New heterocyclic compounds

Abstract

The present invention relates to a compound represented by general formula (I) TIFF2022539604000134.tif26165 (In the formula, R 1 , R 2 , X and Y are as defined herein), compositions containing the compounds, methods for making the compounds, and methods for using the compounds.

Description

[Technical Field]

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

[0002] Endocannabinoids (ECs) are signaling lipids that exert biological effects by interacting with cannabinoid receptors (CBRs) CB1 and CB2. They regulate several physiological processes, including neuroinflammation, neurodegeneration, and tissue regeneration (Iannotti, FA et al., Progress in lipid research 2016, 62, 107-28). In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacidglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase MAGL. MAGL hydrolyzes 85% of 2-AG, and the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, DK et al., Science 2011, 334, 809). MAGL is expressed throughout the brain, as well as in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglia (Chanda, PK et al., Molecular Pharmacology 2010, 78, 996; Viader, A. et al., Cell Reports 2015, 12, 798). Hydrolysis of 2-AG leads to the formation of arachidonic acid (AA), a precursor of prostaglandins (PG) and leukotrienes (LT). Oxidative metabolism of AA is increased in inflammatory tissues. Two major enzymatic pathways involved in the oxidation of arachidonic acid in the inflammatory process are cyclooxygenase, which produces PG, and 5-lipoxygenase, which produces LT. Among the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important. These products have been detected at inflammatory sites, 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- / -) showed a dramatic decrease in 2-AG hydrolase activity and a dramatic increase in 2-AG levels in the nervous system, while other arachidonoyl-containing phospholipids and triglycerides, including anandamide (AEA), and other free fatty acids remained unchanged.Conversely, levels of AA and AA-derived prostaglandins, as well as other eicosanoids including prostaglandin E2 (PGE2), D2 (PGD2), and F2 (PGF2), and thromboxane B2 (TXB2), are significantly reduced. While the phospholipase A2 (PLA2) enzyme has been considered a major source of AA, cPLA2-deficient mice do not alter AA levels in their brains, highlighting the importance of MAGL's role in the brain for regulating AA production and brain inflammatory processes.

[0003] Neuroinflammation is a characteristic pathological alteration of brain diseases, including, but is 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 mental disorders such as anxiety and migraines). In the brain, the production of eicosanoids and prostaglandins regulates neuroinflammatory processes. The pro-inflammatory substance lipopolysaccharide (LPS) results in a robust, time-dependent increase in brain eicosanoids, markedly blunted in Mgll- / - mice. LPS treatment also induces widespread elevations of inflammatory cytokines, including interleukin-1-α (IL-1-α), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), which are prophylactic in Mgll- / - mice.

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

[0005] 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 are widely used in preclinical models of neuroinflammation and neurodegeneration (Long, JZ et al., Nature Chemical Biology 2009, 5, 37). Systemic injection of such inhibitors replicates the Mgll- / - mouse phenotype in the brain, which includes increased 2-AG levels, decreased AA levels and associated eicosanoid production, and suppression of cytokine production and microglial activation after LPS-induced neuroinflammation (Nomura, DK et al., Science 2011, 334, 809), confirming that MAGL is a target that could lead to new drugs.

[0006] Following genetic and / or pharmacological disruption of MAGL activity, endogenous levels of the MAGL native substrate, 2-AG, increase in the brain. 2-AG has been reported to exhibit beneficial effects against pain induced by mental disorders such as depression in mice (Ignatowska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015, 353, 424) and in chronic stress models (Zhong P. et al., Neuropsychopharmacology 2014, 39, 1763).

[0007] Furthermore, oligodendrocytes (OLs) and their precursors (OPCs), myelinated cells of the central nervous system, express cannabinoid receptor 2 (CB2) on their membranes. CB2-AG is an endogenous ligand for CB1 and CB2 receptors. Both cannabinoids and pharmacological inhibition of MAGL have been reported to reduce the vulnerability of OLs and OPCs to excitotoxic injury and thus may be neuroprotective (Bernal-Chico, A. et al., Glia 2015, 63, 163). In addition, pharmacological inhibition of MAGL increased the number of myelinated OLs in the mouse brain, suggesting that MAGL inhibition may promote OPC differentiation in myelinated OLs in vivo (Alpar, A. et al., Nature Communications 2014, 5, 4421). Inhibition of MAGL has also been shown to promote remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu A. et al., Journal of Neuroscience 2017, 37(35), 8385). Finally, in recent years, metabolism, particularly lipid metabolism, has become extremely important in cancer research. Researchers believe that novel fatty acid synthesis plays a crucial role in tumor development. Numerous studies have shown that endocannabinoids possess antitumor effects, including antiproliferative, apoptosis-inducing, and antimetastatic effects. MAGL, as a key degrading enzyme for both lipid metabolism and the endocannabinoid system, further contributes to various aspects of tumorigenesis as part of gene expression signification (Qin, H. et al., Cell Biochem. Biophys. 2014, 70, 33; Nomura DK et al., Cell 2009, 140(1), 49-61; Nomura DK et al., Chem. Biol. 2011, 18(7), 846-856).

[0008] In conclusion, inhibiting the action and / or activation of MAGL is a promising new therapeutic strategy for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, and psychiatric disorders. Furthermore, inhibiting the action and / or activation of MAGL is a promising new therapeutic strategy for achieving neuroprotection and myelin regeneration. Thus, there is a high unmet medical need for new MAGL inhibitors. [Overview of the project]

[0009] In the first aspect, the present invention relates to a compound of formula (I), [ka] (In the formula, R 1 , R 2 The present invention provides X, Y, and X as defined herein, or pharmaceutically acceptable salts thereof.

[0010] In a further embodiment, the present invention provides a method for producing a compound of formula (I) as described in any one of the synthesis schemes disclosed herein.

[0011] In a further embodiment, the present invention provides compounds of formula (I) as described herein, when produced according to the method described herein.

[0012] In a further embodiment, the present invention provides compounds of formula (I) described herein for use as therapeutic agents.

[0013] In a further embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein and a therapeutically inert carrier.

[0014] In a further embodiment, the present invention provides a compound of formula (I) described herein for use in a method for inhibiting monoacylglycerol lipase in mammals.

[0015] In a further embodiment, the present invention provides compounds of formula (I) described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and / or mental disorders in mammals.

[0016] In a further embodiment, the present invention provides compounds of formula (I) 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 cancer development, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and / or pain-associated spasticity in mammals. [Modes for carrying out the invention]

[0017] definition Features, integers, characteristics, compounds, chemical parts, or groups described in connection with a particular aspect, embodiment, or example of the present invention should be understood to be applicable to any other aspect, embodiment, or example described herein, unless they are incompatible. All features disclosed herein (including any appended claims, abstract, and drawings) and / or all steps of any method or process disclosed herein may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the embodiments described herein. The present invention extends to any novel or novel combination of features disclosed herein (including any appended claims, abstract, and drawings), or any novel or novel combination of any steps of any method or process disclosed herein.

[0018] The term "alkyl" refers to a monovalent or polyvalent, linear or branched, saturated hydrocarbon group having 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms ("C1-C6-alkyl"). In some embodiments, alkyl groups contain 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl groups include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred but non-limiting example of alkyl is methyl.

[0019] The term "alkoxy" refers to the alkyl group defined above, bonded to the parent molecule via an oxygen atom. In some preferred embodiments, the alkyl group contains 1 to 6 carbon atoms ("C1-C6-alkyl"), for example, 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, the alkoxy group contains 1 to 4 carbon atoms. In yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 1,1-dimethylpropoxy, 2,2-dimethylpropoxy, and tert-butoxy. A particularly preferred but non-limiting example of an alkoxy is methoxy.

[0020] The term "halogen" or "halo" refers to fluoro(F), chloro(Cl), bromo(Br), or iodine(I). Preferably, the term "halogen" or "halo" refers to fluoro(F), chloro(Cl), or bromo(Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluoro(F) and chloro(Cl).

[0021] As used herein, the term "cycloalkyl" refers to a monocyclic or bicyclic hydrocarbon group having 3 to 14 ring carbon atoms, being saturated or partially unsaturated ("C"). 3-141-Cycloalkyl) In some preferred embodiments, a cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. A "bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having two common carbon atoms, i.e., the bridging separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., a cycloalkyl moiety in which the two rings are linked via one common ring atom. In one embodiment, a cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and 1-bicyclo[1.1.1]pentanyl.

[0022] The term "aryl" refers to a group with a total of 6 to 14 ring members ("C 6-C14 The aryl rings are preferably monocyclic, bicyclic, or tricyclic carbocyclic ring systems having 6 to 12 ring members, more preferably 6 to 10 ring members, wherein at least one ring in the system is aromatic. Preferred but non-limiting examples of aryls include phenyl and 3-bicyclo[4.2.0]octa-1(6),2,4-trienyl.

[0023] The term "heteroaryl" refers to a ring with a total of 5 to 14 members ("C"). 1-13A "heteroaryl" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic, preferably bicyclic, ring system having 5 to 12 ring members, more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5 to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryls include 1H-pyrazole-4-yl, pyridazine, pyridyl, pyrimidinyl, oxazole-5-yl, isoxazole-4-yl, 1H-triazole-5-yl, 1H-imidazole-5-yl, 1H-benzimidazole-2-yl, and thiazolyl.

[0024] The term "hydroxy" refers to the -OH group.

[0025] The term "cyano" refers to the -CN (nitrile) group.

[0026] The term "oxo" refers to double-bonded oxygen (=O).

[0027] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably a fluoro atom. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably a fluoro atom. Particularly preferred but non-limiting examples of haloalkyls are fluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoropropyl, 2,2-difluoropropyl, 1-fluoro-1-methylethyl, 2-fluoro-1,1-dimethylethyl, 2-fluoro-2-methylpropyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0028] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably a fluoro atom. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by a halogen atom, most preferably a fluoro atom. Particularly preferred but non-limiting examples of haloalkoxys are trifluoromethoxy, 3,3,3-trifluoropropoxy, 2,2,2-trifluoro-1-methylethoxy, and 3-fluoro-2-fluoropropoxy.

[0029] The term “alkenyl” refers to a monovalent or divalent linear or branched hydrocarbon group ("C2-C6-alkenyl") consisting of 2 to 6 carbon atoms having at least one double bond (e.g., one or two double bonds). In certain embodiments, an alkenyl has 2 to 4 carbon atoms having at least one double bond (e.g., one or two double bonds). Examples of alkenyls include ethenyl, propenyl, propa-2-enyl, isopropenyl, n-butenyl (e.g., (Z)-buta-1-enyl), iso-butenyl, allyl, 2-methylallyl, 2-methylpropa-1-enyl, and propa-1,2-dienyl.

[0030] The term "alkynyl" refers to a monovalent or divalent linear or branched hydrocarbon group ("C2-C6-alkynyl") consisting of 2 to 6 carbon atoms having at least one triple bond, for example, one or two triple bonds. In certain embodiments, an alkynyl has 2 to 4 carbon atoms having at least one triple bond. Examples of alkynyls include ethynyl, ethindiyl, propynyl, n-butynyl, or isobutynyl.

[0031] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a free base or free acid, and is not biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and especially hydrochloric acid, as well as organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and others. In addition, these salts are prepared by adding an inorganic base or organic base to a free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, and polyimine resins. Certain pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride salts.

[0032] The term “protecting group” (PG) refers to a group that selectively blocks a reaction site in a polyfunctional compound so that a chemical reaction can selectively occur at another unprotected reactive site, in the relevant conventional sense of synthetic chemistry. Protecting groups are removed when appropriate. Exemplary protecting groups are amino protecting groups, carboxy protecting groups, or hydroxy protecting groups. Specific protecting groups include tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenyl methoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butoxycarbonyl (Boc) and fluorenyl methoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their applications in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry," by T.W. Greene and P.G.W. Mutts, 5th edition, 2014, John Wiley & Sons, New York.

[0033] The compound of formula (I) may contain several chiral centers and may exist as an optically pure enantiomer, a mixture of enantiomers such as a racemate, an optically pure diastereoisomer, a mixture of diastereoisomers, a diastereoisomer racemate, or a mixture of diastereoisomer racemates.

[0034] According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can have either an "R" or "S" configuration.

[0035] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably in this specification.

[0036] The term “treatment,” as used herein, includes: (1) suppressing a condition, disorder, or situation (e.g., in the case of maintenance treatment, stopping, reducing, or delaying the onset or recurrence of at least one clinical symptom or asymptomatic disease); and / or (2) alleviating a situation (i.e., causing regression of at least one of the condition, disorder, or situation, or its clinical symptoms or asymptomatics). The benefit to the patient to be treated is either statistically significant or at least recognizable to the patient or physician. However, it will be understood that when a medicine is administered to a patient to treat a disease, the outcome does not necessarily have to be an effective treatment.

[0037] As used herein, the term “prevention” includes, in mammals, preventing or delaying the onset of clinical symptoms of a condition, disorder or condition that develops in humans who are already suffering from or susceptible to a condition, disorder or condition but have not yet experienced or shown any clinical symptoms or asymptomatic symptoms of that condition, disorder or condition. The term “neuroinflammation,” as used herein, refers to acute and chronic inflammation of nerve tissue, which is the major tissue component of the two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branched 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). The term “traumatic brain injury” (also known as “TBI” or “intracranial injury”) refers to brain damage resulting from external mechanical forces such as rapid acceleration or deceleration, impact, blast, or penetration by a projectile.

[0038] The term “neurodegenerative disease” refers to diseases associated with the progressive loss of structure or function of neurons, 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 (ALS).

[0039] The term “mental disorder” (also called mental illness or psychiatric disorder) refers to behavioral or mental patterns that can cause distress or dysfunction in life. These characteristics may occur as persistent, recurrent, remittent, or as a single episode. Examples of mental disorders include, but are not limited to, anxiety disorders and depression.

[0040] The term “pain” refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy-induced neuropathy, phantom limb pain, and psychogenic pain. A specific example of pain is neuropathic pain, which is caused by injury or disease affecting any part of the nervous system involved in bodily feelings (i.e., the somatosensory system). In one embodiment, “pain” is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, “pain” is chemotherapy-induced neuropathy.

[0041] The term "neurotoxicity" refers to toxicity in the nervous system. This occurs when exposure to naturally occurring or artificially produced toxic substances (neurotoxins) alters the normal activity of the nervous system, resulting in damage to nerve tissue. Examples of neurotoxicity include, but are not limited to, exposure to substances used in chemotherapy, radiation therapy, drug therapy, drug abuse, and organ transplantation, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some naturally occurring substances.

[0042] The term “cancer” refers to a disease characterized by the presence of a neoplasm or tumor, resulting from the abnormal and uncontrolled proliferation of cells (such cells are “cancer cells”). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, colon cancer, and ovarian cancer.

[0043] As used herein, the term "mammal" includes both human and non-human mammals, including but not limited to humans, non-human primates, dogs, cats, rats, cows, horses, and pigs. In particularly preferred embodiments, the term "mammal" refers to a human.

[0044] The compounds of the present invention In a first aspect, the present invention provides a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0045] In a second aspect (A2), the present invention relates to a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof (in the formula, X is -CH2CR 3 R 4 -, or -CH=CR 3 And, Y is -O-, -S-, -SO-, or -SO2-, R 1 C6-C 14 -aryl, or 5-14 member heteroaryl, and the C6-C 14-aryl or 5-14 member heteroaryls include C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen, cyano, hydroxy, and [ka] The group is optionally substituted with 1 to 5 substituents independently selected from the group. R 2 is hydrogen or C1-C6 alkyl, R 3 teeth, [ka] It is the basis, R 4 is hydrogen, halogen or hydroxyl, R 5 These are hydrogen, halogen, hydroxyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl, halo-C1-C6-alkoxy, cyano, or oxo. R 6 Hydrogen, halogen, C6-C 14 -aryl, 5-14 member heteroaryl, halo-C1-C6-alkoxy, halo-C1-C6-alkyl, oxo, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C 14 - Cycloalkyl or cyano, A and B are, independently, 5-14 member heteroaryls, C6-C 14 -aryl, 3-14 member heterocyclyl or C3-C 14 -It is a cycloalkyl, n and p are independently 1, 2, 3, 4, or 5.

[0046] The present invention further provides the following enumerated embodiments (E) of the first and second embodiments A1 and A2.

[0047] E1 X is -CH2CR3 R 4 -A compound of formula (I) as described in A1 or A2, or a pharmaceutically acceptable salt thereof.

[0048] A compound of formula (I) described in any of A1, A2, and E1, or a pharmaceutically acceptable salt thereof, wherein E2 Y is -O- or -S-.

[0049] A compound of formula (I) described in any of A1, A2, and E1, where E3 Y is -O-, or a pharmaceutically acceptable salt thereof.

[0050] E4 R 1 However, C6-C 14 -aryl or 5-14 member heteroaryl, and the C6-C 14 -aryl or 5-14 member heteroaryls are C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, halogen, cyano and [ka] A compound of formula (I) described in any of A1, A2, and E1-E3, or a pharmaceutically acceptable salt thereof, substituted with 1 to 3 substituents independently selected from the group.

[0051] E5 R 1 However, C1-C6-alkoxy, halogen and [ka] C6-C substituted with 1-2 substituents independently selected from the group 14 - A compound of formula (I) described in any of A1, A2, and E1-E3, which is an aryl compound, or a pharmaceutically acceptable salt thereof.

[0052] E6 R 1 However, C1-C6-alkoxy, halogen and [ka] C6-C substituted with 2-3 substituents independently selected from the group 14 - A compound of formula (I) described in any of A1, A2, and E1-E3, which is an aryl compound, or a pharmaceutically acceptable salt thereof.

[0053] E7 R 1 However, chloro, methoxy and [ka] A compound of formula (I) described in any of A1, A2, and E1-E3, or a pharmaceutically acceptable salt thereof, which is a phenyl compound substituted with two substituents independently selected from the group.

[0054] E8 R 1 However, chloro, fluoro, methoxy and [ka] A compound of formula (I) described in any of A1, A2, and E1-E3, or a pharmaceutically acceptable salt thereof, which is a phenyl compound substituted with two or three substituents independently selected from the group.

[0055] E9 R 2 A compound of formula (I) described in any of A1, A2, and E1-E8, wherein the compound is hydrogen, or a pharmaceutically acceptable salt thereof.

[0056] E10 R 4 A compound of formula (I) described in any of A1, A2, and E1-E9, wherein the compound is hydrogen or hydroxyl, or a pharmaceutically acceptable salt thereof.

[0057] E11 R 5 A compound of formula (I) described in any of A1, A2, and E1-E10, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen, halogen, hydroxyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl, cyano, or oxo.

[0058] E12 R 5 A compound of formula (I) described in any of A1, A2, and E1-E10, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen, halogen, hydroxyl, or oxo.

[0059] E13 R 5 A compound of formula (I) described in any of A1, A2, and E1-E10, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen, halogen, cyano, hydroxyl, or oxo.

[0060] E14 R 5 A compound of formula (I) described in any of A1, A2, and E1-E10, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen, fluoro, hydroxy, or oxo.

[0061] E15 R 5 A compound of formula (I) described in any of A1, A2, and E1-E10, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen, fluoro, cyano, hydroxy, or oxo.

[0062] E16 R 6 However, hydrogen, halogen, C6-C 14 -aryl, halo-C1-C6-alkoxy, halo-C1-C6-alkyl, oxo, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C 14 -A compound of formula (I) described in any of A1, A2, and E1-E15, which is cycloalkyl or cyano, or a pharmaceutically acceptable salt thereof.

[0063] E17 R 6 However, hydrogen, halogen, C6-C 14 -aryl, 5-14 member heteroaryl, halo-C1-C6-alkoxy, halo-C1-C6-alkyl, oxo, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C 14 -Cycloalkyl or cyano, and the 5-14 member heteroaryl or C6-C14 -An aryl optionally substituted with a substituent selected from halogen, C1-C6-alkyl, and C1-C6-alkoxy, a compound of formula (I) as described in any of A1, A2, and E1-E15, or a pharmaceutically acceptable salt thereof.

[0064] E18 R 6 A compound of formula (I) as described in any of A1, A2, and E1-E15, or a pharmaceutically acceptable salt thereof, wherein is halogen, oxo, halo-C1-C6-alkyl, or halo-C1-C6-alkoxy.

[0065] E19 R 6 A compound of formula (I) as described in any of A1, A2, and E1-E15, or a pharmaceutically acceptable salt thereof, wherein is halogen, oxo, halo-C1-C6-alkyl, or halo-C1-C6-alkoxy.

[0066] E20 R 6 A compound of formula (I) as described in any of A1, A2, and E1-E15, or a pharmaceutically acceptable salt thereof, wherein is chloro, fluoro, trifluoromethyl, or difluoromethoxy.

[0067] E21 R 6 A compound of formula (I) as described in any of A1, A2, and E1-E15, or a pharmaceutically acceptable salt thereof, wherein is chloro, fluoro, oxo, trifluoromethyl, or difluoromethoxy.

[0068] A compound of formula (I) as described in any of A1, A2, and E1-E21, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.

[0069] A compound of formula (I) as described in any of A1, A2, and E1-E21, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0070] A compound of formula (I) described in any of A1, A2, and E1-E23, or a pharmaceutically acceptable salt thereof, wherein E24 p is 1 or 2.

[0071] A compound of formula (I) described in any of A1, A2, and E1-E23, or a pharmaceutically acceptable salt thereof, wherein E25 p is 1, 2, or 3.

[0072] E26 A is a 5-14 member heteroaryl, C6-C 14 - A compound of formula (I) described in any of A1, A2, and E1-E25, which is an aryl or a 3- to 14-membered heterocyclyl, or a pharmaceutically acceptable salt thereof.

[0073] A compound of formula (I) described in any of A1, A2, and E1-E25, or a pharmaceutically acceptable salt thereof, wherein E27 A is a 5-14 member heteroaryl or a 3-14 member heterocyclil.

[0074] A compound of formula (I) described in any of A1, A2, and E1-E25, or a pharmaceutically acceptable salt thereof, wherein A is imidazolyl, pyrazolyl, oxopyridinyl, or 1,2-dihydropyridinyl.

[0075] E29 A compound of formula (I) described in any of A1, A2 and E1-E25, or a pharmaceutically acceptable salt thereof, wherein A is imidazolyl, pyrazolyl, pyrrolyl, or 1,2-dihydropyridinyl.

[0076] E30 B is C6-C 14 - Compounds of formula (I) described in any of A1, A2 and E1-E29, which are aryl, 5-14 membered heteroaryl, or 3-14 membered heterocyclyl, or pharmaceutically acceptable salts thereof.

[0077] E31 B is C6-C 14 - Compounds of formula (I) described in any of A1, A2, and E1-E29, which are aryl or 5- to 14-membered heteroaryl, or pharmaceutically acceptable salts thereof.

[0078] A compound of formula (I) described in any of A1, A2, and E1-E29, or a pharmaceutically acceptable salt thereof, wherein E32 B is phenyl or pyridinyl.

[0079] A compound of formula (I) described in any of A1, A2, and E1-E29, or a pharmaceutically acceptable salt thereof, wherein E33 B is phenyl, 1,2-dihydropyridinyl, or pyridyl.

[0080] E34 X, -CH2CR 3 R 4 -, or -CH=CR 3 And, Y is -O-, R 1 However, C6-C 14 -aryl or 5-14 member heteroaryl, and the C6-C 14 -aryl or 5-14 member heteroaryls are C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, halogen, cyano and [ka] It is substituted with 1 to 3 substituents independently selected from the group. R 2 However, it is hydrogen or C1-C6 alkyl, R 3 but, [ka] It is the basis, R 4 However, it is hydrogen, halogen, or hydroxyl, R 5 However, these are hydrogen, halogen, hydroxyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl, cyano or oxo, R 6 However, hydrogen, halogen, C6-C 14-aryl, halo-C1-C6-alkoxy, halo-C1-C6-alkyl, oxo, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C3-C 14 -cycloalkyl or cyano, A and B are each independently a 5- to 14-member heteroaryl, C6-C 14 -aryl or 3- to 14-member heterocyclyl, The compound of formula (I) according to A1 or A2, wherein n and p are each independently 1 or 2, or a pharmaceutically acceptable salt thereof.

[0081] E35 X is -CH2CR 3 R 4 -, Y is -O-, R 1 is C1-C6-alkoxy, halogen and

Chemical formula

Chemical formula

[0082] E36 X is -CH2CR 3 R 4 -, Y is -O-, R 1 is chloro, methoxy, and

Chemical formula

Chemical formula

[0083] E37 X is -CH2CR 3 R 4 -, or -CH=CR 3 is, Y is O or S, R 1 is C6-C 14-aryl or 5-14 member heteroaryl, and the C6-C 14 -aryl or 5-14 member heteroaryls are C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, halogen, cyano and [ka] It is substituted with 1 to 3 substituents independently selected from the group. R 2 However, it is hydrogen or C1-C6 alkyl, R 3 but, [ka] It is the basis, R 4 However, it is hydrogen, halogen, or hydroxyl, R 5 However, these are hydrogen, halogen, hydroxyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl, cyano or oxo, R 6 However, hydrogen, halogen, C6-C 14 -aryl, 5-14 member heteroaryl, halo-C1-C6-alkoxy, halo-C1-C6-alkyl, oxo, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C 14 -Cycloalkyl or cyano, and the 5-14 member heteroaryl or C6-C 14 -The aryl group is optionally substituted with substituents selected from halogens, C1-C6-alkyl groups, and C1-C6-alkoxy groups. A and B are, independently, 5-14 member heteroaryls, C6-C 14 - Aryl or 3-14 member heterocyclyl, n is 1 or 2, A compound of formula (I) described in A1 or A2, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3.

[0084] E38 X, -CH2CR 3 R 4 -and, Y is -O-, R 1 However, C1-C6-alkoxy, halogen and [ka] C6-C substituted with 1-2 substituents independently selected from the group 14 -Aryl, R 2 However, it is hydrogen, R 3 but, [ka] It is the basis, R 4 However, it is hydrogen or hydroxyl, R 5 However, these are hydrogen, halogen, cyano, hydroxy, or oxo, R 6 However, these are halogens, oxo, halo-C1-C6-alkyl or halo-C1-C6-alkoxy, A is a 5-14 member heteroaryl or a 3-14 member heterocyclyl. B is C6-C 14 - Aryl or 5-14 member heteroaryl, A compound of formula (I) described in A1 or A2, or a pharmaceutically acceptable salt thereof, wherein n and p are independently 1 or 2.

[0085] E39 X, -CH2CR 3 R 4 -and, Y is -O-, R 1 However, chloro, fluoro, methoxy and [ka] Phenyl compounds substituted with 2-3 substituents independently selected from the group, R 2 However, it is hydrogen, R 3 but, [ka] It is the basis, R 4 However, it is hydrogen or hydroxyl, R 5 However, these are hydrogen, fluoro, cyano, hydroxy, or oxo, R 6 However, these are chloro, fluoro, oxo, trifluoromethyl, or difluoromethoxy. A is imidazolyl, pyrazolyl, pyrrolyl, or 1,2-dihydropyridinyl. B is phenyl, 1,2-dihydropyridinyl, or pyridyl. n and p are independently either 1 or 2. A compound of formula (I) as described in A1 or A2, or a pharmaceutically acceptable salt thereof.

[0086] The compound of formula (I) E40, [(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3S,9aR)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3R,9aS)-3-(5-chloro-4-methyl-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3S,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3R,9aR)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(9aS)-3-(4-fluoro-3-phenyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3S,9aS)-3-(1H-benzimidazole-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, (2-Chloro-3-methoxyphenyl)-[rac-(3S,9aR)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3S,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3S,9aR)-3-(3-chloro-4-fluorophenyl)-9a-methyl-1,3,4,6,7,9-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, (2-chloro-3-methoxyphenyl)-[rac-(3S,9aS)-3-(5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3R,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3S,9aR)-3-(2,4-dimethylthiazole-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[rac-(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-imidazole-5-yl)phenyl]methanone, [(3R,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3S,9aS)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, 4-[3-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chlorophenyl]-1H-pyridine-2-one, [(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-hydroxyazetidine-1-yl)phenyl]methanone, [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[rac-(9aS)-3-[6-(trifluoromethyl)-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[rac-(9aS)-3-[4-(difluoromethoxy)phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(5-methyl-1H-pyrazole-4-yl)phenyl]methanone, [(3S,9aS)-3-fluoro-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(9aS)-3-(3-bromo-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3S,9aS)-3-(4-bromo-5-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, 5-[3-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chlorophenyl]-1H-pyridine-2-one, [(9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-bromo-3-methoxyphenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-oxazole-5-ylphenyl)methanone, [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-phenyl-phenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-[5-(trifluoromethyl)-1H-pyrazole-4-yl]phenyl]methanone, 4-[3-[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chlorophenyl]-1H-pyrazole-3-carbonitrile, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-methoxyphenyl)phenyl]methanone, [(9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chlorothieno[2,3-b]pyridine-5-yl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[3-[5-(trifluoromethyl)-1H-pyrazole-4-yl]phenyl]methanone, [(3S,9aS)-3-[5-chloro-4-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methyl-4-pyridyl)phenyl]methanone, [(3S,9aS)-3-hydroxy-3-[5-(trifluoromethyl)-2-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[rac-(9aS)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, 3-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridine-2-one, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-oxa-6-azaspiro[3,3]heptan-6-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-pyridyl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1,5-dimethylpyrazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-triazole-5-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3,5-dimethoxyphenyl)methanone, [(3R,9aS)-3-[4-(difluoromethoxy)phenyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, 3-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridine-2-one, 5-[(9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-2-fluorobenzonitrile, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chloro-3-methyl-1H-indazole-5-yl)methanone, (2-Chloro-3-methoxyphenyl)-[rac-(3R,9aR)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-fluoro-3-methoxyphenyl)methanone, [(3S,9aS)-3-[5-chloro-4-(difluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3S,9aS)-3-(5-chloro-4-methyl-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(9aS)-3-(3-cyclopropyl-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-morpholinophenyl)methanone, 2-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-6-methyl-benzonitrile, [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(difluoromethoxy)phenyl]methanone, [(9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chloro-3-quinolyl)methanone, [(3S,9aS)-3-[5-fluoro-4-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [3-(3-bicyclo[4.2.0]octa-1,3,5trienyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, (2-Chloro-3-methoxyphenyl)-[3-[4-(difluoromethyl)phenyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, (2-Chloro-3-methoxyphenyl)-[rac-(3S,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, 5-[(9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-2-fluoro-benzonitrile, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methylisoxazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-pyridazin-3-yl-phenyl)methanone, (2-chloro-3-methoxyphenyl)-[rac-(9aS)-3-[4-fluoro-3-[rac-(E)-propa-1-enyl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-pyridazin-4-yl-phenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(4-methyl-3-pyridyl)phenyl]methanone, [(9aS)-3-[5-(trifluoromethyl)-2-pyridyl]-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3S,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3S,9aS)-3-hydroxy-3-[5-(trifluoromethyl)-2-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-oxazole-5-yl-phenyl)methanone, [(9aS)-3-(4-fluoro-3-propa-1-inyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(9aS)-3-(4-fluoro-3-phenyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methyl-2-pyridyl)phenyl]methanone, [(3S,9aS)-3-[4-(trifluoromethoxy)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3R,9aR)-3-(1H-benzimidazole-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3,4-dimethoxyphenyl)methanone, 4-(2-chloro-3-((3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxyoctahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-hydroxy-3-(2,4,5trifluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-(2,4,5-trifluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-(isothiazol-4-yl)phenyl)((3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, 4-(2-chloro-3-((3R,9aS)-3-(5-chloro-2-oxo-1,2-dihydropyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile, 5-(2-chloro-3-((3R,9aS)-3-(3,4-dichlorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)oxazole-2(3H)-one, 5-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)oxazole-2(3H)-one, 4-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyoctahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile, 4-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)-5-fluorophenyl)pyridine-2(1H)-one, (2-Chloro-3-methoxyphenyl)((9aS)-3-(4-fluoro-3-(oxazol-5-yl)phenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone, 5-(2-chloro-3-((3R,9aS)-3-(3,4-dichlorophenyl)-3-hydroxyoctahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)oxazole-2(3H)-one, (2-Chloro-3-methoxyphenyl)((9aS)-3-(4-fluoro-3-(1-methyl-1H-pyrrole-3-yl)phenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone, ((3R,9aS)-3-(4-bromo-3-chlorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone, 4-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-6-methylpyridine-2(1H)-one, 5-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-6-methylpyridine-2(1H)-one, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-(2-chlorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-(2,4-dichlorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-hydroxy-3-(2,3,4trifluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-(3-chloro-4-(oxazol-5-yl)phenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone, 4-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)piperazin-2-one, 5-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-1,3,4-oxadiazole-2(3H)-one, ((3R,9aS)-3-(3-bromo-5-chlorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-hydroxy-3-(3-(trifluoromethyl)phenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-(3-Chloro-5-(oxazol-5-yl)phenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, ((3R,9aS)-3-(4-chloro-3-fluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-(2,3-difluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-(2,3-difluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, 3-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-1H-pyrazole-5-carbonitrile, ((3S,9aS)-3-(benzo[d]thiazole-2-yl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone, (2-Chloro-3-methoxyphenyl)((3S,9aS)-3-hydroxy-3-(3-phenylisoxazole-5-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3S,9aS)-3-(2-(4-fluorophenyl)thiazole-4-yl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3S,9aS)-3-hydroxy-3-(2-(6-methoxypyridine-3-yl)thiazole-4-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, (2-Chloro-3-methoxyphenyl)((3S,9aS)-3-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone, ((3S,9aS)-3-(4-bromo-5-methoxythiophen-2-yl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone, ((3S,9aS)-3-(3-bromoisoxazole-5-yl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone, 3-((3R,9aS)-8-(2-chloro-3-methoxybenzoyl)-3-hydroxyoctahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-(trifluoromethyl)pyridine-2(1H)-one, 5-[(3#R!,9#a!#S!)-8-(2-chloro-3-methoxybenzoyl)-3,4,6,7,9,9#a!-hexahydro-1#H!-pyrazino[2,1-c][1,4]oxazin-3-yl]-3-chloro-2-fluorobenzonitrile, 5-(2-chloro-3-((3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxyoctahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)phenyl)-1H-imidazole-2-carbonitrile, (2-Chloro-3-methoxyphenyl)((3R,9aS)-3-hydroxy-3-(2-methyl-6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone, 5-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)pyridazin-4(1H)-one, 5-Chloro-3-((3R,9aS)-8-(2-Chloro-5-fluoro-3-(3-fluoro-1H-pyrazole-4-yl)benzoyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyridine-2(1H)-one, 4-(2-chloro-3-((3R,9aS)-3-(5-chloro-2-oxo-1,2-dihydropyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)-5-fluorophenyl)-1H-pyrrole-2-carbonitrile, 5-Chloro-3-((3R,9aS)-8-(2-Chloro-3-(4-Fluoro-1H-Pyrazole-3-yl)benzoyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyridine-2(1H)-one, 4-(2-chloro-5-fluoro-3-((3R,9aS)-3-(4-oxo-6-(trifluoromethyl)-1,4-dihydropyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile, 4-(2-chloro-5-fluoro-3-((3R,9aS)-3-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile, 4-(2-chloro-5-fluoro-3-((3S,9aS)-3-(4-oxo-6-(trifluoromethyl)-1,4-dihydropyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-1H-pyrrole-2-carbonilicate, 3-((3R,9aS)-8-(2-chloro-3-methoxybenzoyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-(trifluoromethyl)pyridine-2(1H)-one, ((3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-6-fluoro-3-methoxyphenyl)methanone, ((3R,9aS)-3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-6-fluoro-3-methoxyphenyl)methanone, ((3S,9aS)-3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-6-fluoro-3-methoxyphenyl)methanone, 5-Chloro-3-((3R,9aS)-8-(2-chloro-6-fluoro-3-methoxybenzoyl)octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyridine-2(1H)-one, and [(9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiadin-8-yl]-(2-chloro-3-methoxyphenyl)methanone A compound of formula (I) described in A1 or A2, or a pharmaceutically acceptable salt thereof, selected from the above.

