4,4A,5,7,8,8A-Hexapyrido[4,3-B][1,4]oxazin-3-one compounds as MAGL inhibitors

Abstract

The present invention relates to novel heterocyclic compounds having the general formula (I): TIFF2022548028000111.tif32161 (In the formula, A, B, L 1 , X, m, n and R 1 ~R 7 as described herein), compositions comprising said compounds, methods for preparing said compounds and methods for using said compounds as monoacylglycerol lipase (MAGL) inhibitors.

Description

[Technical field]

[0001] The present invention relates to organic compounds useful for therapy or prevention in mammals, in particular monoacylglycerol lipase (MAGL) inhibitors for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, and / or depression in mammals. [Background technology]

[0002] Endocannabinoids (ECs) are signaling lipids that exert their biological effects by interacting with the cannabinoid receptors (CBRs), CB1 and CB2. They regulate multiple physiological processes, including neuroinflammation, neurodegeneration, and tissue regeneration (Iannotti, FA, et al., Progress in lipid research 2016, 62, 107-28). In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacylglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase MAGL. MAGL hydrolyzes 85% of 2-AG, and the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, DK, et al., Science 2011, 334, 809). MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglial cells (Chanda, PK, et al., Molecular pharmacology 2010, 78, 996; Viader, A., et al., Cell reports 2015,12,798). Hydrolysis of 2-AG leads to the formation of arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes (LTs). The oxidative metabolism of AA is increased in inflamed tissues. The two main enzymatic pathways of arachidonic acid oxidation involved in the inflammatory process include cyclooxygenase, which produces PGs, and 5-lipoxygenase, which produces LTs. Among the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important. These products have been detected at sites of inflammation, for example in the cerebrospinal fluid of patients suffering from neurodegenerative disorders, and are thought to contribute to the inflammatory response and disease progression. Mice lacking MAGL (Mgll- / -) show a dramatic reduction in 2-AG hydrolase activity and a dramatic increase in 2-AG levels in the nervous system, while other arachidonoyl-containing phospholipids and neutral lipid species, including anandamide (AEA), as well as other free fatty acids, were unchanged.Conversely, the levels of AA and AA-derived prostaglandins, as well as other eicosanoids including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2), and thromboxane B2 (TXB2), are greatly reduced. Although the phospholipase A2 (PLA2) enzyme has been considered the major source of AA, cPLA2-deficient mice have no altered AA levels in their brains, raising the importance of the role of MAGL in the brain for regulating AA production and brain inflammatory processes.

[0003] Neuroinflammation is a common pathological feature of brain diseases, including but not limited to neurodegenerative diseases (e.g., multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, and psychiatric disorders such as anxiety and migraine). In the brain, the production of eicosanoids and prostaglandins controls the neuroinflammatory process. The inflammatory inducer lipopolysaccharide (LPS) produces a robust, time-dependent increase in brain eicosanoids that is markedly blunted in Mgll- / - mice. LPS treatment also induces widespread elevation of inflammatory cytokines, including interleukin-1-a (IL-1-a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a), which are suppressed in Mgll- / - mice.

[0004] Neuroinflammation is characterized by the activation of innate immune cells of the central nervous system, microglia and astrocytes. It has been reported that anti-inflammatory drugs can suppress glial cell activation and disease progression, including Alzheimer's disease and multiple sclerosis, in preclinical models (Lleo A., Cell Mol Life Sci. 2007, 64, 1403). Importantly, genetic and / or pharmacological disruption of MAGL activity also inhibits LPS-induced activation of microglial cells in the brain ((Nomura, DK, et al., Science 2011, 334, 809)).

[0005] Moreover, genetic and / or pharmacological disruption of MAGL activity has been shown to be protective in several animal models of neurodegeneration, including but not limited to Alzheimer's disease, Parkinson's disease and multiple sclerosis. For example, irreversible MAGL inhibitors have been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, JZ, et al., Nature chemical biology 2009, 5, 37). Systemic injection of such inhibitors recapitulates the Mgll- / - mouse phenotype in the brain, which includes increased 2-AG levels, decreased AA levels and associated eicosanoid production, as well as suppression of cytokine production and microglial activation following LPS-induced neuroinflammation (Nomura, DK, et al., Science 2011, 334, 809), confirming MAGL as a druggable target.

[0006] Following genetic and / or pharmacological disruption of MAGL activity, endogenous levels of the MAGL natural substrate, 2-AG, are increased in the brain. 2-AG has been reported to have beneficial effects on pain, for example antinociceptive effects in mice (Ignatowska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015, 353, 424) and psychiatric disorders such as depression in chronic stress models (Zhong P. et al., Neuropsychopharmacology 2014, 39, 1763).

[0007] Furthermore, oligodendrocytes (OLs) and their precursors (OPCs), which are myelinating cells in the central nervous system, express cannabinoid receptor 2 (CB2) on their membranes. 2-AG is an endogenous ligand for CB1 and CB2 receptors. It has been reported that both cannabinoids and pharmacological inhibition of MAGL attenuate the vulnerability of OLs and OPCs to excitotoxic injury and thus may be neuroprotective (Bernal-Chico, A., et al., Glia 2015, 63, 163). In addition, pharmacological inhibition of MAGL increases the number of myelinating OLs in mouse brains, suggesting that MAGL inhibition may promote the differentiation of OPCs in myelinating OLs in vivo (Alpar, A., et al., Nature communications 2014, 5, 4421). Inhibition of MAGL has also been shown to promote remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu A.et al.,Journal of Neuroscience 2017,37(35),8385.).

[0008] Moreover, in recent years, metabolism, especially lipid metabolism, has been given great importance in cancer research. Researchers believe that de novo fatty acid synthesis plays an important role in tumor development. Many studies have shown that endocannabinoids have antitumor effects, including antiproliferative, apoptosis-inducing and anti-metastatic effects. MAGL, as a key degradative enzyme for both lipid metabolism and the endocannabinoid system, further contributes to various aspects of tumorigenesis, including in glioblastoma, as part of the gene expression signature (Qin, H., et al., Cell Biochem. Biophys. 2014, 70, 33; Nomura DK et al., Cell 2009, 140(1), 49-61; Nomura DK et al., Chem. Biol. 2011, 18(7), 846-856, Jinlong Yin et al, Nature Communications 2020, 11, 2978).

[0009] The endocannabinoid system is also involved in many gastrointestinal physiological and physiopathological actions (Marquez, Suarez et al. 2009). All these effects are primarily promoted through cannabinoid receptors (CB1 and CB2). CB1 receptors are present throughout the gastrointestinal tract in animals and healthy humans, particularly in the enteric nervous system (ENS) and epithelial lining, as well as in smooth muscle cells of blood vessels in the colonic wall (Wright, Rooney et al. 2005), (Duncan, Davison et al. 2005). Activation of CB1 leads to antiemetic, antimotility and anti-inflammatory effects and helps regulate pain (Perisetti, Rimu et al. 2020). CB2 receptors are expressed in immune cells such as plasma cells and macrophages, in the lamina propria of the gastrointestinal tract (Wright, Rooney et al. 2005), and in the epithelium of human colonic tissue, primarily associated with inflammatory bowel disease (IBD). CB2 activation exerts anti-inflammatory effects by reducing pro-inflammatory cytokines. MAGL expression is increased in colonic tissues of UC patients (Marquez, Suarez et al. 2009), and 2-AG levels are increased in the plasma of IBD patients (Grill, Hogenauer et al. 2019). Several animal studies have demonstrated the potential of MAGL inhibitors for the symptomatic treatment of IBD. MAGL inhibition prevents TNBS-induced murine colitis and reduces local and circulating inflammatory markers via CB1 / CB2 MoA (Marquez, Suarez et al. 2009). Furthermore, MAGL inhibition improves intestinal wall integrity and intestinal permeability via CB1-driven MoA (Wang, Zhang et al. 2020).

[0010] In conclusion, inhibiting MAGL action and / or activation is a promising new therapeutic strategy for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, inflammatory bowel disease, abdominal pain, and abdominal pain associated with irritable bowel syndrome. Furthermore, inhibiting MAGL action and / or activation is a promising new therapeutic strategy for providing neuroprotection and myelin regeneration. Thus, there is a high unmet medical need for new MAGL inhibitors. Summary of the Invention

[0011] In a first aspect, the present invention provides a compound of formula (I) [ka]

[0012] (In the formula, A, B, L 1 , X, m, n, and R 1 ~R 7 is as defined herein. In a further aspect, the present invention provides a method of preparing a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, comprising the steps of: 4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one 1 (wherein R 1 and R 2 is as defined herein), [ka]

[0013] Heterocyclic amine 2 (wherein A, B, L 1 , X, m, n and R 3 ~R 7 is as defined herein), [ka]

[0014] Reacting in the presence of a base and a urea forming reagent, Optionally, the method includes forming a pharma- ceutically acceptable salt of the compound of formula (I) above.

[0015] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, when prepared according to the processes described herein.

[0016] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0017] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, and a therapeutically inert carrier.

[0018] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in a method of inhibiting monoacylglycerol lipase in a mammal.

[0019] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

[0020] In a further aspect, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and / or spasticity associated with pain in a mammal. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition

[0022] It should be understood that features, integers, characteristics, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are applicable to any other aspect, embodiment or example described herein, except where inconsistent therewith. All of the features disclosed herein (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, abstract and drawings), or any novel or any novel combination of steps of any method or process so disclosed.

[0023] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, linear or branched saturated hydrocarbon group having 1 to 12 carbon atoms. In some preferred embodiments, an alkyl group is a group having 1 to 6 carbon atoms ("C 1-6 In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, but non-limiting examples of alkyl are methyl and 2,2-dimethylpropyl.

[0024] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. An alkoxy group contains 1 to 12 carbon atoms, unless otherwise specified. In some preferred embodiments, an alkoxy group contains 1 to 6 carbon atoms ("C 1-6In other embodiments, alkoxy groups contain 1-4 carbon atoms. In yet other embodiments, alkoxy groups contain 1-3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0025] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0026] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C 3-10 -cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbocyclic rings having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., a cycloalkyl moiety in which the two rings are joined through one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 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, and cycloheptyl. A particularly preferred, but non-limiting example of cycloalkyl is cyclopropyl.

[0027] The term "aryl" refers to an alkyl group having 6 to 14 total ring members ("C6-C 14"-aryl") is preferably a monocyclic, bicyclic, or tricyclic carbocyclic ring system having 6 to 12 ring members, more preferably 6 to 10 ring members, where at least one ring of 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.

[0028] The term "heteroaryl" refers to a mono- or polyvalent monocyclic, bicyclic, or tricyclic, preferably bicyclic, ring system having a total of 5-14 ring members, preferably 5-12 ring members, more preferably 5-10 ring members, in which at least one ring in the system is aromatic and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from O, S, and N. Some non-limiting examples of heteroaryl include spiro[cyclopropane-1,3'-indoline] (e.g., spiro[cyclopropane-1,3'-indoline]-1'-yl), 2-pyridyl, 3-pyridyl, 4-pyridyl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1H-indazol-3-yl, 1H-ind ...H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, 1H-indazol-5-yl, 1H-indazol-6- Indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, 1,2,4-oxathiazol-3-yl, 1,2,4-oxathiazol-3-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, pyridazin-3-yl, and pyridazin-4-yl. Particularly preferred, but non-limiting examples of heteroaryl are oxadiazolyl, pyridazinyl, pyridyl, and thiazolyl.

[0029] The term "hydroxy" refers to the group --OH.

[0030] The term "cyano" refers to a -CN (nitrile) group.

[0031] The term "amino" refers to the group --NH.

[0032] The term "alkylsulfonyl" refers to alkyl-SO2.

[0033] The term "carbamoyl" refers to the group H2N-C(O)-.

[0034] The term "cycloalkylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced with a cycloalkyl group. Preferably, "cycloalkylalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms, most preferably one hydrogen atom, of the alkoxy group is replaced with a cycloalkyl group. A particularly preferred, but non-limiting example of a cycloalkylalkoxy is cyclopropylmethoxy.

[0035] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting examples of haloalkyl are trifluoromethyl and trifluoroethyl.

[0036] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced by a halogen atom, most preferably fluoro. A particularly preferred, but non-limiting example of a haloalkoxy is trifluoromethoxy (-OCF3).

[0037] The term "cycloalkylalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced with a cycloalkyl group. Preferably, "cycloalkylalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group, most preferably one hydrogen atom, is replaced with a cycloalkyl group. A particularly preferred, but non-limiting example of alkyl is methyl.

[0038] The term "hydroxyalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms, most preferably one hydrogen atom, of the alkyl group is replaced by a hydroxy group. Preferred, but non-limiting examples of hydroxyalkyl are hydroxymethyl and hydroxyethyl (e.g., 2-hydroxyethyl). A particularly preferred, but non-limiting example of hydroxyalkyl is hydroxymethyl.

[0039] The term "aminoalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced with an amino group. Preferably, "aminoalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group, most preferably one hydrogen atom, is replaced with an amino group. Preferred, but non-limiting examples of aminoalkoxy are aminomethoxy and aminoethoxy (e.g., 2-aminoethoxy).

[0040] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, and is not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. In addition, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. A particular pharma- ceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

[0041] The term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction can be selectively carried out at an otherwise unprotected reactive site in the relevant conventional sense of synthetic chemistry. The protecting group can be removed at the appropriate time. Exemplary protecting groups are amino-, carboxy- or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more particular protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their uses in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry", TW Greene and PGM Hutts, 5th Edition, 2014, John Wiley & Sons, New York.

[0042] The term "urea-forming reagent" refers to a compound that can make a first amine react with a second amine, thereby forming a urea derivative. Non-limiting examples of urea-forming reagents include bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, 1,1'-carbonyl-di-(1,2,4-triazole) and 1,1'-carbonyldiimidazole. The urea-forming reagents described in G.Sartori et al., Green Chemistry 2000,2,140 are incorporated herein by reference.

[0043] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0044] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0045] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

[0046] The term "treatment" as used herein includes: (1) suppressing a symptom, disorder or condition (e.g., in the case of maintenance treatment, arresting, reducing or delaying the onset or recurrence of at least one clinical symptom or subclinical disease); and / or (2) alleviating the condition (i.e., causing the regression of the symptom, disorder or condition, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least perceptible to the patient or the physician. However, it will be understood that when a patient is administered a medicine to treat a disease, the outcome may not necessarily be an effective treatment.

[0047] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited the clinical or asymptomatic symptoms of the condition, disorder or condition.

[0048] The term "neuroinflammation" as used herein refers to acute and chronic inflammation of nervous tissue, which is the main tissue component of two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branching peripheral nerves of the peripheral nervous system (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Acute neuroinflammation usually occurs immediately after injury to the central nervous system, for example as a result of traumatic brain injury (TBI).

[0049] The term "traumatic brain injury" (also known as "TBI", "intracranial injury") relates to damage to the brain due to an external mechanical force, such as rapid acceleration or deceleration, impact, blast, or penetration by a projectile.

[0050] The term "neurodegenerative disease" refers to diseases associated with the progressive loss of neuronal structure or function, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0051] The term "mental disorder" (also called mental illness or mental disorder) refers to a behavior or mental pattern that can cause distress or impaired functioning in life. Such characteristics may occur as persistent, relapsing and remitting, or as a single episode. Examples of mental disorders include, but are not limited to, anxiety and depression.

[0052] The term "pain" refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy-induced neuropathy, phantom limb pain, and psychogenic pain. A specific example of pain is neuropathic pain, which is caused by injury or disease that affects any part of the nervous system involved in bodily sensations (i.e., the somatosensory system). In one embodiment, the "pain" is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, the "pain" is chemotherapy-induced neuropathy.

[0053] The term "neurotoxicity" refers to toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances (neurotoxins) alters the normal activity of the nervous system, causing damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, exposure to substances used in chemotherapy, radiation treatment, drug therapy, drug abuse, and organ transplantation, as well as neurotoxicity resulting from exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some naturally occurring substances.

