New heterocyclic compounds

Abstract

The present invention relates to novel heterocyclic compounds having the general formula (I): TIFF2025530639000309.tif36165 (In the formula, A, B, R 1 , R 2 , R 4 , and R 5 as described herein), compositions comprising the compounds, methods of making the compounds, and methods of using the compounds are provided.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for the treatment or prevention in mammals, in particular MAGL inhibitors for the treatment or prevention of diseases or disorders associated with monoacylglycerol lipase (MAGL) in mammals, such as neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or renal disease. [Background technology]

[0002] Endocannabinoids (ECs) are signaling lipids that exert their biological effects by interacting with cannabinoid receptors (CB1 and CB2). They modulate multiple physiological processes, including neuroinflammation, neurodegeneration, and tissue regeneration (Iannotti, FA, et al., Progress in lipid research 2016, 62, 107-28). In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacylglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase MAGL. MAGL hydrolyzes 85% of 2-AG, while the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, DK, et al., Science 2011, 334, 809). MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglial cells (Chanda, P.K., et al., Molecular Pharmacology 2010, 78, 996; Viader, A., et al., Cell Reports 2015, 12, 798). Hydrolysis of 2-AG leads to the formation of arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes (LTs). AA oxidative metabolism is increased in inflamed tissues. Two major enzymatic pathways for arachidonic acid oxidation involved in the inflammatory process are cyclooxygenase, which produces PGs, and 5-lipoxygenase, which produces LTs. Among the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important. These products have been detected at sites of inflammation, for example, in the cerebrospinal fluid of patients with neurodegenerative disorders, and are thought to contribute to the inflammatory response and disease progression. Mice lacking MAGL (Mgll- / -) exhibit a dramatic reduction in 2-AG hydrolase activity and a dramatic increase in 2-AG levels in the nervous system, whereas other arachidonoyl-containing phospholipids and neutral lipid species, including anandamide (AEA), and other free fatty acids, are unchanged.Conversely, levels of AA and AA-derived prostaglandins, as well as other eicosanoids including prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2), and thromboxane B2 (TXB2), are greatly reduced. Although the phospholipase A2 (PLA2) enzyme has been considered the major source of AA, cPLA2-deficient mice have unchanged AA levels in their brains, highlighting the importance of MAGL's role in regulating AA production and brain inflammatory processes.

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

[0004] Neuroinflammation is characterized by the activation of innate immune cells in the central nervous system, microglia, and astrocytes. Anti-inflammatory drugs have been shown to suppress glial cell activation and disease progression in preclinical models, including Alzheimer's disease and multiple sclerosis (Lleo A., Cell Mol Life Sci. 2007, 64, 1403). Importantly, genetic and / or pharmacological disruption of MAGL activity also blocks 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 have been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, JZ, et al., Nature Chemical Biology 2009, 5, 37). Systemic injection of such inhibitors recapitulates the Mgll- / - mouse phenotype in the brain, including increased 2-AG levels, reduced AA levels and related eicosanoid production, and prevention of cytokine production and microglial activation after LPS-induced neuroinflammation (Nomura, DK, et al., Science 2011, 334, 809), confirming MAGL as a druggable target.

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

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

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

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

[0010] In conclusion, inhibiting the action and / or activation of MAGL is a promising new therapeutic strategy for the treatment or prevention of various diseases and disorders.

[0011] WO2020104494 discloses certain MAGL inhibitors. However, it has been found that while these MAGL inhibitors have properties that make them particularly suitable for treating CNS indications such as multiple sclerosis, some properties (e.g., high permeability) mean that they are less suitable when differential exposure across tissues is required. This may make them less suitable for treating certain disorders that may benefit from achieving higher exposure in target tissues than in the rest of the body.

[0012] Thus, there remains a high unmet medical need for novel MAGL inhibitors, especially those with distinct properties such that differential exposure can be achieved in different tissues. Summary of the Invention

[0013] Surprisingly, starting from the compounds disclosed in WO2020104494, several chemical modifications have been made to improve passive permeability (P) while maintaining high cellular potency and excellent overall drug-like properties. app The compounds of the present invention have been found to be particularly useful for indications that benefit from different levels of MAGL inhibition in different tissues, particularly those that benefit from higher levels of MAGL inhibition in the periphery than in the brain.

[0014] In a first aspect, the present invention provides a compound of formula (I) [ka] (In the formula, A, B, R 1 , R 2 , R 4 , and R 5 are described herein) to provide.

[0015] In one aspect, the present invention provides a method for preparing a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, comprising: (a) an amine of formula 1b, where R 1 , R 2 , R 4 , R 5 , A and B are as described herein) [ka] 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2) [ka] reacting in the presence of a base; or (b) 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (2b) [ka] A compound of formula 1c, wherein R 1 , R 2 , R 4 , R 5 , A and B are as described herein) and [ka] Reacting in the presence of a base, forming said compound of formula (I).

[0016] In a further aspect, the present invention provides a compound of formula (I) as described herein when prepared according to the methods described herein.

[0017] In a further aspect, the present invention provides a compound of formula (I) as described herein for use as a therapeutically active substance.

[0018] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0019] In a further aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of a disease or disorder associated with MAGL. DETAILED DESCRIPTION OF THE INVENTION

[0020] definition It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all methods or method steps so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel one or any novel combination of methods or method steps so disclosed.

[0021] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched saturated hydrocarbon group of 1 to 6 carbon atoms ("C1-C6-alkyl"), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, an alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, but non-limiting, example of alkyl is methyl.

[0022] The term "alkoxy" refers to an alkyl group, as defined previously, attached to the parent molecular moiety through an oxygen atom. Unless otherwise specified, an alkoxy group contains 1 to 6 carbon atoms ("C1-C6 alkoxy"). In some preferred embodiments, an alkoxy group contains 1 to 4 carbon atoms. In yet other embodiments, an alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0023] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0024] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C 3~10 In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. A particularly preferred, but non-limiting example of cycloalkyl is cyclopropyl.