[0087] The compound of formula (I) E41, 4-(2-chloro-3-((3R,9aS)-3-(5-chloro-2-oxo-1,2-dihydropyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile, 4-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyoctahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile, 4-(2-chloro-3-((3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)-5-fluorophenyl)pyridine-2(1H)-one, 4-(2-chloro-3-((3R,9aS)-3-(5-chloro-2-oxo-1,2-dihydropyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl)-5-fluorophenyl)-1H-pyrrole-2-carbonitrile, 4-(2-chloro-5-fluoro-3-((3R,9aS)-3-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl)phenyl)-1H-pyrrole-2-carbonitrile, ((3R,9aS)-3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-6-fluoro-3-methoxyphenyl)methanone, [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[rac-(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-imidazole-5-yl)phenyl]methanone, (3R,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3S,9aS)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, 4-[3-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chlorophenyl]-1H-pyridine-2-one, [(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-hydroxyazetidine-1-yl)phenyl]methanone, [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone, [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[rac-(9aS)-3-[6-(trifluoromethyl)-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone, and [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[rac-(9aS)-3-[4-(difluoromethoxy)phenyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone A compound of formula (I) described in A1 or A2, or a pharmaceutically acceptable salt thereof, selected from the above.

[0088] In one embodiment, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, X is -CH2CR 3 R 4 -, or -CH=CR 3 And, R 3 but, [ka] It is the basis, R 4 However, it is hydrogen, halogen, or hydroxyl, R 6 However, hydrogen, halogen, C6-C 14 -aryl, 5-14 member heteroaryl, halo-C1-C6-alkoxy, halo-C1-C6-alkyl, oxo, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C 14 -Cycloalkyl or cyano, and the 5-14 member heteroaryl or C6-C 14 -The aryl group is optionally substituted with substituents selected from halogens, C1-C6-alkyl groups, and C1-C6-alkoxy groups. B is a 5-14 member heteroaryl, C6-C 14 - Aryl or 3-14 member heterocyclyl, Provide p is 1, 2, or 3.

[0089] In preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, X is -CH2CR 3 R 4 -and, R 3 but, [ka] It is the basis, R 4However, it is hydrogen or hydroxyl, R 6 However, these are halogens, oxo, halo-C1-C6-alkyl or halo-C1-C6-alkoxy, B is C6-C 14 - Aryl or 5-14 member heteroaryl, Provide p is either 1 or 2.

[0090] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, X is -CH2CR 3 R 4 -and, R 3 but, [ka] It is the basis, R 4 However, it is hydrogen or hydroxyl, R 6 However, these are chloro, fluoro, oxo, trifluoromethyl, or difluoromethoxy. B is phenyl, 1,2-dihydropyridinyl, or pyridyl. Provide p is either 1 or 2.

[0091] In one embodiment, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 3 but, [ka] It is the basis, R 6 However, hydrogen, halogen, C6-C 14 -aryl, 5-14 member heteroaryl, halo-C1-C6-alkoxy, halo-C1-C6-alkyl, oxo, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C 14-Cycloalkyl or cyano, and the 5-14 member heteroaryl or C6-C 14 -The aryl group is optionally substituted with substituents selected from halogens, C1-C6-alkyl groups, and C1-C6-alkoxy groups. B is a 5-14 member heteroaryl, C6-C 14 - Aryl or 3-14 member heterocyclyl, Provide p is 1, 2, or 3.

[0092] In preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 3 but, [ka] It is the basis, R 6 However, these are halogens, oxo, halo-C1-C6-alkyl or halo-C1-C6-alkoxy, B is C6-C 14 - Aryl or 5-14 member heteroaryl, Provide p is either 1 or 2.

[0093] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 3 but, [ka] It is the basis, R 6 However, these are chloro, fluoro, oxo, trifluoromethyl, or difluoromethoxy. B is phenyl, 1,2-dihydropyridinyl, or pyridyl. Provide p is either 1 or 2.

[0094] In one embodiment, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 1 However, C6-C 14 -aryl or 5-14 member heteroaryl, and the C6-C 14 -aryl or 5-14 member heteroaryls are C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, halogen, cyano and [ka] It is substituted with 1 to 3 substituents independently selected from the group. R 5 However, these are hydrogen, halogen, hydroxyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl, cyano or oxo, A is a 5-14 member heteroaryl, C6-C 14 - Aryl or 3-14 member heterocyclyl, Provide n is 1 or 2.

[0095] In preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 1 However, C1-C6-alkoxy, halogen and [ka] C6-C substituted with 1-2 substituents independently selected from the group 14 -Aryl, R 5 However, these are hydrogen, halogen, cyano, hydroxy, or oxo, A is a 5-14 member heteroaryl or a 3-14 member heterocyclyl. Provide n is 1 or 2.

[0096] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 1 However, chloro, methoxy, and [ka] A phenyl compound substituted with two substituents independently selected from the group, R 5 However, these are hydrogen, fluoro, cyano, hydroxy, or oxo, A is imidazolyl, pyrazolyl, pyrrolyl, or 1,2-dihydropyridinyl. Provides n is 1 or 2.

[0097] In one embodiment, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 5 However, these are hydrogen, halogen, hydroxyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl, cyano or oxo, A is a 5-14 member heteroaryl, C6-C 14 - Aryl or 3-14 member heterocyclyl, Provide n is 1 or 2.

[0098] In preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 5 However, these are hydrogen, halogen, cyano, hydroxy, or oxo, A is a 5-14 member heteroaryl or a 3-14 member heterocyclyl. Provide n is 1 or 2.

[0099] In particularly preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, R 5However, these are hydrogen, fluoro, cyano, hydroxy, or oxo, A is imidazolyl, pyrazolyl, pyrrolyl, or 1,2-dihydropyridinyl. Provide n is 1 or 2.

[0100] In one embodiment, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein R, R 1 but, (a) A 5- to 14-membered heteroaryl substituted with one substituent selected from halogens, or (b) [ka] It is the basis, R 7 However, it is hydrogen or C1-C6 alkoxy, R 8 However, it is hydrogen or C1-C6 alkoxy, R 9 However, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, or [ka] It is the basis, R 5 A and n are as defined herein, R 10 It provides (but is hydrogen, halogen, or cyano).

[0101] In one embodiment, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein, X is -CH2CR 3 R 4 -, or -CH=CR 3 And, Y is -O-, R 1 but, (a) A 5- to 14-membered heteroaryl substituted with one substituent selected from halogens, or (b) [ka] It is the basis, R 2 However, it is hydrogen or C1-C6 alkyl, R 3 but, [ka] It is the basis, R 4 However, it is hydrogen, halogen, or hydroxyl, R 5 However, these are hydrogen, halogen, hydroxyl, halo-C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl, cyano or oxo, R 6 However, hydrogen, halogen, C6-C 14 -aryl, halo-C1-C6-alkoxy, halo-C1-C6-alkyl, oxo, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, cycloalkyl or cyano, R 7 However, it is hydrogen or C1-C6 alkoxy, R 8 However, it is hydrogen or C1-C6 alkoxy, R 9 However, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, or [ka] It is the basis, R 10 However, it is hydrogen, halogen, or cyano, A and B are each independently 5-14 member heteroaryls, C6-C 14 - Aryl or 3-14 member heterocyclyl, Provide n and p (each independently being 1 or 2).

[0102] In preferred embodiments, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is the compound of formula (II). [ka] (In the formula, R 2 , R 3 and R 4 This is as defined herein, R 7 However, it is hydrogen or C1-C6 alkoxy, R 8 However, it is hydrogen or C1-C6 alkoxy, R 9 However, hydrogen, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy or [ka] It is a base (in the formula, R 5 (where A and n are as defined herein), R 10 It provides (but is hydrogen, halogen, or cyano).

[0103] In one embodiment, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein A is (i) A heteroaryl selected from the group consisting of 1H-pyrazole-4-yl, pyridazine, pyridyl, pyrimidinyl, oxazole-5-yl, isoxazole-4-yl, 1H-triazole-5-yl, and 1H-imidazole-5-yl, (ii) phenyl, or (iii) Provides a heterocyclil selected from the group consisting of 1,2-dihydropyridine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, morpholinil, and azetidinil.

[0104] In one embodiment, the present invention relates to a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof (wherein B is (i) A heteroaryl selected from the group consisting of pyridyl, 1H-benzimidazole-2-yl, pyridazine, and thiazolyl, or (ii) an aryl selected from the group consisting of phenyl and 3-bicyclo[4.2.0]octa-1(6),2,4-trienyl, or (iii) Provides 1,2-dihydropyridine)

[0105] 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 the compound of formula (III). [ka]

[0106] 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 the compound of formula (IV). [ka]

[0107] 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 the compound of formula (V). [ka]

[0108] 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 the compound of formula (VI). [ka]

[0109] In certain embodiments, the present invention provides pharmaceutically acceptable salts, particularly hydrochloride salts, of the compounds of formula (I) described herein.

[0110] In more specific embodiments, the present invention provides compounds according to formula (I) described herein.

[0111] In some embodiments, compounds of formula (I) are isotope-labeled by having one or more atoms within them that are replaced by atoms having different atomic masses or mass numbers. Such isotope-labeled (i.e., radioactively labeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, for example. 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Examples include, but are not limited to, formula (I). Certain isotope-labeled compounds of formula (I), for example, those incorporating radioactive isotopes, are useful for studying the tissue distribution of drugs and / or substrates. Radioactive isotope tritium, i.e., 3 H and carbon-14, that is, 14 C is particularly useful for this purpose, considering its ease of incorporation and immediate detection means. For example, the compound of formula (I) can be concentrated at 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0112] Deuterium, that is 2Substitution with heavier isotopes, such as 1H, can lead to certain therapeutic benefits resulting from greater metabolic stability, such as an extended in vivo half-life or a reduction in the required dose. 11 C, 18 F, 15 O and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission tomography (PET) studies to examine the receptor occupancy of a substrate. Compounds of formula (I) with isotope labeling are generally prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the examples below, using appropriate isotope-labeled reagents instead of previously used unlabeled reagents.

[0113] Manufacturing process The compounds of formula (I) of the present invention can be prepared by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to react and purify the resulting products are known to those skilled in the art. Substituents and indices used in the following process description have the meaning given herein unless otherwise indicated.

[0114] If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, a suitable protecting group (such as those described in "Protective Groups in Organic Chemistry" by TW Greene and PGMWutts, 5th edition, 2014, John Wiley & Sons, NY) can be introduced before a critical step by applying methods well known in the art. Such protecting groups can be removed at later stages of synthesis using standard methods described in the literature. If the starting material or intermediate contains a stereocenter, the compound of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemic compounds can be separated into their counterparts via diastereomer salts, for example, by crystallization with an optically pure acid, or by separating the counterparts by a specific chromatographic method using either a chiral adsorbent or a chiral eluent. It is also possible to separate the starting material and intermediate containing a stereocenter to obtain diastereomerically / enantiomerically enriched starting material and intermediate. When such diastereomerically / enantiomerically enriched starting material and intermediate are used in the synthesis of the compound of formula (I), the respective diastereomerically / enantiomerically enriched compounds of formula (I) are generally obtained.

[0115] Those skilled in the art will recognize that, in the synthesis of compounds of formula (I), unless otherwise desired, an "orthogonal protection group strategy" can be applied to cleave several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been documented in the literature (e.g., Barany and RBMerrifield, J.Am.Chem.Soc. 1977, 99, 7363; H.Waldmann et al., Angew.Chem.Int.Ed.Engl. 1996, 35, 2056).

[0116] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and properties of the intermediates.

[0117] More specifically, the compound of formula (I) can be prepared by the method shown below, the method shown in the examples, or a similar method. Suitable reaction conditions for each reaction step are known to those skilled in the art. For reaction conditions described in the literature that may affect the described reaction, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd edition, Richard C. Larock, John Wiley & Sons, New York, NY. 1999). The reaction could be carried out readily with or without a solvent. There are no particular restrictions on the properties of the solvent used, as long as it does not adversely affect the reaction or the reagents involved and can dissolve the reagents to at least some extent. The described reaction can occur over a wide range of temperatures, and the exact reaction temperature is not important to the present invention. It is convenient to carry out the described reaction in the temperature range from -78°C to reflux. The time required for the reaction can also vary considerably, depending on many factors, particularly the reaction temperature and the properties of the reagents. However, obtaining the described intermediates and compounds usually takes only 0.5 hours to a few days. The reaction sequence is not limited to the order shown in the scheme, and the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity.

[0118] If the starting materials or intermediates are not commercially available, or if their synthesis is not documented in the literature, they can be prepared in the same manner as existing procedures for similar analogs, or as outlined in the experimental section. R 1 and R 3 R is defined herein as follows: 2 and R 4 Compounds of formula (I), where is hydrogen, can be synthesized by the general procedure outlined in Scheme 1. [ka]

[0119] Therefore, secondary amine 2 can be acylated with carboxylic acid 1, which can be prepared using commercially available coupling reagents such as HATU, T3P, or EDC in combination with a base such as TEA or DIPEA, under appropriate conditions, either by means of a commercially available product or by a method known to those skilled in the art. By deprotecting the Boc group with an acid such as TFA or HCl, the corresponding intermediate 3 (Scheme 1, steps a and b) is obtained. By treating piperazine 3 with an epoxide 4, which can be commercially available or prepared by a method known to those skilled in the art, in a solvent such as methanol or ethanol at a temperature range of 100°C to 140°C, the corresponding diol 5 is obtained (Scheme 1, step c). By cyclizing the two hydroxyl groups of 5 using an etherifying reagent such as (cyanomethylene)tributylphosphorane (CMBP, Tsunoda reagent), the compound of formula (I) is obtained (Scheme 1, step d).

[0120] R 3 If the compound supports a protecting group, such as a benzyl group as a protecting group for pyridone, a final deprotection step is required using appropriate conditions such as TFA in DCM, and the compound of formula (I) is finally obtained.

[0121] Also, R 1 , R 2 and R 3 R is defined herein as follows: 4 Compounds of formula (I) where is hydrogen can be synthesized by following the general procedure outlined in Scheme 2. [ka] When secondary amine 6 is treated with epoxide 4 in a solvent such as methanol or ethanol at a temperature range of 100°C to 140°C, the corresponding intermediate 7 (Scheme 2, step a) is obtained. The two hydroxyl groups of 7 are cyclized using an etherification reagent such as (cyanomethylene)tributylphosphorane (CMBP, Tsunoda reagent) (Scheme 2, step b). Subsequently, the Boc group is deprotected with an acid such as TFA or HCl to obtain the corresponding morpholine analog 8 (Scheme 2, step c). 3 If the amine supports a protecting group, such as benzyl as a pyridone protecting group, this is also deprotected during acid treatment (Scheme 2, step c). The secondary amine 8 is then acylated with a suitable carboxylic acid 1 using a coupling reagent such as HATU, T3P, or EDC combined with a base such as TEA or DIPEA (Scheme 2, step d) under conditions known in the art, to obtain the compound of formula (I).

[0122] Also, R 1 , R 2 , R 3 and R 4 Compounds of formula (I), as defined herein, can be synthesized by following the general procedure outlined in scheme 3a. [ka]

[0123] Secondary amine 2 can be acylated with a suitable carboxylic acid 1 under conditions known in the art, for example, using coupling reagents such as HATU, T3P, or EDC combined with a base such as TEA or DIPEA. The corresponding intermediate 3 is obtained by deprotecting the Boc group with an acid such as TFA or HCl (Scheme 3a, steps a and b). Treatment of piperazine 3 with halo ketone 9 (which can be obtained by a general procedure outlined in Scheme 4, for example) in a solvent such as THF and a base such as DIPEA at a temperature range of 0°C to 25°C yields the corresponding acetal I, which is R 4This corresponds to the compound of formula (I) where is hydroxyl (Scheme 3a, step c). 4 When a compound of formula (I) in which is hydroxyl is further reacted under dehydration conditions, for example at a high temperature of 50°C to 80°C using TES and TFA in DCM, R 4 A compound of formula (I) is obtained where is hydrogen (Scheme 3a, step d). Depending on the selected conditions, if removal is an additional reaction pathway, an alkene (X=-CH=CR) is obtained. 3 -) can be isolated in some cases.

[0124] R 4 When a compound of formula (I), in which is hydroxyl, is treated with a nucleophilic fluorinating agent such as DAST at a temperature of -78°C to 25°C using a solvent such as DCM, R 4 A compound of formula (I) is obtained in which is a fluoride (Scheme 3a, step e).

[0125] Also, R 1 , R 2 , R 3 and R 4 Compounds of formula (I), as defined herein, can be synthesized by following the general procedure outlined in scheme 3b. [ka]

[0126] When secondary amine 6 is treated with halo ketone 9 in a solvent such as THF and a base such as DIPEA at a temperature range of 0°C to 25°C, the corresponding acetal is obtained by deprotecting the Boc group with an acid such as TFA or HCl. 4 A compound of formula 10 is obtained in which is hydroxyl (Scheme 3b, steps a and b). The secondary amine 10 is acylated with a suitable carboxylic acid 1 using coupling reagents such as HATU, T3P, EDC combined with a base such as TEA or DIPEA, under conditions known in the art, for example, R 4 A compound of formula I containing =OH is obtained (Scheme 3b, step c). 4When a compound of formula (I) in which is hydroxyl is further reacted under dehydration conditions, for example at a high temperature of 50°C to 80°C using TES and TFA in DCM, R 4 A compound of formula (I) is obtained where is hydrogen (Scheme 3, step d). Depending on the selected conditions, if removal is an additional reaction pathway, an alkene (X=-CH=CR) is obtained. 3 -) can be isolated in some cases.

[0127] R 4 When a compound of formula (I), in which is hydroxyl, is treated with a nucleophilic fluorinating agent such as DAST at a temperature of -78°C to 25°C using a solvent such as DCM, R 4 A compound of formula (I) is obtained, in which is a fluoride (Scheme 3b, step e).

[0128] Bromoketone intermediate 9 is obtained by reacting a commercially available ketone 11, which is prepared by a method known to those skilled in the art, with bromine in acetic acid at a high temperature of 60-90°C (Scheme 4). [ka]

[0129] R 1 , R 2 and R 4 R is defined herein as follows: 3 Compounds of formula (I), where B is substituted with bromo, are further modified according to the general procedure outlined in Scheme 5. [ka]

[0130] R 3When a compound of formula I containing bromoaryl is treated under typical conditions of the Suzuki-Miyaura reaction, the Sonogashira reaction, or other organometallic cross-coupling reactions known in the art, substituted compounds of formula I are obtained in which bromine is replaced by an aryl, alkenyl, alkynyl, alkyl, cycloalkyl, heteroaryl, or cyano moiety. This typically requires a suitable reaction partner such as boronic acid, potassium trifluoroborate, pinacol boronate, terminal alkyne, or organozinc compound, a suitable catalyst, and an organic or inorganic base such as sodium carbonate, TEA, TMEDA, or cesium carbonate in a solvent system such as tetrakis(triphenylphosphine)palladium(O), PdCl2(dppf)-CH2Cl2, Pd2(dba)3+xanthophos, cataCXium A Pd G2, dioxane / water, DMF, or toluene / water. The reaction is typically carried out at a high temperature of 100-120°C under an inert atmosphere (argon). In the case of the Sonogashira coupling, R 6 To obtain I, which is an alkynyl, the addition of copper(I) iodide is necessary.

[0131] R 2 , R 3 , R 4 , R 5 and n are as defined herein, R 1 Compounds of formula (I) in which is an aryl or heteroaryl substituted with an aryl, heteroaryl, or heterocyclyl are obtained by the procedure outlined in Scheme 6. [ka]

[0132] When a compound of formula 12 containing a boronic acid or boronic acid ester is treated under typical conditions of the Suzuki-Miyaura reaction, a substituted compound of formula I is obtained in which the boronic acid ester is replaced with an aryl, heteroaryl, or heterocyclyl moiety. This typically involves a suitable reaction partner 13, which may be, for example, a haloaryl, haloheteroaryl, or haloheterocyclyl, and a suitable catalyst, such as PdCl2(DPPF)-CH2Cl2, Pd2(dba)3+xanthophos, (A- ta The reaction requires an organic or inorganic base such as sodium carbonate, TEA, TMEDA, or cesium carbonate in a solvent system such as Phos)2PdCl2, cataCXium A Pd G2, dioxane / water, DMF, or toluene / water. The reaction is typically carried out at a high temperature of 100–120°C under an inert atmosphere (argon).

[0133] Also, R 1 , R 2 , and R 3 R is defined herein as follows: 4 Compounds of formula (I), where is hydrogen and Y is -S-, can be obtained by the general procedure outlined in Scheme 7. [ka]

[0134] Diols 5 or 7 are converted to their corresponding monomesylates by treatment with a base such as methanesulfonyl chloride or triethylamine, and a catalyst such as 4-dimethylaminopyridine. Subsequent reaction with potassium thioacetate in a solvent such as DMSO yields intermediate 13 (Scheme 7, steps a and b). The remaining hydroxyl groups of 13 are then converted to the corresponding chloro intermediate by treatment with, for example, thionyl chloride, followed by the addition of a base such as pyridine. The resulting chloro intermediate is then treated with sodium methoxide to obtain cyclized sulfide I (if Z=-CO-R1) or 14 (if Z=Boc) (Scheme 7, steps c+d). For compound of type 14, the Boc group is deprotected using an acid such as TFA or HCl, and then acylated with a suitable carboxylic acid 1 using a coupling reagent such as HATU, T3P, or EDC in combination with a base such as TEA or DIPEA to obtain the compound of formula I (Scheme 7, steps e+f). Based on Bioorg.Med.Chem.Lett.2016,26(23),p.5695-5702, and U.S. Patent No. 9,573,961.

[0135] R 1 , R 2 , and R 3 R is defined herein as follows: 4 Compounds of formula (I), where Y is hydrogen and Y is sulfur, can be further modified according to the general procedures outlined in Scheme 8. By using methods known to those skilled in the art, for example, by treating thioether I with mCPBA, hydrogen peroxide, or sodium periodate, compounds of formula I can be obtained as mixtures of type I or as pure compounds, depending on the selected conditions, where Y is a sulfoxide and / or sulfone. Mixtures of sulfones and sulfoxides of type I can then be separated by preparative HPLC or SFC to obtain the pure product. [ka]

[0136] Not available on the market, R 5 Carboxylic acid 1, as defined herein, can be prepared by methods known to those skilled in the art, for example, by the methods described in the following schemes 9a to 9e. [ka]

[0137] Starting with bromobenzoic acid 15, intermediate 17 is obtained by using typical conditions for the Suzuki-Miyaura reaction. The reaction involves a suitable boronic acid or boronic acid ester 16, XPhos-Pd-G2, (A- in a solvent system such as THF / H2O or dioxane / H2O). ta The reaction requires a palladium catalyst such as Phos)2PdCl2 or (APhos)2PdCl2, and a base such as K3PO4, K2CO3, or Cs2CO3. The reaction is typically carried out at a high temperature of 100-120°C under an inert atmosphere (argon). The reaction of the 2-heterocyclic boronate is ideally accelerated by the further addition of copper(I) chloride (Scheme 9a, step a). Type 1 carboxylic acids are obtained by saponification with a base such as lithium hydroxide in aqueous solution (Scheme 9a, step b). [ka]

[0138] Furthermore, starting with a boronic acid or benzoic acid boronic ester 18, intermediate 17 can be obtained by using typical conditions for the Suzuki-Miyaura reaction. It is a suitable haloaryl, haloheteroaryl or haloheterocyclyl 19, a palladium catalyst, e.g., XPhos-Pd-G2, (A- taThe reaction requires (Phos)2PdCl2, (APhos)2PdCl2, a base, and K3PO4, K2CO3, or Cs2CO3 in a solvent system such as THF / H2O or dioxane / H2O. The reaction is typically carried out at a high temperature of 100-120°C under an inert atmosphere (argon). The reaction of 2-heteroarylboronates is ideally accelerated by the further addition of copper(I) chloride (Scheme 9b, step a). Type 1 carboxylic acids are obtained by saponification with a base such as lithium hydroxide in aqueous solution (Scheme 9b, step b). [ka]

[0139] Starting with bromobenzoic acid 15, intermediate 21 is obtained by using typical conditions for the Buchwald-Hartwig reaction. This requires a suitable amine 20, a palladium catalyst such as Pd2(dba)3 with a phosphine ligand such as DavePhos or xanthophos, and a base such as K3PO4, K2CO3, or Cs2CO3, in a solvent such as toluene or dioxane. The reaction is typically carried out at a high temperature of 100-120°C under an inert atmosphere using argon (Scheme 9c, step a). Type 1 carboxylic acid is obtained by saponifying 21 with a base such as lithium hydroxide in aqueous solution (Scheme 9c, step b). [ka]

[0140] In some cases, coupling to bromobenzoic acid can be directly achieved by using unsubstituted oxazole 22 (scheme 9d), particularly when A is an oxazole, as described in Org. Lett. 2010, 12(16), pp. 3578-3581. A type 1 carboxylic acid can be obtained by saponifying 16 with a base such as lithium hydroxide in an aqueous solution (Scheme 9d, step b). [ka] The aryl / heteroaryl halide 15 can be cross-coupled with ethynyltrimethylsilane using typical Sonogashira reaction conditions (Pd(dppf)Cl2, copper(I) iodide, diethylamine, DMF, 120°C). Deprotection with potassium carbonate in THF / MeOH at room temperature yields alkyne intermediate 23 (Scheme 9e, steps a+b). Treatment of 23 with azidotrimethylsilane using a suitable copper catalyst such as copper(I) iodide in a solvent system such as DMF / MeOH at a high temperature of 100-130°C yields triazole 24 (Scheme 9e, step c). Saponification of 24 with a base such as lithium hydroxide in aqueous solution yields a type 1 carboxylic acid (Scheme 9e, step b).

[0141] B, R, not available commercially. 6 Oxirane 4, where p is as defined herein, can be prepared by methods known to those skilled in the art, for example, by the methods described below. [ka]

[0142] When aryl halides or heteroaryl halides 25 are treated with potassium trifluoro(vinyl)borate under typical Suzuki-Miyaura conditions (in ethanol, under argon, 100°C to 130°C, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex, triethylamine), vinylarenes or vinyl heteroarenes 26 are obtained (Scheme 10, step a). These can be oxidized to oxiranes 4, for example, by treating them with methyltrioxolenium + 1H-pyrazole and hydrogen peroxide in DCM at 0°C, with NBS in water and dioxane at room temperature, then with aqueous NaOH solution at 0°C, and finally with mCPBA in DCM at room temperature (Scheme 10, step b).

[0143] In one embodiment, the present invention provides a method for producing a compound of formula (I) as described in any one of the schemes disclosed herein.

[0144] In a further embodiment, the present invention relates to a method for producing a compound of formula (I) described herein, (a) Diol 5 [ka] (In the formula, R 1 and R 3 (as defined herein) When reacted with an etherification reagent such as (cyanomethylene)tributylphosphoran (CMBP, Tsunoda reagent), X becomes -CH2CHR 3 - and Y is -O-, R 1 and R 3 R is defined herein as follows: 2 To obtain a compound of formula (I) in which is hydrogen; or (b) Amine 8a [ka] (In the formula, Y, R 2 and R 3 (as defined herein) Carboxylic acid 1 [ka] (In the formula, R 1 (as defined herein) When reacted in the presence of a base such as trimethylamine or diisopropylamine and a coupling reagent such as HATU, T3P, or EDC*HCl, X is -CH2CHR 3 - and Y, R 1 and R 3 R is defined herein as follows: 2 To obtain a compound of formula (I) where is hydrogen; or (c) Y is as defined herein, and X is -CH2CR 3 R 4 - and R 1 ~R 3 R is defined herein as follows: 4 A compound of formula (I) in which is hydroxyl is subjected to dehydration conditions, for example, using TES and TFA at high temperature, where Y is as defined herein and X is -CH2CHR 3 - and R 1 ~R 3 A compound of formula (I) where Y is as defined herein, and / or Y is as defined herein, and X is -CH=CR 3 And R 1 ~R 3 To obtain a compound of formula (I) as defined herein; or (d) Y is as defined herein, and X is -CH2CR 3 R 4 - and R 1 ~R 3 R is defined herein as follows: 4 A compound of formula (I) in which is hydroxyl is reacted with a nucleophilic fluorinating agent such as DAST, and X becomes -CH2CFR 3 - and R 1 ~R 3 To obtain a compound of formula (I) as defined herein; or (e) Formula (I) [ka] (In the formula, R 1 , R 2 , R 4 And B is as defined herein, and R 6 The compound (which is bromo) is subjected to a transition metal-catalyzed cross-coupling reaction such as the Suzuki-Miyaura reaction or the Sonogashira reaction, and formula (I) [ka] (In the formula, R1 , R 2 , R 4 And B is as defined herein, and R 6 To obtain compounds (selected from aryl, alkenyl, alkynyl, alkyl, cyano, cycloalkyl and heteroaryl); or (f) Compound 12 [ka] (R 1 R is an aryl or heteroaryl which is optionally substituted with 1 to 4 substituents independently selected from C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen, and cyano. 2 ~R 4 (as defined herein) compound 13 [ka] (A, R 5 In the Suzuki-Miyaura cross-coupling reaction with n (where n is as defined herein), Transition metal catalysts, e.g., PdCl2(dppf)-CH2Cl2, Pd2(dba)3+xanthophos, (A- ta The mixture of Phos)2PdCl2 or cataCXium A Pd G2 and an organic or inorganic base such as sodium carbonate, triethylamine, TMEDA, or cesium carbonate is subjected to the following reaction: [ka] (R 1 R is an aryl or heteroaryl which is optionally substituted with 1 to 4 substituents independently selected from C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen, and cyano. 2 ~R 5To obtain a compound of (where n is as defined herein); or (g) Formula (I) [ka] (Y is sulfur, R 1 , R 2 and R 3 Compounds of (as defined herein) When reacted with an oxidizing agent such as mCPBA, hydrogen peroxide, or sodium periodate, formula (I) [ka] (Y is a sulfoxide or sulfone, R 1 , R 2 and R 3 To obtain a compound of (as defined herein) We provide a method that includes [this].