[0054] The term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor, resulting from the abnormal and uncontrolled proliferation of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, colon carcinoma, and ovarian cancer.

[0055] The term "mammal" as used herein includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term "mammal" refers to a human. Compounds of the Invention In a first aspect (A1), the present invention relates to a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, wherein A is C6-C 14 -aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl; B is, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, m is 0, n is 0 or 1, and X is CR8 or m is 1, n is 1 or 2, and X is CR 8 or N, R 1 ,R 2 , and R 3 is H and C 1-6 independently selected from alkyl, R 4 , R 5 , R 6 , and R 7 are independently hydrogen, halogen, cyano, hydroxy, C 1-6 -Alkoxy, halo-C 1-6 -Alkoxy, Amino-C 1-6 -Alkoxy, C 1-6 -Alkyl, halo-C 1-6 -Alkyl, Hydroxy-C 1-6 -Alkyl, C 1-6 -Alkyl sulfonyl, SF5, carbamoyl, C 3-10 -Cycloalkyl-C 1-6 -Alkoxy-, C 1-6 -Alkyl-NH-C(O)-, C 1-6 -alkyl-C(O)-NH-, and C 3-10 -cycloalkyl, where each C 3-10 -Cycloalkyl is C 1-6 -Alkyl, and halo-C 1-6 -alkyl; and R 8 is hydrogen, halogen, hydroxy, halo-C 1-6 -Alkyl, and C 1-6 -alkyl.

[0056] The present invention also provides the following enumerated embodiments (E) of the first aspect (A1) of the invention:

[0057] E1. A is C6-C 14 -aryl, or 5- to 14-membered heteroaryl, or a pharma- ceutically acceptable salt thereof.

[0058] E2. A compound of formula (I) according to A1, or a pharma- ceutically acceptable salt thereof, wherein A is phenyl or pyridyl.

[0059] E3. A is C6-C 14 -aryl, or a pharma- ceutically acceptable salt thereof.

[0060] E4. A compound of formula (I) according to A1, or a pharma- ceutically acceptable salt thereof, wherein A is phenyl.

[0061] E5. B, (i) phenyl, L 1 is -O-, or (ii) L is selected from oxadiazolyl, pyridazinyl, pyridyl, and thiazolyl; 1 A compound of formula (I) according to any one of A1 and E1 to E4, or a pharma- ceutically acceptable salt thereof, wherein is a covalent bond or -O-.

[0062] E6. m is 0, n is 0, and X is CR 8 or

[0063] m is 1, n is 1, and X is CR 8 or N.

[0064] E7. m is 0, n is 0, and X is CR 8 A compound of formula (I) according to any one of A1 and E1 to E5,

[0065] E8. R 1 Compounds of formula (I) according to any one of A1 and E1-E7, wherein is halogen.

[0066] E9. R 2 Compounds of formula (I) according to any one of A1 and E1-E8, wherein is halogen.

[0067] E10. R 3 A compound of formula (I) according to any one of A1 and E1-E9, wherein is halogen.

[0068] E11. R 4 A compound of formula (I) according to any one of A1 and E1-E10, wherein is halogen.

[0069] E12. R 5 Compounds of formula (I) according to any one of A1 and E1 to E11, wherein is halogen.

[0070] E13. R 6 But hydrogen, halogen, cyano, C 1-6 -Alkyl, C 1-6 -Alkoxy, halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, and C 1-6 -alkylsulfonyl.

[0071] E14. R 6 are hydrogen, halogen, cyano and C 1-6 -alkyl.

[0072] E15. R 6 Compounds of formula (I) according to any one of A1 and E1-E12, wherein is selected from hydrogen, fluoro, chloro, cyano, methyl and 2,2-dimethylpropyl.

[0073] E16. R 7 are hydrogen, halogens and C 1-6 -alkyl.

[0074] E17. R 7 Compounds of formula (I) according to any one of A1 and E1-E15, wherein is selected from hydrogen, fluoro, and methyl.

[0075] E18. R 7 Compounds of formula (I) according to any one of A1 and E1-E15, wherein is hydrogen or halogen.

[0076] E19. R 7 Compounds of formula (I) according to any one of A1 and E1-E15, wherein is hydrogen or fluoro.

[0077] E20. R 8 Compounds of formula (I) according to any one of A1 and E1-E19, wherein is hydrogen or hydroxy.

[0078] E21. R 8 Compounds of formula (I) according to any one of A1 and E1-E19, wherein is hydrogen.

[0079] E22. [ka] (In the formula, A is C6-C 14 -aryl, B, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, R 6 is hydrogen, halogen, cyano, C 1-6 -Alkyl, C 1-6 -Alkoxy, halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, and C 1-6 -alkylsulfonyl, and R 7 is hydrogen, halogens, and C 1-6 -alkyl), or a pharma- ceutically acceptable salt thereof.

[0080] E23. The compound of formula (I) is represented by the formula (II) [ka] (In the formula, A is C6-C 14 -aryl, B, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, R 6 is hydrogen, halogen, cyano and C 1-6 -alkyl, R 7 is selected from hydrogen and halogen), or a pharma- ceutically acceptable salt thereof.

[0081] E24. The compound of formula (I) is represented by formula (III) [ka] (In the formula, B, (i) phenyl, L 1 is -O-, or (ii) L is selected from oxadiazolyl, pyridazinyl, pyridyl, and thiazolyl; 1 is a covalent bond or -O-, R 6 is selected from hydrogen, fluoro, chloro, cyano, methyl and 2,2-dimethylpropyl, and R 7 is selected from hydrogen and fluoro), or a pharma- ceutically acceptable salt thereof.

[0082] E25. The compound of formula (I) is represented by the formula (IIa) [ka] (In the formula, A is C6-C 14 -aryl or 5-14 membered heteroaryl; B, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, m is 0, n is 0, and X is CR 8 or m is 1, n is 1, and X is CR 8 or N, R 6 is hydrogen, halogen, cyano, C 1-6 -Alkyl, C 1-6 -Alkoxy, halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, and C 1-6 -alkylsulfonyl, R 7 is hydrogen, halogens, and C 1-6 -alkyl, and R 8is selected from hydrogen and hydroxy, or a pharma- ceutically acceptable salt thereof.

[0083] E26. The compound of formula (I) is represented by the formula (IIb) [ka] (In the formula, A is C6-C 14 -aryl or 5-14 membered heteroaryl; B, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, R 6 is hydrogen, halogen, cyano, and C 1-6 -alkyl, R 7 is hydrogen, C 1-6 - alkyl, and halogen; and R 8 is selected from hydrogen and hydroxy, or a pharma- ceutically acceptable salt thereof. E27. The compound of formula (I) is represented by the formula (IIb) [ka] (In the formula, A is phenyl or pyridyl; B, (i) phenyl, L 1 is -O-, or (ii) L is selected from oxadiazolyl, pyridazinyl, pyridyl, and thiazolyl; 1 is a covalent bond or -O-, R 6is selected from hydrogen, fluoro, chloro, cyano, methyl and 2,2-dimethylpropyl; R 7 is selected from hydrogen, methyl and fluoro; R 8 is selected from hydrogen and hydroxy, or a pharma- ceutically acceptable salt thereof.

[0084] E28. R 1 , R 2 , and R 3 or a pharma- ceutically acceptable salt thereof. A compound of formula (I) according to any one of A1 and E1 to E21, wherein all of are hydrogen.

[0085] E29. A is C6-C 14 -aryl, R 4 and R 5 or a pharma- ceutically acceptable salt thereof. A compound of formula (I) according to any one of A1 and E1 to E21, wherein are both hydrogen.

[0086] E30. R 4 and R 5 or a pharma- ceutically acceptable salt thereof. The compound of formula (I) according to any one of A1 and E1 to E21, wherein both are hydrogen. E31. B, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, R 6 But hydrogen, halogen, cyano, C 1-6 -Alkyl, C 1-6 -Alkoxy, halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, and C 1-6 -alkylsulfonyl, and E21, or a pharma- ceutically acceptable salt thereof.

[0087] E32. B, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, R 6 are hydrogen, halogens, cyano and C 1-6 -alkyl, and

[0088] R 7 is selected from hydrogen and halogen, or a pharma- ceutically acceptable salt thereof.

[0089] E33. B, (i) phenyl, L 1 is -O-, or (ii) oxadiazolyl, pyridazinyl, pyridyl and thiazolyl, where L 1 is a covalent bond or -O-, R 6 is selected from hydrogen, fluoro, chloro, cyano, methyl and 2,2-dimethylpropyl; and R 7 is selected from hydrogen and fluoro; or a pharma- ceutically acceptable salt thereof.

[0090] E34. (4aR,8aS)-6-(3-(4-phenoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(2-chlorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-pyrimidin-2-yloxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(2-methyl-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methylpyrimidin-2-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-pyridazin-3-yloxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(4-methyl-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(5-fluoro-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(5-chloro-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-pyridyloxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methylpyridazin-3-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-chloropyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methoxypyrimidin-2-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[4-(trifluoromethyl)pyrimidin-2-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-fluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-fluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2,4-difluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-fluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-chlorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-chlorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-methylphenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-(trifluoromethyl)phenoxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one 2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]phenoxy]benzonitrile; (4aR,8aS)-6-[3-[4-(2-chloropyrimidin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[4-(4-cyclopropylpyrimidin-2-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(6-methyl-2-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(4-chloro-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(3-fluoro-4-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[4-(2-methylsulfonylpyrimidin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(3,6-dimethyl-2-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(1H-pyrazol-5-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[2-(2,2-dimethylpropyl)pyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[1-(2,2-dimethylpropyl)pyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-chloro-2-pyridyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2,4-dimethyloxazol-5-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3,5-dimethylpyrazol-1-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-(2,2-dimethylpropyl)triazol-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[5-(2,2-dimethylpropyl)-1,3,4-oxadiazol-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[2-(2-fluoroethyl)pyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[1-(2-fluoroethyl)pyrazol-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(1-methylpyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(6-fluoropyridin-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-fluoropyridin-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(1-methylpyrazol-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-methylpyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[5-(4-fluorophenoxy)-2-pyridyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(6-(4-fluorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(4-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(3,6-dimethylpyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(6-(2-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(3-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[4-(4-fluorophenoxy)phenyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-hydroxy-3-(4-phenoxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-hydroxy-3-(5-phenoxy-2-pyridyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-(4-phenoxyphenyl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and (4aR,8aS)-6-[4-(4-phenoxyphenyl)piperazine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one or a pharma- ceutically acceptable salt thereof. 2. The compound of formula (I) according to any one of A1 and E1 to E33, selected from:

[0091] E35. (4aR,8aS)-6-(3-(4-phenoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(3-chloropyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[2,4-(difluoromethoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-fluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]phenoxy]benzonitrile; (4aR,8aS)-6-[3-[4-(3-chloro-2-pyridyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[5-(4-fluorophenoxy)-2-pyridyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3,6-dimethylpyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[6-(2-chlorophenoxy)3-piperidyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one and (4aR,8aS)-6-[3-[-3-(4-methylsulfonylphenyl)ethynyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one or a pharma- ceutically acceptable salt thereof. 2. The compound of formula (I) according to any one of A1 and E1 to E33, selected from:

[0092] E36. R 1 and R 2 or a pharma- ceutically acceptable salt thereof. The compound of formula (I) according to any one of A1 and E1 to E21, wherein both are hydrogen.

[0093] E37. R 3 is hydrogen, m is 0, n is 0, and X is CR 8 or m is 1, n is 1, and X is CR 8 or N, and R8 A compound of formula (I) according to any one of A1 and E1 to E21, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or hydroxy.

[0094] E38. R 3 is hydrogen, m is 0, n is 0, and X is CR 8 and R 8 A compound of formula (I) according to any one of A1 and E1 to E21, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or hydroxy.

[0095] E39. A is C6-C 14 -aryl or 5-14 membered heteroaryl; B, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, R 4 and R 5 are both hydrogen, R 6 But hydrogen, halogen, cyano, C 1-6 -Alkyl, C 1-6 -Alkoxy, halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, and C 1-6 -alkylsulfonyl, and R 7 are hydrogen, halogens, and C 1-6 -alkyl, or a pharma- ceutically acceptable salt thereof.

[0096] E40. A is C6-C 14 -aryl or 5-14 membered heteroaryl; B, (i) C6-C 14 -aryl, and L 1 is -O-, or (ii) 5-14 membered heteroaryl, L 1 is a covalent bond or -O-, R 4 and R 5 are both hydrogen, R 6 are hydrogen, halogens, cyano and C 1-6 -alkyl, and R 7 are hydrogen, halogens, and C 1-6 -alkyl, or a pharma- ceutically acceptable salt thereof.

[0097] E41. A is phenyl or pyridyl; B, (i) phenyl, L 1 is -O-, or (ii) L is selected from oxadiazolyl, pyridazinyl, pyridyl, and thiazolyl; 1 is a covalent bond or -O-, R 4 and R 5 are both hydrogen, R 6 is selected from hydrogen, fluoro, chloro, cyano, methyl and 2,2-dimethylpropyl; and R 7 A compound of formula (I) according to any one of A1 and E1 to E21, or a pharma- ceutically acceptable salt thereof, wherein is selected from hydrogen, halogen and methyl.

[0098] In certain embodiments, the present invention provides pharma- ceutically acceptable salts, particularly hydrochloride salts, of the compounds according to formula (I) described herein. In more particular embodiments, the present invention provides compounds according to formula (I) described herein as the free base.

[0099] In some embodiments, the compound of formula (I) is isotopically labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present 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, respectively, e.g. 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 Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. 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.

[0100] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may confer greater metabolic stability and may confer certain therapeutic advantages, for example through increased in vivo half-life or reduced dosage requirements.

[0101] 11 C. 18 F, 15 O and 13Substitution with positron emitting isotopes such as N may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples set forth below, substituting the appropriate isotopically labeled reagent for the non-isotopically labeled reagent previously used. Manufacturing Process

[0102] The preparation of the compounds of formula (I) of the present invention can be carried out in sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indexes used in the following process descriptions have the meanings given herein, unless indicated to the contrary.

[0103] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (as described in "Protective Groups in Organic Chemistry", TW Greene and PG M Hutts, 5th Edition, 2014, John Wiley & Sons, NY) can be introduced prior to the critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0104] When the starting material or intermediates contain a stereocenter, the compound of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods known in the art, such as chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can be separated into their antipodes via diastereomeric salts, for example, by crystallization with optically pure acids, or by separating the antipodes by specific chromatographic methods using either chiral adsorbents or chiral eluents. It is also possible to separate starting materials and intermediates containing stereocenters to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (I) generally results in the respective diastereomerically / enantiomerically enriched compound of formula (I).

[0105] Those skilled in the art will recognize that in the synthesis of compounds of formula (I), unless otherwise desired, an "orthogonal protecting group strategy" can be applied to cleave some protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and RB Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0106] One skilled in the art will recognize that the reaction sequence may be varied depending on the reactivity and nature of the intermediates.

