 79% yield) as a pale yellow solid, MS m / z: 326.1 [M+H] + , ESI pos.

[0891] Intermediate B18: 7-Bromo-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[0892]

[0893] Similar to intermediate B12, the title compound was prepared in step 1) by using 4,4-difluorocyclohexanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. Pale yellow solid, MS m / z: 372.1 / 374.1 [M+H] + , ESI pos.

[0894] Intermediate B19: 7-Chloro-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one

[0895]

[0896] Similar to intermediate B14, the title compound was prepared in step 1) using 4,4-difluorocyclohexanecarboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. Yellow solid, MS m / z: 328.1 [M+H] + , ESI pos.

[0897] Intermediate B20: 7-Bromo-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[0898]

[0899] Similar to intermediate B12, the title compound was prepared in step 1) by using 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. Pale yellow solid, MS m / z: 370.1 [M+H] + , ESI pos.

[0900] Intermediate B21: 7-Chloro-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one

[0901]

[0902] Similar to intermediate B14, the title compound was prepared in step 1) using 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 3-(difluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. Pale yellow solid, MS m / z: 344.1 [M+H] + , ESI pos.

[0903] Intermediate C8: 7-Chloro-2,3-dimethyl-9-[6-(trifluoromethyl)-3-pyridyl]pyrazino[1,2-a]pyrimidin-4-one

[0904]

[0905] 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.

[0906] Step 1: [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] trifluoromethanesulfonate 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyrazino[1,2-a]pyrimidin-4-one

[0907]

[0908] Similar to intermediate B13, intermediate B6 was used instead of intermediate B2 to prepare the title compound. Orange oil, MS m / z: 366.0 [M+H] +(Corresponding to boric acid), ESI pos.

[0909] 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 7-Chloro-2,3-dimethyl-9-[racemic-(1R,5S)-6,6-difluoro-3-bicyclo[3.1.0]hexyl]pyrimidino[1,2-b]pyridazin-4-one

[0910]

[0911] Similar to intermediate B14, the title compound was prepared in step 1) using 6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid instead of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid. Yellow oil, MS m / z: 326.0 [M+H] + , ESI pos.

[0912]

[0913] Chiral separation of intermediate C1:

[0914] 2-(1-methylpyrazol-4-yl)morpholine (intermediate C1) was separated by a chiral SFC (column AD-H, 5 µm, 100 x 4.6 mm, 20% to 40% MeOH + 0.2% diethylamine) to give (+)-2-(1-methylpyrazol-4-yl)morpholine (+)-C1 as the first eluting enantiomer and (-)-2-(1-methylpyrazol-4-yl)morpholine (-)-C1 as the second eluting enantiomer. (+)-2-(1-methylpyrazol-4-yl)morpholine: yellow oil, αD (589 nm) 20 °C = +13.36° (c = 0.1 g / l, MeOH).

[0915] Intermediate C13: 2-Methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine

[0916]

[0917] Intermediate C14

[0918]

[0919] Under argon atmosphere, 3-butyn-1-ol (767 mg, 0.833 ml, 10.94 mmol) was added to a solution of 2-methoxyisononial (1.0 g, 7.29 mmol) in dichloromethane (10 ml). 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 min, 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 rapid chromatography (silica gel, ethyl acetate in heptane 0% to 100%) to give trifluoromethanesulfonic acid [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester (870 mg, yield 32%), as a colorless oil, MS m / z: 340.1 [M+H] + , ESI pos.

[0920] Step 1: 2-chloro-1-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethanone Step 2: 2-[benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazol-4- yl)ethanone

[0921]

[0922] To a solution of trifluoromethanesulfonic acid [6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester (870 mg, 2.31 mmol) in 1,4-dioxane (15 ml), bis(pinacol)diboron (1.17 g, 4.62 mmol), potassium acetate (906 mg, 9.23 mmol), and a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (189 mg, 0.231 mmol, 0.10 eq) were added. The mixture was purged and backfilled three times with argon, then stirred at 90 °C for 2 h. 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 rapid chromatography (silica gel, 0% to 80% ethyl acetate in heptane) to give 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine (656 mg, 81% yield) as a colorless oil, MS m / z: 318.3 [M+H] + , ESI pos.

[0923]

[0924] ​ 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]-2-(trifluoromethyl)pyridine

[0925]

[0926] Similar to intermediate C8, the title compound was prepared by replacing 2-methoxyisononial with 2-(trifluoromethyl)isononial. A pale yellow oil, MS m / z: 356.3 [M+H] + , ESI pos.

[0927] ​ 2-Methyl-6-[1-(oxecyclobutane-3-yl)pyrazol-4-yl]morpholine

[0928]

[0929] ​

[0930]

[0931] Under a nitrogen atmosphere, at -70°C, an isopropyl magnesium chloride-lithium chloride complex (1.3 M, in tetrahydrofuran, 133 ml, 173 mmol) was added to a solution of 4-iodo-1-tetrahydropyran-2-yl-pyrazole (CAS 938066-17-2, 32.0 g, 115 mmol) in tetrahydrofuran (350 ml), and the mixture was stirred at -70°C for 0.5 h. Then, under a nitrogen atmosphere, at -70°C, a solution of 2-chloro-N-methoxy-N-methylacetamide (CAS 67442-07-3, 19 g, 138 mmol) in tetrahydrofuran (100 ml) was added dropwise, and the mixture was stirred at 0°C for 1.5 h. 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 to 2:1) to give a pale yellow oily 2-chloro-1-(1-tetrahydropyran-2-ylpyrazol-4-yl)acetone (25.0 g, 95% yield). MS m / z: 145.0 [M+H] + , ESI pos.

[0932] ​

[0933]

[0934] Potassium carbonate (30.2 g, 219 mmol), potassium iodide (18.15 g, 109.3 mmol), and 1-(benzylamino)prop-2-ol (CAS 27159-32-6, 18.06 g, 109.32 mmol) were added to a pale yellow solution of 2-chloro-1-(1-tetrahydropyran-2-ylpyrazol-4-yl) ketone (25.0 g, 109.32 mmol) in dimethyl sulfoxide (250 ml), 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 µm to 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 and extracted with ethyl acetate (500 ml x 3). The combined organic layers were washed with brine (500 ml), dried over Na₂SO₄, and concentrated under vacuum to give a pale yellow oily 2-[benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazol-4-yl)acetone (26.0 g, yield 66%). MS m / z: 358.2 [M+H] + , ESI pos.

[0935] Step 3: 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]amino]prop-2-ol

[0936]

[0937] Sodium borohydride (8.26 g, 218 mmol, added in multiple batches) was added to a solution of 2-[benzyl(2-hydroxypropyl)amino]-1-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl ketone (26.0 g, 72.7 mmol) in methanol (260 ml) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was then slowly poured into a saturated aqueous solution of ammonium chloride (1000 ml) at 0 °C to 5 °C, stirred for 0.5 h, 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 give a pale yellow oily 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]amino]prop-2-ol (24.0 g, 92% yield). The product was used directly in the next step without further purification. MS m / z: 360.2 [M+H] + , ESI pos.

[0938] Step 4: 4-Benzyl-2-methyl-6-(1H-pyrazol-4-yl)morpholine

[0939]

[0940] Water (48 ml) and hydrochloric acid (37%, in water, 48 ml, 576 mmol) were slowly added to a solution of 1-[benzyl-[2-hydroxy-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)ethyl]amino]prop-2-ol (24.0 g, 66.8 mmol) in 1,4-dioxane (96 ml) at 20 °C. The reaction mixture was stirred at 110 °C for 2 h, then cooled to room temperature, and the pH was adjusted to 8 with a saturated aqueous solution of NaHCO3. 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 µm to 45 µm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile 10% to 15%, flow rate 150 ml / min) to give a pale yellow oily product 4-benzyl-2-methyl-6-(1H-pyrazol-4-yl)morpholine (14.0 g, yield 82%), MS m / z: 258.2 [M+H] + ,ESIpos., 1H 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).

[0941] Step 5: 4-Benzyl-2-methyl-6-[1-(oxecyclobutane-3-yl)pyrazol-4-yl]morpholine

[0942]

[0943] Cesium carbonate (3.17 g, 9.71 mmol) and 3-iodooxetine (1.0 g, 5.83 mmol) were added to a solution of 4-benzyl-2-methyl-6-(1H-pyrazol-4-yl)morpholine (1.0 mg, 3.89 mmol) in dimethylformamide (20 ml), 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 µm to 45 µm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile 40% to 60%, flow rate 70 ml / min) to give a pale yellow oily 4-benzyl-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholine (850 mg, yield 70%). MS m / z: 314.2 [M+H] + , ESI pos.

[0944] Step 6: 2-Methyl-6-[1-(oxecyclobutane-3-yl)pyrazol-4-yl]morpholine

[0945]

[0946] 4-Benzyl-2-methyl-6-[1-(oxecyclobutane-3-yl)pyrazol-4-yl]morpholine A suspension of 2-methyl-6-[1-(oxetane-3-yl)pyrazol-4-yl]morpholine (680 mg, 96% yield) in methanol (20 ml, 1.0 g, 3.19 mmol) was degassed three times with argon, followed by the addition of palladium on carbon (10%, 340 mg), and the gas phase was exchanged for hydrogen three times. The reaction was stirred at 50 °C for 12 h under a hydrogen atmosphere (15 Psi), then cooled to room temperature and filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum to give a pale yellow oily 2-methyl-6-[1-(oxetane-3-yl)pyrazol-4-yl]morpholine (680 mg, 96% yield). MS m / z: 224.2 [M+H] + , ESI pos.

[0947] Intermediate C15: 2-[1-(oxecyclobutane-3-yl)pyrazol-4-yl]morpholine

[0948]

[0949] Similar to intermediate C14, the title compound was prepared in step 2) by replacing 1-(benzylamino)prop-2-ol with 2-(benzylamino)ethanol. It is a pale yellow oil, MS m / z: 210.1 [M+H]. + , ESI pos.

[0950] Intermediate C16: 1-Methyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridin-2-one

[0951]

[0952] Similar to intermediate C8, the title compound was prepared by replacing 2-methoxyisononial with 1-methyl-6-oxo-pyridin-3-carboxaldehyde (CAS 98279-50-6). Brown oil, MS m / z: 318.2 [M+H] + , ESI pos.

[0953] Intermediate C17: Trifluoromethanesulfonic acid [6-(2-bromo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester

[0954]

[0955] In a 100 mL three-necked flask, 2-bromoisonital (2.0 g, 10.75 mmol), 3-butyn-1-ol (1.13 g, 1.23 mL, 40.87 mmol), and dichloromethane (23 mL) were introduced under argon atmosphere 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 min, then at room temperature for 4 h. 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 rapid chromatography (silica gel, 0% to 40% ethyl acetate in heptane) to give the title compound (1.2 g, 23% yield) as a colorless liquid.

[0956] Intermediate C18: 1-Cyclopropyl-4-[2-Methyl-4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole

[0957]

[0958] Similar to intermediate C8, the title compound was prepared by replacing 2-methoxyisononial with 1-cyclopropylpyrazole-4-carboxaldehyde (CAS 1082066-00-9) and 3-butyn-1-ol with 4-pentyn-2-ol. Brown oil, MS m / z: 331.2 [M+H] + , ESI pos.

[0959] Intermediate C19: 1-(oxecyclobutane-3-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxecyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole

[0960]

[0961] Step 1: Trifluoromethanesulfonic acid [6-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester

[0962]

[0963] 1H-pyrazole-4-carboxaldehyde (20.0 g, 208 mmol) was added to a 500 mL three-necked flask, and 3-butyn-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 portions 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. The residue was purified by preparative HPLC (Unisil C18, 250 x 100 mm x 10 µm, water + 0.1% formic acid / acetonitrile, flow rate 350 ml / min) to give trifluoromethanesulfonic acid [6-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester (24.0 g, yield 39%), MS m / z: 299.1 [M+H] + , ESI pos.

[0964] Step 2: Trifluoromethanesulfonic acid [6-[1-(oxecyclobutane-3-yl)pyrazol-4-yl]-3,6-dihydro-2H-pyran- 4-yl] ester

[0965]

[0966] To a solution of trifluoromethanesulfonic acid [6-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester (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 x 40 mm x 15 µm, water + 0.225% formic acid / acetonitrile, flow rate 60 ml / min) to give a yellow, oily trifluoromethanesulfonic acid [6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl] ester (440 mg, yield 9%). MS m / z: 355.0 [M+H] + , ESI pos.

[0967] Step 3: 1-(oxecyclobutane-3-yl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxecyclopentaborane- 2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole

[0968]

[0969] Potassium acetate (965 mg, 2.42 mmol) and a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (66 mg, 0.08 mmol, 0.1 eq) were added to a suspension of trifluoromethanesulfonic acid [6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl] ester (325 mg, 0.81 mmol) and bis(pinacol)diboron (246 mg, 0.97 mmol) in 1,4-dioxane (5 ml). After degassing three times with nitrogen, the resulting mixture was stirred at 90 °C for 1 h under nitrogen. The reaction mixture was added to water (20 ml) and extracted with ethyl acetate (10 ml x 3). The combined organic layers were washed with brine (10 ml), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by chromatography (silica gel, petroleum ether, ether = 1:1) to give the title compound (108 mg, 36% yield) as a pale yellow oil. MS m / z: 333.1 [M+H] + , ESI pos.

