Novel heterocyclic compounds as monoacylglycerol lipase inhibitors.

Abstract

The present invention relates to novel heterocyclic compounds having the general formula (I): (In the formula, A, L, X, m, n, R 1 , and R 2 as described herein), compositions comprising the compounds, methods for making the compounds, and methods for using the compounds are provided.

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 (CB1 and CB2). They regulate multiple physiological processes, including neuroinflammation, neurodegeneration, and tissue regeneration (Iannotti, FA et al., "Progress in lipid research," 2016, Vol. 62, pp. 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, Vol. 334, pp. 809). MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglial cells (Chanda, P.K. 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). AA oxidative metabolism is increased in inflamed tissues. There are two major enzymatic pathways for the oxygenation of arachidonic acid involved in the inflammatory process: 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 with neurodegenerative disorders, and are thought to contribute to the inflammatory response and disease progression. Mice lacking MAGL (Mgll- / -) have dramatically reduced 2-AG hydrolase activity and elevated 2-AG levels in the nervous system, while other arachidonoyl-containing phospholipid and neutral lipid species, including anandamide (AEA) and other free fatty acids, are unchanged.Conversely, 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 strongly reduced. Although the phospholipase A2 (PLA2) enzyme has been considered the major source of AA, cPLA2-deficient mice have unaltered AA levels in their brains, reinforcing the important 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 regulates the neuroinflammatory process. The inflammatory progenitor lipopolysaccharide (LPS) produces a robust, time-dependent increase in brain eicosanoids that is significantly blunted in Mgll- / - mice. LPS treatment also induces a widespread increase in inflammatory cytokines, including interleukin-1-a (IL-1-a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a), which is prevented in Mgll- / - mice.

[0004] Neuroinflammation is characterized by the activation of innate immune cells in the central nervous system, microglia, and astrocytes. It has been reported that anti-inflammatory agents can suppress glial cell activation and the progression of diseases, 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 brain microglial cells (Nomura, DK et al., Science (2011) 334:809).

[0005] Furthermore, 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) Vol. 5, p. 37). Systemic administration of such inhibitors recapitulated the Mgll- / - mouse phenotype in the brain, including increased 2-AG levels, decreased AA levels and related eicosanoid production, and prevention of cytokine production and microglial activation after LPS-induced neuroinflammation, confirming MAGL as a druggable target (Nomura, DK et al., Science (2011) Vol. 334, p. 809).

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

[0007] Furthermore, oligodendrocytes (OLs) and their precursor cells (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 both 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 may therefore be neuroprotective (Bernal-Chico, A. et al., Glia (2015) Vol. 63, p. 163). Additionally, pharmacological inhibition of MAGL increases the number of myelinated OLs in the mouse brain, suggesting that MAGL inhibition may promote the differentiation of OPCs into myelinated OLs in vivo (Alpar, A. et al., Nature Communications (2014) Vol. 5, p. 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) Vol. 37, No. 35, p. 8385).

[0008] Finally, metabolism, especially lipid metabolism, has recently gained 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 antitumorigenic 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 different aspects of tumorigenesis as part of gene expression signatures (Qin, H. et al., Cell Biochem. Biophys. (2014) Vol. 70, p. 33; Nomura DK et al., Cell (2009) Vol. 140, No. 1, pp. 49-61; Nomura DK et al., Chem. Biol. (2011) Vol. 18, No. 7, pp. 846-856).

[0009] In conclusion, inhibiting MAGL activity and / or activation is a promising new therapeutic strategy for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and psychiatric disorders. Furthermore, inhibiting MAGL activity and / or activation is a promising new therapeutic strategy for providing neuroprotection and myelin regeneration. Therefore, there is a high unmet medical need for new MAGL inhibitors. Summary of the Invention

[0010] In a first aspect, the present invention provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein A, L, X, m, n, R 1 , and R 2 is as described herein.

[0011] In one aspect, the present invention provides a method of making a urea compound of formula (I) described herein, comprising: [ka] R 1 is as described herein, preferably R 1 is hydrogen, in the presence of a base and a urea-forming reagent, [ka] A, L, m, n, X, and R 2 with a second amine 2, wherein the formula (I) is as described herein, to form the compound of formula (I).

[0012] In a further aspect, the present invention provides a compound of formula (I) as described herein when prepared according to the methods described herein.

[0013] In a further aspect, the present invention provides a compound of formula (I) as described herein for use as a therapeutically active substance.

[0014] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein and a therapeutically inert carrier.

[0015] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharmaceutical composition as described herein for inhibiting monoacylglycerol lipase (MAGL) in a mammal.

[0016] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharmaceutical composition as described herein for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

[0017] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharmaceutical composition as described herein 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.

[0018] In a further aspect, the present invention provides a compound of formula (I) as described herein or a pharmaceutical composition as described herein 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 pharmaceutical composition as described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

[0020] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein or a pharmaceutical composition as described herein 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.

[0021] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for inhibiting monoacylglycerol lipase in a mammal.

[0022] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

[0023] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein 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.

[0024] In a further aspect, the present invention provides a method for inhibiting monoacylglycerol lipase in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) described herein or a pharmaceutical composition described herein.

[0025] In a further 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, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein or a pharmaceutical composition as described herein.

[0026] In a further aspect, the present invention provides 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, and / or spasticity associated with pain in a mammal, the method comprising administering to the mammal an effective amount of a compound of Formula (I) as described herein or a pharmaceutical composition as described herein. DETAILED DESCRIPTION OF THE INVENTION

[0027] definition

[0028] It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all 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.

[0029] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched saturated hydrocarbon group having 1 to 12 carbon atoms. In some preferred embodiments, an alkyl group has 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 tert-butyl.

[0030] 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 1-6 In other embodiments, alkoxy groups contain 1 to 4 carbon atoms. In yet other embodiments, alkoxy groups contain 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0031] 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).

[0032] 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. 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., 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.

[0033] The terms "heterocyclyl" and "heterocycloalkyl" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings having two ring 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., the two rings are joined via one common ring atom. Some non-limiting examples of monocyclic heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6-oxo-3-piperidyl, morpholino, morpholin-2-yl, and morpholin-3-yl.

[0034] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, preferably 6 to 12 ring members, and more preferably 6 to 10 ring members, wherein 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.

[0035] The term "heteroaryl" refers to a polyvalent monocyclic or bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring of the system is aromatic and at least one ring of 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 to 2 heteroatoms independently selected from O, S, and N. Some preferred, but non-limiting examples of heteroaryl include thiazolyl (e.g., thiazol-2-yl); oxazolyl (e.g., oxazol-2-yl); 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g., 2-pyridyl); pyrazolyl (e.g., pyrazol-1-yl); imidazolyl (e.g., imidazol-1-yl); benzoxazolyl (e.g., benzoxazol-2-yl), and oxazolo[5,4-c]pyridin-2-yl.

[0036] The term "hydroxy" refers to the group --OH.

[0037] The term "cyano" refers to a -CN (nitrile) group.

[0038] The term "haloalkyl" refers to an alkyl group in which at least one of the alkyl group's hydrogen atoms is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three of the alkyl group's hydrogen atoms are replaced by halogen atoms, most preferably fluoro. Particularly preferred, but non-limiting, examples of haloalkyl are trifluoromethyl (CF) and trifluoroethyl (e.g., 2,2,2-trifluoroethyl).

[0039] The term "haloalkoxy" refers to an alkoxy group wherein at least one of the hydrogen atoms of the alkoxy group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkoxy" refers to an alkoxy group wherein one, two, or three hydrogen atoms of the alkoxy group are replaced by halogen atoms, most preferably fluoro. A particularly preferred, but non-limiting example of a haloalkoxy is trifluoromethoxy (-OCF).

[0040] The term "hydroxyalkyl" refers to an alkyl group, wherein at least one of the alkyl group's hydrogen atoms is replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group, wherein one, two, or three, and 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.

[0041] The term "haloaryl" refers to an aryl group, wherein at least one hydrogen atom of the aryl group is replaced by a halogen atom. Preferably, "haloaryl" refers to an aryl group, wherein one, two, or three hydrogen atoms, more preferably one or two hydrogen atoms, and most preferably one hydrogen atom of the aryl group are replaced by a halogen atom. A particularly preferred, but non-limiting example of haloaryl is chlorophenyl, particularly 4-chlorophenyl.

[0042] The term "aryloxy" refers to an aryl group, as defined above, attached to the parent molecular moiety through an oxygen atom. A preferred, but non-limiting example of aryloxy is phenoxy.

[0043] The term "haloaryloxy" refers to a haloaryl group, as defined above, attached to the parent molecular moiety through an oxygen atom. A preferred, but non-limiting example of haloaryloxy is 4-fluorophenoxy.

[0044] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and N-acetylcysteine. In addition, these salts can be prepared by adding an inorganic 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. 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, and polyimine resins. A particular pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

[0045] The term "pharmaceutically acceptable ester" refers to an ester that hydrolyzes in vivo, including esters that readily decompose in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, ester groups derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic, and alkanedioic acids, each of which preferably has 6 or fewer carbon atoms in its alkyl or alkenyl moiety. Representative examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates. Examples of pharmaceutically acceptable prodrug types are described in Higuchi and Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and in Roche, ed., "Bioreversible Carriers in Drug Design," American Pharmaceutical Association and Pergamon Press (1987).

[0046] The term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the sense conventionally associated with synthetic chemistry, can be selectively carried out at an otherwise unprotected reactive site. The protecting group can be removed at the appropriate location. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups, 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). An even more particular protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry," T.W. Greene and P.G.M. Hutts, 5th Edition (2014), John Wiley & Sons, New York.

[0047] The term "urea-forming reagent" refers to a compound that can react a first amine with a second amine to form a urea derivative. Non-limiting examples of urea-forming reagents include bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, and 1,1'-carbonyldiimidazole. The urea-forming reagents described in G. Sartori et al., "Green Chemistry" (2000), Vol. 2, p. 140, are incorporated herein by reference.

[0048] 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, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. In a preferred embodiment, the compounds of formula (I) according to the present invention are cis-enantiomers of formula (Ia) or (Ib), respectively, as described herein.

[0049] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0050] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

[0051] The term "treatment," as used herein, includes: (1) inhibiting the state, disorder, or condition (e.g., in the case of maintenance therapy, arresting, reducing, or delaying the onset or recurrence of at least one clinical or subclinical symptom of the disease); and / or (2) alleviating the condition (i.e., causing regression of the state, disorder, or condition, or at least one of its clinical or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least discernible to the patient or physician. However, it will be understood that when a drug is administered to a patient to treat a disease, the result may not necessarily be effective therapy.

[0052] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder, or condition that occurs in a mammal, particularly in a human who may be affected by or susceptible to the condition, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition.

[0053] The term "neuroinflammation," as used herein, refers to acute and chronic inflammation of nervous tissue, which are the major tissue components 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).

[0054] The term "traumatic brain injury" (also known as "TBI" or "intracranial injury") relates to damage to the brain resulting from an external mechanical force such as rapid acceleration or deceleration, impact, blast wave, or penetration by a projectile.

[0055] 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.

[0056] The term "mental disorder" (also called mental illness or mental disorder) relates to a behavioral or mental pattern that can cause distress or impaired functioning in life. Such characteristics may occur as persistent, relapsing, and remitting or single episodes. Examples of mental disorders include, but are not limited to, anxiety and depression.

[0057] 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 syphilitic pain. A particular example of pain is neuropathic pain, which is caused by injury or disease affecting 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.

[0058] The term "neurotoxicity" relates to toxicity in the nervous system. It occurs when exposure to natural or man-made 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 therapy, drug therapy, drugs of abuse, and organ transplants, 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.

[0059] The term "cancer" refers to diseases characterized by the presence of a neoplasm or tumor, resulting from the abnormal and uncontrolled growth 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.

[0060] 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 particularly preferred embodiments, the term "mammal" refers to humans.

[0061] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, During the ceremony: (i) X is CR 3 m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH) p selected from -, -O-, -OCH2-, -CH2O-, -CH2OCH2-, -CF2CH2-, and -CH2CF2-; or (ii) X is N; m is 1; n is 1 or 2; and L is —(CH) p - or -CF2CH2-; p is selected from 1, 2, and 3; A is the following: (i)R 4 , R 5 , and R 6 aryl substituted with; (ii)R 7 , R 8 , and R 9 heteroaryl substituted with; (iii)R 10 , R 11 , and R 12 heterocycloalkyl substituted with; R 1 is hydrogen or C 1-6 - is alkyl; R 2 is hydrogen, C 1-6 Alkyl and hydroxy-C 1-6 - selected from alkyl; R 3 is hydrogen, halogen, hydroxy, C 1-6 -alkoxy, C 1-6 -Alkyl and halo-C 1-6 - selected from alkyl; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11, and R 12 Each of these is hydrogen, halogen, cyano, hydroxy, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, Hydroxy-C 1-6 -Alkyl, Halo-C 1-5 -Alkyl-CH(OH)-, C 1-6 -Alkoxy, Halo-C 1-6 -Alkoxy, SF5, CH3SO2, C 3-10 -cycloalkyl, R 13 C replaced with 3-10 -cycloalkyl, heterocycloalkyl, R 14 and R 13 and R 14 Each of the 1-6 -Alkyl, Halo-C 1-6 -alkyl, or hydroxy.

[0062] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia): [ka] In the formula, A, L, X, m, n, R 1 , and R 2 is as defined herein. Preferably, the compound of formula (Ia) has an enantiomeric excess (ee) of more than 80%, more preferably more than 90%, especially more than 99%.

[0063] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib): [ka] In the formula, A, L, X, m, n, R 1 , and R2 is as defined herein. Preferably, the compound of formula (Ib) has an enantiomeric excess (ee) of more than 80%, more preferably more than 90%, especially more than 99%.

[0064] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ic): [ka] In the formula, A, L, X, m, n, R 1 , and R 2 is as defined herein. Preferably, the compound of formula (Ic) has an enantiomeric excess (ee) of more than 80%, more preferably more than 90%, especially more than 99%.

[0065] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Id): [ka] In the formula, A, L, X, m, n, R 1 , and R 2 is as defined herein. Preferably, the compound of formula (Id) has an enantiomeric excess (ee) of more than 80%, more preferably more than 90%, especially more than 99%.

[0066] In one embodiment, there is provided a compound of Formula (I) as described herein, wherein X is CR 3 and R 3 When is hydroxy or halogen, L is not —O— or —CH2O—.

[0067] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X is CR 3m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH) p selected from -, -O-, -OCH2-, -CH2O-, and -CH2OCH2-; or (ii) X is N; m and n are both 1; and L is —(CH) p -It is.

[0068] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; and L is -(CH2) p is selected from -, -O-, -OCH2-, and -CH2O-.

[0069] In another preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; L is -(CH2) p selected from -, -O-, -OCH2-, and -CH2O-; R 3 is hydrogen, C 1-6 - selected from alkyl and halogen; and p is 1 or 2.

[0070] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; L is -(CH2) pselected from -, -O-, -OCH2-, and -CH2O-; R 3 is hydrogen; and p is 1 or 2.

[0071] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

[0072] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is: (i)R 4 , R 5 , and R 6 aryl substituted with; (ii)R 7 , R 8 , and R 9 and wherein the heteroaryl is selected from heteroaryl substituted with

[0073] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is: (i)R 4 , R 5 , and R 6 phenyl substituted with; (ii)R 7 , R 8 , and R 9 and oxazolyl substituted with

[0074] In another preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is R 4 , R 5 , and R 6 is an aryl substituted with

[0075] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is R 4 , R 5 , and R6 is a phenyl substituted with

[0076] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is the following: (i)R 4 , R 5 , and R 6 aryl substituted with; (ii)R 7 , R 8 , and R 9 selected from heteroaryl substituted with; R 4 is hydrogen, halogen, halo-C 1-6 -alkoxy and halo-C 1-6 - selected from alkyl; R 5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, C 1-6 -alkoxy, heterocycloalkyl, C 3-10 - selected from cycloalkyl, heteroaryl, and haloaryl; R 6 is hydrogen or halogen; R 7 is hydrogen, C 1-6 -Alkyl, aryl, and halo-C 1-6 - selected from alkyl; R 8 is hydrogen or C 1-6 -alkyl; and R 9 is hydrogen.

[0077] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is the following: (i)R 4 , R 5 , and R 6 aryl substituted with; (ii)R 7 , R 8 , and R9 selected from heteroaryl substituted with; R 4 is a halogen, halo-C 1-6 -alkoxy and halo-C 1-6 - selected from alkyl; R 5 is hydrogen, cyano, halogen, heterocycloalkyl, C 3-10 - selected from cycloalkyl, and haloaryl; R 6 is hydrogen; R 7 is C 1-6 - is alkyl; R 8 is hydrogen; and R 9 is hydrogen.

[0078] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is the following: (i)R 4 , R 5 , and R 6 phenyl substituted with; (ii)R 7 , R 8 , and R 9 oxazolyl substituted with; R 4 is selected from chloro, OCF3, and CF3; R 5 is selected from hydrogen, cyano, fluoro, chloro, pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl; R 6 is hydrogen; R 7 is tert-butyl; R 8 is hydrogen; and R 9 is hydrogen.

[0079] In further specific preferred embodiments, the present invention provides compounds of formula (I) as described herein or pharmaceutically acceptable salts thereof, wherein A is phenyl, 4-tert-butylthiazol-2-yl, 4-tert-butyloxazol-2-yl, 2-chloro-4-fluoro-phenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-chlorophenyl, 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 5-(trifluoromethyl)phenyl, 5-(trifluoromethyl)phenyl, 5-(trifluoromethoxy)phenyl, 5-chlorophenyl, 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 5-(trifluoromethyl)phenyl ... 4-(trifluoromethyl)-2-pyridyl, 4-(trifluoromethyl)pyrazol-1-yl, 2-fluoro-4-(trifluoromethyl)phenyl, 2,4-difluorophenyl, 4-chloro-3-fluoro-phenyl, 4-cyanophenyl, 4,4-difluoro-1-piperidyl, 5-tert-butyloxazol-2-yl, 4-methoxy-2-fluoro-phenyl, 2-chloro-4(trifluoromethyl)phenyl, 6-(trifluoromethyl)-3-pyridyl, 3-(trifluoromethyl)phenyl, 2-chloro-4-(trifluoromethoxy)phenyl yl, 4-chloro-2-fluoro-phenyl, 4-fluoro-2-(trifluoromethyl)phenyl, 2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl, 4-fluoro-2-cyano-phenyl, 2-cyclopentyl-4-(trifluoromethyl)phenyl, 2-chloro-4-cyanophenyl, 4-(trifluoromethyl)imidazol-1-yl, 4-fluoro-2-methyl-phenyl, 4-tert-butylpyrazol-1-yl, 1,3-benzoxazol-2-yl, 4-chloro-3-(4-chlorophenyl)phenyl, 2- (1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl, 2,4-dichlorophenyl, 3-methoxy-4-(trifluoromethyl)phenyl, 5-methyl-6-(trifluoromethyl)-3-pyridyl, 3-chlorophenyl, 2-chlorophenyl, 2-cyclopropyl-4-(trifluoromethyl)phenyl, 2-methyl-4-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 2-fluoro-6-(trifluoromethyl)phenyl, 3-chloro-4-(trifluoromethyl)phenyl, 2,4-Difluoro-5-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 2-methoxy-4-(trifluoromethyl)phenyl, 4-chloro-2-(trifluoromethyl)phenyl, 4-chloro-3-(trifluoromethyl)phenyl, 4-chloro-3-cyclopropyl-phenyl, 4-chloro-3-morpholino-phenyl, 2-cyano-4-(trifluoromethyl)phenyl, oxazolo[5,4-c]pyridin-2-yl, 4-methyl-3-(trifluoromethyl)phenyl, 3-cyclopropyl-4-(trifluoromethyl)phenyl, 2-fluoro-4-methyl-phenyl, 4-methoxy-2-(trifluoromethyl)phenyl, 4-methyl-2-(trifluoromethyl)phenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 5-methyl-6-(trifluoromethyl)-3-pyridyl, 4,5-bis(trifluoromethyl)-2-pyridyl, 2-fluoro-4-(trifluoromethyl) )-phenyl, 2-fluoro-4-(pentafluoro-lambda 6-sulfanyl)phenyl, 2,4-bis(trifluoromethyl)phenyl, 2-methyl-3-(trifluoromethyl)phenyl, 2-methyl-4-(trifluoromethoxy)phenyl, 3-chloro-4-(trifluoromethyl)phenyl, 3-cyclopropyl-4-chloro-phenyl, 2-chloro-3-(trifluoromethyl)phenyl, 2-chloro-3-cyclopropyl-phenyl, 3-(2-azaspiro [3.3]heptan-2-yl)-4-(trifluoromethyl)phenyl, 2-chloro-3-(2-azaspiro[3.3]heptan-2-yl)-phenyl, 2-chloro-3-(5-oxa-2-azaspiro[3.5]nonan-2-yl)phenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-6-(trifluoromethyl)phenyl, and 2-(trifluoromethyl)-4-methyl-phenyl.

[0080] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or methyl.

[0081] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.

[0082] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or C 1-6 - alkyl.

[0083] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or methyl.

[0084] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, halogen, C 1-6 -Alkyl and halo-C 1-6 -alkyl.

[0085] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, halogen, and C 1-6 -alkyl.

[0086] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, fluoro, and methyl.

[0087] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, methyl, fluoro, and trifluoromethyl.

[0088] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, halogen, halo-C 1-6 -alkoxy and halo-C 1-6 -alkyl.

[0089] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is a halogen, halo-C 1-6 -alkoxy and halo-C 1-6 -alkyl.

[0090] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from chloro, OCF3, and CF3.

[0091] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, chloro, fluoro, OCF3, and CF3.

[0092] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, C 1-6 -alkoxy, heterocycloalkyl, C 3-10 - selected from cycloalkyl, heteroaryl, and haloaryl.

[0093] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, cyano, halogen, heterocycloalkyl, C 3-10 -cycloalkyl, and haloaryl.

[0094] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, cyano, fluoro, chloro, pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl.

[0095] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, methyl, methoxy, cyano, fluoro, chloro, pyrrolidinyl, morpholinyl, pyrazolyl, cyclopentyl, cyclopropyl, and 4-chlorophenyl.

[0096] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen or halogen.

[0097] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen or fluoro.

[0098] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.

[0099] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, C 1-6 -Alkyl, aryl, and halo-C 1-6 -alkyl.

[0100] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-6 - alkyl.

[0101] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is tert-butyl.

[0102] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, tert-butyl, phenyl, and CF3.

[0103] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or C 1-6 - alkyl.

[0104] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or methyl.

[0105] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.

[0106] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.

[0107] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is a halogen.

[0108] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is fluoro.

[0109] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is a halogen.

[0110] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is fluoro.

[0111] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 Both are fluoro.

[0112] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen.

[0113] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X is CR 3 m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH) p selected from -, -O-, -OCH2-, -CH2O-, and -CH2OCH2-; or (ii) X is N; m and n are both 1; and L is —(CH) p -is; p is 1 or 2; A is the following: (i)R 4 , R 5 , and R 6 aryl substituted with; (ii)R 7 , R 8 , and R 9 heteroaryl substituted with; (iii)R 10 , R 11 , and R 12heterocycloalkyl substituted with; R 1 is hydrogen or C 1-6 - is alkyl; R 2 is hydrogen or C 1-6 - selected from alkyl; R 3 is hydrogen, halogen, C 1-6 -Alkyl and halo-C 1-6 - selected from alkyl; R 4 is hydrogen, halogen, halo-C 1-6 -alkoxy and halo-C 1-6 - selected from alkyl; R 5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, C 1-6 -alkoxy, heterocycloalkyl, C 3-10 - selected from cycloalkyl, heteroaryl, and haloaryl; R 6 is hydrogen or halogen; R 7 is hydrogen, C 1-6 -Alkyl, aryl, and halo-C 1-6 - selected from alkyl; R 8 is hydrogen or C 1-6 - is alkyl; R 9 is hydrogen; R 10 is a halogen; R 11 is a halogen; and R 12 is hydrogen.

[0114] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; L is -(CH2) p selected from -, -O-, -OCH2-, and -CH2O-; p is 1 or 2; A is the following: (i)R 4 , R 5 , and R 6 aryl substituted with; (ii)R 7 , R 8 , and R 9 selected from heteroaryl substituted with; R 1 is hydrogen; R 2 is hydrogen or C 1-6 - selected from alkyl; R 3 is hydrogen, halogen, and C 1-6 - selected from alkyl; R 4 is a halogen, halo-C 1-6 -alkoxy and halo-C 1-6 - selected from alkyl; R 5 is hydrogen, cyano, halogen, heterocycloalkyl, C 3-10 - selected from cycloalkyl, and haloaryl; R 6 is hydrogen; R 7 is C 1-6 - is alkyl; R 8 is hydrogen; and R 9 is hydrogen.

[0115] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; L is -(CH2) pselected from -, -O-, -OCH2-, and -CH2O-; p is 1 or 2; A is the following: (i)R 4 , R 5 , and R 6 phenyl substituted with; (ii)R 7 , R 8 , and R 9 oxazolyl substituted with; R 1 is hydrogen; R 2 is selected from hydrogen or methyl; R 3 is selected from hydrogen, fluoro, and methyl; R 4 is selected from chloro, OCF3, and CF3; R 5 is selected from hydrogen, cyano, fluoro, chloro, pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl; R 6 is hydrogen; R 7 is tert-butyl; R 8 is hydrogen; and R 9 is hydrogen.

[0116] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: (i) X is CR 3 m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH) p -, -O-, -OCH2-, -CH2OCH2-, -CF2CH2-, -CH2=CH2-, -(CR 16 R 17 ) q selected from —CH2O—, and —CH2CF2—; or (ii) X is N; m is 1; n is 1 or 2; and L is —(CH)p - or -CF2CH2-; p is selected from 1, 2, and 3; q is 0 or 1; A is the following: (i)R 4 , R 5 , and R 6 C6-C substituted with 14 -aryl; (ii)R 7 , R 8 , and R 9 5-14 membered heteroaryl substituted with (iii)R 10 , R 11 , and R 12 selected from 3- to 14-membered heterocycloalkyl substituted with; R 1 is hydrogen or C 1-6 - is alkyl; R 2 is hydrogen, C 1-6 Alkyl and hydroxy-C 1-6 - selected from alkyl; R 3 is hydrogen, halogen, hydroxy, C 1-6 -alkoxy, C 1-6 -Alkyl and halo-C 1-6 - selected from alkyl; R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 Each of these is hydrogen, halogen, cyano, hydroxy, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, Hydroxy-C 1-6 -Alkyl, C 1-6 -Alkanoyl, Halo-C 1-5 -Alkyl-CH(OH)-, C 1-6 -Alkoxy, Halo-C 1-6 -Alkoxy, SF5, CH3SO2, C 3-10-cycloalkyl, R 13 C replaced with 3-10 -cycloalkyl, 3- to 14-membered heterocycloalkyl, R 14 and R 15 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C6-C 14 -Aryl, C6-C 14 -aryloxy, halo-C6-C 14 -aryl and halo-C6-C 14 -independently selected from aryloxy; R 13 , R 14 , and R 15 Each of the 1-6 -Alkyl, C 1-6 -Alkoxy, Halo-C 1-6 -Alkyl, Halo-C 1-6 -independently selected from alkoxy, halogen, and hydroxy; and R 16 and R 17 together with the carbon atoms to which they are attached, form C 3-10 -forming a cycloalkyl.

[0117] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X is CR 3 m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH) p -, -O-, -OCH2-, -CF2CH2-, -CH2=CH2-, -(CR 16 R 17 ) q -CH2O-, and -CH2OCH2-; or (ii) X is N; m and n are both 1; and L is —(CH) p -It is.

[0118] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 2.

[0119] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

[0120] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein q is 0.

[0121] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is: (i)R 4 , R 5 , and R 6 C6-C substituted with 14 -aryl; and (ii)R 7 , R 8 , and R 9 and is selected from 5-14 membered heteroaryl substituted with

[0122] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is: (i)R 4 , R 5 , and R 6 phenyl substituted with; (ii)R 7 , R 8 , and R 9 oxazolyl substituted with; (iii)R 7 , R 8 , and R 9 pyridyl substituted with

[0123] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, halogen, hydroxy, cyano, C 1-6 -Alkyl, C 1-6 -Alkanoyl, SF5, C 1-6 -Alkoxy, Halo-C1-6 -Alkoxy, Halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, 3- to 14-membered heterocyclyl, R 14 and R 15 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, C6-C 14 -aryloxy, and halo-C6-C 14 -aryl.

[0124] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 are halogens, SF5, C 1-6 -Alkyl, C 1-6 -Alkoxy, Halo-C 1-6 -Alkoxy, Halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, and 3- to 14-membered heterocycloalkyl.

[0125] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from chloro, SF5, methyl, methoxy, OCF3, CF3, cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl.

[0126] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C6-C 14 -aryl.

[0127] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, Halo-C 1-6 -alkyl, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl and halo-C6-C 14 -aryl.

[0128] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, CF3, pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl.

[0129] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen, C 1-6 -Alkyl, C6-C 14 -aryl, halo-C6-C 14 -aryl, halo-C6-C 14 -aryloxy, and halo-C 1-6 -alkyl.

[0130] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-6 -Alkyl or halo-C 1-6 - alkyl.

[0131] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is tert-butyl or CF3.

[0132] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen, halogen, C 1-6 -Alkyl and halo-C 1-6-alkyl.

[0133] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or halo-C 1-6 - alkyl.

[0134] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or CF3.

[0135] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 14 is C 1-6 -Alkyl, C 1-6 -alkoxy, and halogen.

[0136] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 15 is hydrogen or halogen.

[0137] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X is CR 3 m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH) p -, -O-, -OCH2-, -(CR 16 R 17 ) q selected from —CH2O—, —CH2OCH2—, —CF2CH2—, and —CH2═CH2—; or (ii) X is N; m and n are both 1; and L is —(CH) p -is; p is 1 or 2; q is 0 or 1; A is the following: (i)R4 , R 5 , and R 6 C6-C substituted with 14 -aryl; (ii)R 7 , R 8 , and R 9 5-14 membered heteroaryl substituted with (iii)R 10 , R 11 , and R 12 selected from 3- to 14-membered heterocycloalkyl substituted with; R 1 is hydrogen or C 1-6 - is alkyl; R 2 is hydrogen or C 1-6 - is alkyl; R 3 is hydrogen, halogen, C 1-6 -Alkyl and halo-C 1-6 - selected from alkyl; R 4 are hydrogen, halogens, cyano, SF5, C 1-6 -Alkyl, C 1-6 -Alkanoyl, C 1-6 -Alkoxy, Halo-C 1-6 -Alkoxy, Halo-C 1-6 -Alkyl, C 3-10 -cycloalkyl, 3- to 14-membered heterocycloalkyl, R 14 and R 15 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, halo-C6-C6 14 -aryl, and C6-C 14 -aryloxy; R 5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C6-C 14 - selected from aryl; R 6is hydrogen or halogen; R 7 is hydrogen, C 1-6 -Alkyl, C6-C 14 -aryl, halo-C6-C 14 -aryl, halo-C6-C 14 -aryloxy, and halo-C 1-6 - selected from alkyl; R 8 is hydrogen, halogen, C 1-6 -Alkyl and halo-C 1-6 - selected from alkyl; R 9 is hydrogen; R 10 is a halogen; R 11 is a halogen; R 12 is hydrogen; R 14 is a halogen, C 1-6 Alkyl, and C 1-6 - selected from alkoxy; R 15 is hydrogen or halogen; and R 16 and R 17 together with the carbon atoms to which they are attached, form C 3-10 -forming a cycloalkyl.