[0107] More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. Also, for reaction conditions described in the literature that affect the reactions described, 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 reactions could be easily carried out with or without a solvent. There is no particular restriction regarding the nature of the solvent used, provided that it does not adversely affect the reaction or the reagents involved, and that it is capable of dissolving the reagents at least to some extent. The reactions described can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reactions described at temperatures ranging from -78°C to reflux. The time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0108] In cases where starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared analogously to existing procedures for similar analogs or as outlined in the experimental section. The following abbreviations are used herein:

[0109] AcOH = acetic acid, ACN = acetonitrile, Bn = benzyl, Boc = tert-butyloxycarbonyl, CAS RN = Chemical Abstracts Registry Number, Cbz = benzyloxycarbonyl, Cs2CO3 = cesium carbonate, CO = carbon monoxide, CuCl = copper(I) chloride, CuCN = copper(I) cyanide, CuI = copper(I) iodide, DAST = (diethylamino)sulfur trifluoride, DBU = 1,8-diazabicyclo[5,4,0]undec-7-ene, DEAD = diethyl azodicarboxylate, DIAD = diisopropyl azodicarboxylate, DMAP = 4-dimethylaminopyridine, DME = dimethoxyethane, DMEDA = N,N'-dimethylethylenediamine, DMF = N,N-dimethylformamide, DIPE A = N,N-diisopropylethylamine, dppf = 1,1 bis(diphenylphosphino)ferrocene, EDC.HCl = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, EI = electron impact, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hours, FA = formic acid, H2O = water, H2SO4 = sulfuric acid, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N',N'-Tetramethyl-uronium-hexafluoro-phosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-1H-benzotriazole; HPLC = high performance liquid chromatography, iPrMgCl = isopropyl magnesium chloride, I2 = iodine, IPA = 2-propanol, ISP = positive ion spray (mode), ISN = negative ion spray (mode), K2CO3 = potassium carbonate, KHCO3 = potassium bicarbonate, KI = potassium iodide, KOH = potassium hydroxide, K3PO4 = tripotassium phosphate, LiAlH4 or LAH = lithium aluminum hydride, LiHMDS = lithium bis(trimethylsilyl)amide, LiOH = lithium hydroxide, mCPBA = metachloroperbenzoic acid, MgSO4 = magnesium sulfate, min = minute, mL = milliliter, MPLC = medium pressure liquid chromatography, MS = mass spectrum, nBuLi = n-butyllithium, NaBH3CN = sodium cyanoborohydride, NaH = sodium hydride, NaHCO3 = sodium bicarbonate, NaNO2 = sodium nitrite, NaBH(OAc)3 = triacetate. Sodium borohydride, NaOH = sodium hydroxide, Na2CO3 = sodium carbonate, Na2SO4 = sodium sulfate, Na2S2O3 = sodium thiosulfate, NBS = N-bromosuccinimide, nBuLi = n-butyl lithium, NEt3 = triethylamine (TEA), NH4Cl = ammonium chloride, NMP = N-methyl-2-pyrrolidone, OAc = acetoxy, T3P = propylphosphonic anhydride, PE = petroleum ether, PG = protecting group, Pd-C = palladium on activated carbon, PdCl2(dppf)-CH2 Cl2 = 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0), Pd(OAc)2 = palladium(II) acetate, Pd(OH)2 = palladium hydroxide, Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0), PTSA = p-toluenesulfonic acid, R = any group, RT = room temperature, SFC = supercritical fluid chromatography, S-PHOS = 2-dicyclohexylphosphino-2',6'-Dimethoxybiphenyl, TBAI = tetrabutylammonium iodide, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMEDA = N,N,N',N'-tetramethylethylenediamine, ZnCl2 = zinc chloride, Hal = halogen.

[0110] A, B, L 1 ,X,m,n,R 1 , R 2 ,R 3 ,R 4 ,R 5 ,R 6 and R 7 Compounds of formula I described herein can be synthesized analogously to literature procedures and / or as shown, for example, in Scheme 1. [ka]

[0111] Scheme 1

[0112] Thus, 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one 1 is reacted with intermediate 2 in the presence of a urea-forming reagent, such as bis(trichloromethyl)carbonate, using a suitable base and a solvent, such as sodium bicarbonate in DCM, to obtain a compound of formula I (step a). Further urea-forming reagents include, but are not limited to, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, or 1,1'-carbonyldiimidazole. This type of reaction and the use of these reagents have been widely described in the literature (e.g., G. Sartori et al., Green Chemistry 2000,2,140). Those skilled in the art will recognize that the order of addition of reagents may be important in this type of reaction for the reactivity and stability of the carbamoyl chloride formed as an intermediate, as well as to avoid the formation of undesired symmetrical urea by-products.

[0113] R1 ~R 7 ,m,n,L 1 Compounds IA, where A and B are as described herein, can be prepared by methods well known to those skilled in the art and as exemplified by the general synthetic procedures outlined in Scheme 1a. [ka]

[0114] Scheme 1a:

[0115] Intermediate 2a, prepared analogously to Scheme 1, is commercially available or can be obtained by, for example, Compounds IA (step a) can be obtained using aryl or heteroaryl boronic acids 7a (Y=B(OH)2) or boronic esters, Y=e.g., 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (pinacol) ester, prepared using literature procedures as described in (Y. et al., J. Clin. Chem. Soc., 1999, 143:1311-1323), in a suitable solvent (e.g., dioxane, dimethoxyethane, water, toluene, DMF or mixtures thereof) and a suitable base (e.g., Na2CO3, NaHCO3, KF, K2CO3 or TEA) at a temperature between room temperature and the boiling point of the solvent or solvent mixture, using a suitable catalyst (e.g., dichloro[1,1'-bis(diphenylphosphine)-ferrocene]palladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate with triphenylphosphine). This type of Suzuki reaction has been widely described in the literature (e.g. Suzuki, Pure Appl. Chem. 1991, 63, 419-422; A. Suzuki, N. Miyaura, Chem. Rev. 1995, 95, 2457-2483; A. Suzuki, J. Organomet. Chem. 1999, 576, 147-168; V. Polshettiwar et al., Chem. Sus. Chem. 2010, 3, 502-522) and is well known to those skilled in the art. Alternatively, aryl- or heteroaryl-trifluoroborates (7a with Y=BF3) can be used in cross-coupling reactions applying a palladium catalyst such as, for example, tetrakis(triphenylphosphine)-palladium(0), palladium(II) acetate or dichloro[1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloromethane adduct in the presence of a suitable base such as cesium carbonate or potassium phosphate in a solvent such as toluene, THF, dioxane, water or mixtures thereof at a temperature between room temperature and the boiling point of the solvent or solvent mixture (step a).

[0116] Alternatively, the bromine or iodine in intermediate 2a can be exchanged for a boronic acid or boronic ester group, for example using the methods described in step a), to give intermediate 2c (step b).

[0117] Intermediate 2c can then be reacted with intermediate 7b, which is either commercially available or prepared analogously to literature methods, where FG is, for example, bromine, to give compound IA applying the reaction conditions previously described (step c).

[0118] Furthermore, intermediate 7b, where Y is preferably bromine, can be reacted with [Ir{dF(CF3)ppy} in the presence of a suitable base, such as anhydrous sodium carbonate, in a solvent, such as DME, to afford 2( dtbpy)]PF 6( Using a suitable photocatalyst such as [4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III)hexafluorophosphate), nickel catalysts such as NiCl2glyme (dichloro(dimethoxyethane)nickel), 4,4'-di-tert-butyl-2,2'-dipyridyl and tris(trimethylsilyl)silane, it can be subjected to cross electrophilic coupling with intermediate 2a, prepared similarly to scheme 1, preferably where FG is bromine, under irradiation of a blue light lamp at 420 nm. This type of reaction is described in the literature, for example in J.Am.Chem.Soc.2016,138,8084. (Step A)

[0119] A, B, R 1 ~R 7 , m, n, and X are as described herein; L 1 Compounds of formula IB where is oxygen can be synthesized following the general procedure outlined in Scheme 1b. [ka]

[0120] Scheme 1b:

[0121] Thus, intermediate 2b (which can be obtained, for example, by the general procedure outlined in Scheme 3) can be converted to compound IB by applying a nucleophilic aromatic substitution reaction. The appropriate heteroaryl compound 7b (wherein Y is a suitable halogen, such as fluorine, chlorine or bromine, preferably fluorine or chlorine, and R 6 and R 7 are described herein), for example 2-chloro-pyrimidine, 2-chloro-4-methylpyrimidine, 3-chloropyridazine, 3,4-dichloropyridazine, 2-chloro-4-methoxypyrimidine, 2-chloro-4-trifluoromethyl)pyrimidine, 3-fluoro-4-methylpyridine, 3,5-difluoropyridine, 3-chloro-5-fluoro-pyridine, 3-fluoropyridine, 2-fluorobenzonitrile, 2-fluoro-6-methylpyridine, 4-bromo-2-chloro-pyrimidine, 2-chloro-4-cyclopropylpyrimidine, 4-chloro-3-fluoropyridine and 4-chloro-2-(methylsulfonyl)pyrimidine, at a temperature ranging from 0° C. to 200° C., in a suitable solvent such as DMSO, DMF or NMP, using a suitable base such as K2CO3 or Cs2CO3, optionally applying microwave heating, to give compounds of formula IB (step a).

[0122] Or A, B, R 1 ~R 7 , m, n, and X are as described herein; L 1 Compounds of formula IB where is oxygen can be synthesized following the general procedure outlined in Scheme 1c. [ka]

[0123] Scheme 1c

[0124] Thus, intermediates of type 2a, where FG is a suitable halogen such as chlorine or bromine, preferably bromine (which can be obtained, for example, by the general procedure outlined in Scheme 4), can be converted to compounds IB by applying a Buchwald-Hartwig cross-coupling reaction. Intermediate 2a can be converted to compounds IB by applying a suitable catalytic system such as Pd(OAc)2 and 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl in a suitable solvent such as toluene, in the presence of a base such as K3PO4, at temperatures ranging from room temperature to the boiling point of the solvent, and optionally applying microwave heating, to give R 6 and R 7 Treatment with an appropriate phenolic compound 8, such as phenol, wherein the formula is as described herein, gives compounds of formula IB (step a).

[0125] Alternatively, the bromine in intermediate 2a can be exchanged for a boronic acid group to give intermediate 2d (which can be obtained, for example, by the general procedure outlined in Scheme 4) (step b).

[0126] Intermediate 2d can then be converted to compound IB by applying the Chan-Lam cross-coupling reaction. Boronic acid intermediate 2d can be reacted with the appropriate R 6 and R 7 as described herein, such as 2-fluorophenol, 3-fluorophenol, 4-fluorophenol, 2,4-difluorophenol, 2-chlorophenol, 3-chlorophenol, 4-chlorophenol, 2-methylphenol and 3-trifluoromethylphenol, to give compounds of formula IB (step c).

[0127] Intermediate 1 can be synthesized, for example, as shown in Scheme 2 and / or analogously to methods described in the literature. [ka]

[0128] Scheme 2

[0129] Thus, 3-aminopiperidin-4-ol derivatives 3, where "PG" represents a suitable protecting group such as a Cbz or Boc protecting group, can be acylated, for example, with acyl chlorides 4, where R 1 is as defined herein, and "LG" denotes a suitable leaving group (e.g., Cl or Br), using a suitable base such as sodium or potassium carbonate, sodium hydroxide or sodium acetate in a suitable solvent such as THF, water, acetone, or mixtures thereof to provide intermediate 5 (step a). Intermediate 4 is either commercially available or can be prepared according to literature methods by converting the achiral (R 1 =H) racemic (R 1 is not H) or in enantiomerically pure form (R 1 is not H).

[0130] Intermediate 5 can be cyclized to intermediate 6 (step b) using methods well known in the art, for example by treating 5 with sodium hydride in THF or potassium tert-butoxide in IPA and water. Reactions of this type are described in the literature (e.g. Z. Rafinski et al., J. Org. Chem. 2015, 80, 7468; S. Dugar et al., Synthesis 2015, 47(5), 712; WO 2005 / 066187).

[0131] The protecting groups in intermediate 6 are removed to give intermediate 1 (step c) applying methods known in the art (e.g., Boc group using TFA in DCM at temperatures between 0° C. and room temperature, Cbz group using hydrogen in the presence of a catalyst such as Pd on charcoal or Pd(OH)2 in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and those described, for example, in “Protective Groups in Organic Chemistry”, TW Greene and PG M Huts, 4th Ed., 2006, Wiley NY).

[0132] Intermediate 1 can be obtained as a mixture of diastereomers and enantiomers, or as a single stereoisomer, depending on whether a racemic mixture or an enantiomerically pure form of cis- or trans-3-aminopiperidin-4-ol derivative 3 is used in their synthesis. Intermediate 3 is commercially available and its synthesis is also described in the literature (e.g. WO 2005 / 066187, WO 2011 / 0059118, WO 2016 / 185279). The optically pure cis-configured intermediates 1B and 1C can be obtained by chiral separation of commercially available rac-(4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (1A) (optionally in the form of a salt, e.g., the hydrochloride salt) using methods known in the art, e.g., diastereomeric salt crystallization or chiral chromatography, for example according to Scheme 3 (Step a).

[0133] In some embodiments, intermediate 2 is an intermediate of type 2b. A is aryl, m=n=0, and R 1 , R 2 , R 3 , R 4 , R 5 and R 8 Intermediate 2b, wherein R is as described herein, can be prepared by methods well known to one skilled in the art, as exemplified by the general synthetic procedure outlined in Scheme 3. [ka]

[0134] Scheme 3

[0135] LG is a suitable leaving group such as bromine or iodine, preferably bromine; m, n and R 3 Protected amine 10, either commercially available or prepared by methods known in the art, where X is bromine and R is a suitable protecting group such as, for example, Boc, Cbz, or Bn, can be reacted with a suitable photocatalyst such as [Ir{dF(CF3)ppy}2(dtbpy)]PF6 ([4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate), a nickel catalyst such as NiCl2glyme (dichloro(dimethoxyethane)nickel), 4,4'-di-tert-butyl-2,2'-dipyridyl, and tris(trimethylsilyl)silane, under irradiation with a 420 nm blue light lamp in the presence of a suitable base such as anhydrous sodium carbonate in a solvent such as DME. 4 and R 5 The amine 13 can then be subjected to cross-electrophilic coupling with an aryl bromide 11, such as 4-bromophenol, where 11 is as described herein. This type of reaction is described in the literature, for example in J.Am.Chem.Soc. 2016,138,8084. (Step a) By applying methods known in the art and described in step c of scheme 2 below, the protecting group is removed from intermediate 12 to give intermediate 13 (step b). Amine 13 can then be coupled with intermediate 1, for example applying the conditions outlined in scheme 1, step a, to give intermediate 2b (step c).

[0136] In some embodiments, intermediate 2 is an intermediate of type 2a, 2c, or 2d. A is aryl, m=n=0, and R 1 , R2 , R 3 , R 4 , R 5 and R 8 Intermediates 2a, 2c and 2d, wherein: are as described herein, can be prepared by methods well known to one skilled in the art, as exemplified by the general synthetic procedure outlined in Scheme 4. [ka]

[0137] Scheme 4

[0138] LG is a suitable leaving group, such as bromine or iodine, preferably iodine, and m, n and R are each a suitable leaving group, such as bromine or iodine, preferably iodine, either commercially available or prepared by methods known in the art. 3Protected amine 10, where is as described herein and PG is a suitable protecting group, for example Boc, Cbz or Bn, can be subjected to Suzuki-Miyaura cross-coupling reaction with arylboronic acid 14, such as 4-bromophenylboronic acid, in the presence of rac-(1R,2R)-2-aminocyclohexan-1-ol and a suitable base, such as sodium bis(trimethylsilyl)amide, using a suitable nickel catalyst, such as nickel(II) iodide, in a suitable solvent, such as iPrOH, dioxane, THF or DME, preferably iPrOH, at a temperature between room temperature and the boiling point of the solvent, optionally applying microwave heating, to obtain intermediate 15. This type of reaction is described in the literature, for example in ChemistrySelect.2017,2,8841. (Step a). Removal of the protecting group from intermediate 15 by applying methods known in the art or as described in step c of scheme 2 below gives intermediate 16 (Step b). Amine 16 can then be coupled with intermediate 1, for example by applying the conditions outlined in scheme 1, step a, to give intermediate 2a (step c). The bromo substituent in intermediate 2a is converted to a boronic acid or boronic acid ester (e.g., pinacol ester) according to literature procedures, for example as described in "Boronic Acids-Preparation and Applications in Organic Synthesis and Medicine" 1st Ed., 2005, John Wiley&Sons, New York) by using PdCl2.CH2Cl2 in the presence of bis(pinacolato)diboron and a suitable base, for example, Na2CO3, NaHCO3, KF, KOAc or TEA, in a suitable solvent, for example, dioxane, THF, DME, water or DMF, or a mixture thereof, preferably at a temperature between room temperature and the boiling point of the solvent, optionally applying microwave heating, to give intermediate 2c (step d).Finally, hydrolysis of the pinacolyl ester in intermediate 2c can be achieved by methods known in the literature (e.g., Tetrahedron letters 2005, 46, 7899) or by using NaIO4 in the presence of NHOAc in a mixture of water and acetone at about room temperature to give intermediate 2d (step e).