[0970] Intermediate C20: Trimethyl-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazol-1-yl]methoxy]ethyl]silane

[0971]

[0972] Step 1: Trifluoromethanesulfonic acid [6-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-3,6-dihydro- 2H-pyran-4-yl] ester

[0973]

[0974] Lithium tert-butoxide (1.075 g, 13.4 mmol) was added to a solution of trifluoromethanesulfonic acid [6-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester (see intermediate C19, step 1, 2.0 g, 6.71 mmol) in tetrahydrofuran (20 ml) at 0 °C, and the solution was stirred at 0 °C for 0.5 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (1.78 ml, 10.06 mmol) was added dropwise, and the mixture was stirred at 20 °C for 2 h under a nitrogen atmosphere. 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 give a yellow oily trifluoromethanesulfonic acid [6-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl] ester (2.0 g, 70% yield), MS m / z: 429.3 [M+H] + , ESI pos.

[0975] Step 2: Trimethyl-[2-[[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3, [6-Dihydro-2H-pyran-6-yl]pyrazol-1-yl]methoxy]ethyl]silane

[0976]

[0977] To a solution of trifluoromethanesulfonic acid [6-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl] ester (2.1 g, 4.9 mmol) in 1,4-dioxane (20 ml), bis(pinacol)diboron (1.49 g, 5.88 mmol), potassium acetate (1.44 g, 14.7 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (200 mg, 0.25 mmol, 0.05 eq) were added, the mixture was degassed three times with nitrogen, and stirred at 90 °C for 2 h. 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 give the title compound (2.1 g, 63% yield) as a brown oil, which was used directly without further purification. MS m / z: 407.3 [M+H] + , ESI pos.

[0978] Intermediate C21: 4-(4-bromotetrahydropyran-2-yl)-1-(trifluoromethyl)pyrazole

[0979]

[0980] Under an argon atmosphere, 1-(trifluoromethyl)pyrazole-4-carboxaldehyde (870 mg, 5.3 mmol) and 3-buten-1-ol (401 mg, 0.48 ml, 5.57 mmol) were combined in dichloromethane (7.5 ml). 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 x 100 ml), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0% to 25% ethyl acetate in heptane) to give a pale yellow oil of 4-(4-bromotetrahydropyran-2-yl)-1-(trifluoromethyl)pyrazole (1.25 g, 79%). MS m / z: 299.0 [M+H] + , ESI pos.

[0981] Intermediate C22: Trimethyl-[2-[(4-morpholin-2-ylpyrazol-1-yl)methoxy]ethyl]silane

[0982]

[0983] Step 1: 2-[[4-(4-benzylmorpholin-2-yl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane

[0984]

[0985] Lithium tert-butoxide (1.02 g, 7.64 mmol) was added to a solution of 4-benzyl-2-(1H-pyrazol-4-yl)morpholine (CAS 2228909-51-9, 930 mg, 3.82 mmol) in tetrahydrofuran (10 ml) at 0 °C, and the solution was stirred at 0 °C for 1 h. 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 h. 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 reversed-phase chromatography (column: spherical C18 20 mm to 45 mm, 100 Å; mobile phase: water / 0.1% formic acid-acetonitrile, 0% to 100%, flow rate: 80 ml / min) to give a colorless oily 2-[[4-(4-benzylmorpholin-2-yl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (1.2 g, yield 84%). MS m / z: 374.2 [M+H] + , ESI pos.

[0986] Step 2: Trimethyl-[2-[(4-morpholin-2-ylpyrazole-1-yl)methoxy]ethyl]silane

[0987]

[0988] Under a nitrogen atmosphere, palladium on carbon (10%, 233 mg) was added to a solution of 2-[[4-(4-benzylmorpholin-2-yl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (820 mg, 2.2 mmol) in methanol (5 ml). The reaction was then degassed under vacuum and hydrogen was added (3 times). The mixture was stirred at 50 °C for 12 h under a hydrogen atmosphere of 45 Psi. The reaction mixture was cooled to room temperature, filtered through a diatomaceous earth pad, and the filtrate was concentrated under vacuum to give a colorless, oily trimethyl-[2-[(4-morpholin-2-ylpyrazol-1-yl)methoxy]ethyl]silane (610 mg, 98% yield). 1HNMR (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).

[0989] Intermediate C23: Trimethyl-[2-[[4-(6-methylmorpholin-2-yl)pyrazol-1-yl]methoxy]ethyl]silane

[0990]

[0991] Similar to intermediate C22, the title compound was prepared in step 1) using 4-benzyl-2-methyl-6-(1H-pyrazol-4-yl)morpholine (see intermediate C14) instead of 4-benzyl-2-(1H-pyrazol-4-yl)morpholine. A pale yellow oil, MS m / z: 298.2 [M+H] + , ESI pos.

[0992] Intermediate C24 4-(4-bromotetrahydropyran-2-yl)-1-(difluoromethyl)pyrazole

[0993]

[0994] Step 1: 4-(4-bromotetrahydropyran-2-yl)-1H-pyrazole

[0995]

[0996] Under argon atmosphere, 3-buten-1-ol (2.46 g, 2.94 ml, 32.8 mmol) was added to a solution of 1H-pyrazole-4-carboxaldehyde (3.0 g, 31.2 mmol) in dichloromethane (43 ml). The mixture was sonicated at 40 °C for 5 min, followed by dropwise addition of hydrobromic acid (33%, in acetic acid, 23.0 g, 16.2 ml, 93.6 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. Saturated NaHCO3 aqueous solution was carefully added until neutral pH was reached, and the mixture was extracted several times with dichloromethane. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by rapid chromatography (silica gel, 0% to 50% ethyl acetate / ethanol 3:1 in heptane) to give 4-(4-bromotetrahydropyran-2-yl)-1H-pyrazole (4.6 g, 64% yield) as a white solid. MS m / z: 231.1 / 233.0 [M+H] + , ESI pos.

[0997] Step 2: 4-(4-bromotetrahydropyran-2-yl)-1-(difluoromethyl)pyrazole

[0998]

[0999] Under argon atmosphere, potassium fluoride (754 mg, 13 mmol) and 4-(4-bromodifluoromethyl)phosphonate diethyl ester (CAS 65094-22-6, 1.73 g, 1.15 ml, 6.49 mmol) in acetonitrile (40 ml) were added at room temperature. The reaction mixture was ultrasonicated for 5 min and then stirred at 40 °C for 8 h. After cooling to room temperature, the mixture was filtered, and the liquid was concentrated to dryness. The crude material was purified by rapid chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give a yellow oil of 4-(4-bromodifluoromethyl)phosphonate (1.3 g, 98% yield). MS m / z: 281.1 / 283.1 [M+H] + , ESI pos.

[1000] Intermediate C25: 2-(1-Cyclobutylpyrazol-4-yl)morpholine

[1001]

[1002] Step 1: 4-Benzyl-2-(1-Cyclobutylpyrazol-4-yl)morpholine

[1003]

[1004] A solution of 4-benzyl-2-(1H-pyrazol-4-yl)morpholine (CAS 2228909-51-9, 500 mg, 2.05 mmol) in dimethylformamide (5 ml) was mixed with bromocyclobutane (832 mg, 6.16 mmol) and potassium carbonate (568 mg, 4.11 mmol) and stirred at 120 °C for 48 h. The mixture was filtered and evaporated. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 150 x 25 mm x 10 µm, water + 0.1% formic acid / acetonitrile, flow rate 60 ml / min) to give a yellow oily 4-benzyl-2-(1-cyclobutylpyrazol-4-yl)morpholine (400 mg, yield 65%). MS m / z: 298.2 [M+H] + , ESI pos.

[1005] Step 2: 2-(1-Cyclobutylpyrazol-4-yl)morpholine

[1006]

[1007] Under nitrogen atmosphere, palladium on carbon (10%, 143 mg) was added to a solution of 4-benzyl-2-(1-cyclobutylpyrazol-4-yl)morpholine (400 mg, 1.34 mmol) in methanol (5 mL). The reaction mixture was degassed three times with hydrogen and stirred at 50 °C for 12 h under a hydrogen atmosphere of 45 Psi. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat. The filtrate was concentrated under vacuum to give the title compound (260 mg, 93% yield) as a colorless oil. 1 H 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).

[1008] Intermediate C26: 1-Cyclobutyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole

[1009]

[1010] Step 1: Trifluoromethanesulfonic acid [6-(1-cyclobutylpyrazole-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester

[1011]

[1012] To a solution of trifluoromethanesulfonic acid [6-(1H-pyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester (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 x 40 mm x 15 µm, water + 0.225% formic acid / acetonitrile, flow rate 60 ml / min) to give a pale yellow oily trifluoromethanesulfonic acid [6-(1-cyclobutylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester (0.35 g, yield 30%). MS m / z: 353.1 [M+H] + , ESI pos.

[1013] Step 2: 1-Cyclobutyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6- [dihydro-2H-pyran-6-yl]pyrazole

[1014]

[1015] To a solution of trifluoromethanesulfonic acid [6-(1-cyclobutylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester (350 mg, 0.99 mmol) in 1,4-dioxane (10 ml), bis(pinacol)diboron (303 mg, 1.19 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (40 mg, 0.05 mmol, 0.05 eq), and potassium acetate (292 mg, 2.98 mmol) were added. The mixture was degassed three times with nitrogen, and the reaction was stirred at 90 °C for 2 h under nitrogen. 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 give the title compound (328 mg, 99% yield) as a pale yellow oil. MS m / z: 331.1 [M+H] + , ESI pos.

[1016] Intermediate C27: Trifluoromethanesulfonic acid [6-[1-(cyclopropylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H- pyran-4-yl] ester

[1017]

[1018] Step 1: Trifluoromethanesulfonic acid [6-(6-oxo-1H-pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl] ester

[1019]

[1020] Under an inert atmosphere, 6-keto-1H-pyridine-3-carboxaldehyde (3 g, 24.4 mmol) and 3-butyn-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 min, and then stirred at room temperature for 4 h. 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 10%) to obtain a pale yellow, colloidal trifluoromethanesulfonic acid [6-(6-oxo-1H-pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl] ester (4.85 g, 60% yield), MS m / z: 326.0 [M+H] + , ESI pos.

[1021] Step 2: Trifluoromethanesulfonic acid [6-[1-(cyclopropylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyridyl] [4-yl] ester

[1022]

[1023] To a solution of trifluoromethanesulfonic acid [6-(6-oxo-1H-pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl] ester (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 h. 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 4%) to obtain the title compound (1.24 g, 67% yield) as a pale yellow solid, MS m / z: 380.1 [M+H] + , ESI pos.

[1024] Intermediate C28: 1-(cyclopropylmethyl)-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridin-2-one

[1025]

[1026] Potassium acetate (828 mg, 8.44 mmol) and bis(pinacol)diborane (803 mg, 3.16 mmol) were added to a solution of trifluoromethanesulfonic acid [6-[1-(cyclopropylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl] ester (intermediate C27, 800 mg, 2.11 mmol) in 1,4-dioxane (12 ml) at room temperature. The mixture was degassed with argon, and then a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (172 mg, 0.211 mmol, 0.10 eq) was added. The reaction mixture was stirred at 90 °C for 2 h, 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 3%) to obtain the title compound as a brown liquid (585 mg, 58% yield), MS m / z: 358.2 [M+H]. + , ESI pos.

[1027] Intermediate C29: Trifluoromethanesulfonic acid [6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester

[1028]

[1029] At room temperature, 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 to a solution of trifluoromethanesulfonic acid [6-(6-oxo-1H-pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl] ester (see intermediate C27, step 1, 1.75 g, 5.38 mmol), in 1,2-dichloroethane (30 ml), and bubbled with air for 3 min. The mixture was stirred overnight at 70 °C under air. 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 40%) to obtain a pale yellow, oily trifluoromethanesulfonic acid [6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester (1.37 g, yield 61%), MS m / z: 366.0 [M+H] + , ESIpos.

[1030] Intermediate C30: 1-Cyclopropyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridin-2-one

[1031]

[1032] Potassium acetate (1.02 g, 10.4 mmol) and bis(pinacol)diborane (991 mg, 3.9 mmol) were added to a solution of trifluoromethanesulfonic acid [6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester (intermediate C29, 950 mg, 2.6 mmol) in 1,4-dioxane (13 ml) at room temperature. The mixture was degassed with argon, and then a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (212 mg, 0.26 mmol, 0.10 eq) was added. The mixture was stirred at 90 °C for 1 h, 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 40%) to obtain the title compound (775 mg, yield 61%, purity 705), brown oil, MS m / z: 344.2 [M+H). + , ESI pos.

[1033] Intermediate C31: 4-(4-bromotetrahydropyran-2-yl)-1-methylpyrazole

[1034]

[1035] Under argon atmosphere, 3-buten-1-ol (1.38 g, 1.64 ml, 19.1 mmol) was added to a solution of 1-methylpyrazol-4-carboxaldehyde (2 g, 18.2 mmol) in dichloromethane (25 ml). Hydrobromic acid (33% solution in acetic acid (13.4 g, 9.9 mL, 54.5 mmol)) was added in a single addition 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 material was purified by rapid chromatography (silica gel, 0% to 50% ethyl acetate / ethanol in heptane = 3:1) to give 4-(4-bromotetrahydropyran-2-yl)-1-methylpyrazol (2.87 g, 62% yield), a pale yellow oil, 245.1 [M+H]. + , ESI pos.