[0145] In one embodiment, the present invention provides a compound of formula (I) as described herein, when produced according to any one of the processes described herein.

[0146] MAGL inhibitory activity The compounds of the present invention are MAGL inhibitors. Accordingly, in one embodiment, the present invention provides the use of the compounds of formula (I) described herein for inhibiting MAGL in mammals.

[0147] In a further embodiment, the present invention provides compounds of formula (I) described herein for use in methods of inhibiting MAGL in mammals.

[0148] In a further embodiment, the present invention provides the use of a compound of formula (I) described herein for the preparation of a pharmaceutical agent that inhibits MAGL in mammals.

[0149] In a further embodiment, the present invention provides a method for inhibiting MAGL in mammals, the method comprising administering an effective amount of the compound of formula (I) described herein to a mammal.

[0150] The compound's MAGL inhibitory activity was profiled by tracking the hydrolysis of its natural substrate, 2-arachidonoylglycerol (2-AG), to obtain arachidonic acid, followed by mass spectrometry to measure enzyme activity. This assay will be hereinafter abbreviated as the "2-AG assay."

[0151] The 2-AG assay was performed in a 384-well assay plate (PP, Greiner, catalog no. 784201) at a total volume of 20 μL. Compound dilutions were prepared in a polypropylene plate using a 3-fold dilution step in 100% DMSO (VWR Chemicals 23500.297) to achieve a final concentration range of 12.5 μM to 0.8 pM in the assay. 0.25 μL of the compound dilution (100% DMSO) was added to 9 μL of MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 mL), 0.01% (v / v) Tween). After shaking, the plate was incubated at room temperature for 15 minutes. To initiate the reaction, 10 μL of 2-arachidonoylglycerol was added to the assay buffer. The final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglyerol. After shaking and incubation at room temperature for 30 minutes, the reaction was quenched by adding 40 μL of ACN containing 4 μM d8-arachidonic acid. The amount of arachidonic acid was tracked using an online SPE system (Agilent Rapidfire) in combination with a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE cartridge (G9205A) was used in an ACN / water liquid setup. The mass spectrometer was operated in negative electrospray mode, following mass transitions of 303.1 → 259.1 for arachidonic acid and 311.1 → 267.0 for d8-arachidonic acid. The activity of the compounds was calculated based on the intensity ratio [arachidonic acid / d8-arachidonic acid].

[0152] [Table 1] TIFF2022539604000072.tif230161 TIFF2022539604000073.tif236161TIFF2022539604000074.tif225161 TIFF2022539604000075.tif225161 TIFF2022539604000076.tif205161 TIFF2022539604000077.tif205161 TIFF2022539604000078.tif216161 TIFF2022539604000079.tif210161 TIFF2022539604000080.tif236161 TIFF2022539604000081.tif216161 TIFF2022539604000082.tif233161 TIFF2022539604000083.tif225161 TIFF2022539604000084.tif222161 TIFF2022539604000085.tif221161 TIFF2022539604000086.tif229161 TIFF2022539604000087.tif205161 TIFF2022539604000088.tif236161 TIFF2022539604000089.tif216161 TIFF2022539604000090.tif216161 TIFF2022539604000091.tif222161 TIFF2022539604000092.tif233161 TIFF2022539604000093.tif230161 TIFF2022539604000094.tif225161 TIFF2022539604000095.tif218161 TIFF2022539604000096.tif218161 TIFF2022539604000097.tif205161 TIFF2022539604000098.tif230161 TIFF2022539604000099.tif216161 TIFF2022539604000100.tif210161 TIFF2022539604000101.tif236161 TIFF2022539604000102.tif205161 TIFF2022539604000103.tif205161 TIFF2022539604000104.tif222161 TIFF2022539604000105.tif236161 TIFF2022539604000106.tif216161

[0153] In one embodiment, the present invention provides compounds of formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, wherein the compounds of formula (I) and pharmaceutically acceptable salts or esters thereof, when measured by the MAGL assay described herein, exhibit an IC50 for MAGL inhibition. 50 The concentration is less than 25 μM, preferably less than 10 μM, and more preferably less than 5 μM. In one embodiment, the compounds of formula (I) described herein and their pharmaceutically acceptable salts or esters are measured by the MAGL assay described herein, and have an IC value. 50 The (MAGL inhibition) value is between 0.000001 μM and 25 μM, and certain compounds exhibit IC50. 50 The value is between 0.000005 μM and 10 μM, and furthermore, certain compounds exhibit IC50. 50 The value is between 0.00005 μM and 5 μM.

[0154] Use of the compound of the present invention In one embodiment, the present invention provides a compound of formula (I) described herein for use as a therapeutically active substance. In a further embodiment, the present invention provides the use of compounds of formula (I) described herein for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and / or mental disorders in mammals.

[0155] In one embodiment, the present invention provides the use of a compound of formula (I) described herein for the treatment or prevention of neuroinflammatory and / or neurodegenerative diseases in mammals.

[0156] In one embodiment, the present invention provides the use of a compound of formula (I) described herein for the treatment or prevention of neurodegenerative diseases in mammals.

[0157] In one embodiment, the present invention provides the use of a compound of formula (I) described herein for the treatment or prevention of cancer in mammals.

[0158] In one embodiment, the present invention provides the use of compounds of formula (I) 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 cancer development, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and / or pain-associated spasticity in mammals.

[0159] In preferred embodiments, the present invention provides the use of compounds of formula (I) described herein for the treatment or prevention of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in mammals.

[0160] In particularly preferred embodiments, the present invention provides the use of compounds of formula (I) described herein for the treatment or prevention of multiple sclerosis in mammals.

[0161] In one embodiment, the present invention provides compounds of formula (I) described herein for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and / or mental disorders in mammals.

[0162] In one embodiment, the present invention provides a compound of formula (I) described herein for use in the treatment or prevention of neuroinflammatory and / or neurodegenerative diseases in mammals.

[0163] In one embodiment, the present invention provides a compound of formula (I) described herein for use in the treatment or prevention of cancer in mammals.

[0164] In one embodiment, the present invention provides a compound of formula (I) described herein for use in the treatment or prevention of neurodegenerative diseases in mammals.

[0165] In one embodiment, the present invention provides compounds of formula (I) 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 cancer development, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and / or pain-associated spasticity in mammals.

[0166] In particularly preferred embodiments, the present invention provides compounds of formula (I) described herein for use in the treatment or prevention of multiple sclerosis in mammals.

[0167] In particularly preferred embodiments, the present invention provides compounds of formula (I) described herein for use in the treatment or prevention of multiple sclerosis in mammals.

[0168] In one embodiment, the present invention provides the use of a compound of formula (I) described herein for preparing a medicament for the treatment or prevention of mammary cancer and / or mental disorders.

[0169] In one embodiment, the present invention provides the use of a compound of formula (I) described herein for preparing a medicament for the treatment or prevention of neuroinflammatory and / or neurodegenerative diseases in mammals.

[0170] In one embodiment, the present invention provides the use of a compound of formula (I) described herein for preparing a medicament for the treatment or prevention of neurodegenerative diseases in mammals.

[0171] In one embodiment, the present invention provides the use of a compound of formula (I) described herein for preparing a pharmacopoeia for the treatment or prevention of cancer in mammals.

[0172] In a further embodiment, the present invention provides the use of compounds of formula (I) described herein for preparing pharmaceuticals 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 cancer development, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, and / or pain-associated spasticity in mammals.

[0173] In preferred embodiments, the present invention provides the use of compounds of formula (I) described herein for preparing pharmaceuticals for the treatment or prevention of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in mammals.

[0174] In particularly preferred embodiments, the present invention provides the use of compounds of formula (I) described herein for preparing pharmaceuticals for the treatment or prevention of multiple sclerosis in mammals.

[0175] In one embodiment, the present invention provides a method for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer and / or mental disorders in mammals, the method comprising administering an effective amount of a compound of formula (I) described herein to a mammal.

[0176] In one embodiment, the present invention provides a method for treating or preventing neuroinflammatory and / or neurodegenerative diseases in mammals, the method comprising administering an effective amount of a compound of formula (I) described herein to a mammal.

[0177] In one embodiment, the present invention provides a method for treating or preventing neurodegenerative diseases in mammals, the method comprising administering an effective amount of a compound of formula (I) described herein to a mammal.

[0178] In one embodiment, 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 and / or pain in mammals, the method comprising administering an effective amount of a compound of formula (I) described herein to a mammal.

[0179] In preferred embodiments, the present invention provides a method for treating or preventing multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in mammals, the method comprising administering an effective amount of a compound of formula (I) described herein to a mammal.

[0180] In a particularly preferred embodiment, the present invention provides a method for treating or preventing multiple sclerosis in mammals, the method comprising administering an effective amount of a compound of formula (I) described herein to a mammal.

[0181] Pharmaceutical composition and administration In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein and a therapeutically inert carrier.

[0182] Compounds of formula (I) and their pharmaceutically acceptable salts and esters may be used as pharmaceuticals (e.g., in the form of pharmaceutical formulations). Pharmaceutical formulations may be administered into the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories). However, administration may also be carried out intramuscularly or intravenously (e.g., in the form of injections).

[0183] Compounds of formula (I) and their pharmaceutically acceptable salts and esters can be treated with pharmaceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc., can be used as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example. Suitable adjuvants for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols.

[0184] Suitable adjuvants for the production of liquid and syrup formulations include, for example, water, polyols, sucrose, invert sugar, and glucose.

[0185] Suitable adjuvants for injection solutions include, for example, water, alcohol, polyol, glycerol, and vegetable oil.

[0186] Suitable adjuvants for suppositories include, for example, natural or hydrogenated oils, waxes, fats, semi-solid or liquid polyols.

[0187] Furthermore, pharmaceutical formulations may contain preservatives, solubilizers, viscosity enhancers, stabilizers, humectants, emulsifiers, sweeteners, colorants, flavorings, salts to alter osmotic pressure, buffers, masking agents, or antioxidants. They may also contain other therapeutically useful substances.

[0188] Dosages can be varied widely and, of course, adapted to the individual requirements of each specific case. Generally, for oral administration, a daily dose of approximately 0.1 mg to 20 mg / kg body weight, preferably approximately 0.5 mg to 4 mg / kg body weight (e.g., approximately 300 mg / person), may be appropriately divided into 1 to 3 individual doses, each consisting of, for example, the same amount. However, it is clear that the upper limits given herein can be exceeded where indicated. [Examples]

[0189] The present invention will be better understood by referring to the following embodiments. However, the claims should not be construed as being limited to the scope of these embodiments.

[0190] If the preparation is obtained as a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0191] Unless otherwise specified, all reaction examples and intermediates were prepared under an argon atmosphere.

[0192] Abbreviation AcOH = Acetic acid, ACN = Acetonitrile, Bn = Benzyl, BINAP = (2,2'-Bis(diphenylphosphin)-1,1'-Binaphthyl), 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 = Sulfur trifluoride (diethylamino), DBU = 1,8-Diazabicyclo[5,4,0]undec-7-ene, DEAD = Diethyl azodicarboxylate, DIAD = Diisopropyl azodicarboxylate, DMAP = 4-Dimethylaminopyridine, DME = Dimethoxyethane, DMEDA = N,N'-Dimethylethylenediamine, DMF = N,N-Dimethylformamine D, DIPEA = N,N-diisopropylethylamine, dppf = 1,1-bis(diphenylphosphino)ferrocene, EDC·HCl = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, EI = electron impulse, ESI = electrospray ionization, SiO = ethyl acetate, EtOH = ethanol, h = time, FA = formic acid, H2O = water, H2SO4 = sulfuric acid, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate, HBTU = O-benzotriazole-N,N,N',N'-Tetramethyluronium-hexafluorophosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-1H-benzotriazole, HPLC = high-performance liquid chromatography, iPrMgCl = isopropylmagnesium 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 LA H = Lithium aluminum hydride, LiHMDS = Lithium bis(trimethylsilyl)amide, LiOH = Lithium hydroxide, mCPBA = Meta-chloroperbenzoic acid, MgSO4 = Magnesium sulfate, min = Minute, mL = Milliliter, MPLC = Medium pressure liquid chromatography, MS = Mass spectrum, nBuLi = n-Butyllithium, NaBH3CN = Sodium borohydride, NaH = Sodium hydride, NBS = N-Bromosuccinimide, 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, NEt3 = Triethylamine (TEA), NH4Cl = Ammonium chloride, NMP = N-methyl-2-pyrrolidone, OAc = Acetoxy, T3P = Propylphosphone anhydride, PE = Petroleum ether, PG = Protecting group, Pd-C = Palladium-activated carbon, PdCl2(dppf)-CH2C l2 = 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, RP = reversed phase, RT = room temperature, SFC = supercritical fluid chromatography, S-PHOS = 2-dicyclohexylphosphino-2',6'-Dimethoxybiphenyl, TBAI = Tetrabutylammonium iodide, TEA = Triethylamine, TES = Triethylsilane, TFA = Trifluoroacetic acid, THF = Tetrahydrofuran, TMEDA = N,N,N',N'-Tetramethylethylenediamine, T3P = 1-Propanephosphonic anhydride, ZnCl2 = Zinc chloride, Hal = Halogen.

[0193] Intermediate 1 (2-chloro-3-methoxyphenyl)-[3-(hydroxymethyl)piperazine-1-yl]methanone 2.5 g, 6.5 mmol of tert-butyl 4-(2-chloro-3-methoxybenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate was dissolved in 4 M HCl in 25 mL of dioxane and stirred at room temperature for 90 minutes. The solvent was removed under reduced pressure, the residue was dissolved in 0.1 M HCl (aqueous solution), extracted with ethyl acetate, basicized with 4 M NaOH (aqueous solution), and re-extracted with EtOAC to obtain the product. Due to the high polarity of the product, several extractions were performed using excess ethyl acetate to separate the product from the basic aqueous layer. The organic fractions were combined, dried over Na₂SO₄, and concentrated under reduced pressure to obtain 1.295 g of intermediate 1. No further purification was performed. ESI (MS) m / z = 285.3 [M + H] +

[0194] a) tert-butyl 4-(2-chloro-3-methoxybenzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate A mixture of 2-chloro-3-methoxybenzoic acid (1.29 g, 6.94 mmol), tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (1500 mg, 6.94 mmol), and HATU (2.51 g, 6.59 mmol) was dissolved in 25 mL of ethyl acetate. DIPEA (1.79 g, 2.42 ml, 13.9 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed twice with saturated NaHCO3, dried over Na2SO4, filtered, evaporated, and then dried under high vacuum. The resulting unpurified residue was purified by flash column chromatography (50 g silica, 40 ml / min, ethyl / heptane 0-100%). The product fractions were combined and evaporated to obtain 2.5 g of the desired product. ESI (MS) m / z = 329.2 [M-56] + .

[0195] Intermediate 1S (2-chloro-3-methoxyphenyl)-[(3S)-3-(hydroxymethyl)piperazine-1-yl]methanone Starting from enantiopurine tert-butyl(S)-2-(hydroxymethyl)piperazine-1-carboxylate, intermediate 1S was synthesized as described for intermediate 1.

[0196] Intermediate 2 (3R,9aS)-3-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine 2.52 g of tert-butyl(3R,9aS)-3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (6.8 mmol) was dissolved in 4 M HCl (17 ml, 68 mmol) in dioxane, and the solution was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was dissolved in 1 M aqueous HCl and washed with phenylethylamine. The aqueous solution was basicized with 4 M NaOH, causing turbidity, which was extracted with phenylethylamine. The organic layers were combined and dried over Na₂SO₄, and the solvent was removed under reduced pressure. 1.52 g of intermediate 2 was obtained as a waxy yellow solid and used directly in the next step. ESI (MS) m / z = 271.2 [M + H] +

[0197] a) 2-(3-chloro-4-fluorophenyl)oxirane 2-Chloro-1-fluoro-4-vinylbenzene (2.97 g, 19 mmol) was dissolved in DCM (100 ml) at 0°C, and then 3-chlorobenzoperoxoic acid (4.91 g, 28.5 mmol) was added. The mixture was slowly warmed to room temperature overnight. The reaction mixture was then washed once each with saturated aqueous Na2S2O3, NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and evaporated to dryness. The unpurified material was purified by flash chromatography (silica gel, 100 g, 0%-70% ethyl acetate in heptane) to obtain the product as a colorless liquid (2.57 g). The compound did not ionize by ESI (MS).

[0198] b) tert-butyl(3S)-4-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate 2-(3-chloro-4-fluorophenyl)oxirane (1.285 g, 7.45 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.42 g, 11.2 mmol) were dissolved in ethanol (20 mL), then placed in a sealed tube and heated in a microwave at 150°C for 40 minutes. The solvent was evaporated, and the unpurified substance was purified by flash chromatography (silica gel, 100 g, heptane, 10%-100% SiO(+10% EtOH)) to obtain 2.57 g of the desired product as a pale yellow oily substance. ESI(MS) m / z = 389.2 [M+H] +

[0199] c) tert-butyl(3R,9aS)-3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate 5.14 g, 13.2 mmol of tert-butyl(3S)-4-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (5.14 g, 13.2 mmol) was dissolved in anhydrous toluene (50 ml). The solution was transferred to an argon-purged flame-drying flask, and the solution was further degassed with argon. Subsequently, 5.58 g, 6.07 ml, 23.1 mmol of 2-(tributyl-15-phosphanylidene)acetonitrile (5.58 g, 6.07 ml, 23.1 mmol) was added all at once. The reaction mixture was stirred at 100°C for 1.5 hours. The reaction mixture was extracted with ethyl acetate / saturated NHCO3, the combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified material was purified twice by flash chromatography (silica gel, 100 g, 0%-100% ethyl acetate in heptane). The product fractions were combined and evaporated to obtain 2.53 g of the desired product as a light brown oil. ESI(MS)m / z=371.2[M+H] + The desired trans isomer (3R, 9aS) was the major product (ratio 4:1).

[0200] Intermediate 3 (9aS)-3-(3-bromo-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine 1.78 g, 4.29 mmol of tert-butyl(S)-3-(3-bromo-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate was dissolved in 21.4 ml of dioxane in 4 M HCl and stirred at room temperature for 120 minutes. The solvent was removed under reduced pressure, the residue was dissolved in 0.1 M HCl (aqueous solution), extracted with ethyl acetate, basicized with 4 M NaOH (aqueous solution), and re-extracted with EtOAC to obtain the product. The organic fractions were combined, dried over Na2SO4, and concentrated under reduced pressure to obtain 1.3 g of intermediate 3. No further purification was performed. ESI (MS) m / z = 315.1 [M + H] +

[0201] a) tert-butyl(S)-4-(2-(3-bromo-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate 2-(3-bromo-4-fluorophenyl)oxirane (1.0 g, 4.6 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (1.49 g, 6.91 mmol) were dissolved in ethanol (17 mL), then placed in a sealed tube and heated in a microwave at 130°C for 80 minutes and then at 150°C for 25 minutes to complete the reaction. The solvent was evaporated, and the unpurified substance was purified by flash chromatography (silica gel, 120 g, heptane with 0%-60% SiO(+10% EtOH)) to obtain 1.57 g of the desired product as a colorless oil. ESI(MS) m / z = 433.1 [M+H] + ]

[0202] b) tert-butyl(S)-3-(3-bromo-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate 3.2 g, 7.38 mmol of tert-butyl(S)-4-(2-(3-bromo-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate was dissolved in 50 ml of anhydrous toluene. The solution was transferred to an argon-purged flame-drying flask, and the solution was further degassed with argon. Subsequently, 3.12 g, 3.39 ml, 12.9 mmol of 2-(tributyl-15-phosphanylidene)acetonitrile was added all at once. The reaction mixture was stirred at 100°C for 1.5 hours. The reaction mixture was extracted with ethyl acetate / saturated NHCO3, the combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified material was purified by flash chromatography (silica gel, 100 g, 0%-60% ethyl acetate in heptane). The product fractions were combined and evaporated to obtain 1.8 g of the desired product as a waxy yellow solid. ESI(MS)m / z=415.2[M+H] + ]

[0203] Intermediate 4 (3R,9aS)-3-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine 350 mg, 944 μmol of tert-butyl 3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate was dissolved in 4.72 ml of dioxane in 4 M HCl and stirred at room temperature for 120 minutes. The solvent was removed under reduced pressure, the residue was dissolved in 0.1 M HCl (aqueous solution), extracted with ethyl acetate, basicized with 4 M NaOH (aqueous solution), and re-extracted with EtOAC to obtain the product. The organic fractions were combined, dried over Na2SO4, and concentrated under reduced pressure to obtain 243 mg of intermediate 4 as a waxy orange solid. No further purification was performed. ESI (MS) m / z = 285.2 [M + H] + ]

[0204] a) tert-butyl 4-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate 2-(3-chloro-4-fluorophenyl)oxirane (843 mg, 3.91 mmol) and tert-butyl 3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate (1 g, 3.91 mmol) were dissolved in ethanol (17 ml), then placed in a sealed tube and irradiated with microwaves at 140°C for 115 minutes and at 150°C for 20 minutes. Almost complete conversion occurred. The solvent was evaporated, and the residue was purified by flash chromatography (120 g of SiO2, heptane with 0%-80% ethyl acetate). The product fractions were combined and evaporated to obtain 950 mg of the desired product as a colorless, waxy solid. ESI (MS) m / z = 403.4 [M + H] + ]

[0205] b) tert-butyl 3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate 950 mg, 2.36 mmol of tert-butyl 4-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate was dissolved in 14.3 ml of anhydrous toluene. The solution was transferred to a flame-dried flask purged with argon, and the solution was further degassed with argon. Subsequently, 1.14 g, 1.24 ml, 4.72 mmol of 2-(tributyl-15-phosphanylidene)acetonitrile was added all at once. The reaction mixture was stirred at 100°C for 5 hours. The reaction mixture was extracted with ethyl acetate / saturated NHCO3, the combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified material was purified by flash chromatography (silica gel, 20 g, 0%-70% ethyl acetate in heptane). The product fractions were combined and evaporated to obtain 340 mg of the desired product as a viscous yellow oil. ESI(MS)m / z=385.3[M+H] +

[0206] Intermediate 5 [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[(3S)-3-(hydroxymethyl)piperazine-1-yl]methanone tert-butyl(S)-4-(2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate (0.151 g, 344 μmol) was combined with 4 M HCl (1.29 ml, 5.16 mmol) in dioxane to obtain a colorless solution. The reaction mixture was stirred at room temperature for 2 hours. This was then concentrated and dissolved in 10 ml of saturated NaHCO3, and extracted with ELISA (2 × 50 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the target compound as a colorless oil (117 mg). ESI (MS) m / z = 339.1 [M + H] + ]

[0207] a) Methyl 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoate Methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (849 mg, 2.86 mmol), 4-bromo-3-fluoro-1H-pyrazole (350 mg, 2.12 mmol), (APhos)2PdCl2 (150 mg, 212 μmol), and K2CO3 (880 mg, 6.36 mmol) were dispersed in 15 ml of dioxane and 4 ml of water, and degassed with argon. This was then reacted in a microwave (90°C, 30 min), followed by pouring into a saturated NaHCO3 solution, extraction twice with ethyl acetate, drying over Na2SO4, and concentration under reduced pressure. The unpurified substance was then purified by flash chromatography (silica gel, 50 g, heptane with 0%-50% ethyl acetate). The product fractions were combined and evaporated to obtain 201 mg of the desired product as a yellow solid. ESI(MS)m / z=255.1[M+H] + ]

[0208] b) 2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid To a 10 ml solution of THF containing methyl 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (326 mg, 1.28 mmol), 1 M LiOH (3.84 ml, 3.84 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was then acidified with 1 M aqueous HCl, extracted twice with 2-MeTHF, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 304 mg of the desired product as a yellow solid. ESI (MS) m / z = 241.1 [M + H] + ]

[0209] c) tert-butyl(S)-4-(2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoyl)-2-(hydroxymethyl)piperazine-1-carboxylate 2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (300 mg, 1.25 mmol), tert-butyl(S)-2-(hydroxymethyl)piperazine-1-carboxylate (200 mg, 0.925 mmol), and HATU (527 mg, 1.39 mmol) were dissolved in DMF (5 ml). DIPEA (359 mg, 2.77 mmol) was added, and the reaction mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then diluted with ethyl acetate, washed twice with saturated NaHCO3, and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, mixed with silica gel, and concentrated under reduced pressure. This was then purified by flash chromatography (silica gel, 20 g, 0%-10% MeOH in DCM), followed by reverse-phase column chromatography (HPLC preparative method F). The product was obtained as a white solid (151 mg). ESI (MS) m / z = 437.3 [MH] -

[0210] Intermediate 6 (3R,9aS)-3-(3-chloro-4-fluorophenyl)-4,6,7,8,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-3-ol tert-butyl(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1 equivalent, 2.356 g) was mixed with 4 M HCl in 27 ml of dioxane and 10 ml of dioxane. The resulting greenish slurry was stirred at room temperature. After 2.5 hours, the mixture was basicized with 4 M NaOH aqueous solution, extracted twice with phenylethylamine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was obtained as a yellowish-white foam (1.75 g) and used in the next step without further purification. ESI(MS)m / z=287.1[M+H] +

[0211] a) tert-butyl(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (1 equivalent, 1.52 g) and DIPEA (1.3 equivalents, 1.6 ml) were dissolved in 25 ml of THF. 2-bromo-1-(3-chloro-4-fluorophenyl)ethane-1-one (1 equivalent, 1.77 g) was added dropwise to 5 ml of THF at room temperature over 10 minutes. After 20 hours, the unpurified product was filtered, then adsorbed onto silica, concentrated under reduced pressure, and purified by silica column chromatography (70 g, heptane with 0%-70% SiO twice). The product was obtained as a yellowish-white foam (2.356 g). ESI (MS) m / z = 387.2 [M + H] + ]

[0212] Intermediate 7 2-Fluoro-5-[rac-(9aS)-1,3,4,6,7,8,9,9a-Octahydropyrazino[2,1-c][1,4]oxazin-3-yl]benzonitrile tert-butyl(9aS)-3-(3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (0.294 g, 813 μmol, impure) was dissolved in 0.5 mL of dioxane in 4 M HCl and stirred at room temperature for 1 hour. This was then concentrated under reduced pressure and used directly in the next step without further purification. ESI (MS) m / z = 262.2 [M + H] +

[0213] a) 2-Fluoro-5-vinylbenzonitrile 5-Bromo-2-fluorobenzonitrile (500 mg, 2.5 mmol), potassium trifluoro(vinyl)borate (402 mg, 3 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (102 mg, 125 μmol), and triethylamine (253 mg, 2.5 mmol) were dispersed in 12 ml of ethanol, degassed with argon, and reacted in a microwave (120°C, 20 min). The mixture was then concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica column chromatography (50 g, ethyl acetate in 0%-50% heptane). The product was obtained as a white solid (312 mg). The product was confirmed by 1H-NMR.

[0214] b) 2-fluoro-5-(oxilan-2-yl)benzonitrile 2-Fluoro-5-vinylbenzonitrile (0.15 g, 1.02 mmol) was dispersed in 2 ml of water and 1 ml of dioxane with vigorous stirring. NBS (218 mg, 1.22 mmol) was dissolved in 2 ml of water and 1 ml of dioxane and added dropwise to the mixture over 15 minutes. The reaction mixture was stirred overnight at room temperature. The mixture was then cooled to 0°C and 4 M NaOH aqueous solution (765 μl, 3.06 mmol) was added dropwise. After 1 hour, the reaction mixture was poured into 15 ml of saturated NaHCO3 aqueous solution and extracted with ELISA (2 × 25 mL). The organic layers were combined, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The target molecule was obtained as a yellow oil (153 mg) and used directly in the next step. The product was confirmed by 1H-NMR.