[0139] R 1 ~R 7 , R 8 , m and n are as described herein; R 6a C 1-6 -alkyl, L 1 is a covalent bond, A is phenyl, and B is 1-(C 1-6 -alkyl)-substituted pyrazol 3-yl or pyrazol 5-yl compounds 31, 32a and 32b can be prepared by methods well known to one skilled in the art, as exemplified by the general synthetic procedures outlined in Scheme 5. [ka]

[0140] Scheme 5

[0141] Commercially available boronic ester intermediate 9 can be subjected to a Suzuki coupling reaction with intermediate 2a, prepared for example according to Scheme 3, applying the reaction conditions described in Scheme 1a, step a, to give compound 31 (step a).

[0142] Compound 31 is chlorine, bromine, iodine, and OSO 2Alkylation with an alkylating agent of type R6aLG, which is a suitable leaving group such as alkyl (e.g., mesylate (methanesulfonate), OSO2 fluoroalkyl (e.g., triflate (trifluoromethanesulfonate) or OSO2 aryl (e.g., tosylate (p-toluenesulfonate)), in a suitable solvent (e.g., sodium hydride in DMF or cesium carbonate in DMF) using a suitable base at a temperature between 0° C. and the boiling point of the solvent, can give the regioisomeric compounds 32a and 32b (step b), which can be separated, for example, by column chromatography.

[0143] R 1 ~R 8 , m and n are as described herein; L 1 Compound 33, where A is a covalent bond, A is phenyl, and B is an optionally further substituted pyridine, can be prepared by methods well known to those skilled in the art, as exemplified by the general synthetic procedures outlined in Scheme 6. [ka]

[0144] Scheme 6

[0145] The bromine in commercially available 2-bromo-3-chloro-pyridine 17 can be converted to intermediate 18 by methods known in the art, for example by first carrying out a bromolithium exchange reaction with n-BuLi in a suitable solvent such as toluene at a temperature range of, for example, −78° C. to room temperature, and then reacting the intermediate lithium species with tri-n-butyltin chloride to convert it to a tri-n-butyltin group (step a).

[0146] Intermediate 18 can be reacted with intermediate 2a using a suitable catalyst and solvent, such as tetrakis(triphenylphosphine)-palladium(0) in DMF at a temperature between room temperature and the boiling point of the solvent or solvent mixture to give compound 33 (step a). Stille reactions of this type are well known in the art and have been described in the literature, for example Org.React.1997,50,1-652, ACS Catal.2015,5,3040-3053.

[0147] In some embodiments, intermediate 2 is an intermediate of type 2e. 3 , R 4 , R 5 , R 8 , m and n are as defined herein; R 6a C 1-6 -alkyl, L 1 Intermediates of type 2e, where A is a covalent bond, A is phenyl, and B is 1-alkyl substituted triazol-5-yl, can be prepared by methods well known to those skilled in the art, as exemplified by the general synthetic procedure outlined in Scheme 7. [ka]

[0148] Scheme 7

[0149] Commercially available 4-nitroaniline can be converted to intermediate 20 by methods known in the art, for example using tert-butyl nitrite and trimethylsilyl azide in a suitable solvent such as ACN (step a).

[0150] The reaction of intermediate 20 with acetophenones (e.g., 4'-bromoacetophenone) and type R in a suitable acid and solvent system, e.g., AcOH in toluene, optionally at elevated temperature using molecular sieves, 6bReaction with an amine of type -NH2 gives the triazole intermediate 21 (step b), where LG is a suitable leaving group, such as halogen, in particular bromo. This type of reaction is described in the literature, for example in Chem. Commun., 2016, 52, 2885.

[0151] Intermediate 21 is an intermediate in which LG is a suitable leaving group such as bromine or iodine, preferably bromine, and m, n and R 3 is as described herein and PG is a suitable protecting group such as Boc, can be subjected to a cross electrophilic coupling reaction with commercially available intermediate 10, applying for example the reaction conditions described in Scheme 1 a, step a, to give intermediate 22 (step c).

[0152] Removal of the protecting group using, for example, TFA in DCM at temperatures between 0° C. and room temperature gives intermediate 2e (step d).

[0153] In some embodiments, intermediate 2 is an intermediate of type 2f. 3 , R 4 , R 5 , R 8 , m and n are as defined herein; R 6a C 1-6 -Alkyl or halo-C 1-6 -alkyl, R 6b is hydrogen, C 1-6 -Alkyl or halo-C 1-6 -alkyl, L 1 Intermediates of type 2f, where A is a covalent bond, A is phenyl and B is pyrazol-1-yl, can be prepared by methods well known to those skilled in the art, as exemplified by the general synthetic procedure outlined in Scheme 8. [ka]

[0154] Scheme 8

[0155] Intermediate 23 can be prepared, for example, by cyclocondensation of 1,3-dicarbonyl compounds with commercially available optionally substituted hydrazines (e.g., (4-bromophenyl)hydrazine) in the presence of copper(II) nitrate trihydrate in a suitable solvent such as ACN (step a).

[0156] Intermediate 23 can be subjected to a cross electrophilic coupling reaction with intermediates of type 10, where PG denotes a suitable protecting group such as Cbz or Boc and LG denotes a suitable leaving group such as a halogen, in particular bromine, applying the reaction conditions described for example in Scheme 1 a, step a, to give intermediate 24 (step b).

[0157] Applying published procedures, removal of the protecting groups as described in step d of scheme 7 gives intermediate 2f (step c).

[0158] In some embodiments, intermediate 2 is an intermediate of type 2g. 3 , R 4 , R 5 , R 8 , m and n are as defined herein; R 6a C 1-6 -alkyl, L 1 Intermediates of type 2g, where A is a covalent bond, A is phenyl, and B is 5-substituted-1,3,4-oxadiazol-2-yl, can be prepared by methods known to those skilled in the art and as exemplified by the general synthetic procedures outlined in Scheme 9. [ka]

[0159] Scheme 9

[0160] Commercially available hydrazides (e.g., 4-bromobenzoic acid hydrazide) and acid chlorides R 6a C(O)Cl can be reacted in the presence of a suitable base in a suitable solvent, for example DIPEA in DCM, to give intermediate 25 (step a).

[0161] Intermediate 25, where LG represents a suitable leaving group such as halogen, especially bromine, can be dehydrated to give intermediate 26 (step b), for example using pTsOH in toluene at elevated temperatures, preferably up to the boiling point of the solvent.

[0162] Intermediate 26 can be subjected to a cross electrophilic coupling reaction with, for example, intermediates of type 10, applying the reaction conditions described, for example, in scheme 1a, step a, to give intermediate 27 (step c).

[0163] Applying published procedures, removal of the protecting groups as described in scheme 7, step d, affords intermediate 2g (step d).

[0164] In some embodiments, intermediate 2 is an intermediate of type 2h. 3 , R 4 , R 5 , R 8 , m and n are as defined herein; R 6a C 1-6 -alkyl, L 1 Intermediates of type 2h, where A is a covalent bond, A is phenyl, and B is 5-substituted-1,2,4-oxadiazol-3-yl, can be prepared by methods well known to those skilled in the art, as exemplified by the general synthetic procedure outlined in Scheme 10. [ka]

[0165] Scheme 10

[0166] Optionally substituted benzonitriles (e.g., 4-bromobenzonitrile), either commercially available or prepared by methods known in the art, can be subjected to a cross-electrophilic coupling reaction with intermediates of type 10, applying the reaction conditions described, for example, in Scheme 1a, step a, to give intermediates 28 (step a).

[0167] Reaction of intermediate 28 with hydroxylamine hydrochloride in a suitable solvent or solvent mixture using a suitable base, for example Na2CO3 in EtOH and water, preferably at elevated temperature, gives the phenylamide oxime intermediate 29 (step b).

[0168] Intermediate 29 can then be reacted with the acid chloride R in the presence of a suitable base and solvent, such as DIPEA in toluene, at temperatures ranging from room temperature to the boiling point of the solvent or solvent mixture. 6a Reaction with C(O)Cl can give intermediate 30 (step c).

[0169] Applying published procedures, removal of the protecting groups as described in scheme 7, step d, affords intermediate 2h (step d). In one aspect, the present invention provides a method for preparing a compound of formula (I) as described herein, comprising the steps of: 4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one 1 (wherein R 1 and R 2 is as defined herein), [ka]

[0170] Heterocyclic amine 2 (wherein A, B, L 1 , X, m, n and R 3 ~R 7 is as defined herein), [ka]

[0171] Reacting in the presence of a base and a coupling reagent, forming a compound of formula (I).

[0172] In one embodiment there is provided a process according to the present invention wherein the base is sodium bicarbonate.

[0173] In one embodiment there is provided a process according to the invention, wherein the urea forming reagent is selected from bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, and 1,1′-carbonyldiimidazole, preferably the urea forming reagent is bis(trichloromethyl)carbonate.

[0174] In one aspect, the present invention provides a compound of formula (I) as described herein when manufactured according to any one of the processes described herein. MAGL inhibitory activity

[0175] The compounds of the present invention are MAGL inhibitors. Thus, in one aspect, the present invention provides the use of a compound of formula (I) as described herein for inhibiting MAGL in a mammal.

[0176] In a further aspect, the invention provides a compound of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.

[0177] In a further aspect, the invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal.

[0178] In a further aspect, the present invention provides a method for inhibiting MAGL in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0179] Compounds of formula (I) may be profiled for MAGL inhibitory activity by determining the enzymatic activity following hydrolysis of the natural substrate 2-arachidonoylglycerol (2-AG) to yield arachidonic acid, followed by mass spectrometry. This assay is hereinafter abbreviated as "2-AG assay."

[0180] The 2-AG assay was performed in a total volume of 20 μL in 384-well assay plates (PP, Greiner, Cat. No. 784201). Compound dilutions were made in 3-fold dilution steps in polypropylene plates in 100% DMSO (VWR Chemicals 23500.297) to give a final concentration range in the assay of 12.5 μM to 0.8 pM. 0.25 μL of compound dilution (100% DMSO) was added to 9 μL of MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100ml), 0.01% (v / v) Tween). After shaking, the plate was incubated at room temperature for 15 min. To start the reaction, 10 μL of 2-arachidonoylglycerol in assay buffer was added. The final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglyerol. After shaking and incubation at room temperature for 30 min, the reaction was quenched by adding 40 μL of ACN containing 4 μM d8-arachidonic acid. The amount of arachidonic acid was followed using an online SPE system (Agilent Rapidfire) in combination with a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE cartridge (G9205A) was used in an ACN / water liquid setup. The mass spectrometer was operated in negative electrospray mode, following the mass transitions 303.1→259.1 for arachidonic acid and 311.1→267.0 for d8-arachidonic acid. The activity of the compounds was calculated based on the intensity ratio [arachidonic acid / d8-arachidonic acid]. [Table 1] TIFF0007609854000027.tif87161

[0181] In one aspect, the present invention provides compounds of formula (I) as described herein, and pharma- ceutically acceptable salts or esters thereof, wherein said compounds of formula (I) and pharma- ceutically acceptable salts or esters thereof have an IC for MAGL inhibition as measured in the MAGL assay as described herein. 50 is less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM.

[0182] In one embodiment, the compounds of formula (I) described herein and their pharma- ceutically acceptable salts or esters have an IC 50 (MAGL inhibition) values ​​range from 0.000001 μM to 25 μM, and certain compounds have IC 50 values ​​are between 0.000005 μM and 10 μM, and certain compounds have IC 50 The values ​​are between 0.00005μM and 5μM. Uses of the Compounds of the Invention

[0183] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0184] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and / or psychiatric disorders in a mammal.

[0185] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prevention of a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0186] In one embodiment, the invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prevention of a neurodegenerative disease in a mammal.

[0187] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prevention of cancer in a mammal.

[0188] In one embodiment, the invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prevention of inflammatory bowel disease in a mammal.

[0189] In one embodiment, the invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prophylaxis of pain in a mammal.

[0190] In one aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and / or spasticity associated with pain in a mammal.

[0191] In a preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in a mammal.

[0192] In a particularly preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the treatment or prophylaxis of multiple sclerosis in a mammal.

[0193] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and / or psychiatric disorders in a mammal.

[0194] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0195] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of cancer in a mammal.

[0196] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of a neurodegenerative disease in a mammal.

[0197] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prevention of inflammatory bowel disease in a mammal.

[0198] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of pain in a mammal.

[0199] In one aspect, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for use in the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and / or spasticity associated with pain in a mammal.

[0200] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in a mammal.

[0201] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of multiple sclerosis in a mammal.

[0202] In one aspect, the invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of neuroinflammation, a neurodegenerative disease, pain, cancer and / or a psychiatric disorder in a mammal.

[0203] In one embodiment, the invention provides the use of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0204] In one embodiment, the invention provides the use of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a neurodegenerative disease in a mammal.

[0205] In one embodiment, the invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of cancer in a mammal.

[0206] In one embodiment, the invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of inflammatory bowel disease in a mammal.

[0207] In one embodiment, the invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of pain in a mammal.

[0208] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and / or spasticity associated with pain in a mammal.

[0209] In a preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in a mammal.

[0210] In a particularly preferred embodiment, the invention provides the use of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis in a mammal.

[0211] In one aspect, the present invention provides a method for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and / or psychiatric disorders in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof.

[0212] In one embodiment, the present invention provides a method for the treatment or prevention of a neuroinflammatory and / or neurodegenerative disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein.

[0213] In one embodiment, the present invention provides a method for the treatment or prevention of a neurodegenerative disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein.

[0214] In one embodiment, the present invention provides a method for the treatment or prevention of cancer in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein.

[0215] In one embodiment, the present invention provides a method for the treatment or prevention of inflammatory bowel disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein.

[0216] In one embodiment, the present invention provides a method for the treatment or prevention of pain in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as described herein.

[0217] In a further aspect, the present invention provides a method of treating or preventing multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain, abdominal pain associated with irritable bowel syndrome and / or visceral pain in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof.

[0218] In a preferred embodiment, the present invention provides a method for the treatment or prevention of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof.

[0219] In a particularly preferred embodiment, the present invention provides a method for the treatment or prevention of multiple sclerosis in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof. Pharmaceutical Compositions and Administration

[0220] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0221] In one embodiment, a pharmaceutical composition according to Example 47 or 48 is provided.

[0222] The compounds of formula (I) and their pharma- ceutically acceptable salts and esters can be used as medicines (e.g., in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, liquids, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories).However, administration can also be parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0223] The compounds of formula (I) and their pharma- ceutically acceptable salts and esters can be treated with pharma- ceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0224] Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols.

[0225] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0226] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.

[0227] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0228] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, and may also contain other therapeutically valuable substances.

[0229] The dosage can vary widely and will of course be adapted to the individual requirements in each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person), preferably divided into 1 to 3 individual doses, for example of the same amount, will be appropriate. However, it is clear that the upper limit given in this specification can be exceeded in indicated cases. EXAMPLES

[0230] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims to the examples.