[0025] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic ring system of 3 to 6 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. Some non-limiting examples of heterocyclyl groups include azetidine, pyrrolidine, piperidine, piperazinyl, and morpholine. A preferred, but non-limiting, example of a heterocyclyl is azetidine.

[0026] The term "cyano" refers to a -CN (nitrile) group.

[0027] The term "oxo" refers to an oxygen atom attached to the parent molecule through a double bond (=O).

[0028] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by halogen atoms, most preferably fluoro. A particularly preferred, but non-limiting example of a haloalkyl is trifluoromethyl (CF).

[0029] The term "halocycloalkyl" refers to a cycloalkyl group in which at least one of the cycloalkyl group's hydrogen atoms has been replaced with a halogen group, preferably CF. Preferably, "haloalkylcycloalkyl" refers to a cycloalkyl group in which one, two, or three hydrogen atoms, particularly one hydrogen atom, of the cycloalkyl group has been replaced with a haloalkyl group, most preferably CF. A particularly preferred, but non-limiting example of a haloalkylcycloalkyl is trifluoromethylcyclopropyl.

[0030] The term "haloalkylheterocyclyl" refers to a heterocyclyl group in which at least one of the heterocyclyl group's hydrogen atoms has been replaced by a haloalkyl group, preferably CF. Preferably, "haloalkylheterocyclyl" refers to a heterocyclyl group in which one, two, or three hydrogen atoms, particularly one hydrogen atom, of the heterocyclyl group has been replaced by a haloalkyl group, most preferably CF. A particularly preferred, but non-limiting example of a haloalkylheterocyclyl is 3-(trifluoromethyl)azetidine.

[0031] The term "haloalkoxy" refers to an alkoxy group in which at least one of the alkoxy group's hydrogen atoms has been replaced by a halogen atom, preferably fluoro. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. A particularly preferred, but non-limiting example of a haloalkoxy is trifluoromethoxy (-OCF).

[0032] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, and organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. These salts may also be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. A particular pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

[0033] The term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the relevant conventional sense of synthetic chemistry, can be carried out selectively at an otherwise unprotected reactive site. The protecting group can be removed at an appropriate time. Exemplary protecting groups are amino-protecting, carboxy-protecting, or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). An even more particular protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described, for example, in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Hutts, 5th Ed., 2014, John Wiley & Sons, NY.

[0034] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g., racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates. In a preferred embodiment, the compounds of formula (I) according to the present invention are cis-enantiomers of formula (Ia) or (Ib), respectively, as described herein.

[0035] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0036] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

[0037] The term "treatment," as used herein, includes: (1) inhibiting a condition, disorder, or symptom (e.g., in the case of maintenance treatment, arresting, reducing, or delaying the onset or recurrence of at least one clinical symptom or subclinical disease thereof), and / or (2) alleviating symptoms (i.e., causing regression of the condition, disorder, or symptom, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least discernible to the patient or physician. However, it will be understood that when a patient is administered a pharmaceutical agent to treat a disease, the outcome need not necessarily be effective treatment.

[0038] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly in a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical symptoms or asymptomatic symptoms of the condition, disorder or condition.

[0039] The term "neuroinflammation," as used herein, refers to acute and chronic inflammation of nervous tissue, which is a major tissue component of two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branching peripheral nerves of the peripheral nervous system (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Acute neuroinflammation usually occurs immediately after central nervous system injury, for example, as a result of traumatic brain injury (TBI).

[0040] The term "traumatic brain injury" (also known as "TBI," "intracranial injury") relates to damage to the brain resulting from an external mechanical force such as rapid acceleration or deceleration, impact, blast, or penetration by a projectile.

[0041] The term "neurodegenerative disease" refers to diseases associated with the progressive loss of neuronal structure or function, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0042] The term "mental disorder" (also called mental illness or mental disorder) relates to a behavioral or mental pattern that can cause distress or impaired functioning in life. Such characteristics may occur as persistent, relapsing, and remitting, or as a single episode. Examples of mental disorders include, but are not limited to, anxiety and depression.

[0043] The term "pain" relates 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 particular example of pain is neuropathic pain, which is caused by injury or disease affecting any part of the nervous system involved in bodily sensations (i.e., the somatosensory system). In one embodiment, the "pain" is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, the "pain" is chemotherapy-induced neuropathy.

[0044] The term "neurotoxicity" relates to toxicity in the nervous system. It occurs when exposure to natural or man-made toxic substances (neurotoxins) alters the normal activity of the nervous system, causing damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, exposure to substances used in chemotherapy, radiation treatment, drug therapy, drug abuse, and organ transplants, as well as neurotoxicity resulting from exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some naturally occurring substances.

[0045] The term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor, resulting from the abnormal and uncontrolled growth of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, colon carcinoma, and ovarian cancer.

[0046] The term "mammal," as used herein, includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term "mammal" refers to humans.

[0047] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: (i) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5 -a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5- a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkyl-, haloC 1~6 Alkyl C 3~6 Cycloalkyl-, (haloC 1~6 Alkyl)-(3-6 membered heterocyclyl)-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl, HaloC 1~6 alkyl, and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is selected from haloC 1~6 optionally substituted with alkyl substituents; X is selected from O and NH; or (ii) A is pyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, hydroxy C 1~6 Alkyl, C 3~6 -cycloalkyl-, haloC 1~6 -Alkyl-C 3~6 -cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl, HaloC 1~6 alkyl, and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is selected from haloC 1~6 optionally substituted with alkyl substituents; and X is selected from O and NH; or (iii) A is phenyl; R 1 is (C1~6 alkyl)2PO- and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl, HaloC 1~6 alkyl, and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is selected from haloC 1~6 optionally substituted with alkyl substituents; and X is selected from O and NH; R 4 and R 5 are each independently hydrogen, halogen and C 1~6 alkyl; and B is [ka] is selected from.