[0215] c) tert-butyl(3R)-4-(2-(3-cyano-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate 2-Fluoro-5-(oxiran-2-yl)benzonitrile (153 mg, 938 μmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (223 mg, 1.03 mmol) were dissolved in MeOH (4 ml) and reacted in a microwave (60 min, 120°C). The mixture was then concentrated under reduced pressure and purified by silica column chromatography (20 g, DCM with 0%-10% MeOH) to obtain 264 mg of the target compound as a yellow oily substance. ESI (MS) m / z = 380.2 [M+H] +

[0216] d) tert-butyl(9aR)-3-(3-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate tert-butyl(3S)-4-(2-(3-cyano-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (0.260 g, 685 μmol) and (cyanomethylene)tributylphosphorane (331 mg, 1.37 mmol) were dissolved in dry toluene (5 ml), degassed with argon, and then reacted at 100°C for 2 hours. The solution was then concentrated under reduced pressure and purified by silica column chromatography (20 g, DCM with 0%-10% MeOH). The desired product was obtained as a light brown oily substance (301 mg) along with residual tributylphosphine oxide. This was used in the next step without further purification. ESI (MS) m / z = 362.2 [M + H] +

[0217] Intermediate 8 (3R,9aS)-3-[6-(trifluoromethyl)-3-pyridyl]-4,6,7,8,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-3-ol 150 mg, 0.372 mmol of tert-butyl(7R,9aR)-7-hydroxy-7-(6-(trifluoromethyl)pyridine-2-yl)octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate was mixed with 6 ml of 4M HCl and 5 ml of dioxane in 6 ml of dioxane and stirred at room temperature. After 4 hours, the mixture was concentrated under reduced pressure, basicized with 4M NaOH aqueous solution, diluted in brine, and extracted with excess siRNA, then with 2-MeTHF. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was obtained as an impure orange oil (165 mg). This was used in the next step without further purification. ESI (MS) m / z = 304.2 [M + H] +

[0218] a) 2-bromo-1-(6-(trifluoromethyl)pyridine-2-yl)ethane-1-one 1-(5-(trifluoromethyl)pyridine-2-yl)ethane-1-one (224 mg, 1.19 mmol), bromine (61 μl, 1.19 mmol), and acetic acid (1.2 ml) were mixed in a pressure tube and reacted at 75°C for 1 hour. The red solution changed to a yellow suspension. This was concentrated under reduced pressure and purified by silica column chromatography (20 g, in heptane, 0%~40% ethyl acetate). The target compound was isolated as a white solid (240 mg). ESI (MS) m / z = 270.0 [M+H] +

[0219] b) tert-butyl(7R,9aR)-7-hydroxy-7-(6-(trifluoromethyl)pyridine-2-yl)octahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate 97 mg, 0.45 mmol of tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate and 97 μl, 0.55 mmol of DIPEA were dissolved in 2 ml of THF and cooled to 0°C. 114 mg, 0.425 mmol of 2-bromo-1-(6-(trifluoromethyl)pyridine-2-yl)ethane-1-one (114 mg, 0.425 mmol) was added dropwise to 1.5 mL of THF over 10 minutes. After 30 minutes, the solution was warmed to room temperature, and after 4 hours, the solution was diluted with water and extracted with ethyl acetate. The aqueous layer was dried over Na₂SO₄, filtered, concentrated under reduced pressure, and purified by silica column chromatography (20 g, heptane, 0%-70% ethyl acetate). The product was obtained as a white solid (150 mg). ESI (MS) m / z = 404.2 [M + H] + ]

[0220] Intermediate 9 (3S,9aS)-3-[5-(trifluoromethyl)-2-pyridyl]-4,6,7,8,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-3-ol Synthesized according to Intermediate 8. ESI(MS)m / z=304.2[M+H] + a) tert-butyl(3S,9aS)-3-hydroxy-3-(5-(trifluoromethyl)pyridine-2-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate 2-Chloro-1-(5-(trifluoromethyl)pyridine-2-yl)ethane-1-one (473 mg, 2.12 mmol), tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (503 mg, 2.33 mmol), and DIPEA (480 μl, 2.75 mmol) were dissolved in 10 mL of dry THF and stirred at 50°C overnight, then at 60°C for 24 hours. The mixture was then concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered, and concentrated again under reduced pressure. The unpurified product was purified by silica column chromatography (50 g, ethyl acetate in heptane at 0%-80%). The target compound was obtained as a grayish-white solid (437 mg). ESI (MS) m / z = 404.2 [M+H] +

[0221] Intermediate 10 (3R,9aS)-3-(3,4-difluorophenyl)-4,6,7,8,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-3-ol hydrochloride Starting with 2-bromo-1-(3,4-difluorophenyl)ethane-1-one (500 mg, 2.13 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (506 mg, 2.34 mmol), the synthesis proceeded according to intermediate 8. Intermediate 10 was obtained as a pale blue solid (596 mg, 1.94 mmol). ESI (MS) m / z = 271.2 [M + H] + ]

[0222] Intermediate 11 (3S,9aS)-3-[6-(trifluoromethyl)pyridazin-3-yl]-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine 266 mg of tert-butyl(9aS)-3-(6-(trifluoromethyl)pyridazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (approximately 50% purity, 0.34 mmol) was dissolved in 1.5 mL of dioxane and 3 mL of dioxane in 4 M HCl and stirred at room temperature. After 90 minutes, the red mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography (HPLC preparative method E). The desired diastereomer was obtained as a white solid (50 mg). ESI (MS) m / z = 289.2 [M + H] +

[0223] a) 3-(trifluoromethyl)-6-vinylpyridazine Starting with 3-chloro-6-(trifluoromethyl)pyridazine (800 mg, 4.38 mmol), the synthesis proceeded according to intermediate 7a). ESI (MS) m / z = 175.0 [M + H] +

[0224] b) 3-(oxiran-2-yl)-6-(trifluoromethyl)pyridazine 3-(trifluoromethyl)-6-vinylpyridazine (592 mg, 3.4 mmol) was dispersed in 6 ml of dioxane and 6 ml of water and cooled to 0°C. NBS (726 mg, 4.08 mmol) dissolved in 6 ml of dioxane and 12 ml of water was added dropwise over 15 minutes, the flask was warmed to room temperature, and after 2 hours it was cooled again to 0°C. NaOH (2.55 mL of 4 M aqueous solution, 10.2 mmol) was added dropwise, and after 30 minutes the flask was warmed to room temperature. After another 30 minutes, the mixture was further diluted with saturated NaHCO3 aqueous solution containing NaCl, extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated under reduced pressure. The unpurified product was purified by silica column chromatography (50 g, ethyl acetate in heptane, 0%~50%) to obtain 272 mg of the product as a light brown solid. ESI(MS)m / z=191.0[M+H] + ]

[0225] c) tert-butyl(3S)-4-(2-hydroxy-2-(6-(trifluoromethyl)pyridazin-3-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate Synthesized according to intermediate 7c). ESI(MS)m / z=407.2[M+H] + ]

[0226] d) tert-butyl(9aS)-3-(6-(trifluoromethyl)pyridazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate Synthesized according to intermediate 7d). ESI(MS)m / z=389.2[M+H] +

[0227] Intermediate 12 3-[(3R,9aS)-3-hydroxy-4,6,7,8,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridine-2-one 527 mg of tert-butyl(3R,9aS)-3-hydroxy-3-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (70% purity, 0.88 mmol) was mixed with 1.6 ml of dioxane and 4.4 ml of 4M HCl in dioxane, and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, basicized with 4M NaOH aqueous solution, diluted with saline solution, extracted with excess ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was then purified by reverse-phase column chromatography (HPLC preparative method). The product was obtained as a pale yellow solid (22.3 mg). ESI (MS) m / z = 320.1 [M + H] +

[0228] a) tert-butyl(3R,9aS)-3-hydroxy-3-(2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate Starting from 3-(2-bromoacetyl)-6-(trifluoromethyl)pyridine-2(1H)-one (400 mg, 1.41 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (335 mg, 1.55 mmol), the compound was synthesized according to intermediate 8b). ESI(MS)m / z=420.3[M+H] +

[0229] Intermediate 13 2-Chloro-3-(5-methyl-1H-pyrazole-4-yl)benzoic acid i) Methyl 3-bromo-2-chlorobenzoate (400 mg, 1.6 mmol), 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.4 mmol), and K3PO4 (4.81 ml of 1 M aqueous solution, 4.81 mmol) were degassed with argon in a microwave vial of THF (3.2 ml). XPhos-Pd-G2 (126 mg, 160 μmol) was added, and the mixture was heated at 100°C for 2 hours. After concentration under reduced pressure, the mixture was purified by flash chromatography (SiO2, Hep / siRNA 35-90% for 40 minutes) to obtain the desired purified product as an orange waxy solid (122 mg, 30%). ESI (MS) m / z = 251.2 [M + H] + ]

[0230] ii) To a solution of methyl 2-chloro-3-(5-methyl-1H-pyrazole-4-yl)benzoate (167 mg, 666 μmol) in THF (3.5 ml), a 1 M aqueous solution of LiOH (1.33 ml, 1.33 mmol) was added, and the resulting mixture was stirred overnight at 22°C. This was then acidified with 1 M HCl, the aqueous layer was extracted with 2-MeTHF, washed with saline solution, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The product was obtained as an orange, viscous oil (142 mg, 90%). ESI (MS) m / z = 237.2 [M + H] +

[0231] Intermediate 14 2-Chloro-3-(4-methyl-3-pyridyl)benzoic acid i) In a microwave vial, methyl 3-bromo-2-chlorobenzoate (200 mg, 802 μmol), (4-methylpyridine-3-yl)boronic acid (137 mg, 1 mmol), and K2CO3 (276 mg, 2.4 mmol) were mixed with dioxane (6 ml) and degassed with argon. (A- ta Phos)2PdCl2 (56.8 mg, 80.2 μmol) was added, and the mixture was heated at 80°C for 15 hours. After concentration under reduced pressure, the residue was purified by flash chromatography (SiO2, Hep / Â 30-90% for 30 minutes) to obtain the desired product as a yellow waxy solid (105 mg, 50%) ESI(MS) m / z = 262.2 [M+H]. +

[0232] ii) To a solution of methyl 2-chloro-3-(4-methylpyridine-3-yl)benzoate (120 mg, 459 μmol) in THF (2.5 ml), a 1 M aqueous solution of LiOH (923 μl, 923 μmol) was added, and the resulting mixture was stirred overnight at 22°C. 3 mL of toluene was added, and the mixture was concentrated under reduced pressure. The yield was not calculated, and this was used in the next step without further purification. ESI (MS) m / z = 248.1 [M + H] +

[0233] Intermediate 15 2-Chloro-3-(3-methyl-4-pyridyl)benzoic acid Synthesized according to intermediate 14. ESI(MS)m / z=248.1[M+H] + ]

[0234] Intermediate 16 2-Chloro-3-(pyridazine-4-yl)benzoic acid Synthesized according to intermediate 14. ESI(MS)m / z=235.2[M+H] + ]

[0235] Intermediate 17 2-Chloro-3-(pyridine-2-yl)benzoic acid i) In a microwave vial, methyl 3-bromo-2-chlorobenzoate (200 mg, 802 μmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (329 mg, 1.6 mmol), Cs2CO3 (522 mg, 1.6 mmol), and copper(I) chloride (79.4 mg, 802 μmol) were dissolved in DMF (8.02 ml) and degassed with argon. XPhos Pd G2 (44.2 mg, 56.1 μmol) was added, and the mixture was reacted at 100°C for 16 hours. After concentration under reduced pressure, the mixture was purified by flash chromatography (SiO2, Hep / siRNA 30-90% for 30 minutes) to obtain the desired product as a pale yellow waxy solid (35 mg, 18%). ESI (MS) m / z = 248.2 [M + H] + ii) According to intermediate 13, ii), the composite ESI(MS) m / z = 234.1 [M + H] +

[0236] Intermediate 18 2-Chloro-3-(pyridazine-3-yl)benzoic acid i) In a microwave vial, methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (215 mg, 725 μmol), 3-chloropyridazine hydrochloride (230 mg, 1.52 mmol), and K2CO3 (411 mg, 2.97 mmol) were mixed with dioxane (4.5 ml) and degassed with argon. (A-taPhos)2PdCl2 (51.3 mg, 72.5 μmol) was added, and the mixture was reacted at 80°C for 80 minutes. After concentration under reduced pressure, the mixture was purified by flash chromatography (SiO2, Hep / Âde 30-100% for 30 minutes) to obtain the desired product as a pale yellow waxy solid (24 mg, 13%). ESI (MS) m / z = 249.1 [M + H] + ii) According to intermediate 13, ii), the composite ESI(MS) m / z = 235.1 [M + H] +

[0237] Intermediate 19 2-Chloro-3-(4-methylpyridazine-3-yl)benzoic acid i) In a microwave vial, methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (219 mg, 739 μmol), 3-chloro-4-methylpyridazine (95 mg, 739 μmol), and K2CO3 (204 mg, 1.48 mmol) were mixed with toluene (2.1 ml) and water (0.23 mL) and degassed with argon. (A-taPhos)2PdCl2 (52.3 mg, 73.9 μmol) was added, and the mixture was reacted at 120°C for 30 minutes. After concentration under reduced pressure, the mixture was purified by flash chromatography (SiO2, Hep / Âde 30-100% for 35 minutes) to obtain the desired product as a yellow waxy solid (30 mg, 16%). ESI (MS) m / z = 263.2 [M + H] + ii) According to intermediate 13, ii), the composite ESI(MS) m / z = 249.1 [M + H] +

[0238] Intermediate 20 2-Chloro-3-(5-methylpyrimidine-4-yl)benzoic acid i) A microwave vial was filled with methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (200 mg, 674 μmol), 4-chloro-5-methylpyrimidine (104 mg, 809 μmol), K2CO3 (186 mg, 1.35 mmol), and toluene (2.25 ml), and degassed with argon. (A- ta Phos)2PdCl2 (47.8 mg, 67.4 μmol) was added, and the mixture was heated at 120°C for 30 minutes. This mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, DCM, 0-10% MeOH), but a completely pure product could not be obtained. The mixture was re-purified with a Hep / siRNA gradient from 0-60%, and the desired product was obtained as a yellow oil (130 mg, 73%). ESI (MS) m / z = 263.2 [M + H] +

[0239] ii) Synthesized according to intermediate 13. ESI(MS)m / z=249.1[M+H] +

[0240] Intermediate 21 2-Chloro-3-(1H-imidazole-4-yl)benzoic acid i) In a microwave vial, methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (300 mg, 1.01 mmol), 4-iodo-1H-imidazole (196 mg, 1.01 mmol), and K2CO3 (2.53 ml, 3.03 mmol) were mixed with dioxane (7.5 ml) and water (2.5 ml), and degassed with argon. (APhos)2PdCl2 (71.6 mg, 101 μmol) was added, and the mixture was reacted at 115°C for 30 minutes. After concentration under reduced pressure, the mixture was purified by flash chromatography (SiO2, DCM / MeOH 0-10% for 35 minutes), followed by reverse-phase column chromatography to obtain the desired product as a white solid (60.1 mg, 25%). ESI (MS) m / z = 237.2 [M + H] + ii) Synthesized according to intermediate 13. ESI(MS)m / z=223.1[M+H] +

[0241] Intermediate 22 2-Chloro-3-(3-methylpyridine-2-yl)benzoic acid i) Synthesized according to intermediate 19,i). ESI(MS)m / z=262.2[M+H] + ] ii) Synthesized according to intermediate 13,ii). ESI(MS)m / z=248.2[M+H] +

[0242] Intermediate 23 2-Chloro-3-(1H-pyrazole-4-yl)benzoic acid i) In a microwave vial, methyl 3-bromo-2-chlorobenzoate (300 mg, 1.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (350 mg, 1.8 mmol), and K2CO3 (3.01 ml, 3.61 mmol) were mixed with dioxane (9 ml) and water (3 ml), and degassed with argon. (APhos)2PdCl2 (85.1 mg, 120 μmol) was added, and the mixture was reacted at 115°C for 30 minutes. After concentration under reduced pressure, the mixture was purified by flash chromatography (SiO2, DCM / MeOH 0-8% for 35 minutes), followed by reverse-phase column chromatography to obtain the desired product as a white solid (34 mg, 12%). ESI (MS) m / z = 237.2 [M + H] + ii) Synthesized according to intermediate 13,ii). ESI(MS)m / z=223.1[M+H] +

[0243] Intermediate 24 2-Chloro-3-(1,5-dimethyl-1H-pyrazole-4-yl)benzoic acid i) In a microwave vial, methyl 2-chloro-3-(5-methyl-1H-pyrazole-4-yl)benzoate (described in intermediate 13i), 70 mg, 279 μmol, and Cs2CO3 (136 mg, 419 μmol) were dissolved in DMF (2 ml), treated with methyl iodide (198 mg, 1.4 mmol), and then reacted at 100°C for 15 minutes. The reaction product was then diluted with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by flash chromatography (SiO2, Hep / siRNA 0-100%) to obtain the desired product as a yellow oil (23 mg, 31%). ESI (MS) m / z = 265.2 [M + H] + ] ii) Synthesized according to intermediate 13,ii). ESI(MS)m / z=251.2[M+H] +

[0244] Intermediate 25 2-Chloro-3-(3-methylisoxazole-4-yl)benzoic acid i) In a microwave vial, methyl 3-bromo-2-chlorobenzoate (200 mg, 802 μmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoxazole (251 mg, 1.2 mmol), and K3PO4 (1.6 ml of 1 M aqueous solution, 1.6 mmol) were mixed with THF (1.6 ml) and degassed with argon. XPhos-Pd-G2 (44.2 mg, 56.1 μmol) was added, and the mixture was reacted at 60°C for 1 hour. After concentration under reduced pressure, the mixture was purified by flash chromatography (SiO2, Hep / siRNA 0-40% for 35 minutes) to obtain the desired product as a yellow oil (171 mg, 85%). ESI (MS) m / z = 252.1 [M + H] + ii) Synthesized according to intermediate 13,ii). ESI(MS)m / z=238.1[M+H] +

[0245] Intermediate 26 2-Chloro-3-(2-oxa-6-azaspiro[3,3]heptan-6-yl)benzoic acid i) In a pressure vial, methyl 3-bromo-2-chlorobenzoate (250 mg, 1 mmol), 2-oxa-6-azaspiro[3.3]heptane (199 mg, 2 mmol), K3PO4 (425 mg, 2 mmol), Pd2(dba)3 (91.8 mg, 100 μmol), and DavePhos (59.2 mg, 150 μmol) were mixed with toluene (4 ml) and then degassed with argon. The mixture was then reacted at 100°C for 16 hours, followed by concentration under reduced pressure. Purification by flash chromatography (SiO2, Hep / siRNA 0-45%) yielded the desired product as a dark red oily substance (210 mg, 78%). ESI(MS) m / z = 268.3 [M+H] + ]

[0246] ii) To a solution of methyl 2-chloro-3-(2-oxa-6-azaspiro[3,3]heptan-6-yl)benzoate (210 mg, 784 μmol) in THF (5 ml), a 1 M aqueous solution of LiOH (1.57 ml, 1.57 mmol) was added, and the resulting mixture was stirred at 22°C overnight, then at 50°C for 4 hours. The mixture was acidified with 1 M HCl, the aqueous layer was extracted with 2-MeTHF, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The product was obtained as a pale yellow solid, 233 mg (94%, purity 80%). This was used directly in the next step. ESI (MS) m / z = 254.2 [M + H] +

[0247] Intermediate 27 2-Chloro-3-morpholinobenzoic acid i) Synthesized according to intermediate 26,i). ESI(MS)m / z=256.2[M+H] + ii) Synthesized according to intermediate 26,ii). ESI(MS)m / z=242.2[M+H] +

[0248] Intermediate 28 2-Chloro-3-(1H-1,2,3-triazol-4-yl)benzoic acid Ester cleavage was performed according to intermediate 13,ii). ESI(MS)m / z=224.1[M+H] + ]

[0249] a) Methyl 2-chloro-3-((trimethylsilyl)ethynyl)benzoate Methyl 3-bromo-2-chlorobenzoate (800 mg, 3.21 mmol), PdCl2 (DPPF) (262 mg, 321 μmol), and copper(I) iodide (30.5 mg, 160 μmol) were dissolved in dry DMF (2 ml), and diethylamine (11.7 g, 160 mmol) was added. The reaction mixture was degassed with argon, and ethynyltrimethylsilane (472 mg, 4.81 mmol) was added. The mixture was then reacted at 120°C for 30 minutes under microwave irradiation. This mixture was then concentrated under reduced pressure and purified by flash chromatography (SiO2, Hep / Â50%) to obtain the desired product as a yellow liquid (580 mg, 68%). The product was confirmed by 1H-NMR.

[0250] b) Methyl 2-chloro-3-ethynylbenzoate Methyl 2-chloro-3-((trimethylsilyl)ethynyl)benzoate (270 mg, 1.01 mmol) was dissolved in THF (4 ml) and MeOH (4 ml), and potassium carbonate (559 mg, 4.05 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, and then residual potassium carbonate was removed by filtration, followed by removal of the solvent under reduced pressure. The unpurified pale red solid product (200 mg, 100%) was used in the next step without further purification. ESI (MS) m / z = 195.0 [M + H] +

[0251] c) Methyl 2-chloro-3-(1H-1,2,3-triazol-4-yl)benzoate In a microwave vial, copper(I) iodide (9.79 mg, 51.4 μmol), methyl 2-chloro-3-ethynylbenzoate (200 mg, 1.03 mmol), and azidotrimethylsilane (317 mg, 2.57 mmol) were suspended in DMF (3.6 ml) and MeOH (0.6 ml). The mixture was degassed with argon, then stirred at 100°C for 7 hours, concentrated under reduced pressure, and purified by flash chromatography (SiO2, Hep / Â 10-70%) to obtain the desired product as a pale yellow solid (185 mg, 76%) ESI (MS) m / z = 238.2 [M+H]. +

[0252] Intermediate 29 2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid i) Synthesized according to intermediate 21,i). ESI(MS)m / z=255.2[M+H] + ] ii) Synthesized according to intermediate 13,ii). ESI(MS)m / z=241.1[M+H] +

[0253] Intermediate 30 2-Chloro-2'-methoxy-[1,1'-biphenyl]-3-carboxylic acid i) Methyl 3-bromo-2-chlorobenzoate (150 mg, 601 μmol), (2-methoxyphenyl)boronic acid (119 mg, 782 μmol), and K3PO4 (255 mg, 1.2 mmol) in THF (1.2 ml) were degassed with argon in a microwave vial. XPhos-Pd-G2 (23.7 mg, 30.1 μmol) was added, and the mixture was reacted at 60°C for 35 minutes. After dilution with water, extraction with butyl, drying, concentration under reduced pressure, and purification by flash chromatography (SiO2, Hep / butyl 0-30%) yielded the desired product as a brown oily substance (131 mg, 79%). ESI (MS) m / z = 277.1 [M + H] +

[0254] ii) Synthesized according to intermediate 13,ii). ESI(MS)m / z=263.1[M+H] +

[0255] Intermediate 31 2-Chloro-3-(3-hydroxyazetidine-1-yl)lithium benzoate i) In a sealed tube, methyl 3-bromo-2-chlorobenzoate (CAS RN 871224-19-0, 0.1 g, 0.401 mmol), cesium carbonate (0.261 g, 0.802 mmol), Pd2(dba)3 (0.037 g, 0.040 mmol), and xanthophos (23.2 mg, 40.1 μmol) were mixed in dioxane (1 mL). The mixture was degassed with argon, and then azetidine-3-ol (CAS RN 45347-82-8, 0.059 g, 0.802 mmol) was added, and the reaction mixture was heated at 100 °C for 16 hours. The mixture was diluted with siRNA and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0%-50% ethyl ammonium in heptane) to obtain methyl 2-chloro-3-(3-hydroxyazetidine-1-yl)benzoate (0.034 g, 35%) as an orange, viscous oil. MS(ESI): m / z = 242.1[M+H] + .

[0256] ii) To a solution of methyl 2-chloro-3-(3-hydroxyazetidine-1-yl)benzoate (0.035 g, 0.145 mmol) in THF (0.35 mL), 1 M LiOH aqueous solution (0.29 mL, 290 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, the residue was pulverized in diisopropyl ether, filtered, and further dried under high vacuum to obtain the unpurified labeled compound (0.032 g, 82%) as a lithium salt, as a light brown solid. MS(ESI): m / z = 228.1 [M + H] + .

[0257] Intermediate 32 2-Chloro-3-(oxazol-5-yl)benzoic acid i) Methyl 3-bromo-2-chlorobenzoate (300 mg, 1.2 mmol), oxazole (166 mg, 2.4 mmol), palladium acetate (13.5 mg, 0.06 mmol), potassium carbonate (500 mg, 3.61 mmol), pivalic acid (49 mg, 0.48 mmol), and di-tert-butyl (2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphane (58 mg, 0.12 mmol) were dispersed in 6.6 mL of DMA, degassed with argon, and reacted at 110°C for 15 hours. After the reaction was complete, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (ethyl acetate / heptane 0% to 50%). The product was obtained as a pale yellow solid (89 mg, purity approximately 75%, yield 23%). MS(ESI): m / z = 238.1[M+H] +

[0258] ii) Synthesized according to intermediate 14,ii). ESI(MS)(m / z) = 224.0[M+H] + ]

[0259] Intermediate 33 2-Fluoro-3-(3-Fluoro-1H-pyrazole-4-yl)benzoic acid i) Following intermediate 21 i), starting with 4-bromo-3-fluoro-1H-pyrazole and methyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 49% methyl 2-fluoro-3-(3-fluoro-1H-pyrazole-4-yl)benzoate was obtained as a yellow solid. MS(ESI): m / z = 239.1[M+H] +

[0260] ii) Synthesized according to intermediate 14,ii). MS(ESI): m / z = 225.1[M+H] +

[0261] Intermediate 34 2-Chloro-3-(3-cyano-1H-pyrazole-4-yl)benzoic acid i) Following intermediate 21 i), starting from 4-bromo-1H-pyrazole-3-carbonitride and methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, methyl 2-chloro-3-(3-cyano-1H-pyrazole-4-yl)benzoate was obtained as a red solid. m / z = 260.1 [MH] -

[0262] ii) Synthesized according to intermediate 14,ii). m / z = 246.1 [MH] -

[0263] Intermediate 35A / 35B [(3R,9aS)-3-(2-benzyloxy-5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone and [(3S,9aS)-3-(2-benzyloxy-5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone

[0264] ((3S)-4-(2-(2-(benzyloxy)-5-chloropyridine-3-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazin-1-yl)(2-chloro-3-methoxyphenyl)methanone (197 mg, 361 μmol) and 2-(tributyl-15-phosphanylidene)acetonitrile (174 mg, 721 μmol) were dissolved in 2.5 mL of dry toluene, degassed, and heated to 110°C. After 5 hours, the solution was concentrated under reduced pressure and purified by silica column chromatography (EA in heptane). Both diastereomers were separated.

[0265] Intermediate 35A (the first diastereomer to elute) was obtained as a brownish oily substance (44.7 mg, 23.5%). ESI (MS) m / z = 528.2 [M + H]+

[0266] Intermediate 35B (the second diastereomer to elute) was obtained as a brownish oily substance (31.6 mg, 16.6%). ESI (MS) m / z = 528.2 [M + H] + a) 2-(benzyloxy)-3-bromo-5-chloropyridine 3-Bromo-5-chloropyridine-2(1H)-one (600 mg, 2.88 mmol), silver carbonate (1.06 g, 3.84 mmol), and benzyl bromide (591 mg, 3.45 mmol) were weighed in a round-bottom flask lined with aluminum in the dark and mixed with 5 ml of toluene. The mixture was reacted at 50°C. After 28 hours, the mixture was cooled to room temperature, filtered, washed with saturated bicarbonate aqueous solution, and then washed twice with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The unpurified residue was purified by silica column chromatography (Â / heptane 0%~50%), and the target compound was isolated as a white solid (895 mg, 95%). MS(ESI): m / z = 300.0[M+H]+.

[0267] b) 2-(benzyloxy)-5-chloro-3-vinylpyridine 2-(benzyloxy)-3-bromo-5-chloropyridine (595 mg, 1.99 mmol), potassium trifluoro(vinyl)borate (320 mg, 2.39 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (82 mg, 0.1 mmol), and triethylamine (202 mg, 1.99 mmol) were dispersed in 15 ml of EtOH and degassed with argon. This was reacted in a microwave (120°C, 20 mins), then concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over Na2SO4, filtered, adsorbed onto silica, and concentrated under reduced pressure. This was purified by silica column chromatography (ethyl acetate / heptane 0%~10%). The product was isolated as a colorless oil and, upon standing, changed to a white solid (443 mg, 91%). MS(ESI): m / z = 246.1[M+H]+.

[0268] c) 2-(benzyloxy)-5-chloro-3-(oxiran-2-yl)pyridine i) Synthesize intermediate 7 according to step b). MS(ESI): m / z = 262.1[M+H]+.

[0269] d)((3S)-4-(2-(2-(benzyloxy)-5-chloropyridine-3-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-yl)(2-chloro-3-methoxyphenyl)methanone 2-(benzyloxy)-5-chloro-3-(oxiran-2-yl)pyridine (365 mg, 1.39 mmol) and (S)-(2-chloro-3-methoxyphenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 1S, 437 mg, 1.53 mmol) were dissolved in 2.5 ml of THF and 2.5 ml of EtOH and reacted in a microwave (120°C, 70 min), then reacted again (130°C, 30 min). The mixture was then concentrated under reduced pressure and purified by silica column chromatography (MeOH 0%~10% in DCM). ((3S)-4-(2-(2-(benzyloxy)-5-chloropyridine-3-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-yl)(2-chloro-3-methoxyphenyl)methanone was isolated as a yellow oil (197 mg, 26%). ESI(MS)m / z=546.2[M+H] +

[0270] Intermediate 36 2-(3-bicyclo[4.2.0]octa-1(6),2,4-trienyl)oxirane 3-Vinylbicyclo[4.2.0]octa-1,3,5-triene (170 mg, 1.31 mmol) was dissolved in 2.4 ml of DCM. Methyltrioxorenium (3.2 mg, 0.013 mmol) and 1H-pyrazole (10.7 mg, 0.157 mmol) were added. The purple solution was cooled to 0°C, and hydrogen peroxide (225 μl of 35% aqueous solution, 2.61 mmol) was added, causing the solution to turn yellow. This was stirred vigorously for 60 minutes. A small amount of manganese dioxide particles were added, and after no more bubbles were observed, the reaction mixture was diluted with saturated bicarbonate aqueous solution and extracted twice in DCM. This was then dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by silica column chromatography (siRNA / heptane 0%-10%). The product was obtained as a colorless oil (132 mg, 69%). The structure was confirmed by 1H-NMR.

[0271] Intermediate 37

[0272] 4,5-Dichloro-2-(oxiran-2-yl)pyridine Intermediate 7, following step b), the process started with 4,5-dichloro-2-vinylpyridine. ESI(MS): m / z = 190.0[M+H] + a) 4,5-Dichloro-2-vinylpyridine 2-Bromo-4,5-dichloropyridine (500 mg, 2.2 mmol), potassium vinyl trifluoroborate (1.2 equivalents, 354 mg), a complex of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (0.05 equivalents, 90 mg), and TEA (307 μL, 2.2 mol) were dispersed in 12 mL of ethanol in a large microvape vial. The mixture was degassed with argon and heated in a microwave (120°C, 20 min). This was then concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was purified by silica column chromatography (in heptane, ethyl acetate 0%-50%). The product was obtained as a pale yellow oily substance (278 mg, 73%). 1This was confirmed by 1H-NMR.

[0273] Intermediate 38 (9aS)-3-(5-bromopyridine-2-yl)octahydropyrazino[2,1-c][1,4]oxazine hydrochloride Boc deprotection was performed according to intermediate 7, tert-butyl(9aS)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylate. ESI(MS): m / z = 300.0[M+H]+. a) tert-butyl(3S)-4-(2-(5-bromopyridine-2-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate 5-Bromo-2-(oxiran-2-yl)pyridine (44 mg, 0.22 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (52 mg, 0.242 mmol) were dissolved in 1.5 ml of MeOH and reacted in microwaves (60 minutes, 120°C). The mixture was then concentrated under reduced pressure and purified by silica column chromatography (MeOH / DCM 0%~10%). The product was isolated as a slightly yellowish oily substance (60 mg, 66%). ESI (MS): m / z = 418.2 [M+H] +

[0274] b) tert-butyl(9aS)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylate 60 mg, 0.144 mmol of tert-butyl(3S)-4-(2-(5-bromopyridine-2-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate and 69 mg, 0.288 mmol of (cyanomethylene)tributylphosphoran were dissolved in 1 ml of dry toluene. The solution was degassed with argon and then heated to 100°C. After 2 hours, it was concentrated under reduced pressure and purified by silica column chromatography (MeOH / DCM 0%~10%). The product was obtained as a brown oily substance (39 mg, purity approximately 30%, yield 20%) and used in the next step without further purification. MS(ESI): m / z = 398.2[M+H] +

[0275] Intermediate 39

[0276] 5-Chloro-4-methyl-2-(oxiran-2-yl)pyridine Intermediate 7, following step b, starts from 5-chloro-4-methyl-2-vinylpyridine. MS(ESI): m / z = 170.0 [M + H] + a) 5-Chloro-4-methyl-2-vinylpyridine Intermediate 7, following step a, starts from 2,5-dichloro-4-methylpyridine. MS(ESI): m / z = 154.0[M+H]+.

[0277] Intermediate 40 5-Chloro-2-(oxiran-2-yl)-4-(trifluoromethyl)pyridine Intermediate 7, following step b, starts from 5-chloro-4-(trifluoromethyl)-2-vinylpyridine. The structure was confirmed by 1H-NMR. a) 5-Chloro-4-(trifluoromethyl)-2-vinylpyridine Intermediate 7, following step a, starts from 2,5-dichloro-4-(trifluoromethyl)pyridine. Its structure was confirmed by 1H-NMR.

[0278] Intermediate 41 2-(oxiran-2-yl)-4-(trifluoromethoxy)pyridine Intermediate 7, following step b, starts from 4-trifluoromethoxy-2-vinylpyridine. MS(ESI): m / z = 206.0[M+H]+ a) 4-trifluoromethoxy-2-vinylpyridine Intermediate 7, following step a, starts from 2-chloro-4-(lifluoromethoxy)pyridine. MS(ESI): m / z = 190.0[M+H]+.

[0279] Intermediate 42 5-Fluoro-2-(oxiran-2-yl)-4-(trifluoromethyl)pyridine Intermediate 7, following step b, starts from 5-fluoro-4-(trifluoromethyl)-2-vinylpyridine. The structure was confirmed by 1H-NMR. a) 5-Fluoro-4-(trifluoromethyl)-2-vinylpyridine Intermediate 7, following step a, starts from 2-chloro-5-fluoro-4-(trifluoromethyl)pyridine. Its structure was confirmed by 1H-NMR.

[0280] Intermediate 43

[0281] 5-Chloro-4-(difluoromethyl)-2-(oxiran-2-yl)pyridine Intermediate 7, following step b, starts from 5-chloro-4-(difluoromethyl)-2-vinylpyridine. MS(ESI): m / z = 206.0 [M + H] + a) 5-Chloro-4-(difluoromethyl)-2-vinylpyridine Intermediate 7, following step a, starts with 2,5-dichloro-4-(difluoromethyl)pyridine. After silica column chromatography, the solvent was not completely removed due to suspected volatility of the compound. MS(ESI): m / z=189.9[M+H] +

[0282] Intermediate 44

[0283] 4-Bromo-5-chloro-2-(oxiran-2-yl)pyridine Intermediate 7, following step b, starts from 4-bromo-5-chloro-2-vinylpyridine. MS(ESI): m / z = 236.0 [M + H] + a)-Bromo-5-chloro-2-vinylpyridine Intermediate 7, following step a, starts with 2,4-dibromo-5-chloropyridine. After silica column chromatography, the solvent was not completely removed due to suspected volatility of the compound. MS(ESI): m / z=219.9[M+H] +

[0284] Intermediate 45 2-Fluoro-3-(5-(trifluoromethyl)-1H-pyrazole-4-yl)benzoic acid Intermediate 13, following step ii), starts with methyl 2-fluoro-3-(5-(trifluoromethyl)-1H-pyrazole-4-yl)benzoate. MS(ESI): m / z = 275.1[M+H]+.