[0231] Where the preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0232] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere. Method A1 Example 1 (4aR,8aS)-6-(3-(4-phenoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0233] In a sealed tube, (4aR,8aS)-6-[3-(4-bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB4 step c, 0.04 g, 0.110 mmol), phenol (0.014, 0.152 mmol), Pd(OAc)2 (0.004 g, 0.016 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.01 g, 0.024 mmol), and KPO 4( 0.043 g, 0.203 mmol) were mixed in toluene (0.68 mL). The reaction mixture was heated to 100° C. overnight. The mixture was diluted with EtOAc, poured into water, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude was purified by preparative HPLC to give the title compound as an off-white foam (0.008, 17%). MS (ESI): m / z=408.2 [M+H] + . Method A2 Example 2 (4aR,8aS)-6-[3-[4-(2-chlorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0234] To a solution of 4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]phenyl]boronic acid (BB4, 0.025 g, 0.07 mmol), 2-chlorophenol (0.027 g, 0.21 mmol) and TEA (0.043 mL, 0.42 mmol) in MeCN (2 mL) was added 4 A molecular sieves (0.03 g) and anhydrous cupric acetate (0.038 g, 0.21 mmol). The reaction mixture was stirred at 30 °C under an atmosphere of O for 16 h. The mixture was quenched with NH4OH (0.3 mL) and HO (2 mL) and extracted with EtOAc (3 × 2 mL). The combined organic layers were evaporated to dryness and the residue was purified by preparative HPLC to give the title product (0.007 g, 23%) as an off-white solid. MS (ESI): m / z=442.1 [M+H] + . Method A3 Example 3 (4aR,8aS)-6-[3-(4-pyrimidin-2-yloxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0235] In a sealed tube, (4aR,8aS)-6-[3-(4-hydroxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB3, 0.05 g, 0.150 mmol), 2-chloro-pyrimidine (0.026 g, 0.230 mmol, CAS RN 1722-12-9) and potassium carbonate (0.062 g, 0.450 mmol, CAS RN 584-08-7) were mixed in DMSO (2.5 mL). The reaction mixture was then heated to 80° C. for 12 h. The mixture was diluted with EtOAc, poured into water and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC to give the title product as a white solid (0.039 g, 63%). MS(ESI): m / z=410.4 [M+H] + . Method A4 Example 4 (4aR,8aS)-6-[3-[4-[(2-methyl-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0236] In a sealed tube, (4aR,8aS)-6-[3-(4-hydroxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB3, 0.050 g, 0.150 mmol), 3-fluoro-pyridine (0.046 g, 0.410 mmol) and CsCO 3(0.197 g, 0.6 mmol) was mixed in NMP (2 mL). The reaction mixture was then heated at 200° C. for 1 h under microwave irradiation. The mixture was diluted with EtOAc, poured into water, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC to give the desired product (0.007 g, 11%) as a white solid. MS (ESI): m / z=423.1 [M+H] + . Method B1 Example 30 (4aR,8aS)-6-[3-[4-[(3,6-dimethyl-2-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0237] Methylboronic acid (0.014 g, 0.24 mmol), KCO 3( To a solution of (4aR,8aS)-6-[3-[4-[(3-bromo-6-methyl-2-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (0.06g, 0.48 mmol) and (4aR,8aS)-6-[3-[4-[(3-bromo-6-methyl-2-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (0.06g, 0.12 mmol) in dioxane (2 mL) and water (0.5 mL) was added Pd(dppf)Cl2 (0.008g, 0.01mmol) and the reaction mixture was heated to 100°C for 12 h. The reaction mixture was filtered and the filtrate was diluted with water (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by preparative HPLC to give the title compound (0.009 g, 16%) as an off-white solid. MS (ESI): m / z=437.2 [M+H] + . Step a) (4aR,8aS)-6-[3-[4-[3-bromo-6-methyl-2-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0238] (4aR,8aS)-6-[3-(4-hydroxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB3, 0.1 g, 0.3 mmol), CsCO 3( To a solution of 3-bromo-2-fluoro-6-methyl-pyridine (0.086 g, 0.45 mmol) (0.394 g, 1.21 mmol) in DMSO (5 mL) was added 3-bromo-2-fluoro-6-methyl-pyridine (0.086 g, 0.45 mmol) and the reaction mixture was heated to 50° C. for 12 h. The mixture was filtered and the filtrate was purified by preparative HPLC to give the title product (0.08 g, 53%) as a colorless foam. MS (ESI): m / z=503.2 [M+2+H] + .

[0239] The following examples listed in Table 2 were prepared similarly to the reaction methods described herein by using the indicated intermediates and commercially available compounds. [Table 2] TIFF0007609854000035.tif203161 TIFF0007609854000036.tif214161 TIFF0007609854000037.tif209161 TIFF0007609854000038.tif202161 TIFF0007609854000039.tif204161 TIFF0007609854000040.tif219161 TIFF0007609854000041.tif204161 TIFF0007609854000042.tif80161 Example 31 (4aR,8aS)-6-[3-[4-(1H-pyrazol-5-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0240] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (147.7 mg, 0.760 mmol; CAS RN 269410-08-4), (4aR,8aS)-6-[3-(4-bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB4 step c, 200.0 mg, 0.510 mmol) and KCO 3( To a solution of Pd(dppf)Cl2 (140.22 mg, 1.01 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added Pd(dppf)Cl2 (66.12 mg, 0.100 mmol, CAS RN 12150-46-8) and the mixture was stirred at 90 °C for 12 h. The suspension was filtered and the filtrate was evaporated. The residue was purified by preparative HPLC (0.225% v / v water and FA in ACN) to give the desired product (6.5 mg, 0.020 mmol, 3.3%) as an off-white solid. MS (ESI): m / z = 382.4 [M + H] + . Examples 32a and 32b (4aR,8aS)-6-[3-[4-[2-(2,2-dimethylpropyl)pyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one, and (4aR,8aS)-6-[3-[4-[1-(2,2-dimethylpropyl)pyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0241] [ka]

[0242] (4aR,8aS)-6-[3-[4-(1H-pyrazol-5-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (Example 31, 140.0 mg, 0.370 mmol), 1-bromo-2,2-dimethylpropane (110.88 mg, 0.730 mmol) and CsCO 3( A solution of ex.HR 1 (239.18 mg, 0.730 mmol) in DMF (2.6 mL) was stirred at 80 °C for 12 h. The mixture was diluted with water and extracted three times with EtOAc (10 mL each). The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified and the regioisomers were separated by preparative HPLC (0.225% v / v water and FA in ACN) to give ex.HR 1 (2.5 mg, 0.010 mmol, 2.6%) and ex.HR 2 (31.4 mg, 0.070 mmol, 32.5%), respectively, as pale yellow solids. For both enantiomers, MS (ESI): m / z = 452.3 [M+H] + . Example 33 (4aR,8aS)-6-[3-[4-(3-chloro-2-pyridyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0243] To a solution of tributyl-(3-chloro-2-pyridyl)stannane (122.5 mg, 0.300 mmol, CAS RN 206357-78-0) and (4aR,8aS)-6-[3-(4-bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB4 step c, 100.0 mg, 0.250 mmol) in DMF (5 mL) was added Pd(PPh3)4 (58.64 mg, 0.050 mmol) and the mixture was stirred at 100° C. under N2 atmosphere for 12 h. The mixture was poured into water (20 mL) and extracted three times with EtOAc (5 mL each). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was evaporated. The residue was purified by reverse-phase flash column chromatography (0.1% v / v water and FA in ACN) followed by preparative HPLC (0.225% v / v water and FA in ACN) to give the desired compound as a white solid (2.8 mg, 99.4% pure, 2.6%). MS (ESI): m / z=427.2 [M+H] + . Step a) Tributyl-(3-chloro-2-pyridyl)stannane [ka]

[0244] To a solution of 2-bromo-3-chloropyridine (576.0 mg, 2.99 mmol, CAS RN 96424-68-9) in toluene (20 mL) under N2 was added n-BuLi in hexanes (2.5 M, 1.32 mL, 3.29 mmol) dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 2 h, after which tributyltin chloride (1071.73 mg, 3.29 mmol) was added. The reaction mixture was stirred at -78 °C for an additional 2 h, then warmed to room temperature and stirred for an additional 12 h. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL). The mixture was extracted three times with EtOAc (30 mL each) and the combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the desired product (1100 mg, 2.73 mmol, 91.3%) as a light brown solid, which was used in the next step without further purification. MS (ESI): m / z=404.1 [M+H] + . Example 34 (4aR,8aS)-6-[3-[4-(2,4-dimethyloxazol-5-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0245] (4aR,8aS)-6-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB4 step d, 80.0 mg, 0.180 mmol), Na2CO3 (38.42 mg, 0.360 mmol) and 5-bromo-2,4-dimethyl-oxazole (31.91 mg, 0.180 mmol, CAS RN 187399-73-1) in 1,4-dioxane (4 mL) and water (1 To a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (13.3 mg, 0.020 mmol) in 1 mL of ethyl acetate was added and the mixture was stirred at 100° C. under nitrogen atmosphere for 12 h. The mixture was poured into water (20 mL) and extracted three times with EtOAc (10 mL each). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative HPLC (0.5% water and ammonia in ACN) to give the desired compound as a pink solid (23.7 mg, 0.060 mmol, 30.6%). MS (ESI): m / z=411.2 [M+H] + . Example 35 (4aR,8aS)-6-[3-[4-(3,5-dimethylpyrazol-1-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0246] To a solution of 1-[4-(azetidin-3-yl)phenyl]-3,5-dimethyl-pyrazole(trifluoroacetate) (150.0 mg, 0.440 mmol) in ACN (5 mL) was added DIPEA (340.14 mg, 2.64 mmol) followed by (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (169.43 mg, 0.530 mmol, BB2a) and the reaction mixture was stirred at 80° C. for 12 h. The solution was concentrated and the residue was purified by preparative HPLC (0.225% v / v TFA in water and ACN) to give the desired product as a pale yellow solid (53.9 mg, 0.130 mmol, 27.7%, purity 92.4%). MS(ESI): m / z=410.0[M+H] + . Step a) 1-(4-bromophenyl)-3,5-dimethyl-pyrazole [ka]

[0247] A solution of (4-bromophenyl)hydrazine (500.0 mg, 2.67 mmol, CAS RN 41931-18-4) and acetylacetone (294.41 mg, 2.94 mmol, CAS RN 123-54-6), copper(II) nitrate trihydrate (128.31 mg, 0.530 mmol, CAS RN 10031-43-3) in ACN (12 mL) was stirred at 20° C. for 2 h. The mixture was diluted with EtOAc (20 mL), washed with water and then with brine, and the organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE:EtOAc=20:1) to give the desired product as a pale yellow oil (400 mg, 1.59 mmol, 71.2%). MS (ESI): m / z=251.0 [M+H] + . Step b) tert-Butyl 3-[4-(3,5-dimethylpyrazol-1-yl)phenyl]azetidine-1-carboxylate [ka]

[0248] In a 40 mL vial equipped with a stir bar, add tert-butyl 3-bromoazetidine-1-carboxylate (329.08 mg, 1.39 mmol, CAS RN 1064194-10-0), 1-(4-bromophenyl)-3,5-dimethyl-pyrazole (350.0 mg, 1.39 mmol, CAS RN 62546-27-4), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (7.81 mg, 0.010 mmol), NiCl2·glyme (1.84 mg, 0.010 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (2.24 mg, 0.010 mmol), bis(trimethylsilyl)silyl-trimethyl-silane (346.57 mg, 1.39 mmol), and Na2CO 3( 295.45 mg, 2.79 mmol) followed by DME (10 mL) were added. The vial was sealed and placed under nitrogen. The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (7 cm distance) and the reaction temperature was maintained at 25° C. for 14 h using a cooling fan. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase flash column chromatography (0.1% v / v water and FA in ACN) to give the desired product as a yellow oil (300 mg, 0.920 mmol, 65.7%). MS (ESI): m / z=328.1 [M+H] + . Step c) 1-[4-(azetidin-3-yl)phenyl]-3,5-dimethyl-pyrazole, trifluoroacetate [ka]

[0249] To a solution of tert-butyl 3-[4-(3,5-dimethylpyrazol-1-yl)phenyl]azetidine-1-carboxylate (150.0 mg, 0.460 mmol) in DCM (5 mL) was added TFA (1.0 mL). The mixture was stirred at 20° C. for 3 h and then concentrated to give the desired crude product (150 mg, 0.440 mmol, 95.9%) as a yellow oil. MS (ESI): m / z=228.1 [M+H] + . Example 36 (4aR,8aS)-6-[3-[4-[3-(2,2-dimethylpropyl)triazol-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0250] A mixture of (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (66.2 mg, 0.210 mmol, BB 2a), DIPEA (241.9 mg, 1.87 mmol) and 5-[4-(azetidin-3-yl)phenyl]-1-(2,2-dimethylpropyl)triazole trifluoroacetate (72.0 mg, 0.190 mmol) in ACN (3 mL) was stirred at 80° C. for 12 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (0.025% water and FA in ACN) to give the desired compound as a pale yellow solid (18 mg, 0.040 mmol, 20.5%). MS (ESI): m / z=453.0 [M+H] + . Step a) 1-Azido-4-nitro-benzene [ka]

[0251] 4-Nitroaniline (2000.0 mg, 14.48 mmol) was dissolved in ACN (20 mL) and cooled to 0 °C in an ice-salt bath. To the stirred solution was added tert-butyl nitrite (1791.8 mg, 17.38 mmol) and the mixture was stirred for 10 min. Azidotrimethylsilane (2.88 mL, 21.72 mmol) was then added dropwise and the resulting brown solution was stirred at 25 °C for 2 h. The reaction mixture was poured into water (100 mL), extracted three times with EtOAc (100 mL each) and the organic layer was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (100% PE) to give 1-azido-4-nitro-benzene (2100 mg, 12.64 mmol, 87.3) as a yellow solid. Step b) 5-(4-bromophenyl)-1-(2,2-dimethylpropyl)triazole [ka]

[0252] To a solution of 4'-bromoacetophenone (1940.4 mg, 9.75 mmol), neopentylamine (1104.6 mg, 12.67 mmol), 1-azido-4-nitro-benzene (1600.0 mg, 9.75 mmol), AcOH (175.6 mg, 2.92 mmol) in toluene (64 mL) was added molecular sieves (4 Å, 500 mg) and the reaction was stirred at 100° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=3:1) to give the desired compound as a yellow gum (997 mg, 3.39 mmol, 34.8%). Step c) tert-Butyl 3-[4-[3-(2,2-dimethylpropyl)triazol-4-yl]phenyl]azetidine-1-carboxylate [ka]

[0253] The title compound was prepared from 5-(4-bromophenyl)-1-(2,2-dimethylpropyl)triazole and tert-butyl 3-bromoazetidine-1-carboxylate in analogy to step b) of Example 35. Yellow gum (75.9%). MS (ESI): m / z=371.0 [M+H] + . Step d) 5-[4-(azetidin-3-yl)phenyl]-1-(2,2-dimethylpropyl)triazole, trifluoroacetate [ka]

[0254] To a solution of tert-butyl 3-[4-[3-(2,2-dimethylpropyl)triazol-4-yl]phenyl]azetidine-1-carboxylate (70.0 mg, 0.190 mmol) in DCM (2 mL) was added TFA (0.5 mL). The mixture was stirred at 20° C. for 12 h and then evaporated under reduced pressure to give the crude desired compound as a yellow oil (72 mg, 0.190 mmol, 99.1%). MS (ESI): m / z=270.9 [M+H] + . Example 37 (4aR,8aS)-6-[3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0255] To a solution of 3-[4-(azetidin-3-yl)phenyl]-5-(2,2-dimethylpropyl)-1,2,4-oxadiazole, trifluoroacetate (150.0 mg, 0.390 mmol) in ACN (4 mL) was added DIPEA (301.3 mg, 2.34 mmol) and (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4 a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (150.07 mg, 0.470 mmol, BB2a) and the reaction was stirred for 12 h at 80° C. The reaction mixture was evaporated and the residue was purified by preparative HPLC (0.225% v / v water and FA in ACN) to give the desired product as a pale yellow solid (54.4 mg, 0.120 mmol, 30.4%). MS(ESI): m / z=454.4[M+H] + . Step a) tert-Butyl 3-(4-cyanophenyl)azetidine-1-carboxylate [ka]