[0048] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is a 9-membered bicyclic heteroaryl containing 1-5 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, Hydroxy C 1~6 Alkyl, C 3~6 -cycloalkyl-, haloC 1~6 -Alkyl-C 3~6 -cycloalkyl-, haloC 1~6 Alkoxy, (C 1~ 6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; X is selected from O and NH; or R 4 and R 5 are each independently hydrogen, halogen and C 1~6 alkyl; and B is [ka] (selected from)

[0049] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (ii) A is pyridyl; R 1is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, hydroxy C 1~6 Alkyl, C 3~6 -cycloalkyl-, haloC 1~6 Alkyl-C 3~6 -cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (iii) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1 ,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, and 2H-indazole; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC1~6 Alkyl, Hydroxy C 1~6 Alkyl, C 3~6 -cycloalkyl-, haloC 1~6 Alkyl-C 3~6 -cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; X is selected from O and NH; R 4 and R 5 are each independently hydrogen, halogen and C 1~6 alkyl; and B is [ka] is selected from.

[0050] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is a compound of formula (Ia): [ka] During the ceremony, (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (ii) A is pyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkyl C 3~6 Cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (iii) A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1,2-dihydropyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkyl C3~6 Cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; and B is [ka] is selected from.

[0051] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl, HaloC 1~6 Alkyl, and (haloC 1~6 alkyl)-(4- to 6-membered heterocyclyl); and X is selected from O and NH; or (ii) A is pyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkyl C 3~6 Cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, C 1~6 selected from alkyl and cyano; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (iii) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1 ,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5 -a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R 1 is C 1~6 Alkoxy, HaloC 1~6 Alkyl, hydroxy C 1~6 Alkyl, C 3~6 Cycloalkyl-, haloC 1~6 Alkyl C 3~6 Cycloalkyl-, (haloC 1~6 Alkyl)-(3-6 membered heterocyclyl)-, haloC 1~6 Alkoxy, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is Haro C 1~6 is alkyl; and X is selected from O and NH.

[0052] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (ii) A is pyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 -Alkyl C 3~6 Cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, C 1~6selected from alkyl and cyano; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (iii) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1 ,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, and 2H-indazole; R 1 is C 1~6 Alkoxy, HaloC 1~6 Alkyl, Hydroxy C 1~6 Alkyl, 3~6 -cycloalkyl-, halo 1~6 Alkyl-C 3~6 -cycloalkyl-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is Haro C 1~6 is alkyl; and X is selected from O and NH.

[0053] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (ii) A is pyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 -Alkyl C 3~6 Cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, C 1~6 selected from alkyl and cyano; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (iii) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1 ,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, and 2H-indazole; R 1 is C 1~6 Alkoxy, HaloC 1~6 Alkyl, hydroxy C 1~6 Alkyl, 3~6 Cycloalkyl-, halo 1~6 Alkyl-C 3~6 -cycloalkyl-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is Haro C 1~6 is alkyl; and X is selected from O and NH.

[0054] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (ii) A is pyridyl; R 1 is Haro C 1~6 Alkyl, HaloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is selected from hydrogen, halogen and cyano; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (iii) A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1,2-dihydropyridyl; R 1 is Haro C 1~6 Alkyl and HaloC 1~6 Alkyl-C 3~6 -cycloalkyl-; and R 2 is hydrogen, halogen, cyano, oxo, C 1~6Alkyl and HaloC 1~6 alkyl.

[0055] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO-, group [ka] and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3a is Haro C 1~6 is alkyl; and R 3b is C 1~6 Alkyl and Halo CC 1~6 alkyl; or (ii) A is pyridyl; R 1 is Haro C 1~6 Alkyl, HaloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, group [ka] and groups [ka] Selected from; R 2 is selected from hydrogen, halogen and cyano; R 3a is Haro C 1~6 is alkyl; and R 3b is C 1~6 Alkyl and Halo CC 1~6 alkyl; or (iii) A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1,2-dihydropyridyl; R 1 is Haro C 1~6 Alkyl and HaloC 1~6 Alkyl-C 3~6 -cycloalkyl-; and R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl.

[0056] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is O; or (ii) A is pyridyl; R 1 is halogen and haloC 1~6 alkyl; R 2is selected from hydrogen and halogen; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 is Haro C 1~6 is alkyl; and R 2 is hydrogen.

[0057] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (CH3)2PO- and the group [ka] Selected from; R 2 is selected from hydrogen, fluoro and CF3; R 3 is selected from methyl and CF3; and X is O; or (ii) A is pyridyl; R 1 is selected from fluoro and CF3; R 2 is selected from hydrogen and fluoro; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 is CF3; and R 2 is hydrogen.

[0058] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is O; or (ii) A is pyridyl; R 1 is halogen and haloC 1~6 alkyl; R 2 is selected from hydrogen and halogen; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 is Haro C 1~6 is alkyl; and R 2 is hydrogen; and B is [ka] is selected from.

[0059] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (CH3)2PO- and the group [ka] Selected from; R 2 is selected from hydrogen, fluoro and CF3; R 3 is selected from methyl and CF3; and X is O; or (ii) A is pyridyl; R 1 is selected from fluoro and CF3; R 2 is selected from hydrogen and fluoro; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 is CF3; and R 2 is hydrogen; and B is [ka] is selected from.

[0060] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH.

[0061] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is pyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 -Alkyl-C 3~6 -Cycloalkyl, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH.

[0062] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is pyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 -Alkyl C 3~6 Cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, C 1~6 selected from alkyl and cyano; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH.

[0063] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a ]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a] Pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine , pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R 1 is C 1~6 Alkoxy, HaloC 1~6 Alkyl, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkyl-, haloC 1~6 Alkyl C 3~6 Cycloalkyl-, (haloC 1~6 Alkyl)-(3-6 membered heterocyclyl)-, haloC 1~6 Alkoxy, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is Haro C 1~6 is alkyl; and X is selected from O and NH.