[0138] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; L is -(CH2) p selected from -, -O-, -OCH2-, and -CH2O-; p is 1 or 2; A is the following: (i)R 4 , R 5 , and R 6 C6-C substituted with14 -aryl; and (ii)R 7 , R 8 , and R 9 selected from 5-14 membered heteroaryl substituted with R 1 is hydrogen; R 2 is hydrogen or C 1-6 - is alkyl; R 3 is hydrogen, halogen, and C 1-6 - selected from alkyl; R 4 are halogens, SF5, C 1-6 -Alkyl, C 1-6 -Alkoxy, Halo-C 1-6 -Alkoxy, Halo-C 1-6 -Alkyl, C 3-10 - selected from cycloalkyl, and 3- to 14-membered heterocycloalkyl; R 5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, Halo-C 1-6 -alkyl, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl and halo-C6-C 14 - selected from aryl; R 6 is hydrogen; R 7 is C 1-6 -Alkyl or halo-C 1-6 - is alkyl; R 8 is hydrogen or halo-C 1-6 -alkyl; and R 9 is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; L is -(CH2)p selected from -, -O-, -OCH2-, and -CH2O-; p is 1 or 2; A is the following: (i)R 4 , R 5 , and R 6 phenyl substituted with; (ii)R 7 , R 8 , and R 9 oxazolyl substituted with; (iii)R 7 , R 8 , and R 9 pyridyl substituted with; R 1 is hydrogen; R 2 is hydrogen or methyl; R 3 is selected from hydrogen, fluoro, and methyl; R 4 is selected from chloro, SF5, methyl, methoxy, OCF3, CF3, cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl; R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, CF3, pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl; R 6 is hydrogen; R 7 is selected from tert-butyl, methyl, and CF3; R 8 is hydrogen or CF3; and R 9 is hydrogen.

[0139] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 and R 3 is hydrogen, halogen, and C 1-6 -alkyl.

[0140] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 and R 3 is selected from hydrogen, fluoro, and methyl.

[0141] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X is CR 3 m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH) p -, -O-, -OCH2-, -(CR 16 R 17 ) q selected from —CH2O—, —CH2OCH2—, —CF2CH2—, and —CH2═CH2—; or (ii) X is N; m and n are both 1; and L is —(CH) p -is; p is 1 or 2; q is 0 or 1; R 3 is hydrogen, halogen, and C 1-6 - selected from alkyl; and R 16 and R 17 together with the carbon atoms to which they are attached, form C 3-10 -forming a cycloalkyl.

[0142] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; L is -(CH2) pselected from -, -O-, -OCH2-, and -CH2O-; p is 1 or 2; and R 3 is hydrogen, halogen, and C 1-6 -alkyl.

[0143] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CR 3 is; m and n are both 0; or m and n are both 1; L is -(CH2) p selected from -, -O-, -OCH2-, and -CH2O-; p is 1 or 2; and R 3 is selected from hydrogen, fluoro, and methyl.

[0144] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is the following: (i)R 4 , R 5 , and R 6 C6-C substituted with 14 -aryl; (ii)R 7 , R 8 , and R 9 5-14 membered heteroaryl substituted with (iii)R 10 , R 11 , and R 12 selected from 3- to 14-membered heterocycloalkyl substituted with; R 4 are hydrogen, halogens, cyano, SF5, C 1-6 -Alkyl, C 1-6 -Alkanoyl, C 1-6 -Alkoxy, Halo-C 1-6 -Alkoxy, Halo-C 1-6 -Alkyl, C 3-10-cycloalkyl, 3- to 14-membered heterocycloalkyl, R 14 and R 15 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, halo-C6-C6 14 -aryl, and C6-C 14 -aryloxy; R 5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, Halo-C 1-6 -Alkyl, C 1-6 -alkoxy, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C6-C 14 - selected from aryl; R 6 is hydrogen or halogen; R 7 is hydrogen, C 1-6 -Alkyl, C6-C 14 -aryl, halo-C6-C 14 -aryl, halo-C6-C 14 -aryloxy, and halo-C 1-6 - selected from alkyl; R 8 is hydrogen, halogen, C 1-6 -Alkyl and halo-C 1-6 - selected from alkyl; R 9 is hydrogen; R 10 is a halogen; R 11 is a halogen; R 12 is hydrogen; R 14 is a halogen, C 1-6 Alkyl, and C 1-6 -alkoxy; and R 15 is hydrogen or halogen.

[0145] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is the following: (i)R 4 , R 5 , and R 6 C6-C substituted with 14 -aryl; and (ii)R 7 , R 8 , and R 9 selected from 5-14 membered heteroaryl substituted with R 4 are halogens, SF5, C 1-6 -Alkyl, C 1-6 -Alkoxy, Halo-C 1-6 -Alkoxy, Halo-C 1-6 -Alkyl, C 3-10 - selected from cycloalkyl, and 3- to 14-membered heterocycloalkyl; R 5 is hydrogen, cyano, halogen, C 1-6 -Alkyl, Halo-C 1-6 -alkyl, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl and halo-C6-C 14 - selected from aryl; R 6 is hydrogen; R 7 is C 1-6 -Alkyl or halo-C 1-6 - is alkyl; R 8 is hydrogen or halo-C 1-6 -alkyl; and R 9 is hydrogen.

[0146] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is the following: (i)R 4 , R 5 , and R 6 phenyl substituted with; (ii)R 7 , R 8 , and R 9oxazolyl substituted with; (iii)R 7 , R 8 , and R 9 pyridyl substituted with; R 4 is selected from chloro, SF5, methyl, methoxy, OCF3, CF3, cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl; R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, CF3, pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl; R 6 is hydrogen; R 7 are tert-butyl, methyl, and CF3; R 8 is hydrogen or CF3; and R 9 is hydrogen.

[0147] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH; m and n are both 0; L is -CH2O-; A is R 4 , R 5 , and R 6 C6-C substituted with 14 -aryl; R 1 , R 2 , and R 6 are all hydrogen; R 4 is Halo-C 1-6 -alkyl; and R 5 is a halogen or C 1-6 - alkyl.

[0148] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH; m and n are both 0; L is -CH2O-; A is R 4 , R 5 , and R 6 C6-C substituted with 14 -aryl; R 1 , R 2 , and R 6 are all hydrogen; R 4 is Halo-C 1-6 -alkyl; and R 5 is a halogen.

[0149] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH; m and n are both 0; L is -CH2O-; A is R 4 , R 5 , and R 6 is phenyl substituted with; R 1 , R 2 , and R 6 are all hydrogen; R 4 is CF3; and R 5 is fluoro or methyl.

[0150] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: X is CH; m and n are both 0; L is -CH2O-; A is R 4 , R 5 , and R 6 is phenyl substituted with; R1 , R 2 , and R 6 are all hydrogen; R 4 is CF3; and R 5 is fluoro.

[0151] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the compounds disclosed in Table 1 below.

[0152] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, comprising: (+)-(4aR,8aS)-6-(4-((4-(tert-butyl)oxazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-(4aR,8aS)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-(4-(trifluoromethoxy)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-(4-chloro-3-fluorobenzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-(2-chloro-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-(3-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-[4-[[2-chloro-4-(trifluoromethoxy)phenoxy]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (-)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((4-chloro-2-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((4-fluoro-2-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-[4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (-)-3-chloro-4-((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-yl)methoxy)benzonitrile; (+)- or (-)-(4aR,8aS)-6-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((4',6-dichloro-[1,1'-biphenyl]-3-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(cis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(3-((2-chloro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[(2,4-dichlorophenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[3-chloro-4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-5-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 6-(3-((2,4-bis(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[3-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-methyl-4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((3,4-dichlorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2,5-dichlorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(2-methyl-3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-2-methylazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2-fluoro-4-(pentafluoro- lambda 6-Sulfa D benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((4-methyl-2-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-(2-fluoro-4-methyl-phenyl)ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[4-methoxy-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-[2-methyl-3-[[2-methyl-4-(trifluoromethoxy)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[2-methyl-3-[[2-methyl-3-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[2-chloro-3-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(2-chloro-3-cyclopropyl-phenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-2-chloro-phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-chloro-3-(5-oxa-2-azaspiro[3.5]nonan-2-yl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(E)-2-(2-fluoro-4-methyl-phenyl)vinyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-((E)-2-fluoro-6-(trifluoromethyl)styryl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; and (4aR,8aS)-6-(3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.

[0153] In one embodiment, the present invention provides a pharmaceutically acceptable salt or ester of a compound according to formula (I) described herein. In a particular embodiment, the present invention provides a pharmaceutically acceptable salt, particularly a hydrochloride salt, of a compound according to formula (I) described herein. In a more particular embodiment, the present invention provides a pharmaceutically acceptable ester of a compound according to formula (I) described herein. In an even more particular embodiment, the present invention provides a compound according to formula (I) described herein.

[0154] In some embodiments, compounds of formula (I) are 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. Exemplary 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.

[0155] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability, for example, a longer in vivo half-life or lower dosage requirements, which may result in certain therapeutic advantages.

[0156] 11 C. 18 F, 15 O, and 13 Substitution with positron-emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples set forth below, by substituting an appropriate isotopically labeled reagent for a previously employed non-isotopically labeled reagent.

[0157] Manufacturing Process The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The techniques required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the description of the following processes have the meanings given herein unless otherwise indicated.

[0158] 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 (e.g., as described in "Protective Groups in Organic Chemistry," T.W. Greene and P.G.M. Hutts, 5th Edition (2014), John Wiley & Sons, New York) can be introduced prior to a 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.

[0159] When the starting material or intermediate contains a stereocenter, the compound of formula (I) may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with an optically pure acid, or by separating the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. Starting materials and intermediates containing a stereocenter can also be separated 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) typically results in the respective diastereomerically / enantiomerically enriched compound of formula (I).

[0160] 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 several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and R.B. Merrifield, J. Am. Chem. Soc. (1977) 99:7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. (1996) 35:2056).

[0161] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0162] More specifically, compounds of formula (I) can be prepared by the methods described below, the methods described in the Examples, or similar methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the described reactions, see, for example, "Comprehensive Organic Transformations: A Guide to Functional Group Preparations," 2nd ed., Richard C. Larock, John Wiley & Sons, New York, NY (1999). The reactions could be easily carried out with or without a solvent. There are no particular restrictions on the nature of the solvent used, so long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions 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 produce 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.

[0163] If starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared by analogy with existing procedures for analogous materials or as outlined in the experimental section. The following abbreviations are used in the text:

[0164] 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, DCM = dichloromethane, DEAD = diethyl azodicarboxylate, DIAD = diisopropyl azodicarboxylate, DMAP = 4-dimethylaminopyridine, DME = dimethoxyethane, DMEDA = N,N'-dimethylethylenediamine, DMF = N,N-dimethylformamide, DIPEA = 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 = hour, 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-hexafluorophosphate, 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, MgSO4 = magnesium sulfate, mi n = minutes, mL = milliliters, 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 = sodium triacetoxyborohydride, NaOH = sodium hydroxide, Na2CO3 = sodium carbonate, Na2SO4 = sodium sulfate, Na2S2O3 = sodium thiosulfate, NBS = N-bromosuccinimide, nBuLi = n-butyllithium palladium, 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)-CH2Cl2 = 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.

[0165] A, L, X, m, n, R 1 , and R 2 Compounds of formula I described herein can be synthesized analogously to literature procedures and / or as shown, for example, in Scheme 1. [ka]

[0166] 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 give a compound of Formula I (Step a). Additional 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) Vol. 2, p. 140). Those skilled in the art will recognize that the order of addition of reagents can be important in this type of reaction due to the reactivity and stability of the carbamoyl chloride formed as an intermediate and to avoid the formation of undesired symmetrical urea by-products.

[0167] Intermediate 1 can be synthesized, for example, as shown in Scheme 2 and / or analogously to methods described in the literature. [ka]

[0168] 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 with, for example, acyl chlorides 4, where R 1is as defined herein, and "LG" represents 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 a mixture thereof to provide intermediate 5 (step a). Intermediate 4 is either commercially available or can be prepared by achiral (R 1 =H) racemic (R 1 is not H) or in enantiomerically pure form (R 1 can be prepared either by

[0169] 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. This type of reaction has been described in the literature (e.g., Z. Rafinski et al., J. Org. Chem. (2015) Vol. 80, p. 7468; S. Dugar et al., Synthesis (2015) Vol. 47, No. 5, p. 712; WO 2005 / 066187).

[0170] Removal of the protecting groups in intermediate 6, 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 suitable catalyst such as Pd on charcoal or Pd(OH) in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and groups as described, for example, in "Protective Groups in Organic Chemistry", T.W. Greene and P.G.M. Butts, 4th Edition (2006), Wiley, New York) gives intermediate 1 (step c).

[0171] 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 or intermediate 4 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, such as diastereomeric salt crystallization or chiral chromatography, for example, according to Scheme 3 (Step a). [ka]

[0172] In some embodiments, intermediate 2 is an intermediate of type B. Intermediates of type B (where A, m, n, and R 2 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 4. [ka]

[0173] Ketone 7, either commercially available or prepared by methods known in the art, can undergo a Wittig reaction with alkylidene triphenylphosphorane of type 8a in a suitable solvent such as THF, methyl-THF, or DMSO to afford intermediate 9 (Step a). Phosphorane 8a can be formed by treating the corresponding phosphonium salt with a suitable base such as BuLi, NaH, or KOtBu in a suitable solvent such as THF, dioxane, or methyl-THF, and can be isolated or used in situ. Similarly, phosphonium salts are readily available from aryl / heteroaryl / heterocycle-substituted alkyl halides (halides are Cl, Br, and iodine) and triphenylphosphine in a suitable solvent such as toluene. Heating may be used to accelerate the reaction or drive the reaction to completion (see, for example, H.J. Cristau, F. Plenat, in "PATAI'S Chemistry of Functional Groups," editor: Frank R. Hartley (August 7, 2006), series editor: Prof. Saul Patai).

[0174] Alternatively, intermediate 9 can be obtained using a Horner-Wadsworth-Emmons (HWE) reaction with ketone 7 and phosphonate 8b, where R a is alkyl, e.g., methyl or ethyl. Phosphonate 8b is α-metallated in situ using a suitable base and solvent, such as NaH, nBuLi, or KOtBu in THF (Step a). Phosphonate 8b is readily prepared using, for example, the Arbuzov reaction by alkylating aryl / heteroaryl / heterocyclic halides (halides are Cl, Br, and iodo) with commercially available trialkyl phosphites (e.g., Chem. Rev. (1984) 84, 577).

[0175] Both types of olefination reactions have been widely described in the literature (e.g., Current Org. Chem. (2015) Vol. 19, No. 9, p. 744; Chem. Rev. (1989) Vol. 89, No. 4, p. 863; Org. React. (1977) Vol. 25, p. 73; Liebigs Ann. / Recueil (1997) p. 1283; Acc. Chem. Res. (1983) Vol. 16, p. 411).

[0176] Reduction of the double bond in intermediate 9 with, for example, hydrogen in the presence of a suitable catalyst, such as palladium on charcoal, in a suitable solvent or solvent mixture, such as EtOAc, MeOH, or AcOH, gives compound 10 (step b).

[0177] Removal of the protecting groups from intermediate 10 applying methods known in the art (e.g., Boc group using TFA in DCM or 4 M HCl in dioxane at temperatures between 0° C. and room temperature, Cbz group using hydrogen in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH) in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and groups as described, for example, in "Protective Groups in Organic Chemistry", T.W. Greene and P.G.M. Butts, 4th Edition (2006), Wiley, New York) gives intermediate B (step c).

[0178] In some embodiments, intermediate 2 is an intermediate of type C. Intermediates of type C (where A, R 2 and p is as described herein, r=0, 1, or 2, and (m+n)=2 or 3), can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 5. [ka]

[0179] Alkylation of optionally mono-protected piperazine or 1,4-diazepane derivatives 11a,b (either commercially available or synthesized analogously to literature methods) with aryl / heteroaryl / heterocyclyl-substituted alkyl derivatives 12, which are either commercially available or synthesized according to literature procedures (where LG represents a suitable leaving group such as chlorine, bromine, iodine, OSO2 alkyl (e.g., mesylate (methanesulfonate)), OSO2 fluoroalkyl (e.g., triflate (trifluoromethanesulfonate)), or OSO2 aryl (e.g., tosylate (p-toluenesulfonate)), using a suitable base in a suitable solvent (e.g., sodium hydride in DMF) at a temperature between 0 °C and the boiling point of the solvent, gives intermediates 14a,b (Step a).

[0180] Alternatively, compounds 11a,b can be converted to the type 11a,b using a suitable reducing agent and solvent such as NaBH3CN in MeOH, AcOH, or mixtures thereof. 13 can be subjected to a reductive amination reaction with an aldehyde to give intermediates 14a,b (step a).

[0181] Removal of the protecting group from intermediate 14b applying methods known in the art (e.g., Boc group using TFA in DCM or 4 M HCl in dioxane at temperatures between 0° C. and room temperature, Cbz group using hydrogen in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH) in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and groups as described, for example, in "Protective Groups in Organic Chemistry", T.W. Greene and P.G.M. Butts, 4th Edition (2006), Wiley, New York) gives intermediate C (step c).

[0182] In some embodiments, the compound of formula I is a compound of type Ie. A, p, R 1 , and R 2Compounds Ie, where m is defined as herein and (m+n)=2 or 3, can be prepared analogously to literature procedures or the procedures described in Scheme 6 below. [ka]

[0183] Compound 1 can be coupled with piperazine or 1,4-diazepane derivative 11a, for example applying the conditions outlined in Scheme 1, step a, to give intermediate 15 (step a).

[0184] Intermediate 15 can be converted to compound IC (step b) analogously to the procedure described in Scheme 5, step a.

[0185] Alternatively, compound 1 can be coupled with a monoprotected piperazine or 1,4-diazepane derivative 11b (where PG denotes a suitable protecting group such as a Cbz or Boc protecting group applying the conditions outlined in Scheme 1, step a) to give intermediate 16 (step c).

[0186] Removal of the protecting group by known methods or as described in Scheme 5, step c, gives intermediate 15 (step d).

[0187] In some embodiments, intermediate 2 is an intermediate of type D. Intermediates of type D (where A, m, n, and R 2 is as described herein, and R 3 are hydrogen, halogen, C 1-6 -alkoxy, C 1-6 -Alkyl and halo-C 1-6 -alkyl) can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 7. [ka]

[0188] Alcohols of type 17 can be reacted with intermediate 18, where PG is a suitable protecting group such as Cbz, Boc, or Bn, in a suitable solvent such as THF using a suitable phosphine, such as triphenylphosphine, and a dialkyl azodicarboxylate, such as DEAD or DIAD (step a), to give intermediate 19. This type of Mitsunobu reaction has been widely described in the literature (e.g., Org. Chem. Front. (2015) Vol. 2, p. 739; Chem. Rev. (2009) Vol. 109, No. 6, p. 2551).

[0189] Removal of the protecting group from intermediate 19 by applying literature methods and methods described, for example, in Scheme 3, step c below, gives intermediate D (step b).

[0190] Alternatively, intermediate 19 may be prepared from alcohol 17, which can be alkylated with compound 20, where LG is a suitable leaving group such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate) using a suitable base in a suitable solvent (e.g., sodium hydride in DMF) at a temperature between 0°C and the boiling point of the solvent (step c).

[0191] Furthermore, intermediate 19 can be synthesized via alkylation of alcohols of type 18 with compound 21 under the conditions described in step c (step d).

[0192] In another embodiment, intermediate 2 is an intermediate of type E. Intermediates of type E (wherein A, m, n, R 2 , and R 3 (wherein R is as described herein) can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 8. 3 When is a hydroxy group, suitable protecting group strategies known to those skilled in the art can be applied. [ka]

[0193] The carboxylic acid functionality in derivatives 22, where PG means a suitable protecting group such as, for example, a Boc, Cbz, or Bn protecting group, is either commercially available or can be prepared by methods known in the art and can be converted into the acid chloride (LG=Cl) or Weinreb amide (LG=NMeOMe) by applying methods widely described in the literature to give intermediates 23 (step a).

[0194] Intermediate 23 is either commercially available or can be synthesized by methods known in the art and can be reacted with compounds of type 24 as described below to produce intermediate 25 (step b).

[0195] If compounds 24 are not commercially available, they can be prepared analogously to literature methods. For example, deprotonation of the reactive methyl group in optionally substituted heterocycle 27 with a suitable base such as nBuLi or LiHMDS in a suitable solvent, e.g., THF, hexane, or a mixture thereof, at temperatures ranging from −78° C. to room temperature, gives intermediate 24, where MX=Li (step d).

[0196] Compounds 24 (Grignard reagents) where MX = MgHal, where Hal is Cl, Br, or I, can be prepared by reaction of the corresponding substituted benzyl halide 28 with magnesium in a suitable solvent such as THF, optionally in the presence of a catalytic amount of iodine, at a temperature ranging between 0°C and the boiling point of the solvent (step d).

[0197] Compound 25 can be further converted to compound 26 by a deoxyfluorination reaction using a suitable fluorinating agent such as DAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or aminodifluorosulfinium tetrafluoroborate (e.g., XtalFluor-E®, XtalFluor-M® in the presence of triethylamine trihydrofluoride and TEA or DBU) in a suitable solvent such as DCM or ACN (step d).

[0198] Removal of the protecting group from intermediate 26 by applying literature methods and methods described, for example, in Scheme 3, step c below, gives intermediate E (step e).

[0199] In a further embodiment, intermediate 2 is an intermediate of type F. Intermediate F (where A, m, n, R 2 , and R 3 (wherein R is as described herein) can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 9. 3 When is a hydroxy group, suitable protecting group strategies known to those skilled in the art can be applied. [ka]

[0200] The carboxylic acid functionality in intermediate 29, where PG means a suitable protecting group such as, for example, a Boc, Cbz, or Bn protecting group, is either commercially available or can be prepared by methods known in the art, e.g., by conversion into the acid chloride (LG=Cl) or Weinreb amide (LG=NMeOMe) applying methods widely described in the literature, to give intermediate 30 (step a).

[0201] Intermediate 30 is either commercially available or can be synthesized by methods known in the art and can be reacted with compounds of type 31 as described below to produce intermediate 32 (step b).

[0202] If compounds 31 are not commercially available, they can be prepared analogously to literature methods. For example, deprotonation of the optionally substituted aryl or heteroaryl ring 33 with a suitable base such as n-BuLi, sec-BuLi, tert-BuLi, LiHMDS, NaH, or KH in a suitable solvent such as THF, n-hexane, or a mixture thereof at temperatures ranging from −78° C. to room temperature provides intermediate 31, where MX=Li, Na, or K, depending on the base used (step c).

[0203] Compounds 31 (Grignard reagents) in which MX = MgHal and Hal is Cl, Br, or I can be prepared by reaction of the corresponding optionally substituted aryl or heteroaryl halides 34 by direct magnesium insertion (e.g., powder in the presence of catalytic amounts of iodine, LiCl, or Rieke magnesium, magnesium turnings, optionally in the presence of an organic halide) or by halogen-magnesium exchange by treating 34, in which Hal is preferably bromine or iodine, with an alkylmagnesium halide such as iPrMgCl (optionally in the presence of LiCl) in a suitable solvent such as diethyl ether or THF at a temperature ranging between 0°C and the boiling point of the solvent (step d).

[0204] Compound 32 can be further converted to compound 35 by a deoxyfluorination reaction using a suitable fluorinating agent such as DAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or aminodifluorosulfinium tetrafluoroborate (e.g., XtalFluor-E®, XtalFluor-M® in the presence of triethylamine trihydrofluoride and TEA or DBU) in a suitable solvent such as DCM or ACN (step e).

[0205] Removal of the protecting group from intermediate 35 by applying literature methods and methods described, for example, in Scheme 3, step c below, gives intermediate F (step f).

[0206] In some embodiments, intermediate 2 is an intermediate of type G. Intermediates of type G (where A, m, n, R 2 is as described herein, and R 3 is hydrogen, C 1-6 -alkoxy, C 1-6 -Alkyl and halo-C 1-6 -alkyl) can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 10. [ka]

[0207] Intermediate 38 can be prepared from alcohol 36, in which PG is a suitable protecting group, such as Cbz, Boc, or Bn, and can be alkylated with compound 37, in which LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base, such as sodium hydride, potassium tert-butoxide, in a suitable solvent (e.g., DMF or THF) at a temperature between 0°C and the boiling point of the solvent (Step a).

[0208] Removal of the protecting group from intermediate 38 by applying literature methods and methods described, for example, in Scheme 4, step c below, gives intermediate G (step b).

[0209] In some embodiments, intermediate 2 is an intermediate of type H. Intermediates of type H (where A, m, n, R 2 , and R 3 (as described herein) can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 11. [ka]

[0210] Alcohols of type 17 can be reacted with intermediate 39, where PG is a suitable protecting group such as Cbz, Boc, or Bn, in a suitable solvent such as THF using a suitable phosphine, such as triphenylphosphine, and a dialkyl azodicarboxylate, such as DEAD or DIAD (step a), to give intermediate 41. This type of Mitsunobu reaction has been widely described in the literature (e.g., Org. Chem. Front. (2015) Vol. 2, p. 739; Chem. Rev. (2009) Vol. 109, No. 6, p. 2551).

[0211] Removal of the protecting group from intermediate 41 by applying literature methods or methods described for example in step c of scheme 4 below gives intermediate H (step b).

[0212] Alternatively, intermediate 41 may be prepared from alcohol 17, which can be alkylated with compound 40, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base such as Cs2CO3, NaH, or the like, in a suitable solvent, such as DMF, at a temperature between 0°C and the boiling point of the solvent (step c).

[0213] Reaction of intermediate H with intermediate 1, for example using the conditions described in Scheme 1, step a, gives compounds of type If, ​​where A, R 1 , R 2 , R 3 , m, and n are as defined herein. [ka]

[0214] Alternatively, compounds of type If can be prepared according to Scheme 12. [ka]

[0215] Alcohols of type 17 can be subjected to the Mitsunobu reaction of intermediate 42 with an appropriate phosphine, such as triphenylphosphine, and a dialkyl azodicarboxylate, such as DEAD or DIAD, in a suitable solvent, such as THF, to give compounds ID (step a). This type of Mitsunobu reaction has been widely described in the literature (e.g., Org. Chem. Front. (2015) Vol. 2, p. 739; Chem. Rev. (2009) Vol. 109, No. 6, p. 2551).

[0216] Alternatively, compound ID may be prepared directly from alcohol 17, which can be alkylated with compound 43, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base such as Cs2CO3, NaH, or the like, in a suitable solvent, such as DMF, at a temperature between 0°C and the boiling point of the solvent (step b).

[0217] In some embodiments, intermediate 2 is an intermediate of type J. Intermediates of type J (where A, m, n, R 2 , and R 3 (as described herein) can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 13. [ka]

[0218] Intermediate 46 may be prepared from heterocycloalkyl or heteroaryl 45, which can be alkylated with compound 44, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base such as Cs2CO3, K2CO3, NaH, in a suitable solvent such as DMF at a temperature between 0°C and the boiling point of the solvent (step a).

[0219] Removal of the protecting group from intermediate 46 by applying literature methods or methods described for example in step c of scheme 4 below gives intermediate J (step b).

[0220] Reaction of intermediate J with intermediate 1 gives compounds of type Ig, where A, R 1 , R 2 , R3 , m, and n are as defined herein. [ka]

[0221] Alternatively, compounds of type Ig may be prepared directly from heterocycloalkyl or heteroaryl 45, which can be alkylated with compound 47, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base such as Cs2CO3, K2CO3, NaH, in a suitable solvent such as DMF at a temperature between 0 °C and the boiling point of the solvent (Scheme 14). [ka]

[0222] In some embodiments, intermediate 2 is a type K intermediate. Type K intermediates (where A, m, n, R 2 , and R 3 as described herein) can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 15. [ka]

[0223] Alcohols of type 48 can be reacted with intermediate 39, where PG is a suitable protecting group such as Cbz, Boc, or Bn, to afford intermediate 49 (step a) using an appropriate phosphine, such as triphenylphosphine, and a dialkyl azodicarboxylate, such as DEAD or DIAD, in a suitable solvent, such as THF (Mitsunobu reaction). This type of Mitsunobu reaction has been widely described in the literature (e.g., Org. Chem. Front. (2015) Vol. 2, p. 739; Chem. Rev. (2009) Vol. 109, No. 6, p. 2551).

[0224] Removal of the protecting group from intermediate 49 by applying literature methods and methods described, for example, in step c of scheme 4 below, gives intermediate K (step b).

[0225] Alternatively, intermediate 49 may be prepared from alcohol 48, which can be alkylated with compound 40, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base such as Cs2CO3, NaH, or the like, in a suitable solvent, such as DMF, at a temperature between 0°C and the boiling point of the solvent (step c).

[0226] In some embodiments, intermediate 2 is an intermediate of type L. Intermediates of type L (where A, m, n, R 2 , and R 3 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 16. [ka]

[0227] Intermediate 51 is either commercially available or prepared by methods known in the art and can be prepared from aldehyde 50 using, for example, a Wittig reaction or a Horner-Wadsworth-Emmons (HWE) reaction using alkylidene triphenylphosphoranes of type 8a and phosphonates 8b, respectively, as described in Scheme 4, step a (step a).

[0228] The double bond in intermediate 51 is reduced applying the conditions described in step b of scheme 4 to give compound 52 (step b).

[0229] Removal of the protecting group from intermediate 52 as outlined in step c of scheme 4, applying methods known in the art, gives intermediate L (step c).

[0230] Removal of the protecting group from intermediate 51 as outlined in Scheme 4, step c, applying methods known in the art, gives intermediate M (step d). In one aspect, the present invention provides a method of making a urea compound of formula (I) described herein, comprising: R 1 is as described herein, preferably R 1 is hydrogen, [ka]

[0231] In the presence of a base and a urea-forming reagent, A, L, m, n, X, and R 2 is as described herein, [ka] forming the compound of formula (I).

[0232] In one embodiment there is provided a method according to the present invention wherein the base is sodium bicarbonate.

[0233] In one embodiment, there is provided a process according to the present 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.

[0234] In one aspect, the present invention provides a compound of formula (I) as described herein when prepared according to any one of the methods described herein.

[0235] MAGL inhibitory activity 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) described herein for inhibiting MAGL in a mammal.

[0236] In a further aspect, the present invention provides a compound of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.

[0237] In a further aspect, the present 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.

[0238] 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) described herein.

[0239] Compounds were profiled for MAGL inhibitory activity by measuring the enzymatic activity of MAGL following the hydrolysis of 4-nitrophenylacetate to yield 4-nitrophenol, which absorbs at 405-412 nm (G.G.Muccioli, G.Labar, D.M.Lambert, Chem. Bio. Chem. (2008) 9, 2704-2710). This assay is hereafter abbreviated as the "4-NPA assay."

[0240] The 4-NPA assay was performed in a total volume of 40 μL in a 384-well assay plate (black, clear-bottom, non-binding surface treatment, Corning reference number 3655). Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in 3-fold dilution steps in polypropylene plates to give a final concentration range in the assay of 25 μM to 1.7 nM. 1 μL of compound dilution (100% DMSO) was added to 19 μL of MAGL (recombinant wild-type) in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100ml)). The plate was shaken (Variomag Teleshake) at 2000 rpm for 1 minute and then incubated at room temperature for 15 minutes. To initiate the reaction, 20 μL of 4-nitrophenylacetate (Sigma, N-8130) was added in assay buffer containing 6% EtOH. The final concentrations in the assay were 1 nM MAGL and 300 μM 4-nitrophenylacetate. After shaking (1 min, 2000 rpm) and incubation at room temperature for 5 min, the absorbance at 405 nm was measured (Molecular Devices, SpectraMax Paradigm). A second measurement was then taken after 80 min of incubation at room temperature. The slope was calculated from the two measurements by subtracting the first measurement from the second.

[0241] Alternatively, compounds were profiled for MAGL inhibitory activity by detecting enzymatic activity following hydrolysis of the natural substrate, 2-arachidonoylglycerol, to generate arachidonic acid, followed by mass spectrometry. This assay is hereinafter abbreviated as the "2-AG assay."