[0256] The title compound was prepared from 4-bromobenzonitrile and tert-butyl 3-bromoazetidine-1-carboxylate in analogy to step b) of Example 35. Light brown oil (1976 mg, 7.65 mmol, 69.6%). MS (ESI): m / z=203.6 [M-56+H] + . Step b) tert-Butyl 3-[4-(N-hydroxycarbamimidoyl)phenyl]azetidine-1-carboxylate [ka]

[0257] To a solution of hydroxylamine hydrochloride (349.7 mg, 5.03 mmol) in EtOH (8 mL) was added a solution of Na2CO3 (266.7 mg, 2.52 mmol) in water (2 mL) and the mixture was stirred at 20 °C for 25 min. Then tert-butyl 3-(4-cyanophenyl)azetidine-1-carboxylate (1000.0 mg, 3.87 mmol) was added and the mixture was stirred at 95 °C for 12 h. The mixture was diluted with water and concentrated in vacuo to remove EtOH, and the residue was partitioned between EtOAc (100 mL) and water (100 mL) and extracted three times with water. The organic layer was washed with saturated NaCl solution (50 mL), dried over Na2SO4 and evaporated to give the desired product as a pale yellow oil (773 mg, 2.65 mmol, 68.5%). MS (ESI): m / z = 292.5 [M + H] + . Step c) tert-Butyl 3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl]phenyl]azetidine-1-carboxylate [ka]

[0258] To a solution of tert-butyl 3-[4-(N-hydroxycarbamimidoyl)phenyl]azetidine-1-carboxylate (770.0 mg, 2.64 mmol) and DIPEA (1.41 mL, 7.93 mmol) in toluene (6 mL) was added 3,3-dimethylbutyryl chloride (426.9 mg, 3.17 mmol) at 0° C., the mixture was stirred at 25° C. for 10 min, then warmed to 80° C. and stirred for 12 h. The mixture was evaporated and the residue was purified by silica gel column chromatography (PE:EA=10:1) to give the desired product (620 mg, 1.67 mmol, 63.2%) as a light brown oil. MS(ESI):m / z=316.5[M-56+H] + . Step d) 3-[4-(azetidin-3-yl)phenyl]-5-(2,2-dimethylpropyl)-1,2,4-oxadiazole (trifluoroacetate) [ka]

[0259] To a solution of tert-butyl 3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl]phenyl]azetidine-1-carboxylate (300.0 mg, 0.810 mmol) in DCM (3 mL) was added TFA (0.6 mL, 7.79 mmol) and the mixture was stirred at 20° C. for 12 h. The mixture was evaporated to give the desired crude product as a pale yellow oil (300 mg, 0.780 mmol, 96.4%). MS (ESI): m / z=272.6 [M+H] + . Example 38 (4aR,8aS)-6-[3-[4-[5-(2,2-dimethylpropyl)-1,3,4-oxadiazol-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0260] To a solution of 2-[4-(azetidin-3-yl)phenyl]-5-(2,2-dimethylpropyl)-1,3,4-oxadiazole, trifluoroacetate (100.0 mg, 0.260 mmol) in ACN (2.5 mL) was added DIPEA (200.8 mg, 1.56 mmol) and (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (100.04 mg, 0.310 mmol, BB2a) and the reaction was stirred for 12 h at 80° C. The reaction mixture was evaporated and the residue was purified by preparative HPLC (0.225% v / v water and FA in ACN) to give the desired product as a pale yellow solid (48.3 mg, 0.110 mmol, 40.6%). MS(ESI): m / z=454.3[M+H] + . Step a) 4-Bromo-N'-(3,3-dimethylbutanoyl)benzoic acid hydrazide [ka]

[0261] To a solution of 4-bromobenzoic acid hydrazide (5.0 g, 23.25 mmol, CAS RN 5933-32-4) and DIPEA (12.4 mL, 69.75 mmol, CAS RN 7087-68-5) in DCM (50 mL) was added 3,3-dimethylbutyryl chloride (3.76 g, 27.9 mmol, CAS RN 122-94-1) at 0 °C and the mixture was warmed to 20 °C. After stirring for 12 h, the mixture was diluted with water, extracted three times with EtOAc (200 mL each), and the combined organic layers were washed three times with water (100 mL each). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the desired product as a pale yellow solid (7 g, 22.4 mmol, 96.1%). MS (ESI): m / z = 315.4 [M + H] + . Step b) 2-(4-bromophenyl)-5-(2,2-dimethylpropyl)-1,3,4-oxadiazole [ka]

[0262] To a solution of 4-bromo-N'-(3,3-dimethylbutanoyl)benzoic acid hydrazide (5000.0 mg, 16.0 mmol) in toluene (102 mL) was added TsOH (5498.3 mg, 31.9 mmol) and the mixture was stirred at 110°C for 12 h. The mixture was concentrated and the residue was purified by silica gel chromatography eluting with PE:EtOAc (10:1) to give the desired product as a pale yellow solid (1000 mg, 3.4 mmol, 21.2%). MS (ESI): m / z = 295.4 [M+H] + . Step c) tert-Butyl 3-[4-[5-(2,2-dimethylpropyl)-1,3,4-oxadiazol-2-yl]phenyl]azetidine-1-carboxylate [ka]

[0263] The title compound was prepared from 2-(4-bromophenyl)-5-(2,2-dimethylpropyl)-1,3,4-oxadiazole and tert-butyl 3-bromoazetidine-1-carboxylate in analogy to step b) of Example 35. Light brown oil. MS (ESI): m / z=372.5 [M+H] + . Step d) 2-[4-(azetidin-3-yl)phenyl]-5-(2,2-dimethylpropyl)-1,3,4-oxadiazole (trifluoroacetate) [ka]

[0264] To a solution of tert-butyl 3-[4-[5-(2,2-dimethylpropyl)-1,3,4-oxadiazol-2-yl]phenyl]azetidine-1-carboxylate (200.0 mg, 0.540 mmol) in DCM (2 mL) was added TFA (0.4 mL) and the mixture was stirred at 20° C. for 12 h. The mixture was evaporated to give the desired crude product as a light brown oil (201 mg, 0.520 mmol, 96.9%). MS (ESI): m / z=272.6 [M+H] + . Example 39 (4aR,8aS)-6-[3-[4-[2-(2-fluoroethyl)pyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0265] To a solution of 5-[4-(azetidin-3-yl)phenyl]-1-(2-fluoroethyl)pyrazole (110 mg, 0.380 mmol) and (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (124 mg, 0.390 mmol, BB2a) in MeCN (6 mL) was added N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) with stirring at 60° C. The solution was stirred at 60° C. for 16 h. The solution was concentrated in vacuo to give a residue which was purified by HPLC (TFA conditions) to give (4aR,8aS)-6-[3-[4-[2-(2-fluoroethyl)pyrazol-3-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (80 mg, 45%) as a white solid. MS(ESI): m / z=428.4 [M+H] + . Step a) 5-(4-bromophenyl)-1-(2-fluoroethyl)pyrazole [ka]

[0266] To a stirred solution of 2-fluoroethylhydrazine (330 mg, 4.23 mmol, CAS RN 126889-84-7) in DMF (20 mL) at 20° C. was added (E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one (752 mg, 2.96 mmol, CAS RN 849619-11-0). The mixture was stirred at 25° C. for 1 h and then at 70° C. for 5 h. The solution was concentrated under vacuum to give a residue which was purified by flash column chromatography (petroleum ether: EtOAc 3:1) to give 5-(4-bromophenyl)-1-(2-fluoroethyl)pyrazole (450 mg, 39%) as a white solid. MS (ESI): m / z=269.0 / 271.0 [M+H] + Step b) tert-Butyl 3-[4-[2-(2-fluoroethyl)pyrazol-3-yl]phenyl]azetidine-1-carboxylate [ka]

[0267] tert-Butyl 3-bromoazetidine-1-carboxylate (395 mg, 1.67 mmol, CAS RN 1064194-10-0), 5-(4-bromophenyl)-1-(2-fluoroethyl)pyrazole (450 mg, 1.67 mmol), [Ir{dF(CF3)ppy}2(dtbpy)]PF6 (19 mg, 0.020 mmol, CAS RN 870987-63-6), dichloronickel 1,2-dimethoxyethane (2.0 mg, 0.010 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (3.0 mg, 0.010 mmol), (mmol), bis(trimethylsilyl)silyltrimethylsilane (416 mg, 1.67 mmol) and sodium carbonate (355 mg, 3.35 mmol) were mixed in DME (15 mL). The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (distance 7 cm) and the reaction temperature was maintained at 25 °C for 14 h using a cooling fan. The solution was poured into brine (30 mL) and extracted with EtOAc (20 mL). The organic layer was concentrated under vacuum to give a residue, which was purified by preparative TLC (petroleum ether: EtOAc 1:1) to give tert-butyl 3-[4-[2-(2-fluoroethyl)pyrazol-3-yl]phenyl]azetidine-1-carboxylate (450 mg, 69%) as a pale yellow oil MS (ESI): m / z = 346.1 [M + H] + . Step c) 5-[4-(azetidin-3-yl)phenyl]-1-(2-fluoroethyl)pyrazole [ka]

[0268] A solution of tert-butyl 3-[4-[2-(2-fluoroethyl)pyrazol-3-yl]phenyl]azetidine-1-carboxylate (160 mg, 0.410 mmol) in HCl in MeOH (4.0 mL, 16 mmol) was stirred at 25° C. for 4 h. The solution was concentrated in vacuo to give 5-[4-(azetidin-3-yl)phenyl]-1-(2-fluoroethyl)pyrazole (110 mg, 92%) as a pale yellow oil, which was used in the next step without further purification. MS (ESI): m / z=246.1 [M+H] + . Example 40 (4aR,8aS)-6-[3-[4-[1-(2-fluoroethyl)pyrazol-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0269] 1-(2-Fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (58 mg, 0.24 mmol, CAS RN A mixture of 1049730-39-3), (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (BB4 step c, 80 mg, 0.20 mmol), K2CO3 (2.0 mg, 0.02 mmol), Cs2CO3 (198 mg, 0.610 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol) in DMSO (4 mL) and HO (0.5 mL) was stirred at 80 °C under nitrogen atmosphere for 16 h. The mixture was filtered and then purified by preparative HPLC (basic conditions) to give the title compound as a grey solid (41 mg, 44%). LC-MS: 428.2 [M+H] + . Example 41 (4aR,8aS)-6-[3-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0270] The title compound was prepared from 4-nitrophenyl (4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate and 2-(4-(azetidin-3-yl)phenyl)-4-methylthiazole 4-methylbenzenesulfonate in a similar manner to the intermediate in Example 31. Colorless foam (37%). MS (ESI): m / z=413.3 [M+H] + . Step a) tert-Butyl 3-[4-(4-methylpyrazol-2-yl)phenyl]azetidine-1-carboxylate [ka]

[0271] The title compound was prepared from 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazole (Maybridge) and tert-butyl 3-iodoazetidine-1-carboxylate (CAS RN 254454-54-1) analogously to BB4, step a). The colorless oil was used in the next step without further purification. MS (ESI): m / z=331.2 [M+H] + . Step b) 2-[4-(azetidin-3-yl)phenyl]-4-methyl-thiazole; 4-methylbenzenesulfonic acid [ka]

[0272] A suspension of tert-butyl 3-(4-(4-methylthiazol-2-yl)phenyl)azetidine-1-carboxylate (28 mg, 84.7 μmol) and 4-methylbenzenesulfonic acid hydrate (19.3 mg, 102 μmol) in EtOAc (0.3 mL) was refluxed with stirring for 2 h. The mixture was completely evaporated to give the desired compound, which was used in the next step without further purification. MS (ESI): m / z=231.1 [M+H] + . Example 42 (4aR,8aS)-6-[3-[4-(1-methylpyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0273] (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (16 mg, 40.6 μmol, BB4, step c) and (1-methyl-1H-pyrazol-3-yl)boronic acid (5.11 mg, 40.6 μmol, CAS RN 869973-96-6) and tetrakis(triphenylphosphine)palladium(0) (2.34 mg, 2.03 μmol) were dissolved in THF (600 μL) and water (60 μl) and the reaction was stirred at 80° C. overnight. The reaction mixture was extracted with EtOAc and HO and the organic layer was dried over NaSO and evaporated. The crude product was purified by preparative HPLC to give the compound as a white solid. MS(ESI): m / z=396.2 [M+H] + . Example 43 (4aR,8aS)-6-[3-[4-(6-fluoropyridin-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0274] The title compound was prepared from (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (BB4, step c) and 2-fluoropyridine-5-boronic acid (CAS RN:351019-18-6) in analogy to Example 42. White solid. MS(ESI): m / z=411.2 [M+H] + . Example 44 (4aR,8aS)-6-[3-[4-(2-fluoropyridin-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0275] The title compound was prepared from (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (BB4, step c) and (2-fluoropyridin-4-yl)boronic acid (CAS RN: 401815-98-3) in analogy to Example 42. Yellow powder (84%). MS (ESI): m / z=411.2 [M+H] + . Example 45 (4aR,8aS)-6-[3-[4-(1-methylpyrazol-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0276] The title compound was prepared from (4aR,8aS)-6-(3-(4-bromophenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (BB4, step c) and 1-methyl-1H-pyrazole-4-boronic acid (CAS RN:763120-58-7) in analogy to Example 42. Light yellow powder (57%). MS (ESI): m / z=396.2 [M+H] + . Example 46 (4aR,8aS)-6-[3-[4-(2-methylpyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0277] The title compound was prepared from 4-nitrophenyl (4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate and 5-(4-(azetidin-3-yl)phenyl)-1-methyl-1H-pyrazole 4-methylbenzenesulfonate in a similar manner to the intermediate in Example 31. Colorless solid (25%). MS (ESI): m / z=396.2 [M+H] + . Step a) tert-Butyl 3-[4-(2-methylpyrazol-3-yl)phenyl]azetidine-1-carboxylate [ka]

[0278] The title compound was prepared from tert-butyl 3-iodoazetidine-1-carboxylate (CAS RN 254454-54-1) and (4-(1-methyl-1H-pyrazol-5-yl)phenyl)boronic acid (ChemBridge Corp.) in analogy to step a of Example BB4. The colorless oil was used in the next step without further purification. MS (ESI): m / z=314.3 [M+H]+ . Step b) 5-[4-(azetidin-3-yl)phenyl]-1-methyl-thiazole; 4-methylbenzenesulfonic acid The title compound was prepared from tert-butyl 3-[4-(2-methylpyrazol-3-yl)phenyl]azetidine-1-carboxylate in analogy to step b of Example 41. Light brown gum. MS (ESI): m / z=214.1 [M+H] + . Example 47 (4aR,8aS)-6-[3-[5-(4-fluorophenoxy)-2-pyridyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0279] To a solution of 2-(azetidin-3-yl)-5-(4-fluorophenoxy)pyridine (50 mg, 0.17 mmol) and DIPEA (0.17 mL, 1.04 mmol) in ACN (2 mL) was added (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (67 mg, 0.21 mmol, BB2a) at 25° C. The mixture was stirred at 90° C. for 12 h, concentrated under reduced pressure, purified by preparative HPLC (0.225% TFA), and lyophilized to give the title compound (22.1 mg, 0.050 mmol, 28.5% yield) as a pale yellow solid. MS (ESI): m / z=427.2 [M+H] + . Step a) tert-Butyl 3-[5-(4-fluorophenoxy)-2-pyridyl]-3-hydroxy-azetidine-1-carboxylate