[0064] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5- a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, and 2H-indazole; R 1 is C 1~6 Alkoxy, HaloC 1~6 Alkyl, hydroxy C 1~6 Alkyl-, C 3~6 -Cycloalkyl, haloC 1~6 Alkyl-C 3~6 -cycloalkyl-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is Haro C 1~6 is alkyl; and X is selected from O and NH.

[0065] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1,2-dihydropyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 Alkyl-C 3~6 -Cycloalkyl, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH.

[0066] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH.

[0067] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is pyridyl; R 1 is halogen, halo C 1~6 Alkyl, HaloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is selected from hydrogen, halogen and cyano; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH.

[0068] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, and 1,2-dihydropyridyl; R 1 is Haro C 1~6 Alkyl and HaloC 1~6 Alkyl-C 3~6 -cycloalkyl-; and R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl.

[0069] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is phenyl; R 1 is (C 1~6 alkyl)2PO-, group [ka] and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3a is Haro C 1~6 is alkyl; and R 3b is C 1~6 Alkyl and HaloC 1~6 alkyl.

[0070] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is pyridyl; R 1 is halogen, halo C 1~6 Alkyl, HaloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, group [ka] and groups [ka] Selected from; R 2 is selected from hydrogen, halogen and cyano; R 3a is Haro C 1~6 is alkyl; and R 3b is C 1~6 Alkyl and HaloC 1~6 alkyl.

[0071] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is O.

[0072] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is pyridyl; R 1 is halogen and haloC 1~6 alkyl; and R 2 is selected from hydrogen and halogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from pyrazinyl and pyrazolyl; R 1 is Haro C 1~6 is alkyl; and R 2 is hydrogen.

[0073] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is phenyl; R 1 is (CH3)2PO- and the group [ka] Selected from; R 2 is selected from hydrogen, fluoro and CF3; R 3 is selected from methyl and CF3; and X is O.

[0074] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is pyridyl; R 1 is selected from fluoro and CF3; R 2 is selected from hydrogen and fluoro.

[0075] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from pyrazinyl and pyrazolyl; R 1 is CF3; and R 2 is hydrogen.

[0076] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is a 9-membered bicyclic heteroaryl containing 1 to 5 heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon.

[0077] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is a 9-membered bicyclic heteroaryl containing 1 to 5 nitrogen atoms, and the remaining ring atoms are carbon.

[0078] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is a 9-membered bicyclic heteroaryl containing 1 to 3 nitrogen atoms, and the remaining ring atoms are carbon.

[0079] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[2,3-b ... [3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, and 2H-indazole.

[0080] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is [ka] is selected from.

[0081] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is [ka] is selected from.

[0082] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is [ka] is.

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

[0084] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is [ka] is.

[0085] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 4 is hydrogen, halogen and C 1~6 alkyl; and R 5 is selected from hydrogen and halogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 4 and R 5 are both hydrogen; or R 4 and R 5 are both halogens; or R 4 C 1~6 Alkyl and R 5 is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 4 and R 5 are both hydrogen; or R 4 and R 5are both fluoro; or R 4 is methyl and R 5 is hydrogen.

[0086] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are both hydrogen.

[0087] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are both fluoro.

[0088] In particularly preferred embodiments, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl and R 5 is hydrogen.

[0089] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl, HaloC 1~6 Alkyl, and (haloC 1~6 alkyl)-(4- to 6-membered heterocyclyl); and X is selected from O and NH; or (ii) A is pyridyl; R 1 is a halogen, C 1~6 Alkyl, C 1~6 Alkoxy, HaloC 1~6 Alkyl, HaloC 1~6 -Alkyl C 3~6 Cycloalkyl-, haloC 1~6 Alkoxy, (C 1~6 alkyl)2PO-, and groups [ka] Selected from; R 2 is hydrogen, halogen, C 1~6 selected from alkyl and cyano; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is selected from O and NH; or (iii) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1 ,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5 -a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R 1 is C 1~6 Alkoxy, HaloC 1~6 Alkyl, Hydroxy C 1~6 Alkyl, C 3~6 Cycloalkyl-, haloC 1~6 Alkyl C 3~6 Cycloalkyl-, (haloC 1~6 Alkyl)-(3-6 membered heterocyclyl)-, haloC 1~6 Alkoxy, and groups [ka] Selected from; R 2 is hydrogen, halogen, cyano, oxo, C 1~6 Alkyl and HaloC 1~6 alkyl; R 3 is Haro C 1~6 is alkyl; X is selected from O and NH; R 4 and R 5 are both hydrogen; or R 4 and R 5 are both halogens; or R 4 C 1~6 alkyl, and R 5 is hydrogen; and B is [ka] is selected from.

[0090] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (C 1~6 alkyl)2PO- and groups [ka] Selected from; R 2 are hydrogen, halogens, and haloC 1~6 alkyl; R 3 is C 1~6 Alkyl and HaloC 1~6 alkyl; and X is O; or (ii) A is pyridyl; R 1 is halogen and haloC 1~6alkyl; R 2 is selected from hydrogen and halogen; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 is Haro C 1~6 is alkyl; and R 2 is hydrogen; R 4 and R 5 are both hydrogen; and B is [ka] is selected from.

[0091] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: (i) A is phenyl; R 1 is (CH3)2PO- and the group [ka] Selected from; R 2 is selected from hydrogen, fluoro and CF3; R 3 is selected from methyl and CF3; and X is O; or (ii) A is pyridyl; R 1 is selected from fluoro and CF3; R 2 is selected from hydrogen and fluoro; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 is CF3; and R 2 is hydrogen; R4 and R 5 are both hydrogen; and B is [ka] is selected from.