[0242] The 2-AG assay was performed in a 384-well assay plate (PP, Greiner, catalog no. 784201) in a total volume of 20 μL. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in 3-fold dilution steps in the polypropylene plate 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% (vol / vol) Tween). After shaking, the plate was incubated at room temperature for 15 minutes. 10 μL of 2-arachidonoylglycerol in assay buffer was added to initiate the reaction. The final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglycerol. After shaking and incubation at room temperature for 30 min, the reaction was quenched by adding 40 μL of acetonitrile containing 4 μM d8-arachidonic acid. The amount of arachidonic acid was monitored using an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE cartridge (G9205A) was used with an acetonitrile / water liquid setup. The mass spectrometer was operated in negative electrospray mode, following the mass transitions of 303.1 → 259.1 for arachidonic acid and 311.1 → 267.0 for d8-arachidonic acid. Compound activity was calculated based on the intensity ratio (arachidonic acid / d8-arachidonic acid). [Table 1] TIFF0007637049000030.tif236169 TIFF0007637049000031.tif233169 TIFF0007637049000032.tif233169 TIFF0007637049000033.tif233169 TIFF0007637049000034.tif77169

[0243] In one aspect, the present invention provides compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein, wherein the compounds of formula (I) and their pharmaceutically acceptable salts or esters have an IC50 or IC60 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.

[0244] In one embodiment, the compounds of formula (I) and their pharmaceutically acceptable salts or esters described herein have an IC 50 (MAGL inhibition) values ​​range from 0.000001 μM to 25 μM, and certain compounds have IC 50 The IC value is 0.000005 μM to 10 μM, and certain compounds have IC 50 The value is 0.00005 μM to 5 μM.

[0245] In one embodiment, the present invention provides compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein, wherein the compounds of formula (I) and their pharmaceutically acceptable salts or esters have an IC50 activity against MAGL when measured in an assay comprising the steps of: 50 is less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM: (a) providing a solution of compound formula (I) or a pharmaceutically acceptable salt or ester thereof in DMSO; (b) providing a solution of MAGL (recombinant wild-type) in assay buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM ethylenediaminetetraacetic acid); (c) Addition of 1 μL of compound solution from step (a) to 19 μL of MAGL solution from step (b); (d) shaking the mixture at 2000 rpm for 1 min; (e) incubation at room temperature for 15 min; (f) addition of 20 μL of 4-nitrophenylacetate solution in assay buffer (50 mM tris(hydroxymethyl)aminomethane; 1 mM ethylenediaminetetraacetic acid, 6% EtOH); (g) shaking the mixture at 2000 rpm for 1 min; (h) incubation at room temperature for 5 min; (i) First, measure the absorbance of the mixture at 405 nm; (j) incubation at room temperature for another 80 min; (k) measuring the absorbance of the mixture at 405 nm a second time; (l) Calculation of the absorbance slope by subtracting the absorbance measured in (i) from the absorbance measured in (k); where: i) the concentration of the compound of formula (I) or a pharmaceutically acceptable salt or ester thereof in the assay after step (f) is in the range of 25 μM to 1.7 nM; ii) the concentration of MAGL in the assay after step (f) is 1 nM; iii) the concentration of 4-nitrophenylacetate in the assay after step (f) is 300 μM; and iv) Repeating steps (a)-(l) at least three times, each time with different concentrations of the compound of formula (I) or a pharmaceutically acceptable salt or ester thereof.

[0246] Uses of the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I) as described herein for use as a therapeutically active substance.

[0247] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

[0248] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for treating or preventing a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0249] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for treating or preventing a neurodegenerative disease in a mammal.

[0250] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for treating or preventing cancer in a mammal.

[0251] In one aspect, the present invention provides the use of a compound of formula (I) as described herein 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.

[0252] In a preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein for treating or preventing multiple sclerosis, Alzheimer's disease, and / or Parkinson's disease in a mammal.

[0253] In a particularly preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein for treating or preventing multiple sclerosis in a mammal.

[0254] In one aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

[0255] In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0256] In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of cancer in a mammal.

[0257] In one embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of a neurodegenerative disease in a mammal.

[0258] In one aspect, the present invention provides a compound of formula (I) as described herein 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.

[0259] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, and / or Parkinson's disease in a mammal.

[0260] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of multiple sclerosis in a mammal.

[0261] In one aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

[0262] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for treating or preventing a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0263] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for treating or preventing a neurodegenerative disease in a mammal.

[0264] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for treating or preventing cancer in a mammal.

[0265] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein 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.

[0266] In a preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, and / or Parkinson's disease in a mammal.

[0267] In a particularly preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for treating or preventing multiple sclerosis in a mammal.

[0268] 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, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0269] 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) as described herein.

[0270] 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) as described herein.

[0271] In one aspect, the present invention provides a method for the treatment or prevention of spasticity associated with multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, and / or pain in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0272] 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, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0273] In a particularly preferred embodiment, the present invention provides a method for the treatment or prevention of multiple sclerosis in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0274] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein and a therapeutically inert carrier.

[0275] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (e.g., in the form of nasal drops), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0276] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert inorganic or organic adjuvants for the preparation 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.

[0277] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0278] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0279] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0280] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0281] Furthermore, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, and may also contain other therapeutically valuable substances.

[0282] Dosage can vary widely and will of course be adapted to the individual requirements of each particular case.Generally, 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 (for example, about 300 mg / person) will be appropriate, preferably divided into 1 to 3 individual doses, for example, of the same amount.However, it is clear that the upper limit given herein can be exceeded if this is indicated.

[0283] According to the present invention, the compounds of formula (I) or pharmaceutically acceptable salts and esters thereof can be used for the treatment or prevention of type 2 diabetes related microvascular complications (such as, but not limited to, diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy), coronary artery disease, obesity, and underlying inflammatory diseases, chronic inflammatory and autoimmune / inflammatory diseases. [Example]

[0284] The present invention will be more fully understood by reference to the following examples, the claims of which, however, should not be construed as limiting the scope of these examples.

[0285] Where 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.

[0286] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0287] Method A1 Example 11 rac-(4aR,8aS)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0288] To a solution of 4-nitrophenyl 4-(4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (100 mg, 245 μmol, BB2) in DMF (1.5 mL) was added rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (45.9 mg, 294 μmol, ChemBridge Corporation, BB1) and TEA (49.6 mg, 68.3 μL, 490 μmol). The resulting reaction mixture was heated at 80° C. for 18 h. The reaction mixture was diluted with EtOAc and washed three times with HO and NaHCO. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, eluting with a gradient of MeOH / EtOAc 0-10%) to give the title compound as an off-white oil (0.045 g; 43.2%). MS (ESI): m / z=426.4 [M+H] + .

[0289] Method A2 Example 3 rac-(4aR,8aS)-6-[4-[(4-tert-butylthiazol-2-yl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0290] To an ice-cold suspension of bis(trichloromethyl)carbonate (45.3 mg, 153 μmol, CAS RN: 32315-10-9) and NaHCO (73.3 mg, 873 μmol) in DCM (2 mL) was added a portion of 4-tert-butyl-2-(4-piperidylmethyl)thiazole hydrochloride (60 mg, 218 μmol, Enamine Ltd), and the mixture was stirred at room temperature overnight. The suspension was filtered, and the filtrate was evaporated. The residue was diluted in DCM (1 mL) and added dropwise to an ice-cold solution of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (50 mg, 218 μmol, ChemBridge Corporation, BB1) and DIPEA (152 μL, 870 μmol) in DCM (1 mL). The suspension was stirred at room temperature for 19 hours to give a solution. The reaction mixture was poured onto H2O and DCM, and the layers were separated. The aqueous layer was extracted three times with DCM. The organic layer was washed twice with water, dried over MgSO4, filtered, treated with silica gel, and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of DCM:MeOH (100:0 to 90:10) to give the desired compound as a colorless foam (0.039 g; 42.5%). MS (ESI): m / z = 421.2 [M+H] + .

[0291] Method A3 Example 34 (+)- or (-)-4-[[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-4-piperidyl]methyl]benzonitrile [ka]

[0292] To an ice-cold solution of bis(trichloromethyl)carbonate (39.9 mg, 134 μmol, CAS RN: 32315-10-9) in DCM was added NaHCO (64.5 mg, 768 μmol) and (+)-cis-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (30 mg, 192 μmol, BB1a), and the mixture was stirred at room temperature overnight. To the suspension was added 4-(piperidin-4-ylmethyl)benzonitrile (38.5 mg, 192 μmol, CAS RN: 333987-57-8) and DIPEA (99.3 mg, 134 μL, 768 μmol). The suspension was stirred at room temperature for 4.5 h. The reaction mixture was poured onto HO and DCM, and the layers were separated. The aqueous layer was extracted three times with DCM. The organic layer was washed twice with HO, dried over MgSO, filtered, treated with silica gel, and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of DCM:MeOH (100:0 to 90:10) to give the desired compound as a colorless gum (0.023 g; 31.3%). MS (ESI): m / z = 383.2 [M+H] + .

[0293] Method A4 Example 79 (4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0294] To a solution of 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (25 mg, 77.8 μmol, BB7a) in NMP (1 mL) was added DIPEA (25.1 mg, 34 μL, 195 μmol) and 4-((2-chloro-4-fluorophenoxy)methyl)-4-methylpiperidine hydrochloride (19.5 mg, 66.1 μmol, BB12). The reaction vial was stirred at 140° C. for 45 min. The crude material was purified by reverse-phase HPLC to yield 23.2 mg of the desired product. MS (ESI): m / z=440.2 [M+H] + .

[0295] Method A5 Example 64 (4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0296] A microwave vial was dried with a heat gun and charged with bis(trichloromethyl)carbonate (26.6 mg, 89.6 μmol) and sodium bicarbonate (32.3 mg, 384 μmol). The flask was placed under argon and DCM (1 mL) was added to give a suspension. The suspension was cooled in an ice bath and 4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine hydrochloride (36.1 mg, 121 μmol, BB15) was added. The mixture was stirred at 0° C. for 15 minutes and at room temperature overnight. The reaction mixture was cooled in an ice bath, and DCM (500 μL) and DIPEA (49.7 mg, 67.1 μL, 384 μmol) were added, followed by (4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (21.1 mg, 47.5 μmol, BB1a). The resulting off-white suspension was stirred at room temperature for 7 h. The reaction mixture was poured onto water, DCM was added, and the layers were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated to give a yellow oil (58 mg). The crude product was purified by reverse-phase HPLC and lyophilized to give the title compound as a white solid (21.1 mg, 37.1% yield). MS (ESI): m / z=444.2 [M+H] + .

[0297] Method A6 Example 39 (4aR,8aS)-6-[4-[(2-fluoro-4-methoxyphenoxy)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0298] To a solution of 2-fluoro-4-methoxyphenol (16.5 mg, 13 μL, 116 μmol), (4aR,8aS)-6-[4-(hydroxymethyl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (34.5 mg, 116 μmol, BB16), and triphenylphosphine (33.5 mg, 128 μmol) in DCM (580 μL) was added dropwise DIAD (25.8 mg, 24.8 μL, 128 μmol), and the reaction was stirred at room temperature for 22 h. The reaction mixture was diluted with DCM and washed with 1 M aqueous NaOH. The phases were separated, and the aqueous phase was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to dryness to give a red oil (99 mg). The crude product was purified by reverse-phase HPLC and lyophilized to give the desired compound (20 mg, 40.9% yield) as a white solid. MS (ESI): m / z = 422.3 [M+H] + .

[0299] Method A7 Examples 42 and 43 (4aS,8aR)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 42) and (4aR,8aS)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 43) [ka]

[0300] Step (a) rac-(4aR,8aS)-6-(4-(chloromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0301] To a solution of rac-(4aR,8aS)-6-(4-(hydroxymethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (80 mg, 269 μmol, BB16) in dry DMF (2 mL), DIPEA (52.2 mg, 70.5 μL, 404 μmol), DMAP (1.64 mg, 13.5 μmol), and methanesulfonyl chloride (46.2 mg, 404 μmol) were added, and the reaction mixture was stirred at room temperature for 2 h. 4,4-Difluoropiperidine hydrochloride (84.8 mg, 538 μmol) was added, and DIPEA (139 mg, 188 μL, 1.08 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction was then stirred at 70° C. for 14 h. The crude reaction was subjected to reverse phase HPLC purification to yield the title compound as a by-product (35 mg). MS (ESI): m / z = 315.1 [M+H] + .

[0302] Step (b) (4aS,8aR)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 42) and (4aR,8aS)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 43) [ka]

[0303] To a solution of rac-(4aR,8aS)-6-(4-(chloromethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (70 mg, 222 μmol) in dry DMF (1 mL) was added 6-(trifluoromethyl)pyridin-3-ol (54.2 mg, 332 μmol) and CsCO (108 mg, 332 μmol). The reaction mixture was stirred at 95 °C for 18 h. Insoluble material was removed by filtration through Celite, the filtrate was concentrated to dryness, and the crude residue was purified and the enantiomers separated by chiral SFC to yield Example 42 (33.8 mg) and Example 43 (32.5 mg). For both examples, MS (ESI): m / z = 443.2 [M+H] + .

[0304] Method A8 Example 26 (4aS,8aR)-6-(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0305] To a solution of rac-(4aR,8aS)-6-(4-(hydroxymethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (75 mg, 252 μmol, BB16) in dry DMF (2 mL), DIPEA (39.1 mg, 52.9 μL, 303 μmol), DMAP (3.08 mg, 25.2 μmol), and methanesulfonyl chloride (30.3 mg, 265 μmol) were added, and the reaction mixture was stirred at room temperature for 2 h. 4-(Trifluoromethyl)-1H-pyrazole (68.6 mg, 504 μmol) and KCO (87.1 mg, 631 μmol) were added, and the reaction mixture was stirred at 90 °C for 18 h. The insoluble material was removed by filtering through Celite, the filtrate was concentrated to dryness in vacuo, and the crude residue was directly purified by flash chromatography with eluent mixtures of DCM and MeOH (0%-10%) to yield 90 mg of the desired product as a racemate. This was subjected to SFC chiral separation to yield Example 26 (25 mg) as a colorless oil and the enantiomer (31 mg) as a colorless oil. MS (ESI): m / z = 416.2 [M+H] + .

[0306] Method A9 Example 37 (4aR,8aS)-6-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0307] To a solution of (4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (40 mg, 256 μmol, BB1a) in dry DMF (2 mL) cooled to 0 °C, DIPEA (39.7 mg, 53.7 μL, 307 μmol) and 4-nitrophenyl chloroformate (61.9 mg, 307 μmol) were added. The reaction mixture was stirred at 0 °C for 20 min. LCMS control indicated the formation of the intermediate carbamate. DIPEA (116 mg, 157 μL, 896 μmol) and 4,4-difluoro-1-(piperidin-4-ylmethyl)piperidine dihydrochloride (89.5 mg, 307 μmol, BB17) were added, and the reaction mixture was stirred at room temperature for 30 min, followed by stirring at 100 °C for 14 h. The volatiles were removed in vacuo and the crude residue was subjected directly to SFC purification to yield the desired compound (9.5 mg) as a light orange oil. MS (ESI): m / z=401.3 [M+H] + .

[0308] Method A10 Example 125 (+)-(4aR,8aS)-6-[4-[2-(2-chlorophenyl)ethynyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0309] In a sealed tube, 4-[2-(2-chlorophenyl)ethynyl]piperidine (BB18, 0.02 g, 0.078 mmol) and 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB7a, 0.025 g, 0.078 mmol) were mixed in ACN (0.6 mL). Huenig's base (0.041 mL, 0.234 mmol) was then added, followed by DMAP (0.005 g, 0.039 mmol), and the reaction mixture was heated at 90 °C overnight. The mixture was evaporated to dryness, and the crude residue was purified by reverse-phase HPLC to give the title compound (0.013 g, 41%) as a colorless solid. MS (ESI): m / z = 402.2 [M+H] + .

[0310] Method B1 Example 1 (+)-(4aR,8aS)-6-(4-((4-(tert-butyl)thiazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0311] The enantiomers of Example 3 were separated by preparative chiral HPLC (Chiralcel OD column) using an isocratic mixture of EtOH (containing 0.05% NHOAc):n-heptane (20:80). Evaporation of the fractions afforded the desired compound as a colorless solid (0.012 g; 34.3%). MS (ESI): m / z = 421.2 [M+H] + .

[0312] Method B2 Example 12 (+)- or (-)-(4aR,8aS)-6-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0313] The enantiomers of Example 13 were separated by preparative chiral HPLC (Chiralpak AD column) using an isocratic mixture of EtOH (containing 0.05% NHOAc):n-heptane (40:60). Evaporation of the fractions yielded the desired compound as a light brown oil (0.013 g; 28.4%). MS (ESI): m / z = 428.2 [M+H] + .

[0314] Method B3 Examples 103, 104, and 105 (4aR,8aS)-6-[2-methyl-3-[[4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (Isomer A+B, Isomer C, Isomer D) [ka]

[0315] The stereoisomers of Example 117 were separated by preparative chiral HPLC (Reprosil Chiral NR column) using an isocratic mixture of EtOH (containing 0.05% NHOAc):n-heptane (40:60) to give Examples 103 and 104 as single isomers and Example 105 as a mixture of two stereoisomers. Evaporation of the fractions gave the desired compound as a colorless solid.

[0316] Method C Example 21 rac-(4aR,8aS)-6-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0317] A mixture of rac-cis-6-(piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (35 mg, 130 μmol, BB3), 4-(trifluoromethyl)benzaldehyde (22.7 mg, 17.4 μL, 130 μmol), and sodium triacetoxyborohydride (27.6 mg, 130 μmol) in DCM (1 mL) was stirred at room temperature for 15 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give the desired compound as a white solid (8 mg, 14.4%). MS (ESI): m / z = 427.4 [M+H] + .

[0318] Unless otherwise indicated, the following examples were synthesized from rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (ChemBridge Corporation) and appropriate building blocks similar to the reaction methods described herein.

[0319] [Table 2] TIFF0007637049000052.tif217169 TIFF0007637049000053.tif217169 TIFF0007637049000054.tif221169 TIFF0007637049000055.tif214169 TIFF0007637049000056.tif200169 TIFF0007637049000057.tif244169 TIFF0007637049000058.tif225169 TIFF0007637049000059.tif232169 TIFF0007637049000060.tif239169 TIFF0007637049000061.tif243169 TIFF0007637049000062.tif238169 TIFF0007637049000063.tif232169 TIFF0007637049000064.tif226169 TIFF0007637049000065.tif244169 TIFF0007637049000066.tif250169 TIFF0007637049000067.tif241169 TIFF0007637049000068.tif199169 TIFF0007637049000069.tif242169 TIFF0007637049000070.tif243169 TIFF0007637049000071.tif226169 TIFF0007637049000072.tif206169 TIFF0007637049000073.tif253169 TIFF0007637049000074.tif247169 TIFF0007637049000075.tif198169 TIFF0007637049000076.tif238169 TIFF0007637049000077.tif222169 TIFF0007637049000078.tif225169 TIFF0007637049000079.tif222169 TIFF0007637049000080.tif244169 TIFF0007637049000081.tif245169 TIFF0007637049000082.tif227169 TIFF0007637049000083.tif245169 TIFF0007637049000084.tif231169 TIFF0007637049000085.tif254169 TIFF0007637049000086.tif202169 TIFF0007637049000087.tif252169 TIFF0007637049000088.tif239169 TIFF0007637049000089.tif244169 TIFF0007637049000090.tif238169 TIFF0007637049000091.tif237169 TIFF0007637049000092.tif244169 TIFF0007637049000093.tif239169 TIFF0007637049000094.tif244169 TIFF0007637049000095.tif247169 TIFF0007637049000096.tif238169 TIFF0007637049000097.tif241169 TIFF0007637049000098.tif240169 TIFF0007637049000099.tif225169 TIFF0007637049000100.tif226169 TIFF0007637049000101.tif248169 TIFF0007637049000102.tif254169 TIFF0007637049000103.tif231169 TIFF0007637049000104.tif246169 TIFF0007637049000105.tif231169 TIFF0007637049000106.tif201169 TIFF0007637049000107.tif208169 TIFF0007637049000108.tif200169 TIFF0007637049000109.tif202169 TIFF0007637049000110.tif200169 TIFF0007637049000111.tif230169 TIFF0007637049000112.tif224169 TIFF0007637049000113.tif240169 TIFF0007637049000114.tif230169 TIFF0007637049000115.tif253169 TIFF0007637049000116.tif236169 TIFF0007637049000117.tif236169 TIFF0007637049000118.tif235169

[0320] Example 222 (4aR,8aS)-6-[3-[[6-fluoro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0321] Step (a) tert-butyl 3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate

[0322] To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS Registry Number 142253-56-3) (2.60 g, 13.9 mmol) and 2,6-dichloro-4-(trifluoromethyl)pyridine (CAS Registry Number 39890-98-7) (3.00 g, 13.9 mmol) in THF (60 mL) was added NaH (60%, 1.11 g, 27.8 mmol), and the mixture was stirred for 3 h at 25 °C. The solution was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were concentrated in vacuo to give crude tert-butyl 3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate (3.00 g, 59%) as a colorless oil. This was used directly in the next step. LC-MS (ESI): m / z=367.1 [M+H] + .

[0323] Step (b) 2-(azetidin-3-ylmethoxy)-6-chloro-4-(trifluoromethyl)pyridine

[0324] A solution of trifluoroacetic acid (6.3 mL, 81.8 mmol, 10 equiv.) and tert-butyl 3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate (3.00 g, 8.18 mmol) in DCM (30 mL) was stirred at 25° C. for 4 h. The solution was concentrated in vacuo to give a residue, which was purified by preparative HPLC (HCl conditions) to give 2-(azetidin-3-ylmethoxy)-6-chloro-4-(trifluoromethyl)pyridine (1.00 g, 46%) as a white solid. LC-MS (ESI): m / z=267.0 [M+H] + .

[0325] Step (c) (4aR,8aS)-6-[3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

[0326] A solution of 2-(azetidin-3-ylmethoxy)-6-chloro-4-(trifluoromethyl)pyridine (150 mg, 0.560 mmol), N,N-diisopropylethylamine (0.29 mL, 1.69 mmol), and 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB7a) (199 mg, 0.620 mmol) in ACN (5 mL) was stirred for 16 h at 25° C. The solution was concentrated in vacuo to give a residue. This was purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (100 mg, 40%) as a colorless oil. LC-MS (ESI): m / z = 449.2 [M+H] + .

[0327] Step (d) (4aR,8aS)-6-[3-[[6-fluoro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

[0328] A solution of (4aR,8aS)-6-[3-[[6-chloro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (75 mg, 0.17 mmol) and cesium fluoride (101 mg, 0.670 mmol) in DMSO (3 mL) was stirred at 80 °C for 16 h. The solution was filtered and purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[3-[[6-fluoro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (22 mg, 28%) as a white solid. LC-MS (ESI): m / z = 433.0 [M+H] + .

[0329] Example 223 (4aR,8aS)-6-[3-[[6-fluoro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0330] Step (a) tert-butyl 3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate

[0331] To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS Registry Number 142253-56-3) (1.56 g, 8.33 mmol) in THF (50 mL) was added NaH (60%, 741 mg, 18.5 mmol), followed by 2,6-dichloro-3-(trifluoromethyl)pyridine (CAS Registry Number 55304-75-1) (2.00 g, 9.26 mmol). The resulting mixture was stirred at 25 °C for 3 h. The solution was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were concentrated in vacuo to give a residue. This was purified by flash column chromatography (petroleum ether: EtOAc = 5:1) to give tert-butyl 3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate (1.10 g, 32%) as a colorless oil. LC-MS (ESI): m / z = 311.0 [M-56+H] + .

[0332] Step (b) 6-(azetidin-3-ylmethoxy)-2-chloro-3-(trifluoromethyl)pyridine

[0333] A solution of trifluoroacetic acid (0.37 mL, 4.8 mmol) and tert-butyl 3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carboxylate (1.1 g, 3.0 mmol) in DCM (30 mL) was stirred at 25° C. for 4 hours. The solution was concentrated in vacuo to give a residue, which was purified by preparative HPLC (HCl conditions) to give 6-(azetidin-3-ylmethoxy)-2-chloro-3-(trifluoromethyl)pyridine (600 mg, 75%) as a white solid. LC-MS (ESI): m / z=267.0 [M+H] + .

[0334] Step (c) (4aR,8aS)-6-[3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

[0335] To a solution of 6-(azetidin-3-ylmethoxy)-2-chloro-3-(trifluoromethyl)pyridine (100 mg, 0.380 mmol) and 4-nitrophenyl(4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB7a) (120 mg, 0.380 mmol) in ACN (5 mL) was added N,N-diisopropylethylamine (0.13 mL, 0.75 mmol) with stirring at 25 °C. The solution was stirred at 25 °C for 16 h. The solution was concentrated in vacuo to give a residue. This was purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (76 mg, 45%) as a white solid. LC-MS (ESI): m / z = 449.1 [M+H] + .

[0336] Step (d) (4aR,8aS)-6-[3-[[6-fluoro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

[0337] A solution of (4aR,8aS)-6-[3-[[6-chloro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (70 mg, 0.16 mmol) and cesium fluoride (95 mg, 0.62 mmol) in DMSO (3 mL) was stirred at 60 °C for 24 h. The solution was filtered and then purified by preparative HPLC (TFA conditions) to give (4aR,8aS)-6-[3-[[6-fluoro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (38 mg, 49%) as a white solid. LC-MS (ESI): m / z = 433.3 [M+H] + .

[0338] Building Block Synthesis 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

[0339] 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).

[0340] 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] + .

[0341] 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] + .

[0342] BB2 (4-Nitrophenyl)4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

[0343] To a solution of 4-(4-(trifluoromethyl)benzyl)piperidine (100 mg, 411 μmol, CAS RN: 192990-03-7) in DCM (1 mL) was added TEA (83.2 mg, 115 μL, 822 μmol). Upon cooling to 0 °C, 4-nitrophenyl chloroformate (91.1 mg, 452 μmol, CAS RN: 7693-46-1) was added, and the reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was diluted with DCM and subsequently washed with HO and saturated aqueous NaHCO. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (10 g silica, eluting with 0-50% EtOAc / heptane) to afford the title compound as a bright yellow solid (0.165 g; 98.3%). MS (ESI): m / z = 409.3 [M+H] + .

[0344] BB3 rac-(4aR,8aS)-6-(piperazine-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

[0345] To a mixture of rac-tert-butyl 4-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperazine-1-carboxylate (100 mg, 271 μmol) in DCM (3 mL) was added TFA (155 mg, 105 μL, 1.36 mmol) and the mixture was stirred at room temperature for 15 h under an argon atmosphere. The reaction mixture was washed with saturated aqueous NaHCO3. The H2O layer was concentrated in vacuo to give a white solid, which was triturated with DCM for 30 min and then filtered. The filtrate was concentrated to give a light yellow gum (70 mg, 96.1%). MS (ESI): m / z = 269.3 [M+H] + .

[0346] Step (a) rac-tert-butyl 4-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperazine-1-carboxylate

[0347] To a mixture of triphosgene (1.29 g, 4.36 mmol) and Na2CO3 (1.98 g, 18.7 mmol) in THF (3 mL) at 0 °C was added dropwise a solution of tert-butyl piperazine-1-carboxylate (1.16 g, 6.23 mmol, CAS RN: 57260-71-6) in THF (90 mL). The reaction mixture was stirred for 10 min at 0 °C, then allowed to warm to room temperature and continued stirring at room temperature for 5 h. The suspension was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in THF (40 mL) and added dropwise to a stirred suspension of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one hydrochloride (1200 mg, 6.23 mmol, Chembridge Corporation) and DIPEA (4.83 g, 6.53 mL, 37.4 mmol) in THF (40 mL) at 0 °C. After 30 min at 0 °C, the reaction mixture was warmed to room temperature and stirred at room temperature for 15 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was diluted with DCM and washed with water, aqueous NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to give a white solid (1.13 g, 58.6%). MS (ESI): m / z = 313.3 [M+H] + .

[0348] BB4 (4-Nitrophenyl)4-(phenoxymethyl)piperidine-1-carboxylate

[0349] This compound was prepared analogously to BB2 using 4-(phenoxymethyl)piperidine (CAS N63614-86-8) to give the title compound as a white solid, which was used in the next step without further purification.

[0350] BB5 2-(4-piperidylmethyl)-5-(trifluoromethyl)pyridine hydrochloride

[0351] tert-Butyl 4-[[5-(trifluoromethyl)-2-pyridyl]methyl]piperidine-1-carboxylate (320 mg, 0.930 mmol) was dissolved in 4 M HCl in EtOAc (10.0 mL, 40 mmol), and the solution was stirred at 20 °C for 2 h. The mixture was concentrated to afford the desired compound as a bright yellow solid (0.259, 94.8%). MS (ESI): m / z = 245.0 [M-HCl + H] + .

[0352] Step (a) tert-butyl 4-[[5-(trifluoromethyl)-2-pyridyl]methyl]piperidine-1-carboxylate

[0353] 2-Bromo-5-(trifluoromethyl)pyridine (500.0 mg, 2.21 mmol, CAS RN: 1000773-62-5) was degassed, and then a 0.5 M solution of 9-BBN in THF (4.87 mL, 2.43 mmol, CAS RN: 280-64-8) was added. The resulting solution was refluxed for 1 hour. After cooling to room temperature, the solution was added to a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (480.1 mg, 2.43 mmol, CAS RN: 159635-49-1), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (161.89 mg, 0.220 mmol, CAS RN: 72287-26-4), and K2CO3 (611.56 mg, 4.42 mmol) in DMF (5 mL) and water (0.5 mL). The resulting mixture was heated at 80 °C for 4 h. The mixture was cooled to room temperature, poured into water, the pH was adjusted to 11 with 10% aqueous NaOH, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated to give a crude oil. This was purified by column chromatography (silica adsorbent; PE: EtOAc 10:1, then a gradient of 5:1) to yield the desired compound as a light yellow oil (320 mg, 0.930 mmol, 42%). MS (ESI): m / z = 289.0 [M-C4H8+H] + .

[0354] BB6 rac-(4aS,8aS)-Hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0355] rac-Benzyl (4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (125 mg, 431 μmol) was dissolved in MeOH (5 mL). The reaction solution was degassed in vacuo and backfilled with argon. Pd—C (20 mg, 188 μmol) was added under an argon atmosphere. Argon was evacuated from the reaction mixture and backfilled with hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 15 hours. The reaction mixture was syringe filtered and concentrated in vacuo to give the desired product as a white solid (62 mg, 92.2%). MS (ESI): m / z=157.098 [M+H] + .

[0356] Step (a) rac-benzyl (3S,4S)-3-(2-chloroacetamido)-4-hydroxypiperidine-1-carboxylate

[0357] To a stirred suspension of rac-benzyl (3S,4S)-3-amino-4-hydroxypiperidine-1-carboxylate (317 mg, 1.27 mmol, synthesized according to U.S. Patent Application Publication No. 2011 / 59118 A1) and sodium acetate (208 mg, 2.53 mmol, CAS RN: 127-09-3) in a mixture of acetone (4 mL) and HO (0.5 mL) was added dropwise a solution of chloroacetyl chloride (150 mg, 107 μL, 1.33 mmol, CAS RN: 79-04-9) in acetone (3 mL) at 0-5 °C. After the addition, the reaction mixture was stirred at room temperature for 1 h and then evaporated to dryness to give a yellow gum. The crude product was purified by silica gel chromatography to give the desired product as a yellow solid (385 mg, 93%). MS (ESI): m / z = 325.2 [M−H] - .

[0358] Step (b) rac-benzyl (4aS,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate

[0359] To a stirred solution of rac-benzyl (3S,4S)-3-(2-chloroacetamido)-4-hydroxypiperidine-1-carboxylate (385 mg, 1.18 mmol) in dry THF (4 mL) was added NaH (67.9 mg, 1.7 mmol) at 0 °C. The mixture was allowed to reach room temperature and then stirred under an argon atmosphere for 90 min. H2O (5 mL) was added and stirring was continued at room temperature for 10 min. THF was removed from the reaction mixture in vacuo. The residue was treated with DCM, and the organic phase was washed with H2O and brine, dried over Na2SO4, filtered, and then concentrated in vacuo. The residue was purified by flash chromatography (12 g reverse phase column, gradient 0-100% ACN (0.1% FA) in water (0.1% FA) to give the desired product as a white solid (133 mg, 38.9%). MS (ESI): m / z = 291.3 [M+H] + .