[1036] Intermediate C32: 1-(2-Methoxyethyl)-4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazole

[1037]

[1038] Similar to intermediate C26, the title compound was prepared in step 1 using 2-bromoethylmethyl ether instead of iodocyclobutane. Yellow solid, MS m / z: 335.1 [M+H] + , ESI pos.

[1039] Intermediate C33: Trifluoromethanesulfonic acid [6-[1-(oxetane-3-ylmethyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl] ester

[1040]

[1041] To a solution of trifluoromethanesulfonic acid [6-(6-oxo-1H-pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl] ester (see intermediate C27, step 1, 1.25 g, 3.84 mmol) in acetonitrile (17 ml), 3-(bromomethyl)oxetane (871 mg, 625 μL, 5.76 mmol) and potassium carbonate (1.06 g, 7.69 mmol) were added, and the mixture was stirred at 90 °C for 4 h. 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 10%) to obtain the title compound (1.06 g, 66% yield), MS m / z: 396.1 [M+H] + , ESI pos.

[1042] Intermediate C34: 2-Chloro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine

[1043]

[1044] Similar to intermediate C8, the title compound was prepared by replacing 2-methoxyisononial with 2-chloroisononial. A pale yellow oil, MS m / z: 322.2 [M+H] + , ESI pos.

[1045] Intermediate C35: 2-Methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridine

[1046]

[1047] Similar to intermediate C8, the title compound was prepared by replacing 2-methoxyisocyanuric acid with 6-methoxynicotinic acid. Yellow oil, MS m / z: 318.3 [M+H] + , ESI pos.

[1048] Intermediate C36: Trifluoromethanesulfonic acid [6-(6-oxo-1H-pyridin-3-yl)-3,6-dihydro-2H-pyran-4-yl] ester

[1049]

[1050] Similar to intermediate C8 (step 1), the title compound was prepared by replacing 2-methoxyisoninoxanal with 6-keto-1H-pyridine-3-carboxaldehyde. Brown oil, MS m / z: 326.1 [M+H] + , ESI pos.

[1051] Intermediate C37: Trifluoromethanesulfonic acid [6-(1,5-dimethylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester

[1052]

[1053] Similar to intermediate C8 (step 1), the title compound was prepared by replacing 2-methoxyisononial with 1,5-dimethylpyrazol-4-carboxaldehyde. Pale yellow liquid, MS m / z: 327.4 [M+H] + , ESI pos.

[1054] Intermediate C38: Trifluoromethanesulfonic acid [6-(1,3-dimethylpyrazol-4-yl)-3,6-dihydro-2H-pyran-4-yl] ester

[1055]

[1056] Similar to intermediate C8 (step 1), the title compound was prepared by replacing 2-methoxyisononial with 1,3-dimethylpyrazol-4-carboxaldehyde. Pale yellow liquid, MS m / z: 327.5 [M+H] + , ESI pos.

[1057] Intermediate C39: Trifluoromethanesulfonic acid [6-(1-methyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester

[1058]

[1059] Similar to intermediate C8 (step 1), the title compound was prepared by replacing 2-methoxyisononial with 2-keto-1-methylisononial. A pale yellow oil, MS m / z: 340.1 [M+H] + , ESI pos.

[1060] Intermediate C40: Trifluoromethanesulfonic acid [6-(1-cyclobutyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester

[1061]

[1062] Similar to intermediate C8 (step 1), the title compound was prepared by replacing 2-methoxyisoninaldehyde with 1-cyclobutyl-6-keto-nicotinaldehyde. A pale yellow oil, MS m / z: 358.3 [M+H] + , ESI pos.

[1063] Intermediate C41: 1-Cyclobutyl-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridin-2-one

[1064]

[1065] Similar to intermediate C8, the title compound was prepared by replacing 2-methoxyisoninaldehyde with 1-cyclobutyl-6-keto-nicotinaldehyde. A pale yellow oil, MS m / z: 358.3 [M+H] + , ESI pos.

[1066] Intermediate C42: Trifluoromethanesulfonic acid [6-(1-isopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester

[1067]

[1068] Similar to intermediate C8 (step 1), the title compound was prepared by replacing 2-methoxyisoninaldehyde with 1-isopropyl-6-keto-nicotinaldehyde. Brown oil, MS m / z: 368.1 [M+H] + , ESI pos.

[1069] Intermediate C43: Trifluoromethanesulfonic acid [6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester

[1070]

[1071] Similar to intermediate C8 (step 1), the title compound was prepared by replacing 2-methoxyisononaldehyde with 2-methylisononaldehyde. Orange oil, MS m / z: 324.1 [M+H] + , ESI pos.

[1072] Intermediate C44: Trifluoromethanesulfonic acid [6-(2-cyclopropyl-4-pyridinyl)-3,6-dihydro-2H-pyran-4-yl] ester

[1073]

[1074] Similar to intermediate C8 (step 1), the title compound was prepared by replacing 2-methoxyisoninoxanal with 2-cyclopropylpyridine-4-carboxaldehyde. Yellow oil, MS m / z: 350.0 [M+H] + , ESI pos.

[1075] Intermediate C45: Trifluoromethanesulfonic acid [6-[1-(3,3-difluorocyclobutyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl] ester

[1076]

[1077] Step 1: Methyl 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxylate

[1078]

[1079] At 0 °C, (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 to a solution of methyl 6-ketopyran-3-carboxylate (CAS 6018-41-3, 3.3 g, 21.4 mmol) in N,N-dimethylformamide (30 ml). After stirring at 0 °C for 30 min, 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 was continued overnight at room temperature. 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 rapid chromatography (silica gel, 10% to 100% ethyl acetate in heptane) to give methyl 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxylate (1.44 g, 28% yield) as a yellow solid. MS m / z: 244.1 [M+H] + , ESI pos.

[1080] Step 2: 1-(3,3-difluorocyclobutyl)-5-(hydroxymethyl)pyridin-2-one

[1081]

[1082] Under argon atmosphere, at -78 °C, a solution of diisobutylaluminum hydride (1.2 M, in toluene, 10.28 ml, 12.34 mmol) was added dropwise to a solution of methyl 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxylate (1 g, 4.11 mmol) in toluene (30 ml), and the mixture was stirred at -78 °C for 3 hours. Then, diethyl ether was added, and the mixture was warmed to 0 °C. Water (10 µl), 1 M sodium hydroxide solution (0.5 ml), and water (20 µl) were added again, and the resulting mixture was stirred at room temperature for 10 min. Na₂SO₄ was added, and the mixture was stirred at room temperature for another 10 min. The suspension was filtered, the solid was washed with dichloromethane / methanol, and the resulting solution was concentrated to dryness and used for the next step without further purification. Orange solid, MS m / z: 216.1 [M+H] + , ESI pos.

[1083] Step 3: 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxaldehyde

[1084]

[1085] To a solution of 1-(3,3-difluorocyclobutyl)-5-(hydroxymethyl)pyridin-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 diatomaceous earth, and the solvent was evaporated under reduced pressure to give an orange solid, 1-(3,3-difluorocyclobutyl)-6-oxo-pyridin-3-carboxaldehyde, which was used for subsequent reactions without further purification. MS m / z: 214.1 [M+H] + , ESI pos.

[1086] Step 4: Trifluoromethanesulfonic acid [6-[1-(3,3-difluorocyclobutyl)-6-oxo-3-pyridyl]-3,6-dihydro-2H- pyran-4-yl] ester

[1087]

[1088] Under an argon atmosphere, 3-butyn-1-ol (146 mg, 158 µl, 2.08 mmol) was added to a solution of 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxaldehyde (590 mg, 1.38 mmol) in dichloromethane (8 ml) at room temperature. The reaction 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 h, then at room temperature for 3.5 h. 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 material was used directly in subsequent reactions without further purification (662 mg, yield 35%, purity 30%), a red gel, MS m / z: 416.1 [M+H]. + , ESI pos.

[1089] Intermediate C46: 1-(3,3-Difluorocyclobutyl)-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyridin-2-one

[1090]

[1091] Similar to intermediate C28, the title compound was prepared by replacing intermediate C27 with intermediate C45. Red solid, MS m / z: 394.3 [M+H] + , ESI pos.

[1092] Intermediate C47: 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran-6-yl]-1-(trifluoromethyl)pyridin-2-one

[1093]

[1094] Step 1: Methyl 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxylate

[1095]

[1096] 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) dichloromethane complex (177 mg, 0.217 mmol) and triethylamine (1.78 g, 2.45 ml, 17.85 mmol) were added. The reactor was purged three times with argon at 7 bar and five times with carbon monoxide at 10 bar. The reactor was then filled with carbon monoxide at 8 bar, heated to 70 °C, and stirred overnight for 18 hours. The reaction mixture was concentrated under reduced pressure, and the crude product obtained was purified by column chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give methyl 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxylate (1.23 g, 90% yield), a white solid, MS m / z: 222.1 [M+H]. + , ESI pos.

[1097] Step 2: 5-(hydroxymethyl)-1-(trifluoromethyl)pyridin-2-one

[1098]

[1099] Under argon atmosphere, at -78°C, a solution of diisobutylaluminum hydride (1.2 M, 8.5 ml, 10.2 mmol in toluene) was added to a solution of methyl 1-(3,3-difluorocyclobutyl)-6-oxo-pyridine-3-carboxylate (750 mg, 3.39 mmol) in toluene (22 ml). The reaction mixture was stirred at -78°C for 1.5 h 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 min and warmed to room temperature. Na₂SO₄ was added to dry the mixture. The suspension was stirred again at room temperature for 10 min and then filtered. The filter residue was washed with dichloromethane and methanol, and the filtrate was concentrated to dryness to obtain a crude product, which was used in the next step without further purification. Red solid, MS m / z: 194.1 [M+H] + , ESI pos.

[1100] Step 3: 6-oxo-1-(trifluoromethyl)pyridine-3-carboxaldehyde

[1101]

[1102] Manganese dioxide (2.34 g, 26.9 mmol) was added to a solution of 5-(hydroxymethyl)-1-(trifluoromethyl)pyridin-2-one (520 mg, 2.69 mmol) in dichloromethane (20 ml), and the reaction mixture was stirred at room temperature for 96 hours. The mixture was filtered through diatomaceous earth, and the resulting filtrate was concentrated under reduced pressure to give a red oily 6-oxo-1-(trifluoromethyl)pyridin-3-carboxaldehyde (175 mg, 14%, purity 40%), which was used for subsequent reactions without further purification. MS m / z: 192.1 [M+H] + , ESI pos.

[1103] Step 4: Trifluoromethanesulfonic acid [6-[6-oxo-1-(trifluoromethyl)-3-pyridyl]-3,6-dihydro-2H-pyran- 4-yl] ester

[1104]

[1105] Under an argon atmosphere, 3-butyn-1-ol (48 mg, 52 µl, 0.688 µmol) was added to a solution of 6-oxo-1-(trifluoromethyl)pyridine-3-carboxaldehyde (175 mg, 0.458 mmol) in dichloromethane (3 ml) at room temperature. The reaction was cooled to -10 °C, and trifluoromethanesulfonic acid (206 mg, 121 µl, 1.37 mmol) was added dropwise via syringe. The mixture was stirred at -10 °C for 60 min, then allowed to reach room temperature and stirred at ambient temperature for 3 h. After 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 rapid chromatography (silica gel, 0% to 5% methanol in dichloromethane) to give a pale yellow liquid [6-[6-oxo-1-(trifluoromethyl)-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl] ester (35 mg, 14%, 70% purity), MS m / z: 394.1 [M+H] + , ESIpos.

[1106] Step 5: 5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyridine] [6-yl]-1-(trifluoromethyl)pyridin-2-one

[1107]

[1108] Potassium acetate (35 mg, 0.356 mmol) and bis(pinacol)diborane (29 mg, 0.116 mmol) were added to a solution of trifluoromethanesulfonic acid [6-[6-oxo-1-(trifluoromethyl)-3-pyridyl]-3,6-dihydro-2H-pyran-4-yl] ester (35 mg, 89 µmol) in 1,4-dioxane (1 ml). The mixture was degassed with argon, and then 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (7.3 mg, 8.9 μmol, 0.100 eq) was added. The reaction mixture was stirred at 80 °C for 2 h. 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 to give the title compound (59 mg, 89% yield, 50% purity) as a brown liquid, which was used directly in subsequent steps without further purification. MS m / z: 372.3 [M+H] + , ESI pos.

[1109] Intermediate D1:4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxylic acid

[1110]

[1111] Step 1: Ethyl 4-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate

[1112]

[1113] Trifluoromethanesulfonic anhydride (7.62 g, 4.56 ml, 27.0 mmol) was added to a mixture of ethyl 4-ketotetrahydropyran-2-carboxylate (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) 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 an ice-cold sodium bicarbonate solution (60 ml) with 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. The crude material was purified by rapid chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give a colorless liquid ethyl 4-(trifluoromethanesulfonyloxy)-3,6-dihydro-2H-pyran-2-carboxylate (1.67 g, 41%).

[1114] Step 2: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7- Ethyl 3,6-dihydro-2H-pyran-2-carboxylate

[1115]

[1116] Under an argon atmosphere, 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(diphenylphosphino)ferrocene-palladium(II) chloride (402 mg, 0.542 mmol, 0.10 eq) were added to a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrazino[1,2-a]pyrimidin-4-one (intermediate B13, 2.33 g, 5.42 mmol) in 1,4-dioxane (108 ml) and water (18 ml). The reaction mixture was stirred at 60 °C for 2.5 h. The reaction mixture was filtered through diatomaceous earth. 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 rapid chromatography (silica gel, 0% to 10% methanol in dichloromethane). The product was suspended in ethyl acetate and then filtered to give ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.07 g, 79%) as a yellow solid. MS m / z: 458.2 [M+H] + , ESIpos.