[0092] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of: (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-fluoro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(4-fluoro-2-methylsulfonyl-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-methylsulfonylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(2-fluoro-4-methylsulfonyl-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-dimethylphosphoryl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 5-[[2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-3-(trifluoromethyl)pyridine-2-carbonitrile; 5-[[2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carbonitrile; (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-oxo-5-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-methylsulfonyl-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-methylsulfonyl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-dimethylphosphoryl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-methyl-5-(trifluoromethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(2,2,2-trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)oxazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-chloro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[2-fluoro-4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[4-(methylsulfonimidoyl)-3-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[3-(methylsulfonimidoyl)-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-dimethylphosphoryl-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(R)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(S)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(S)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(R)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(R)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(S)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(S)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(R)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[4-fluoro-2-(methylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-dimethylphosphoryl-5-fluoro-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[4-(methylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[3-(methylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-dimethylphosphorylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[(5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 5-[[(6S)-2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6R)-2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; (4aR,8aS)-6-[(6S)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[4-(trifluoromethyl)oxazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[4-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[3-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[(5-chloro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[7-[(5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-indazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(trifluoromethyl)indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)indoxazen-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-methoxy-5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(4-triflylpyrazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonimidoyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(2,2,2-trifluoroethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-mesyl-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2-hydroxyethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(1S)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)-4-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[4-[3-(trifluoromethyl)azetidin-1-yl]sulfonylbenzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]-4-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)imidazo[1,2-a]pyrimidin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[2-methoxy-5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[3-(trifluoromethyl)azetidin-1-yl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)indoxazen-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-keto-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-keto-1H-imidazo[1,2-c]pyrimidin-7-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-oxo-5-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-oxo-1-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrimidin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-(1H-pyrazolo[4,3-b]pyridin-5-ylmethyl)-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-methoxypyrrolo[2,3-c]pyridin-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[7-[[2-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0093] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of: (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(2-fluoro-4-methylsulfonyl-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-dimethylphosphoryl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and (4aR,8aS)-6-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0094] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0095] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0096] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0097] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0098] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[6-[(2-fluoro-4-methylsulfonyl-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0099] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[6-[[3-dimethylphosphoryl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0100] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0101] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0102] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0103] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is (4aR,8aS)-6-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0104] In certain embodiments, the present invention provides pharmaceutically acceptable salts, particularly hydrochloride salts, of compounds according to formula (I) described herein. In more particular embodiments, the present invention provides compounds according to formula (I) described herein.

[0105] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that may be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P,32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0106] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability and may confer certain therapeutic advantages, for example, by increasing in vivo half-life or requiring lower dosages.

[0107] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, substituting an appropriate isotopically labeled reagent for the previously employed non-isotopically labeled reagent.

[0108] Manufacturing method The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the following method descriptions have the meanings indicated herein unless otherwise indicated.

[0109] If one of the starting materials, intermediates, or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (described in "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Hutts, 5th Ed., 2014, John Wiley & Sons, NY) can be introduced prior to a critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0110] When the starting material or intermediate contains a stereocenter, the compound of formula (I) is obtained as a mixture of diastereomers or enantiomers, which can be separated by methods known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with an optically pure acid, or by separating the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. Starting materials and intermediates containing a stereocenter can also be separated to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (I) generally results in the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0111] Those skilled in the art will recognize that in the synthesis of compounds of formula (I), unless otherwise desired, an "orthogonal protecting group strategy" may be applied to cleave several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and R.B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0112] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0113] More specifically, compounds of formula (I) can be prepared by the methods described below, the methods shown in the Examples, or similar methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. For literature-described reaction conditions affecting the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock, John Wiley & Sons, New York, NY, 1999. The reactions could be easily carried out with or without a solvent. There are no particular restrictions on the nature of the solvent used, so long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions at temperatures ranging from -78°C to reflux. The reaction time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction order is not limited to the order shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0114] If the starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared analogously to existing procedures for similar analogs or as outlined in the experimental section.

[0115] The following abbreviations are used herein: AcOH = acetic acid, ACN = acetonitrile, Bn = benzyl, BINAP = (2,2'-bis(diphenylphosphino)-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, DABCO = 1,4-diazabicyclo[2.2.2]octane; triethylenediamine, DAST = (diethylamino)sulfur trifluoride, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, DCE = 1,2-dichloroethane, DEAD = diethyl azodicarboxylate, DIAD = diisopropyl azodicarboxylate, DIBAL-H = diisobutylaluminum hydride, DMAP = 4-dimethylaminopyridine, DME = dimethoxyethane, D MEDA = N,N'-dimethylethylenediamine, DMF = N,N-dimethylformamide, DIPEA = N,N-diisopropylethylamine, dppf = 1,1-bis(diphenylphosphino)ferrocene, EDC.HCl = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, EI = electron impact, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour, FA = formic acid, H2O = water, H2SO4 = sulfuric acid, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N'N'-Tetramethyl-uronium-hexafluorophosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-1H-benzotriazole, HPLC = high performance liquid chromatography, iPrMgCl = isopropyl magnesium chloride, I2 = iodine, IPA = 2-propanol, ISP = positive ion spray (mode), ISN = negative ion spray (mode), K2CO3 = potassium carbonate, KHCO3 = potassium bicarbonate, KI = potassium iodide, KOH = potassium hydroxide, K3PO4 = tripotassium phosphate, LiAlH4 or LAH = hydrogen Lithium aluminum chloride, 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, MTBE = tert-butyl methyl ether, nBuLi = n-butyllithium, NaBH3CN = sodium cyanoborohydride, NaH = sodium hydride, NBS = N-bromosuccinimide, NaHCO3 = sodium bicarbonate, NaNO2 = nitrous acid Sodium, NaBH(OAc)3 = sodium triacetoxyborohydride, NaOH = sodium hydroxide, Na2CO3 = sodium carbonate, Na2SO4 = sodium sulfate, Na2S2O3 = sodium thiosulfate, NEt3 = triethylamine (TEA), NH4Cl = ammonium chloride, NMP = N-methyl-2-pyrrolidone, OAc = acetoxy, T3P = propylphosphonic anhydride, PE = petroleum ether, PG = protecting group, Pd-C = palladium on activated carbon, PdCl2(dppf)-CH2Cl2 = 1,1'-bis(diphenylphosphino) Ferrocene-palladium(II) dichloride dichloromethane complex, Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0), Pd(OAc)2 = palladium(II) acetate, Pd(OH)2 = palladium hydroxide, Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0), PMP = 1,2,2,6,6-pentamethylpiperidine, 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, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMEDA = N,N,N',N'-tetramethylethylenediamine, TS-TPP = triphenylphosphine-polymer-bound, ZnCl2 = zinc chloride, Hal = halogen, prep-TLC = preparative thin-layer chromatography.