[0360] BB7a and BB7b 4-Nitrophenyl (4aR,8aS)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB7a) and 4-Nitrophenyl (4aS,8aR)-3-oxohexahydro-2H-pyrido[4,3-b][1,4]oxazine-6(5H)-carboxylate (BB7b)

[0361] 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 mixture was diluted with DCM and transferred to a separatory funnel for extraction with saturated aqueous NaCO. The organic phase was collected, and the aqueous phase was back-extracted with DCM. The combined organic phases were dried over NaSO and evaporated to dryness to yield 6.62 g of crude racemic product (BB7) as a yellow solid. The crude material was subjected directly to chiral SFC separation to yield enantiomer BB7b (2.72 g, second eluting enantiomer) as a yellow solid and enantiomer BB7a (3.25 g, first eluting enantiomer) as a light beige solid, but contaminated with BB7b. Further SFC chiral separation yielded 2.71 g of BB7a. MS (ESI): m / z = 322.2 [M+H] for both enantiomers. + .

[0362] BB8 5-tert-Butyl-2-(4-piperidylmethyl)oxazole; Hydrochloride

[0363] A solution of tert-butyl 4-[(5-tert-butyloxazol-2-yl)methyl]piperidine-1-carboxylate (167 mg, 518 μmol) in 2 M HCl in diethyl ether (2.59 mL, 5.18 mmol) was stirred at room temperature for 5 hours, after which another 1.29 mL (2.59 mmol) of 2 M HCl in diethyl ether was added. The white suspension was stirred at room temperature overnight. The mixture was cooled in an ice bath, then filtered and washed with diethyl ether to give the desired compound as a colorless solid (0.126 g, 94.0%). MS (ESI): m / z = 223.2 [M+H] + .

[0364] Step (a) (5-tert-butyloxazol-2-yl)methyl-triphenyl-phosphonium bromide

[0365] To a solution of 2-(bromomethyl)-5-(tert-butyl)oxazole (600 mg, 2.75 mmol, CAS RN: 1334492-54-4) in diethyl ether (5 mL), triphenylphosphine (722 mg, 2.75 mmol, CAS RN: 603-35-0) was added, and the mixture was stirred at room temperature for 64 hours. The suspension was cooled in an ice bath and then filtered. The filter cake was washed with a small amount of cold diethyl ether to give the desired compound as a bright yellow solid (0.864 g, 65.4%). MS (ESI): m / z = 400.2 [M-Br+H] + .

[0366] Step (b) tert-butyl 4-[(5-tert-butyloxazol-2-yl)methylene]piperidine-1-carboxylate

[0367] To an ice-cooled suspension of (5-tert-butyloxazol-2-yl)methyl-triphenyl-phosphonium bromide (355 mg, 739 μmol) in THF (7 mL) was added a 1 M solution of potassium tert-butylate in THF (738 μL, 738 μmol), and the reaction was stirred at this temperature for 15 min. Then, tert-butyl 4-oxopiperidine-1-carboxylate (162 mg, 813 μmol, CAS RN: 79099-07-3) was added to the turbid mixture, followed by an orange solution. Stirring was continued at 0°C for another 15 min, then at room temperature for 42 h. The reaction mixture was poured into half-saturated aqueous NH4Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, treated with silica gel, and evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc (100:0 to 50:50) to give the desired compound as a colorless solid (0.180 mg; 76.0%). MS (ESI): m / z = 321.3 [M+H] + .

[0368] Step (c) tert-butyl 4-[(5-tert-butyloxazol-2-yl)methyl]piperidine-1-carboxylate

[0369] To a solution of tert-butyl 4-[(5-tert-butyloxazol-2-yl)methylene]piperidine-1-carboxylate (180 mg, 562 μmol) in MeOH (1 mL) and EtOAc (1 mL) was added Pd / C 10% (17.9 mg, 16.9 μmol), and the suspension was stirred under a hydrogen atmosphere at 1.3 bar for 2 h. The suspension was microfiltered, and the filtrate was evaporated to give the desired compound as a colorless oil (0.167 g; 92.2%). MS (ESI): m / z = 323.3 [M+H] + .

[0370] BB12 4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-methyl-piperidine; hydrochloride

[0371] To a solution of tert-butyl 4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-methyl-piperidine-1-carboxylate (186 mg, 0.520 mmol) in EtOAc (1.5 mL) was added HCl in EtOAc (4 M, 1.5 mL) at 0 °C. The solution was stirred at 15 °C for 3 h. The solution was concentrated in vacuo and then lyophilized to dryness to give the desired product as a white solid (64.0 mg, 0.220 mmol, 40.3% yield). MS (ESI): m / z = 258 [M + H] + .

[0372] Step (a) tert-butyl 4-methyl-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate

[0373] To a solution of tert-butyl 4-(hydroxymethyl)-4-methyl-piperidine-1-carboxylate (500 mg, 2.14 mmol, CAS RN: 614730-97-1) in DCM (5 mL) was added NEt (0.45 mL, 3.22 mmol) and methanesulfonyl chloride (0.23 mL, 3.0 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was washed twice with water (3 mL each) at 0 °C and dried over Na SO . The organic layer was concentrated in vacuo to afford the desired compound as a colorless oil (766 mg, 2.46 mmol, 98.5%), which was used in the next step without further purification. MS (ESI): m / z = 256 [M-56 + H] + .

[0374] Step (b) tert-butyl 4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-methyl-piperidine-1-carboxylate

[0375] To a solution of tert-butyl 4-methyl-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (450 mg, 1.46 mmol) in DMF (5 mL) was added CsCO (620 mg, 1.9 mmol) and 2-chloro-4-fluorophenol (0.14 mL, 1.46 mmol) at 15 °C. The mixture was heated to 90 °C and stirred for 16 h. The reaction solution was diluted with EtOAc (10 mL), washed twice with brine (10 mL each), and dried over NaSO. The organic layer was concentrated in vacuo to give the crude product (0.7 g) as a light yellow oil. The crude product was purified by preparative HPLC and lyophilized to give the desired compound as a colorless solid (186 mg, 0.520 mmol, 35.5% yield). MS (ESI): m / z = 302 [M-56 + H] + .

[0376] BB15 4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-fluoro-piperidine; hydrochloride

[0377] To a solution of tert-butyl 4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-fluoro-piperidine-1-carboxylate (220 mg, 0.610 mmol) in EtOAc (2 mL) was added HCl / EtOAc (0.4 mL, 3.6 mmol) at 0° C. The solution was stirred at 15° C. for 2.5 hours. The solution was concentrated in vacuo and then lyophilized to dryness to give the desired product as a white solid (136.7 mg, 75.4%).

[0378] Step (a) tert-butyl 4-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate

[0379] To a solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (500 mg, 2.14 mmol) in DCM (5 mL) was added NEt (0.45 mL, 3.22 mmol) and methanesulfonyl chloride (0.23 mL, 3 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h. The mixture was washed twice with HO (3 mL each) at 0 °C and dried over NaSO. The organic layer was concentrated to give the compound as a colorless oil (766 mg, 98.5%), which was used in the next step without further purification. MS (ESI): m / z = 256 [M -56 + H] + .

[0380] Step (b) tert-butyl 4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-fluoro-piperidine-1-carboxylate

[0381] To a solution of tert-butyl 4-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (383 mg, 1.23 mmol) in DMF (4 mL) was added CsCO (601 mg, 1.85 mmol), 2-chloro-4-fluorophenol (0.13 mL, 1.35 mmol), and 2-chloro-4-fluorophenol (0.13 mL, 1.35 mmol) at 15 °C. The mixture was heated to 85 °C and stirred for 16 h. The mixture was extracted three times with EtOAc (5 mL each) at 15 °C, and the combined organic layers were washed three times with brine (5 mL each), dried over NaSO, filtered, and evaporated. The crude product was purified by preparative HPLC and lyophilized to give the desired compound as a light yellow oil (275 mg, 0.760 mmol, 61.5%). MS (ESI): m / z = 306 [M-56 + H] + .

[0382] BB16 rac-(4aR,8aS)-6-(4-(hydroxymethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0383] To a suspension of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; dihydrochloride (450 mg, 1.96 mmol, BB1) in dry DMF (9 mL) cooled to 0 °C under an inert atmosphere, DIPEA (787 mg, 1.06 mL, 6.09 mmol) and 4-nitrophenyl chloroformate (475 mg, 2.36 mmol) were added. The reaction mixture was stirred at 0 °C for 30 min. Piperidin-4-ylmethanol (271 mg, 2.36 mmol, CAS RN: 6457-49-4) and DIPEA (381 mg, 515 μL, 2.95 mmol) were added, and the reaction mixture was stirred at 100 °C for 14 h. The volatiles were removed in vacuo and the crude residue was purified by flash chromatography on a 24 g SiO column using an eluent mixture of DCM and MeOH (5%-25%). The crude product was subjected to SFC purification to yield the desired compound as a light yellow oil (338 mg). MS (ESI): m / z = 298.3 [M+H] + .

[0384] BB17 4,4-Difluoro-1-(piperidin-4-ylmethyl)piperidine; dihydrochloride

[0385] To a solution of tert-butyl 4-((4,4-difluoropiperidin-1-yl)methyl)piperidine-1-carboxylate (453 mg, 1.07 mmol) in dioxane (2.5 mL) was added HCl (4.0 M solution in dioxane) (2.67 mL, 10.7 mmol), and the reaction mixture was stirred at room temperature for 14 hours. The volatiles were removed in vacuo to yield the desired compound as a white solid (286 mg), which was used in the next step without further purification. MS (ESI): m / z = 219.3 [M+H] + .

[0386] Step (a) tert-butyl 4-((4,4-difluoropiperidin-1-yl)methyl)piperidine-1-carboxylate

[0387] To a solution of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.5 g, 1.8 mmol, CAS RN: 158407-04-6) in dry DMF (4 mL) was added 4,4-difluoropiperidine dihydrochloride (425 mg, 2.7 mmol) and CsCO (1.17 g, 3.59 mmol). The reaction mixture was then stirred at 80 °C under microwave irradiation for 60 min. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The resulting crude residue was suspended in DCM and filtered through a pad of Celite to give a crude yellow oil. This was purified by flash chromatography on a SiO column using an eluent mixture of n-heptane and EtOAc (10% to 60%) to afford the desired product as a colorless oil (453 mg). The compound was carried on to the next step without further purification. MS (ESI): m / z = 319.3 [M+H] + .

[0388] BB19 N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-amine; Bis(trifluoroacetate) salt

[0389] To a solution of tert-butyl 3-(((2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate (1 g, 2.42 mmol) in DCM (10 mL) was added TFA (5.53 g, 3.74 mL, 48.5 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to afford the desired compound as a colorless oil (1.29 g). MS (ESI): m / z = 313.5 [M+H] + .

[0390] Step (a) tert-butyl 3-(((2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate

[0391] To a dry flask equipped with a septum under nitrogen was added tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (0.852 g, 4.57 mmol), triethylamine (1.39 g, 1.91 mL, 13.7 mmol), 2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-one (1.11 g, 780 μL, 4.57 mmol), and dry DCM (28 mL). 1 M titanium tetrachloride in DCM (2.29 mL, 2.29 mmol) was added via syringe to the ice-cooled flask (exothermic). The reaction was stirred overnight at room temperature and then carefully quenched with a solution of NaCNBH (862 mg, 13.7 mmol) in MeOH (8.79 g, 11.1 mL, 274 mmol) and stirred overnight. The reaction was basified with saturated NaHCO solution. The resulting insoluble material was filtered over Celite. The filtrate was extracted with DCM, and the organic layers were combined, washed with brine, dried over NaSO, and concentrated. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in n-heptane) to yield tert-butyl 3-(((2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate, which was used in the next step without further purification.

[0392] BB26 3-Chloro-4-(4-piperidylmethoxy)benzonitrile; Hydrochloride

[0393] To a solution of tert-butyl 4-[(2-chloro-4-cyano-phenoxy)methyl]piperidine-1-carboxylate (300 mg, 0.860 mmol) in EtOAc (3 mL) was added HCl in EtOAc (4 M, 2.0 mL) at 0° C. The solution was stirred at 15° C. for 3 h. The solution was concentrated in vacuo and then lyophilized to dryness to give the desired product as a white solid (238 mg, 0.830 mmol, 96% yield). MS (ESI): m / z=251 [M+H] + .

[0394] Step (a) tert-butyl 4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

[0395] To a solution of N-Boc-4-piperidinemethanol (10.0 g, 46.5 mmol, 1 eq.) in DCM (200 mL) was added NEt3 (7.04 g, 69.7 mmol), followed by methanesulfonyl chloride (3.95 mL, 51.1 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. The mixture was poured into ice water, and the aqueous phase was extracted twice with DCM (50 mL each). The combined organic layers were washed with brine (50 mL) and concentrated in vacuo. The residue was used directly without any purification. MS (ESI): m / z = 238.1 [M+H] + .

[0396] Step (b) tert-butyl 4-[(2-chloro-4-cyano-phenoxy)methyl]piperidine-1-carboxylate

[0397] To a solution of tert-butyl 4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (700 mg, 2.39 mmol) in DMF (7 mL) was added CsCO (855 mg, 2.62 mmol) and 3-chloro-4-hydroxybenzonitrile (0.25 mL, 2.39 mmol) at 15 °C. The mixture was heated to 85 °C and stirred for 16 h. The reaction mixture was diluted with EtOAc (8 mL) at 15 °C, washed three times with brine (8 mL each), and the combined organic layers were dried over NaSO and evaporated. The colorless residue (0.75 g) was purified by preparative HPLC and dried by lyophilization to give the desired product as a white solid (531 mg, 1.51 mmol, 53.4%). MS (ESI): m / z = 295 [M -56 + H] + .

[0398] BB27 4-((4-(trifluoromethyl)-1H-imidazol-1-yl)methyl)piperidine hydrochloride

[0399] To a solution of tert-butyl 4-((4-(trifluoromethyl)-1H-imidazol-1-yl)methyl)piperidine-1-carboxylate (430 mg, 1.29 mmol) in dioxane (3 mL) was added HCl (4 M solution in dioxane; 3.22 mL, 12.9 mmol) and the reaction mixture was stirred at room temperature for 14 h. The volatiles were removed in vacuo to give the crude product (362 mg), which was used in the next step without further purification. MS (ESI): m / z = 234.2 [M+H] + .

[0400] Step (a) tert-butyl 4-((4-(trifluoromethyl)-1H-imidazol-1-yl)methyl)piperidine-1-carboxylate

[0401] To a solution of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.5 g, 1.8 mmol, CAS RN: 158407-04-6) in dry DMF (4 mL) was added 4-(trifluoromethyl)-1H-imidazole (293 mg, 2.16 mmol) and CsCO (1.17 g, 3.59 mmol). The reaction mixture was then stirred at 80 °C for 14 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The crude residue was suspended in DCM and filtered through a pad of Celite to give a yellow oil. This was purified by flash chromatography on a SiO column using an eluent mixture of n-heptane and EtOAc (10% to 90%). This gave a first fraction (301 mg) of the desired product as a colorless oil, and a second fraction (261 mg) of a mixture of the desired product and impurities. The second fraction was subjected to SFC purification and the purified product was combined with the first fraction to yield 430 mg of the desired product as a colorless oil. MS (ESI): m / z = 334.2 [M+H] + .

[0402] BB29 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine

[0403] Trifluoroacetic acid (2 g, 1.35 mL, 17.5 mmol) was added to a solution of tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carboxylate (320 mg, 875 μmol) in DCM (4.37 mL), and the solution was stirred at room temperature for 2 h. The solvent was removed under reduced pressure, and the resulting pale oil (470 mg) was diluted with EtOAc and washed with aqueous Na2CO3. The aqueous phase was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give the compound as a yellow oil (259 mg, 877 μmol). MS (ESI): m / z = 266.1 [M+H] + .

[0404] Step (a) tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carboxylate

[0405] To a solution of 2-chloro-4-(trifluoromethyl)phenol (525 mg, 357 μL, 2.67 mmol), tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (500 mg, 2.67 mmol, CAS RN: 142253-56-3), and triphenylphosphine (770 mg, 2.94 mmol) in DCM (13.4 mL) was added dropwise DIAD (594 mg, 571 μL, 2.94 mmol), and the reaction was stirred at room temperature for 17 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO (20 mL). The phases were separated, and the aqueous phase was extracted twice with DCM. The combined organic layers were dried over NaSO and concentrated to dryness. The residue was dissolved in EtOH (7 mL), and a homogeneous solution of zinc chloride (218 mg, 1.6 mmol) in EtOH (2 mL, 0.5 M) was added. The mixture was stirred for 30 minutes, during which time a white solid precipitated. The white solid was filtered off and washed with EtOH. The filtrate was concentrated to give a yellow oil with a white precipitate. The crude material was immobilized on Isolute and purified by column chromatography (40 g, 0-30% EtOAc in heptane) to give the title compound as a white solid (764.6 mg, 1.99 mmol, 74.4%). MS (ESI): m / z=310.1 [M-56+H] + .

[0406] BB30 N-Benzyl-N-(2-hydroxyethyl)piperidine-4-carboxamide hydrochloride

[0407] To a solution of tert-butyl 4-(benzyl(2-hydroxyethyl)carbamoyl)piperidine-1-carboxylate (0.080 g, 221 μmol) in DCM (1 mL) was added 2 M HCl in diethyl ether (1.1 mL, 2.21 mmol). The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under vacuum at 22° C. to yield the desired compound as a colorless oil (63 mg) (BB30). MS (ESI): m / z=263.18 [M+H] + .

[0408] Step (a) tert-butyl 4-(benzyl(2-hydroxyethyl)carbamoyl)piperidine-1-carboxylate

[0409] In a 10 mL glass tube, 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.1 g, 436 μmol) in DMF (2 mL) was added 2-(benzylamino)ethan-1-ol (72.5 mg, 480 μmol), DIPEA (169 mg, 229 μL, 1.31 mmol), and HATU (182 mg, 480 μmol), stirred at room temperature for 1 h, and extracted with H2O / DCM. The crude material was purified by flash chromatography (silica gel, 20 g, 50% to 100% EtOAc in n-heptane) to afford the compound (156 mg) as a light yellow oil.

[0410] BB31 N-Benzylpiperidine-4-carboxamide hydrochloride

[0411] tert-Butyl 4-(benzylcarbamoyl)piperidine-1-carboxylate (0.138 g, 433 μmol) was dissolved in DCM (1 mL) and 2 M HCl in diethyl ether (2.17 mL, 4.33 mmol) was added. The reaction mixture was stirred for 2 hours. The residue was concentrated in vacuo to yield the compound (108 mg) as a colorless oil. MS (ESI): m / z = 219.15 [M+H] + .

[0412] Step (a) tert-Butyl 4-(benzylcarbamoyl)piperidine-1-carboxylate

[0413] In a 10 mL glass tube, phenylmethanamine (51.4 mg, 52.4 μL, 480 μmol), DIPEA (169 mg, 229 μL, 1.31 mmol), and HATU (182 mg, 480 μmol) were added to 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (0.1 g, 436 μmol) in DMF (2 mL), stirred at room temperature for 2 h, and extracted with HO / DCM. The crude material was purified by flash chromatography (silica gel, 20 g, 50% to 100% EtOAc in n-heptane) to afford the compound (0.138 g) as a colorless oil.

[0414] BB32 4-((4-(tert-butyl)-1H-pyrazol-1-yl)methyl)piperidine hydrochloride

[0415] To a solution of tert-butyl 4-((4-(tert-butyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate (100 mg, 311 μmol) in dioxane (1 mL) was added HCl (4.0 M solution in dioxane; 1.17 mL, 4.67 mmol) and the reaction mixture was stirred at room temperature for 14 hours. The volatiles were removed in vacuo to give 84 mg of crude product, which was used in the next step without further purification. MS (ESI): m / z=222.3 [M+H] + .

[0416] Step (a) tert-butyl 4-((4-(tert-butyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

[0417] To a solution of tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (0.5 g, 1.8 mmol, CAS RN: 158407-04-6) in dry DMF (4 mL) was added 4-(tert-butyl)-1H-pyrazole (268 mg, 2.16 mmol) and NaH (86.3 mg, 2.16 mmol). The reaction mixture was stirred at 80 °C for 14 h. The reaction was quenched by adding a few drops of saturated aqueous NH4Cl and transferred to a separatory funnel to separate DCM and saturated aqueous NaHCO3. The organic phase was collected, and the aqueous phase was back-extracted with DCM. The combined organic phases were dried over Na2SO4 and evaporated to dryness. The crude material was purified by flash chromatography using a SiO2 column eluted with a mixture of n-heptane and EtOAc (5%-60%) to yield the desired compound as a colorless oil (102 mg). MS (ESI): m / z = 322.3 [M+H] + .

[0418] BB33 (2R,4aR,8aS)-2-Methyl-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

[0419] To a solution of 6-benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (isomer A, 1.10 g, 4.26 mmol) in 16 mL of EtOAc and 16 mL of MeOH was added Pd—C (227 mg, 213 μmol) under argon, and the suspension was stirred at 1 bar under a hydrogen atmosphere (balloon) for 24 h. The suspension was filtered through a microfiber filter and washed with 20 mL of EtOAc under inert gas. The filtrate was evaporated to give BB33 as a colorless solid (715 mg). MS (ESI): m / z = 170.8 [M+H] + Note: Only a single enantiomer formed during reduction.

[0420] Step (a) 2-methyl-4H-pyrido[4,3-b][1,4]oxazin-3-one

[0421] To a solution of 3-aminopyridin-4-ol (2.5 g, 22.7 mmol) in DMF (100 mL) was added dropwise 2-chloropropanoyl chloride (3.03 g, 2.31 mL, 23.8 mmol), and the mixture was stirred at room temperature for 30 min. After adding K2CO3 (7.84 g, 56.8 mmol), the suspension was heated to 100 °C (oil bath) for 20 h. DMF was removed in vacuo, followed by the addition of 100 mL of EtOAc, stirring at room temperature for 10 min, washing with 50 mL of HO, and extraction three times with EtOAc. The organic phases were combined, dried over MgSO4, and concentrated in vacuo to yield 3.72 g of 2-methyl-4H-pyrido[4,3-b][1,4]oxazin-3-one, which was used in the next step without further purification.

[0422] Step (b) 6-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-6-ium bromide

[0423] A suspension of 2-methyl-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (3.72 g, 22.7 mmol) in DCM (32 mL) and MeOH (8 mL) was treated with (bromomethyl)benzene (4.65 g, 3.23 mL, 27.2 mmol), and the mixture was stirred at room temperature for 60 h. A suspension formed, which was cooled to 0 °C, and 20 mL of n-hexane was added, followed by filtration of the precipitate. The residue was washed with 15 mL of cold DCM / n-hexane to yield the compound as an off-white solid (5.2 g). MS (ESI): m / z = 255 [M+H] + .

[0424] Step (c) 6-benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0425] To a suspension of 6-benzyl-2-methyl-3-oxo-3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazin-6-ium bromide (5.2 g, 15.5 mmol) in EtOH (38 mL) was added NaBH (763 mg, 20.2 mmol) (exothermic, 22-30 °C, yellow suspension) in portions. After the exothermic reaction subsided, the mixture was stirred at room temperature for 3 h, then at 60 °C for 1 h, and at 22 °C for 1 h. The reaction mixture was evaporated, partitioned between H O and EtOAc, and the layers were separated. The aqueous layer was extracted once with EtOAc. The organic layer was washed twice with H O, dried over MgSO, filtered, treated with silica gel, and evaporated. The compound was purified by silica gel chromatography on a 120 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc (50 to 100 in 30 min) to give the compound as a light yellow solid (2.48 g), which could be used in the next step without further purification.

[0426] Step (d) 6-benzyl-2-methyl-5,6,7,8-tetrahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

[0427] The enantiomers were separated by preparative chiral HPLC (Chiralcel OD column) using an isocratic mixture of EtOH (containing 0.05% NHOAc):n-heptane (10:90). Evaporation of the fractions afforded the desired compounds as light yellow solids (Isomer A 1.17 g, Isomer B 1.10 g).

[0428] BB34 N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethan-1-amine

[0429] In a 100 mL two-neck flask, benzyl 3-(((2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate (0.913 g, 2.05 mmol) was dissolved in a mixture of THF (5 mL) and MeOH (5 mL). Pd / C 10% (109 mg, 102 μmol) was added under argon. The flask was purged and backfilled with H gas (3 times). The reaction mixture was then stirred at 25 °C for 4 h. The suspension was filtered through decalite and concentrated to give the title compound (611 mg, colorless oil) which was used directly in the next step. MS (ESI): m / z = 313.4 [M+H] + .

[0430] Step (a) Benzyl 3-(((2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate

[0431] To a dry flask equipped with a septum was added benzyl 3-(aminomethyl)azetidine-1-carboxylate (0.5 g, 2.27 mmol), NEt (689 mg, 949 μL, 6.81 mmol), 2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethan-1-one (554 mg, 391 μL, 2.27 mmol), and dry DCM (15 mL). 1 M titanium tetrachloride in DCM (1.13 mL, 1.13 mmol) was added via syringe, and the flask was cooled in an ice bath (exothermic). The reaction was stirred overnight at room temperature and carefully quenched with a solution of NaCNBH (428 mg, 6.81 mmol) in MeOH (4.36 g, 5.51 mL, 136 mmol) and acetic acid (0.1 mL) and stirred overnight at room temperature. The reaction was basified with saturated aqueous NaHCO3, and the resulting insoluble material was removed by filtration through Celite. The filtrate was extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in n-heptane) to yield the desired compound as a colorless oil (913 mg). MS (ESI): m / z = 447.2 [M+H]+ .

[0432] BB35 N-(azetidin-3-ylmethyl)-1-(2,4-dichlorophenyl)-2,2,2-trifluoroethan-1-amine

[0433] In a 100 mL two-neck flask, benzyl 3-(((1-(2,4-dichlorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate (0.660 g, 1.48 mmol) was dissolved in EtOAc (20 mL) to give a colorless solution. Pd / C 10% (78.5 mg, 73.8 μmol) was added under argon. The flask was purged and backfilled with H gas (3 times). The reaction mixture was stirred at 25 °C for 4 h. LC-MS showed a mixture of the title product N-(azetidin-3-ylmethyl)-1-(2,4-dichlorophenyl)-2,2,2-trifluoroethan-1-amine and the dehalogenated by-products N-(azetidin-3-ylmethyl)-1-(2-chlorophenyl)-2,2,2-trifluoroethan-1-amine and N-(azetidin-3-ylmethyl)-1-phenyl-2,2,2-trifluoroethan-1-amine. The reaction mixture was filtered over decalite, concentrated in vacuo, and used directly in the next step.

[0434] Step (a) Benzyl 3-[[[1-(2,4-dichlorophenyl)-2,2,2-trifluoro-ethylidene]amino]methyl]azetidine-1-carboxylate

[0435] Into a dry flask equipped with a septum, under nitrogen, add benzyl 3-(aminomethyl)azetidine-1-carboxylate (0.500 g, 2.27 mmol, CAS RN:1016731-24-0), NEt (689 mg, 949 μL, 6.81 mmol), 1-(2,4-dichlorophenyl)-2,2,2-trifluoroethan-1-one (556 mg, 2.27 mmol), and dry DCM (16.4 mL) were added. Titanium tetrachloride (1 M solution in DCM; 1.13 mL, 1.13 mmol) was added via syringe to the ice-cooled flask (exothermic). The reaction was stirred overnight at room temperature and carefully quenched with a solution of NaCNBH (428 mg, 6.81 mmol) in MeOH (4.36 g, 5.51 mL, 136 mmol) and stirred for 6 h. LCMS showed the reaction was quenched with the imine.

[0436] The reaction was basified with saturated NaHCO. The resulting insoluble material was filtered over Celite, and the filtrate was extracted with DCM. The organic layers were combined, washed with brine, dried over NaSO, and concentrated. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in n-heptane) to give the desired compound (1 g) as a colorless oil.

[0437] Step (b) Benzyl 3-(((1-(2,4-dichlorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate

[0438] In a 25 mL two-neck flask, benzyl 3-[[[1-(2,4-dichlorophenyl)-2,2,2-trifluoro-ethylidene]amino]methyl]azetidine-1-carboxylate (1 g, 2.25 mmol) was dissolved in THF (10 mL) and MeOH (1 mL) to give a colorless solution. Acetic acid (135 mg, 129 μL, 2.25 mmol) and NaCNBH3 (423 mg, 6.74 mmol) were added. The reaction mixture was stirred at 25 °C for 6 h. The reaction was basified with saturated NaHCO3. The resulting insoluble material was filtered over Celite, and the filtrate was extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to give the title compound as a colorless oil (660 mg), which was used in the next step without further purification.

[0439] BB36 cis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine hydrochloride

[0440] tert-Butyl cis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carboxylate (115 mg, 321 μmol) was dissolved in DCM (2 mL) and 2 M HCl in ether (161 μL, 321 μmol) was added. The reaction was stirred at room temperature for 6 h, then the solvent was removed in vacuo. The crude product (94 mg, colorless foam) was used in the next step without purification. MS (ESI): m / z = 258.2 [M+H] + .

[0441] Step (a) tert-butyl cis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carboxylate

[0442] Mitsunobu reaction: In a 50 mL four-neck sulfonation flask under argon, tert-butyl cis-4-(hydroxymethyl)-3-methylpiperidine-1-carboxylate (840 mg, 3.66 mmol) was dissolved in THF (15 mL) and 2-chloro-4-fluorophenol (590 mg, 439 μL, 4.03 mmol) and triphenylphosphine (1.06 g, 4.03 mmol) were added. The clear solution was stirred at room temperature for 5 min, then cooled to 0-2 °C, and DEAD (702 mg, 638 μL, 4.03 mmol) was added over 10 min. The reaction mixture was stirred at 2-4 °C for 1 h and then at room temperature overnight. 50 mL of diethyl ether was added, and the mixture was washed with 2 × 25 mL of water, 3 × 20 mL of 1N NaOH, and 1 × 20 mL of brine. The organic phase was dried over MgSO. After removing the solvent in vacuo, 2.7 g of a yellow oil was obtained. To remove triphenylphosphinoxide, the residue was stirred in n-heptane / diethyl ether for 30 min. The solid was filtered off, and the filtrate was concentrated in vacuo to give 1.8 g of crude product. This was purified by flash chromatography (silica gel, 50 g, 0% to 30% EtOAc in heptane, 40 min): tert-butyl cis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carboxylate, 1.21 g of a white solid.

[0443] BB39 3-((2-Fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine; Trifluoroacetate

[0444] To a solution of tert-butyl 3-((2-fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carboxylate (415 mg, 1.14 mmol) in DCM (5 mL) was added TFA (1.3 g, 875 μL, 11.4 mmol) and the reaction mixture was stirred at room temperature for 3 h. The volatiles were removed in vacuo to yield 455 mg of a light yellow oil, which was used in the next step without further purification. MS (ESI): m / z = 266.1 [M+H] + .

[0445] Step (a) tert-butyl 3-((2-fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carboxylate

[0446] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (200 mg, 1.15 mmol) in dry THF (5 mL) was added potassium tert-butoxide (735 μL of a 1.65 M solution in THF, 1.21 mmol). The reaction mixture was stirred at room temperature for 15 minutes, after which 1-(bromomethyl)-2-fluoro-4-(trifluoromethoxy)benzene (315 mg, 1.15 mmol) was added. The reaction mixture was then stirred at room temperature for 14 hours. The crude reaction was diluted with EtOAc and extracted with 1 M aqueous NaHCO3. The organic phase was collected, and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over NaSO4 and evaporated to dryness to yield 418 mg of crude product, which was used in the next step without further purification. MS (ESI): m / z = 310.1 [M -56 + H] + .

[0447] BB40 N-(azetidin-3-yl)-2-chloro-4-fluorobenzamide; trifluoroacetate

[0448] To a solution of tert-butyl 3-[(2-chloro-4-fluoro-benzoyl)amino]azetidine-1-carboxylate (346 mg, 1.05 mmol) in DCM (3.5 mL) was added TFA (0.7 mL) at 0 °C. The solution was stirred at 0 °C for 2 h. The reaction was concentrated in vacuo to give the crude product (600 mg) as a light yellow oil. The crude product was purified by preparative HPLC (0.1% TFA in HO and MeCN) and dried by lyophilization to give the desired compound as a colorless solid (223 mg, 0.650 mmol, 59.2% yield). MS (ESI): m / z = 229 [M+H] + .