[0285] a) Methyl 2-fluoro-3-(5-(trifluoromethyl)-1H-pyrazole-4-yl)benzoate Methyl 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (CAS 1638847-77-4, 292 mg, 75% purity, 0.7 mmol), 4-bromo-5-(trifluoromethyl)-1H-pyrazole (168 mg, 0.78 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (55 mg, 0.078 mmol), and K2CO3 (324 mg, 2.35 mmol) were mixed with 4.5 ml of dioxane and 1.5 ml of water, degassed with argon, and reacted in a microwave (115°C, 30 minutes). This was diluted with water, extracted twice with ethyl acetate, dried over Na2SO4, filtered, adsorbed onto silica, concentrated under reduced pressure, and purified by silica column chromatography (20 g, ethyl acetate / heptane 0%-40%). The desired product was isolated as a yellow oil (123 mg, 55%). MS(ESI): m / z = 289.1[M+H]+.

[0286] Intermediate 46 3-(5-(trifluoromethyl)-1H-pyrazole-4-yl)benzoic acid Intermediate 13, following step ii), starts with ethyl 3-(5-(trifluoromethyl)-1H-pyrazole-4-yl)benzoate. MS(ESI): m / z = 257.1[M+H] +

[0287] a) Ethyl 3-(5-(trifluoromethyl)-1H-pyrazole-4-yl)benzoate Intermediate 45, following step b, starts with ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate. MS(ESI): m / z = 285.1 [M + H] +

[0288] Intermediate 47 2-Chloro-3-(2-oxo-1,2-dihydropyridine-4-yl)lithium benzoate Intermediate 13, following step ii), starts with methyl 2-chloro-3-(2-oxo-1,2-dihydropyridine-4-yl)benzoate. The target compound was not extracted in an organic solvent; the reaction mixture was freeze-dried and used in the next step without further purification. MS(ESI): m / z = 250.1[M+H] + a) Methyl 2-chloro-3-(2-oxo-1,2-dihydropyridine-4-yl)benzoate Following intermediate 21, step i), MS(ESI): m / z = 264.1 [M + H] is synthesized starting from 4-bromopyridine-2(1H)-one. +

[0289] Intermediate 48 2-Chloro-3-(6-oxo-1H-pyridine-3-yl)benzoic acid Methyl 2-chloro-3-(6-oxo-1,6-dihydropyridine-3-yl)benzoate (120 mg, 0.455 mmol) and LiOH monohydrate (57 mg, 1.37 mmol) were dispersed in 1.4 ml of water, 0.5 ml of MeOH, and 3.9 ml of THF, and stirred at 22°C. After 19 hours, the mixture was acidified with 1 M aqueous HCl and diluted with saline solution. This was concentrated under reduced pressure, suspended in EtOH, vigorously stirred for several minutes, and filtered. The process was repeated twice, the filtered solutions were combined, and concentrated under reduced pressure. The target compound was obtained as a white solid along with residual NaCl and LiCl. a) Methyl 2-chloro-3-(6-oxo-1,6-dihydropyridine-3-yl)benzoate Intermediate 21, following step i), starts from 5-bromopyridine-2(1H)-one. MS(ESI): m / z = 264.1[M+H] +

[0290] Intermediate 49 5-Chloro-3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyridine-2-ol 2,2,2-trifluoroacetate 29.2 mg, 63.5 μmol of tert-butyl(3R,9aS)-3-(2-(benzyloxy)-5-chloropyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate was dissolved in 1.5 mL of DCM. 50 μL of TFA was added, and the yellow solution was stirred at room temperature. After 4 hours, another portion of TFA (1 mL) was slowly added. After 3 hours, the mixture was concentrated under reduced pressure, redissolved in toluene, and concentrated again under reduced pressure to obtain a brown solid. The unpurified product was used in the next step without further purification. MS(ESI): m / z = 270.2[M+H]+.

[0291] a) tert-butyl(3S)-4-(2-(2-(benzyloxy)-5-chloropyridine-3-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate The compound was synthesized according to intermediates 35A / 35B and step d, starting with 2-(benzyloxy)-5-chloro-3-(oxiran-2-yl)pyridine (see intermediates 35A / 35B for synthesis, 208 mg, 795 μmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (189 mg, 874 μmol). The product was obtained as a yellow oily substance. 181 mg (47.6%). MS(ESI): m / z = 478.3 [M + H] +

[0292] b) tert-butyl(3R,9aS)-3-(2-(benzyloxy)-5-chloropyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

[0293] 132 mg, 276 μmol of tert-butyl(3S)-4-(2-(2-(benzyloxy)-5-chloropyridine-3-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate was dissolved in 1.7 mL of dry toluene. 133 mg, 552 μmol of 2-(tributyl-15-phosphanylidene)acetonitrile was added to 0.3 mL of dry toluene, and the mixture was heated to 100°C. After 5 hours, another 100 mg, 414 μmol of 2-(tributyl-15-phosphanylidene)acetonitrile was added to 0.2 mL of dry toluene. The solution was heated to 110°C. After 5 hours, the reaction mixture was concentrated and purified by column chromatography (EA 0%-90% in heptane). The first diastereomer eluted was proceeded to the next step. The product was obtained as a yellow oily substance. 29.2 mg (23%). MS(ESI): m / z = 460.3[M+H] +

[0294] Intermediate 50 (3-Bromo-2-chloro-5-fluorophenyl)((3R,9aS)-3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (3R,9aS)-3-(3-chloro-4-fluorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine (intermediate 2, 1 equivalent, 74.6 mg), 3-bromo-2-chloro-5-fluorobenzoic acid (1.35 equivalents, 105 mg), and HATU (1.35 equivalents, 141 mg) were mixed with 2 mL of dry DMF and cooled to 0°C. Upon addition of DIPEA (3 equivalents, 144 μL), a yellow solution was produced. After 10 minutes, this was warmed to room temperature. After 3 hours, this was diluted with ethyl acetate, washed with cold water, then saturated bicarbonate aqueous solution, and finally brine. The mixture was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was purified by silica column chromatography (10 g, ethyl acetate in 30%-80% heptane). The product was obtained as a white solid (102 mg, purity approximately 80%, yield approximately 59%).

[0295] Furthermore, a fraction recovered from waste was also obtained: 19 mg, purity approximately 80%, yield approximately 11%.

[0296] Intermediate 51a (3R,9aS)-3-(3,4-dichlorophenyl)-4,6,7,8,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-3-ol Intermediate 52, following step b, starts from (3R,9aS)-3-(3,4-dichlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxylate tert-butyl. MS(ESI): m / z = 303.2[M+H]+.

[0297] a) tert-butyl(3R,9aS)-3-(3,4-dichlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxylate

[0298] Intermediate 52 is synthesized according to step a, starting from 2-bromo-1-(3,4-dichlorophenyl)ethane-1-one and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate. MS(ESI): m / z = 403.3[M+H]+.

[0299] Intermediate 51b (3R,9aS)-3-(3,4-dichlorophenyl)-1,3,4,6,7,8,9,9a-octahydropyrazino[2,1-c][1,4]oxazine Following intermediate 53, the synthesis starts from tert-butyl(3R,9aS)-3-(3,4-dichlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxylate (product of step a, intermediate 51a). MS(ESI): m / z = 287.2[M+H]+.

[0300] Intermediate 52 (2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)((3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone Bis(pinacolato)diborone (327 mg, 1.29 mmol), [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(3-bromo-2-chlorophenyl)methanone (0.500 g, 992 μmol), and potassium acetate (292 mg, 2.98 mmol) were dispersed in dioxane (4 ml) and degassed. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex (121 mg, 149 μmol) was added. This was reacted in microwaves (30 minutes, 100°C). This was then extracted with ELISA and water. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The unpurified substance was purified by silica column chromatography (Â / Hept 0%~80%). The product was obtained as a brown oily substance (234 mg, purity approximately 72%, yield 42%) and used in the next step without further purification. MS(ESI): m / z = 551.3 [MH] - .

[0301] a) tert-butyl(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxylate Tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (1 equivalent, 1.52 g) and Hünig base (1.3 equivalents, 1.6 mL) were dissolved in 25 mL of THF. 2-bromo-1-(3-chloro-4-fluorophenyl)ethane-1-one (1 equivalent, 1.77 g) was added dropwise to 5 mL of THF over 10 minutes at 0°C. The reaction mixture was stirred at room temperature for 20 hours. The unpurified product was then filtered, and the yellow mother liquor solution was concentrated under reduced pressure and purified by silica column chromatography (siRNA / Hept 0%~70%). The product was isolated as a pale yellow foam (2.3 g, 85%). ESI (MS): m / z = 387.1 [M+H] +

[0302] b) (3R,9aS)-3-(3-chloro-4-fluorophenyl)-4,6,7,8,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-3-ol 2.3 g, 5.95 mmol of tert-butyl(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxylate was mixed with 29.7 ml, 119 mmol of 4 M HCl in dioxane and 10 ml of dioxane, and stirred at room temperature for 2.5 hours. The mixture was then diluted with SiO2, basicized with 4 M NaOH, and extracted twice with SiO2. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was obtained as a pale yellow foam (1.7 g, purity approximately 80%, yield 99%) and used in the next step without further purification. MS(ESI): m / z = 287.1 [M + H] +

[0303] c)[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(3-bromo-2-chlorophenyl)methanone (3R,9aS)-3-(3-chloro-4-fluorophenyl)-4,6,7,8,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-ol (1 g, 3.49 mmol), 3-bromo-2-chlorobenzoic acid (985 mg, 4.19 mmol), and HATU (1.59 g, 4.19 mmol) were mixed with DMF (20 ml). Hünig base (1.35 g, 1.83 ml, 10.5 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. This was then extracted with water and ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The unpurified material was purified by silica column chromatography (ethyl acetate / Hept 0%~100%). The product was obtained as a yellow oil (1.48 g, 84%). ESI (MS): m / z) = 505.1 [M + H] +

[0304] Intermediate 53 (3R,9aS)-3-(4-bromo-3-chlorophenyl)octahydropyrazino[2,1-c][1,4]oxazine tert-butyl(3R,9aS)-3-(4-bromo-3-chlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxylate (0.959 g, 2.14 mmol) was mixed with triethylsilane (747 mg, 1.03 ml, 6.43 mmol) and DCM (11 ml). Trifluoroacetic acid (7.33 g, 4.92 ml, 64.3 mmol) was added, and the solution was heated at 45°C for 2 hours. The unpurified yellow solution was concentrated under reduced pressure, mixed with water / 1 M HCl, and washed with diethyl ether. The organic layer was back-extracted twice with 0.5 M HCl. The combined aqueous layer was then basicized with 4 M NaOH with added NaCl and extracted twice with ELISA. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oily substance (0.643 g, 91%). The diastereomer ratio eq / ax estimated by NMR was approximately 8:1. ESI(MS): m / z=333.2[M+H] +

[0305] a) tert-butyl(3R,9aS)-3-(4-bromo-3-chlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carboxylate

[0306] Intermediate 52 is synthesized according to step a, starting from 2-bromo-1-(4-bromo-3-chlorophenyl)ethane-1-one and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate. MS(ESI): m / z = 449.2[M+H] +

[0307] Intermediate 54 2-Chloro-3-(3-oxopiperazine-1-yl)benzoic acid To a solution of methyl 2-chloro-3-(3-oxopiperazin-1-yl)benzoate (0.175 g, 651 μmol) in THF (2 ml), 1.95 ml of 1 M LiOH (1.95 mmol) in H2O was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 1 M HCl and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was obtained as a pale yellow oil (100 mg, purity approximately 72%, yield 60%) and used in the next step without further purification. MS(ESI): m / z = 255.05 [M + H] +

[0308] a) Methyl 2-chloro-3-(3-oxopiperazine-1-yl)benzoate A solution of methyl 3-bromo-2-chlorobenzoate (0.600 g, 2.4 mmol), piperazine-2-one (265 mg, 2.65 mmol), and cesium carbonate (1.57 g, 4.81 mmol) in dioxane (15 ml) was degassed with argon. Pd(OAc)2 (54 mg, 240 μmol) and xanthophos (139 mg, 240 μmol) were added, the reaction mixture was degassed again, and the reaction mixture was stirred overnight at 90°C. The reaction mixture was filtered through a decalite and concentrated under reduced pressure. The yellow oily substance was then dissolved in ethyl acetate and extracted with water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The unpurified substance was purified by Si-amine column chromatography (MeOH / DCM 0%~10%). The product was isolated as a yellow oily substance (175 mg, 27%). ESI(MS): m / z=269, 2[M+H] +

[0309] Intermediate 55 2-Chloro-3-(5-cyano-1H-pyrrole-3-yl)benzoic acid Following intermediate 54, saponification is carried out starting from methyl 2-chloro-3-(5-cyano-1H-pyrrole-3-yl)benzoate. MS(ESI): m / z = 245.1 [MH] -

[0310] a) Methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Following intermediate 52, borylation is performed starting from methyl 3-bromo-2-chlorobenzoate. MS(ESI): m / z = 297.2[M+H] +

[0311] b) Methyl 2-chloro-3-(5-cyano-1H-pyrrole-3-yl)benzoate Methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.203 g, 685 μmol), 4-bromo-1H-pyrrole-2-carbonitrile (129 mg, 753 μmol), and potassium carbonate (284 mg, 2.05 mmol) were mixed with dioxane (5 ml) and water (850 μl). The reaction mixture was degassed, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (48.5 mg, 68.5 μmol) was added. The reaction mixture was heated at 80°C for 2 hours, and then extracted with saturated NaHCO3 solution / Âi. The organic layer was washed with saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The unpurified material was purified by silica column chromatography (MeOH / DCM 0%~10%). The desired product was obtained as a yellow oily substance (177 mg, 99%). ESI (MS): m / z = 259.1 [MH] -

[0312] Intermediate 56 2-Chloro-3-(2-cyano-1H-imidazole-5-yl)benzoic acid Following intermediate 54, saponification is performed starting from methyl 2-chloro-3-(2-cyano-1H-imidazole-5-yl)benzoate. MS(ESI): m / z = 248.1[M+H] +

[0313] a) Methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate Following intermediate 52, borylation is performed starting from methyl 3-bromo-2-chlorobenzoate. MS(ESI): m / z = 297.2[M+H] +

[0314] b) Methyl 2-chloro-3-(2-cyano-1H-imidazole-5-yl)benzoate Intermediate 55 is cross-coupled according to step b, starting with methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and 5-bromo-1H-imidazole-2-carbonitrile. MS(ESI): m / z = 262.1 [M + H] +

[0315] Intermediate 57 2-Chloro-3-(2-oxo-3H-1,3,4-oxadiazole-5-yl)benzoic acid 5-(3-bromo-2-chlorophenyl)-3H-1,3,4-oxadiazole-2-one (1 equivalent, 138 mg) was dissolved in 3 mL of dry THF at 0°C, and isopropyl magnesium chloride LiCl complex (1.1 equivalents, 1.3 M solution in 425 μL of THF) was added dropwise, causing the solution to turn orange, and then dark red. After the addition, the mixture was warmed to room temperature. The metal exchange reaction was monitored by LC-MS. After 20 minutes, approximately 30% of the metal exchange reaction was observed, and this did not change after 40 minutes, so an additional 400 μL of isopropyl magnesium chloride LiCl complex was added, thereby forming a precipitate. After 20 minutes, LC-MS confirmed that the metal exchange reaction was complete. Gaseous CO2 was bubbling through the suspension via a balloon, and after 5 minutes, an additional 5 mL of dry THF was added to the flask to ensure good bubbling and stirring. This was diluted with 1NNaOH and washed twice with siRNA. The aqueous phase was acidified with 1M HCl, a small amount of NaCl was added, and then extracted twice with siRNA. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a grayish-white solid (68 mg). MS(ESI): m / z = 241.1[M+H] +

[0316] a) 3-bromo-2-chlorobenzohydrazide Methyl 3-bromo-2-chlorobenzoate (1 equivalent, 500 mg) and hydrazine hydrate (5 equivalents, 490 μL) were dissolved in 15 mL of EtOH and heated at 80°C for 2.5 days. The mixture was then concentrated under reduced pressure and purified by silica column chromatography (50 g, 40%-100% Â in n-heptane). The product was isolated as a white solid (315 mg, 63%). MS(ESI): m / z = 251.0 [M+H] +

[0317] 5-(3-bromo-2-chlorophenyl)-3H-1,3,4-oxadiazole-2-one 3-Bromo-2-chlorobenzohydrazide (1 equivalent, 271 mg) and TEA (1.4 equivalents, 212 μL) were dispersed in 4 mL of dry THF at 0°C. Then, carbonyldiimidazole (1.1 equivalents, 194 mg) in 2 mL of dry THF was added dropwise, and the mixture was slowly warmed to room temperature, thereby forming a clear yellow solution. Even if the reaction was not completely complete, this was diluted with siRNA, washed with 1 M HCl, saturated bicarbonate, and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a bright, crystalline white solid (236 mg, 79%). MS(ESI): m / z = 274.9 [MH] -

[0318] Intermediate 58 2-Chloro-3-(2-oxo-2,3-dihydroxazol-5-yl)benzoic acid 5-(3-bromo-2-chlorophenyl)-3H-oxazole-2-one (1 equivalent, 71 mg) was dissolved in 1.2 mL of dry THF using sonication and cooled to 0°C. Isopropyl magnesium chloride LiCl complex (1.3 equivalents, 1.3 M solution in 233 μL of THF) was slowly added, causing the mixture to darken. After 15 minutes, the mixture was slowly warmed to room temperature. An orange-red mixture was formed. 30 minutes after addition, an 8% metal exchange reaction was observed, and another 120 μL of isopropyl magnesium chloride LiCl complex was added at 0°C, followed by warming the mixture to room temperature. After 30 minutes, approximately 50% metal exchange was observed. Although the metal exchange reaction was not yet complete, gaseous CO2 (1 balloon) bubbled at approximately 10°C. A further 2 mL of dry THF was added, and another balloon of CO2 was bubbled in an ultrasonic device at room temperature. A yellowish suspension was formed, which was diluted with approximately 0.5 M NaOH and washed twice with diethyl ether. The aqueous layer was acidified with 1 M HCl, treated with NaCl, and then extracted twice with siRNA. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The impure product was obtained as an orange solid (61 mg). MS(ESI): m / z = 238.1 [MH] -

[0319] a) 2-Bromo-1-(3-Bromo-2-chlorophenyl)ethanone 1-(3-bromo-2-chlorophenyl)ethane-1-one (1 equivalent, 340 mg), NBS (1.05 equivalent, 272 mg), and pTsOH monohydrate (0.11 equivalent, 30 mg) were mixed with 12 mL of dry DCM and reacted in a microwave (90°C for 9 minutes, 80 minutes), then again (90°C for 40 minutes). The mixture was diluted with DCM and washed with saturated bicarbonate solution, water, and then brine. The combined aqueous layer was back-extracted into DCM, and the combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain an unpurified yellow oil (460 mg). This was purified by silica column chromatography (50 g, 0-30% ethyl acetate in heptane). The target compound was obtained as a yellow oil (429 mg, purity approximately 80%, yield 75%). 1This was confirmed by 1H-NMR.

[0320] b) 3-(2-(3-bromo-2-chlorophenyl)-2-oxo-ethyl)thiazolidined-2,4-dione 2-Bromo-1-(3-bromo-2-chlorophenyl)ethanone (1 equivalent, 226 mg), thiazolidinedione-2,4-dione (1 equivalent, 68 mg), potassium carbonate (1.05 equivalent, 84 mg), and TBAI (0.1 equivalent, 21 mg) were mixed with 3 mL of DMF, and the resulting yellow solution was stirred at room temperature. After 20 minutes, the mixture turned slightly orange, and after 1 hour, an orange suspension was formed. After 70 minutes, the mixture was diluted with ethyl acetate, washed with ice water (2 ×), then saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired compound as a red solid (249 mg, approximately 100%) MS(ESI): m / z = 346.1 [MH]. -

[0321] c) 5-(3-bromo-2-chlorophenyl)-3H-oxazole-2-one 3-(2-(3-bromo-2-chlorophenyl)-2-oxo-ethyl)thiazolidined-2,4-dione (1 equivalent, 248 mg; purity approximately 80%) and triethylamine (2.5 equivalents, 200 μL) were mixed in 2.8 mL of EtOH in a pressure vial and heated to 80°C in a sand bath. After 15 hours of reaction, 70% conversion was observed (UV). The reaction mixture was diluted with ethyl acetate, washed with semi-saturated ammonium chloride solution, then saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain a red / white solid (241 mg). The residue was adsorbed onto silica and purified by silica column chromatography (20 g, 20%-60% ethyl acetate in n-heptane). The product was isolated as a white solid with some red parts (123 mg, purity approximately 90%, yield 71%). MS(ESI): m / z=274.0[M+H] +

[0322] Intermediate 59 2-Chloro-3-(6-methyl-2-oxo-1,2-dihydropyridine-4-yl)benzoic acid Following intermediate 54, saponification begins with methyl 2-chloro-3-(2-methyl-6-oxo-1H-pyridine-4-yl)benzoate. MS(ESI): m / z = 264.2[M+H] +

[0323] a) Methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate In a microwave vial, 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.3 equivalents, 1.32 g), methyl 3-bromo-2-chlorobenzoate (1 equivalent, 1 g), PdCl2(DPPF) (0.1 equivalents, 327 mg), and potassium acetate (3 equivalents, 1.18 g) were dispersed in 17 mL of dioxane and degassed. This was reacted in a microwave (80°C, 25 mins). The mixture was filtered through an extraction funnel, washed with water, then saline solution, back-extracted with some ethyl acetate, dried over sodium sulfate, filtered, adsorbed onto silica, and concentrated under reduced pressure. This was purified by silica column chromatography (70 g, 0%-10% ethyl acetate in n-heptane). The product was isolated as a white solid with tetramethyloxirane (1.41 g, impure, 36% yield). MS(ESI): m / z = 297.2 [M + H] +

[0324] b) Methyl 2-chloro-3-(2-methyl-6-oxo-1H-pyridine-4-yl)benzoate 4-Bromo-6-methylpyridine-2(1H)-one (1 equivalent, 125 mg), methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.1 equivalents, 361 mg, purity approximately 60%), (APhos)2PdCl2 (0.1 equivalents, 47 mg), and potassium carbonate (3 equivalents, 276 mg) were mixed with 3 mL of dioxane and 1 mL of water, and degassed with argon. The mixture was then reacted in a microwave (115°C, 30 min), diluted with ethyl acetate, and washed with brine. The aqueous layer was back-extracted, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was purified by silica column chromatography (20 g, MeOH 0%~10% in DCM). The product was isolated as a green-white solid (206 mg, 112%, impure). MS(ESI): m / z = 278.2[M+H] +

[0325] Intermediate 60 2-Chloro-3-(2-methyl-6-oxo-1,6-dihydropyridine-3-yl)benzoic acid Methyl 2-chloro-3-(6-methoxy-2-methyl-3-pyridyl)benzoate (1 equivalent, 106 mg) was mixed with 4 mL of 7.6 M aqueous HCl solution, and the colorless mixture was heated to 120°C in a pressure vial and sand bath. After 22 hours, complete monodemethylation and partial dimethylation were observed. After 30 hours, the reaction product was converted by approximately 80% (UV), cooled to room temperature, the flask was rinsed with some water / MeCN, and the solvent was evaporated with toluene to obtain a grayish-white solid (56 mg, 58%) MS(ESI): m / z = 264.1 [M + H]. +

[0326] a) Methyl 2-chloro-3-(6-methoxy-2-methyl-3-pyridyl)benzoate Methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1 equivalent, 232 mg, purity approximately 60%), 3-bromo-6-methoxy-2-methylpyridine (1.35 equivalents, 128 mg), Pd dppf DCM complex (0.1 equivalents, 38 mg), and potassium carbonate (3 equivalents, 195 mg) were suspended in 3 mL of dioxane and 1 mL of water, degassed with argon, and reacted in a microwave (115°C, 30 min). After cooling to room temperature, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was then purified by silica column chromatography (20 g, 0%-50% ethyl acetate in n-heptane). The product was isolated as a pale yellow oily substance with 25% ethyl acetate, partially together with impurities (total 119 mg, 71% yield). MS(ESI): m / z = 292.2[M+H] +

[0327] Intermediate 61 2-Chloro-3-(4-oxo-1H-pyridazine-5-yl)benzoic acid Unpurified 3-(5-benzyloxypyridazin-4-yl)-2-chlorobenzoic acid (1 equivalent, 45 mg) was dissolved in 2.5 mL of MeOH in a 25 mL flask. The flask was purged three times with argon / vacuum. Palladium carbon (0.1 equivalent, 14 mg) was added, and the flask was purged three more times with argon. A hydrogen balloon was added, the flask was purged three more times, and then stirred at room temperature. After 100 minutes, it was evident that approximately 60% (by LC-UV) had been converted. The following morning, this was filtered through Celite and concentrated under reduced pressure to obtain a green, unpurified solid (40 mg), which was used in the next step without purification. MS(ESI): m / z=251.1[M+H] +

[0328] a) 4-benzyloxy-5-chloropyridazine Work in the dark. In a flask lined with aluminum foil, 5-chloropyridazine-4(1H)-one (1 equivalent, 300 mg), benzyl bromide (1.2 equivalents, 330 μL), and silver carbonate (1.2 equivalents, 760 mg) were dispersed in 5 mL of dry toluene. The mixture was heated at 85°C for 30 minutes, then at 50°C for 1 hour. This was then diluted with semisaturated saline and extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was purified by silica column chromatography (50 g, ethyl acetate in n-heptane 30%-100%). The product was obtained as a yellow oil (85 mg, 17%). MS(ESI): m / z = 221.1[M+H] +

[0329] b) Methyl 3-(5-benzyloxypyridazine-4-yl)-2-chlorobenzoate Methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.05 equivalents, approximately 122 mg, purity approximately 60%), 4-benzyloxy-5-chloropyridazine (1 equivalent, 52 mg), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.1 equivalent, 19 mg), and potassium carbonate (3 equivalents, 98 mg) were mixed with 2.4 mL of dioxane and 0.8 mL of water, degassed, and reacted in a microwave (115°C, 30 min). This was purified by silica column chromatography (20 g, 0%~80% ethyl acetate in n-heptane). The product was obtained as an orange oily substance (47 mg, 34%). MS(ESI): m / z = 355.1 [M+H] +

[0330] c) 3-(5-benzyloxypyridazine-4-yl)-2-chlorobenzoic acid Methyl 3-(5-benzyloxypyridazin-4-yl)-2-chlorobenzoate (1 equivalent, 47 mg) was mixed with 1.5 mL of 7.6 M HCl aqueous solution and heated at 120°C for 16 hours in a sand bath and pressure vial. After cooling to room temperature, acetonitrile was added to obtain a homogeneous solution, and LCM indicated that ester hydrolysis was complete. This was concentrated under reduced pressure to obtain a yellow / orange oily substance (45 mg, 100%), which was used in the next step without further purification. MS(ESI): m / z = 341.1 [M + H] +

[0331] Intermediate 62 2-Chloro-3-(5-cyano-1H-pyrazole-3-yl)benzoic acid Following intermediate 54, saponification is performed starting from methyl 2-chloro-3-(5-cyano-1H-pyrazole-3-yl)benzoate. MS(ESI): m / z = 248.1[M+H] +

[0332] a) 5-bromo-1H-pyrazole-3-carboxamide Methyl 5-bromo-1H-pyrazole-3-carboxylate (1 equivalent, 140 mg) was dissolved in 3 mL of MeOH. A 25% aqueous solution of ammonium hydroxide (10 equivalents, 1 mL) was added, and the solution was heated to 60°C. After 40 minutes, approximately 20% re-esterification to the methyl ester was observed, but no amide bond formation was detected. After 1 hour, the temperature was raised to 80°C. After 18 hours, the solution was concentrated under reduced pressure to remove excess ammonia. A white solid was obtained (120 mg, 100%). MS(ESI): m / z = 251.1[M+H] +

[0333] b) 5-bromo-1H-pyrazole-3-carbonitrile 5-bromo-1H-pyrazole-3-carbocianamide (unpurified, 1 equivalent, 120 mg) was dissolved in 3.5 ml of pyridine and cooled to 0°C. Trifluoroacetic anhydride (4 equivalents, 360 μL) was added dropwise. White fumes were immediately generated. After 40 minutes, this was diluted with Â, washed twice with saturated bicarbonate aqueous solution, then twice with 1 M HCl, dried over sodium sulfate, and concentrated under reduced pressure to obtain a light brown solid (121 mg). This was purified by silica column chromatography (10 g, Â in n-heptane 0%~50%). The product was obtained as a white solid (56 mg, 51%) MS(ESI): m / z = 172.0 [M+H] + .

[0334] c) Methyl 2-chloro-3-(5-cyano-1H-pyrazole-3-yl)benzoate 5-bromo-1H-pyrazole-3-carbonitrile (1 equivalent, 56 mg), methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.3 equivalents, 209 mg, purity approximately 60%), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.1 equivalent, 26 mg), and potassium carbonate (3 equivalents, 135 mg) were mixed with 1.8 ml of dioxane and 600 μl of water, degassed, and reacted in a microwave (30 minutes, 115°C). Further addition of 40 mg (0.3 equivalents) of methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and a handful of Pd catalyst, the mixture was degassed and reacted again (120°C, 30 minutes). The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, then with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was then purified by silica column chromatography (10 g, 0%-50% ethyl acetate in n-heptane). The product was isolated as an orange / yellow oil (24 mg, 28%). MS(ESI): m / z = 262.2 [M+H] +

[0335] Intermediate 63 3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-(trifluoromethyl)pyridine-2(1H)-one hydrobromide tert-butyl(3R,9aS)-3-(2-methoxy-6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (0.160 g, 383 μmol) was dissolved in AcOH (1.92 ml), and a 33% HBr solution in AcOH (7 mL) was added. The reaction mixture was stirred at 100 °C for 2 hours. The mixture was then concentrated under reduced pressure and evaporated twice with toluene. The product was obtained as a brown powder without further purification (182 mg, unpurified, 100%). MS(ESI): m / z = 304.1 [M+H] +

[0336] a) 2-Methoxy-6-(trifluoromethyl)-3-vinylpyridine 3-Bromo-2-methoxy-6-(trifluoromethyl)pyridine (1 g, 3.91 mmol), potassium trifluoro(vinyl)borate (628 mg, 4.69 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (159 mg, 195 μmol), and triethylamine (395 mg, 544 μl, 3.91 mmol) were dispersed in degassed ethanol (29.4 ml). The reaction mixture was then heated in a sealed tube at 130°C for 1 hour. This was then concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered, adsorbed onto silica, and concentrated under reduced pressure. This was purified by silica column chromatography (50 g, 0-15% EA in heptane). The product was obtained as a colorless oil (610 mg, 77%). MS(ESI): m / z = 204.0[M+H] +

[0337] b) 2-Methoxy-3-(oxiran-2-yl)-6-(trifluoromethyl)pyridine 2-Methoxy-6-(trifluoromethyl)-3-vinylpyridine (0.61 g, 3 mmol) was dispersed in 70 mL of water and 70 mL of dioxane. 1-Bromopyrrolidine-2,5-dione (641 mg, 3.6 mmol) was added dropwise to the 70 mL of water and 70 mL of dioxane. The mixture was stirred at room temperature for 7 hours. LC-MS showed that all the starting material was consumed and bromohydrin was formed. The reaction mixture was cooled to 0°C and 4 M NaOH solution (2.25 ml) was added dropwise. The ice bath was removed and the RM was stirred at room temperature overnight. LC-MS showed that a complete reaction had occurred and the desired product had been formed. This was mixed with a saturated bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was obtained as a colorless oil. 620 mg, 94%. 1 Follow the H-NMR spectrum.