[0116] The present compounds of formula I can be prepared by reacting an activated intermediate of formula 2 with a nucleophilic spirocyclic amine 1 by heating in a solvent such as DMF or CHCN in the presence of a base such as DIPEA (Scheme 1). Alternatively, the activated intermediate can be formed onto another coupling partner (1) to generate the urea of ​​formula I. [ka] Scheme 1

[0117] The activated intermediate 2 can be generated by reacting amine 3 with a coupling agent such as di(1H-1,2,4-triazol-1-yl)methanone (4) either transiently in the reaction mixture or in a solvent such as acetonitrile in the presence of a base such as DIPEA (Scheme 2). Alternatively, the same strategy as in Schemes 1 and 2 can be used, but the activated intermediate is first constructed on the spirocyclic amine 1 before coupling with amine 3. [ka] Scheme 2

[0118] The building blocks of Formula 1 can be generated by Suzuki reaction (e.g., Pd(dppf)Cl, KCO, dioxane / HO), (X = Br, I), followed by hydrogenation (e.g., Pd / C, H) and deprotection (e.g., using TsOH or TFA when PG = Boc) (Scheme 3). The requisite boronate intermediate 5 can be generated by reacting the ketone with 4,4,5,5-tetramethyl-2-[(tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (LiTMP, THF, -78 °C). When A = N-linked heteroaryl, a Chan-Lam-type coupling can be used instead of Suzuki reaction (e.g., using Cu(OAc) under oxygen atmosphere), followed by hydrogenation / deprotection. A similar sequence can also be used to generate building blocks where R4 = Me and R5 = H, bearing an additional Me group on the alkene carbon bearing the boronate, starting, for example, from an appropriately functionalized boronate 5. In some cases, when A = heteroaryl bearing a free NH group (e.g., NH-pyrazole or fused NH-pyrazole), it was beneficial to use an additional protecting group on the NH group (e.g., SEM protection, which can be introduced using standard techniques and typically deprotected under acidic conditions in a final deprotection step). [ka] Scheme 3

[0119] Alternatively, building blocks of Formula 1 where A = N-linked heteroaryl can be prepared by reacting the nucleophilic heterocycle A (8) with an appropriately protected building block 9 (X = OMs, leaving group such as I, Br, etc.) in the presence of a base such as Cs2CO3, followed by deprotection under standard conditions (e.g., with TsOH when PG = Boc) (Scheme 4). Typically, mesylate building block 9 is used (X = OMs), which can be conveniently generated from the hydroxyl analog by reaction with MsCl in the presence of a mild base such as Et3N. [ka] Scheme 4

[0120] Alternatively, the building blocks of formula 1 can be prepared by a Mitsunobu-type reaction of heterocycle A (8) with hydroxyl building block 10 (e.g., using diisopropyl azodicarboxylate and triphenylphosphine, or Tsunoda reagent (cyanomethylenetrimethylphosphorane)), followed by deprotection under standard conditions (e.g., with TsOH when PG = Boc). (Scheme 5) Alternatively, the building blocks of formula 1 can be prepared by conversion of hydroxyl building block 10 to a mesylate (e.g., using MsCl, Et3N), followed by S-coupling with heterocycle A (8) in the presence of a base such as NaH. N It can be prepared by two reactions. [ka] Scheme 5

[0121] Alternatively, building blocks of formula 1 where A is a C-linked heteroaryl can be prepared using standard heterocyclic synthesis techniques, starting, for example, from the appropriate carboxylic acid (11) or ester, nitrile (12) or diketone (13) derivative. The nitrile derivative can be prepared from the hydroxyl derivative (10) by conversion to the mesylate (e.g., using MsCl, EtN), followed by conversion of the mesylate group with S-cyanide. N The diketone derivative can be prepared from the ester derivative (14) by di-substitution (e.g., using KCN). (Scheme 6) [ka] Scheme 6

[0122] The (hetero)aryltrifluoromethylcyclopropyl building block 15 is not commonly available and was instead generated from the halogenated building block 16 ((X = I, Br)) by Suzuki reaction with 1-(trifluoromethyl)vinylboronic acid to give 17. Cyclopropanation using diphenyl(methyl)sulfonium tetrafluoroborate and LiHMDS afforded the required building block 15. (Scheme 7) This sequence can also be performed in other synthetic schemes, for example, between steps of the N-linked heteroaryl ring A; these functionalization steps can also be performed after the Chan-Lam coupling / hydrogenation sequence but before final deprotection while preparing the building block of formula 1 (see Scheme 3). Alternatively, the (hetero)aryltrifluoromethylcyclopropyl building block can be generated from commercially available building blocks via standard heterocyclic synthetic techniques. [ka] Scheme 7

[0123] Building blocks of formula 18 where R4 = R5 = F can be generated by deoxyfluorination of the appropriate ketone 20 (e.g., using DAST, diethylaminosulfur trifluoride) followed by appropriate deprotection (e.g., using TsOH or TFA where PG = Boc). The ketone can be generated using oxidation of the benzyl CH2 group on the appropriate intermediate 19 (generated in Scheme 3), e.g., using SeO2, or alternatively via nucleophilic attack of the metalated anion derivative of the appropriate (hetero)aryl 22 onto the Weinreb amide 23. Intermediate 22 can be generated from the appropriate (hetero)aryl halide derivative 21 (X = Br, I, Cl) by metallation (e.g., using nBuLi). (Scheme 8) [ka] Scheme 8

[0124] In some cases, when A = fused (hetero)aryl, an appropriately substituted monocyclic A ring was introduced as described above (e.g., Scheme 3), followed by the introduction of the fused (hetero)aryl ring using standard heterocyclic synthesis techniques (e.g., a substituted (hetero)aryl ring A bearing both a ketone and an ortho-fluoro group can be cyclized to a fused oxazole using hydroxylamine hydrochloride). Introduction of the fused (hetero)aryl was typically carried out on an intermediate in the synthesis process, in most cases prior to deprotection of building block 1.