[0449] Step (a) tert-butyl 3-[(2-chloro-4-fluoro-benzoyl)amino]azetidine-1-carboxylate

[0450] To a solution of 2-chloro-4-fluorobenzoic acid (500 mg, 2.86 mmol), 1-Boc-3-(amino)azetidine (493 mg, 2.86 mmol), and DMAP (35.0 mg, 0.290 mmol) in THF (10 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (714 mg, 3.72 mmol) at 0 °C. The mixture was heated to 30 °C and stirred for 16 h. The reaction solution was diluted with EtOAc (5 mL), washed three times with brine (10 mL each), and dried over Na SO . The organic layer was concentrated in vacuo to give the crude product (0.72 g) as a light yellow oil. The crude product was purified by preparative HPLC and lyophilized to give the desired compound as a colorless solid (546 mg, 1.66 mmol, 57.9% yield). MS (ESI): m / z = 273 [M-56 + H] + .

[0451] BB41 N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-N-methyl-1-[4-(trifluoromethyl)phenyl]ethanamine; Trifluoroacetate

[0452] To a solution of tert-butyl 3-((methyl(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate (0.256 g, 600 μmol) in DCM (5 mL) was added TFA (1.37 g, 925 μL, 12 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the desired compound as a colorless oil (268 mg). MS (ESI): m / z=327.4 [M+H] + .

[0453] Step (a) tert-butyl 3-((methyl(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate

[0454] A dry flask equipped with a septum and 3 Å molecular sieves was charged with tert-butyl 3-((methylamino)methyl)azetidine-1-carboxylate (0.300 g, 293 μL, 1.5 mmol), TEA (455 mg, 626 μL, 4.49 mmol), 2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethan-1-one (363 mg, 255 μL, 1.5 mmol), and dry DCM (9.86 mL) under nitrogen. 1 M titanium tetrachloride in DCM (749 μL, 749 μmol) was added to the ice-cooled flask via syringe (exothermic). The reaction was stirred overnight at room temperature and carefully quenched with a solution of NaCNBH (3.64 mL, 89.9 mmol) in MeOH (282 mg, 4.49 mmol) and stirred at room temperature for 2 h. The reaction was basified with saturated NaHCO3 solution. The resulting insoluble material was filtered over Celite, and the filtrate was extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in n-heptane) and used directly in the next step.

[0455] BB42 N-Methyl-N-(piperidin-4-yl)-1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamide hydrochloride

[0456] To a solution of tert-butyl 4-(N-methyl-1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate (0.301 g, 706 μmol) in DCM (2 mL) was added 2 M HCl in diethyl ether (3.53 mL, 7.06 mmol). The resulting reaction mixture was stirred at room temperature overnight and then concentrated under vacuum at 22° C. to give 256 mg of BB42 as an off-white solid. MS (ESI): m / z=327.2 [M+H] +

[0457] Step (a) tert-butyl 4-(N-methyl-1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)piperidine-1-carboxylate

[0458] To 1-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acid (177 mg, 770 μmol) in DMF (5 mL) in a 20 mL glass tube, HATU (293 mg, 770 μmol) and DIPEA (271 mg, 367 μL, 2.1 mmol) were added. The reaction mixture was stirred for 15 minutes, and then tert-butyl 4-(methylamino)piperidine-1-carboxylate (0.15 g, 700 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with water / DCM. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in heptane) to yield the desired compound as a light yellow oil (301 mg). MS (ESI): m / z = 371.2 [M-56+H] +

[0459] BB43 2-(2-chloro-3-(trifluoromethyl)phenyl)-N-methyl-N-(piperidin-4-yl)acetamide; hydrochloride

[0460] To a solution of tert-butyl 4-(2-(2-chloro-3-(trifluoromethyl)phenyl)-N-methylacetamido)piperidine-1-carboxylate (0.301 g, 692 μmol) in DCM (2 mL) was added HCl (3.46 mL, 6.92 mmol). The resulting reaction mixture was stirred at room temperature for 2 days and then concentrated under vacuum at 22° C. to yield 252 mg of BB43 as an off-white solid. MS (ESI): m / z=335.1 [M+H] + .

[0461] Step (a) tert-butyl 4-(2-(2-chloro-3-(trifluoromethyl)phenyl)-N-methylacetamido)piperidine-1-carboxylate

[0462] In a 20 mL glass tube, 2-(2-chloro-3-(trifluoromethyl)phenyl)acetic acid (184 mg, 770 μmol) in DMF (5 mL) was added HATU (293 mg, 770 μmol), DIPEA (271 mg, 367 μL, 2.1 mmol). The reaction mixture was stirred for 15 min, and then tert-butyl 4-(methylamino)piperidine-1-carboxylate (0.150 g, 700 μmol) was added. The reaction mixture was stirred at room temperature for 2 h and then extracted with water / DCM. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in heptane) to produce tert-butyl 4-(2-(2-chloro-3-(trifluoromethyl)phenyl)-N-methylacetamido)piperidine-1-carboxylate as a light yellow oil (301 mg). MS (ESI): m / z = 379.1 [M-56 + H] +

[0463] BB44 2-(2-chloro-5-(trifluoromethyl)phenyl)-N-methyl-N-(piperidin-4-yl)acetamide; Hydrochloride

[0464] Synthesis from 2-(2-chloro-5-(trifluoromethyl)phenyl)acetic acid and tert-butyl 4-(methylamino)piperidine-1-carboxylate. See synthesis of BB43 for details. MS(ESI): m / z=335.1 [M+H] + .

[0465] BB46 3-Methyl-5-(piperidin-4-ylmethoxy)-2-(trifluoromethyl)pyridine; dihydrochloride

[0466] In a 25 mL tube, tert-butyl 4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (87 mg, 232 μmol) was dissolved in DCM (2 mL), then 2 M HCl in ether (697 μL, 1.39 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo to give 80 mg of BB46 as a white solid. MS (ESI): m / z = 275.2 [M+H] + .

[0467] Step (a) tert-butyl 4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate

[0468] In a 5 mL tube, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (80.7 mg, 375 μmol) was dissolved in DMF (1.5 mL), and then NaH (18 mg, 450 μmol) in 60% oil was added at room temperature. The mixture was stirred for 20 min, followed by the addition of 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (90 mg, 60 μL, 375 μmol), which was stirred at room temperature for 2 h to give a brown solution. 10 mL of saturated NH4Cl was added, which was extracted with water / ethyl acetate, dried over MgSO4, and the solvent was removed at 40 °C / 150 mbar. The crude product was purified by flash chromatography (silica gel, 20 g, 0-40% EtOAc in n-heptane, 35 min) to yield 87 mg of tert-butyl 4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carboxylate. MS (ESI): m / z = 319.2 [M-56+H] +

[0469] BB58 N-(azetidin-3-ylmethyl)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine

[0470] In a 100 mL two-neck flask, benzyl 3-(((1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate (707 mg, 1.64 mmol) was combined in THF (5 mL) and MeOH (5 mL) to give a colorless solution. Pd / C 10% (87.3 mg, 82.1 μmol) was added under argon. The flask was purged and backfilled with H2 (3 times). The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was filtered over decalite, concentrated, and used directly in the next step. Colorless oil (472 mg). MS (ESI): m / z = 263.2 [M+H] + (The ortho chlorine is lost during hydrogenation).

[0471] Step (a): Benzyl 3-(((1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate

[0472] To a dry flask under a stream of nitrogen was added benzyl 3-(aminomethyl)azetidine-1-carboxylate (0.5 g, 2.27 mmol), triethylamine (689 mg, 949 μL, 6.81 mmol), 1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethanone (519 mg, 2.27 mmol), and dry DCM (15 mL). 1 M titanium tetrachloride in DCM (1.13 mL, 1.13 mmol) was added to the ice-cooled flask via syringe (exothermic). The reaction was stirred overnight at room temperature and carefully quenched with a methanolic solution of sodium cyanoborohydride (428 mg, 6.81 mmol) in methanol (4.36 g, 5.51 mL, 136 mmol) and acetic acid (0.1 mL) and stirred overnight at room temperature. The reaction was basified with saturated NaHCO3. The resulting insoluble material was removed by filtration over Celite, the filtrate was extracted with DCM, and the organic layers were combined, washed with brine, dried over Na2SO4, and concentrated. Purification: The crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in heptane) to yield 707 mg of benzyl 3-(((1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate as a colorless oil. MS (ESI): m / z = 431.2 [M+H] + .

[0473] BB59 2,2,2-Trifluoro-1-(piperidin-4-yl)-N-(3-(trifluoromethyl)benzyl)ethan-1-amine; Hydrochloride

[0474] To a solution of tert-butyl 4-(2,2,2-trifluoro-1-((3-(trifluoromethyl)benzyl)amino)ethyl)piperidine-1-carboxylate (0.140 g, 318 μmol) in DCM (2 mL) was added 2 M HCl in diethyl ether (1.59 mL, 3.18 mmol). The resulting reaction mixture was stirred at room temperature overnight and then concentrated under vacuum at 22° C. to yield 119 mg of the title compound as an off-white solid. MS (ESI): m / z=340.8 [M+H]+ .

[0475] Step (a) tert-butyl 4-(2,2,2-trifluoro-1-((3-(trifluoromethyl)benzyl)amino)ethyl)piperidine-1-carboxylate

[0476] A solution of tert-butyl 4-(1-amino-2,2,2-trifluoroethyl)piperidine-1-carboxylate (0.150 g, 531 μmol) and 3-(trifluoromethyl)benzaldehyde (92.5 mg, 71.1 μL, 531 μmol) in 1,2-DCE (1 mL) was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (225 mg, 1.06 mmol) was then added at 0 °C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured onto saturated NaHCO and extracted with DCM. The organic layers were combined, washed with brine, dried over NaSO, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in heptane) to yield 145 mg of the desired compound as a colorless oil. MS (ESI): m / z = 383.1 [M -56 + H] +

[0477] BB69 2-Methyl-3-((4-(trifluoromethyl)benzyl)oxy)azetidine; Trifluoroacetate

[0478] To a solution of tert-butyl 2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)azetidine-1-carboxylate (0.36 g, 1.04 mmol) in DCM (4 mL) was added trifluoroacetic acid (1.19 g, 10.4 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under high vacuum to yield BB69 as a light yellow oil, 399 mg, a mixture of all four stereoisomers. MS (ESI): m / z = 246.1 [M+H] + .

[0479] Step (a) tert-butyl 2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)azetidine-1-carboxylate

[0480] In a 25 mL two-neck flask, tert-butyl-3-hydroxy-2-methylazetidine-1-carboxylate (215 mg, 1.15 mmol) was dissolved in DMF (5 mL) to give a colorless solution. Sodium hydride (60% dispersion in mineral oil) (41.8 mg, 1.05 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes. Then, 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.250 g, 1.05 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 20 mL of saturated NH4Cl and extracted with EtOAc (2 × 50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 70% EtOAc in heptane) to yield 360 mg of tert-butyl 2-methyl-3-((4-(trifluoromethyl)benzyl)oxy)azetidine-1-carboxylate as a colorless oil. MS (ESI): m / z = 290.1 ​​[M-56+H] +

[0481] BB87 3-Fluoro-5-(trifluoromethyl) 4-methylbenzenesulfonate benzyl

[0482] To a solution of (3-fluoro-5-(trifluoromethyl)phenyl)methanol (100 mg, 72.5 μL, 515 μmol, equiv: 1) in DCM (2.58 mL) was added p-toluenesulfonic anhydride (185 mg, 567 μmol), DIPEA (79.9 mg, 108 μL, 618 μmol), and DMAP (6.29 mg, 51.5 μmol). The reaction mixture was stirred at 0° C. for 4 h and at room temperature for 2 days. The reaction mixture was taken up in EtOAc and washed with water and brine. The organic layer was dried over MgSO and concentrated in vacuo to give a yellow oil (178 mg), which was used without further purification.

[0483] Analogous to BB39, unless otherwise specified, the intermediates shown in the following tables were prepared from commercially available benzyl bromide or prepared tosylate intermediates and the corresponding tert-butyl 3-hydroxyazetidine-1-carboxylate building blocks.

[0484] [Table 3] TIFF0007637049000122.tif246165

[0485] Similar to BB29, intermediates BB20, BB25, and BB61 in the table below were prepared from commercially available phenols. Where a trifluoroacetate salt is indicated, the crude product resulting from concentration of the reaction mixture was used directly without further neutralization or purification.

[0486] [Table 4]

[0487] Similar to BB26, intermediates BB21-BB24 and BB28 in the table below were prepared from commercially available phenols.

[0488] [Table 5] TIFF0007637049000125.tif154165

[0489] Method D1 BB9 4-[2-chloro-4-(trifluoromethyl)phenoxy]piperidine; Trifluoroacetate

[0490] A mixture of tert-butyl 4-[2-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (750.0 mg, 1.97 mmol) in DCM (20 mL) and TFA (0.76 mL) was stirred at 20 °C for 12 h. The mixture was concentrated. The residue was dissolved in HO (20 mL) and washed twice with PE:EA = 10:1 (20 mL each). The aqueous layer was lyophilized to give the desired product as a bright yellow solid (716 mg, 1.82 mmol, 87.8%). MS (ESI): m / z = 280.1 [M+H] + .

[0491] Step (a) tert-butyl 4-[2-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0492] A mixture of 2-chloro-4-(trifluoromethyl)phenol (500 mg, 2.54 mmol), 1-Boc-4-hydroxypiperidine (768 mg, 3.82 mmol), and triphenylphosphine (1334 mg, 5.09 mmol) in THF (10 mL) was stirred at 0 °C until complete dissolution. DIAD (1542 mg, 7.63 mmol) was slowly added dropwise at 0 °C. The mixture was stirred at 20 °C for 3 h and then concentrated under vacuum. The residue was purified by preparative HPLC to give the desired compound as a bright yellow solid (760 mg, 2 mmol, 78.7% yield). MS (ESI): m / z = 324.0 [M -56 + H] + .

[0493] BB57 3-(((2-Fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine; Trifluoroacetate

[0494] To a solution of tert-butyl 3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine-1-carboxylate (158 mg, 435 μmol) in DCM (1.74 mL) was added TFA (793 mg, 536 μL, 6.96 mmol) and the reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated to give 3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine; trifluoroacetate salt (202 mg, 434 μmol, 99.7% yield) as a colorless oil. The crude material was used without further purification. MS (ESI): m / z = 264.1 [M+H] + .

[0495] Step (a) Tert-butyl 3-(((2-fluoro-4-(trifluoromethyl)benzyl)oxy)methyl)azetidine-1-carboxylate

[0496] To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (100 mg, 534 μmol) in dry THF (2.67 mL) was added a 1.65 M solution of potassium tert-butoxide in THF (340 μL, 561 μmol). The cloudy reaction mixture was stirred at room temperature for 15 minutes, after which 1-(bromomethyl)-2-fluoro-6-(trifluoromethyl)benzene (137 mg, 534 μmol) was added. The reaction mixture was then stirred at room temperature for 3 hours. The crude reaction mixture was diluted with ethyl acetate and extracted with saturated aqueous NaHCO3. The organic phase was collected, and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness to yield a clear oil. The crude product was immobilized on Isolute and purified by column chromatography eluting with 0-30% EtOAc in heptane to give tert-butyl 3-(((2-fluoro-6-(trifluoromethyl)benzyl)oxy)methyl)azetidine-1-carboxylate (158 mg, 413 μmol, 77.3% yield) as a colorless oil. MS (ESI): m / z = 308.1 [M-56+H] +

[0497] Method D2 BB10 4-[[2-Cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine; Formate

[0498] A mixture of tert-butyl 4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate (440 mg, 0.610 mmol) in EtOAc (10 mL) and 5.0 mL of 4 M HCl in EtOAc was stirred at 20 °C for 12 h. The mixture was concentrated in vacuo. The residue was redissolved in HO (5 mL) and washed twice with PE:EA (3:1; 10 mL each), and the layers were separated. The aqueous layer was purified by preparative HPLC to give the desired compound as a bright yellow solid (124 mg, 0.350 mmol, 65.3% yield). MS (ESI): m / z = 312.2 [M+H] + .

[0499] Step (a) tert-butyl 4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

[0500] tert-Butyl 4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (500 mg, 1.19 mmol), cyclopentyl bromide (266 mg, 1.78 mmol), Ir(dF(CF3)ppy)2(dtbbpy)PF6 (13.4 mg, 0.010 mmol, CAS RN: 870987-63-6), NiCl2 glyme (0.77 mg, 0.060 mmol), dtbbpy (19.2 mg, 0.070 mmol, CAS RN: 72914-19-3), TTMSS (296 mg, 1.19 mmol, CAS A solution of Na2CO3 (252 mg, 2.38 mmol) was degassed by bubbling argon for 20 minutes. The reaction mixture was irradiated with a blue LED (4 × 1) at 25 °C for 16 hours. The reaction mixture was diluted with HO and then extracted three times with EtOAc (100 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC to give the compound as a colorless oil (460 mg, 1.12 mmol, 53.8%). MS (ESI): m / z = 354.1 [M-56 + H] + .

[0501] Step (b) tert-butyl 4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

[0502] To a mixture of tert-butyl 4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (460 mg, 0.640 mmol) in EtOAc (10 mL) was added wet Pd / C (40 mg), and the mixture was then stirred at 20 °C for 12 h under H (1520 mmHg). The mixture was filtered, and the filtrate was concentrated to give the compound as a colorless oil (460 mg, 1.12 mmol, 99.5%). MS (ESI): m / z = 356.1 [M + H - 56] + .

[0503] BB11 2-(4-piperidylmethyl)-1,3-benzoxazole; formate

[0504] A solution of 2-aminophenol (1.0 g, 9.16 mmol) and 1-Boc-4-piperidylacetic acid (2.68 g, 11 mmol) in polyphosphoric acid (2.2 g) was stirred at 180 °C for 2 h. The mixture was diluted with a mixture of 12 M aqueous NH OH and ice to pH > 7, then extracted three times with EtOAc (10 mL each). The combined organic layers were washed with brine, dried over Na SO , filtered, concentrated, and the residue was purified by preparative HPLC to give the desired compound as a brown oil (251 mg, 0.960 mmol, 9.7%). MS (ESI): m / z = 217.2 [M+H] + .

[0505] Method D3 BB13 4-[4-chloro-3-(4-chlorophenyl)phenoxy]piperidine hydrochloride

[0506] A solution of tert-butyl 4-[4-chloro-3-(4-chlorophenyl)phenoxy]piperidine-1-carboxylate (1000 mg, 2.37 mmol) in a 4 M solution of HCl in dioxane (50 mL) was stirred at 20° C. for 12 hours. The mixture was concentrated to give the title compound as a white solid (845 mg, 2.35 mmol, 96.2%). MS (ESI): m / z=322.0 [M+H] + .

[0507] Step (a) tert-butyl 4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate

[0508] A mixture of 3-bromo-4-chlorophenol (1000 mg, 4.82 mmol), 1-Boc-4-hydroxypiperidine (1164 mg, 5.78 mmol), and triphenylphosphine (2529 mg, 9.64 mmol) was stirred in THF (10 mL) until completely dissolved. DIAD (1948 mg, 9.64 mmol) was then slowly added dropwise at 0° C. The mixture was stirred at 20° C. for 12 hours, concentrated, and the residue was purified by reverse flash chromatography to give the compound as a yellow oil (1300 mg, 3.33 mmol, 69.0%). MS (ESI): m / z = 336.0 [M-56+H] + .

[0509] Step (b) tert-butyl 4-[4-chloro-3-(4-chlorophenyl)phenoxy]piperidine-1-carboxylate

[0510] To a solution of tert-butyl 4-(3-bromo-4-chlorophenoxy)piperidine-1-carboxylate (1150 mg, 2.94 mmol), 4-chlorophenylboronic acid (506 mg, 3.24 mmol), and NaCO (1248 mg, 11.8 mmol) in 1,4-dioxane (20 mL) and HO (5 mL), tetrakis(triphenylphosphine)palladium(0) (340 mg, 0.290 mmol, CAS RN: 14221-01-3) was added, and the mixture was stirred at 110 °C under a N atmosphere for 12 h. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with a 5–20% EtOAc-PE gradient to give the desired compound as a light yellow oil (1100 mg, 2.6 mmol, 88.5%). MS (ESI): m / z = 366.1 [M-56 + H] + .

[0511] BB14 4-[[2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperidine; Trifluoroacetate

[0512] To a mixture of tert-butyl 4-[[2-(1-tert-butoxycarbonylpyrazol-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate (150.0 mg, 0.290 mmol) in DCM (5 mL) was added TFA (1.0 mL). The mixture was stirred at 20° C. for 15 hours. The mixture was concentrated in vacuo and then lyophilized to give the title compound as a light yellow gum (149 mg, 0.280 mmol, 85.1% yield). MS (ESI): m / z=310.0 [M+H] + .

[0513] Step (a) tert-butyl 4-[[2-(1-tert-butoxycarbonylpyrazol-4-yl)-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

[0514] A mixture of tert-butyl 4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (600 mg, 1.43 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyrazole-1-carboxylate (846 mg, 2.86 mmol), and KCO (592 mg, 4.28 mmol) in DMF (10 mL) and HO (0.5 mL) was stirred at 80 °C for 12 h. The mixture was poured into HO (30 mL) and extracted twice with EtOAc (50 mL each). The combined organic layers were washed with brine (30 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the compound as a light yellow oil (520 mg, 1.02 mmol, 71.8% yield). MS (ESI): m / z = 308.1 [M+H] + .

[0515] Step (b) tert-butyl 4-[[2-(1-tert-butoxycarbonylpyrazol-4-yl)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

[0516] A mixture of tert-butyl 4-[[2-(1-tert-butoxycarbonylpyrazol-4-yl)-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (180 mg, 0.350 mmol) and wet Pd / C (18 mg) in EtOAc (10 mL) was stirred at 30 °C for 24 h under an H atmosphere (approximately 1520 mmHg). The mixture was filtered and concentrated in vacuo to give the compound as a brown oil (150 mg, 0.290 mmol, 83%). MS (ESI): m / z = 354.1 [M -56-100 + H] + .

[0517] BB18 4-[2-(2-chlorophenyl)ethynyl]piperidine

[0518] To a suspension of tert-butyl 4-((2-chlorophenyl)ethynyl)piperidine-1-carboxylate (0.05 g, 0.156 mmol) in MeOH (3 mL) was added 4 M HCl in dioxane (0.391 mL, 1.56 mmol), and the reaction mixture was stirred at room temperature for 2 h. The mixture was evaporated to dryness, and the residue was triturated with diisopropyl ether, filtered off, and further dried under high vacuum to give the title compound as a white solid, hydrochloride salt (0.02 g, 50%). MS (ESI): m / z = 220.1 [M+H] + .

[0519] Step (a) tert-butyl 4-[2-(2-chlorophenyl)ethynyl]piperidine-1-carboxylate

[0520] In a sealed tube, a mixture of tert-butyl 4-ethynylpiperidine-1-carboxylate (0.1 g, 0.478 mmol, CAS RN: 287192-97-6), 1-bromo-2-chlorobenzene (0.084 mL, 0.717 mmol), copper(I) iodide (0.002 g, 0.009 mmol), triethanolamine (0.666 mL, 4.78 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.027 g, 0.038 mmol) in THF (2.8 mL) was degassed under argon for 5 minutes. The reaction mixture was then heated to 70 °C and stirred for 4 hours. The mixture was filtered onto a pad of Dicalite, washed with EtOAc, and the mother liquor was evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a gradient of 0-50% EtOAc / n-heptane to give the title compound as a white solid (0.05 g, 33%). MS (ESI): m / z = 264.1 [M-56+H] + .

[0521] BB48a tert-Butyl 4-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

[0522] A degassed solution of tert-butyl 4-methylenepiperidine-1-carboxylate (4465 mg, 22.6 mmol, CAS RN: 159635-49-1) in 9-BBN (45.3 mL, 22.6 mmol) was refluxed for 1 hour. After cooling to room temperature, the solution was added to a solution of 4-bromo-3-fluorobenzotrifluoride (5.0 g, 20.6 mmol, CAS RN: 40161-54-4), Pd(dppf)Cl (1514 mg, 2.06 mmol), and KCO (5687 mg, 41.1 mmol) in DMF (50 mL) and water (5 mL). The resulting mixture was heated at 80 °C for 5 hours. After cooling to room temperature, the mixture was poured into water, the pH was adjusted to 11 with 10% aqueous NaOH, and the mixture was extracted with EtOAc. The combined organic extracts were dried with brine and Na2SO4, filtered, and evaporated to give a residue, which was further purified by column chromatography (silica gel, PE: EtOAc = 10:1 to 5:1) to give the compound as a bright yellow solid (240 mg, 3.2%). MS (ESI): m / z = 306 [M+H-56] + .

[0523] BB51a A mixture of tert-butyl 4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (1000 mg, 2.62 mmol) and PtO2 (100 mg, 0.440 mmol) in EtOAc (20 mL) was stirred at 20 °C for 12 h under an H2 atmosphere (1520 mmHg). The mixture was filtered and the filtrate was concentrated to give the compound as a bright yellow solid (940 mg, 93.5%). MS (ESI): m / z = 328.2 [M+H] + .

[0524] Step (a) 2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene

[0525] A mixture of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (5.5 g, 23.0 mmol, CAS RN: 128-08-5), benzoyl peroxide (835 mg, 3.45 mmol), and NBS (4.07 g, 23.01 mmol) in CCl (50.0 mL, 23.0 mmol) was stirred at 70 °C for 5 h. The mixture was poured into water (20 mL) and extracted twice with DCM (20 mL each). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give the desired compound as a light yellow oil (7.1 g, 97%), which was used in the next step without further purification.

[0526] Step (b) 2-Bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene

[0527] A mixture of 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (7.1 g, 22.3 mmol) and triethyl phosphite (30 mL) was stirred at 155 °C for 5 h. The mixture was concentrated in vacuo to remove triethyl phosphite, and the residue was diluted with water (100 mL) and extracted three times with EtOAc (100 mL each). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE: EtOAc = 100:1 to 10:1) to give the compound as a light yellow oil, which was used in the next step without further purification (8 g, 95.5%).

[0528] Step (c) tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzylidene)piperidine-1-carboxylate

[0529] To a mixture of 2-bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene (6.9 g, 18.4 mmol) in THF (100 mL) was added sodium hydride (2.21 g, 55.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, and then 1-Boc-4-piperidone (7.33 g, 36.79 mmol, CAS RN: 79099-07-3) was added, and the mixture was stirred at 20 °C for 12 h. The mixture was poured into water (100 mL) and extracted three times with EtOAc (100 mL each). The combined organic layers were washed with brine (100 mL), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 100:1 to 50:1) to afford the desired compound as an off-white solid (4 g, 51.7%). MS (ESI): m / z = 365.9 [M-56 + H] + .

[0530] Step (d) tert-butyl 4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

[0531] A mixture of tert-butyl 4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (2.0 g, 4.76 mmol), cyclopropylboronic acid (818 mg, 9.52 mmol, CAS RN: 411235-57-9), and potassium carbonate (1973 mg, 14.3 mmol) in DMF (10 mL) and water (0.5 mL) was stirred at 80 °C under a nitrogen atmosphere for 12 hours. The mixture was poured into water (50 mL) and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine (50 mL), dried over Na SO , and concentrated in vacuo. The residue was purified by preparative HPLC to give the compound as a light yellow oil (1020 mg, 56.2% yield). MS (ESI): m / z = 326.0 [M-56+H] + .

[0532] BB53a tert-Butyl 3-[(4-chlorophenyl)methoxy]pyrrolidine-1-carboxylate

[0533] To a solution of N-Boc-3-hydroxypyrrolidine (1.0 g, 5.34 mmol) and 4-chlorobenzyl bromide (1.32 g, 6.41 mmol) in ACN (10 mL) was added potassium carbonate (1.48 g, 10.68 mmol). The mixture was stirred at 80 °C for 15 h. The mixture was then concentrated, diluted with water, and extracted three times with EtOAc (10 mL each). The combined organic layers were concentrated to give the desired compound as a colorless oil (326 mg, 19.6% yield). MS (ESI): m / z = 256.0 [M-56 + H] + .

[0534] Method D4 BB70 3-[4-(trifluoromethyl)phenoxy]azetidine

[0535] To a solution of tert-butyl 3-[4-(trifluoromethyl)phenoxy]azetidine-1-carboxylate (500 mg, 1.58 mmol, BB70a) in DCM (3 mL) was added TFA (1.0 mL, 0.950 mmol) at 25 °C, and the reaction was stirred at this temperature for 12 h. The mixture was concentrated, and the residue was purified by preparative HPLC to give the compound as a colorless solid (150 mg, 0.690 mmol, 43.8%). MS (ESI): m / z = 218.1 [M+H] + .

[0536] BB72a tert-Butyl 4-(4-chloro-3-cyclopropyl-phenoxy)piperidine-1-carboxylate

[0537] To a solution of tert-butyl 4-(3-bromo-4-chlorophenoxy)piperidine-1-carboxylate (500 mg, 1.28 mmol, BB90), potassium carbonate (354 mg, 2.56 mmol), and cyclopropylboronic acid (121 mg, 1.41 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (187.28 mg, 0.260 mmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was diluted with EtOAc (30 mL), washed with water, then brine, and the organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel column elution (5% to 10% EtOAc-PE gradient) to give the compound as a bright yellow oil (220 mg, 48.9%). MS (ESI): m / z = 296.1 [M-56 + H] + .

[0538] BB73a tert-Butyl 4-(4-chloro-3-morpholino-phenoxy)piperidine-1-carboxylate

[0539] To a solution of tert-butyl 4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate (500 mg, 1.28 mmol, BB90), cesium carbonate (834 mg, 2.56 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (159 mg, 0.260 mmol), and morpholine (112 mg, 1.28 mmol) in DMF (10 mL) was added tris(dibenzylideneacetone)dipalladium(0) (187 mg, 0.260 mmol), and the mixture was stirred at 110° C. under a nitrogen atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was diluted with EtOAc (30 mL), washed with water, then brine, and the organic phase was dried over NaSO and concentrated. The residue was purified by silica gel column chromatography (eluting with a gradient of 5% to 10% EtOAc-PE) to give the desired compound (360 mg, 70.9% yield) as a light yellow oil. MS (ESI): m / z = 397.1 [M+H]+ .

[0540] BB74a tert-Butyl 4-[2-methyl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0541] To a solution of tert-butyl 4-[2-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (2.0 g, 4.71 mmol, BB74b) in THF (40 mL) was added lithium methide (11.8 mL, 18.9 mmol) dropwise at −70° C. The mixture was stirred at −70° C. for 1 h and then at 20° C. for 12 h. The mixture was poured into ice water (100 mL) and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine (100 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to afford the compound as a bright yellow solid (780 mg, 46%). MS (ESI): m / z=260.1 [M−100+H] + .

[0542] BB75a tert-Butyl 4-[2-cyano-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0543] To a solution of zinc cyanide (2214 mg, 18.9 mmol) and tert-butyl 4-[2-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (1600 mg, 3.77 mmol, BB74b) in DMA (30 mL) was added dppf (627 mg, 1.13 mmol), N,N-diisopropylethylamine (1.97 mL, 11.3 mmol), zinc dust (245 mg, 3.77 mmol), and Pd(dba) (1036 mg, 1.13 mmol) at 20 °C. The mixture was then stirred at 140 °C under a nitrogen atmosphere for 4 h. The mixture was filtered. The filtrate was poured into water (100 mL) and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the title compound as a light brown solid (2.3 g, crude). MS (ESI): m / z=315.0 [M-56+H] + .

[0544] BB76a tert-Butyl 4-(oxazolo[5,4-c]pyridin-2-ylmethyl)piperidine-1-carboxylate

[0545] To a solution of hexachloroethane (2.47 g, 10.4 mmol) in toluene (20 mL) was added triphenylphosphine (3.28 g, 12.5 mmol) and NEt (4.65 mL, 33.4 mmol). The mixture was stirred at 80 °C for 5 min, and then tert-butyl 4-[2-[(3-hydroxy-4-pyridyl)amino]-2-oxo-ethyl]piperidine-1-carboxylate (1.4 g, 4.17 mmol) was added and stirred at 80 °C for 12 h. The mixture was concentrated to remove toluene, then diluted with water (100 mL) and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (PE:EtOAc = 10:1 to 1:0) to give the compound as a yellow oil (814 mg, 21% yield). MS (ESI): m / z = 318.1 [M+H] + .