[0280] 2-Bromo-5-(4-fluorophenoxy)pyridine (350 mg, 1.31 mmol, CAS RN1643917-85-4) was dissolved in toluene (15 mL) and cooled to -78 °C. nBuLi (0.57 mL, 1.44 mmol) in hexanes was added dropwise and the mixture was stirred at -78 °C under N2 atmosphere for 30 min. 1-Boc-3-azetidinone (246 mg, 1.44 mmol, CAS RN 398489-26-4) in toluene (2 mL) was added. The reaction mixture was stirred at 0 °C for 4 h, quenched with saturated NH4Cl (20 mL) and extracted with EtOAC (2x15 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by reverse-phase flash chromatography to give the title compound (171 mg, 0.470 mmol, 36.3% yield) as a white solid. MS (ESI): m / z=361.2 [M+H] + . Step b) tert-Butyl 3-chloro-3-[5-(4-fluorophenoxy)-2-pyridyl]azetidine-1-carboxylate

[0281] To a solution of tert-butyl 3-[5-(4-fluorophenoxy)-2-pyridyl]-3-hydroxy-azetidine-1-carboxylate (500 mg, 1.39 mmol) in DCM (15 mL) was added thionyl chloride (990 mg, 8.32 mmol) at 0° C. The mixture was stirred at 20° C. for 12 h, poured into saturated Na2CO3 solution (15 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo and purified by reverse phase flash chromatography (0.05% TFA) to give the title compound (230 mg, 0.610 mmol, 43.8% yield) as a pale yellow oil. MS (ESI): m / z=322.8[M-C4H8+H] + . Step c) 2-(azetidin-3-yl)-5-(4-fluorophenoxy)pyridine

[0282] To a solution of tert-butyl 3-chloro-3-[5-(4-fluorophenoxy)-2-pyridyl]azetidine-1-carboxylate (200 mg, 0.530 mmol) and formic acid (121 mg, 2.64 mmol) in methanol (12 mL) was added wet Pd / C (100 mg, 0.530 mmol). The resulting mixture was stirred at 50° C. for 12 h and filtered. The filtrate was concentrated in vacuo to give a yellow residue which was purified by reverse phase flash chromatography (0.05% TFA) to give the title compound (50 mg, 0.200 mmol, 38.8% yield) as a colorless oil and tert-butyl 3-[5-(4-fluorophenoxy)-2-pyridyl]azetidine-1-carboxylate (54 mg, 0.160 mmol, 29.7% yield) as a light brown oil. MS(ESI): m / z=245.2 [M+H] + . Example 48 (4aR,8aS)-6-(3-(6-(4-fluorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0283] A solution of (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one(2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (54.3 mg, 100 μmol) and di(1H-1,2,4-triazol-1-yl)methanone (16 mg, 100 μmol) in ACN (2 mL) and TEA (73 mg, 100 μL, 717 μmol) was shaken at room temperature for 90 min. 5-(azetidin-3-yl)-2-(4-fluorophenoxy)pyridine 4-methylbenzenesulfonate (42 mg, 0.1 mmol) was added and the mixture was shaken at room temperature for 30 min, followed by 60 °C for 90 min. The clear solution was filtered through a Hypersep Amino SPE Column (1g, part number: 60108-432). The column was washed with ACN (total 6mL), the solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound (15mg, 35.4μmol, 35.4% yield) as a colorless waxy solid. MS(ESI): m / z=427.2 [M+H] + . Step a) tert-Butyl 3-(6-phenoxypyridin-3-yl)azetidine-1-carboxylate

[0284] DME (6 mL) was added to a mixture of 5-bromo-2-(4-fluorophenoxy)pyridine (686 mg, 2.56 mmol, CAS RN 936343-65-6), tert-butyl 3-bromoazetidine-1-carboxylate (604 mg, 2.56 mmol, CAS RN 1064194-10-0), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (29 mg, 25.6 μmol, CAS RN 870987-63-6), tris(trimethylsilyl)silane (636 mg, 789 μL, 2.56 mmol) and anhydrous sodium carbonate (407 mg, 3.84 mmol). The mixture was stirred for 5 min while bubbling argon through the suspension. The reaction vessel was sealed. A separate vial was charged with nickel(II) chloride ethylene glycol dimethyl ether complex (2.8 mg, 12.8 μmol, CAS RN 29046-78-4) and 4,4'-di-tert-butyl-2,2'-bipyridine (3.4 mg, 12.8 μmol). DME (616 μL) was added. The vial was sealed, purged with argon, sonicated for 5 min, and then poured into a reaction vessel. The reaction mixture was stirred and irradiated with a 420 nm lamp under an argon atmosphere for 3 h. The solids were filtered off, washed with ethyl acetate, and the filtrate was evaporated. The crude product was absorbed on isolated HM-N, dried, and purified by flash chromatography to give the title compound (296 mg, 774 μmol, 30.2% yield) as a pale yellow waxy solid. MS (ESI): m / z=361.2 [M+H] + . Step b) 5-(azetidin-3-yl)-2-(4-fluorophenoxy)pyridine 4-methylbenzenesulfonate

[0285] To a solution of tert-butyl 3-(6-phenoxypyridin-3-yl)azetidine-1-carboxylate (296 mg, 907 μmol) in ethyl acetate (7 mL) was added 4-methylbenzenesulfonic acid hydrate (77 mg, 407 μmol). The mixture was heated under reflux for 18 h, cooled to room temperature, diluted with 3 mL of diethyl ether, stirred for 1 h, and filtered. The solid was washed with ether (3×1 mL) and dried under vacuum to give the title compound (285 mg, 684 μmol, 75.4% yield) as white crystals. MS (ESI): m / z=245.1 [M+H] + . Example 49 (4aR,8aS)-6-(3-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0286] In a similar manner to the procedure described in Example 48, (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate was reacted with 5-(azetidin-3-yl)-2-(4-(trifluoromethoxy)phenoxy)pyridine 4-methylbenzenesulfonate to give the title compound as a white foam. MS(ESI): m / z=493.2 [M+H] + . Step a) tert-Butyl 3-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)azetidine-1-carboxylate In a similar manner to the procedure described in Example 48a, 5-bromo-2-(4-(trifluoromethoxy)phenoxy)pyridine (CAS RN 909849-01-0) was reacted with tert-butyl 3-bromoazetidine-1-carboxylate to give the title compound as a pale yellow waxy solid. MS (ESI): m / z=411.2 [M+H] + . Step b) 5-(azetidin-3-yl)-2-(4-(trifluoromethoxy)phenoxy)pyridine 4-methylbenzenesulfonate In a similar manner to the procedure described in Example 48b, tert-butyl 3-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)azetidine-1-carboxylate was reacted with 4-methylbenzenesulfonic acid hydrate to give the title compound as white crystals. MS (ESI): m / z=311.1 [M+H] + . Example 50 (4aR,8aS)-6-(3-(6-(4-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0287] In a similar manner to the procedure described in Example 48, (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate was reacted with 5-(azetidin-3-yl)-2-(4-chlorophenoxy)pyridine 4-methylbenzenesulfonate to give the title compound as a white foam. MS(ESI): m / z=443.2 [M+H] + . Step a) tert-Butyl 3-(6-(4-chlorophenoxy)pyridin-3-yl)azetidine-1-carboxylate In a similar manner to the procedure described in Example 48a, 5-bromo-2-(4-chlorophenoxy)pyridine (CAS RN 28231-69-8) was reacted with tert-butyl 3-bromoazetidine-1-carboxylate to give the title compound as an off-white solid. MS (ESI): m / z=361.2 [M+H] + . Step b) 5-(azetidin-3-yl)-2-(4-chlorophenoxy)pyridine 4-methylbenzenesulfonate In a similar manner to the procedure described in Example 48b, tert-butyl 3-(6-(4-chlorophenoxy)pyridin-3-yl)azetidine-1-carboxylate was reacted with 4-methylbenzenesulfonic acid hydrate to give the title compound as white crystals. MS (ESI): m / z=261.1 [M+H] + . Example 51 (4aR,8aS)-6-[3-[4-(3,6-dimethylpyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0288] A mixture of (4aR,8aS)-6-(3-(4-hydroxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (50 mg, 151 μmol, BB3), 4-chloro-3,6-dimethylpyridazine (23.7 mg, 166 μmol, CAS RN 68206-05-3) and K2CO3 (41.7 mg, 302 μmol) in DMSO (0.5 mL) was stirred at ambient temperature in a sealed tube for 14 h and purified by reverse phase flash chromatography to give the title compound (20 mg, 30%) as an off-white solid. MS (ESI): m / z=438.3 [M+H] + . Example 52 (4aR,8aS)-6-(3-(6-(2-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0289] In a similar manner to the procedure described in Example 48, (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate was reacted with 5-(azetidin-3-yl)-2-(2-chlorophenoxy)pyridine 4-methylbenzenesulfonate to give the title compound as an off-white solid. MS (ESI): m / z=443.3 [M+H] + . Step a) tert-Butyl 3-(6-(2-chlorophenoxy)pyridin-3-yl)azetidine-1-carboxylate In a similar manner to the procedure described in Example 48a, 5-bromo-2-(2-chlorophenoxy)pyridine (CAS RN 1240670-82-9) was reacted with tert-butyl 3-bromoazetidine-1-carboxylate to give the title compound as a yellow oil. MS (ESI): m / z=361.2 [M+H] + . Step b) 5-(azetidin-3-yl)-2-(2-chlorophenoxy)pyridine 4-methylbenzenesulfonate In a similar manner to the procedure described in Example 48b, tert-butyl 3-(6-(2-chlorophenoxy)pyridin-3-yl)azetidine-1-carboxylate was reacted with 4-methylbenzenesulfonic acid hydrate to give the title compound as white crystals. MS (ESI): m / z=261.1 [M+H] + . Example 53 (4aR,8aS)-6-(3-(6-(3-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0290] In a similar manner to the procedure described in Example 48, (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate was reacted with 5-(azetidin-3-yl)-2-(3-chlorophenoxy)pyridine 4-methylbenzenesulfonate to give the title compound as an off-white solid. MS (ESI): m / z=443.3 [M+H] + . Step a) tert-Butyl 3-(6-(3-chlorophenoxy)pyridin-3-yl)azetidine-1-carboxylate In a similar manner to the procedure described in Example 48a, 5-bromo-2-(3-chlorophenoxy)pyridine (CAS RN 1240670-82-9) was reacted with tert-butyl 3-bromoazetidine-1-carboxylate to give the title compound as an off-white solid. MS (ESI): m / z=361.2 [M+H] + . Step b) 5-(azetidin-3-yl)-2-(3-chlorophenoxy)pyridine 4-methylbenzenesulfonate In a similar manner to the procedure described in Example 48b, tert-butyl 3-(6-(3-chlorophenoxy)pyridin-3-yl)azetidine-1-carboxylate was reacted with 4-methylbenzenesulfonic acid hydrate to give the title compound as white crystals. MS (ESI): m / z=261.2 [M+H] + . Example 54 (4aR,8aS)-6-[4-[4-(4-fluorophenoxy)phenyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0291] A mixture of (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (90.1 mg, 0.280 mmol, BB2a), DIPEA (362.1 mg, 2.8 mmol) and 4-[4-(4-fluorophenoxy)phenyl]piperidine;2,2,2-trifluoroacetic acid (50 mg, 0.130 mmol, TFA salt of CAS RN 224449-70-1) in ACN (1 mL) was stirred at 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (0.225% TFA) and lyophilized to give the title compound (19.6 mg, 0.040 mmol, 32.5% yield) as a yellow solid. MS(ESI): m / z=454.4 [M+H] + . Example 55 (4aR,8aS)-6-[3-hydroxy-3-(4-phenoxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0292] In a similar manner to the procedure described in Example 47, (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate was reacted with 3-(4-phenoxyphenyl)azetidin-3-ol;2,2,2-trifluoroacetic acid (TFA salt of CAS RN 2229540-84-3) to give the title compound as a white solid. MS (ESI): m / z=424.1 [M+H] + . Example 56 (4aR,8aS)-6-[3-hydroxy-3-(5-phenoxy-2-pyridyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0293] In a similar manner to the procedure described in Example 47, (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate was reacted with 3-(5-phenoxy-2-pyridyl)azetidin-3-ol;2,2,2-trifluoroacetic acid (TFA salt of CAS RN 2355937-31-2) to give the title compound as a pale yellow solid. MS (ESI): m / z=425.3 [M+H] + . Example 57 (4aR,8aS)-6-[4-(4-phenoxyphenyl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0294] In a similar manner to the procedure described in Example 47, (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate was reacted with 4-(4-phenoxyphenyl)piperidine;2,2,2-trifluoroacetic acid (CAS RN 1247029-36-2) to give the title compound as a white solid. MS (ESI): m / z=436.1 [M+H] + . Example 58 (4aR,8aS)-6-[4-(4-phenoxyphenyl)piperazine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0295] In a similar manner to the procedure described in Example 47, (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate was reacted with 1-(4-phenoxyphenyl)piperazine; 2,2,2-trifluoroacetic acid (TFA salt of CAS RN 62755-61-7) was added to give the title compound as a pale red solid. MS (ESI): m / z=437.3 [M+H] + . Synthesis of building blocks BB1a and BB1b (+)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one And (-)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one [ka]

[0296] The enantiomers of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (BB1, 500 mg, 2.18 mmol, ChemBridge Corporation) were separated by preparative chiral HPLC (ReprosilChiral NR column) using an isocratic mixture of EtOH (containing 0.05% NHOAc):n-heptane (30:70). First eluting enantiomer: (+)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (BB1a). Yellow solid (0.150 g; 44.0%). MS (ESI): m / z=157.1 [M+H] + . Second eluting enantiomer: (-)-cis-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one. (BB1b). Yellow solid (0.152 g; 44.6%). MS(ESI): m / z=157.1 [M+H]+ . BB2a and BB2b 4-Nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB2a) And 4-Nitrophenyl(4aS,8aR)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB2b) [ka]

[0297] To a suspension of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; dihydrochloride (4.5 g, 19.6 mmol, BB1) in dry DCM (125 mL) at 0° C., DIPEA (6.35 g, 8.58 mL, 49.1 mmol) was added, followed by 4-nitrophenyl chloroformate (4.35 g, 21.6 mmol). The reaction mixture was stirred at 0° C. for 10 min and at room temperature for 2 h. The crude reaction was diluted with DCM and transferred into a separatory funnel for extraction with saturated aqueous Na2CO3. The organic phase was collected and the aqueous phase was back-extracted with DCM. The combined organic phase was dried over Na2SO4 and evaporated to dryness to give 6.62 g of crude racemic product (BB7) as a yellow solid. The crude material was subjected directly to chiral SFC separation to give enantiomer BB2b (2.72 g, second eluting enantiomer) as a yellow solid and enantiomer BB2a (3.25 g, first eluting enantiomer) as a light beige solid, but contaminated with BB2b. Further SFC chiral separation gave 2.71 g of BB2a. For both enantiomers, MS (ESI): m / z=322.2 [M+H] + . BB3 (4aR,8aS)-6-[3-(4-hydroxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0298] To a solution of (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (BB2a, 1.22 g, 3.8 mmol) and 4-(azetidin-3-yl)phenol trifluoroacetate (1 g, 3.8 mmol) in ACN (10 mL) was added DIPEA (4.91 g, 37.99 mmol) and the reaction mixture was heated to 80° C. for 12 h. The solution was evaporated to dryness and the residue was dissolved in ACN (20 mL). The resulting solid precipitate was filtered, washed with ACN and further dried to give the title compound (0.65 g, 51.6%) as an off-white solid. MS (ESI): m / z=332.1 [M+H] + . Step a) tert-Butyl 3-(4-hydroxyphenyl)azetidine-1-carboxylate [ka]