[1117] Step 3: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7- [B]Tetrahydropyran-2-carboxylic acid ethyl ester

[1118]

[1119] Under argon atmosphere, triethylamine (106 mg, 146 µl, 1.05 mmol), magnesium oxide (352 mg, 8.74 mmol), and palladium on carbon (10%, 186 mg) were added to a solution of ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-4-keto-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (400 mg, 0.874 mmol) in ethyl acetate (60 mL). The mixture was degassed several times with argon and then stirred at room temperature for 40 min under hydrogen atmosphere (balloon pressure). The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was concentrated, and the crude material was purified by rapid chromatography (HP C18 RediSep Gold, 0% to 70% acetonitrile in water) to give a yellow, foamy ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxylate (230 mg, 52%). MS m / z: 460.2 [M+H] + , ESI pos.

[1120] Step 4: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7- Tetrahydropyran-2-carboxylic acid

[1121]

[1122] To a solution of ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxylate (246 mg, 0.535 mmol) in tetrahydrofuran (2 ml) and ethanol (1 ml), an aqueous solution of lithium hydroxide (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 give the title compound (248 mg, 97%) as a yellow foam. MS m / z: 432.2 [M+H] + , ESI pos.

[1123] Intermediate D2: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidino[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid

[1124]

[1125] Step 1: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydro-2H-pyran- ethyl 2-formate

[1126]

[1127] To a solution of ethyl 4-(trifluoromethanesulfonyloxy)-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(pinacol)diboron (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 eq) were added. The mixture was then degassed three times with nitrogen, and the reaction was stirred at 90 °C for 2 h 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 to 3:1) to give a pale yellow oil of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-3,6-dihydro-2H-pyran-2-carboxylate (14.0 g, 62% yield). MS m / z: 283.2 [M+H] + , ESI pos.

[1128] Step 2: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidino[1,2-b]pyridazine-7- Ethyl 3,6-dihydro-2H-pyran-2-carboxylate

[1129]

[1130] To a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethylpyrimidino[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-dioxane-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 eq) were added. The reaction was then degassed three times with nitrogen and stirred at 25 °C for 2 h under a nitrogen atmosphere. The mixture was poured into water (200 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100:1 to 1:3) to give ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidino[1,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.6 g, 91% yield) as a pale yellow solid. MS m / z: 458.1 [M+H] + , ESI pos.

[1131] Step 3: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidino[1,2-b]pyridazine-7- [B]Tetrahydropyran-2-carboxylic acid ethyl ester

[1132]

[1133] Under nitrogen atmosphere, ethyl acetate (25 ml) containing 2.0 g (4.37 mmol) of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidino[1,2-b]pyridazin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (2.0 g, 4.37 mmol), dimethylformamide (10 mL), magnesium oxide (1.76 g, 43.7 mmol), and triethylamine (530 mg, 5.24 mmol) were added to a suspension of platinum oxide (198 mg, 0.87 mmol, 0.2 eq) in ethyl acetate (25 ml), along with dimethylformamide (10 mL), magnesium oxide (1.76 g, 43.7 mmol), and triethylamine (530 mg, 5.24 mmol). The reaction mixture was degassed three times with hydrogen and then stirred at 25 °C for 4 hours under hydrogen atmosphere (15 Psi). The reaction mixture was filtered through a diatomaceous earth mat, 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) and dried over Na₂SO₄, 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 give ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidino[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.

[1134] Step 4: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidino[1,2-b]pyridazine-7- Tetrahydropyran-2-carboxylic acid

[1135]

[1136] Ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrimidino[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylate (1.3 g, 2.83 mmol) in tetrahydrofuran (12 ml) and water (4 ml) was added to a solution of lithium hydroxide monohydrate (178 mg, 4.24 mmol), and the reaction was stirred at 20 °C for 1 h. The mixture was poured into water (100 ml), the pH was adjusted to 6 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (80 ml x 3). The combined organic layers were washed with brine (80 ml), dried over Na2SO4, and concentrated under vacuum to give the title compound as a yellow solid (1.2 g, 98% yield). MS m / z: 432.1 [M+H] + , ESI pos.

[1137] Intermediate D3: 4-[9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxylic acid

[1138]

[1139] Similar to intermediate D2, intermediate B17 was used instead of intermediate B3 in step 2 to prepare the title compound. Pale yellow solid, MS m / z: 420.2 [M+H] + , ESI pos.

[1140] Intermediate D4: 4-[9-(4,4-difluorocyclohexyl)-2,3-dimethyl-4-oxo-pyrimido[1,2-b]pyridazin-7-yl]tetrahydropyran-2-carboxylic acid

[1141]

[1142] Similar to intermediate D2, intermediate B16 was used instead of intermediate B3 in step 2 to prepare the title compound. White solid, MS m / z: 422.1 [M+H] + , ESI pos.

[1143] Example 1: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1144]

[1145] At room temperature, (2S)-2-(1-methylpyrazol-4-yl)morpholine (intermediate (+)-C1, 39 mg, 0.235 mmol) and cesium carbonate (192 mg, 0.589 mmol) were added to a suspension of 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one (intermediate B1, 75 mg, 0.196 mmol) in 1,4-dioxane (2 ml). The mixture was degassed with argon, and then tris(dibenzylacetone)dipalladium (9 mg, 0.0098 mmol, 0.05 eq) and Xantphos (11 mg, 0.0196 mmol, 0.10 eq) 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 5%) to obtain the title compound as a pale yellow solid (38 mg, 41% yield), MS m / z: 468.1 [M+H]. + , ESI pos., any specified absolute stereochemical structure.

[1146] Example 2: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1147]

[1148] Similar to Example 1, the title compound was prepared by replacing the intermediate (+)-C1 with the intermediate (-)-C1. Light brown solid, MS m / z: 468.2 [M+H] + , ESI pos., any specified absolute stereochemical structure.

[1149] Example 3: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1150]

[1151] Similar to Example 1, the title compound was prepared by replacing intermediate B1 with intermediate B2. Orange solid, MS m / z: 469.1 [M+H] + , ESI pos., any specified absolute stereochemical structure.

[1152] Examples 4 and 5: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1153]

[1154] To a suspension of 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-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 eq) and Xantphos (7.5 mg, 0.01 mmol, 0.1 eq) were added, and the mixture was stirred at 100 °C for 16 hours under nitrogen. The reaction mixture was poured into water (40 ml) and extracted with ethyl acetate (20 ml × 2). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative MPLC (column: Spherical C18, 20 µm to 45 µm, 100 Å; water / acetonitrile containing 0.1% formic acid, flow rate 50 ml / min) to give 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one (40 mg). The racemic mixture was separated by chiral SFC (Daicel Chiralpak AD column 250 mm × 30 mm, 10 µm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 70 ml / min) to obtain a white solid 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one as the first eluting enantiomer (retention time 0.848 min), MS m / z: 479.2 [M+H] +ESI pos.; and as the second eluted enantiomer (retention time 1.289 min), a white solid 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one, MS m / z: 479.1 [M+H] + , ESI pos., any specified absolute stereochemical structure.

[1155] Similar to Examples 4 and 5, Examples 6 through 13 were prepared by replacing intermediate C2 with the indicated intermediate. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1156]

[1157] Example 14: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one

[1158]

[1159] To a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one (intermediate B3, 100 mg, 0.30 mmol) in acetonitrile (3 ml), 2-(1-methylpyrazol-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 h. 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 10%) to give the title compound (19 mg, 14% yield) as a light brown solid, MS m / z: 469.2 [M+H] + , ESIpos.

[1160] Example 15: 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one

[1161]

[1162] Step 1: 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-methoxy-4-pyridyl)-3,6-dihydro-2H-pyran- 4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one

[1163]

[1164] Add 2-methoxy-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane[1,2-a]pyrimidin-4-one (intermediate B1, 50 mg, 0.131 mmol) to a solution of 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one (intermediate B1, 50 mg, 0.170 mmol) in 1,4-dioxane (1.5 ml) followed by a solution of potassium carbonate (54 mg, 0.393 mmol) in water (0.30 ml). The mixture was purged with argon for 5 min, followed by the addition of a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (11 mg, 0.013 mmol, 0.10 eq). Purging with argon was continued for another 5 min, the tube was then sealed and heated to 60°C for 1 hour. A saturated NaHCO3 solution (10 ml) was added, and the mixture was extracted with ethyl acetate (2 x 10 ml). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel, 0% to 70% ethyl acetate in heptane) to give a light brown solid 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-methoxy-4-pyridinyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one (51 mg, 79% yield), MS m / z: 492.3 [M+H] + , ESI pos.

[1165] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3- Dimethyl-pyrido[1,2-a]pyrimidin-4-one

[1166]

[1167] A solution of 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-methoxy-4-pyridinyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one (47 mg, 0.096 mmol) in ethyl acetate (2 ml) was purged with nitrogen and backfilled (3 times). Palladium (10%, on activated carbon, 10 mg, 0.0096 mmol, 0.10 eq) was then added. The mixture was purged with hydrogen and backfilled, and stirred overnight at 22°C using an attached hydrogen-filled balloon. The catalyst was filtered off, washed with ethyl acetate (3 x 5 ml), and the filtrate was concentrated under vacuum. The residue was purified by rapid column chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give the title compound (44 mg, 93% yield) as a pale yellow oil, MS m / z: 494.3 [M+H] + , ESI pos.

[1168] Example 16: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one

[1169]

[1170] Racemic 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one was separated by chiral SFC (column IB, 250 mm × 20 mm, 5 µm, 30% methanol) to obtain a white powder of 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one as the first eluting enantiomer (retention time 2.582 min), MS m / z: 494.4 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1171] Example 17: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one

[1172]

[1173] Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholin-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) to obtain a pale yellow solid of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one as the second eluting enantiomer (retention time 4.033 min), MS m / z: 469.2 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1174] Example 18: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1175]

[1176] Similar to Example 15, the title compound was prepared by replacing intermediate C8 with intermediate C9. Pale yellow powder, MS m / z: 467.3 [M+H] + , ESI pos.

[1177] Example 19: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one

[1178]

[1179] Similar to Example 14, the title compound was prepared by replacing intermediate C1 with intermediate C2. Light brown solid, MS m / z: 480.2 [M+H] + , ESI pos.

[1180] Example 20: 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[1,2-a]pyrimidin-4-one

[1181]

[1182] Similar to Example 1, the title compound was prepared by replacing intermediate B1 with intermediate B4. Pale yellow powder, MS m / z: 450.4 [M+H] +, ESI pos.

[1183] Examples 21 and 22: 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1184]

[1185] Similar to Example 15, the title compound was prepared by replacing intermediate B1 with intermediate B2. The resulting racemic 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one was separated by a chiral SFC (Chiralpak Cel-SZ column, 250 mm × 20 mm, 5 µm, 40% methanol) to give a white powder of 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one as the first eluting enantiomer (retention time 3.63 min), MS m / z: 495.4 [M+H] + , ESI pos.; and as the second eluted enantiomer (retention time 4.04 min), a white powder of 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one, MS m / z: 495.4 [M+H] + , ESIpos. Absolute stereochemistry is arbitrarily specified.

[1186] Similar to Examples 4 and 5, Examples 23 through 26 were prepared by starting with the indicated intermediates. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1187]

[1188] Examples 27 and 28: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one

[1189]

[1190] Similar to Example 15, the title compound was prepared by replacing intermediate C8 with intermediate C11. The racemic mixture was separated by a chiral SFC (column: chiral IJ, 250 mm × 20 mm, 5 µm, 20% methanol) to give 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one, a white powder, as the first eluting enantiomer (retention time 1.921 min), MS m / z: 493.4 [M+H]. + , ESI pos.; and as the second eluted enantiomer (retention time 2.398 min), a white powder of 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one, MS m / z: 493.4 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1191] Example 29: 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1192]

[1193] Similar to Example 15, intermediate B4 was used instead of intermediate B1 and intermediate C9 was used instead of intermediate C8 to prepare the title compound. The racemic mixture was separated by a chiral SFC (Chiralpak Cel-SZ, 250 mm × 20 mm, 5 µm, 53% methanol) to give 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one as the first eluting enantiomer (retention time 2.809 min), a white powder. MS m / z: 449.4 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1194] Example 30: 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1195]

[1196] Similar to Example 15, intermediate B2 was used instead of intermediate B1, and intermediate C11 was used instead of intermediate C8 to prepare the title compound. Pale yellow powder, MS m / z: 494.4 [M+H] + , ESI pos. This compound is a racemic mixture.

[1197] Similar to Examples 4 and 5, Examples 31 through 33 were prepared by starting with the indicated intermediates. Example 32 is a racemic mixture, the relative stereochemistry of which was determined by NMR.