[0546] Step (a) tert-butyl 4-[2-[(3-hydroxy-4-pyridyl)amino]-2-oxo-ethyl]piperidine-1-carboxylate

[0547] To a solution of 4-aminopyridin-3-ol (3.0 g, 27.3 mmol) and 1-Boc-4-piperidylacetic acid (7.95 g, 32.7 mmol) in DMF (30 mL) was added HOBt (6.26 g, 40.9 mmol), EDCI (6.34 g, 40.87 mmol), and NEt (11.39 mL, 81.74 mmol). The mixture was stirred at 20 °C for 15 h. The mixture was then concentrated, and the residue was taken up in water (100 mL), followed by three extractions with EtOAc (20 mL each). The organic phase was washed with brine, dried over Na SO , and concentrated. The residue was purified by reverse phase chromatography and lyophilized to give two batches of the desired compound. Batch 1 is a colorless solid (1.2 g, 85% purity, 11.1%), and batch 2 is a colorless solid (520 mg, 76.7% purity, 4.4% yield). For both batches, MS (ESI): m / z = 336.1 [M+H] + .

[0548] BB77 4-chloro-3-(2-piperidin-4-ylethynyl)pyridine

[0549] Intermediate BB77 was prepared similarly to BB18, but using 3-bromo-4-chloro-pyridine in step (a) to afford the title compound as an orange solid. MS (ESI): m / z=221.1 [M+H] + .

[0550] BB78 3-chloro-2-(2-piperidin-4-ylethynyl)pyridine

[0551] Intermediate BB78 was prepared similarly to BB18, but using 2-bromo-3-chloro-pyridine in step (a) to afford the title compound as a yellow solid. MS (ESI): m / z=221.1 [M+H]+ .

[0552] BB79 4-[2-(2-chloro-4-fluorophenyl)ethynyl]piperidine

[0553] Intermediate BB79 was prepared similarly to BB18, but using 1-bromo-2-chloro-4-fluoro-benzene in step (a) to afford the title compound as a white solid. MS (ESI): m / z=238.1 [M+H] + .

[0554] BB80 4-[2-(3-chlorophenyl)ethynyl]piperidine

[0555] Intermediate BB80 was prepared similarly to BB18, but using 1-bromo-3-chlorobenzene in step (a), to afford the title compound as a colorless amorphous solid. MS (ESI): m / z = 220.2 [M+H] + .

[0556] BB81 4-[2-(4-chlorophenyl)ethynyl]piperidine

[0557] Intermediate BB81 was prepared analogously to BB18, but using 1-bromo-4-chlorobenzene in step (a), to afford the title compound as a yellow amorphous solid. MS (ESI): m / z = 220.2 [M+H] + .

[0558] BB82 4-[2-(2-chloro-4-chlorophenyl)ethynyl]piperidine

[0559] Intermediate BB82 was prepared similarly to BB18, but using 1-bromo-2,4-dichloro-benzene in step (a), to afford the title compound as a light yellow amorphous solid. MS (ESI): m / z=254.1 [M+H] + .

[0560] BB83 4-[2-(2-chlorophenyl)ethynyl]piperidin-4-ol

[0561] Intermediate BB83 was prepared similarly to BB18, except that tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylate (CAS RN: 275387-83-2) was used in step (a) to afford the title compound as a yellow amorphous solid. MS (ESI): m / z = 218.1 [M-HO + H] + .

[0562] BB84 3-[2-(2-chlorophenyl)ethynyl]azetidine

[0563] To a solution of tert-butyl 3-[2-(2-chlorophenyl)ethynyl]azetidine-1-carboxylate (0.035 g, 0.120 mmol) in DCM (0.6 mL) was added TFA (0.92.4 mL, 1.2 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with DCM, poured into saturated aqueous NaHCO3, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated, and further dried under high vacuum to give the crude title compound (0.02 g, 87%) as a light yellow oil. MS (ESI): m / z = 192.0 [M+H] + .

[0564] Step (a) tert-butyl 3-[2-(2-chlorophenyl)ethynyl]azetidine-1-carboxylate

[0565] The compound was prepared similarly to intermediate BB18, but using tert-butyl 3-ethynylazetidine-1-carboxylate (CAS RN: 287193-01-5) in step (a) to give the title compound as a white solid. MS (ESI): m / z = 236.1 [M-56 + H] + .

[0566] BB85 3-[2-(2,4-dichlorophenyl)ethynyl]azetidine

[0567] Intermediate BB85 was prepared similarly to BB84, but using 1-bromo-2,4-dichloro-benzene in step (a) to afford the title compound as a light yellow oil. MS (ESI): m / z=226.1 [M+H] + .

[0568] BB86 3-[2-(2-chloro-4-fluoro-phenyl)ethynyl]azetidine

[0569] Intermediate BB86 was prepared similarly to BB84, but using 1-bromo-2-chloro-4-fluoro-benzene in step (a) to afford the title compound as a yellow oil. MS (ESI): m / z=210.1 [M+H] + .

[0570] Similar to BB9a, the following building blocks were prepared from the respective building blocks:

[0571] [Table 6]

[0572] Similar to BB15a, the following building blocks were prepared from the respective building blocks:

[0573] [Table 7]

[0574] Similar to step (a) of BB9, the following building blocks were prepared from the respective starting materials.

[0575] [Table 8]

[0576] Method D5 BB51 4-[[2-Cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine formate

[0577] To a mixture of tert-butyl 4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate (940 mg, 2.45 mmol, BB51a) in DCM (10 mL) was added TFA (2.0 mL, 2.45 mmol). The mixture was stirred at 20° C. for 12 h. The mixture was concentrated in vacuo. The residue was purified twice by preparative HPLC to give the desired compound as a light yellow gum (111 mg, 12.4%). MS (ESI): m / z=284.2 [M+H] + .

[0578] Step (a) 2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene

[0579] A mixture of 2-bromo-1-methyl-4-(trifluoromethyl)benzene (5.5 g, 23.0 mmol, CAS RN: 128-08-5), benzoyl peroxide (835 mg, 3.45 mmol), and NBS (4.07 g, 23.0 mmol) in CCl (50.0 mL, 23.0 mmol) was stirred at 70 °C for 5 h. The mixture was poured into water (20 mL) and extracted twice with DCM (20 mL each). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give the compound as a light yellow oil (7.1 g, 97%), which was used in the next step without further purification.

[0580] Step (b) 2-Bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene

[0581] A mixture of 2-bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene (7.1 g, 22.3 mmol) and triethyl phosphite (30.0 mL) was stirred at 155 °C for 5 hours. The mixture was concentrated in vacuo to remove triethyl phosphite. The residue was diluted with water (100 mL) and extracted three times with EtOAc (100 mL each). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (PE:EA = 100:1 to 10:1) to give the title compound as a light yellow oil (8 g, 21.3 mmol, 95.5%), which was used in the next step without further purification.

[0582] Step (c) tert-butyl 4-(2-bromo-4-(trifluoromethyl)benzylidene)piperidine-1-carboxylate

[0583] To a mixture of 2-bromo-1-(diethoxyphosphorylmethyl)-4-(trifluoromethyl)benzene (6.9 g, 18.4 mmol) in THF (100 mL) was added NaH (2.21 g, 55.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h, then 1-Boc-4-piperidone (7.33 g, 36.8 mmol, CAS RN: 79099-07-3) was added and the mixture was stirred at 20 °C for 12 h. The mixture was poured into water (100 mL) and extracted three times with EtOAc (100 mL each). The combined organic layers were washed with brine (100 mL), dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 100:1 to 50:1) to give the desired compound as an off-white solid (4 g, 9.52 mmol, 51.7%). MS (ESI): m / z = 365.9 [M-56+H] + .

[0584] Step (d) tert-butyl 4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

[0585] A mixture of tert-butyl 4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (2.0 g, 4.76 mmol), cyclopropylboronic acid (818 mg, 9.52 mmol, CAS RN: 411235-57-9), and potassium carbonate (1973 mg, 14.3 mmol) in DMF (10 mL) and water (0.5 mL) was stirred at 80 °C under a nitrogen atmosphere for 12 hours. The mixture was poured into water (50 mL) and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine (50 mL), dried over Na SO , and concentrated in vacuo. The residue was purified by preparative HPLC to give the compound as a light yellow oil (1020 mg, 56.2% yield). MS (ESI): m / z = 326.0 [M-56+H] + .

[0586] Step (e) tert-butyl 4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

[0587] A mixture of tert-butyl 4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (1000 mg, 2.62 mmol) and PtO2 (100 mg, 0.440 mmol) in EtOAc (20 mL) was stirred under a hydrogen atmosphere (1520 mmHg) at 20 °C for 12 hours. The mixture was then filtered, and the filtrate was concentrated to afford the compound as a bright yellow solid (940 mg, 93.5% yield). MS (ESI): m / z = 328.2 [M+H] + .

[0588] Method D6 BB92 N-Methyl-N-[4-(trifluoromethyl)phenyl]piperidin-4-amine; Trifluoroacetate

[0589] To a solution of tert-butyl 4-[N-methyl-4-(trifluoromethyl)anilino]piperidine-1-carboxylate (150 mg, 0.420 mmol) in DCM (1 mL) was added TFA (0.1 mL) at 0° C. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (in the presence of TFA) to give the desired product as a yellow solid (120 mg, 77.0%). MS (ESI): m / z=259.2 [M+H] + .

[0590] Step (a) tert-butyl 4-[4-(trifluoromethyl)anilino]piperidine-1-carboxylate

[0591] To a solution of p-trifluoromethylaniline (1.17 mL, 9.31 mmol, CAS RN: 455-14-1) in DCM (30 mL) was added AcOH (0.560 g, 9.31 mmol) and 1-BOC-4-piperidone (2.78 g, 14.0 mmol, CAS RN: 79099-07-3). Then, 1 M BH / THF solution (27.9 mL, 27.9 mmol) was carefully added at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 12 h. The mixture was poured into saturated aqueous NH Cl (30 mL) and extracted three times with EtOAc. The combined organic layers were washed twice with water, then with brine, dried over Na SO , and concentrated in vacuo to give a yellow residue. This was purified on a silica gel column eluted with a gradient of PE: EtOAc (20:1 to 5:1) to give the desired product as a white solid (2.0 g, 62.4%). MS (ESI): m / z = 289.1 [M-56+H] + .

[0592] Step (b) tert-butyl 4-[N-methyl-4-(trifluoromethyl)anilino]piperidine-1-carboxylate

[0593] To a solution of NaH (52.3 mg, 60.0% wt%, 1.31 mmol) in DMF (5 mL) was added tert-butyl 4-[4-(trifluoromethyl)anilino]piperidine-1-carboxylate (300 mg, 0.870 mmol) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 15 min, and then iodomethane (371 mg, 2.61 mmol) was added. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was poured into water (20 mL) and extracted three times with EtOAc. The combined organic layers were washed twice with water and brine, dried over sodium sulfate, and concentrated in vacuo to give a bright yellow residue. This was purified on a silica gel column eluted with a gradient of PE:EtOAc (20:1 to 5:1) to give the desired product as a white solid (160 mg, 51.3%). MS (ESI): m / z = 303.1 [M-56 + H] + .

[0594] BB93 N-Methyl-N-(4-(trifluoromethyl)phenyl)azetidin-3-amine (trifluoroacetate)

[0595] The title compound was prepared from tert-butyl 3-[N-methyl-4-(trifluoromethyl)anilino]azetidine-1-carboxylate (48%) in analogy to Method D6. MS (ESI): m / z=231.1 [M+H] + .

[0596] Step (a) tert-butyl 3-[4-(trifluoromethyl)anilino]azetidine-1-carboxylate

[0597] To a solution of p-trifluoromethylaniline (0.780 mL, 6.21 mmol, CAS RN: 455-14-1), AcOH (1.86 g, 31.0 mmol), and 1-BOC-3-azetidinone (2.13 g, 12.4 mmol, CAS RN: 398489-26-4) in EtOH (10 mL) was added NaBHCN (1.95 g, 31.0 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated aqueous NH Cl (20 mL) and extracted twice with EtOAc. The combined organic layers were washed twice with HO and brine, dried over sodium sulfate, and concentrated in vacuo to give a yellow residue. This was purified by silica gel column eluting with a gradient of PE: EtOAc (10:1 to 5:1) to give the desired product as a white solid (340 mg, 17.3%). MS (ESI): m / z = 261.1 [M-56+H] + .

[0598] Step (b) tert-butyl 3-[N-methyl-4-(trifluoromethyl)anilino]azetidine-1-carboxylate

[0599] To a solution of tert-butyl 3-[4-(trifluoromethyl)anilino]azetidine-1-carboxylate (300 mg, 0.950 mmol) in DMF (5 mL) was added NaH (45.5 mg, 60% wt%, 1.14 mmol) at 0 °C. The mixture was stirred for 15 min, and then iodomethane (404 mg, 2.85 mmol) was added. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into HO (20 mL) and extracted twice with EtOAc. The combined organic layers were washed three times with HO and brine, dried over NaSO, and concentrated in vacuo to give a yellow residue. The residue was purified on a silica gel column eluted with a gradient of PE:EtOAc (10:1 to 5:1) to give the desired product as a white solid (310 mg, 98.9%). MS (ESI): m / z = 275.2 [M-56+H] + .

[0600] Method D7 BB94 N-Methyl-N-(piperidin-4-yl)-2-(3-(trifluoromethyl)phenyl)acetamide hydrochloride

[0601] To a solution of tert-butyl 4-[methyl-[2-[3-(trifluoromethyl)phenyl]acetyl]amino]piperidine-1-carboxylate (0.080 g, 200 μmol) in DCM (1 mL) was added 2 M HCl solution in diethyl ether (999 μL, 2 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo to give the title compound (67 mg, 199 μmol) as an off-white solid. MS (ESI): m / z=301.2 [M+H] + .

[0602] Step (a) tert-butyl 4-[methyl-[2-[3-(trifluoromethyl)phenyl]acetyl]amino]piperidine-1-carboxylate

[0603] To a stirred mixture of 2-(3-(trifluoromethyl)phenyl)acetic acid (105 mg, 513 μmol, CAS RN: 351-35-9) in DMF (5 mL) was added HATU (195 mg, 513 μmol) and DIPEA (181 mg, 244 μL, 1.4 mmol). After 15 min of stirring, tert-butyl 4-(methylamino)piperidine-1-carboxylate (0.100 g, 467 μmol, CAS RN: 147539-41-1) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM and washed with HO. The organic phase was concentrated to give the crude product. This was purified by flash chromatography on a 20 g SiO column using an eluent mixture of n-heptane and EtOAc (0% to 100%) to give the desired compound as a light yellow oil (85 mg, 213 μmol). MS(ESI):m / z=459.259[M+CH3CN+NH4] + .

[0604] Method D8 BB194 3-(4-chloro-3-cyclopropylphenoxy)azetidine

[0605] To a solution of tert-butyl 3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carboxylate (0.023 g, 0.057 mmol) in DCM (1 mL) was added TFA (0.088 mL, 1.14 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The mixture was diluted with DCM, poured into saturated aqueous NaHCO3, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated to dryness to yield the crude title compound (0.007 g, 35%) as a colorless oil. MS (ESI): m / z = 224.1 [M+H] + .

[0606] Step (a) tert-butyl 3-(3-bromo-4-chlorophenoxy)azetidine-1-carboxylate

[0607] In a sealed tube, 3-bromo-4-chlorophenol (0.1 mg, 0.482 mmol) and tert-butyl 3-hydroxyazetidine-1-carboxylate (0.083 g, 0.482 mmol) were dissolved in toluene (1.5 mL). The vial was degassed with argon, then (tributylphosphoranylidene)acetonitrile (CAS RN: 157141-27-0, 0.195 mL, 0.723 mmol) was added, and the reaction mixture was heated to 100 °C for 30 min. The mixture was diluted with EtOAc and poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a gradient of 0–20% EtOAc / heptane to afford the title compound (0.116 g, 53%) as a yellow oil. MS (ESI): m / z = 308.1 [M-56 + H] + .

[0608] Step (b) tert-butyl 3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carboxylate

[0609] In a microwave vial, tert-butyl 3-(3-bromo-4-chlorophenoxy)azetidine-1-carboxylate (0.075 g, 0.165 mmol), cyclopropylboronic acid (0.021 g, 0.248 mmol), and K2CO3 (0.046 g, 0.331 mmol) were mixed in dioxane (1.6 mL). Water (0.4 mL) was then added, followed by bis(triphenylphosphine)palladium(II) chloride (0.012 g, 0.016 mmol), and the reaction mixture was heated at 130 °C under microwave irradiation for 1 hour. The reaction mixture was diluted with EtOAc, poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a gradient of 0-10% EtOAc / heptane to give the title compound (0.023 g, 43%) as a colorless oil. MS (ESI): m / z = 268.2 [M-56+H] + .

[0610] Method D9 BB197 3-(2-chloro-3-cyclopropylphenoxy)azetidine, trifluoroacetate

[0611] To a solution of tert-butyl 3-(2-chloro-3-cyclopropyl-phenoxy)azetidine-1-carboxylate (0.1 g, 0.310 mmol) in DCM (2.5 mL) was added TFA (0.25 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the crude title compound (0.083 g, 80% yield) as a dark brown oil. MS (ESI): m / z = 224.6 [M+H] + .

[0612] Step (a) tert-butyl 3-(3-bromo-2-chloro-phenoxy)azetidine-1-carboxylate

[0613] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (0.5 g, 2.89 mmol) and 3-bromo-2-chlorophenol (0.5 g, 2.41 mmol) in THF (10 mL) was added PPh3 (0.948 g, 3.62 mmol), followed by diethyl azodicarboxylate (0.47 mL, 3.62 mmol), and the reaction mixture was stirred at room temperature for 12 hours. The mixture was purified by reverse-phase HPLC to give the title product (0.4 g, 46%) as a light yellow oil. MS (ESI): m / z = 308.3 [M-56 + H] + .

[0614] Step (b) tert-butyl 3-(2-chloro-3-cyclopropylphenoxy)azetidine-1-carboxylate

[0615] In a sealed tube, cyclopropylboronic acid (0.071 g, 0.830 mmol), tert-butyl 3-(3-bromo-2-chloro-phenoxy)azetidine-1-carboxylate (0.2 g, 0.550 mmol), and Na2CO3 (0.117 g, 1.1 mmol) were mixed in 1,4-dioxane (5 mL) and water (1 mL). Pd(dppf)Cl2 (0.040 g, 0.060 mmol) was then added, and the mixture was stirred at 110 °C for 12 h. The mixture was purified by reverse-phase HPLC to give the title compound (0.12 g, 67%) as a light yellow oil. MS (ESI): m / z = 268.1 [M-56 + H] + .

[0616] Method D10 BB202 5-(4-piperidyloxy)-2-(trifluoromethyl)benzonitrile, trifluoroacetate

[0617] To a solution of tert-butyl 4-[3-cyano-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (0.05 g, 0.140 mmol) in DCM (1.5 mL) was added TFA (0.2 mL), and the reaction mixture was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo to give the crude title compound (0.051 g, 98%) as a light brown oil. MS (ESI): m / z = 271.6 [M+H] + .

[0618] Step (a) tert-butyl 4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0619] To a solution of 3-bromo-4-(trifluoromethyl)phenol (0.5 g, 2.54 mmol) and 1-Boc-4-hydroxypiperidine (0.512 g, 2.54 mmol) in THF (8.5 mL) was added PPh3 (1 g, 3.82 mmol), followed by diethyl azodicarboxylate (0.665 g, 3.82 mmol), and the reaction mixture was stirred at room temperature for 12 h. The mixture was purified by silica gel flash chromatography eluting with PE:EtOAc 5:1 to afford the title compound (0.5 g, 47%) as a light yellow oil. MS (ESI): m / z = 370.2 [M-56+H] + .

[0620] Step (b) tert-butyl 4-[3-cyano-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0621] In a sealed tube, tert-butyl 4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (0.2 g, 0.470 mmol), Zn(CN) (0.111 g, 0.940 mmol), and CuI (0.09 g, 0.470 mmol) were mixed in DMF (10 mL). Pd(PPh) (0.109 g, 0.090 mmol) was then added, and the reaction mixture was stirred at 130 °C for 16 h. The mixture was purified by reverse-phase HPLC to give the title product (0.05 g, 29%) as a colorless oil. MS (ESI): m / z = 315.5 [M -56 + H] + .

[0622] Method E Example 263 (+)-5-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]oxy-2-(trifluoromethyl)benzonitrile [ka]

[0623] In a sealed tube, (+)-(4aR,8aS)-6-[3-[3-bromo-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB205, 0.2 g, 0.420 mmol), Zn(CN) (0.098 g, 0.840 mmol), Zn (0.027 g, 0.420 mmol), dppf (0.232 g, 0.420 mmol), and Hunig's base (0.108 g, 0.840 mmol) were combined in DMA (10 mL), and the mixture was degassed. Pd2(dba)3 (76.59 mg, 0.080 mmol) was then added, and the reaction mixture was stirred at 130 °C for 16 h. The mixture was purified by reverse-phase HPLC to give the title compound (0.055 g, 30%) as a bright yellow solid. MS (ESI): m / z = 425.3 [M+H] + .

[0624] Method F Example 265 (+)-(4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka]

[0625] In a sealed tube, (+)-(4aR,8aS)-6-[3-[3-bromo-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB203, 0.2 g, 0.420 mmol), 2-azaspiro[3.3]heptane (CAS RN: 665-04-03, 0.117 g, 0.630 mmol), BINAP (0.052 g, 0.080 mmol), and KCO (0.173 g, 1.25 mmol) were mixed in DMF (10 mL), and the mixture was degassed. Pd2(dba)3 (76.59 mg, 0.080 mmol) was then added and the reaction mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered off and the filtrate was diluted with water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (0.06 g, 29%) as a white solid. MS (ESI): m / z = 495.1 [M+H] + .

[0626] Method G Example 293 (4aR,8aS)-6-(3-(4-hydroxy-2-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one [ka]

[0627] Boron tribromide (11.3 mg, 4.29 μL, 45.3 μmol) was added to an ice-cold solution of (4aR,8aS)-6-(3-(4-methoxy-2-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 216, 20 mg, 45.3 μmol) in DCM (0.5 mL). The reaction mixture was stirred at ambient temperature for 3 h. Saturated aqueous NaHCO3 was added and the mixture was extracted with AcOEt. The layers were separated, the organic layer was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to give the title compound (19%) as a colorless solid. MS (ESI): m / z = 427.2 [M+H] + .

[0628] The following examples listed in the table below were prepared similarly to the procedures described for the preparation of Example 265, using the indicated intermediates and / or commercially available compounds, and using purification methods previously described, such as reverse-phase HPLC or silica gel flash chromatography.

[0629] [Table 9] TIFF0007637049000133.tif226169 TIFF0007637049000134.tif216169 TIFF0007637049000135.tif254169 TIFF0007637049000136.tif62169

[0630] Analogous to the methods described herein above, the following building blocks were prepared from the respective starting materials shown in the table below.

[0631] [Table 10] TIFF0007637049000138.tif207169

[0632] BB91 4-[[2-Pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methyl]piperidine; Formate

[0633] A solution of tert-butyl 4-[[2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate (500 mg, 1.21 mmol) in 6 M HCl in MeOH solution (10.0 mL) was stirred at 20° C. for 1 hour. The mixture was concentrated in vacuo and purified by reverse phase column chromatography to give the title compound as an orange oil (84.4 mg, 21.8% yield). MS (ESI): m / z=313.2 [M+H] + .

[0634] Step (a) Tert-butyl 4-[[2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

[0635] To a solution of tert-butyl 4-[[2-bromo-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (800 mg, 1.90 mmol; BB51, step (c)), pyrrolidine (163 mg, 2.28 mmol), Ruphos (4.25 mg, 0.010 mmol), and potassium tert-butoxide (320 mg, 2.86 mmol) in toluene (15 mL) was added palladium(II) acetate (1.28 mg, 0.010 mmol). The mixture was stirred at 80 °C under a N atmosphere for 15 h. The mixture was filtered and concentrated in vacuo to remove the toluene. The mixture was diluted with HO (40 mL) and extracted three times with EtOAc (40 mL each). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 1:0 to 8:1) to give the compound as a light yellow oil (552 mg, 1.34 mmol, 36.7%). MS (ESI): m / z = 411.1 [M+H] + .

[0636] Step (b) Tert-butyl 4-[[2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

[0637] To a solution of tert-butyl 4-[[2-pyrrolidin-1-yl-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (525 mg, 0.660 mmol) in MeOH (20 mL) was added wet Pd / C (approximately 52 mg), and the mixture was stirred at 20 °C under a H atmosphere (balloon) for 1 h. The mixture was filtered and concentrated in vacuo to give the desired compound as a colorless oil (500 mg), which was used in the next step without further purification.

[0638] BB95 3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine 4-methylbenzenesulfonate

[0639] To a solution of 3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate (50 mg, 144 μmol, equiv.: 1) in EtOAc (0.8 mL) was added 4-methylbenzenesulfonic acid monohydrate (29.7 mg, 173 μmol, equiv.: 1.2) and the mixture was heated under reflux for 1.5 h. The clear, colorless solution was cooled to room temperature. No precipitation occurred. The solution was evaporated to give the desired product as a colorless foam. MS (ESI): m / z = 248.1 [M-TsOH+H]+.

[0640] Step (a) tert-butyl 3-[(E)-2-[2-fluoro-6-(trifluoromethyl)phenyl]ethenyl]azetidine-1-carboxylate

[0641] To an ice-cold solution of diethyl (2-fluoro-4-(trifluoromethyl)benzyl)phosphonate (300 mg, 955 μmol) in THF (2 mL) was added 55% sodium hydride in mineral oil (41.7 mg, 955 μmol), and the mixture was stirred at this temperature for 30 minutes. To the light brown mixture was added dropwise a solution of tert-butyl 3-formylazetidine-1-carboxylate (177 mg, 955 μmol) in THF (1 mL). This resulted in an immediate discoloration of the reaction mixture. Stirring was continued at ice bath temperature for 1 hour, then at room temperature for 1.5 hours. The reaction mixture was poured onto water, ethyl acetate was poured in, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed once with brine, dried over MgSO4, filtered, treated with silica gel, and evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 25:75) to give the desired compound as a colorless solid (0.108 g; 32.8%). MS (ESI): m / z = 290.2 [M-56+H]+.

[0642] Step (b) tert-butyl 3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carboxylate

[0643] To a solution of tert-butyl (E)-3-(2-fluoro-4-(trifluoromethyl)styryl)azetidine-1-carboxylate (105 mg, 304 μmol) in MeOH (1 mL) and ethyl acetate (1 mL) was added Pd / C 10% (11 mg, 304 μmol), and the mixture was stirred under a hydrogen atmosphere at 1.7 bar and room temperature for 30 minutes. The suspension was filtered. The filtrate was evaporated to give the desired compound as a colorless oil (0.104 g; 98.5%). MS (ESI): m / z = 292.2 [M-56 + H] + .

[0644] BB96 4-((2-chloro-4-fluorophenoxy)methyl)azepane hydrochloride

[0645] To a solution of tert-butyl 4-((2-chloro-4-fluorophenoxy)methyl)azepane-1-carboxylate (620 mg, 1.73 mmol) in DCM (7.5 ml) was added 2 M HCl in ether (10 ml, 20 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the crude material was recovered as a white solid (490 mg, 1.67 mmol, 96.1%) and used directly in the next step. LC-MS (ESI): m / z: 258.2 [M+H]+

[0646] Step (a) tert-butyl 4-((2-chloro-4-fluorophenoxy)methyl)azepane-1-carboxylate

[0647] In a 25 mL four-neck sulfonation flask under argon, tert-butyl 4-(hydroxymethyl)azepane-1-carboxylate (480 mg, 2.09 mmol) was dissolved in THF (10 mL). Subsequently, 2-chloro-4-fluorophenol (337 mg, 251 μL, 2.3 mmol) and triphenylphosphine (604 mg, 2.3 mmol) were added, and the clear solution was stirred at room temperature for 5 minutes. The mixture was cooled to 0°C, and DEAD (401 mg, 365 μL, 2.3 mmol) was added in portions over 10 minutes. The mixture was stirred at 0°C for 1 hour and then overnight at room temperature. The mixture was stripped from EtOAc (50 mL) and washed with water (2 × 25 mL). The organic phase was washed with 1 M NaOH (3 × 25 mL), brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was dissolved in n-heptane / diethyl ether, the mixture was stirred for 30 min, the TPPO precipitate was filtered, and the crude material was concentrated in vacuo. The crude material was adsorbed onto Isolute® and purified by flash column chromatography (0–30% EtOAc / heptane) on silica gel (50 g) to give the desired product (630 mg, 1.76 mmol, 84.1%) as a yellow oil. LC-MS (ESI): m / z: 302.1 [M-56+H]+

[0648] BB97 4-[[4-(trifluoromethyl)phenyl]methyl]azepane hydrochloride

[0649] To a solution of tert-butyl 4-(4-(trifluoromethyl)benzyl)azepane-1-carboxylate (88 mg, 246 μmol, equiv: 1) in DCM (1.5 ml) was added 2 M HCl in ether (3.08 ml, 6.16 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the crude material was recovered as a white solid (71 mg, 0.24 mmol, 98.2%) and used directly in the next step. LC-MS (ESI): m / z: 258.2 [M+H]

[0650] Step a: Triphenyl(4-(trifluoromethyl)benzyl)phosphonium bromide

[0651] Triphenylphosphine (1.84 g, 7 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.61 g, 6.74 mmol) were dissolved in xylene (35 ml). The reaction mixture was heated at reflux at 155° C. for 3.5 hours and then cooled to room temperature. The precipitated white crystalline solid was collected by filtration, washed with diethyl ether, and dried in vacuo. The final compound (3.30 g, 6.58 mmol, 97.7% yield) was obtained as a white powder, which was used directly in the next step. LC-MS (ESI): m / z: 421.2 [M+H]+

[0652] Step b: tert-butyl (E)-4-(4-(trifluoromethyl)benzylidene)azepane-1-carboxylate

[0653] A suspension of sodium hydride (88.6 mg, 2.22 mmol) in DMF (7.5 mL) was cooled in an ice bath, and then triphenyl(4-(trifluoromethyl)benzyl)phosphonium bromide (1.11 g, 2.22 mmol) was added. The suspension was stirred at 0 °C for 5 minutes and then at room temperature for 25 minutes. tert-Butyl 4-oxoazepane-1-carboxylate (315 mg, 1.48 mmol) was added, and the resulting mixture was stirred at 80 °C for 28 hours. The mixture was concentrated in vacuo, diluted with water (50 mL) and EtOAc (40 mL), and the EtOAc was extracted (3 × 30 mL). The combined organic fractions were washed with water, 10% LiCl solution, dried over Na SO , and concentrated in vacuo. The residual oil was treated with Et O to precipitate triphenyl phosphonium, which was removed by filtration. The solution was concentrated in vacuo, and the residue was purified by flash column chromatography (0–35% EtOAc / heptane) on silica gel (50 g) to give the desired product (92 mg, 259 μmol, 17.5% yield) as a yellow oil. LC-MS (ESI): m / z: 300.2 [M-56+H]+

[0654] Step c: tert-butyl 4-(4-(trifluoromethyl)benzyl)azepane-1-carboxylate

[0655] A solution of tert-butyl (E)-4-(4-(trifluoromethyl)benzylidene)azepane-1-carboxylate (90 mg, 253 μmol) was dissolved in MeOH (2.5 ml). The reaction vessel was evacuated and backfilled with argon five times. Under argon, Pd—C (13.5 mg, 12.7 μmol) was added and the atmosphere was replaced with hydrogen three times. The reaction was stirred under a hydrogen atmosphere at 1 bar for 24 hours. The atmosphere was replaced with argon and the reaction mixture was filtered over a pad of Dicalite. The filter cake was washed with methanol. The filtrate was concentrated in vacuo to give the desired product (89 mg, 249 μmol, 98.3% yield) as a colorless oil, which was used without further purification. LC-MS (ESI): m / z: 302.2 [M-56+H]+

[0656] BB98 3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine 2,2,2-trifluoroacetate

[0657] tert-Butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate (110 mg, 299 μmol) was dissolved in DCM (2 mL) and TFA (273 mg, 184 μL, 2.39 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The volatiles were removed in vacuo to yield 110 mg of a bright yellow solid (96%). MS (ESI): m / z=268.1 [M+H] + .