[0125] In some cases, compounds of formula I can be further functionalized to provide other compounds of formula I. For example, compounds of formula I bearing (hetero)aryl bromides or iodides can be further functionalized with other groups, such as amines or alkyl groups, using metal-catalyzed cross-coupling conditions such as the Buchwald or Suzuki reaction.

[0126] In some cases, the building blocks can be converted to other groups, e.g., lower amines, lower alkyls, using standard functional group interconversion techniques (e.g., introduction of halides (e.g., using NIS or NBS), removal of halides (e.g., under hydrogenation conditions), conversion of halides to other groups, e.g., lower amines, lower alkyls, using metal-catalyzed cross-coupling conditions such as the Buchwald reaction or Suzuki reaction, conversion of iodides to trifluoromethyl groups using trifluoromethylation reagents (e.g., diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate), introduction and removal of protecting groups, hydrolysis of esters to acids, formation of amides from acids and small amines, conversion of boron-containing groups to hydroxyls using alkaline peroxide conditions, cycloaddition of azidotrimethylsilane with nitriles to form tetrazoles, Sandmeyer reaction of anilines with bromides, oxidation of thioethers to sulfones, oxidation of thioethers to sulfoximines using PhI(OAc)2 and NH2COONH4, S NAlkylation of hydroxyl or amine groups by 2-reaction or reductive amination, acylation with activated carbonyl derivatives, or introduction of -SO2Me or -SO2CF3 groups from iodo- or bromo-building blocks using literature techniques, N Heteroaromatic compounds can be generated from commercially available fragments using either alkylation or Chan-Lam-type conditions using alkylboronates to install small alkyl groups or rings such as cyclopropyl on the heteroaromatic nitrogen, cyclopropanation of alkenes, or installation of a dimethylphosphoryl group in place of a (hetero)aromatic halide (X = Br, I) group via Pd-catalyzed cross-coupling with dimethylphosphine oxide in the presence of a base such as EtN. Such techniques can also be used to elaborate commercially available fragments before, after, or during the synthetic sequence described above.

[0127] In one aspect, the present invention provides a method for preparing a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, comprising: (a) an amine of formula 1b, where R 1 , R 2 , R 4 , R 5 , A and B are as described herein) [ka] 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2) [ka] reacting in the presence of a base; or (b) 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (2b) [ka] A compound of formula 1c, wherein R 1 , R 2 , R 4 , R 5 , A and B are as described herein) and [ka] Reacting in the presence of a base, forming said compound of formula (I).

[0128] In one embodiment, the present invention provides a method for preparing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, comprising: (a) an amine of formula 1, wherein R 1 , R 2 , A and B are as described herein) [ka] 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2) [ka] reacting in the presence of a base; or (b) 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (2a) [ka]

[0129] Formula 1a (where R 1 , R 2 and A and B are as described herein. [ka] Reacting in the presence of a base, forming said compound of formula (I).

[0130] In one embodiment, the base is DIPEA.

[0131] In one embodiment, said step (a) or (b) is carried out in a solvent, preferably DMF or CH3CN.

[0132] In one embodiment, the amine of formula 1 is (c) Formula 6 (where R 1 , R 2 and A is as defined herein and X is bromo or iodo, [ka] Formula 5, where B is as defined herein and R is C 1~6 with boronates of alkyl [ka] Suzuki coupling in the presence of a base and a palladium catalyst affords the compound of formula (7), 1 , R 2 , wherein A and B are as defined herein, and PG is a suitable amino protecting group; [ka] Next, (d) hydrogenating the compound of formula 7 to obtain the compound of formula 7a; [ka] and (e) removing the amino protecting group PG from the compound of formula 7a to obtain said compound of formula 1. is obtained by

[0133] In one embodiment, the palladium catalyst in step (c) is selected from PdCl(crotyl)(PtBu3) and Pd(dppf)Cl2.

[0134] In one embodiment, the base in step (c) is K2CO3.

[0135] In one embodiment, said Suzuki coupling of step (c) is carried out in a solvent mixture comprising dioxane and water.

[0136] In one embodiment, the suitable amino protecting group is tert-butyloxycarbonyl (BOC).

[0137] In one embodiment, said hydrogenation in step (d) is carried out under a hydrogen atmosphere using palladium on charcoal as a catalyst.

[0138] In one embodiment, the hydrogenation in step (d) is carried out under high pressure hydrogen, preferably at about 22800 mmHg.

[0139] In one embodiment, the hydrogenation in step (d) is carried out in ethyl acetate.

[0140] In one embodiment, the suitable amino protecting group PG is BOC and is removed in step (e) using p-toluenesulfonic acid.

[0141] In one embodiment, the amine of formula 1 is (c1) amine of formula 8 [ka] with an alcohol of formula 9, where PG is a suitable amino protecting group [ka] via a Mitsunobu-type reaction in the presence of phosphine and a dialkyl azodicarboxylate; forming a compound of formula 10, wherein PG is a suitable amino protecting group; [ka] and (d1) Removal of the amino protecting group PG from a compound of formula 10 to obtain said compound of formula 1. is obtained by

[0142] In one embodiment, the phosphine is triphenylphosphine.

[0143] In one embodiment, the dialkyl azodicarboxylate is selected from DEAD and DIAD.

[0144] In one embodiment, the Mitsunobu-type reaction is carried out in a solvent, preferably THF.

[0145] In one embodiment, said suitable amino protecting group PG is BOC and is removed in step (d1) using p-toluenesulfonic acid.

[0146] In one aspect, the present invention provides a compound of formula (I) as described herein when prepared according to any one of the methods described herein.