[1198]

[1199] Examples 34 and 35: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1200]

[1201] Similar to Example 15, intermediate B2 was used instead of intermediate B1 and intermediate C13 was used instead of intermediate C8 to prepare the title compound. The resulting racemic mixture was separated by a chiral SFC (column: chiral IB, 250 mm × 20 mm, 5 µm, 25% methanol) to give a pale yellow oily 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one as the first eluting enantiomer (retention time 1.875 min), MS m / z: 533.4 [M+H] + ESI pos.; and as the second eluted enantiomer (retention time 2.094 min), a pale yellow oily 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one, MS m / z: 533.4 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1202] Examples 36 and 37: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1203]

[1204] Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one was separated by chiral SFC (column: chiral AD-H, 250 mm × 20 mm, 5 µm, 40% methanol) to obtain a light brown solid of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one as the first eluting enantiomer (retention time 3.25 min), MS m / z: 471.4 [M+H] +ESI pos.; and as the second eluted enantiomer (retention time 3.82 min), a light brown solid of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one, MS m / z: 471.3 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1205] Example 38: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1206]

[1207] Similar to Example 15, intermediate B2 was used instead of intermediate B1, and intermediate C9 was used instead of intermediate C8 to prepare the title compound. Pale yellow solid, MS m / z: 468.3 [M+H] + , ESI pos.

[1208] Examples 39 and 40: 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one carbamate

[1209]

[1210] Diisopropylethylamine (0.15 ml, 0.86 mmol) and 2-(1-cyclopropylpyrazol-4-yl)morpholine (intermediate C5, 166 mg, 0.86 mmol) were added to a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one (intermediate B3, 97 mg, 0.29 mmol) in dimethyl sulfoxide (10 mL), 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 x 25 mm x 10 µm, water + 0.225% formic acid / acetonitrile, flow rate 25 ml / min) and extracted with ethyl acetate to give a yellow oily 9-(4-chloro-2-fluoro-phenyl)-7-[2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one (100 mg). The racemic mixture was separated by a chiral SFC (Chiralpak AD column, 250 mm x 30 mm, 10 µm, 30% ethanol) to give a grayish-white solid, 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one (37 mg, 37% yield), as the first eluting enantiomer, MS m / z: 495.1 [M+H] + ESI pos.; and as the second eluted enantiomer, a grayish-white solid 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazine-4-one carbamate (34 mg, 34% yield), MS m / z: 495.1 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1211] Example 41: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1212]

[1213] Similar to Example 15, intermediate B6 was used instead of intermediate B1 and intermediate C9 was used instead of intermediate C8 to prepare the title compound. Pale yellow solid, MS m / z: 486.3 [M+H] + , ESI pos.

[1214] Example 42: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one

[1215]

[1216] To a solution of 7-chloro-9-(4-chloro-2,6-difluorophenyl)-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one (intermediate B7, 50 mg, 0.14 mmol) in acetonitrile (1.4 mL), (2S)-2-(1-methylpyrazol-4-yl)morpholine (intermediate (+)-C1, 23.5 mg, 0.140 mmol) and 3 M tripotassium phosphate aqueous solution (3.25 M, 0.140 mL, 0.421 mmol) were added. The mixture was stirred at 80 °C for 6 h. 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 material was purified by rapid chromatography (silica gel, 0% to 100% ethyl acetate in heptane, followed by 0% to 6% methanol in dichloromethane) to obtain the title compound (38 mg, 56% yield) as a light brown solid, MS m / z: 487.3 [M+H] + , ESI pos.

[1217] Similar to Examples 39 and 40, Examples 43 to 46 were prepared by starting with the indicated intermediates. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1218]

[1219] Example 47: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one

[1220]

[1221] Similar to Example 15, intermediate B3 was used instead of intermediate B1 and intermediate C9 was used instead of intermediate C8 to prepare the title compound. Yellow solid, MS m / z: 468.3 [M+H] + , ESI pos.

[1222] Example 48: 9-(4-chloro-2-fluoro-phenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[1,2-a]pyrimidin-4-one

[1223]

[1224] Similar to Example 1, intermediate B8 was used instead of intermediate B1 to prepare the title compound. Yellow solid, MS m / z: 454.4 [M+H] + , ESI pos.

[1225] Similar to Example 42, Examples 49 through 56 are prepared by starting with the indicated intermediate. Chiral separation is performed as described for Examples 4 and 5. Absolute stereochemistry is arbitrarily specified.

[1226]

[1227] Example 57: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one

[1228]

[1229] Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimidino[1,2-b]pyridazin-4-one (Example 47) was separated by chiral SFC (chiral NR, 250 mm × 20 mm, 5 µm, 50% methanol) to give the title compound as a light brown solid as the second eluting enantiomer (retention time 5.406 min), MS m / z: 468.4 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1230] Example 58: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1H-pyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1231]

[1232] Step 1: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl) [Pyrazol-4-yl]morpholino-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1233]

[1234] Trimethyl-[2-[(4-morpholino-2-ylpyrazol-1-yl)methoxy]ethyl]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 eq) were added to a solution of 7-bromo-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one (intermediate B1, 400 mg, 1.05 mmol), in tert-amyl alcohol (4.0 ml). The mixture was then degassed three times with nitrogen and stirred at 90 °C for 16 h under a nitrogen atmosphere. 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) and dried over Na2SO4. The residue was purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 1:1) to obtain a pale yellow oily 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one (220 mg, yield 36%), MS m / z: 584.4 [M+H] + , ESI pos.

[1235] Step 2: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1H-pyrazol-4-yl)morpholin-4-yl]pyridine pyrimido[1,2-a]pyrimidin-4-one

[1236]

[1237] Trifluoroacetic acid (5.0 ml, 67 mmol) was added to a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one (210 mg, 0.36 mmol) in dichloromethane (10 ml), and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was added to water (40 ml), and an aqueous sodium carbonate solution was added to the reaction mixture to adjust the pH to 7 to 8. The mixture was extracted three times with ethyl acetate, and the combined extracts were washed with brine, dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by reversed-phase chromatography (column: spherical C18, 20 mm to 45 mm 100 Å, mobile phase: water / 0.1% formic acid-acetonitrile, 0% to 100%, flow rate: 80 ml / min) to give the title compound (120 mg, yield 74%) as a pale yellow solid, MS m / z: 454.2 [M+H] + , ESI pos.

[1238] Similar to Examples 4 and 5, Examples 59 to 61 were prepared by starting with the indicated intermediates, with the relative stereochemistry determined by NMR.

[1239]

[1240] Examples 62, 63, 64, and 65: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxetane-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxetane-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxetane-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-[1-(oxetane-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one

[1241]

[1242] Similar to Examples 39 and 40, intermediate C14 was used instead of intermediate C5 to prepare the title compound. All white solids had an MS m / z of 525.2 [M+H]. + ESI pos. Absolute stereochemistry is determined by arbitrary partitioning, and relative stereochemistry is determined by NMR.

[1243] Examples 66 and 67: 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one

[1244]

[1245] In a glove box, 2-(1-cyclopropylpyrazol-4-yl)morpholine (intermediate C5, 86 mg, 0.44 mmol), cesium carbonate (433 mg, 1.33 mmol), and Xantphos-Pd-G4 (43 mg, 0.04 mmol, 0.1 eq) were added to a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (intermediate B2, 150 mg, 0.44 mmol), in 1,4-dioxane (5 ml), 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 x 25 mm x 10 µm, mobile phase: water / 0.25% formic acid-acetonitrile, 0% to 100%, flow rate 25 ml / min) to give racemic 9-(4-chloro-2-fluoro-phenyl)-7-[2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one. The material was isolated into enantiomers by chiral SFC (Daicel Chiralpak AD, 250 mm x 30 mm, 10 µm, CO2 / ethanol containing 0.1% ammonium hydroxide) to obtain 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (20 mg, 30% yield) and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (22 mg, 32% yield), both yellow solids, MS m / z: 495.1 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1246] Examples 68 and 69: 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one

[1247]

[1248] Similar to Examples 66 and 67, intermediate C4 was used instead of intermediate C5 to prepare the title compound. Yellow solid with MS m / z: 496.1 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1249] Similar to Example 15, Examples 70 to 73 were prepared by starting with the indicated intermediate. Chiral separation was performed as described for Examples 34 and 35. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1250]

[1251] Example 74: 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrazino[1,2-a]pyrimidin-4-one

[1252]

[1253] Add 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-pyrazino[1,2-a]pyrimidin-4-one (intermediate B10, 75 mg, 0.16 mmol) to a solution of (2S)-2-(1-methylpyrazol-4-yl)morpholine (intermediate (+)-C1, 76 mg, 0.45 mmol) in ethanol (4.5 ml) and microwave the mixture at 150 °C for 5 hours. The volatiles were evaporated, and the residue was purified by chromatography (silica gel, 0% to 100% ethyl acetate in heptane) to give a yellow powder of 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrazino[1,2-a]pyrimidin-4-one (9 mg, 9% yield), MS m / z: 505.4 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1254] Example 75: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1255]

[1256] Similar to Example 15, intermediate B6 was used instead of intermediate B1 and intermediate C11 was used instead of intermediate C8 to prepare the title compound. Yellow solid, MS m / z: 512.3 [M+H] + , ESI pos.

[1257] Example 76: 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one

[1258]

[1259] Similar to Example 42, intermediate B11 was used instead of intermediate B7 to prepare the title compound. White solid, MS m / z: 505.4 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1260] Example 77: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one

[1261]

[1262] Similar to Example 15, intermediate B3 was used instead of intermediate B1 and intermediate C11 was used instead of intermediate C8 to prepare the title compound. Yellow solid, MS m / z: 494.3 [M+H] + , ESI pos.

[1263] Example 78: 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one

[1264]

[1265] Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one (Example 77) was separated by chiral SFC (column: chiral OD-H, 5 µm, 250 x 20 mm, 33% methanol) to give the title compound as the first eluting enantiomer (retention time 3.184 min), a yellow solid, MS m / z: 494.1 [M+H]. + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1266] Similar to Examples 39 and 40, Examples 79 to 82 were prepared by starting with the indicated intermediates. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1267]

[1268] Example 83: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-methyl-6-oxopyridin-3-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one

[1269]

[1270] Similar to Example 15, the title compound was prepared by replacing intermediate B1 with intermediate B3 and intermediate C8 with intermediate C16. Pale yellow solid, MS m / z: 495.3 [M+H] + , ESI pos.

[1271] 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]pentyl]pyrazino[1,2-a]pyrimidin-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]pentyl]pyrazino[1,2-a]pyrimidin-4-one

[1272]

[1273] Similar to Example 15, the title compound was prepared by replacing intermediate B1 with intermediate B12 and intermediate C8 with intermediate C11. Chiral separation was performed as described with respect to Examples 34 and 35. Absolute stereochemistry was arbitrarily specified. Pale yellow solid, MS m / z: 500.2 [M+H] + , ESI pos.

[1274] Similar to Examples 4 and 5, Examples 86 and 87 were prepared by starting with the indicated intermediates. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1275]

[1276] Example 88: 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one

[1277]

[1278] Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one (Example 77) was separated by chiral SFC (column: chiral OD-H, 5 µm, 250 x 20 mm, 33% methanol) to give the title compound as a yellow solid as the second eluting enantiomer (retention time 4.030 min), MS m / z: 494.1 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1279] Similar to Example 15, Examples 89 to 91 were prepared by starting with the indicated intermediate. Chiral separation was performed as described for Examples 34 and 35. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1280]

[1281] Example 92: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1282]

[1283] Step 1: 7-[6-(2-bromo-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-9-(4-chloro-2-fluoro-benzene) 2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1284]

[1285] Under argon atmosphere, a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrazino[1,2-a]pyrimidin-4-one (intermediate B13, 1.8 g, 4.2 mmol) in 1,4-dioxane (60 ml) and water (10 ml) was prepared by adding trifluoromethanesulfonic acid [6-(2-bromo-4-pyridinyl)-3,6-dihydro-2H-pyran-4-yl] ester (intermediate C17, 1.63 g, 4.2 mmol), potassium carbonate (1.74 g, 12.6 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (347 mg, 0.420 mmol, 0.10 mmol) to a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrazino[1,2-a]pyrimidin-4-one (intermediate B13, 1.8 g, 4.2 mmol) (intermediate C17, 1.63 g, 4.2 mmol), potassium carbonate (1.74 g, 12.6 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (347 mg, 0.420 mmol, 0.10 mmol) to a solution of 1,4-dioxane (60 ml) and water (10 ml). 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. The residue was purified by rapid chromatography (silica gel, 0% to 50% ethyl acetate in heptane) to give a pale yellow solid 7-[6-(2-bromo-4-pyridinyl)-3,6-dihydro-2H-pyran-4-yl]-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (710 mg, 30% yield), MS m / z: 541.2 [MH]. + , ESI neg.

[1286] Step 2: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro- 2H-pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1287]

[1288] Under argon atmosphere, 2,4,6-trimethyl-1,3,5,2,4,6-trioxadione (3.5 M solution in tetrahydrofuran, 0.450 ml, 1.58 mmol), potassium carbonate (543 mg, 3.93 mmol), and a 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (108 mg, 0.131 mmol, 0.10 eq) were added to a solution of 7-[6-(2-bromo-4-pyridinyl)-3,6-dihydro-2H-pyran-4-yl]-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (710 mg, 1.31 mmol) in 1,4-dioxane (12 ml), and the mixture was heated to 90 °C and stirred for 2 hours. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth 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 rapid chromatography (silica gel, ethyl acetate + ethanol 3 / 1-heptane 0% to 50%) to give an orange foamy 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (482 mg, 73% yield), MS m / z: 477.2 [M+H] + , ESI pos.