[0658] Step (a) tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate

[0659] In a 20 mL glass tube, a 1 M solution of potassium tert-butoxide in THF (2.17 mL, 2.17 mmol) was added to a solution of 2-chloro-4-(trifluoromethyl)benzenethiol (440 mg, 2.07 mmol) in dry THF (6 mL). The yellow reaction mixture was stirred at room temperature for 15 min, after which tert-butyl 3-bromoazetidine-1-carboxylate (489 mg, 2.07 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and then at 70 °C overnight. The crude reaction mixture was diluted with EtOAc and extracted with HO. The organic phase was collected, and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over NaSO and evaporated to dryness. The residue was purified by chromatography (SiO, n-hexane / EtOAc (0–40%, over 40 min)) to afford the product as a viscous oil (467 mg, 61%). MS (ESI): m / z = 312.1 [M-56] + .

[0660] BB99 3-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)azetidine 2,2,2-trifluoroacetate

[0661] tert-Butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)azetidine-1-carboxylate (100 mg, 250 μmol) was dissolved in DCM and TFA (228 mg, 154 μL, 2 mmol) was added. The reaction mixture was stirred at room temperature for 8 hours. The volatiles were removed in vacuo to yield the desired compound as a bright yellow solid (102 mg, 98%). MS (ESI): m / z=300.0 [M+H] + .

[0662] Step (a) tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate

[0663] In a 20 mL glass tube, a 1 M solution of potassium tert-butoxide in THF (2.17 mL, 2.17 mmol) was added to a solution of 2-chloro-4-(trifluoromethyl)benzenethiol (440 mg, 2.07 mmol) in dry THF (6 mL). The yellow reaction mixture was stirred at room temperature for 15 min, after which tert-butyl 3-bromoazetidine-1-carboxylate (489 mg, 2.07 mmol) was added. The reaction mixture was stirred at room temperature for 5 h and then at 70 °C overnight. The crude reaction was diluted with EtOAc and extracted with HO. The organic phase was collected, and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over NaSO and evaporated to dryness. The residue was purified by column chromatography (SiO, n-hexane / EtOAc (0–40%, over 40 min)) to afford the desired product as a viscous oil (467 mg, 61%). MS (ESI): m / z = 312.1 [M-56 + H] + .

[0664] Step (b) tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)azetidine-1-carboxylate

[0665] mCPBA (347 mg, 1.41 mmol) was added in one portion to a stirred solution of tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate (345 mg, 938 μmol) in DCM (6 mL) in an ice bath. The reaction was stirred at room temperature for 20 min. The reaction mixture was poured into 5 mL of saturated Na2CO3 solution and extracted twice with DCM (20 mL each). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by preparative HPLC (YMC-Triart C18, ACN / H2O+0.1% HCOOH) to give the product as a white powder (253 mg, 67.5%). MS (ESI): m / z=344.0 [M-56+H] + .

[0666] BB100 3-((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine 2,2,2-trifluoroacetate

[0667] tert-Butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine-1-carboxylate (50 mg, 130 μmol) was dissolved in DCM (1.5 mL), TFA (149 mg, 100 μL, 1.3 mmol) was added, and the reaction mixture was stirred at room temperature for 8 hours. Volatiles were removed in vacuo to yield the compound as a white solid (51 mg, 98%). MS (ESI): m / z=284.1 [M+H] + .

[0668] Step (a) tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)thio)azetidine-1-carboxylate

[0669] The compound was prepared analogously to step a of BB99 and used in the next step without further purification. Step (b) tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)azetidine-1-carboxylate

[0670] The sulfoxide intermediate was isolated from step b of the synthesis of the sulfone building block BB99 described above. The product was obtained as a white lyophilized powder (50 mg, 13.9%). MS (ESI): m / z = 328.1 [M-56 + H] + .

[0671] BB101 3-(((2-chloro-4-(trifluoromethyl)phenyl)thio)methyl)azetidine 2,2,2-trifluoroacetate

[0672] To a solution of tert-butyl 3-(((2-chloro-4-(trifluoromethyl)phenyl)thio)methyl)azetidine-1-carboxylate (0.200 g, 524 μmol) in DCM (3 mL) was added TFA (478 mg, 323 μL, 4.19 mmol) and the reaction mixture was stirred at room temperature for 3 h. The volatiles were removed in vacuo to yield the compound as a light yellow oil, which was used in the next step without further purification (267 mg). MS (ESI): m / z=282.2 [M+H] + .

[0673] Step (a) tert-butyl 3-[[2-chloro-4-(trifluoromethyl)phenyl]sulfanylmethyl]azetidine-1-carboxylate

[0674] To a solution of 2-chloro-4-(trifluoromethyl)benzenethiol (0.400 g, 1.88 mmol) in dry THF (6 mL) was added a 1 M solution of potassium tert-butoxide in THF (1.98 mL, 1.98 mmol). The cloudy reaction mixture was stirred at room temperature for 15 minutes, after which tert-butyl 3-(bromomethyl)azetidine-1-carboxylate (471 mg, 1.88 mmol) was added. The reaction mixture was then stirred at room temperature for 19 hours. The crude reaction was diluted with EtOAc and extracted with 1 M aqueous NaHCO3. The organic phase was collected, and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the crude product, which was used in the next step without further purification (762 mg). MS (ESI): m / z = 326.1 [M -56 + H] + .

[0675] BB102 3-((2-Fluoro-6-(trifluoromethyl)benzyl)sulfonyl)azetidine 2,2,2-trifluoroacetate

[0676] tert-Butyl 3-((2-fluoro-6-(trifluoromethyl)phenyl)methylsulfonyl)azetidine-1-carboxylate (0.047 g, 118 μmol) was dissolved in DCM (0.5 mL) and TFA (108 mg, 72.9 μL, 946 μmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo to yield the compound as a yellow oil (56 mg), which was used in the next step without further purification. MS (ESI): m / z=298.2 [M+H] + .

[0677] Step (a) tert-butyl 3-((2-fluoro-6-(trifluoromethyl)benzyl)thio)azetidine-1-carboxylate

[0678] To a solution of tert-butyl 3-mercaptoazetidine-1-carboxylate (0.400 g, 2.11 mmol) in dry THF (5 mL) was added a 1 M solution of potassium tert-butoxide in THF (2.22 mL, 2.22 mmol). The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene (CAS RN: 239087-08-2). The reaction mixture was then stirred at room temperature for 14 hours. The crude reaction was diluted with EtOAc and extracted with 1 M aqueous NaHCO3. The organic phase was collected, and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over NaSO4 and evaporated to dryness to yield the crude product (805 mg), which was used in the next step without further purification. MS (ESI): m / z = 310.2 [M -56 + H] + .

[0679] Step (b) tert-butyl 3-[[2-fluoro-6-(trifluoromethyl)phenyl]methylsulfonyl]azetidine-1-carboxylate

[0680] 3-Chloroperbenzoic acid (283 mg, 1.64 mmol) was added portionwise to a stirred solution of tert-butyl 3-((2-fluoro-6-(trifluoromethyl)benzyl)thio)azetidine-1-carboxylate (0.300 g, 821 μmol) in DCM (5 mL) in an ice bath. The reaction mixture was stirred at room temperature for 15 min, poured into 5 mL of saturated aqueous NaHCO3, and extracted twice with DCM (10 mL each). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, 20 g, 0% to 100% EtOAc in n-heptane) to give the desired product as a colorless oil (47 mg, 15%). MS (ESI): m / z = 415.1 [M+NH4] + .

[0681] BB103 3-((2-fluoro-6-(trifluoromethyl)benzyl)sulfinyl)azetidine 2,2,2-trifluoroacetate

[0682] tert-Butyl 3-[[2-fluoro-6-(trifluoromethyl)phenyl]methylsulfinyl]azetidine-1-carboxylate (0.086 g, 225 μmol) was dissolved in DCM (1 mL) and TFA (206 mg, 139 μL, 1.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo to yield the compound as a yellow oil (93 mg), which was used in the next step without further purification. MS (ESI): m / z = 282.2 [M+H] + .

[0683] Step (a) tert-butyl 3-[[2-fluoro-6-(trifluoromethyl)phenyl]methylsulfinyl]azetidine-1-carboxylate

[0684] The sulfoxide intermediate was isolated from step b of the synthesis of BB102 as a colorless oil (86 mg, 28%). MS (ESI): m / z = 404.1 [M+Na] + .

[0685] BB104 3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)methyl)azetidine 2,2,2-trifluoroacetate

[0686] tert-Butyl 3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)methyl)azetidine-1-carboxylate (0.145 g, 350 μmol) was dissolved in DCM (2 mL) and TFA (320 mg, 216 μL, 2.8 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo to yield the compound as a yellow oil (181 mg), which was used in the next step without further purification. MS (ESI): m / z=314.1 [M+H] + .

[0687] Step (a) tert-butyl 3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfonyl)methyl)azetidine-1-carboxylate

[0688] 3-Chloroperbenzoic acid (352 mg, 1.57 mmol) was added portionwise to a stirred solution of tert-butyl 3-(((2-chloro-4-(trifluoromethyl)phenyl)thio)methyl)azetidine-1-carboxylate (BB101, step a) (0.300 g, 786 μmol) in DCM (5 mL) in an ice bath. The reaction mixture was stirred at room temperature for 15 min, poured into 5 mL of saturated aqueous NaHCO3, and extracted twice with DCM (10 mL each). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in n-heptane) to give the desired product as a colorless oil (145 mg, 45%). MS (ESI): m / z = 314.0 [M -56 + H] + .

[0689] BB105 3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine 2,2,2-trifluoroacetate

[0690] tert-Butyl 3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine-1-carboxylate (0.086 g, 216 μmol) was dissolved in DCM (1 mL) and TFA (197 mg, 133 μL, 1.73 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo to yield the compound as a yellow oil (99 mg), which was used in the next step without further purification. MS (ESI): m / z=298.1 [M+H] + .

[0691] Step (a) tert-butyl 3-(((2-chloro-4-(trifluoromethyl)phenyl)sulfinyl)methyl)azetidine-1-carboxylate

[0692] The sulfoxide intermediate was isolated from the synthesis of BB104, step a. The desired product was obtained as a yellow oil (80 mg, 25.6%). MS (ESI): m / z = 398.1 [M+H] + .

[0693] BB106 3-((2-fluoro-4-(trifluoromethyl)benzyl)thio)azetidine 2,2,2-trifluoroacetate

[0694] To a solution of tert-butyl 3-((2-fluoro-4-(trifluoromethyl)benzyl)thio)azetidine-1-carboxylate (0.282 g, 772 μmol) in DCM (3 mL) was added TFA (880 mg, 595 μL, 7.72 mmol) and the reaction mixture was stirred at room temperature for 3 h. The volatiles were removed in vacuo to yield the desired compound as a colorless oil (302 mg), which was used in the next step without further purification. MS (ESI): m / z = 266.2 [M+H] + .

[0695] Step (a) tert-butyl 3-[[2-fluoro-4-(trifluoromethyl)phenyl]methylsulfanyl]azetidine-1-carboxylate

[0696] To a solution of tert-butyl 3-mercaptoazetidine-1-carboxylate (0.200 g, 1.06 mmol) in dry THF (2 mL) was added a 1 M solution of potassium tert-butoxide in THF (1.11 mL, 1.11 mmol). The reaction mixture was stirred at room temperature for 15 min, followed by the addition of 1-(bromomethyl)-2-fluoro-4-(trifluoromethyl)benzene (272 mg, 1.06 mmol, CAS RN: 239087-07-1). The reaction mixture was then stirred at room temperature for 14 h. The crude reaction was diluted with EtOAc and extracted with 1 M aqueous NaHCO3. The organic phase was collected, and the aqueous phase was back-extracted with EtOAc. The combined organic phases were dried over NaSO4, evaporated to dryness, and purified by flash chromatography (silica gel, 20 g, 0% to 80% EtOAc in n-heptane) to give the desired product as a colorless oil (288 mg, 75%). MS (ESI): m / z = 310.2 [M-56 + H] + .

[0697] Similar to BB84, the following intermediates were each prepared from commercially available starting materials.

[0698] [Table 11] TIFF0007637049000140.tif198169

[0699] Similarly to BB18, the following intermediates were each prepared from commercially available starting materials.

[0700] [Table 12]

[0701] BB149 1-[2-(azetidin-3-yl)ethynyl]cyclopentanol hydrochloride

[0702] To a solution of tert-butyl 3-[2-(1-hydroxycyclopentyl)ethynyl]azetidine-1-carboxylate (0.02 g, 0.075 mmol) in dioxane (0.5 mL) was added 4 M HCl in dioxane (0.094 mL, 0.377 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The mixture was evaporated to dryness, and the residue was triturated with diisopropyl ether, filtered, and further dried under high vacuum to give the title compound as a white solid, hydrochloride salt (0.013 g, 87%). MS (ESI): m / z = 166.1 [M+H] + .

[0703] Step (a) tert-butyl 3-[2-(1-hydroxycyclopentyl)ethynyl]azetidine-1-carboxylate

[0704] To a solution of tert-butyl 3-ethynylazetidine-1-carboxylate (0.2 g, 1.1 mmol) in THF (6.5 mL) at −78 °C, nBuLi (0.759 mL, 1.21 mmol) was added dropwise, and the reaction mixture was stirred at this temperature for 1 h. Then, cyclopentanone (0.107 mL, 1.21 mmol) in THF (3 mL) was added dropwise to the mixture, which was stirred at −78 °C for 2 h. The mixture was warmed to 0 °C, poured into saturated aqueous NH OH, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and evaporated. The residue was purified by silica gel flash chromatography eluting with a gradient of EtOAc:n-heptane (0–100%) to afford the title compound as a light yellow oil (0.020 g, 7%). MS (ESI): m / z = 192.2 [M-56-18 + H] + .

[0705] BB150 4-[3-pyrazol-1-yl-5-(trifluoromethyl)phenoxy]piperidine formate

[0706] A mixture of tert-butyl 4-[3-pyrazol-1-yl-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (400.0 mg, 0.970 mmol) and TFA (1.0 mL, 0.970 mmol) in DCM (10 mL) was stirred at 20° C. for 12 h. The mixture was purified by preparative HPLC (ACN and water containing 0.225% v / v FA) to give the desired product (300 mg, 94.4%) as a colorless gum. MS (ESI): m / z = 312.1 [M+H] + .

[0707] Step a: tert-butyl 4-[3-bromo-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0708] To a solution of 3-bromo-5-(trifluoromethyl)phenol (2.0 g, 8.3 mmol), 1-BOC-4-hydroxypiperidine (1.84 g, 9.13 mmol, CAS RN: 106-52-5), and PPh3 (2.61 g, 9.96 mmol) in THF (32.6 mL) was added diisopropyl azodicarboxylate (1.96 mL, 9.96 mmol), and the reaction mixture was stirred at 20 °C for 15 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (ACN and water containing 0.225% v / v FA) and concentrated in vacuo to give the desired product as a light yellow oil (2.6 g, 73.9% yield). MS (ESI): m / z = 367.9 [M-56 + H] + .

[0709] Step (b) tert-butyl 4-[3-pyrazol-1-yl-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0710] A mixture of tert-butyl 4-[3-bromo-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0 mg, 1.18 mmol), pyrazole (160.47 mg, 2.36 mmol), CuI (22.37 mg, 0.120 mmol), cesium carbonate (1152 mg, 3.54 mmol), and N,N'-dimethylethylenediamine (519.15 mg, 5.89 mmol) in DMF (5 mL) was stirred at 110 °C for 12 h. The mixture was poured into HO (30 mL) and extracted three times with EtOAc (50 mL). The combined organic layers were washed with ammonia (10 mL), brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the desired product (400 mg, 82.5% yield) as a light yellow oil. MS (ESI): m / z = 356.2 [M-56 + H] + .

[0711] BB151 4-[[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methyl]piperidine

[0712] A mixture of 4-[[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methylene]piperidine (250.0 mg, 0.740 mmol) and Pd / C (50.0 mg, 10 wt%) in THF (10 mL) was stirred under H (1520 mmHg) at 20 °C for 12 h. The mixture was filtered and concentrated in vacuo to give the desired compound (240 mg, 95.4%) as a light brown gum. MS (ESI): m / z = 342.1 [M+H] + .

[0713] Step (a) tert-butyl 4-(p-tolylsulfonylhydrazono)piperidine-1-carboxylate

[0714] To a solution of 4-methylbenzenesulfonhydrazide (9.35 g, 50.19 mmol, CAS RN: 1576-35-8) in MeOH (100 mL) was added 1-BOC-4-piperidone (10.0 g, 50.19 mmol, CAS RN: 17502-28-8) and the mixture was stirred at 25 °C for 12 h. The mixture was concentrated to give the desired product (18.4 g, 99.8%) as an off-white solid. MS (ESI): m / z = 368.2 [M+H] + .

[0715] Step (b) 2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)benzaldehyde

[0716] A mixture of NaH (187.39 mg, 60% dispersion in mineral oil, 4.68 mmol) in 2,2,2-trifluoroethanol (16.67 mL, 228.74 mmol, CAS RN: 75-89-8) was stirred at 0 °C. The cooling bath was removed, and the mixture was stirred at 20 °C for 2 h. Then 2-fluoro-4-(trifluoromethyl)benzaldehyde (1.0 g, 5.21 mmol, CAS RN: 763-93-9) was added, and the mixture was stirred at 20 °C for 12 h. The mixture was poured into HO (30 mL) and extracted twice with EtOAc (30 mL each). The combined organic layers were washed with brine (30 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the desired product (1.2 g, 84.7%) as a bright yellow solid. 1 H NMR(400MHz,DMSO-d6)δ10.44-10.34(m,1H),7.93(d,J=8.1Hz,1H),7.75(s,1H),7.55(d,J=8.1Hz,1H),5.11(q,J=8.7Hz,2H).

[0717] Step (c) tert-butyl 4-[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)benzoyl]piperidine-1-carboxylate

[0718] A mixture of 2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)benzaldehyde (1000.0 mg, 3.67 mmol), tert-butyl 4-(p-tolylsulfonylhydrazono)piperidine-1-carboxylate (1350.3 mg, 3.67 mmol), and cesium carbonate (1795.9 mg, 5.51 mmol) in 1,4-dioxane (30 mL) was stirred at 110 °C for 12 hours under a N atmosphere. The mixture was poured into HO (50 mL) and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (MeCN and water containing 0.225% v / v FA) to give the desired product (980 mg, 58.6%) as a light yellow gum. MS (ESI): m / z = 400.1 [M-56+H] + .

[0719] Step (d) tert-butyl 4-[hydroxy-[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

[0720] To a solution of tert-butyl 4-[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)benzoyl]piperidine-1-carboxylate (900.0 mg, 1.98 mmol) in MeOH (45 mL) was added NaBH4 (149.54 mg, 3.95 mmol) at 0 °C, and the mixture was stirred at 20 °C for 12 h. The mixture was purified by preparative HPLC (MeCN and water containing 0.225% v / v FA) (650 mg, 71.9%) as a light yellow oil. MS (ESI): m / z = 384.0 [M-56-OH+H] + .

[0721] Step (e) 4-[[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methylene]piperidine

[0722] A mixture of tert-butyl 4-[hydroxy-[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate (400.0 mg, 0.870 mmol) and MsOH (840.43 mg, 8.74 mmol) in DCM (4 mL) was stirred at 40 °C for 24 h. The mixture was poured into saturated aqueous NaCO solution (5 mL) and extracted three times with EtOAc (10 mL each). The combined organic layers were washed with brine (10 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo to give the desired compound as a light yellow oil (260 mg, 76.2%). MS (ESI): m / z = 340.1 [M+H] + .

[0723] BB152 4-[3-(1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidine trifluoroacetate

[0724] To a mixture of tert-butyl 4-[3-(1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (240.0 mg, 0.580 mmol) in DCM (10 mL) was added TFA (1.0 mL). The mixture was stirred at 20° C. for 12 hours and then concentrated in vacuo to give 4-[3-(1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidine 2,2,2-trifluoroacetate (240 mg, 96.7%) as a bright yellow gum. MS (ESI): m / z=313.1 [M+H] + .

[0725] Step (a) tert-butyl 4-[3-(1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0726] A mixture of tert-butyl 4-[3-bromo-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0 mg, 1.18 mmol, BB98, Intermediate a), 1,2,4-triazole (162.8 mg, 2.36 mmol), and CuI (22.37 mg, 0.120 mmol) in DMF (5 mL) was stirred at 110 °C for 12 h. The mixture was poured into HO (20 mL) and extracted three times with EtOAc (30 mL each). The combined organic layers were washed with ammonia (20 mL), brine (20 mL, 3 times), dried over NaSO, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (PE:EA = 50:1 to 3:1) to give the desired product (240 mg, 49.4%) as a bright yellow solid. MS (ESI): m / z = 357.1 [M-56 + H] + .

[0727] BB153 3-[4-chloro-3-(trifluoromethyl)phenoxy]azetidine trifluoroacetate

[0728] To a solution of tert-butyl 3-[4-chloro-3-(trifluoromethyl)phenoxy]azetidine-1-carboxylate (300.0 mg, 0.530 mmol) in DCM (7.5 mL) was added TFA (1.04 mL) at 0° C., and the mixture was stirred at 20° C. for 2 hours. The mixture was concentrated to give the title compound as a yellow oil (280 mg, 97%). MS (ESI): m / z=252.0 [M+H] + .

[0729] Step (a) tert-butyl 3-[4-chloro-3-(trifluoromethyl)phenoxy]azetidine-1-carboxylate

[0730] To a solution of 2-chloro-5-hydroxybenzotrifluoride (1 g, 5.1 mmol, CAS RN: 6294-93-5), tert-butyl 3-hydroxyazetidine-1-carboxylate (0.97 g, 5.6 mmol, CAS RN: 141699-55-0), and triphenylphosphine (1.6 g, 6.11 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (1.2 mL, 6.11 mmol), and the mixture was stirred at 20 °C for 15 h. The mixture was concentrated and purified by reverse-phase chromatography (MeCN and water containing 0.225% v / v FA) to afford the title compound (820 mg, 28.7%) as a brown solid. MS (ESI): m / z = 295.9 [M-56+H] + .

[0731] BB154 4-(4-chloro-3-pyrazol-1-yl-phenoxy)piperidine trifluoroacetate

[0732] To a solution of tert-butyl 4-(4-chloro-3-pyrazol-1-yl-phenoxy)piperidine-1-carboxylate (260.0 mg, 0.690 mmol) in DCM (5.38 mL) was added TFA (1.34 mL, 17.46 mmol) at 0° C., and the mixture was stirred at 20° C. for 1 hour. The mixture was concentrated to give the title compound as an orange oil (250 mg, 92.7% yield). MS (ESI): m / z=278.1 [M+H] + .

[0733] Step (a) tert-butyl 4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate

[0734] To a solution of 1-BOC-4-hydroxypiperidine (2.04 g, 10.12 mmol, CAS RN: 106-52-5), 3-bromo-4-chlorophenol (2.0 g, 9.64 mmol, CAS RN: 2402-82-6), and triphenylphosphine (3.03 g, 11.57 mmol) in THF (50 mL) was added diisopropyl azodicarboxylate (2.28 mL, 11.57 mmol), and the mixture was stirred at 20 °C for 15 h. The mixture was then concentrated, and the residue was purified by reverse flash chromatography (MeCN and water containing 0.1% v / v FA) to give the desired product (2.8 g, 74.3%) as a light yellow oil. MS (ESI): m / z = 335.9 [M -56 + H] + .

[0735] Step (b) tert-butyl 4-(4-chloro-3-pyrazol-1-yl-phenoxy)piperidine-1-carboxylate

[0736] To a mixture of tert-butyl 4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate (1.0 g, 2.56 mmol), pyrazole (139.4 mg, 2.05 mmol), cesium carbonate (2501.8 mg, 7.68 mmol), and 1,10-phenanthroline (225.49 mg, 2.56 mmol) in DMF (20 mL) was added CuI (48.59 mg, 0.260 mmol), and the mixture was stirred at 110 °C for 12 h under a N atmosphere. The mixture was concentrated, diluted with HO (20 mL), and extracted three times with EtOAc (10 mL). The combined organic layers were concentrated, and the residue was purified by reverse-phase chromatography (ACN and water containing 0.1% v / v FA) to give the desired product (265 mg, 22.5%, 82% pure) as a yellow oil. MS (ESI): m / z = 378.1 [M+H] + .

[0737] BB155 4-[5-(4-piperidyloxy)-2-(trifluoromethyl)phenyl]morpholine trifluoroacetate

[0738] To a solution of tert-butyl 4-[3-morpholino-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (400.0 mg, 0.93 mmol) in DCM (3 mL) was added TFA (1.0 mL) and the reaction mixture was stirred at 25° C. for 12 hours. The reaction was concentrated in vacuo to give the crude product (300 mg) as a yellow oil, which was used in the next step without further purification. MS (ESI): m / z=331.2 [M+H] + .

[0739] Step (a) tert-butyl 4-(3-bromo-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

[0740] To a solution of 3-bromo-4-(trifluoromethyl)phenol (500.0 mg, 2.54 mmol, CAS RN: 1214385-56-4) and 1-BOC-4-hydroxypiperidine (512 mg, 2.54 mmol, CAS RN: 106-52-5) in THF (8.5 mL) was added PPh3 (1000.9 mg, 3.82 mmol) and diethyl azodicarboxylate (664.53 mg, 3.82 mmol), and the mixture was stirred at 25 °C for 12 h. The mixture was purified by silica gel chromatography using PE:EA = 5:1 as the eluent to give the desired product (503 mg, 46.6% yield) as a light yellow oil. MS (ESI): m / z = 369.2 [M-56 + H] + .

[0741] Step (b) tert-butyl 4-(3-morpholino-4-(trifluoromethyl)phenoxy)piperidine-1-carboxylate

[0742] A mixture of tert-butyl 4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0 mg, 1.18 mmol), morpholine (154 mg, 1.77 mmol, CAS RN: 110-91-8), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (146.77 mg, 0.24 mmol, CAS RN: 76189-55-4), cesium carbonate (1.15 g, 3.54 mmol), and tris(dibenzylideneacetone)dipalladium(0) (172.47 mg, 0.240 mmol, CAS RN: 76971-72-7) in DMF (10 mL) was stirred at 110° C. for 12 h. The mixture was poured into HO and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (gradient of 5% to 33% EtOAc in PE) to give the desired product (480 mg, 94.6%) as a light yellow solid. MS (ESI): m / z = 431.1 [M+H] + .

[0743] BB156 4-(4-chloro-3-(1,2,4-triazol-1-yl)phenoxy)piperidine trifluoroacetate

[0744] To a solution of tert-butyl 4-[4-chloro-3-(1,2,4-triazol-1-yl)phenoxy]piperidine-1-carboxylate (196.0 mg, 0.520 mmol) in DCM (5 mL) was added TFA (1.01 mL, 13.13 mmol) at 0° C., and the mixture was stirred at 20° C. for 1 h. The mixture was concentrated to give the title compound (178 mg, 87.6%) as a brown oil. MS (ESI): m / z=279.1 [M+H] + .

[0745] Step (a) tert-butyl 4-[4-chloro-3-(1,2,4-triazol-1-yl)phenoxy]piperidine-1-carboxylate

[0746] A mixture of tert-butyl 4-(3-bromo-4-chloro-phenoxy)piperidine-1-carboxylate (500.0 mg, 1.28 mmol, BB102, Intermediate a), 1,2,4-triazole (176.8 mg, 2.56 mmol), CuI (24.3 mg, 0.130 mmol), cesium carbonate (1250.9 mg, 3.84 mmol), and dimethylglycine (1.0 mL, 1.28 mmol) in DMF (10 mL) was stirred at 120 °C for 12 h. The mixture was concentrated to remove DMF, diluted with HO (50 mL), and extracted three times with EtOAc (20 mL each). The combined organic layers were evaporated, and the residue was purified by reverse-phase flash chromatography (ACN and water containing 0.1% v / v FA) to give the title compound (196 mg, 37.1%) as a colorless oil. MS (ESI): m / z = 323.0 [M-56 + H] + .

[0747] BB157 4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine trifluoroacetate

[0748] To a mixture of tert-butyl 4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (360.0 mg, 0.930 mmol) in DCM (18 mL) was added TFA (1.8 mL). The mixture was stirred at 25° C. for 12 hours. The mixture was concentrated in vacuo to give the desired compound as a light yellow gum (370 mg, 99.2%). MS (ESI): m / z=286.2 [M+H] + .

[0749] Step (a) tert-butyl 4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0750] A mixture of tert-butyl 4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0 mg, 1.18 mmol, BB103, intermediate b), cyclopropylboronic acid (151.86 mg, 1.77 mmol), NaCO (374.74 mg, 3.54 mmol), and Pd(PPh) (13.6 mg, 0.010 mmol) in 1,4-dioxane (10 mL) and HO (1 mL) was stirred at 95 °C for 12 h. The mixture was poured into HO (50 mL) and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo and purified by column chromatography (PE: EtOAc = 20:1 to 5:1) to give the desired product (380 mg, 83.7%) as a colorless gum. MS (ESI): m / z = 330.1 [M-56+H] + .

[0751] BB158 4-[3-pyrazol-1-yl-4-(trifluoromethyl)phenoxy]piperidine trifluoroacetate

[0752] To a solution of tert-butyl 4-[3-pyrazol-1-yl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (180.0 mg, 0.440 mmol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at 25° C. for 12 hours and then concentrated in vacuo to give the desired product (180 mg, 96.7%) as a light yellow gum. MS (ESI): m / z=312.1 [M+H] + .

[0753] Step (a) tert-butyl 4-[3-pyrazol-1-yl-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

[0754] A mixture of tert-butyl 4-[3-bromo-4-(trifluoromethyl)phenoxy]piperidine-1-carboxylate (500.0 mg, 1.18 mmol, BB103, intermediate b), pyrazole (120.35 mg, 1.77 mmol), CuI (22.37 mg, 0.120 mmol), N,N'-dimethylethylenediamine (519.45 mg, 5.89 mmol), and CsCO (767.99 mg, 2.36 mmol) in DMF (10 mL) was stirred at 110 °C for 12 h. The mixture was poured into HO (30 mL) and extracted three times with EtOAc (50 mL each). The combined organic layers were washed with ammonia (20 mL), brine (50 mL), dried over NaSO, and filtered. The filtrate was concentrated, and the crude product was purified by preparative TLC (PE:EA=5:1) to give the desired product (190 mg, 39.2%) as a colorless oil. MS (ESI): m / z=356.1 [M-56+H] + .

[0755] BB159 4-[[2,6-Difluoro-4-(trifluoromethyl)phenyl]methyl]piperidine trifluoroacetate

[0756] To a solution of tert-butyl 4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate (70.0 mg, 0.180 mmol) in DCM (1 mL) was added TFA (0.2 mL) and the mixture was stirred at 20° C. for 1 h. The mixture was concentrated to give the title compound (50 mg, 68.9%) as a brown oil. MS (ESI): m / z=280.1 [M+H] + .

[0757] Step (a) 2-(diethoxyphosphorylmethyl)-1,3-difluoro-5-(trifluoromethyl)benzene

[0758] A solution of 2-(bromomethyl)-1,3-difluoro-5-(trifluoromethyl)benzene (1.29 mL, 3.27 mmol, CAS RN: 493038-91-8) in triethyl phosphite (5.44 g, 32.73 mmol) was stirred at 160° C. for 5 hours. The mixture was concentrated in vacuo to give the title compound (600 mg, 55.2%; colorless oil), which was used in the next step without further purification.