[0299] 4-Bromophenol (3.6 g, 21.18 mmol, CAS RN 106-41-2), tert-butyl 3-bromoazetidine-1-carboxylate (5 g, 21.18 mmol, CAS RN 1064194-10-0), Ir[dF(CF3)ppy] 2(To a solution of dtbbpy)PF6 (0.237 g, 0.210 mmol), NiCl2-glyme (0.023 g, 0.110 mmol), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.034 g, 0.130 mmol), bis(trimethylsilyl)silyl-trimethyl-silane (5.26 g, 21.18 mmol) and Na2CO3 (4.49 g, 42.35 mmol) in DME (100 mL). The reaction mixture was stirred and irradiated with a 34 W blue LED lamp (distance 7 cm) and the reaction temperature was maintained at 25 °C for 14 h using a cooling fan. The reaction was filtered and the filtrate was evaporated and purified by preparative HPLC to give the title compound (1.8 g, 34%) as a pale yellow solid. MS (ESI): m / z = 194.0 [M + H-56] + . Step b) 4-(azetidin-3-yl)phenol; trifluoroacetate [ka]

[0300] To a solution of tert-butyl 3-(4-hydroxyphenyl)azetidine-1-carboxylate (1 g, 4.01 mmol) in DCM (30 mL) was added TFA (5.0 mL) and the reaction mixture was stirred at room temperature for 12 h. The mixture was evaporated in vacuo to give the crude title compound (1 g, 94.7% yield) as a yellow oil. MS (ESI): m / z=150.1 [M+H] + . BB4 [4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]phenyl]boronic acid [ka]

[0301] To a solution of (4aR,8aS)-6-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (0.2 g, 0.453 mmol) in HO (1.2 mL) and acetone (2.4 mL) were added NaIO (0.29 g, 1.36 mmol) and NHOAc (0.21 g, 2.72 mmol) at room temperature. The reaction mixture was then stirred at 30 °C for 16 h. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layers were dried over NaSO, filtered and concentrated in vacuo to give the crude title compound (0.176 g) as a white solid. MS(ESI): m / z=360.2 [M+H] + . Step a) tert-Butyl 3-(4-bromophenyl)azetidine-1-carboxylate [ka]

[0302] To a solution of tert-butyl 3-iodoazetidine-1-carboxylate (3.0 g, 10.6 mmol, CAS RN 254454-54-1) in 2-propanol (30 mL) was added a solution of 4-bromophenylboronic acid (4.26 g, 21.19 mmol, CAS RN 5467-74-3) in 2-propanol (15 mL) at room temperature. Then rac-(1R,2R)-2-aminocyclohexan-1-ol (73.18 mg, 0.640 mmol), a 1M solution of sodium bis(trimethylsilyl)amide in THF (21.19 mL, 21.19 mmol) and nickel(II) iodide (198.69 mg, 0.640 mmol) were added to the mixture, which was stirred at room temperature for 30 minutes. The mixture was transferred to 10 sealed tubes and heated at 80° C. under microwave irradiation for 30 minutes. The mixture was combined, diluted with water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by MPLC to give the title compound (2.8 g, 84.6%) as a yellow oil. MS (ESI): m / z=256.0 [M+H-56] + . Step b) 3-(4-bromophenyl)azetidine; trifluoroacetate [ka]

[0303] To a solution of tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate (2.7 g, 8.65 mmol) in DCM (50 mL) was added TFA (8.0 mL) and the reaction mixture was stirred at room temperature for 12 h. The mixture was evaporated to dryness to give the crude title compound (2.8 g, 99.3%) as a yellow oil. MS (ESI): m / z = 214.0 [M + H] + . Step c) (4aR,8aS)-6-[3-(4-bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0304] To a solution of (4-nitrophenyl)(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carboxylate (BB2a, 2.36 g, 7.36 mmol) and 3-(4-bromophenyl)azetidine trifluoroacetate salt (2 g, 6.13 mmol) in ACN (20 mL) was added DIPEA (7.92 g, 61.33 mmol) and the reaction mixture was heated to 80° C. for 12 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC to give the title compound (1.1 g, 45.5%) as a yellow gum. MS (ESI): m / z=396.1 [M+2+H] + . Step d) (4aR,8aS)-6-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0305] In a sealed tube, bis(pinacolato)diboron (0.97 g, 3.8 mmol), KOAc (0.747 g, 7.61 mmol) and (4aR,8aS)-6-[3-(4-bromophenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (1 g, 2.54 mmol) were mixed in dioxane (20 mL). PdCl2(dppf).CH2Cl2 (0.207 g, 0.250 mmol) was then added and the reaction mixture was purged with N2 and heated to 90 °C for 12 h. The mixture was filtered, the filtrate was evaporated and the residue was purified by preparative HPLC to give the title compound (0.65 g, 58%) as a light brown solid as a 3 / 2 mixture of boronic acid / boronic ester. MS(ESI): m / z=442.1 [M+H]+ . Example 59

[0306] The compounds of formula (I) can be used in a manner known per se as active ingredient to prepare tablets of the following composition: Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg Example 60 The compounds of formula (I) can be used, in a manner known per se, as active ingredient to prepare capsules of the following composition: Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, A is C ６ -C １４ - selected from aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl; B is, (i) C ６ -C １４ -aryl, and L １ is -O-, or (ii) 5-14 membered heteroaryl, L １ is a covalent bond or -O-, m is 0, n is 0 or 1, and X is CR ８ or m is 1, n is 1 or 2, and X is CR ８ or N, R １ , R ２ and R ３ is hydrogen and C １－６ independently selected from alkyl, R ４ , R ５ , R ６ , and R ７ are independently hydrogen, halogen, cyano, hydroxy, C １－６ -Alkoxy, halo-C １－６ -Alkoxy, amino-C １－６ -Alkoxy, C １－６ -Alkyl, halo-C １－６ -Alkyl, hydroxy-C １－６ -Alkyl, C １－６ -Alkylsulfonyl, SF ５ , Carbamoyl, C ３－１０ -Cycloalkyl-C １－６ -alkoxy-, C １－６ -Alkyl-NH-C(O)-, C １－６ -alkyl-C(O)-NH-, and C ３－１０ -cycloalkyl, where each C ３－１０ Cycloalkyl is C １－６ -alkyl, and halo-C １－６ -alkyl; and R ８ is hydrogen, halogen, hydroxy, halo-C １－６ -Alkyl, and C １－６ -alkyl).

2. A is C ６ -C １４ 2. The compound of formula (I) according to claim 1, wherein -aryl or 5-14 membered heteroaryl, or a pharma- ceutically acceptable salt thereof.

3. 2. The compound of formula (I) according to claim 1, wherein A is phenyl or pyridyl, or a pharma- ceutically acceptable salt thereof.

4. In the formula, B is (i) is phenyl, and L １ is —O—, or (ii) is selected from oxadiazolyl, pyridazinyl, pyridyl, and thiazolyl; L １ is a covalent bond or -O-; A compound of formula (I) according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

5. During the ceremony, m is 0, n is 0, and X is CR ８ or m is 1, n is 1, and X is CR ８ or N, A compound of formula (I) according to any one of claims 1 to 4.

6. m is 0, n is 0, and X is CR ８ A compound of formula (I) according to any one of claims 1 to 4,

7. R １ A compound of formula (I) according to any one of claims 1 to 6, wherein is hydrogen.

8. R ２ A compound of formula (I) according to any one of claims 1 to 7, wherein is hydrogen.

9. R ３ A compound of formula (I) according to any one of claims 1 to 8, wherein is hydrogen.

10. R ４ A compound of formula (I) according to any one of claims 1 to 9, wherein is hydrogen.

11. R ５ A compound of formula (I) according to any one of claims 1 to 10, wherein is hydrogen.

12. R ６ is hydrogen, halogen, cyano, C １－６ -Alkyl, C １－６ -Alkoxy, halo-C １－６ -Alkyl, C ３－１０ -cycloalkyl, and C １－６ 12. The compound of formula (I) according to any one of claims 1 to 11, selected from - alkylsulfonyl.

13. R ６ is hydrogen, halogen, cyano and C １－６ 12. The compound of formula (I) according to any one of claims 1 to 11, wherein: - alkyl is selected from:

14. R ６ A compound of formula (I) according to any one of claims 1 to 11, wherein is selected from hydrogen, fluoro, chloro, cyano, methyl and 2,2-dimethylpropyl.

15. R ７ is hydrogen, halogen, and C １－６ 15. The compound of formula (I) according to any one of claims 1 to 14, wherein: - alkyl is selected from:

16. R ７ A compound of formula (I) according to any one of claims 1 to 14, wherein is selected from hydrogen, fluoro and methyl.

17. R ８ A compound of formula (I) according to any one of claims 1 to 16, wherein is hydrogen or hydroxy.

18. The compound of formula (I) is represented by formula (IIa) 【Chemistry 2】 (In the formula, A is C ６ -C １４ -aryl or 5-14 membered heteroaryl, B is, (i) C ６ -C １４ -aryl, and L １ is -O-, or (ii) 5-14 membered heteroaryl, L １ is a covalent bond or -O-, m is 0, n is 0, and X is CR ８ or m is 1, n is 1, and X is CR ８ or N, R ６ is hydrogen, halogen, cyano, C １－６ -Alkyl, C １－６ -Alkoxy, halo-C １－６ -Alkyl, C ３－１０ -cycloalkyl, and C １－６ - alkylsulfonyl, R ７ is hydrogen, halogen, and C １－６ - alkyl, and R ８ is selected from hydrogen and hydroxy, or a pharma- ceutically acceptable salt thereof.

19. The compound of formula (I) is represented by formula (IIb) 【Chemistry 3】 (In the formula, A is C ６ -C １４ -aryl or 5-14 membered heteroaryl, B is, (i) C ６ -C １４ -aryl, and L １ is -O-, or (ii) 5-14 membered heteroaryl, L １ is a covalent bond or -O-, R ６ is hydrogen, halogen, cyano, and C １－６ - alkyl, R ７ is hydrogen, C １－６ - alkyl, and halogen; R ８ is selected from hydrogen and hydroxy, or a pharma- ceutically acceptable salt thereof.

20. The compound of formula (I) is represented by formula (IIb) 【Chemistry 4】 (In the formula, A is phenyl or pyridyl; B is, (i) is phenyl, and L １ is -O-, or (ii) is selected from oxadiazolyl, pyridazinyl, pyridyl, and thiazolyl; L １ is a covalent bond or -O-, R ６ is selected from hydrogen, fluoro, chloro, cyano, methyl and 2,2-dimethylpropyl; R ７ is selected from hydrogen, methyl and fluoro; R ８ is selected from hydrogen and hydroxy, or a pharma- ceutically acceptable salt thereof.

21. below: (4aR,8aS)-6-(3-(4-phenoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(2-chlorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-pyrimidin-2-yloxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(2-methyl-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methylpyrimidin-2-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-pyridazin-3-yloxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (4aR,8aS)-6-[3-[4-[(4-methyl-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(5-fluoro-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(5-chloro-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-pyridyloxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methylpyridazin-3-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-chloropyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methoxypyrimidin-2-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[4-(trifluoromethyl)pyrimidin-2-yl]oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-fluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-fluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2,4-difluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-fluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-chlorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-chlorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (4aR,8aS)-6-[3-[4-(2-methylphenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (4aR,8aS)-6-[3-[4-[3-(trifluoromethyl)phenoxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]phenoxy]benzonitrile; (4aR,8aS)-6-[3-[4-(2-chloropyrimidin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[4-(4-cyclopropylpyrimidin-2-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(6-methyl-2-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(4-chloro-3-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(3-fluoro-4-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[4-(2-methylsulfonylpyrimidin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[(3,6-dimethyl-2-pyridyl)oxy]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(1H-pyrazol-5-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[2-(2,2-dimethylpropyl)pyrazol-3-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[1-(2,2-dimethylpropyl)pyrazol-3-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3-chloro-2-pyridyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2,4-dimethyloxazol-5-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3,5-dimethylpyrazol-1-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[3-(2,2-dimethylpropyl)triazol-4-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[5-(2,2-dimethylpropyl)-1,3,4-oxadiazol-2-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[2-(2-fluoroethyl)pyrazol-3-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[1-(2-fluoroethyl)pyrazol-4-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(1-methylpyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(6-fluoropyridin-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-fluoropyridin-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(1-methylpyrazol-4-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-methylpyrazol-3-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[5-(4-fluorophenoxy)-2-pyridyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(6-(4-fluorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(4-(trifluoromethoxy)phenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(4-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(3,6-dimethylpyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(6-(2-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(6-(3-chlorophenoxy)pyridin-3-yl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[4-(4-fluorophenoxy)phenyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-hydroxy-3-(4-phenoxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-hydroxy-3-(5-phenoxy-2-pyridyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-(4-phenoxyphenyl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and 21. The compound of formula (I) according to any one of claims 1 to 20, selected from (4aR,8aS)-6-[4-(4-phenoxyphenyl)piperazine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one, or a pharma- ceutically acceptable salt thereof.

22. below: (4aR,8aS)-6-(3-(4-phenoxyphenyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[4-(3-chloropyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2,4-difluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(2-fluorophenoxy)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 2-[4-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]phenoxy]benzonitrile; (4aR,8aS)-6-[3-[4-(3-chloro-2-pyridyl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-[5-(2,2-dimethylpropyl)-1,2,4-oxadiazol-3-yl]phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(4-methyl-1,3-thiazol-2-yl)phenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[5-(4-fluorophenoxy)-2-pyridyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(3,6-dimethylpyridazin-4-yl)oxyphenyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[6-(2-chlorophenoxy)-3-pyridyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and (4aR,8aS)-6-[3-hydroxy-3-(4-phenoxyphenyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 21. A compound of formula (I) according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof.

23. A process for preparing a compound of formula (I) according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, comprising the steps of: 4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one 1 (wherein R １ and R ２ as defined in any one of claims 1 to 22, 【Chemistry 5】 Heterocyclic amine 2 (wherein A, B, L １ , X, m, n and R ３ ~R ７ as defined in any one of claims 1 to 22), 【Chemistry 6】 Reacting in the presence of a base and a urea forming reagent, A process for preparing a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

24. The compound of formula (I) or a pharma- ceutically acceptable salt thereof has an IC for monoacylglycerol lipase of less than 10 μM. ５０ 23. The compound of formula (I) according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, having the formula:

25. A compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 22 and 24 for use as a therapeutically active substance.

26. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 22 and 24, or a pharma- ceutically acceptable salt thereof, and a therapeutically inert carrier.

27. Use of a compound of formula (I) as defined in any one of claims 1 to 22 and 24 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 26, for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, and / or inflammatory bowel disease in a non-human mammal.

28. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 22 and 24, or a pharmaceutical composition as defined in claim 26, for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinogenesis, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, pain associated spasticity, abdominal pain, abdominal pain and / or visceral pain associated with irritable bowel syndrome in a non-human mammal.

29. A compound of formula (I) as defined in any one of claims 1 to 22 and 24 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 26, for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a mammal.

30. A compound of formula (I) as defined in any one of claims 1 to 22 and 24 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 26, for use in the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinogenesis, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain, abdominal pain associated with irritable bowel syndrome and / or visceral pain in a mammal.

31. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 22 and 24 for the manufacture of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a mammal.

32. 25. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 22 and 24 for the manufacture of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinogenesis, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain, abdominal pain associated with irritable bowel syndrome and / or visceral pain in a mammal.

33. A method for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a non-human mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as defined in any one of claims 1 to 22 and 24 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 26.

34. A method for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy induced neuropathy, acute pain, chronic pain, spasticity associated with pain in a mammal, abdominal pain, abdominal pain associated with irritable bowel syndrome and / or visceral pain in a non-human mammal, comprising administering to said mammal an effective amount of a compound of formula (I) as defined in any one of claims 1 to 22 and 24 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 26.

35. A pharmaceutical composition for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a mammal, comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 22 and 24.

36. A pharmaceutical composition for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy induced neuropathy, acute pain, chronic pain, spasticity associated with pain in a mammal, abdominal pain, abdominal pain associated with irritable bowel syndrome and / or visceral pain in a mammal, comprising a compound of formula (I) as defined in any one of claims 1 to 22 and 24 or a pharma- ceutical composition comprising a compound of formula (I) or a pharma-ceutical acceptable salt thereof.

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