[1289] Step 3: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridine) [Pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1290]

[1291] In a 100 ml round-bottom flask, 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (482 mg, 1.01 mmol) was dissolved in methanol (25 ml). The mixture was degassed with argon, then palladium on carbon (10%, 108 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere (balloon). The reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was concentrated under vacuum. The residue was purified by rapid chromatography (silica gel, ethyl acetate + ethanol 3 / 1-heptane 0% to 50%) and subsequent second chromatography (HP C18 RediSep Gold, 0% to 70% acetonitrile in water) to give the yellow, foamy title compound (210 mg, 43%), MS m / z: 479.2 [M+H). + , ESI pos.

[1292] Examples 93 and 94: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1293]

[1294] Racemic 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (Example 92) was separated by a chiral SFC (column: chiral IH, 5 µm, 250 x 20 mm, 22% methanol + 0.2% diethylamine) to obtain 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one as the first eluting enantiomer (retention time 1.571 min) and as the second eluting enantiomer (retention time 2.185 min). 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one, both pale yellow solids, have an MS m / z of 479.3 [M+H]. + , ESIpos. Absolute stereochemistry is arbitrarily specified.

[1295] Examples 95 and 96: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1296]

[1297] Racemic 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one (Example 38) was subjected to a chiral SFC (column Daicel Chiralpak, 250 x 30 mm, 10 µm, ethanol + 0.1%). The enantiomers were separated using ammonium hydroxide to obtain 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one as the first eluting enantiomer and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one as the second eluting enantiomer, both white solids with MS m / z: 468.2 [M+H]. + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1298] Example 97: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1299]

[1300] The title compound was isolated as a minor 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.

[1301] Example 98: 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one

[1302]

[1303] Similar to Example 15, intermediate B7 was used instead of intermediate B1 and intermediate C9 was used instead of intermediate C8 to prepare the title compound. Chiral separation was performed by a chiral SFC (column: chiral IK, 250 mm × 20 mm, 5 µm, 37% methanol), with a second elution of the enantiomer. Yellow solid, MS m / z: 486.2 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1304] Similar to Example 15, Examples 99 to 109 were prepared by starting with the indicated intermediate. Chiral separation was performed as described for Examples 95 and 96. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1305]

[1306] Examples 110 and 111: 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1307]

[1308] Racemic 9-(4-chloro-2,6-difluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (Example 75) was passed through a chiral SFC (column: chiral Cellulose-SZ, 250 x 20 mm, 5 µm, 45%). Methanol was separated into two enantiomers: 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one as the first eluting enantiomer and 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazole-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one as the second eluting enantiomer, both pale yellow solids with MS m / z: 512.3 [M+H]. + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1309] Similar to Example 15, Examples 112 to 123 were prepared by starting with the indicated intermediate. Separation of diastereomers was performed by preparative HPLC (Waters Xbridge C18 column, 150 x 25 mm x 10 µm, 50% to 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 determined by... 1 The evaluation of H-NMR measurement results is used to assign absolute stereochemistry by arbitrary allocation.

[1310]

[1311] Examples 124 and 125: 7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimido[1,2-b]pyridazin-4-one and 7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimido[1,2-b]pyridazin-4-one

[1312]

[1313] Similar to Examples 39 and 40, B18 was used instead of intermediate B3 to prepare the title compound. A pale yellow solid with MS m / z: 501.3 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1314] Similar to Example 15, Examples 126 to 130 were prepared by starting with the indicated intermediate. Chiral separation was performed as described for Examples 95 and 96. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1315]

[1316] Examples 131 and 132: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1317]

[1318] Step 1: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-[1-(2-trimethylsilylethoxymethyl) [[1,2-a]pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1319]

[1320] Add 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazol-1-yl]methoxy]ethyl]silane (intermediate C20, 600 mg, 1.48 mmol) to a solution of trimethyl-[2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-pyrimidin-4-one (intermediate B2, 1.25 g, 2.21 mmol), sodium carbonate (469 mg, 4.43 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (120 mg, 0.15 mmol, 0.1 eq) to a solution of trimethyl-[2-[[4-[4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyran-6-yl]pyrazol-1-yl]methoxy]ethyl]silane (intermediate C20, 600 mg, 1.48 mmol) in 1,4-dioxane (10 ml) and water (2 ml) to a solution of 1,4-dioxane (10 ml) and water (2 ml). The reaction mixture was degassed three times with nitrogen, and stirred at 90 °C for 2 hours under a nitrogen atmosphere. 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 to 1:1) to give a yellow oily 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (400 mg, 46% yield), MS m / z: 582.2 [M+H] + , ESI pos.

[1321] Step 2: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl) [Pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1322]

[1323] A suspension of palladium on carbon (10%, 73 mg) in ethyl acetate (1 ml) under nitrogen atmosphere was supplemented with a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]-3,6-dihydro-2H-pyran-4-yl]pyrazino[1,2-a]pyrimidin-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 h under a hydrogen atmosphere (balloon). The reaction mixture was filtered through a diatomaceous earth pad to give a yellow oily 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (330 mg, 28% yield), MS m / z: 584.2 [M+H] + , ESI pos.

[1324] Step 3: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazol-4-yl)tetrahydro [Pyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)- 2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1325]

[1326] Trifluoroacetic acid (4.0 ml, 0.72 mmol) was added to a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (700 mg, 0.72 mmol) in dichloromethane (8 ml) at room temperature, and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was carefully poured into an aqueous solution of sodium bicarbonate (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 x 25 mm x 10 µm, mobile phase: water / 0.25% formic acid-acetonitrile, 0% to 100%, flow rate 25 ml / min) to give a racemic compound (220 mg, yield 67%). 60 mg of this compound was separated by chiral SFC (Daicel Chiralpak OD 250 mm × 30 mm, 10 µm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 75 ml / min) to give a yellow solid 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (first eluting enantiomer, 13...). mg (yield 22%), MS m / z: 454.1 [M+H] + ESI pos.; and yellow solid 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (second eluted enantiomer, 18 mg, 30% yield). MS m / z: 454.1 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1327] Examples 133 and 134: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one

[1328]

[1329] 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 the mixture, and the mixture was ultrasonicated for 20 min and further stirred overnight at room temperature to obtain a black suspension of highly reactive Rieke zinc.

[1330] 4-(4-bromotetrahydropyran-2-yl)-1-(trifluoromethyl)pyrazole (intermediate C21, 600 mg, 2.01 mmol) was dissolved in tetrahydrofuran (ultra-dry, 2 ml), and argon gas was bubbled into the solution for 2 to 5 min. 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).

[1331] Xantphos palladacycle G3 (80 mg, 74 µmol, 0.10 eq) was added to a solution of 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (intermediate B2, 250 mg, 0.74 mmol) in tetrahydrofuran (ultra-dry, 2 ml). The flask was degassed three times with argon, and then a solution of zinc bromo-[2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl] (0.23 M, 5.1 ml, 1.18 mmol) was added. The mixture was stirred at room temperature for 30 min, and then at 45 °C for 1.5 h. The reaction mixture was filtered through diatomaceous earth and concentrated under reduced pressure. A saturated ammonium chloride solution was added to the residue, and the resulting solution was extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography (column: YMCTriart C18, 100 mm × 30 mm, 5 µm, mobile phase: water / 0.1% formic acid-acetonitrile, 0% to 100%) to give 50 mg of racemic 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one. Separation was performed by chiral SFC (column: chiral OD, 5 µm, 250 x 20 mm, 20% methanol) to obtain a pale yellow powder of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (first elution enantiomer, 12 mg, 24%), MS m / z: 522.1 [M+H]. + ESI pos.; and pale yellow powder 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one (second eluted enantiomer, 12 mg, 24%), MS m / z: 522.1 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1332] Similar to Example 15, Examples 135 to 140 were prepared by starting with the indicated intermediate. Chiral separation was performed as described for Examples 95 and 96. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1333]

[1334] Examples 141, 142, and 143: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one. [[2-oxadiazol-2-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1335]

[1336] Step 1: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7- [N'-(cyclopropanecarbonyl)tetrahydropyran-2-carbazide]

[1337]

[1338] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-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 cyclopropanecarbazide (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 µm to 45 µm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile, flow rate 50 ml / min) to give a pale yellow solid, 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]-N'-(cyclopropanecarbonyl)tetrahydropyran-2-carbazine (110 mg, 92% yield). MS m / z: 514.2 [M+H] + , ESI pos.

[1339] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetracycline [Hydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S, 4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidine 4-Pyridine-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl) [Tetrahydropyran-4-yl]-2,3-dimethylpyrazin[1,2-a]pyrimidin-4-one

[1340]

[1341] Burgess reagent (CAS 29684-56-8, 417 mg, 1.75 mmol) was added to a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]-N'-(cyclopropanecarbonyl)tetrahydropyran-2-carbazine (90 mg, 0.18 mmol) in tetrahydrofuran (3 ml), and the mixture was stirred at 130 °C for 0.5 h 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 x 25 mm x 10 µm, mobile phase: water / 0.25% formic acid-acetonitrile, 0% to 82%, flow rate 25 ml / min) to give a racemic compound, which was then separated by chiral SFC (Daicel Chiralpak AS 250 mm × 30 mm, 10 µm, acetonitrile / isopropanol / 0.1% ammonium hydroxide, flow rate 75 ml / min) to give a pale yellow solid, 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (18 mg, yield 28%), as the first eluting enantiomer. m / z: 496.2 [M+H] + ESI pos.; and as the second eluted enantiomer, a pale yellow solid 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (17 mg, yield 26%), MS m / z: 496.2 [M+H + ESI pos.; and as a racemic, pale yellow solid 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (10 mg, 15% yield), MS m / z: 496.2 [M+H + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1342] Similar to Example 58, Examples 144 to 149 were prepared by starting with the indicated intermediate. Separation of diastereomers was performed by preparative HPLC (Phenomenex Luna column, C18, 150 x 25 mm x 10 µm, mobile phase: water / 0.25% formic acid-acetonitrile, 0% to 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 determined by... 1 The evaluation of H-NMR measurement results is used to assign absolute stereochemistry by arbitrary allocation.

[1343]

[1344] Examples 150 and 151 contain 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1345]

[1346] Similar to Examples 133 and 134, intermediate C24 was used instead of intermediate C21 to prepare the title compound. Yellow solid with MS m / z: 504.2 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1347] Examples 152 and 153: 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclobutylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclobutylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1348]

[1349] Similar to Examples 66 and 67, intermediate C25 was used instead of intermediate C5 to prepare the title compound. Yellow solid with MS m / z: 509.1 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1350] Similar to Example 15, Examples 154 to 165 were prepared by starting with the indicated intermediate. The reduction in step 2 was performed by adding magnesium oxide and triethylamine, as described for Examples 131 and 132. Chiral separation was performed as described for Examples 95 and 96. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry by NMR.

[1351]

[1352] Examples 166, 167, and 168: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one. [[3-oxadiazol-3-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1353]

[1354] Step 1: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7- [2-Tetrahydropyran-2-carboxamide]

[1355]

[1356] Ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxylate (see Intermediate D1, Step 3, 150 mg, 0.33 mmol) was reacted in a sealed tube at 60 °C for 16 h. The reaction mixture was then concentrated under vacuum to give a pale yellow solid of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxamide (140 mg, 99% yield). MS m / z: 431.1 [M+H] + , ESIpos.

[1357] Step 2: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7- [2-Tetrahydropyran-2-carboxynitrile]

[1358]

[1359] Pyridine (0.08 ml, 0.97 mmol) was added to a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxamide (140 mg, 0.32 mmol) in tetrahydrofuran (4 ml) at 25 °C, followed by dropwise addition of trifluoroacetic anhydride (0.14 ml, 0.97 mmol) at 0 °C, and 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 layers were 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 give a pale yellow solid, 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxylon (100 mg, 74% yield). MS m / z: 413.1 [M+H] + , ESI pos.

[1360] Step 3: 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine-7- [N-hydroxy-tetrahydropyran-2-formamidinium]

[1361]

[1362] A solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-carboxynitrile (100 mg, 0.24 mmol) in 1,4-dioxane (2 ml) was added to a well-stirred solution of hydroxylamine hydrochloride (50 mg, 0.73 mmol) and triethylamine (98 mg, 0.97 mmol) in 1,4-dioxane (1 ml). The reaction mixture was then heated to 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 layers were washed with brine (50 ml), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by preparative MPLC (column: Spherical C18, 20 µm to 45 µm, 100 Å; mobile phase: water + 0.1% formic acid / acetonitrile 54% to 62%, flow rate 50 ml / min). The eluent was adjusted to 8 with saturated NaHCO3 aqueous solution and then extracted to give a pale yellow solid, 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]-N-hydroxy-tetrahydropyran-2-formamidinium (80 mg, yield 74%). MS m / z: 446.1 [M+H] + , ESI pos.

[1363] Step 4: N-[C-[4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidine [Pyridine-7-yl]tetrahydropyran-2-yl]-N-hydroxy-carbonimide]cyclopropaneformamide

[1364]

[1365] To a solution of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]-N-hydroxy-tetrahydropyran-2-formamidinium (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 layers were washed with brine (50 ml), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by preparative TLC (silica gel, ethyl acetate) to give a pale yellow solid, N-[C-[4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-yl]-N-hydroxy-carbonimide]cyclopropaneformamide (80 mg, 87% yield). MS m / z: 514.1 [M+H] + , ESIpos.