[0338] c) tert-butyl(3S)-4-(2-hydroxy-2-(2-methoxy-6-(trifluoromethyl)pyridine-3-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate 2-Methoxy-3-(oxiran-2-yl)-6-(trifluoromethyl)pyridine (0.62 g, 2.83 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (673 mg, 3.11 mmol) were dissolved in ethanol (10.7 ml) and tetrahydrofuran (10.7 ml) and heated overnight at 130°C in a sealed tube. The mixture was then concentrated under reduced pressure and purified by silica column chromatography (20 g, DCM with 0%-5% MeOH). The product was obtained as a colorless oil. 750 mg, 61%. MS(ESI): m / z=436.2[M+H] +

[0339] d) tert-butyl(3R,9aS)-3-(2-methoxy-6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

[0340] tert-butyl(3S)-4-(2-hydroxy-2-(2-methoxy-6-(trifluoromethyl)pyridine-3-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (0.75 g, 1.72 mmol) was dissolved in dry toluene (12.5 ml). 2-(tributyl-15-phosphanylidene)acetonitrile (831 mg, 904 μl, 3.44 mmol) was added to the dry toluene (12.5 ml), and the mixture was heated to 105°C. The toluene was evaporated, and the residue was purified by silica column chromatography (20 g, EA in Hept 0%~50%). The first eluted diastereomer (low polarity) was isolated and, expected to be the more active conformation, was used in the next step. The product was obtained as a dark brown oily substance. 160 mg, 22%. MS(ESI): m / z=418.2[M+H] +

[0341] Intermediate 64 2-Chloro-3-(5-cyano-1H-pyrrole-3-yl)-5-fluorobenzoic acid To a solution of methyl 2-chloro-3-(5-cyano-1H-pyrrole-3-yl)-5-fluorobenzoate (1.2 g, 4.31 mmol) in THF (21.5 ml), 11.2 ml, 5.6 mmol, aqueous lithium hydroxide solution, was added dropwise, and the reaction mixture was heated to 70°C for 2 hours. The solvent was removed under reduced pressure, and the residue was acidified with 1 M HCl (pH=2). This residue was then extracted twice with ethyl acetate, dried, filtered, and concentrated under reduced pressure to obtain the desired product as an orange solid. MS(ESI): m / z = 263.0 [M+H] +

[0342] a) Methyl 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate In a microwave vial, methyl 3-bromo-2-chloro-5-fluorobenzoate (4.0 g, 15 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (4.56 g, 17.9 mmol), and potassium acetate (4.4 g, 44.9 mmol) were dispersed in dioxane (59.6 ml) and degassed. Then, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.83 g, 2.24 mmol) was added. The red suspension was reacted on a heated plate (105°C, 2 hours). The unpurified material was purified by flash chromatography (silica gel, 50 g, 0%-20% ethyl acetate in heptane, 40 minutes). The product was obtained as a white solid. 3.52 g, 75%. 1 Follow the H-NMR spectrum.

[0343] b) Methyl 2-chloro-3-(5-cyano-1H-pyrrole-3-yl)-5-fluorobenzoate Methyl 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.5 g, 9.12 mmol), 4-bromo-1H-pyrrole-2-carbonitrile (1.72 g, 10 mmol), (APhos)2PdCl2 (646 mg, 912 μmol), and K2CO3 (3.78 g, 27.4 mmol) were dispersed in dioxane (50.8 ml) and water (9.24 ml) and degassed with argon. This was then heated at 80°C for 2 hours. The mixture was poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified orange oily substance was purified by silica gel chromatography (20 g, DCM / MeOH 0-10% for 30 minutes). The product was obtained as a yellow solid. 1.2 g, 47%. MS(ESI): m / z = 277.1 [MH] -

[0344] Intermediate 65 2-Chloro-5-fluoro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid Starting with methyl 2-chloro-5-fluoro-3-(3-fluoro-1H-pyrazole-4-yl)benzoate (80 mg, 293 μmol), saponification was carried out as described for intermediate 64. The product was obtained as a white solid. 20 mg, 26%. MS(ESI): m / z = 259.1 [M + H] +

[0345] a) Methyl 2-chloro-5-fluoro-3-(3-fluoro-1H-pyrazole-4-yl)benzoate Methyl 2-chloro-5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (732 mg, 2.33 mmol), 4-bromo-3-fluoro-1H-pyrazole (320 mg, 1.94 mmol), (APhos)2PdCl2 (137 mg, 194 μmol), and K2CO3 (804 mg, 5.82 mmol) were dispersed in dioxane (9.57 ml) and water (3.19 ml) and degassed with argon (yellow suspension). This was then heated at 60°C for 30 minutes and at 110°C for 3 hours. The mixture was poured into saturated NaHCO3 and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unrefined yellow oily substance was purified by silica gel chromatography (n-heptane and ethyl acetate, 0-70%, for 40 minutes) to obtain the desired product as a pale yellow oily substance (80 mg, 15%). MS(ESI): m / z = 273.1[M+H] +

[0346] Intermediate 66 3-Chloro-2-fluoro-5-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)benzonitrile trifluoroacetate

[0347] tert-butyl(3R,9aS)-3-(3-chloro-5-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (0.160 g, 404 μmol) was dissolved in DCM (8.79 ml). Trifluoroacetic acid (1.38 g, 928 μl, 12.1 mmol) was added, and the orange solution was stirred at room temperature. The mixture was concentrated under reduced pressure, redissolved in toluene, and concentrated again under reduced pressure to obtain an orange oily substance. The unpurified product was used in the next step without further purification. (200 mg, 100%) MS(ESI): m / z = 290.2 [M + H] +

[0348] a) tert-butyl(3S)-4-(2-(3-chloro-5-cyano-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate 3-Chloro-2-fluoro-5-(oxiran-2-yl)benzonitrile (1.3 g, 6.58 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (1.57 g, 7.24 mmol) were dissolved in EtOH (15 ml) and THF (15 ml) and heated overnight at 130°C in a sealed tube. This was then concentrated under reduced pressure and purified by silica column chromatography (50 g, DCM with 0%-5% MeOH). The product was obtained as a yellow oily substance. 1.68 g, 62%. MS(ESI): m / z = 414.3 [M+H] +

[0349] b) tert-butyl(3R,9aS)-3-(3-chloro-5-cyano-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

[0350] 1.68 g, 4.06 mmol of tert-butyl(3S)-4-(2-(3-chloro-5-cyano-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate was dissolved in 29.4 ml of dry toluene. 1.96 g, 8.12 mmol of 2-(tributyl-15-phosphanylidene)acetonitrile was added dropwise to the 29.4 ml of dry toluene, and the mixture was heated overnight at 110°C. The toluene was evaporated, and the residue was purified by silica column chromatography (50 g, EA 0%~50% in Hept). Two diastereomers appeared as a single spot and were collected together. The product was obtained as a red oily substance (160 mg, 10%). MS(ESI): m / z = 396.2 [M+H] +

[0351] Intermediate 67 5-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)-2-(trifluoromethyl)pyridine-4(1H)-one hydrobromide tert-butyl(3R,9aS)-3-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (0.674 g, 1.61 mmol) was dissolved in AcOH (8.07 ml), and 33% HBr in AcOH (28 mL) was added. The mixture was stirred at 100°C for 3 hours. Then, it was concentrated under reduced pressure and evaporated twice with toluene. The product was used without further purification and obtained as a dark brown foam (1 g, unpurified, 100%). MS(ESI): m / z = 304.1 [M + H] +

[0352] a) 4-Methoxy-2-(trifluoromethyl)-5-vinylpyridine 5-Bromo-4-methoxy-2-(trifluoromethyl)pyridine (1.3 g, 5.08 mmol), potassium trifluoro(vinyl)borate (816 mg, 6.09 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (207 mg, 254 μmol, equivalent), and triethylamine (514 mg, 708 μl, 5.08 mmol) were dispersed in degassed ethanol (38.2 ml). The reaction mixture was then heated in a sealed tube at 130°C for 1 hour. This was then concentrated under reduced pressure, diluted with ethylethanol, washed with water, dried over sodium sulfate, filtered, adsorbed onto silica, and concentrated under reduced pressure. This was purified by silica column chromatography (50 g, 0-15% EA in heptane). The product was obtained as a pale yellow oily substance (838 mg, 81%). MS(ESI): m / z = 204.0[M+H] +

[0353] b) 4-Methoxy-5-(oxiran-2-yl)-2-(trifluoromethyl)pyridine 4-Methoxy-2-(trifluoromethyl)-5-vinylpyridine (0.838 g, 4.12 mmol) was dispersed in 8 mL of water and 8 mL of dioxane. 1-Bromopyrrolidine-2,5-dione (881 mg, 4.95 mmol) was added dropwise to the 8 mL of water and 8 mL of dioxane. The mixture was stirred at room temperature for 4 hours, then cooled to 0°C, and 4 M NaOH solution was added dropwise. The ice bath was removed, the mixture was stirred at room temperature overnight, mixed with saturated bicarbonate solution, and extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was purified by silica column chromatography (20 g, 0-50% EA in heptane). The product was obtained as a colorless oil (554 mg, 61%). MS(ESI): m / z = 220.1[M+H] +

[0354] c) tert-butyl(3S)-4-(2-hydroxy-2-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate 4-Methoxy-5-(oxiran-2-yl)-2-(trifluoromethyl)pyridine (0.550 g, 2.51 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (597 mg, 2.76 mmol) were dissolved in ethanol (9.51 ml) and tetrahydrofuran (9.51 ml) and heated overnight at 130°C in a sealed tube. The mixture was then concentrated under reduced pressure and purified by silica column chromatography (20 g, DCM with 0%-5% MeOH). The desired product was obtained as a colorless oil (1.05 g, 96%). MS(ESI): m / z = 436.3 [M+H] +

[0355] d) tert-butyl(3R,9aS)-3-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate

[0356] tert-butyl(3S)-4-(2-hydroxy-2-(4-methoxy-6-(trifluoromethyl)pyridine-3-yl)ethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.05 g, 2.41 mmol) was dissolved in dry toluene (17.5 ml). 2-(tributyl-15-phosphanylidene)acetonitrile (1.16 g, 4.82 mmol) was added to the dry toluene (17.5 ml), and the mixture was heated to 100°C. The toluene was evaporated, and the residue was purified by silica column chromatography (50 g, heptane, EA 0%~90%). Yield: 734 mg, 73%, mixture of both diastereomers. MS(ESI): m / z = 418.2 [M+H] +

[0357] Intermediate 68 (3S,9aS)-3-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)octahydropyrazino[2,1-c][1,4]oxazinetrifluoroacetate Starting with tert-butyl(3S,9aS)-3-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (200 mg, 474 μmol), Boc deprotection was carried out as described in Example 66. The product was obtained as an orange oily substance (274 mg, unpurified, 100%). MS(ESI): m / z = 322.1 [M + H] +

[0358] 3-Chloro-2-(trifluoromethyl)-6-vinylpyridine Starting with 3,6-dichloro-2-(trifluoromethyl)pyridine (2 g, 9.26 mmol), the mixture was vinylinated as described in intermediate 67, step a. The product was obtained as a colorless oil (1.28 g, 67%). MS(ESI): m / z = 207.9 [M + H] +

[0359] b) 3-chloro-6-(oxiran-2-yl)-2-(trifluoromethyl)pyridine Starting with 3-chloro-2-(trifluoromethyl)-6-vinylpyridine (1.28 g, 6.17 mmol), the mixture was epoxidized as described in intermediate 67, step b. The product was obtained as a colorless oil (0.5 g, 36%). MS(ESI): m / z = 224.2 [M + H] +

[0360] c) tert-butyl(3S)-4-(2-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate As described for intermediate 66, step a, the reaction was carried out with 3-chloro-6-(oxiran-2-yl)-2-(trifluoromethyl)pyridine (0.53 g, 2.37 mmol) and tert-butyl(S)-3-(hydroxymethyl)piperazine-1-carboxylate (564 mg, 2.61 mmol). The product was obtained as a pale yellow oily substance (1.04 g, 99%). MS(ESI): m / z = 440.3 [M + H] +

[0361] d) tert-butyl(3S,9aS)-3-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate Starting with tert-butyl(3S)-4-(2-(5-chloro-6-(trifluoromethyl)pyridine-2-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (1.05 g, 2.39 mmol), the compound was cyclized as described in intermediate 66, step b. The product was obtained as a red oily substance (200 mg, 20%). MS(ESI): m / z = 422.3 [M + H] +

[0362] Intermediate 69 2-Chloro-3-(4-fluoro-1H-pyrazole-3-yl)benzoic acid As described for intermediate 64, saponification was carried out starting with methyl 2-chloro-3-(4-fluoro-1H-pyrazole-3-yl)benzoate (227 mg, 891 μmol). The product was obtained as a yellow oily substance. 193 mg, 90%. MS(ESI): m / z = 241.0 [M + H] +

[0363] a) Methyl 2-chloro-3-(4-fluoro-1H-pyrazole-3-yl)benzoate Starting with methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (420 mg, 1.42 mmol) and 3-bromo-4-fluoro-1H-pyrazole (100 mg, 1.56 mmol), cross-coupling was carried out as described for intermediate 65, step a. The product was obtained as a yellow oily substance. 227 mg, 63%. 1 Follow the H-NMR spectrum.

[0364] Intermediate 70 2-Bromo-1-(2-(6-methoxypyridine-3-yl)thiazole-4-yl)ethane-1-one Intermediate 70 was synthesized starting from 6-methoxypyridine-carbothioamide and 1,4-dibromo-2,3-butanedione. The reaction mixture was dissolved in DMF, and 2,6-di-tert.butylpyridine was added. After stirring the mixture at room temperature, the product was isolated.

[0365] Common methods and columns used for reverse-phase HPLC and SFC purification: HPLC preparative method A: GeminiNX, 12nm, 5μm, 100×30mm, run time 15min, underwater gradient 30-50-65-100ACN + 0.1%HCOOH

[0366] HPLC preparative method B: GeminiNX, 12nm, 5μm, 100×30mm, run time 15min, underwater gradient 20-40-55-100ACN + 0.1% HCOOH

[0367] HPLC preparative method C: GeminiNX, 12nm, 5μm, 100×30mm, run time 15min, 40ml / min, water gradient 30-80ACN + 0.1% HCOOH

[0368] HPLC preparative method D: YMC-TriartC18, 12nm, 5μm, 100×30mm, run time 15min, underwater gradient 20-40-60-100 ACN + 0.1% HCOOH

[0369] HPLC separation method E: GeminiNX, 12nm, 5μm, 100×30mm, reaction time 15 minutes, 40ml / min, mixed in water with 30~80 ACN + 0.1% TEA

[0370] HPLC separation method F: YMC-TriartC18, 12nm, 5μm, 100×30mm, realization time 11 minutes, water mixing 30-50-65-100 CAN+0.1% HCOOH

[0371] HPLC separation method G: GeminiNX, 12nm, 5μm, 100×30mm, realization time 11 minutes, mixed in water with 10-25-40-100 ACN + 0.1% HCOOH

[0372] HPLC separation method H: GeminiNX, 12nm, 5μm, 100×30mm, realization time 11 minutes, mixed in water 15-35-50-100 ACN + 0.1% HCOOH

[0373] HPLC Separation Method J: GeminiNX, 12nm, 5μm, 100×30mm, realization time 15 minutes, mixed in water with 20-40-55-100ACN + 0.1%HCOOH

[0374] HPLC separation method K: YMC-TriartC18, 12nm, 5μm, 100×30mm, sedimentation time 11 minutes, mixed in water with 20-98 ACN + 0.1% HCOOH

[0375] HPLC separation method L: GeminiNX, 12nm, 5μm, 100×30mm, realization time 15 minutes, mixed in water with 5-50-100 ACN + 0.1% HCOOH

[0376] SFC Method A ChiralPak IB, 12nm, 5μm, 250×4.6mm, 25% MeOH

[0377] SFC method B: ChiralPak AY-H, 12nm, 5μm, 250 x 4.6 mm, gradient 30~40% EtOAC

[0378] LCMS method C: ChiralPak IB, 12nm, 5μm, 250×4.6mm, 35% MeOH

[0379] SFC method D: ChiralPak IC, 12nm, 5μm, 250×4.6mm, 40% MeOH + 0.2% diethylamine

[0380] SEC method E: ChiralPak AY-H, 12nm, 5μm, 250x4.6mm, 25% MeOH

[0381] Example 47 [3-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone i) (2-chloro-3-methoxyphenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 1,695 μmol, 198 mg dissolved in 2 mL of MeOH) was added to 2-(3-bicyclo[4.2.0]octa-1(6),2,4-trienyl)oxirane (intermediate 36, 94 mg, 580 μmol) in a microwave vial. The vial was sealed and the mixture was heated at 120°C for 100 minutes. This was concentrated under reduced pressure and purified by silica column chromatography (0%~20% MeOH in DCM). The product eluted with impurities. This was again purified in ethyl acetate / heptane, and the product eluted as a very broad peak at 100% ethyl acetate. The product was obtained as a colorless oil (45 mg, 18%). ESI (MS) m / z = 431.3 [M+H] +

[0382] ii) (4-(2-(bicyclo[4.2.0]octa-1,3,5trien-3-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazin-1-yl)(2-chloro-3-methoxyphenyl)methanone (104 μmol, 45 mg) was dissolved in 0.9 ml of dry toluene and 0.2 ml of dry THF to aid dissolution, and cyanomethylenetributylphosphoran (125 μmol, 36 mg) in 100 μL of dry toluene was added to the microwave vial. The vial was capped, degassed with argon, and heated at 100°C under argon with stirring. LCMS showed that there was little conversion to the product, so cyanomethylenetributylphosphoran (total 90 mg, 208 μmol) was added three more times over the next 30 hours while continuing to stir at 100°C. The solvent was partially evaporated, and the orange-brown solution was subjected to silica column purification (0%-15% MeOH in DCM). Further SFC purification was performed to remove co-eluting tributylphosphinoxide, and the pure product was obtained as a colorless oily substance (a mixture of all four stereoisomers, 3.7 mg, 7.8%). ESI(MS) m / z = 413.3 [M+H] +

[0383] Example 48 (2-Chloro-3-methoxyphenyl)-[3-[4-(difluoromethyl)phenyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Example 48 was obtained from intermediate 1 (104 mg, 365 μmol) and 2-(4-(difluoromethyl)phenyl)oxirane (CAS 1546906-13-1, 82 mg, 482 μmol) using the same procedure as described for Example 47. It was obtained as a colorless oily substance, a mixture of all four stereoisomers. 6.9 mg (18%). ESI (MS) m / z = 437.3 [M + H] +

[0384] Example 9 [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-fluoro-3-methoxyphenyl)methanone A mixture of (9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine (intermediate 2, 0.080 g, 295 μmol), 2-fluoro-3-methoxybenzoic acid (55.3 mg, 325 μmol), and HATU (124 mg, 325 μmol) was dissolved in DMF (2 ml), and then DIPEA (115 mg, 155 μl, 886 μmol) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. The unpurified product was purified by preparative HPLC (Method C) to obtain a pure product as a white lyophilized powder. 41 mg (32.8%) MS ESI (m / z): 423.13 [M+H] + The following examples were prepared according to the same procedure as described for Example 9: [Table 2] TIFF2022539604000108.tif236170 TIFF2022539604000109.tif242170 TIFF2022539604000110.tif165170

[0385] Example 6 [(3R,9aS)-3-(3-bromo-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone A mixture of (9aS)-3-(3-bromo-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine (intermediate 3, 1.36 g, 3.87 mmol), 2-chloro-3-methoxybenzoic acid (722 mg, 3.87 mmol), and HATU (1.4 g, 3.67 mmol) was dissolved in DMF (15 ml), and then DIPEA (1.5 mg, 2.03 ml, 11.6 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 30 minutes. The unpurified product was purified by preparative HPLC (Method C) to obtain a pure product as a white lyophilized powder. 1.46 g (78%). ESI (MS) m / z = 485.1 [M + H] +

[0386] Example 10 (2-Chloro-3-methoxyphenyl)-[rac-(3R,9aS)-3-[4-fluoro-3-[rac-(E)-propa-1-enyl]phenyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone In a microwave vial, a solution of [(3R,9aS)-3-(3-bromo-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone (Example 6, 54 mg, 112 μmol), sodium carbonate (29.6 mg, 279 μmol), and (E)-propa-1-en-1-ylboronic acid (14.4 mg, 167 μmol) in dioxane (1.2 ml) / water (120 μl) was degassed with argon. Tetrakis(triphenylphosphine)palladium(0) (25.8 mg, 22.3 μmol) was added, and the mixture was heated in a microwave at 110°C for 35 minutes. The mixture was diluted with water and extracted three times with DCM. The combined organic layers were washed with saturated bicarbonate solution and saline solution, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography using silica gel to obtain the desired product as a grayish-white powder. 26 mg (52%) ESI (MS) m / z = 445.2 [M+H] +

[0387] The following examples were prepared as described in Example 10. [Table 3]

[0388] Example 13 [(3R,9aS)-3-(4-fluoro-3-propa-1-inylphenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone [(3R,9aS)-3-(3-bromo-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone (Example 6, 43 mg, 88.9 μmol), TEA (27 mg, 37.2 μl, 267 μmol), trimethyl(propa-1-in-1-yl)silane (39.9 mg, 52.7 μl, 356 μmol), PdCl2(DPPF)-CH2Cl2 adduct (7.26 mg, 8.89 μmol), and copper(I) iodide (2.5 mg, 13.3 μmol) in a microwave vial were degassed with argon. Subsequently, 1 M TBAF (133 μl, 133 μmol) was added to THF, and the reaction mixture was stirred in microwave at 120°C for 2.5 hours. The mixture was diluted with water and extracted three times by DCM. The combined organic layers were washed with saturated bicarbonate solution and saline solution, dried (Na2SO4), filtered, and concentrated. The residue was purified by SFC (Method C). 5 mg (10.5%) ESI (MS) m / z = 443.2 [M+H] +

[0389] Example 14 [(3R,9aS)-3-(3-cyano-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone A microwave vial was filled with [(3R,9aS)-3-(3-bromo-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone (Example 6, 62 mg, 128 μmol), dicyanozinc (10.1 mg, 85.9 μmol), and TMEDA (4.47 mg, 5.8 μl, 38.4 μmol), and placed under argon. Anhydrous DMF (1 ml) was added, and the mixture was degassed for 5 minutes. Pd2(dba)3 (11.7 mg, 12.8 μmol) and xanthophos (11.1 mg, 19.2 μmol) were added, and the mixture was degassed for 5 minutes. The vial was sealed and irradiated in a microwave at 110°C for 40 minutes. The reaction mixture was diluted with DCM, poured into 5% NaHCO3, and extracted three times with DCM. The organic layer was washed with saline, dried over Na2SO4, filtered, and concentrated under reduced pressure. This was then purified by preparative HPLC (Method C) to obtain the final compound as a white lyophilized powder (lyophpowder) (34 mg, 59.2%). ESI (MS) m / z = 430.1 [M + H] +

[0390] Example 24 [(3R,9aS)-3-(3-cyclopropyl-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone ((3R,9aS)-3-(3-bromo-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone (Example 6, 67 mg, 138 μmol), potassium cyclopropyltrifluoroborate (26.6 mg, 180 μmol), and cesium carbonate (135 mg, 415 μmol) were charged into a microwave vial in toluene (1.0 ml) / water (100 μl), and the mixture was degassed with argon. CataCXium A Pd G2 (9.26 mg, 13.8 μmol) was added, and the mixture was heated at 100°C for 16 hours. The mixture was extracted with toluene / water (3×), dried over Na2SO4, and concentrated under reduced pressure. The product was pre-purified by SiO2 flash chromatography, and the product was isolated as a white lyophilized powder by preparative HPLC (Method C) (2 mg, 3.2%). ESI (MS) m / z = 445.2 [M + H] +

[0391] Examples 32 and 33 (2-chloro-3-methoxyphenyl)-[(rel-3R,9aS)-3-(3-chloro-4-fluorophenyl)-9a-methyl-1,3,4,6,7,9-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone and (2-chloro-3-methoxyphenyl)-[(rel-3S,9aR)-3-(3-chloro-4-fluorophenyl)-9a-methyl-1,3,4,6,7,9-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone A mixture of 2-chloro-3-methoxybenzoic acid (56.6 mg, 304 μmol), 3-(3-chloro-4-fluorophenyl)-9a-methyloctahydropyrazino[2,1-c][1,4]oxazine hydrochloride (intermediate 4, 75 mg, 233 μmol), and HATU (133 mg, 350 μmol) was dissolved in DMF (2.08 ml). Then, DIPEA (151 mg, 204 μl, 1.17 mmol) was added to the solution, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted with HCl / saturated NaHCO3 (3 × 30 ml) and saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. Two products were obtained by purification by SFC (Method C) and HPLC (Method A). Example 32: Freeze-dried white powder (21 mg, 18%), ESI (MS) m / z = 453.1 [M + H] + Example 33: Freeze-dried white powder (10 mg, 9%), ESI (MS) m / z = 453.1 [M + H] +

[0392] Examples 45 and 46 (2-chloro-3-methoxyphenyl)-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone and (2-chloro-3-methoxyphenyl)-[(3S,9aR)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone In a 25 mL round-bottom flask, (2-chloro-3-methoxyphenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 1,143 mg, 502 μmol) was mixed with tetrahydrofuran (2.5 ml) to obtain a colorless solution. DIPEA (84.4 mg, 114 μl, 653 μmol) and 2-bromo-1-(3-chloro-4-fluorophenyl)ethane-1-one (126 mg, 502 μmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution, dried over NaSO4, filtered, and concentrated. The solvent was removed under reduced pressure, and the unpurified product was purified by flash chromatography (DCM / MeOH 0-20%). 222 mg of the product was isolated, and isomers were separated by chiral SFC (Method E). Example 45 85 mg (37%), light brown solid. ESI(MS)m / z=455.3[M+H] + Example 46 81 mg (35%), light brown solid. ESI(MS)m / z=455.3[M+H] +

[0393] Examples 51 and 52 (2-chloro-3-methoxyphenyl)-[rel-(3S,9aS)-3-(2,4-dimethylthiazole-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone and (2-chloro-3-methoxyphenyl)-[rel-(3R,9aR)-3-(2,4-dimethylthiazole-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone i) (2-chloro-3-methoxyphenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 1,164 mg, 577 μmol) and 2-bromo-1-(2,4-dimethylthiazole-5-yl)ethane-1-one (135 mg, 0.577 μmol) were dissolved / dispersed in 8 mL of THF. DIPEA (130 μL, 750 μmol) was added dropwise over 10 minutes. The dark green reaction mixture was stirred at room temperature. After 18 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 solution, the aqueous layer was back-extracted with ethyl acetate, the combined organic layers were dried over NaSO4, filtered, adsorbed onto silica, and concentrated under reduced pressure. The unpurified product was purified by silica column chromatography (SiO2, DCM:MeOH 100:0~90:10). rac-(2-chloro-3-methoxyphenyl)((3R,9aS)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone was isolated as a racemic mixture (100 mg, 40%).

[0394] ii) rac-(2-chloro-3-methoxyphenyl)((3R,9aS)-3-(2,4-dimethylthiazole-5-yl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (60 mg, 137 μmol) was dissolved in 4.4 mL of DCM and 2.2 mL of TFA. Triethylsilane (66 μL, 411 μmol) was added, and the mixture was stirred at 45°C. After 48 hours, an additional 1 mL of TFA and 30 μL of silane were added, and the mixture was heated to 65°C. After a further 72 hours, the mixture was concentrated under reduced pressure and purified by silica column chromatography (DCM / MeOH). Two distinct enantiomers were obtained by chiral SFC (Method A) (1.8 mg, 2.4%; 2.1 mg, 3%). ESI(MS)m / z=422.2[M+H] +

[0395] Examples 53 and 54 (2-chloro-3-methoxyphenyl)-[rac-(3R,9aR)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone and (2-chloro-3-methoxyphenyl)-[rac-(3S,9aR)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone i) In a microwave vial, 2-chloro-3-methoxyphenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 1, 218 mg, 765 μmol) and 5-bromo-2-(oxiran-2-yl)pyridine (CAS 1335050-95-7, 153 mg, 765 μmol) were dissolved in 2 mL of MeOH and heated in a microwave at 120°C for 85 minutes. This was then purified by silica column chromatography (DCM / MeOH) to obtain (4-(2-(5-bromopyridine-2-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazin-1-yl)(2-chloro-3-methoxyphenyl)methanone as a dark red oil (262 mg, 71%). ESI (MS) m / z = 486.2 [M + H] +

[0396] (4-(2-(5-bromopyridine-2-yl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazin-1-yl)(2-chloro-3-methoxyphenyl)methanone (73 mg, 151 μmol) was dissolved in 1.2 mL of dry toluene. 2-(tributyl-15-phosphanylidene)acetonitrile (127 mg, 527 μmol) was added to 0.3 mL of toluene, and the mixture was degassed with argon and then heated to 100°C for 4 hours. The mixture was concentrated under reduced pressure and purified by silica column chromatography (DCM / MeOH 100 / 0~90 / 10). The still-impure compound was obtained as a brownish viscous oil (66 mg), which was subjected to SFC to separate two diastereomers. Example 53 (trans) 1.7 mg, 2.4%; ESI (MS) m / z = 468.1 [M + H]+ Example 54 (cis) 4.7 mg, 6.7%; ESI (MS) m / z=468.1 [M+H] +

[0397] Examples 58 and 59 (2-chloro-3-methoxyphenyl)-[rac-(3S,9aS)-3-(5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone and (2-chloro-3-methoxyphenyl)-[rac-(3R,9aS)-3-(5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 3-chloro-5-(oxiran-2-yl)pyridine (CAS 1335057-62-9, 72 mg, 464 μmol) and intermediate 1 (120 mg, 0.42 mmol), Examples 58 and 59 were synthesized following the procedure described for Examples 53 and 54. Example 58 (cis), 5.4 mg, ESI (MS) m / z = 422.2 [M + H] + Example 59 (trans), 5.8 mg, ESI (MS) m / z = 422.2 [M + H] +60

[0398] Examples 60 and 61 (2-chloro-3-methoxyphenyl)-[rel-(3S,9aS)-3-(1H-benzimidazole-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone and (2-chloro-3-methoxyphenyl)-[rel-(3R,9aR)-3-(1H-benzimidazole-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone (2-chloro-3-methoxyphenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 1, 96 mg, 337 μmol) and DIPEA (65 μL, 371 μmol) were dispersed in 2 mL of dry THF and cooled in an ice bath. 1-(1H-benzo[d]imidazole-2-yl)-2-chloroethane-1-one (79 mg, 405 μmol) was dissolved in 1 mL of dry THF and added dropwise to the solution over 10 minutes. This was then heated overnight to 70°C. This was concentrated under reduced pressure and then purified by silica column chromatography (DCM:MeOH 100:0~90:10). The compound was obtained as a yellow solid (47 mg, 24%), and the two enantiomers were separated by chiral SFC (Method D). Example 60 (Enantiomer A) 10.9 mg, ESI (MS) m / z = 443.2 [M + H] + Example 61 (Enantiomer B) 16.2 mg, ESI (MS) m / z = 443.2 [M + H] +

[0399] Example 63 (2-Chloro-3-methoxyphenyl)-[rel-(3S,9aS)-3-[6-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 2-(oxyran-2-yl)-6-(trifluoromethyl)pyridine (CAS 1346534-02-8, 187 mg, 989 μmol) and intermediate 1 (262 mg, 920 μmol), Example 63 was synthesized following the procedure described for Examples 53 and 54. Purification by SFC (twice, methods C and E) yielded four enantiopurine stereoisomers. Example 63 (more abundant stereoisomer, trans, enantiomer A), 13.8 mg (6.4%), colorless oily substance, ESI (MS) m / z = 456.2 [M + H] +

[0400] Examples 66 and 67 (2-chloro-3-methoxyphenyl)-[rel-(3R,9aR)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone and (2-chloro-3-methoxyphenyl)-[rel-(3S,9aS)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 4,5-dichloro-2-(oxiran-2-yl)pyridine (intermediate 37,159 mg, 669 μmol) and intermediate 1 (170 mg, 284 μmol), Examples 66 and 67 were synthesized following the procedure described for Examples 53 and 54. The products were isolated as two distinct enantiomers (both trans) after chiral SFC. Example 66 (Enantiomer A): 8.7 mg, 4.6%, ESI (MS) m / z = 456.1 [M + H] + Example 67 (Enantiomer B): 9.6 mg, 5.4%, ESI (MS) m / z = 456.1 [M + H] +