[0759] Step (b) tert-butyl 4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate

[0760] A mixture of 2-(diethoxyphosphorylmethyl)-1,3-difluoro-5-(trifluoromethyl)benzene (400.0 mg, 1.2 mmol) in THF (4 mL) was added to sodium hydride (144.49 mg, 3.61 mmol) in THF (4 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour, and then 1-BOC-4-piperidone (479.83 mg, 2.41 mmol, CAS RN: 79099-07-3) was added to the above mixture. The mixture was stirred at 20 °C for 12 hours. The mixture was poured into H2O (50 mL) and extracted three times with EtOAc (20 mL each). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (PE:EA = 1:0 to 2:1) to give the title compound (100 mg, 22.0%) as a colorless oil. MS (ESI): m / z = 322.0 [M-56+H] + .

[0761] Step (c) tert-butyl 4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate

[0762] To a solution of tert-butyl 4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methylene]piperidine-1-carboxylate (100.0 mg, 0.270 mmol) in MeOH (8 mL) was added Pd / C (10.0 mg, 10 wt%). The mixture was stirred at 20 °C under an atmosphere of H for 1 h, then filtered and concentrated to give the title compound as a colorless oil (70 mg, 69.6%). MS (ESI): m / z = 324.1 [M-56 + H] + .

[0763] BB160 4-[4-chloro-3-(4-chlorophenyl)-2-fluoro-phenoxy]piperidine trifluoroacetate

[0764] To a mixture of tert-butyl 4-[4-chloro-3-(4-chlorophenyl)-2-fluoro-phenoxy]piperidine-1-carboxylate (145.0 mg, 0.330 mmol) in DCM (10 mL) was added TFA (1.0 mL). The mixture was stirred at 20° C. for 5 hours. The mixture was concentrated in vacuo to give the desired product (149 mg, 99.6%) as a light brown gum. MS (ESI): m / z=340.1 [M+H] + .

[0765] Step (a) 1-chloro-2-(4-chlorophenyl)-3-fluoro-4-methoxy-benzene

[0766] A mixture of 4-bromochlorobenzene (1.41 g, 7.34 mmol, CAS RN: 106-39-8), (6-chloro-2-fluoro-3-methoxy-phenyl)boronic acid (1.0 g, 4.89 mmol, CAS RN: 867333-04-8), and KCO (2.03 g, 14.68 mmol) in 1,4-dioxane (15 mL) and HO (1.5 mL) was stirred in a microwave oven at 110 °C for 1 h under a N atmosphere. The mixture was poured into HO (20 mL) and extracted three times with EtOAc (20 mL each). The combined organic layers were washed with brine (20 mL), dried over NaSO, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography using PE as the eluent to give the desired product (110 mg, 8.3%) as a colorless oil. This was used in the next step without further purification.

[0767] Step (b) 4-chloro-3-(4-chlorophenyl)-2-fluoro-phenol

[0768] To a mixture of 1-chloro-2-(4-chlorophenyl)-3-fluoro-4-methoxy-benzene (215.0 mg, 0.790 mmol) in DCM (7 mL) was added dropwise a solution of BBr3 (993.36 mg, 3.97 mmol) in DCM (7 mL) at -78 °C. The mixture was stirred at 20 °C for 12 h. The reaction was quenched by adding MeOH (1 mL) followed by water (10 mL), and the mixture was extracted three times with DCM (10 mL each). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo to give the desired product (120 mg, 57.5%) as a light brown solid, which was used in the next step without further purification.

[0769] Step (c) tert-butyl 4-[4-chloro-3-(4-chlorophenyl)-2-fluoro-phenoxy]piperidine-1-carboxylate

[0770] A mixture of 4-chloro-3-(4-chlorophenyl)-2-fluorophenol (120.0 mg, 0.470 mmol), 1-BOC-4-hydroxypiperidine (187.88 mg, 0.930 mmol, CAS RN: 106-52-5), PPh3 (244.85 mg, 0.930 mmol), and DIAD (0.18 mL, 0.930 mmol) in THF (12 mL) was stirred at 20 °C for 12 h. The mixture was poured into HO and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (PE:EA = 1:0 to 20:1) to give the desired product as a bright yellow gum (150 mg, 73%). MS (ESI): m / z = 384.0 [M-56+H] + .

[0771] BB161 3-[2-chloro-4-(trifluoromethyl)phenoxy]azetidine trifluoroacetate

[0772] To a solution of tert-butyl 3-[2-chloro-4-(trifluoromethyl)phenoxy]azetidine-1-carboxylate (400.0 mg, 1.14 mmol) in DCM (10 mL) was added TFA (2.0 mL) at 20° C. After stirring for 2 h, the mixture was concentrated to give the crude product (410 mg, 98.6%) as a light yellow oil, which was used in the next step without further purification.

[0773] Step (a) tert-butyl 3-[2-chloro-4-(trifluoromethyl)phenoxy]azetidine-1-carboxylate

[0774] To a solution of 2-chloro-4-(trifluoromethyl)phenol (1000.0 mg, 5.09 mmol, CAS RN: 35852-58-5) and tert-butyl 3-hydroxyazetidine-1-carboxylate (1057.5 mg, 6.11 mmol, CAS RN: 141699-55-0) in THF (20 mL) was added PPh3 (1999.49 mg, 7.63 mmol) and diethyl azodicarboxylate (1329.05 mg, 7.63 mmol), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was evaporated in vacuo, and the residue was purified by reverse-phase flash flash (0.1% v / v FA) to give the desired product (800 mg, 2.27 mmol, 44.7% yield) as a light yellow oil. MS (ESI): m / z = 296.0 [M-56+H] + .

[0775] BB162 3-((2-fluoro-6-(trifluoromethyl)benzyl)oxy)azetidine trifluoroacetate

[0776] To a solution of tert-butyl 3-[[2-fluoro-6-(trifluoromethyl)phenyl]methoxy]azetidine-1-carboxylate (400.0 mg, 1.15 mmol) in dry DCM (10 mL) was added TFA (2.0 mL) at 25 °C, and the mixture was stirred at 25 °C fo...

Claims

1. A compound of formula (I): 【Chemistry 1】 During the ceremony: (i) X is C-R ３ m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH ２ ) ｐ -, -O-, -OCH ２ --, --CH ２ OCH ２ -, -CF ２ CH ２ -, -CH=CH-, -(CR １６ R １７ ) ｑ -CH ２ O- and -CH ２ CF ２ - selected from; or (ii) X is N; m is 1; n is 1 or 2; and L is -(CH ２ ) ｐ -or-CF ２ CH ２ - is; p is selected from 1, 2, and 3; q is 0 or 1; A is the following: (i) R ４ , R ５ , and R ６ C substituted with ６ -C １４ -aryl; (ii) R ７ , R ８ , and R ９ 5-14 membered heteroaryl substituted with (iii) R １０ , R １１ , and R １２ 3- to 14-membered heterocycloalkyl substituted with R １ is hydrogen or C １－６ - alkyl; R ２ is hydrogen, C １－６ Alkyl and hydroxy-C １－６ - selected from alkyl; R ３ is hydrogen, halogen, hydroxy, C １－６ -Alkoxy, C １－６ -alkyl and halo-C １－６ - selected from alkyl; R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , and R １２ Each of the groups is hydrogen, halogen, cyano, hydroxy, C １－６ -Alkyl, halo-C １－６ -Alkyl, hydroxy-C １－６ -Alkyl, C １－６ -Alkanoyl, halo-C １－５ -alkyl-CH(OH)-, C １－６ -Alkoxy, halo-C １－６ -Alkoxy, SF ５ , C.H. ３ SO ２ , C ３－１０ -cycloalkyl, R １３ C substituted with ３－１０ -cycloalkyl, 3- to 14-membered heterocycloalkyl, R １４ and R １５ 3- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, substituted with C ６ -C １４ -Aryl, C ６ -C １４ -aryloxy, halo-C ６ -C １４ -aryl and halo-C ６ -C １４ -aryloxy; R １３ , R １４ , and R １５ Each of the above is C １－６ -Alkyl, C １－６ -Alkoxy, halo-C １－６ -Alkyl, halo-C １－６ - independently selected from alkoxy, halogen, and hydroxy; and R １６ and R １７ together with the carbon atom to which they are attached, C ３－１０ -cycloalkyl (excluding (4aS,8aS)-hexahydro-6-[[4-(phenylmethyl)-1-piperidinyl]carbonyl]-2H-pyrido[4,3-b]-1,4-oxazin-3(4H)-one), or a pharma- ceutically acceptable salt thereof.

2. The compound of formula (I) is a compound of formula (Ia): 【Chemistry 2】 In the formula, A, L, X, m, n, R １ , and R ２ 2. The compound of formula (I) according to claim 1, wherein:

3. The compound of formula (I) is a compound of formula (Ib): 【Chemistry 3】 In the formula, A, L, X, m, n, R １ , and R ２ 2. The compound of formula (I) according to claim 1, wherein:

4. During the ceremony: (i) X is C-R ３ m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH ２ ) ｐ -, -O-, -OCH ２ -, -CF ２ CH ２ -, -CH=CH-, -(CR １６ R １７ ) ｑ -CH ２ O- and -CH ２ OCH ２ - selected from; or (ii) X is N; m and n are both 1; and L is -(CH ２ ) ｐ 4. The compound of formula I according to any one of claims 1 to 3, wherein - or a pharma- ceutically acceptable salt thereof.

5. During the ceremony: X is C-R ３ is; m and n are both 0; or m and n are both 1; and L is -(CH ２ ) ｐ -, -O-, -OCH ２ - and -CH ２ 5. The compound of formula I according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, selected from: O-.

6. 6. A compound of formula I according to any one of claims 1 to 5, wherein p is 1 or 2, or a pharma- ceutically acceptable salt thereof.

7. 6. A compound of formula I according to any one of claims 1 to 5, wherein p is 2, or a pharma- ceutically acceptable salt thereof.

8. A compound of formula I according to any one of claims 1 to 7, wherein q is 0 or 1, or a pharma- ceutically acceptable salt thereof.

9. 8. The compound of formula I according to any one of claims 1 to 7, wherein q is 0, or a pharma- ceutically acceptable salt thereof.

10. A is the following: (i) R ４ , R ５ , and R ６ C substituted with ６ -C １４ -aryl; and (ii) R ７ , R ８ , and R ９ 10. The compound of formula I according to any one of claims 1 to 9, wherein the heteroaryl is selected from 5-14 membered heteroaryl substituted with: or a pharma- ceutically acceptable salt thereof.

11. A is the following: (i) R ４ , R ５ , and R ６ phenyl substituted with; (ii) R ７ , R ８ , and R ９ oxazolyl substituted with (iii) R ７ , R ８ , and R ９ 10. The compound of formula I according to any one of claims 1 to 9, selected from pyridyl substituted with - or a pharma- ceutically acceptable salt thereof.

12. R １ A compound of formula I according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

13. R ２ is hydrogen or C １－６ 13. The compound of formula I according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein: - alkyl.

14. R ２ A compound of formula I according to any one of claims 1 to 12, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or methyl.

15. R ３ But hydrogen, halogen, C １－６ -alkyl and halo-C １－６ 15. The compound of formula I according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein: - alkyl is selected from:

16. R ３ is hydrogen, halogen, and C １－６ 15. The compound of formula I according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein: - alkyl is selected from:

17. R ３ A compound of formula I according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein is selected from hydrogen, fluoro, and methyl.

18. R ４ is hydrogen, halogen, hydroxy, cyano, C １－６ -Alkyl, C １－６ -Alkanoyl, SF ５ , C １－６ -Alkoxy, halo-C １－６ -Alkoxy, halo-C １－６ -Alkyl, C ３－１０ -cycloalkyl, 3- to 14-membered heterocyclyl, R １４ and R １５ 3- to 14-membered heterocycloalkyl, 5- to 14-membered heteroaryl, substituted with C ６ -C １４ -aryloxy and halo-C ６ -C １４ 18. The compound of formula I according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, selected from: -aryl.

19. R ４ But halogen, SF ５ , C １－６ -Alkyl, C １－６ -Alkoxy, halo-C １－６ -Alkoxy, halo-C １－６ -Alkyl, C ３－１０ 18. The compound of formula I according to any one of claims 1 to 17, wherein R is selected from: -cycloalkyl, and 3- to 14-membered heterocycloalkyl; or a pharma- ceutically acceptable salt thereof.

20. R ４ But Chrollo, SF ５ , methyl, methoxy, OCF ３ , C.F. ３ 18. The compound of formula I according to any one of claims 1 to 17, wherein R is selected from the group consisting of cyclopropyl, cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl, or a pharma- ceutically acceptable salt thereof.

21. R ５ is hydrogen, cyano, halogen, C １－６ -Alkyl, halo-C １－６ -Alkyl, C １－６ -alkoxy, 3- to 14-membered heterocycloalkyl, C ３－１０ -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C ６ -C １４ 21. The compound of formula I according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, selected from: -aryl.

22. R ５ is hydrogen, cyano, halogen, C １－６ -Alkyl, halo-C １－６ -alkyl, 3- to 14-membered heterocycloalkyl, C ３－１０ -cycloalkyl and halo-C ６ -C １４ 21. The compound of formula I according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, selected from: -aryl.

23. R ５ is hydrogen, cyano, fluoro, chloro, methyl, CF ３ 21. The compound of formula I according to any one of claims 1 to 20, wherein R is selected from the group consisting of aryl, pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl, or a pharma- ceutically acceptable salt thereof.

24. R ６ 24. The compound of formula I according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or halogen.

25. R ６ 24. A compound of formula I according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

26. R ７ is hydrogen, C １－６ -Alkyl, C ６ -C １４ -aryl, halo-C ６ -C １４ -aryl, halo-C ６ -C １４ -aryloxy and halo-C １－６ 26. The compound of formula I according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, wherein R is selected from -alkyl.

27. R ７ But, C １－６ -alkyl or halo-C １－６ 26. The compound of formula I according to any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, wherein: - alkyl.

28. R ７ is tert-butyl or CF ３ 26. The compound of formula I according to any one of claims 1 to 25, which is: or a pharma- ceutically acceptable salt thereof.

29. R ８ But hydrogen, halogen, C １－６ -alkyl and halo-C １－６ 29. The compound of formula I according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein: - alkyl is selected from:

30. R ８ is hydrogen or halo-C １－６ 29. The compound of formula I according to any one of claims 1 to 28, or a pharma- ceutically acceptable salt thereof, wherein: - alkyl.

31. R ８ is hydrogen or CF ３ 29. The compound of formula I according to any one of claims 1 to 28, which is: or a pharma- ceutically acceptable salt thereof.

32. R ９ 32. The compound of formula I according to any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

33. R １０ 33. The compound of formula I according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

34. R １１ 34. The compound of formula I according to any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, wherein is halogen.

35. R １２ 35. The compound of formula I according to any one of claims 1 to 34, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

36. R １４ But, C １－６ -Alkyl, C １－６ 36. The compound of formula I according to any one of claims 1 to 35, or a pharma- ceutically acceptable salt thereof, wherein R is selected from -alkoxy, and halogen.

37. R １５ 37. The compound of formula I according to any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or halogen.

38. During the ceremony: (i) X is C-R ３ m is 0 or 1; n is selected from 0, 1, and 2; and L is -(CH ２ ) ｐ -, -O-, -OCH ２ -, - (CR １６ R １７ ) ｑ -CH ２ O-, -CH ２ OCH ２ -, -CF ２ CH ２ -, and -CH=CH-; or (ii) X is N; m and n are both 1; and L is -(CH ２ ) ｐ - is; p is 1 or 2; q is 0 or 1; A is the following: (i) R ４ , R ５ , and R ６ C substituted with ６ -C １４ -aryl; (ii) R ７ , R ８ , and R ９ 5-14 membered heteroaryl substituted with (iii) R １０ , R １１ , and R １２ 3- to 14-membered heterocycloalkyl substituted with R １ is hydrogen or C １－６ - alkyl; R ２ is hydrogen or C １－６ - alkyl; R ３ But hydrogen, halogen, C １－６ -alkyl and halo-C １－６ - selected from alkyl; R ４ However, hydrogen, halogen, cyano, SF ５ , C １－６ -Alkyl, C １－６ -Alkanoyl, C １－６ -Alkoxy, halo-C １－６ -Alkoxy, halo-C １－６ -Alkyl, C ３－１０ -cycloalkyl, 3- to 14-membered heterocycloalkyl, R １４ and R １５ 3-14 membered heterocycloalkyl, 5-14 membered heteroaryl, halo-C ６ -C １４ -aryl, and C ６ -C １４ -aryloxy; R ５ is hydrogen, cyano, halogen, C １－６ -Alkyl, halo-C １－６ -Alkyl, C １－６ -alkoxy, 3- to 14-membered heterocycloalkyl, C ３－１０ -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C ６ -C １４ - selected from aryl; R ６ is hydrogen or halogen; R ７ is hydrogen, C １－６ -Alkyl, C ６ -C １４ -aryl, halo-C ６ -C １４ -aryl, halo-C ６ -C １４ -aryloxy and halo-C １－６ - selected from alkyl; R ８ But hydrogen, halogen, C １－６ -alkyl and halo-C １－６ - selected from alkyl; R ９ is hydrogen; R １０ is a halogen; R １１ is a halogen; R １２ is hydrogen; R １４ But halogen, C １－６ Alkyl, and C １－６ - selected from alkoxy; R １５ is hydrogen or halogen; and R １６ and R １７ together with the carbon atom to which they are attached, C ３－１０ - cycloalkyl-forming compounds of formula I as claimed in any one of claims 1 to 3 or pharma- ceutically acceptable salts thereof.

39. During the ceremony: X is C-R ３ is; m and n are both 0; or m and n are both 1; L is -(CH ２ ) ｐ -, -O-, -OCH ２ - and -CH ２ Selected from: O-; p is 1 or 2; A is the following: (i) R ４ , R ５ , and R ６ C substituted with ６ -C １４ -aryl; and (ii) R ７ , R ８ , and R ９ 5-14 membered heteroaryl substituted with R １ is hydrogen; R ２ is hydrogen or C １－６ - alkyl; R ３ is hydrogen, halogen, and C １－６ - selected from alkyl; R ４ But halogen, SF ５ , C １－６ -Alkyl, C １－６ -Alkoxy, halo-C １－６ -Alkoxy, halo-C １－６ -Alkyl, C ３－１０ - selected from cycloalkyl, and 3- to 14-membered heterocycloalkyl; R ５ is hydrogen, cyano, halogen, C １－６ -Alkyl, halo-C １－６ -alkyl, 3- to 14-membered heterocycloalkyl, C ３－１０ -cycloalkyl and halo-C ６ -C １４ - selected from aryl; R ６ is hydrogen; R ７ But, C １－６ -alkyl or halo-C １－６ - alkyl; R ８ is hydrogen or halo-C １－６ -alkyl; and R ９ A compound of formula I according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

40. During the ceremony: X is C-R ３ is; m and n are both 0; or m and n are both 1; L is -(CH ２ ) ｐ -, -O-, -OCH ２ - and -CH ２ Selected from: O-; p is 1 or 2; A is the following: (i) R ４ , R ５ , and R ６ phenyl substituted with; (ii) R ７ , R ８ , and R ９ oxazolyl substituted with (iii) R ７ , R ８ , and R ９ pyridyl substituted with R １ is hydrogen; R ２ is hydrogen or methyl; R ３ is selected from hydrogen, fluoro, and methyl; R ４ But Chrollo, SF ５ , methyl, methoxy, OCF ３ , C.F. ３ , cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl; R ５ is hydrogen, cyano, fluoro, chloro, methyl, CF ３ , pyrrolidinyl, cyclopentyl, cyclopropyl, and chlorophenyl; R ６ is hydrogen; R ７ tert-butyl, methyl, and CF ３ Selected from: R ８ is hydrogen or CF ３ and R ９ A compound of formula I according to any one of claims 1 to 3, wherein is hydrogen.

41. below: (+)-(4aR,8aS)-6-(4-((4-(tert-butyl)thiazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-(4aR,8aS)-6-(4-((4-(tert-butyl)oxazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-[4-[(4-tert-butylthiazol-2-yl)methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-(4-((4-(tert-butyl)oxazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (−)-(4aS,8aR)-6-(4-((4-(tert-butyl)thiazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (−)-(4aS,8aR)-6-(4-((4-(tert-butyl)oxazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-(4aR,8aS)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-(4-((4-chlorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-(4-chlorobenzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (−)-(4aR,8aS)-6-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-(4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-(4aS,8aS)-6-(4-(4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-[4-(phenoxymethyl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-(4-((5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aS,8aS)-6-(4-(4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-((3-phenyl-1,2,4-oxadiazol-5-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (−)-(4aR,8aR)-6-(4-(4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (-)-(4aS,8aR)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(4-(4-chlorobenzyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (−)-(4aS,8aR)-6-(4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-[4-[[5-(trifluoromethyl)-2-pyridyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-(4-((4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aS,8aR)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(4-(trifluoromethoxy)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2,4-difluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(4-chloro-3-fluorobenzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-4-[[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-4-piperidyl]methyl]benzonitrile; (+)- or (−)-(4aR,8aS)-6-(4-(4-chlorobenzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-[3-[[4-(trifluoromethyl)phenyl]methyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (−)-(4aR,8aS)-6-(4-((4,4-difluoropiperidin-1-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((5-(tert-butyl)oxazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-[4-[(2-fluoro-4-methoxyphenoxy)methyl]piperidine-1-carbonyl]hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(2-chloro-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aS,8aR)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(3-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aS,8aR)-6-[4-[[2-chloro-4-(trifluoromethoxy)phenoxy]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (-)-(4aR,8aS)-6-[4-[[2-chloro-4-(trifluoromethoxy)phenoxy]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aS,8aR)-6-[4-[(2-chloro-4-fluorophenoxy)methyl]-4-methylpiperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (−)-(4aS,8aR)-6-(4-((2,4-difluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((4-chloro-2-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((4-fluoro-2-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-2-[[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-4-piperidyl]methoxy]-5-fluoro-benzonitrile; (+)- or (−)-(4aR,8aS)-6-(4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-chloro-4-fluorophenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-[4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (−)-3-chloro-4-((1-(3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-yl)methoxy)benzonitrile; (+)- or (−)-(4aR,8aS)-6-(4-((4-(trifluoromethyl)-1H-imidazol-1-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((4-fluoro-2-methylphenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((4-(tert-butyl)-1H-pyrazol-1-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (2R,4aR,8aS)-2-methyl-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (−)-(4aR,8aS)-6-(4-(benzo[d]oxazol-2-ylmethyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((4',6-dichloro-[1,1'-biphenyl]-3-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-cis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-chloro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(2-(1H-pyrazol-4-yl)-4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[(2,4-dichlorophenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[3-methoxy-4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[5-methyl-6-(trifluoromethyl)pyridin-3-yl]oxymethyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(3-chlorophenoxy)methyl]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(2-chlorophenoxy)methyl]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(2-chlorophenyl)methoxy]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(3-chlorophenyl)methoxy]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(4-chlorophenoxy)methyl]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(4-chlorophenyl)methoxy]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-methyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-chloro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[4-(trifluoromethyl)phenyl]methyl]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[3-fluoro-5-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-6-(trifluoromethyl)phenyl]methoxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-methyl-3-[[4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[3-chloro-4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(2-chloro-4-fluorophenoxy)methyl]-3-fluoroazetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]-3-(trifluoromethyl)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]-3-methylazetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2,4-difluoro-5-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-5-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[3-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-methoxy-4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[4-chloro-2-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-methyl-3-[[4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[4-chloro-3-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-(4-chloro-3-cyclopropylphenoxy)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-(4-chloro-3-morpholin-4-ylphenoxy)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[2-methyl-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 2-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]piperidin-4-yl]oxy-5-(trifluoromethyl)benzonitrile; (4aR,8aS)-6-[4-(oxazolo[5,4-c]pyridin-2-ylmethyl)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[(2-chloro-4-fluorophenoxy)methyl]azepane-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]azepane-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[3-pyrazol-1-yl-5-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-(2,2,2-trifluoroethoxy)-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[3-(1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[4-chloro-3-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-(4-chloro-3-pyrazol-1-yl-phenoxy)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(4-(3-morpholino-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[4-chloro-3-(1,2,4-triazol-1-yl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[3-pyrazol-1-yl-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-(4-chlorophenoxy)piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[4-chloro-3-(4-chlorophenyl)-2-fluoro-phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-chloro-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-6-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-(2-fluoro-4-methyl-phenyl)ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[4-methoxy-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[4-methyl-2-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[2-methoxy-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[2-acetyl-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[2-bromo-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[6-fluoro-4-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[6-fluoro-5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(3,4-dichlorophenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(2,5-dichlorophenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[3-(trifluoromethoxy)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-methyl-3-[[4-methyl-3-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[5-(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[rel-(3R,4R)-3-methyl-4-[[5-methyl-6-(trifluoromethyl)-3-pyridyl]oxymethyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[rel-(3S,4S)-3-methyl-4-[[5-methyl-6-(trifluoromethyl)-3-pyridyl]oxymethyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]-2-methyl-azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[4,5-bis(trifluoromethyl)-2-pyridyl]oxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxymethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(4-chloro-2-phenoxy-phenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-4-(pentafluoro-lambda 6-sulfanyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[1-(2,4-dichlorophenyl)cyclopropyl]methoxy]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)-4-(trifluoromethyl)-2-pyridyl]methoxy]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)-5-(trifluoromethyl)-2-pyridyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[4-(4-fluorophenyl)thiazol-2-yl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]-3-(trifluoromethyl)pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[rac-(2R,3S)-3-[2-bromo-5-(trifluoromethyl)phenoxy]-2-methyl-pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[rel-(2R,3S)-3-[2-bromo-5-(trifluoromethyl)phenoxy]-2-methyl-pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[rel-(2S,3R)-3-[2-bromo-5-(trifluoromethyl)phenoxy]-2-methyl-pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[[2,4-bis(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-(3-((2-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-(4aR,8aS)-6-(3-((4-methyl-2-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[2-methyl-3-[[2-methyl-4-(trifluoromethoxy)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-methyl-3-[[2-methyl-3-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[4-[2-fluoro-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[4-[3-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[4-[2-chloro-3-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-(3-bromo-2-chloro-phenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-(2-chloro-3-cyclopropyl-phenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-chloro-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-5-[[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-4-piperidyl]oxy]-2-(trifluoromethyl)benzonitrile; (+)-5-[1-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]azetidin-3-yl]oxy-2-(trifluoromethyl)benzonitrile; (+)-(4aR,8aS)-6-[3-(3-bromo-4-chlorophenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-(3-methylazetidin-1-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-(3,3-difluoroazetidin-1-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-(3-fluoro-3-methyl-azetidin-1-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-(6,6-difluoro-2-azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-2-chloro-phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[2-chloro-3-(3-methylazetidin-1-yl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[2-chloro-3-(3-fluoro-3-methyl-azetidin-1-yl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-(3-(3-(3-(tert-butoxy)azetidin-1-yl)-2-chlorophenoxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-(4aR,8aS)-6-[3-[2-chloro-3-(5-oxa-2-azaspiro[3.4]octan-2-yl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[2-chloro-3-(5-oxa-2-azaspiro[3.5]nonan-2-yl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-5-chloro-phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-[3-(3-chloro-5-pyrrolidin-1-yl-phenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[2-fluoro-4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[4-fluoro-2-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2,2-difluoro-2-[4-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[3-(trifluoromethoxy)phenyl]methyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-fluoro-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-chloro-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(3R or 3S)-3-[2-fluoro-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(3S or 3R)-3-[2-fluoro-5-(trifluoromethyl)phenoxy]pyrrolidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(E)-2-(2-fluoro-4-methyl-phenyl)vinyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-((3-fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((E)-2-fluoro-6-(trifluoromethyl)styryl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2,3-dimethylbenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2,4-dimethylbenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2-methyl-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(4-hydroxy-2-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; and (4aR,8aS)-6-[3-[[4-methyl-3-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one 2. The compound of formula (I) according to claim 1, selected from:

42. below: (+)-(4aR,8aS)-6-(4-((4-(tert-butyl)oxazol-2-yl)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)-(4aR,8aS)-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-chloro-4-fluorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(4-(trifluoromethoxy)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(4-chloro-3-fluorobenzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(2-chloro-4-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(3-(trifluoromethyl)phenoxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-[4-[[2-chloro-4-(trifluoromethoxy)phenoxy]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((4-chloro-2-fluorophenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((4-fluoro-2-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-(2-(pyrrolidin-1-yl)-4-(trifluoromethyl)benzyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-[4-[[2-cyclopentyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (+)- or (−)-3-chloro-4-((1-((4aR,8aS)-3-oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine-6-carbonyl)piperidin-4-yl)methoxy)benzonitrile; (+)- or (−)-(4aR,8aS)-6-(3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (-)-(4aR,8aS)-6-(4-((4',6-dichloro-[1,1'-biphenyl]-3-yl)oxy)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(cis-4-((2-chloro-4-fluorophenoxy)methyl)-3-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-chloro-4-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (+)- or (−)-(4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-methylpiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[3-[(2,4-dichlorophenyl)methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[[2-cyclopropyl-4-(trifluoromethyl)phenyl]methyl]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[3-chloro-4-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[[2-fluoro-5-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[2-fluoro-6-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-(2-fluoro-4-(trifluoromethyl)phenethyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 6-(3-((2,4-bis(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[3-chloro-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-methyl-4-(((5-methyl-6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((3,4-dichlorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2,5-dichlorobenzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(2-methyl-3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-(((4,5-bis(trifluoromethyl)pyridin-2-yl)oxy)methyl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-(3-((2-fluoro-4-(trifluoromethyl)benzyl)oxy)-2-methylazetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2-fluoro-4-(pentafluoro-lambda 6-sulfanyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((4-methyl-2-(trifluoromethoxy)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-[4-[3-cyclopropyl-4-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-(2-fluoro-4-methyl-phenyl)ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[4-methoxy-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-[4-methyl-2-(trifluoromethyl)phenyl]ethyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)-6-(3-((2-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)-6-[2-methyl-3-[[2-methyl-4-(trifluoromethoxy)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[2-methyl-3-[[2-methyl-3-(trifluoromethyl)phenyl]methoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(4-chloro-3-cyclopropylphenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[4-[2-chloro-3-(trifluoromethyl)phenoxy]piperidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-(2-chloro-3-cyclopropyl-phenoxy)azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[3-(2-azaspiro[3.3]heptan-2-yl)-2-chloro-phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[2-chloro-3-(5-oxa-2-azaspiro[3.5]nonan-2-yl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[3-[(E)-2-(2-fluoro-4-methyl-phenyl)vinyl]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-(3-((E)-2-fluoro-6-(trifluoromethyl)styryl)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; And, (4aR,8aS)-6-(3-((4-methyl-3-(trifluoromethyl)benzyl)oxy)azetidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one 2. The compound of formula (I) according to claim 1, selected from:

43. 【Chemical 4】 2. The compound of formula (I) according to claim 1, which is: or a pharma- ceutically acceptable salt thereof.

44. 【Chemical 5】 2. The compound of formula (I) according to claim 1, which is: or a pharma- ceutically acceptable salt thereof.

45. 【Chemical 6】 2. The compound of formula (I) according to claim 1, which is: or a pharma- ceutically acceptable salt thereof.

46. 【Chemical 7】 2. The compound of formula (I) according to claim 1, which is: or a pharma- ceutically acceptable salt thereof.

47. 【Chemical 8】 2. The compound of formula (I) according to claim 1, which is: or a pharma- ceutically acceptable salt thereof.

48. 【Chemical 9】 2. The compound of formula (I) according to claim 1, which is: or a pharma- ceutically acceptable salt thereof.

49. R １ is as defined in any one of claims 1 to 40, 【Chemistry 10】 In the presence of a base and a urea forming reagent, A, L, m, n, X, and R ２ is as defined in any one of claims 1 to 40, 【Chemistry 11】 Forming a compound of formula (I) 49. A process for preparing a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 48, comprising:

50. The compound of formula (I) has an IC for monoacylglycerol lipase of less than 10 μM. ５０ 49. The compound of formula (I) according to any one of claims 1 to 48, or a pharma- ceutically acceptable salt thereof, having the formula:

51. A compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 48 and 50 for use as a therapeutically active substance.

52. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 48 and 50, or a pharma- ceutically acceptable salt thereof.

53. The pharmaceutical composition of claim 52 for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

54. The pharmaceutical composition of claim 52 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.

55. 51. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 48 and 50 for the preparation of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and / or psychiatric disorders in a mammal.

56. 51. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in any one of claims 1 to 48 and 50 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.

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