[1366] Step 5: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetracycline [Hydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S, 4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidine Pyridine-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl) [Tetrahydropyran-4-yl]-2,3-dimethylpyrazin[1,2-a]pyrimidin-4-one

[1367]

[1368] Sodium acetate (22 mg, 0.27 mmol) was added to a solution of N-[C-[4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimidin-7-yl]tetrahydropyran-2-yl]-N-hydroxy-carbonimide]cyclopropaneformamide (70 mg, 0.14 mmol) in ethanol (1 ml) and water (0.8 ml), and the reaction was stirred at 80 °C for 48 h. 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 give 9-(4-chloro-2-fluoro-phenyl)-7-[2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one, which was then passed through a chiral SFC (Daicel Chiralpak AS250 mm × 30 mm, 10 µm, ethanol / 0.1% ammonium hydroxide, flow rate 80). Separation was performed at a rate of ml / min to obtain a pale yellow solid, 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (13 mg, 18% yield), as the first eluting enantiomer, MS m / z: 496.2 [M+H] + ESI pos.; and as the second eluted enantiomer, a pale yellow solid 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (10 mg, 14% yield), MS m / z: 496.2 [M+H] + ESI pos.; and as a racemic, pale yellow solid 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (6 mg, 8% yield), MS m / z: 496.2 [M+H + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1369] Examples 169, 170, and 171 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one

[1370]

[1371] Similar to Examples 166 to 168, the title compound was prepared in step 1 using ethyl 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-b]pyridin-7-yl]-3,6-dihydro-2H-pyran-2-carboxylate (see intermediate D2) instead of 4-[9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-4-oxo-pyrazino[1,2-a]pyrimino-7-yl]tetrahydropyran-2-carboxylate. Pale yellow solid, MS m / z: 496.2 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1372] Similar to Examples 141 to 143, Examples 172 to 176 were prepared by replacing intermediate D1 with the indicated intermediate. Absolute stereochemistry was arbitrarily partitioned, and relative stereochemistry was determined by NMR.

[1373]

[1374] Example 177 2,3-Dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]-9-[6-(trifluoromethyl)pyridin-3-yl]pyrazino[1,2-a]pyrimidin-4-one

[1375]

[1376] 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] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1377] Examples 178 and 179: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one

[1378]

[1379] The title compound was prepared by chiral separation of 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-methyl-6-oxopyridin-3-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one (Example 83) using a chiral SFC (column: chiral AD-H, 250 mm × 30 mm, 5 µm, 55% methanol + 0.2% diethylamine). Absolute stereochemistry is arbitrarily specified. Yellow solid, MS m / z: 495.2 [M+H] + , ESI pos.

[1380] Similar to Example 15, Examples 180 to 190 were prepared by starting with the indicated intermediate. The reduction in step 2 was performed by adding magnesium oxide and triethylamine, as described for Examples 131 and 132. Chiral separation was performed as described for Examples 178 and 179. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry by NMR.

[1381]

[1382] Examples 191 and 192: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1383]

[1384] Step 1: 9-(4-chloro-2-fluoro-phenyl)-7-[6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro- 2H-pyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1385]

[1386] Under an argon atmosphere, a solution of trifluoromethanesulfonic acid [6-(1-cyclopropyl-6-oxo-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl] ester (intermediate C29, 400 mg, 1.09 mmol) in 1,4-dioxane (12 ml) and water (2.5 ml) was added to 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)pyrazino[1,2-a]pyrimidin-4-one (intermediate B13, 470 mg, 1.09 mmol), potassium carbonate (454 mg, 3.28 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (81 mg, 0.11 mmol, 0.10 eq). The reaction mixture was heated to 60 °C and stirred for 2.5 h, then filtered through diatomaceous earth 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 rapid chromatography (silica gel, methanol in dichloromethane, 0% to 10%) to give a light brown, foamy 9-(4-chloro-2-fluoro-phenyl)-7-[6-(1-cyclopropyl-6-keto-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (566 mg, 90% yield), MS m / z: 519.2 [M+H] + , ESI pos.

[1387] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydro [Pyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)- 2-(1-Cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1388]

[1389] Under argon atmosphere, triethylamine (58 mg, 80 µl, 0.578 mmol), magnesium oxide (194 mg, 4.82 mmol), and palladium on carbon (10%, 102 mg) were added to a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[6-(1-cyclopropyl-6-keto-3-pyridyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one (250 mg, 0.482 mmol) in ethyl acetate (11 ml). The mixture was degassed several times with argon and then stirred at room temperature for 4 hours under a hydrogen atmosphere (balloon pressure). The reaction mixture was filtered through diatomaceous earth, and the mother liquor was concentrated under vacuum. The residue was purified by reversed-phase chromatography (column C18, acetonitrile in water, 10% to 70%) to give 9-(4-chloro-2-fluoro-phenyl)-7-[2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one. Enantiomers were separated by chiral SFC (Chiralpak SZ column, 250 mm × 20 mm, 5 µm, 55% methanol) to give a yellow solid 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one as the first eluting enantiomer (19 mg, 8% yield), MS m / z: 521.2 [M+H] + ESI pos.; and yellow solid 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one as the second eluted enantiomer (15 mg, 6% yield). MS m / z: 521.2 [M+H] + , ESIpos. Absolute stereochemistry is arbitrarily specified.

[1390] Similar to Examples 191 and 192, Examples 193 to 196 were prepared by replacing intermediate C29 with the indicated intermediate. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1391]

[1392] Example 197: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one

[1393]

[1394] Step 1: 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-chloro-4-pyridyl)-3,6-dihydro-2H-pyran-4-] ]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one

[1395]

[1396] Add potassium carbonate (1.23 g, 8.87 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) (219 mg, 0.296 mmol, 0.10 eq) to a solution of 2-chloro-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-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-fluoro-phenyl)-2,3-dimethyl-pyrimidino[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 with argon and backfilled three times, then heated to 60°C and stirred for 1.5 hours. The reaction mixture was filtered through diatomaceous earth 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 rapid chromatography (silica gel, 0% to 70% ethyl acetate in heptane) to give a grayish-white solid 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-chloro-4-pyridinyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one (930 mg, 51% yield), MS m / z: 495.2 [MH]. + , ESI neg.

[1397] Step 2: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro- 2H-pyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one

[1398]

[1399] Under an argon atmosphere, a solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxadiborane (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) chloride (107.39 mg, 0.145 mmol, 0.10 eq) was added to a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[6-(2-chloro-4-pyridinyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one (720 mg, 1.45 mmol) in 1,4-dioxane (12 ml). The reaction mixture was heated to 90 °C and stirred for 2 hours. After cooling to room temperature, the solution was filtered through diatomaceous earth 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 rapid chromatography (Si-Amine, 0% to 70% ethyl acetate in heptane) to give a yellow, foamy 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,4-dihydro-2H-pyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one (380 mg, 52% yield), MS m / z: 477.2 [M+H]. + , ESI pos.

[1400] Step 3: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridine) [Pyridyl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one

[1401]

[1402] Under argon atmosphere, palladium on carbon (10%, 84 mg) was added to a solution of 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[6-(2-methyl-4-pyridyl)-3,6-dihydro-2H-pyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one (380 mg, 0.757 mmol) in ethanol (15 ml), and the mixture was stirred at room temperature for 10 hours under hydrogen atmosphere (balloon pressure). The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated under vacuum and purified by rapid chromatography (column C18, acetonitrile in water, 0% to 50%). 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 over Na₂SO₄ and concentrated under vacuum to give the yellow, foamy title compound (205 mg, 54% yield), MS m / z: 479.2 [M+H]. + , ESI pos.

[1403] Examples 198 and 199: 9-(4-chloro-2-fluoro-phenyl)-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-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one

[1404]

[1405] Racemic 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one (Example 197) was separated by a chiral SFC (column: chiral SZ, 5 µm, 250 x 20 mm, 43% methanol) to give 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one as the first eluting enantiomer (retention time 3.595 min) and 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one as the second eluting enantiomer (retention time 4.843 min). 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one (min), were all yellow foamy substances with MS m / z: 479.2 [M+H]. +, ESI pos. Absolute stereochemistry is arbitrarily specified.

[1406] Example 200: 9-(2-fluorophenyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one

[1407]

[1408] This compound was formed as a byproduct of the hydrogenation step during the synthesis of Examples 89 and 90, and was subsequently separated by column chromatography (silica gel, 10% methanol in dichloromethane) (yield 18%) as a yellow solid, MS m / z: 461.4 [M+H]. + , ESI pos.

[1409] Examples 201 and 202: 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one

[1410]

[1411] Step 1: 9-(4-chloro-2-fluoro-phenyl)-7-[6-(6-methoxy-3-pyridyl)-3,6-dihydro-2H-pyran- 4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one

[1412]

[1413] Add a solution of 2-methoxy-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxane-[1,2-b]pyridazin-4-one (intermediate B3, 1.8 g, 5.32 mmol) in 1,4-dioxane (62 ml) and water (10 ml) to 7-chloro-9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one (intermediate B3, 1.8 g, 5.32 mmol) (intermediate C35, 2.19 g, 6.92 mmol). Degas the mixture with nitrogen and backfill three times. Potassium carbonate (2.21 g, 16.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (395 mg, 0.532 mmol, 0.10 eq) were then added, and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was filtered through diatomaceous earth 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. The residue was purified by rapid chromatography (silica gel, 0% to 80% ethyl acetate in heptane) to give a pale yellow solid 9-(4-chloro-2-fluoro-phenyl)-7-[6-(6-methoxy-3-pyridinyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one (1.95 g, 74% yield), MS m / z: 493.3 [M+H] + , ESI pos. .

[1414] Step 2: 9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3- Dimethylpyrimidino[1,2-b]pyridazin-4-one

[1415]

[1416] Under argon atmosphere, platinum oxide (IV) (29 mg, 0.128 mmol, 0.20 eq) was added to a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[6-(6-methoxy-3-pyridinyl)-3,6-dihydro-2H-pyran-4-yl]-2,3-dimethyl-pyrimidino[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), and the reaction mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth and evaporated. The crude material was purified by rapid chromatography (silica gel, ethyl acetate / ethanol in heptane = 3:1, 0% to 20%) to give a yellow solid 9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one (184 mg, yield 58%), MS m / z: 493.3 [M+H] + , ESI pos.

[1417] Step 3: 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyridine] [4-yl]pyrimidino[1,2-b]pyridazin-4-one

[1418]

[1419] Trimethylchlorosilane (29 mg, 34 µl, 0.27 mmol) was added to a solution of 9-(4-chloro-2-fluoro-phenyl)-7-[2-(6-methoxy-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one (134 mg, 0.27 mmol) and sodium iodide (40.5 mg, 0.27 mmol) in acetonitrile (5.5 ml), and the mixture was stirred at 65 °C for 3 hours. The solvent was removed under vacuum, and the residue was purified by chromatography (silica gel, ethyl acetate / ethanol in heptane = 3:1, 0% to 90%) to give 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one (107 mg, 78% yield) as a yellow powder, MS m / z: 481.3 [M+H] + , ESI pos.

[1420] Step 4: 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran- 4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6- [keto-1H-pyridin-3-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one

[1421]

[1422] Racemic 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(6-oxo-1H-pyridin-3-yl)tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one was separated by chiral SFC (column: chiral NR, 250 mm × 20 mm, 5 µm, 60% methanol) to obtain an orange powder of 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one as the first eluting enantiomer, MS m / z: 481.3 [M+H] + ESI pos.; and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one as the second eluted enantiomer, MS m / z: 481.3 [M+H] + , ESI pos. Absolute stereochemistry is arbitrarily specified.

[1423] Similar to Examples 191 and 192, Examples 203 to 206 were prepared by replacing intermediate C29 with the indicated intermediate. Absolute stereochemistry was determined by arbitrary partitioning, and relative stereochemistry was determined by NMR.

[1424]

[1425] Examples 207 and 208: 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one and 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[6...

Claims

1. A compound of formula (I) (I) Or its pharmaceutically acceptable salt, wherein: A 1 X 1 and X 2 Each is independently selected from N and CH; A 2 Selected from O and CR 5 R 6 ; R 1 Selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 Selected from C6-C 10 -Aryl, 5- to 6-membered heteroaryl and C3-C 10 -cycloalkyl, wherein the C6-C 10 -Aryl, 5- to 6-membered heteroaryl and C3-C 10 -The cycloalkyl group is optionally substituted with 1 to 3 independent substituents selected from halogens, C1-C6-alkyl groups and halo-C1-C6-alkyl groups; R 3 Selected from 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic groups, wherein the 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclic groups are optionally derived from 1 to 3 independently selected from halogen, cyano, amino, hydroxyl, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 Substitution of -cycloalkoxy, 3- to 6-membered heterocyclic, halo-3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic-C1-C6-alkyl, 3- to 6-membered heterocyclic-C1-C6-alkoxy and 3- to 6-membered heterocyclic groups; R 4 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.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i)X 1 and X 2 Both are CH; or (ii)X 1 For CH and X 2 For N; or (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i)X 1 For CH and X 2 For N; or (ii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH.

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

5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein A 1 Let N be the number of elements in the array.

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

7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: A 2 Selected from O and CR 5 R 6 ; R 5 and R 6 Both are hydrogen, or R 5 and R 6 Both are fluorine.

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

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

10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from methyl and CHF2.

11. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C6-C 10 -Aryl, C3-C 10 -Cycloalkyl and a 5- to 6-membered heteroaryl group comprising 1 to 2 heteroatoms independently selected from N, O, and S, wherein the C6-C 10 -Aryl, the C3-C 10 -The cycloalkyl group and the 5- to 6-membered heteroaryl group are optionally substituted with 1 to 3 independent substituents selected from halogens and halogenated -C1-C6-alkyl groups.