[0401] Example 65 [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)pyridine-3-yl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone (S)-(2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl)(3-(hydroxymethyl)piperazine-1-yl)methanone (intermediate 5, 40 mg, 118 μmol) and DIPEA (16.8 mg, 130 μmol) were dispersed in 0.8 mL of dry THF and cooled to 0°C. 2-bromo-1-(6-(trifluoromethyl)pyridine-2-yl)ethane-1-one (CAS 1379332-23-6, 32 mg, 118 μmol) was dissolved in 0.5 mL of dry THF and added dropwise to the solution over 10 minutes. After 5 hours, the reaction mixture was warmed to room temperature and stirred overnight. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure, and purified by silica column chromatography (MeOH 0%~10% in DCM). The product was obtained as a white solid. 30.8 mg, 48%. ESI(MS)m / z=526.2[M+H] +

[0402] Example 68 [(9aS)-3-[6-(trifluoromethyl)-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)pyridine-3-yl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone (Example 65, 5.7 mg, 10.8 μmol) was dissolved in 0.3 mL of dry DCM and 0.15 mL of TFA. TES (5.2 μL, 32.5 μmol) was added to the yellowish solution and stirred at 60°C for 64 hours, at which point the solution turned red. The reaction mixture was concentrated under reduced pressure, and the residual TFA was co-evaporated with toluene. The unpurified product was then purified by reverse-phase HPLC (Method B) to obtain the compound of interest as a white solid (2.5 mg, 45%). A mixture of two diastereomers (trans / cis 2:1). ESI(MS)m / z=510.2[M+H]+

[0403] Example 69 [[2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[(3R,9aS)-3-[4-(difluoromethoxy)phenyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone (S)-(2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 5, 37 mg, 109 μmol) and DIPEA (23 μL, 131 μmol) were dispersed in 1.1 mL of dry THF and cooled to 0°C. 2-bromo-1-(4-(difluoromethoxy)phenyl)ethane-1-one (CAS 141134-24-9, 32 mg, 120 μmol) was dissolved in 0.3 mL of dry THF and added dropwise to the solution over 10 minutes. After stirring overnight at room temperature, the reaction mixture was cooled again, and 6 μL of DIPEA and 10 mg of 2-bromo-1-(4-(difluoromethoxy)phenyl)ethane-1-one in 0.3 mL of dry THF were added. After 30 minutes, the mixture was warmed to room temperature. 3.5 hours later, the mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica column chromatography (DCM with 0%-10% MeOH). The product was isolated as a yellow solid (28.8 mg, 50%). ESI (MS) m / z = 523.2 [M+H] +

[0404] Example 73 (2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl)((9aS)-3-(4-(difluoromethoxy)phenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone Starting from Example 69 (10.9 mg, 20.8 μmol), Example 73 was prepared as described for Example 68. The reaction was completed after 3 hours, and the product was obtained as a white solid (10.3 mg, 97%). A trans / cis 3:1 mixture of diastereomers. ESI(MS)m / z=507.2[M+H] +

[0405] Example 70 [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[(9aS)-3-(6-bromo-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone (9aS)-3-(5-bromopyridine-2-yl)octahydropyrazino[2,1-c][1,4]oxazine hydrochloride (intermediate 38, 25 mg, 74.7 μmol), 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (intermediate 29, 24.3 mg, 101 μmol), and HATU (38.3 mg, 101 μmol) were dissolved in 800 μL of DMF. DIPEA (46 μL, 261 μmol) was added, and the reaction was stirred at room temperature. After 3 hours, it was concentrated under reduced pressure and separated by preparative HPLC. 2.7 mg (6%) of the desired product was obtained as a white lyophilized solid. A mixture of both diastereomers was obtained. ESI (MS) m / z = 522.2 [M + H] +

[0406] Example 71 [(3S,9aS)-3-hydroxy-3-(1-methylbenzimidazole-2-yl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediates 1S and 2-bromo-1-(1-methyl-1H-benzo[d]imidazole-2-yl)ethane-1-one, Example 71 was synthesized as described in Example 65. Yield 203 mg, 80.1%. ESI(MS)m / z=457.3[M+H] +

[0407] Example 74 3-[(3S,9aS)-8-(2-chloro-3-methoxybenzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridine-2-one ((3S,9aS)-3-(2-(benzyloxy)-5-chloropyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone (intermediate 35B, 31.6 mg, 59.8 μmol) was dissolved in 1 mL of dry DCM, and 1 mL of TFA was added dropwise. After 1.5 hours, the mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with saturated bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica chromatography (MeOH 0%~10% in DCM). The desired product was obtained as an orange-brown solid (19.3 mg, 66%). ESI (MS) m / z = 438.2 [M+H] +

[0408] Example 75 3-[(3R,9aS)-8-(2-chloro-3-methoxybenzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridine-2-one ((3S,9aS)-3-(2-(benzyloxy)-5-chloropyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone (intermediate 35A, 44.7 mg, 84.6 μmol) was dissolved in 1.3 mL of dry DCM, and 1.3 mL of TFA was added dropwise. After 1.5 hours, the mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with saturated bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was then purified by silica chromatography (MeOH 0%~10% in DCM). The desired product was obtained as a light brown solid (34.3 mg, 93%). ESI (MS) m / z = 438.2 [M+H] +

[0409] Example 77 3-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridine-2-one Starting from 5-chloro-3-((3R,9aS)-octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyridine-2-ol 2,2,2-trifluoroacetate (intermediate 49, 24 mg, 62.5 μmol) and intermediate 29 (24.5 mg, 101 μmol), Example 77 was prepared as described in Example 70. The product was purified by preparative HPLC (Method G) and obtained as a white lyophilized solid (5.4 mg, 14.6%). ESI (MS) m / z = 492.2 [M + H] +

[0410] Examples 83 and 84 (2-chloro-3-methoxyphenyl)((3S,9aS)-3-(5-chloro-4-methylpyridine-2-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone and (2-chloro-3-methoxyphenyl)((3R,9aS)-3-(5-chloro-4-methylpyridine-2-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone Starting with 5-chloro-4-methyl-2-(oxiran-2-yl)pyridine (intermediate 39,130 ​​mg, 766 μmol) and intermediate 1S (291 mg, 0.92 mmol), Examples 83 and 84 were synthesized according to the procedure described for Examples 53 and 54. The two diastereomers were obtained separately by preparative HPLC. Example 83 (more abundant stereoisomer, trans), yellow solid, 47 mg, ESI (MS) m / z = 436.2 [M + H] + Example 84 (The cis stereoisomer, a small amount, contains approximately 30% of the trans stereoisomer), yellow solid, 25.8 mg (9.8%), ESI (MS) m / z = 436.2 [M + H] +

[0411] Example 89 (2-Chloro-3-methoxyphenyl)-[(3S,9aS)-3-[6-(trifluoromethyl)pyridazin-3-yl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 3-(oxiran-2-yl)-6-(trifluoromethyl)pyridazine (intermediate 11, see steps a+b, 72 mg, 379 μmol) and intermediate 1S (178 mg, 530 μmol), Example 89 was synthesized according to the procedure described for Examples 53 and 54. Two diastereomers were obtained separately by preparative HPLC. Example 89 (more abundant stereoisomer, trans), white lyophilized solid, 5.3 mg (4.0%), ESI (MS) m / z = 457.2 [M + H] +

[0412] Examples 90 and 91 [(3R,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone and [(3R,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting with 4-chloro-2-(oxiran-2-yl)pyridine (CAS 115548-57-7, 90 mg, 578 μmol) and intermediate 1S (220 mg, 694 μmol), Examples 90 and 91 were synthesized according to the procedure described for Examples 53 and 54. Two diastereomers were obtained separately by purification by preparative HPLC. Example 90 (small amount of stereoisomer, cis), light brown solid, 17.2 mg, ESI (MS) m / z = 422.1 [M + H] + Example 91 (more abundant stereoisomer, trans), light brown solid, 18.7 mg, ESI (MS) m / z = 422.1 [M + H] +

[0413] Example 98 (2-Chloro-3-methoxyphenyl)-[(3S,9aS)-3-[5-Chloro-4-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 5-chloro-2-(oxiran-2-yl)-4-(trifluoromethyl)pyridine (intermediate 40,192 mg, 859 μmol) and intermediate 1S (353 mg, 1.12 mmol), Example 98 was synthesized following the procedure described for Examples 53 and 54. Two diastereomers were obtained separately by preparative HPLC. Example 98 (more abundant stereoisomer, trans), white lyophilized solid, 22.8 mg (9.1%) ESI (MS) m / z = 490.2 [M + H] +

[0414] Example 99 (2-Chloro-3-methoxyphenyl)-[(3S,9aS)-3-[4-(trifluoromethoxy)-2-pyridyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 2-(oxiran-2-yl)-4-(trifluoromethoxy)pyridine (intermediate 41,218 mg, 1.06 mmol) and intermediate 1S (403 mg, 1.28 mmol), Example 99 was synthesized according to the procedure described for Examples 53 and 54. Two diastereomers were obtained separately by preparative HPLC. Example 99 (more abundant stereoisomer, trans), pale yellow lyophilized solid, 51.1 mg (16%) ESI (MS) m / z = 472.2 [M + H]+

[0415] Example 101 (2-Chloro-3-methoxyphenyl)-[(3S,9aS)-3-[5-fluoro-4-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 5-fluoro-2-(oxiran-2-yl)-4-(trifluoromethyl)pyridine (intermediate 42,308 mg, 1.49 mmol) and intermediate 1S (508 mg, 1.78 mmol), Example 101 was synthesized according to the procedure described for Examples 53 and 54. Two diastereomers were obtained separately by preparative HPLC. Example 101 (more abundant stereoisomer, trans), grayish-white lyophilized solid, 30.6 mg (12.8%) ESI (MS) m / z = 474.2 [M + H] +

[0416] Example 104 (2-Chloro-3-methoxyphenyl)-[(3S,9aS)-3-[5-Chloro-4-(difluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 5-chloro-4-(difluoromethyl)-2-(oxiran-2-yl)pyridine (intermediate 43,350 mg, 1.53 mmol) and intermediate 1S (524 mg, 1.84 mmol), Example 104 was synthesized according to the procedure described for Examples 53 and 54. Two diastereomers were obtained separately by preparative HPLC. Example 104 (more abundant stereoisomer, trans), grayish-white lyophilized solid, 68.2 mg (14.1%) ESI (MS) m / z = 472.2 [M + H] +

[0417] Example 107 (2-Chloro-3-methoxyphenyl)-[(3S,9aS)-3-(5-Chloro-4-bromo-2-pyridyl]-3,4,6,7,9,9a-Hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone Starting with 4-bromo-5-chloro-2-(oxiran-2-yl)pyridine (intermediate 44,304 mg, 908 μmol, purity 70%) and intermediate 1S (315 mg, 1.22 mmol), Example 107 was synthesized according to the procedure described for Examples 53 and 54. Two diastereomers were obtained separately by preparative HPLC purification. Example 107 (more abundant stereoisomer, trans), grayish-white lyophilized solid, 23 mg (8.4%) ESI (MS) m / z = 502.1 [M + H] +

[0418] Example 102 [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-[5-(trifluoromethyl)-1H-pyrazole-4-yl]phenyl]methanone (3R,9aS)-3-(3-chloro-4-fluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine (intermediate 2, 26.5 mg, 97.9 μmol), 2-fluoro-3-(5-(trifluoromethyl)-1H-pyrazole-4-yl)benzoic acid (intermediate 45, 33.5 mg, 97.9 μmol), and DIPEA (56 μL, 323 μmol) were mixed with 1 mL of dry THF and cooled to 0°C. T3P (93 mg in 50% wt / wt HCl solution, 147 μmol) was added dropwise to 0.2 mL of dry THF over 10 minutes. After 20 minutes, the mixture was warmed to room temperature. After 30 minutes, the mixture was diluted with HCl, washed with saturated bicarbonate solution, then with saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was purified by silica column chromatography (DCM with 0%-10% MeOH). The compound was obtained as a yellow solid (30.5 mg, 51%). ESI (MS) m / z = 527.2 [M+H] +

[0419] Example 103 [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[3-[5-(trifluoromethyl)-1H-pyrazole-4-yl]phenyl]methanone Starting with intermediate 2 (22.9 mg, 84.6 μmol) and 3-(5-(trifluoromethyl)-1H-pyrazole-4-yl)benzoic acid (intermediate 46 mg, 26 mg, 102 μmol), Example 103 was prepared as described in Example 102. The unpurified product was purified by silica column chromatography (MeOH 0%~10% in DCM). The compound was obtained as a white solid (19.9 mg, 37.4%). ESI (MS) m / z = 509.2 [M+H] +

[0420] Example 105 4-[3-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chlorophenyl]-1H-pyridine-2-one Example 105 was prepared as described in Example 102, starting with intermediate 2 (40 mg, 148 μmol) and lithium 2-chloro-3-(2-oxo-1,2-dihydropyridine-4-yl)benzoate (intermediate 47, 37.8 mg, 148 μmol). The unpurified product was purified by silica column chromatography (DCM with 0%-10% MeOH). The compound was obtained as a grayish-white solid (14.7 mg, 17.2%). ESI (MS) m / z = 502.2 [M+H] +

[0421] Example 106 5-[3-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chlorophenyl]-1H-pyridine-2-one Example 106 was prepared as described in Example 102, starting with intermediate 2 (60 mg, 222 μmol) and 2-chloro-3-(6-oxo-1,6-dihydropyridine-3-yl)benzoic acid (intermediate 48, 55 mg, 222 μmol). The unpurified product was purified by silica column chromatography (MeOH in DCM 0%~10%). The compound was obtained as a white solid (12.8 mg, 10.8%). ESI (MS) m / z = 502.2 [M+H] +

[0422] Example 78 [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone Starting with intermediate 8 (33.8 mg, 89.2 μmol) and 2-fluoro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (intermediate 33, 20 mg, 89.2 μmol), Example 78 was prepared as described in Example 102. The unpurified product was purified by silica column chromatography (MeOH 0%~10% in DCM). The compound was obtained as a grayish-white solid (14.7 mg, 29.8%). ESI (MS) m / z = 510.2 [M+H] +

[0423] Example 80 4-[3-[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chlorophenyl]-1H-pyrazole-3-carbonil Example 80 was prepared as described in Example 102, starting with intermediate 8 (23.3 mg, 68.6 μmol) and 2-chloro-3-(3-cyano-1H-pyrazole-4-yl)benzoic acid (intermediate 34, 17 mg, 68.6 μmol). The unpurified product was purified by silica column chromatography (DCM with 0%-10% MeOH). The compound was obtained as a grayish-white solid (15.1 mg, 31%). ESI (MS) m / z = 533.2 [M + H] +

[0424] Example 81 [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone Starting with intermediate 8 (188 mg, 554 μmol) and 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (intermediate 29,127 mg, 528 μmol), Example 81 was prepared as described in Example 102. The unpurified product was purified by silica column chromatography (MeOH in DCM 0%~10%). Dechlorinated Example 81 was isolated as a by-product (the main product was Example 65). The compound was obtained as a grayish-white solid (23.2 mg, 8.1%). ESI (MS) m / z = 492.3 [M + H] +

[0425] Example 85 [(3S,9aS)-3-hydroxy-3-[5-(trifluoromethyl)-2-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone Starting with intermediate 9 (33.8 mg, 99.5 μmol) and 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (intermediate 29, 22.8 mg, 94.8 μmol), Example 85 was prepared as described in Example 102. The unpurified product was purified by silica column chromatography (MeOH 0%~10% in DCM). Dechlorinated Example 81 was isolated as a by-product (the main product was Example 65). The compound was obtained as a grayish-white solid (6.9 mg, 13.8%). ESI (MS) m / z = 526.2 [M + H] +

[0426] Example 86 [(3S,9aS)-3-hydroxy-3-[5-(trifluoromethyl)-2-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-oxazole-4-yl-phenyl)methanone Starting with intermediate 9 (41 mg, 121 μmol) and 2-chloro-3-(oxazole-5-yl)benzoic acid (intermediate 32, 27 mg, 121 μmol), Example 86 was prepared as described in Example 102. The unpurified product was purified by silica column chromatography (MeOH 0%~10% in DCM). The compound was obtained as a white solid (7 mg, 11.4%). ESI (MS) m / z = 509.2 [M+H] +

[0427] Example 97 [(3S,9aS)-3-[6-(trifluoromethyl)pyridazin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone Starting with intermediate 11 (22 mg, 76.3 μmol) and 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (intermediate 29, 27.5 mg, 91.6 μmol), Example 97 was prepared as described in Example 102. The unpurified product was purified by reverse-phase chromatography (Method B). The compound was obtained as a white solid (8.2 mg, 20.5%). ESI (MS) m / z = 511.2 [M + H] +

[0428] Example 82 [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazole-4-yl)phenyl]methanone (2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)((3R,9aS)-3-hydroxy-3-(6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (0.064 g, 113 μmol, unpurified), 4-bromo-1H-pyrazole (18.2 mg, 124 μmol), and K2CO3 (46.7 mg, 338 μmol) were placed in a microwave vial and mixed with dioxane (1.5 ml) and water (0.5 ml). The reaction mixture was degassed and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.98 mg, 11.3 μmol) was added. Next, this was heated at 115°C for 30 minutes. The reaction mixture was poured into 2 mL of saturated NaHCO3 and extracted with Â(2 × 5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified material was purified by flash chromatography (silica gel, 0%-10% MeOH in DCM): 10 mg of the desired product + impurities mixture was obtained. The yellow oily substance was purified by preparative HPLC (Method B) to obtain the product as a white lyophilized powder (2.1 mg, 3%). ESI (MS) m / z = 506.31 [MH] -

[0429] a) (3-bromo-2-chlorophenyl)((3R,9aS)-3-hydroxy-3-(6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone In a 25 mL two-necked flask, (3R,9aS)-3-(6-(trifluoromethyl)pyridine-3-yl)octahydropyrazino[2,1-c][1,4]oxazine-3-ol hydrochloride (intermediate 8, 0.100 g, 294 μmol), 3-bromo-2-chlorobenzoic acid (83.2 mg, 353 μmol), and HATU (134 mg, 353 μmol) were mixed with DMF (3 ml) to obtain a yellow solution. DIPEA (114 mg, 154 μl, 883 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 5 mL of H2O and extracted with ethyl acetate (2 × 10 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified material was purified by flash chromatography (silica gel, heptane, 0% to 100% ethyl acetate). The product was obtained as a colorless oil (132 mg, 86%). ESI (MS) m / z = 522.1 [M + H] +

[0430] b) (2-Chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)((3R,9aS)-3-hydroxy-3-(6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone In a microwave vial, bis(pinacolato)diborone (83.7 mg, 330 μmol), (3-bromo-2-chlorophenyl)((3R,9aS)-3-hydroxy-3-(6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (0.132 g, 253 μmol), and potassium acetate (74.6 mg, 760 μmol) were dispersed in dioxane (1 ml) and degassed. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (31.1 mg, 38 μmol) was added. This was reacted in MW (microwave) (100, 60 min). Next, this was mixed with water and extracted twice with butyl. The combined organic layer was washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure. Attempts were made to purify the unpurified substance twice by flash chromatography (50%-100% ethyl silica gel in heptane; 0%-10% MeOH in silica gel in DCM), but the two could not be separated. Therefore, the unpurified product (brownish oily substance, 64 mg, 44.5%) was used directly in the process. ESI (MS) m / z = 568.3 [M + H] +

[0431] Example 87 [3-(1,3-benzothiazole-2-yl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone (3-(benzo[d]thiazole-2-yl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone (150 mg, 326 μmol) was dissolved in 9 mL of DCM and 4.5 mL of TFA. TES (420 μL, 2.61 mmol) was added, and the reddish mixture was stirred under argon in a sealed pressure vial at room temperature. After 2 hours, it was heated to 60°C. After 2 days, the reaction product was concentrated under reduced pressure, poured onto ethyl acetate, washed with saturated bicarbonate solution, filtered, adsorbed onto silica, and purified by silica column chromatography (Hept: ethyl acetate 80:20~10:90). The described removal product was the main product, obtained as a yellow solid (40 mg, 28%). ESI (MS) m / z = 442.2 [M+H] +

[0432] (3-(benzo[d]thiazole-2-yl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone (2-chloro-3-methoxyphenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 1, 96 mg, 337 μmol) and DIPEA (65 μL, 371 μmol) were dissolved in 2 mL of dry THF and cooled in an ice bath. 1-(benzo[d]thiazole-2-yl)-2-bromoethane-1-one (88 mg, 345 μmol) was dissolved in 1 mL of dry THF and added dropwise to the solution over 10 minutes. After 4 hours, this was concentrated under reduced pressure. The red foam was dissolved in SiO2, washed with a saturated bicarbonate solution, then with water, dried, and concentrated under reduced pressure with (Na2SO4). The compound was obtained as a slightly impure yellow-gold oily molten material. 153 mg. This was used in the next step without further purification.

[0433] Example 88 [2-Chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]-[(3S,9aS)-3-fluoro-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-Hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone (2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl)((3R,9aS)-3-hydroxy-3-(6-(trifluoromethyl)pyridine-3-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (Example 65, 16.7 mg, 31.8 μmol) was dissolved in 0.7 mL of dry DCM and cooled to -78°C. DAST (6.6 mg, 41.3 μmol) dissolved in 0.3 mL of dry DCM was added dropwise. After 40 minutes, the white suspension was warmed to room temperature. After stirring overnight, approximately 20-30% conversion was observed, so the flask was cooled again to -78°C, and DAST (12 mg, 64 μmol) in 0.2 mL of dry DCM was added. After 2 hours, this was warmed to room temperature. Since no further progression was observed, the mixture was cooled again to -78°C, and DAST (19 mg, 95 μmol) in 0.2 mL of dry DCM was added. After 40 minutes, it was warmed to room temperature. After 2 hours, it was concentrated under reduced pressure, diluted with saturated bicarbonate solution, and extracted twice with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica column chromatography (silica gel, 0%-10% MeOH in DCM). The product was obtained as a slightly orange solid (13.9 mg, 68%). ESI (MS) m / z = 528.2 [M + H] +

[0434] Examples 92 and 93 [(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone and [(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone (3R,9aS)-3-(3,4-difluorophenyl)octahydropyrazino[2,1-c][1,4]oxazine-3-ol hydrochloride (intermediate 10,134 mg, 436 μmol), 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (intermediate 29,100 mg, 416 μmol), and DIPEA (231 mg, 312 μl, 1.79 mmol) were mixed with 3.5 mL of dry THF and cooled to 0°C. T3P (410 mg, 644 μmol) dissolved in 1 mL of dry THF was added dropwise over 15 minutes. After 20 minutes, the mixture was warmed to room temperature, and after 1 hour, it was concentrated under reduced pressure, diluted with ethyl acetate, washed with saturated ammonium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified product was purified by silica column chromatography (0%-10% MeOH in DCM). This was then purified by preparative HPLC (Method B) to separate the two products. Example 92 32.2 mg (13.8%), white lyophilized powder, ESI(MS) m / z=493.1[M+H] + Example 93 11.4 mg (5.4%), white lyophilized powder, ESI(MS) m / z=459.2[M+H] +

[0435] Example 94 [(9aS)-3-[5-(trifluoromethyl)-2-pyridyl]-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone (S)-3-(5-(trifluoromethyl)pyridine-2-yl)-1,6,7,8,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine (23 mg, 80.6 μmol), 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (intermediate 29, 24.2 mg, 80.6 μmol), and DIPEA (42 μL, 242 μmol) were dissolved in 0.6 mL of DMSO-d6 and 0.2 mL of dry THF and cooled to 0°C. T3P (1.5 equivalents, 77 mg in 50% wt / wt ethyl acetate solution) was added dropwise to 0.2 mL of dry THF. After 20 minutes, the mixture was warmed to room temperature. It was partially solid due to the frozen DMSO, but quickly turned into a yellow solution upon removal from the ice bath. The following morning, since the reaction was not yet complete, an additional 20 μL (1.5 equivalents) of DIPEA and 38 mg (0.75 equivalents) of T3P were added. After 2 hours, this was diluted with saturated bicarbonate solution, extracted twice with ethyl acetate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by reverse-phase HPLC (Method B) and obtained as a bright yellow solid (7.5 mg, 18.3%). ESI (MS) m / z = 508.2 [M + H] +

[0436] a)S)-3-(5-(trifluoromethyl)pyridine-2-yl)-1,6,7,8,9,9a-Hexahydropyrazino[2,1-c][1,4]oxazine (3S,9aS)-3-(5-(trifluoromethyl)pyridine-2-yl)octahydropyrazino[2,1-c][1,4]oxazine-3-ol hydrochloride (intermediate 9,130 ​​mg, 383 μmol) was dissolved in 5.3 mL of TFA and 10.6 mL of dry DCM, to which TES (183 μL, 1.15 mmol) was added, and the yellow solution was stirred at room temperature. After heating at 70°C for 2.5 days, the bright yellow solution was concentrated under reduced pressure, diluted with 1 M HCl, and washed twice with diethyl ether. The ether layer was then back-extracted with saline. The yellow aqueous solution was basicized with 4 M NaOH, treated with sodium chloride, extracted to excess ethyl phosphate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was obtained as a neon yellow solid (24 mg, 22%). In contrast to the desired dehydroxylated product, dehydration occurred, yielding an unsaturated product. ESI(MS)m / z=286.2[M+H] +

[0437] Examples 95 and 96 [(3R,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone and [(3S,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl]methanone (2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)phenyl)((3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (Example 92, 18 mg, 36.5 μmol) was dissolved in 1 mL of dry DCM. 2,2,2-trifluoroacetic acid (750 mg, 506 μl, 6.57 mmol) and triethylsilane (12.7 mg, 17.5 μl, 110 μmol) were added. The resulting colorless solution was stirred at room temperature for 3 hours. The unpurified product was diluted with ELISA, washed with saturated NaHCO3 solution, filtered, and concentrated under reduced pressure. The unpurified substance was purified by preparative HPLC (Method B). Example 95: The more abundant isomer (trans), 8.6 mg (49.4%), white lyophilized powder, ESI (MS) m / z = 477.1 [M + H] + Example 96: Small amount of isomer (cis), 1.5 mg (8.6%), white lyophilized powder, ESI (MS) m / z = 477.2 [M + H] +

[0438] Example 100 3-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridine-2-one 3-((3R,9aS)-3-hydroxyoctahydropyrazino[2,1-c][1,4]oxazin-3-yl)-6-(trifluoromethyl)pyridine-2(1H)-one (intermediate 12, 15 mg, 47 μmol), 2-chloro-3-(3-fluoro-1H-pyrazole-4-yl)benzoic acid (intermediate 29, 12.5 mg, 51.7 μmol), EDC hydrochloride (13.5 mg, 70.5 μmol), and HOBT monohydrate (8 mg, 51.7 μmol) were mixed with 0.6 mL of dry DMF, and DIPEA (25 μL, 141 μmol) was added. The yellow mixture was stirred at room temperature. After 4.5 hours, the mixture was diluted with ethyl acetate and washed with saturated bicarbonate solution, then with saline solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified yellow substance was purified by silica column chromatography (DCM with 0%-10% MeOH). The resulting solid was not yet pure and was further purified by reverse-phase HPLC (Method B). The product was obtained as a pale yellow solid (2.5 mg, 9%). ESI (MS) m / z = 542.2 [M + H] +

[0439] Example 109 4-[3-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chlorophenyl]-1H-pyrrole-2-carbonitrile Starting from intermediates 52 and 4-bromo-1H-pyrrole-2-carbonitrile, the synthesis of Example 109 was carried out as described in Example 127. Purification by preparative HPLC (Method B). Yield 2.4 mg, 4%. ESI (MS) m / z = 515.3 [M + H] +

[0440] Example 114 4-[3-[(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-carbonyl]-2-chloro-5-fluorophenyl]-1H-pyridine-2-one (3-bromo-2-chloro-5-fluorophenyl)((3R,9aS)-3-(3-chloro-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (intermediate 50, 1 equivalent, 50 mg), (2-oxo-1,2-dihydropyridine-4-yl)boronic acid (1.2 equivalents, 16.5 mg), potassium carbonate (3 equivalents, 41 mg), and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane complex (0.1 equivalent, 8 mg) were mixed with 0.9 ml of dioxane and 0.1 ml of water, degassed with argon, and reacted in a microwave (115°C, 25 min). Further 30 mg of (2-oxo-1,2-dihydropyridine-4-yl)boronic acid and 30 μL of DIPEA were added, and the mixture was reacted again (115°C, 30 min). The reaction was not yet complete, but since boronate had been consumed again, a further 40 mg of (2-oxo-1,2-dihydropyridine-4-yl)boronic acid and 30 μL of DIPEA were added, and the mixture was reacted again (115°C, 30 min). The reaction was not yet complete, but since boronate had been consumed again, a further 60 mg of boronic acid and 30 μL of DIPEA were added, and the mixture was reacted again (115°C, 30 min). The reaction was not yet complete, but workup was carried out nonetheless: it was diluted with Â, washed with water, then washed with saturated bicarbonate aqueous solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. This was purified by silica column chromatography (10 g, 0%~10% MeOH in DCM). The unpurified product was subjected to HPLC purification (Method B) and obtained as a white solid. (10 mg, 19%) ESI (MS) m / z = 520.3 [M + H] +

[0441] Example 119 [(3R,9aS)-3-hydroxy-3-[4-(trifluoromethyl)phenyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(4-(trifluoromethyl)phenyl)ethane-1-one (CAS 383-53-9), Example 119 was synthesized as described in Example 65. Yield 145 mg, 78%. ESI (MS) m / z = 471.3 [M + H] +

[0442] Example 120 [(3R,9aS)-3-(4-chloro-3-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(4-chloro-3-fluorophenyl)ethane-1-one (CAS 63529-30-6), Example 120 was synthesized as described in Example 65. Yield 165 mg, 82%. ESI (MS) m / z = 455.2 [M + H] +

[0443] Example 125 [(3R,9aS)-3-(3-bromo-5-chlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(3-bromo-5-chlorophenyl)ethane-1-one (CAS 41011-01-2), Example 125 was synthesized as described in Example 65. Yield 119 mg, 66%. ESI (MS) m / z = 517.2 [M + H] +

[0444] Example 127 [(3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-isothiazole-4-ylphenyl)methanone In a microwave vial, (2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)((3R,9aS)-3-(3-chloro-4-fluorophenyl)-3-hydroxyhexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (intermediate 52, 0.060 g, 109 μmol), 4-bromoisothiazole (19.6 mg, 120 μmol), and K2CO3 (45.1 mg, 327 μmol) were mixed with dioxane (1.5 ml) and water (250 μl). The reaction mixture was degassed, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (APhos2PdCl2, 7.71 mg, 10.9 μmol) was added. The vial was sealed and heated at 80°C for 2 hours. The reaction mixture was poured into 2 mL of saturated NaHCO3 and extracted with Depositphotos (2 × 5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified material was purified by flash chromatography (silica gel, 20 g, 0%~10% MeOH in DCM) to obtain the unpurified product, which was further purified by preparative HPLC (Method J). Finally, the product was obtained as 4 mg (7%) of a white lyophilized powder. ESI (MS) m / z = 508.1 [M + H] +

[0445] Example 128 [(3R,9aS)-3-(2,4,5-trifluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone (2-chloro-3-methoxyphenyl)((3R,9aS)-3-hydroxy-3-(2,4,5trifluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)methanone (Example 144, 1 equivalent, 37 mg) was dissolved in 1 mL of dry DCM and 0.5 mL of TFA at room temperature. TES (3 equivalents, 35 μL) was added, and the yellowish solution was stirred at 40°C for 5 hours, then at room temperature overnight. This was then concentrated under reduced pressure and purified by silica column chromatography (10 g, DCM with 0%~10% MeOH). The product was obtained as a yellow oil (28 mg, 80%). ESI (MS) m / z = 441.2 [M+H] +

[0446] Example 129 [(3R,9aS)-3-(2,4-dichlorolophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(2,4-dichlorophenyl)ethane-1-one (CAS 2631-72-3), Example 129 was synthesized as described in Example 65. Yield 163 mg, 82%. ESI (MS) m / z = 473.2 [M + H] +

[0447] Example 130 [(3R,9aS)-3-hydroxy-3-[2,3,4-trifluorophenyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(2,3,4-trifluorophenyl)ethane-1-one (CAS 1214345-02-4), Example 130 was synthesized as described in Example 65. Yield 109 mg, 55%. ESI (MS) m / z = 457.3 [M + H] +