12. The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 2 The compounds are selected from phenyl, pyridyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane, wherein the phenyl, the cyclohexyl, the bicyclo[3.1.0]hexane and the bicyclo[1.1.1]pentane are optionally substituted with 1 to 3 substituents independently selected from fluorine, chlorine, CHF2 and CF3.

13. The compound of formula (I) according to claim 11, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from C6-C 10 -Aryl and C3-C 10 -cycloalkyl, wherein the C6-C 10 -Aryl and C3-C 10 -The cycloalkyl group is substituted with 1 to 3 substituents independently selected from halogens and halogenated -C1-C6-alkyl groups.

14. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentanes substituted with 1 to 3 substituents independently selected from fluorine, chlorine and CHF2.

15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: 。 16. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 3 The atom is selected from 1 to 3 heteroatoms independently selected from N, O, and S, with the remaining atoms being 5- to 6-membered heteroaryl groups of carbon, and 1 to 2 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon, wherein the 5- to 6-membered heteroaryl groups are optionally derived from 1 to 2 heteroatoms independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 -cycloalkoxy, 3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic-C1-C6-alkyl, and 3- to 6-membered heterocyclic-C1-C6-alkoxy substituents, wherein the 3- to 6-membered heterocyclic group is optionally substituted with 1 to 2 substituents independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 Substitution with cycloalkoxy, 3- to 6-membered heterocyclic groups, 3- to 6-membered heterocyclic -C1-C6-alkyl, 3- to 6-membered heterocyclic -C1-C6-alkoxy, and oxo substituents.

17. The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are optionally substituted with 1 to 2 substituents independently selected from methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutoxy, oxetyl, oxetylmethyl, and oxetylmethoxy, and wherein the 1,2-dihydropyridine is optionally substituted with 1 to 2 substituents. The substituent is independently selected from methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutoxy, oxetane, oxetanemethyl, oxetanemethoxy, and oxo.

18. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R 3 The atom is selected from 1 to 3 heteroatoms independently selected from N, O, and S, with the remaining atoms being 5- to 6-membered heteroaryls of carbon, and 1 to 2 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon, wherein the 5- to 6-membered heteroaryl group is derived from 1 C1-C6-alkyl, C1-C6-alkoxy, C3-C... 10 -Cycloalkyl and 3- to 6-membered heterocyclic groups are substituted, wherein said 3- to 6-membered heterocyclic groups are oxidized and optionally selected from C1-C6-alkyl, halo-C1-C6-alkyl and C3-C 10 -Other substituents of cycloalkyl groups.

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

20. The compound of formula (I) according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from: 。 21. The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen and methyl.

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

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

24. The compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 7 It is a C1-C6-alkyl group.

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

26. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i)X 1 and X 2 Both are CH; or (ii)X 1 For CH and X 2 For N; or (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH; A 1 Selected from N and CH; A 2 Selected from O and CR 5 R 6 ; R 1 Selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 Selected from C6-C 10 -Aryl, C3-C 10 -Cycloalkyl and a 5- to 6-membered heteroaryl group comprising 1 to 2 heteroatoms independently selected from N, O, and S, wherein the C6-C 10 -Aryl, the C3-C 10 -The cycloalkyl group and the 5- to 6-membered heteroaryl group are optionally substituted by 1 to 3 independent substituents selected from halogens and halogenated -C1-C6-alkyl groups; R 3 The atom is selected from 1 to 3 heteroatoms independently selected from N, O, and S, with the remaining atoms being 5- to 6-membered heteroaryl groups of carbon, and 1 to 2 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon, wherein the 5- to 6-membered heteroaryl groups are optionally derived from 1 to 2 heteroatoms independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 -cycloalkoxy, 3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic-C1-C6-alkyl, and 3- to 6-membered heterocyclic-C1-C6-alkoxy substituents, wherein the 3- to 6-membered heterocyclic group is optionally substituted with 1 to 2 substituents independently selected from C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkoxy, C3-C 10 -Cycloalkyl, halogenated-C3-C 10 -Cycloalkyl, C3-C 10 -Cycloalkyl-C1-C6-alkyl, C3-C 10 -cycloalkyl-C1-C6-alkoxy, C3-C 10 -Cycloalkoxy, 3- to 6-membered heterocyclic, 3- to 6-membered heterocyclic -C1-C6-alkyl, 3- to 6-membered heterocyclic -C1-C6-alkoxy and oxo substituents; R 4 Selected from hydrogen and C1-C6-alkyl; R 5 and R 6 Both are hydrogen, or R 5 and R 6 Both are halogens; and R 7 Selected from hydrogen and C1-C6-alkyl.

27. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i)X 1 and X 2 Both are CH; or (ii)X 1 For CH and X 2 For N; or (iii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH; A 1 Selected from N and CH; A 2 Selected from O and CR 5 R 6 ; R 1 Selected from methyl and CHF2; R 2 The compounds are selected from phenyl, pyridyl, cyclohexyl, bicyclo[3.1.0]hexane and bicyclo[1.1.1]pentane, wherein the phenyl, the cyclohexyl, the bicyclo[3.1.0]hexane and the bicyclo[1.1.1]pentane are optionally substituted with 1 to 3 substituents independently selected from fluorine, chlorine, CHF2 and CF3; R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, and 1,2-dihydropyridine, wherein the pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, and 1,2,4-oxadiazolyl are 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, cyclobutoxy, oxetyl, oxetylmethyl, and oxetylmethoxy, and wherein the 1,2-dihydropyridine is optionally substituted with one... The substituent is selected from 2 independently selected substituents, namely methyl, ethyl, isopropyl, CHF2, CF3, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methoxy, 2-methoxyethyl, cyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopropylmethyl, cyclobutoxy, oxetane, oxetanemethyl, oxetanemethoxy, and oxo; R 4 Selected from hydrogen and methyl; R 5 and R 6 Both are hydrogen, or R 5 and R 6 Both are fluorine; and R 7 Selected from hydrogen and methyl.

28. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i)X 1 For CH and X 2 For N; or (ii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH; A 1 For CH; A 2 is O; R 1 Selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 2 Selected from C6-C 10 -Aryl and C3-C 10 -cycloalkyl, wherein the C6-C 10 -Aryl and C3-C 10 -The cycloalkyl group is substituted with 1 to 3 independent substituents selected from halogens and halo-C1-C6-alkyl groups; R 3 The atom is selected from 1 to 3 heteroatoms independently selected from N, O, and S, with the remaining atoms being 5- to 6-membered heteroaryls of carbon, and 1 to 2 heteroatoms independently selected from N, O, and S, with the remaining atoms being 3- to 6-membered heterocyclic groups of carbon, wherein the 5- to 6-membered heteroaryl group is derived from 1 C1-C6-alkyl, C1-C6-alkoxy, C3-C... 10 The cyclic alkyl group is substituted with a 3- to 6-membered heterocyclic group, wherein the 3- to 6-membered heterocyclic group is oxidized and optionally selected from C1-C6-alkyl, halo-C1-C6-alkyl, and C3-C6-alkyl groups. 10 -Other substituents of cycloalkyl groups; R 4 It is hydrogen; and R 7 It is a C1-C6-alkyl group.

29. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i)X 1 For CH and X 2 For N; or (ii)X 1 Let N be the number of elements and X be the number of elements. 2 For CH; A 1 For CH; A 2 is O; R 1 Selected from methyl and CHF2; R 2 Selected from phenyl, cyclohexyl and bicyclo[1.1.1]pentanes substituted with 1 to 3 substituents independently selected from fluorine, chlorine and CHF2; R 3 The compound is selected from pyridinyl, pyrazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl and 1,2-dihydropyridine, wherein the pyridinyl, the pyrazolyl, the 1,3,4-oxadiazolyl and the 1,2,4-oxadiazolyl are substituted with one substituent selected from methyl, methoxy, cyclopropyl and oxetane, and wherein the 1,2-dihydropyridine is substituted with an oxo and optionally with another substituent selected from methyl, isopropyl, 2,2,2-trifluoroethyl and cyclopropyl; R 4 It is hydrogen; and R 7 It is a methyl group.

30. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from: 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(3S)-3-(1-methylpyrazol-4-yl)-1-piperidinyl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(3S)-4,4-difluoro-3-(1-methylpyrazol-4-yl)-1-piperidinyl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(2-methylpyridin-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-Chlorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[2-(trifluoromethyl)-4-pyridyl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one carboxylate; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(2-methoxy-4-pyridyl)morpholin-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(5-methyl-1,3,4-oxadiazol-2-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[2-(1H-pyrazol-4-yl)morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chlorophenyl)-2,3-dimethyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S)-2-(2-methoxypyridin-4-yl)morpholin-4-yl]-2,3-dimethylpyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-3-methyl-7-[(2S)-2-(1-methylpyrazol-4-yl)morpholino]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]morpholin-4-yl]pyrido[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(1-methyl-6-oxopyridin-3-yl)oxacyclohexane-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(2-methyl-4-pyridyl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluorophenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)oxacyclohexane-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2,6-difluorophenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexan-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-Cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-Cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[racemic-(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazin[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazin[1,2-a]pyrimidin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 7-[racemic-(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R,6S)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S,6R)-2-(1-cyclopropylpyrazol-4-yl)-6-methyl-tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2S)-2-(1-Cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R)-2-(1-cyclopropylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 2,3-Dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one; 2,3-Dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1H-pyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(trifluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4R)-2-(1-methylpyrazol-4-yl)tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6S)-2-methyl-6-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,6S)-2-methyl-6-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,6R)-2-methyl-6-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S)-2-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R)-2-(1H-pyrazol-4-yl)morpholin-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(difluoromethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S)-2-(1-cyclobutylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R)-2-(1-cyclobutylpyrazol-4-yl)morpholin-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2-(difluoromethyl)-3-methyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclobutylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclobutylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 2,3-Dimethyl-7-[(2R,4S)-2-(1-methylpyrazol-4-yl)oxacyclohexane-4-yl]-9-[6-(trifluoromethyl)pyridin-3-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(2-methoxyethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(2-methoxyethyl)pyrazol-4-yl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-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]pentyl]pyrimidino[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]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 7-[racemic-(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-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]pentyl]pyrazino[1,2-a]pyrimidin-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]pentyl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(cyclopropylmethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[racemic-(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(2-fluorophenyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4R)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[6-keto-1-(oxetane-3-ylmethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentyl]-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[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-dimethyl-pyrimido[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-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-7-[racemic-(2R,4R)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 2,3-Dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 2,3-Dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 2,3-Dimethyl-7-[racemic-(2R,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]-9-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentyl]pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(6-keto-1H-pyridin-3-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-ethyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(2-methoxy-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-2-(difluoromethyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-3-methylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[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-dimethyl-pyrimido[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-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2R,4S)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclobutyl-6-keto-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1,5-dimethylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1,5-dimethylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1,3-dimethylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1,3-dimethylpyrazol-4-yl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-(2-methyl-4-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[2-(cyclopropylmethoxy)-4-pyridyl]tetrahydropyran-4-yl]-2,3-dimethylpyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(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-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[2-[2-(oxecyclobutane-3-ylmethoxy)-4-pyridinyl]tetrahydropyran-4-yl]pyrimido[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-(1-cyclopropylpyrazol-4-yl)tetrahydropyran-4-yl]-9-[(1R,5S)-6,6-difluoro-3-bicyclo[3.1.0]hexyl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-cyclobutyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethylpyrimido[1,2-b]pyridazin-4-one; 7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-7-[racemic-(2R,4S)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(2,2-difluoroethyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[6-keto-1-(2,2,2-trifluoroethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(1-isopropyl-6-one-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-[1-(3,3-difluorocyclobutyl)-6-keto-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[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-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4,4-difluorocyclohexyl)-7-[(2S,4R)-2-(6-keto-1-methyl-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2R,4S)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-2,3-dimethyl-7-[(2S,4R)-2-(1-methyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]pyrimidino[1,2-b]pyridazin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2R,4S)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4,4-difluorocyclohexyl)-2,3-dimethyl-7-[(2S,4R)-2-[1-(oxecyclobutan-3-yl)pyrazol-4-yl]tetrahydropyran-4-yl]pyrazino[1,2-a]pyrimidin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[racemic-(2R,4S)-2-[6-keto-1-(trifluoromethyl)-3-pyridyl]tetrahydropyran-4-yl]-2,3-dimethyl-pyrimido[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2R,4S)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2-fluoro-phenyl)-7-[(2S,4R)-2-(2-cyclopropyl-4-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2R,4S)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[1,2-b]pyridazin-4-one; 9-(4-chloro-2,6-difluoro-phenyl)-7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-2,3-dimethyl-pyrimidino[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-dimethyl-pyrazino[1,2-a]pyrimidin-4-one; and 7-[(2S,4R)-2-(1-cyclopropyl-6-oxo-3-pyridyl)tetrahydropyran-4-yl]-9-(4,4-difluorocyclohexyl)-2,3-dimethyl-pyrazino[1,2-a]pyrimidin-4-one.

31. The compound of formula (I) according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, used 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 inert carrier.

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

34. The method of claim 33, wherein the condition associated with loss of function of human TREM2 is selected from Parkinson's disease, rheumatoid arthritis, Alzheimer's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, frontotemporal dementia, multiple sclerosis, prions, and stroke.

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

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

38. The present invention as described above.

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