[0448] Example 131 [(3S,9aS)-3-(4-bromo-5-methoxy-2-thienyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(4-bromo-5-methoxythiophen-2-yl)ethane-1-one (CAS 882748-05-2), Example 131 was synthesized as described in Example 65. Purification by HPLC and Method J yielded 22.6 mg, 22%. ESI (MS) m / z = 519.2 [M + H] +

[0449] Example 136 3-[(3R,9aS)-8-(2-chloro-3-methoxybenzoyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridine-2-one Starting from intermediate 1S and 3-(2-bromoacetyl)-6-(trifluoromethyl)pyridine-2(1H)-one (CAS 1000931-76-9), Example 136 was synthesized as described in Example 65. HPLC, purification by Method B, yield 10.4 mg, 7.5%. ESI (MS) m / z = 488.3 [M + H] +

[0450] Example 137 [(3R,9aS)-3-(3-chloro-4-oxazole5-ylphenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone ((3R,9aS)-3-(4-bromo-3-chlorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone (Example 110, 0.075 g, 150 μmol), oxazole (20.7 mg, 300 μmol, formula: 2), Pd(OAc)2 (1.68 mg, 7.5 μmol), potassium carbonate (62.2 mg, 450 μmol), pivalic acid (6.13 mg, 60 μmol), and di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphane (7.21 mg, 15 μmol) were dispersed in DMA (2 ml), degassed, and heated in a thermoblock at 110 °C for 2 hours. Next, this was cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The organic layers were combined, washed with brine (x2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified substance was purified by flash chromatography (silica gel, 20 g, 0%-10% MeOH in DCM). Yield: 29 mg, 35%. ESI (MS) m / z = 488.3 [M+H] +

[0451] Example 139 [(3S,9aS)-3-[2-(4-fluorophenyl)thiazole-4-yl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(2-(4-fluorophenyl)thiazole-4-yl)ethane-1-one (CAS 937079-09-9), Example 139 was synthesized as described in Example 65. Yield 68 mg, 75%. ESI (MS) m / z = 504.3 [M + H] +

[0452] Example 141 [(3R,9aS)-3-hydroxy-3-[3-(trifluoromethyl)phenyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(3-(trifluoromethyl)phenyl)ethane-1-one (CAS 2003-10-3), Example 141 was synthesized as described in Example 65. Yield 135 mg, 71%. ESI (MS) m / z = 471.3 [M + H] +

[0453] Example 142 [(3R,9aS)-3-(2,3-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(2,3-difluorophenyl)ethane-1-one (CAS 886762-77-2), Example 142 was synthesized as described in Example 65. Yield 150 mg, 72%. ESI (MS) m / z = 439.2 [M + H] +

[0454] Example 143 [(3S,9aS)-3-hydroxy-3-(3-phenylisoxazol-5-yl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(3-phenylisoxazole-5-yl)ethane-1-one (CAS 14731-14-7), Example 143 was synthesized as described in Example 65. Yield 124 mg, 70%. ESI (MS) m / z = 470.3 [M + H] +

[0455] Example 144 [(3R,9aS)-3-hydroxy-3-(2,4,5-trifluorophenyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(2,4,5-trifluorophenyl)ethane-1-one (CAS 193977-34-3), Example 144 was synthesized as described in Example 65. Yield 58 mg, 36%. ESI (MS) m / z = 457.2 [M + H] +

[0456] Example 145 [(9aS)-3-(4-fluoro-3-oxazole-5-ylphenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone ((9aS)-3-(3-bromo-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone (Example 6, 0.075g, 155μmol), oxazole (21.4mg, 310μmol), Pd(OAc)2 (1.74mg, 7.75μmol), potassium carbonate (64.3mg, 4 65 μmol) of di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine (tBuXPhos) (7.45 mg, 15.5 μmol) was dispersed in DMA (2 ml), degassed, and heated in a thermoblock at 110°C for 2 hours. The mixture was then cooled to room temperature, diluted with water, and extracted twice with ethyl acetate. The organic layers were combined, washed with brine (x2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The unpurified substance was purified by flash chromatography (silica gel, 20 g, 0%-10% MeOH in DCM). Yield: 38 mg, 48%, light brown oily substance. ESI (MS) m / z = 472.3 [M+H] +

[0457] Example 146 [(3S,9aS)-3-(1,3-benzothiazole-2-yl)]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 1-(1,3-benzothiazole-2-yl)-2-bromoethane-1-one (CAS 54223-20-0), Example 146 was synthesized as described in Example 65. Yield 118 mg, 68%. ESI (MS) m / z = 460.3 [M + H] +

[0458] Example 149 [(3R,9aS)-3-(2,3-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone [(3R,9aS)-3-(2,3-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone (Example 142, 50 mg, 114 μmol) was dissolved in 575 μl of dry DCM and 262 μl of TFA at room temperature. TES (55 μL, 342 μmol) was added, and the yellowish solution was stirred at 45°C for 2 hours. This was then concentrated under reduced pressure and purified by silica column chromatography (10 g, DCM with 0%~10% MeOH) and subsequently by preparative HPLC (Method B). The product was obtained as a yellow oil (20 mg, 39%). ESI (MS) m / z = 423.2 [M + H] +

[0459] Example 150 [(3R,9aS)-3-(2-chlorolophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(2-chlorophenyl)ethane-1-one (CAS 5000-66-8), Example 150 was synthesized as described in Example 65. Yield 128 mg, 62%. ESI (MS) m / z = 437.3 [M + H] +

[0460] Example 153 [(3R,9aS)-3-hydroxy-3-[2-methyl-6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(2-methyl-6-(trifluoromethyl)pyridine-3-yl)ethane-1-one, bromide salt (CAS 1377962-47-4), Example 153 was synthesized as described in Example 65. Yield 63 mg, 67%. ESI (MS) m / z = 486.3 [M + H] +

[0461] Example 154 [(3R,9aS)-3-(3-chloro-5-oxazole-5-ylphenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from [(3R,9aS)-3-(3-bromo-5-chlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone (Example 125, 91 mg, 176 μmol) and oxazole (24.3 mg, 252 μmol), the synthesis was carried out as described in Example 145. Yellow oily substance, yield 46 mg, 51%. ESI(MS) m / z = 504.3 [M+H] +

[0462] Example 156 [(9aS)-3-[4-fluoro-3-(1-methylpyrrole-3-yl)phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone ((9aS)-3-(3-bromo-4-fluorophenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-yl)(2-chloro-3-methoxyphenyl)methanone (Example 6, 0.075 g, 155 μmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (32.1 mg, 155 μmol), and K2CO3 (64.3 mg, 465 μmol) were mixed with dioxane (1.5 ml) and water (0.25 ml) in a microwave vial. The reaction mixture was degassed, and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11 mg, 15.5 μmol) was added. The reaction mixture was heated at 80°C for 2 hours, then poured into 2 mL of saturated NaHCO3 and extracted with siRNA (2 × 5 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The unpurified substance was purified by flash chromatography (silica gel, 20 g, 0%~10% MeOH in DCM) to obtain 77 mg of the unpurified product, which was further purified by preparative HPLC (Method B). The product was obtained as a yellow lyophilized powder. Yield 28 mg, 36%. ESI (MS) m / z = 484.4 [M + H] +

[0463] Example 157 [(3S,9aS)-3-(3-bromoisoxazole-5-yl)]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(3-bromoisoxazole-5-yl)ethane-1-one (CAS 76596-54-8), Example 157 was synthesized as described in Example 65. Yield 13.6 mg, 15%. ESI (MS) m / z = 474.2 [M + H] +

[0464] Example 160 [(3S,9aS)-3-hydroxy-3-[2-(6-methoxy-3-pyridyl)thiazole-4-yl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Starting from intermediate 1S and 2-bromo-1-(2-(6-methoxypyridine-3-yl)thiazole-4-yl)ethane-1-one (intermediate 70), Example 160 was synthesized as described in Example 65. Yield 10 mg, 19%. ESI (MS) m / z = 517.3 [M + H] +

[0465] Examples 161 and 162 [(9aS)-3-(3-chloro-4-fluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiadin-8-yl]-(2-chloro-3-methoxyphenyl)methanone Under argon, in a 25 ml glass tube, S-(((2S)-1-(2-chloro-2-(3-chloro-4-fluorophenyl)ethyl)-4-(2-chloro-3-methoxybenzoyl)piperazine-2-yl)methyl)ethanethioate (100 mg, 187 μmol) in THF (10 ml) was treated with 25% sodium methoxide in methanol (121 mg, 129 μl, 562 μmol). The yellow mixture was stirred under argon at 20-22°C for 1 hour. LC-MS showed that the desired product was formed as a pair of diastereomers. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried, and evaporated to dryness to obtain the unpurified product as a yellow oil (95 mg). The crude product was purified by SFC, Reprosher 100 PEI, and 10% MeOH. Example 161, first eluted diastereomer, 23 mg (26%), ESI (MS) m / z = 455.2 [M + H] + Example 162, second diastereomer eluted, 24 mg (27%), ESI (MS) m / z = 455.2 [M + H] +

[0466] a) (2-chloro-3-methoxyphenyl)(4-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazine-1-yl)methanone 2-(3-chloro-4-fluorophenyl)oxirane (210 mg, 1.22 mmol) and (S)-(2-chloro-3-methoxyphenyl)(3-(hydroxymethyl)piperazin-1-yl)methanone (intermediate 1S, 440 mg, 1.54 mmol) were dissolved in 7 mL of MeOH and reacted in a microwave (120°C, 60 min). This was concentrated under reduced pressure and purified by silica column chromatography (70 g, DCM with 0%-10% MeOH). The product was obtained as a yellow oily substance (206 mg, 37%). ESI (MS) m / z = 457.2 [M+H] +

[0467] b) S-(((2S)-4-(2-chloro-3-methoxybenzoyl)-1-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)piperazine-2-yl)methyl)ethanethioate Under argon, (2-chloro-3-methoxyphenyl)(4-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-3-(hydroxymethyl)piperazin-1-yl)methanone (175 mg, 383 μmol) was dissolved in THF (3.8 ml) in a 25 ml glass tube and cooled to 0°C. After adding TEA (46.5 mg, 64 μl, 459 μmol), methanesulfonyl chloride (48.2 mg, 32.8 μl, 421 μmol) and DMAP (4.68 mg, 38.3 μmol) were added. The ice bath was removed and the mixture was stirred for 2 hours. The reaction mixture was then concentrated under reduced pressure. The resulting substance was redissolved in 3 ml of DMSO and treated with potassium thioacetate (58.1 mg, 509 μmol). The reaction mixture was stirred overnight under argon at room temperature. The mixture was diluted with ethyl acetate, washed with water (three times) and saline solution, dried (Na₂SO₄), filtered, and concentrated. The unpurified product was purified by flash chromatography (silica gel, 100% heptane to 80% ethyl acetate / heptane) to obtain the desired product as a light brown oily substance (110 mg, 50%). ESI (MS) m / z = 515.3 [M + H] +

[0468] c)S-(((2S)-1-(2-chloro-2-(3-chloro-4-fluorophenyl)ethyl)-4-(2-chloro-3-methoxybenzoyl)piperazin-2-yl)methyl)ethanethioate Under argon, in a 25 ml glass tube, thionyl chloride (76.2 mg, 46.7 μl, 640 μmol) was added to S-(((2S)-4-(2-chloro-3-methoxybenzoyl)-1-(2-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)piperazine-2-yl)methyl)ethanethioate (110 mg, 213 μmol) in 2.5 ml of DCM. The mixture was cooled in an ice bath, and pyridine (67.5 mg, 69 μl, 854 μmol) was added dropwise to 0.5 ml of DCM. The reaction mixture was stirred at 0-2°C for 20 minutes, then heated to room temperature over 1 hour, and finally stirred overnight at room temperature. The reaction mixture was concentrated, the residue was diluted with ethyl acetate, and washed with 2 × 10 ml of water and saline. The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The product obtained as a yellow oily substance was used directly in the next step (105 mg, unpurified). ESI(MS)m / z=535.3[M+H] +

[0469] Example 163 The compound of formula (I) can be used as an active ingredient in a manner known to itself to produce tablets of the following composition. per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropylmethylcellulose 20mg 425mg

[0470] Example 164 The compound of formula (I) can be used in a manner known to itself as an active ingredient to produce capsules of the following composition. per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, X is -CH ２ CR ３ R ４ - ＊ or -CH=CR ３ - ＊ (the asterisk indicates the point where X is attached to Y), Y is -O-, -S-, -SO-, or -SO ２ - and R １ teeth, (a) a 5- to 14-membered heteroaryl substituted with one substituent selected from halogen, or (b) 【Chemistry 2】 It is based on R ２ is hydrogen or C １ -C ６ is alkyl, R ３ teeth, 【Chemistry 3】 It is based on R ４ is hydrogen, halogen or hydroxy; R ５ is hydrogen, halogen, hydroxy, amino, halo-C １ -C ６ -Alkyl, C １ -C ６ -Alkoxy, C １ -C ６ -Alkyl, halo-C １ -C ６ -alkoxy, cyano or oxo, R ６ is hydrogen, halogen, C ６ -C １４ -aryl, 5- to 14-membered heteroaryl, halo-C １ -C ６ -Alkoxy, halo-C １ -C ６ -Alkyl, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkoxy, C ２ -C ６ -Alkenyl, C ２ -C ６ -Alkynyl, C ３ -C １４ -cycloalkyl or cyano, and said 5- to 14-membered heteroaryl or C ６ -C １４ Aryl is halogen, cyano, amino, hydroxy, C １ -C ６ -Alkyl and C １ -C ６ -alkoxy; R ７ is hydrogen or C １ -C ６ is an alkoxy; R ８ is hydrogen or C １ -C ６ is an alkoxy; R ９ is hydrogen, C １ -C ６ -Alkyl, C １ -C ６ -Alkoxy, halo-C １ -C ６ -alkoxy, or the following formula: 【Chemistry 4】 Based on R １０ is hydrogen, halogen, or cyano; A and B are each independently 5-14 membered heteroaryl; C ６ -C １４ -aryl, 3- to 14-membered heterocyclyl or C ３ -C １４ -cycloalkyl, n and p are each independently 1, 2, 3, 4 or 5. or a pharma- ceutically acceptable salt thereof.

2. X is -CH ２ CR ３ R ４ 2. The compound of formula (I) according to claim 1, wherein -, or a pharma- ceutically acceptable salt thereof.

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

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

5. R ２ 5. A compound of formula (I) according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

6. R ４ 6. A compound of formula (I) according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen or hydroxy.

7. R ５ is hydrogen, halogen, hydroxy, halo-C １ -C ６ -Alkyl, C １ -C ６ -Alkoxy, C １ -C ６ - alkyl, cyano or oxo, or a pharma- ceutically acceptable salt thereof.

8. R ５ 7. A compound of formula (I) according to any one of claims 1 to 6, wherein is hydrogen, halogen, cyano, hydroxy or oxo, or a pharma- ceutically acceptable salt thereof.

9. R ５ 7. A compound of formula (I) according to any one of claims 1 to 6, wherein is hydrogen, fluoro, cyano, hydroxy or oxo, or a pharma- ceutically acceptable salt thereof.

10. R ６ But hydrogen, halogen, C ６ -C １４ -aryl, 5- to 14-membered heteroaryl, halo-C １ -C ６ -Alkoxy, halo-C １ -C ６ -Alkyl, oxo, C １ -C ６ -Alkyl, C １ -C ６ -Alkoxy, C ２ -C ６ -Alkenyl, C ２ -C ６ -Alkynyl, C ３ -C １４ -cycloalkyl or cyano, and said 5- to 14-membered heteroaryl or C ６ -C １４ Aryl is halogen, C １ -C ６ -Alkyl and C １ -C ６ 10. A compound of formula (I) according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, optionally substituted with one substituent selected from: -alkoxy.

11. R ６ is halogen, oxo, halo-C １ -C ６ -alkyl or halo-C １ -C ６ 10. The compound of formula (I) according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt thereof, wherein R is -alkoxy.

12. R ６ 10. A compound of formula (I) according to any one of claims 1 to 9, wherein is chloro, fluoro, oxo, trifluoromethyl or difluoromethoxy, or a pharma- ceutically acceptable salt thereof.

13. 13. A compound of formula (I) according to any one of claims 1 to 12, wherein n is 1 or 2, or a pharma- ceutically acceptable salt thereof.

14. 14. A compound of formula (I) according to any one of claims 1 to 13, wherein p is 1, 2 or 3, or a pharma- ceutically acceptable salt thereof.

15. 14. A compound of formula (I) according to any one of claims 1 to 13, wherein p is 1 or 2, or a pharma- ceutically acceptable salt thereof.

16. A is a 5- to 14-membered heteroaryl; C ６ -C １４ -aryl or 3-14 membered heterocyclyl, or a pharma- ceutically acceptable salt thereof.

17. 16. The compound of formula (I) according to any one of claims 1 to 15, wherein A is a 5-14 membered heteroaryl or a 3-14 membered heterocyclyl, or a pharma- ceutically acceptable salt thereof.

18. 16. A compound of formula (I) according to any one of claims 1 to 15, wherein A is imidazolyl, pyrazolyl, pyrrolyl or 1,2-dihydropyridinyl, or a pharma- ceutically acceptable salt thereof.

19. B is C ６ -C １４ -aryl, 5-14 membered heteroaryl or 3-14 membered heterocyclyl, or a pharma- ceutically acceptable salt thereof.

20. 19. The compound of formula (I) according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein B is phenyl, 1,2-dihydropyridinyl or pyridyl.

21. The compound of formula (I) may be the compound: [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; (2-Bromo-3-methoxy-phenyl)-[rac-(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (4-chlorothieno[2,3-b]pyridin-5-yl)-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3R,9aS)-3-(3-bromo-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chloro-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-fluoro-3-methoxy-phenyl)methanone; (2-chloro-3-methoxyphenyl)-[(3R,9aS)-3-[4-fluoro-3-[rac-(E)-prop-1-enyl]phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3R,9aS)-3-(4-fluoro-3-phenyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3S,9aS)-3-(4-fluoro-3-phenyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(4-fluoro-3-prop-1-ynyl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; [(3,9aS)-3-(3-cyano-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chloro-3-quinolyl)methanone; [(3S,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3,5-dimethoxy-phenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3,5-dimethoxy-phenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3,4-dimethoxy-phenyl)methanone; 2-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-6-methyl-benzonitrile; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-(trifluoromethoxy)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-phenyl-phenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-methoxyphenyl)phenyl]methanone; [(3R,9aS)-3-(3-cyclopropyl-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(difluoromethoxy)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(5-methyl-1H-pyrazol-4-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(4-methyl-3-pyridyl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methyl-4-pyridyl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-pyridazin-4-yl-phenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-pyridyl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-pyridazin-3-yl-phenyl)methanone; (2-chloro-3-methoxyphenyl)-[(rel-3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-9a-methyl-1,3,4,6,7,9-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[(rel-3S,9aR)-3-(3-chloro-4-fluoro-phenyl)-9a-methyl-1,3,4,6,7,9-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(4-methylpyridazin-3-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(5-methylpyrimidin-4-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-imidazol-5-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methyl-2-pyridyl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazol-4-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1,5-dimethylpyrazol-4-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-methylisoxazol-4-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(4-chloro-3-methyl-1H-indazol-5-yl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-morpholino-phenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-triazol-5-yl)phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; [(3S,9aR)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [3-(3-bicyclo[4.2.0]octa-1,3,5-trienyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; (2-chloro-3-methoxy-phenyl)-[3-[4-(difluoromethyl)phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [(3S,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; (2-chloro-3-methoxyphenyl)-[rel-(3S,9aS)-3-(2,4-dimethylthiazol-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[rel-(3R,9aR)-3-(2,4-dimethylthiazol-5-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxy-phenyl)-[rac-(3R,9aR)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[rac-(3S,9aR)-3-(5-bromo-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[rac-(3S,9aS)-3-(5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[rac-(3R,9aS)-3-(5-chloro-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[rel-(3S,9aS)-3-(1H-benzimidazol-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[rel-(3R,9aR)-3-(1H-benzimidazol-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxy-phenyl)-[rel-(3S,9aS)-3-[6-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)pyridin-3-yl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; (2-chloro-3-methoxyphenyl)-[rel-(3R,9aR)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxy-phenyl)-[rel-(3S,9aS)-3-(4,5-dichloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(9aS)-3-[6-(trifluoromethyl)-3-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[(3R,9aS)-3-[4-(difluoromethoxy)phenyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[(9aS)-3-(6-bromo-3-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3S,9aS)-3-hydroxy-3-(1-methylbenzimidazol-2-yl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; 5-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-2-fluoro-benzonitrile; (2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl)((9aS)-3-(4-(difluoromethoxy)phenyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone; 3-[(3S,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one; 3-[(3R,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-oxazol-5-yl-phenyl)methanone; 3-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one; [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; 4-[3-[(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chlorophenyl]-1H-pyrazole-3-carbonitrile; [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [(3R,9aS)-3-hydroxy-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(1H-pyrazol-4-yl)phenyl]methanone; (2-chloro-3-methoxyphenyl)((3S,9aS)-3-(5-chloro-4-methylpyridin-2-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone; (2-chloro-3-methoxyphenyl)((3R,9aS)-3-(5-chloro-4-methylpyridin-2-yl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methanone; [(3S,9aS)-3-hydroxy-3-[5-(trifluoromethyl)-2-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [(3S,9aS)-3-hydroxy-3-[5-(trifluoromethyl)-2-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-oxazol-4-yl-phenyl)methanone; [3-(1,3-benzothiazol-2-yl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; [2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]-[(3S,9aS)-3-fluoro-3-[6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[(3S,9aS)-3-[6-(trifluoromethyl)pyridazin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3R,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; [(3S,9aS)-3-(4-chloro-2-pyridyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; [(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-[3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [(9aS)-3-[5-(trifluoromethyl)-2-pyridyl]-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [(3R,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [(3S,9aS)-3-(3,4-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; [(3S,9aS)-3-[6-(trifluoromethyl)pyridazin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)phenyl]methanone; (2-chloro-3-methoxyphenyl)-[(3S,9aS)-3-[5-chloro-4-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; (2-chloro-3-methoxyphenyl)-[(3S,9aS)-3-[4-(trifluoromethoxy)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; 3-[(3R,9aS)-8-[2-chloro-3-(3-fluoro-1H-pyrazol-4-yl)benzoyl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridin-2-one; (2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[5-fluoro-4-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-fluoro-3-[5-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[3-[5-(trifluoromethyl)-1H-pyrazol-4-yl]phenyl]methanone; (2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[4-(difluoromethyl)-5-fluoro-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; 4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chlorophenyl]-1H-pyridin-2-one; 5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyridin-2-one; (2-chloro-3-methoxy-phenyl)-[(3S,9aS)-3-[5-chloro-4-bromo-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-[2-chloro-3-(3-hydroxyazetidin-1-yl)phenyl]methanone; 4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrrole-2-carbonitrile; [(3R,9aS)-3-(4-bromo-3-chloro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-6-fluoro-3-methoxyphenyl)methanone; 4-[3-[(3R,9aS)-3-[2-oxo-6-(trifluoromethyl)-1H-pyridin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile; 4-[3-[(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrrole-2-carbonitrile; 4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyridin-2-one; 4-[3-[(3R,9aS)-3-(5-chloro-2-oxo-1H-pyridin-3-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-6-fluoro-3-methoxy-phenyl)methanone; 4-[3-[(3R,9aS)-3-(5-chloro-2-oxo-1H-pyridin-3-yl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrrole-2-carbonitrile; 5-[3-[(3R,9aS)-3-(3,4-dichlorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-3H-oxazol-2-one; [(3R,9aS)-3-hydroxy-3-[4-(trifluoromethyl)phenyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(4-chloro-3-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; 5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-3H-oxazol-2-one; 5-[3-[(3R,9aS)-3-(3,4-dichlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-3H-oxazol-2-one; 4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-6-methyl-1H-pyridin-2-one; 5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-6-methyl-1H-pyridin-2-one; [(3R,9aS)-3-(3-bromo-5-chloro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; 4-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]piperazin-2-one; [(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-isothiazol-4-yl-phenyl)methanone; [(3R,9aS)-3-(2,4,5-trifluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(2,4-dichlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-hydroxy-3-(2,3,4-trifluorophenyl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3S,9aS)-3-(4-bromo-5-methoxy-2-thienyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; 4-[3-[(3R,9aS)-3-[4-oxo-6-(trifluoromethyl)-1H-pyridin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile; 3-[(3R,9aS)-8-[2-chloro-5-fluoro-3-(3-fluoro-1H-pyrazol-4-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one; 5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-3H-1,3,4-oxadiazol-2-one; 5-[(3R,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-3-chloro-2-fluoro-benzonitrile; 3-[(3R,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridin-2-one; [(3R,9aS)-3-(3-chloro-4-oxazol-5-yl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; 3-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyrazole-5-carbonitrile; [(3S,9aS)-3-[2-(4-fluorophenyl)thiazol-4-yl]-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; 3-[(3R,9aS)-8-[2-chloro-3-(4-fluoro-1H-pyrazol-3-yl)benzoyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one; [(3R,9aS)-3-hydroxy-3-[3-(trifluoromethyl)phenyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(2,3-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3S,9aS)-3-hydroxy-3-(3-phenylisoxazol-5-yl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-hydroxy-3-(2,4,5-trifluorophenyl)-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(9aS)-3-(4-fluoro-3-oxazol-5-yl-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3S,9aS)-3-(1,3-benzothiazol-2-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; 3-[(3R,9aS)-8-(2-chloro-6-fluoro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-5-chloro-1H-pyridin-2-one; [(3S,9aS)-3-[5-chloro-6-(trifluoromethyl)-2-pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; [(3R,9aS)-3-(2,3-difluorophenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(2-chlorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; 4-[3-[(3S,9aS)-3-[4-oxo-6-(trifluoromethyl)-1H-pyridin-3-yl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-5-fluoro-phenyl]-1H-pyrrole-2-carbonitrile; 5-[3-[(3R,9aS)-3-(3,4-difluorophenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-imidazole-2-carbonitrile; [(3R,9aS)-3-hydroxy-3-[2-methyl-6-(trifluoromethyl)-3-pyridyl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3R,9aS)-3-(3-chloro-5-oxazol-5-yl-phenyl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; 3-[(3R,9aS)-8-(2-chloro-3-methoxy-benzoyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-3-yl]-6-(trifluoromethyl)-1H-pyridin-2-one; [(9aS)-3-[4-fluoro-3-(1-methylpyrrol-3-yl)phenyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; [(3S,9aS)-3-(3-bromoisoxazol-5-yl)-3-hydroxy-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; 5-[3-[(3R,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carbonyl]-2-chloro-phenyl]-1H-pyridazin-4-one; [(3S,9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-6-fluoro-3-methoxyphenyl)methanone; [(3S,9aS)-3-hydroxy-3-[2-(6-methoxy-3-pyridyl)thiazol-4-yl]-1,4,6,7,9,9a-hexahydropyrazino[2,1-c][1,4]oxazin-8-yl]-(2-chloro-3-methoxyphenyl)methanone; [(9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone; and [(9aS)-3-(3-chloro-4-fluoro-phenyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]thiazin-8-yl]-(2-chloro-3-methoxy-phenyl)methanone 2. The compound of formula (I) according to claim 1, selected from:

22. A process for preparing a compound of formula (I) according to any one of claims 1 to 21, comprising the steps of: (a) Diol 5 【Chemistry 5】 (In the formula, R １ and R ３ is as defined in claim 1) with an etherification agent to form a compound having a structure in which X is -CH ２ CHR ３ -, Y is -O-, and R １ and R ３ is as defined in claim 1, R ２ is hydrogen; or (b) Amine 8a 【Chemistry 6】 (In the formula, Y, R ２ and R ３ is as defined in claim 1, Carboxylic Acid 1 【Chemistry 7】 (In the formula, R １ is as defined in claim 1) in the presence of a base and a coupling reagent to form a compound in which X is -CH ２ CHR ３ - and Y, R １ and R ３ is as defined in claim 1, R ２ is hydrogen; or (c) Y is as defined in claim 1 and X is -CH ２ CR ３ R ４ - and R １ ~R ３ is as defined in claim 1, R ４ is subjected to dehydration conditions to give a compound of formula (I) where Y is as defined in claim 1 and X is -CH ２ CHR ３ - and R １ ~R ３ as defined in claim 1 and / or compounds of formula (I) in which Y is as defined in claim 1 and X is -CH=CR ３ - and R １ ~R ３ or obtaining a compound of formula (I) in which (d) Y is as defined in claim 1 and X is -CH ２ CR ３ R ４ - and R １ ~R ３ is as defined in claim 1, R ４ A compound of formula (I) where X is hydroxy is reacted with a nucleophilic fluorinating agent to form a compound where X is -CH ２ CFR ３ - and R １ ~R ３ obtaining a compound of formula (I) wherein or (e) a compound of formula (I) 【Chemistry 8】 (In the formula, R １ , R ２ , R ４ and B is as defined in claim 1; R ６ is bromo) is subjected to a transition metal catalyzed cross-coupling reaction to obtain a compound of formula (I) 【Chemistry 9】 (In the formula, R １ , R ２ , R ４ and B is as defined in claim 1; R ６ is selected from C 6 -C 14 -aryl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkyl, cyano, C 3 -C 14 -cycloalkyl and 5- to 14-membered heteroaryl; to obtain a compound of formula (I); or (f) Compound 12 【Chemistry 10】 (R a is represented by the following formula: 【Chemistry 11】 (R 7 , R 8 and R 10 are as defined in claim 1 and the asterisk indicates the point of attachment of B(OR) 2 to R a ). Based on R 2 to R 4 are as defined in claim 1. of, Compound 13 【Chemistry 12】 (A, R ５ and n is as defined in claim 1. in the presence of a transition metal catalyst and an organic or inorganic base, to obtain a compound represented by the formula (I). 【Chemistry 13】 (R a is as defined above for compound 12, R ２ ~R ５ and n is as defined in claim 1. or (g) Formula (I) 【Chemistry 14】 (R １ , R ２ and R ３ is as defined in claim 1) with an oxidizing agent to obtain a compound of formula (I) 【Chemistry 15】 (R １ , R ２ and R ３ is as defined in claim 1) To obtain the compound A method comprising:

23. 23. A method for preparing a compound of formula (I) according to claim 22, comprising the steps of: (a) the etherification reagent is (cyanomethylene)tributylphosphorane (CMBP, Tsunoda's reagent); (b) the base is trimethylamine or diisopropylamine and the coupling reagent is HATU, propylphosphonic anhydride or EDC.HCl; (c) dehydration conditions are provided using TES and TEA at elevated temperature; (d) the nucleophilic fluorinating agent is DAST; (e) the transition metal-catalyzed cross-coupling reaction is a Suzuki-Miyaura reaction or a Sonogashira reaction; (f) The transition metal catalyst is PdCl ２ (dppf)-CH ２ C ２ , tris(dibenzylideneacetone)dipalladium(0) (Pd ２ (dba) ３ ) + (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphorane) (Xantphos), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) ((A- ｔａ Phos) ２ PdCl ２ ), or chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (cataCXium A Pd G2), and the organic or inorganic base is sodium carbonate, triethylamine, TMEDA, or cesium carbonate; (g) the oxidizing agent is mCPBA, hydrogen peroxide or sodium periodate; method.

24. The compound of formula (I) has an IC50 activity against monoacylglycerol lipase of less than 10 μM. ５０ 22. A compound of formula (I) according to any one of claims 1 to 21, having the formula:

25. 25. A compound of formula (I) according to any one of claims 1 to 21 and 24 for use as a therapeutically active substance.

26. 25. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 21 and 24 and a therapeutically inert carrier.

27. 27. The pharmaceutical composition of claim 26 for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer and / or psychiatric disorders in a mammal.

28. 28. The pharmaceutical composition of claim 27 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 cancer development, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and / or spasticity associated with pain in a mammal.

29. 25. A compound of formula (I) as defined in any one of claims 1 to 21 and 24 for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and / or psychiatric disorders in a mammal.

30. 25. A compound of formula (I) as defined in any one of claims 1 to 21 and 24 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.

31. 30. Use of a compound of formula (I) as defined in any one of claims 1 to 21 and 24 for the preparation of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and / or psychiatric disorders in a mammal.

32. 25. Use of a compound of formula (I) as defined in any one of claims 1 to 21 and 24 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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