[0147] MAGL inhibitory activity The compounds of the invention are MAGL inhibitors. Thus, in one aspect, the invention provides the use of a compound of formula (I) as described herein for inhibiting MAGL in a mammal.

[0148] In a further aspect, the present invention provides a compound of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.

[0149] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal.

[0150] In a further aspect, the present invention provides a method for inhibiting MAGL in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0151] The compounds of formula (I) according to the present invention may be profiled for MAGL inhibitory activity by determining the enzymatic activity following the hydrolysis of the natural substrate, 2-arachidonoylglycerol, to yield arachidonic acid, followed by mass spectrometry analysis. This assay is hereinafter abbreviated as "2-AG assay."

[0152] The 2-AG assay was performed in a 384-well assay plate (PP, Greiner, catalog no. 784201) in a total volume of 20 μL. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in 3-fold dilution steps in the polypropylene plate to give a final concentration range in the assay of 12.5 μM to 0.8 pM. 0.25 μL of compound dilution (100% DMSO) was added to 9 μL of MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100ml), 0.01% (vol / vol) Tween). After shaking, the plate was incubated at room temperature for 15 minutes. 10 μL of 2-arachidonoylglycerol in assay buffer was added to initiate the reaction. The final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglyerol. After shaking and incubation at room temperature for 30 min, the reaction was quenched by adding 40 μL of acetonitrile containing 4 μM d8-arachidonic acid. The amount of arachidonic acid was monitored using an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE cartridge (G9205A) was used with an acetonitrile / water liquid setup. The mass spectrometer was operated in negative electrospray mode, following the mass transitions of 303.1 → 259.1 for arachidonic acid and 311.1 → 267.0 for d8-arachidonic acid. Compound activity was calculated based on the intensity ratio [arachidonic acid / d8-arachidonic acid]. [Table 1] TIFF2025530639000095.tif245170 TIFF2025530639000096.tif245170 TIFF2025530639000097.tif101170

[0153] In one aspect, the present invention provides compounds of formula (I) as described herein, and pharmaceutically acceptable salts or esters thereof, wherein said compounds of formula (I) and pharmaceutically acceptable salts or esters thereof have an IC for MAGL inhibition as measured in the MAGL assay described herein. 50 The present invention provides compounds of formula (I), and pharmaceutically acceptable salts or esters thereof, wherein the .DELTA.I. of the compound is less than 25 .mu.M, preferably less than 10 .mu.M, more preferably less than 5 .mu.M.

[0154] In one embodiment, the compounds of formula (I) described herein and their pharmaceutically acceptable salts or esters have an IC 50 (MAGL inhibition) values ​​range from 0.000001 μM to 25 μM, and certain compounds have IC 50 IC values ​​range from 0.000005 μM to 10 μM, and certain compounds have IC 50 The value is 0.00005 μM to 5 μM.

[0155] P obtained as part of a one-way P-gp screen app (passive permeability measurements) Experiment Description A typical assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human P-gp or mouse P-gp cultured on 96-well semi-permeable filter membrane plates, where these cells form a polarized monolayer with tight junctions, which act as a barrier between the apical and basolateral compartments.

[0156] P-gp is expressed in the apical membrane of the monolayer.

[0157] The adhesion of the cell monolayer and the functional activity of P-gp are confirmed by the addition of the cell-impermeable marker Lucifer Yellow and the reference P-gp substrate edoxaban, respectively.

[0158] The assay is fully automated on a Tecan liquid handling robot.

[0159] Data analysis and interpretation For substrate testing, the assay measures the unidirectional permeability (P) of test compounds by administering them to the apical (i.e., donor compartment) side of the cell monolayer in the absence and presence of the specific P-gp inhibitor zosuquidar and measuring the movement of the compound into the basolateral (i.e., receiver) compartment over a 3-hour incubation at 37°C. app The effect of P-gp is measured by expressing the apical efflux ratio (AP-ER, Equation 2). The mean permeability (P app is determined in the absence of P-gp via zosuquidar conditions. AP-ER and mean P app is used to classify compound properties for the degree of efflux and permeability (Table 2).

number

[0160] formula 1P app , A, C0, and dQ / dt represent the apparent permeability, filter surface area, initial concentration, and transport rate per unit time, respectively. app Values ​​are calculated based on a single time point.

number

[0161] Equation 2: Calculation of the apical-to-basolateral efflux ratio (AP-ER). Papp,inh(A>B) is the permeability value in the apical-to-basolateral direction in the presence of an inhibitor, and Papp(A>B) is the permeability value in the apical-to-basolateral direction in the absence of an inhibitor.

[0162] result The compounds of the present invention surprisingly exhibit reduced P values ​​compared to the compounds disclosed in WO2020104494 while retaining overall drug-like properties. app Therefore, the compound (P appThe passive permeability of ) typically reaches the 250-350 nm / sec range (Table 2), at which point it becomes extremely difficult to establish exposure gradients across tissue. In contrast, the passive permeability of the compounds of the present invention is typically in the 30-250 nm / sec range (Table 3), more preferably in the 50-200 nm / sec range, which, when combined with other appropriate properties, allows for the establishment of exposure gradients across tissue. [Table 2] [Table 3] TIFF2025530639000102.tif245170 TIFF2025530639000103.tif245170 TIFF2025530639000104.tif133170

[0163] Compared to the heteroaryl analogs where L=O disclosed in WO2020104494, the heteroaryl group and CR 4 R 5 Linker (wherein R 4 and R 5 is as defined herein), resulting in app A reduction in P is also observed. In a matched pair comparison of WO 2020104494 from 2015 and the current Example 3, it was surprising to see that P app The wavelength has decreased from 293 nm / sec to 133 nm / sec.

[0164] Uses of the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I) as described herein for use as a therapeutically active substance.

[0165] In a further aspect, the present invention provides compounds of formula (I) as described herein for use in the treatment or prevention of diseases and disorders associated with MAGL.

[0166] In a further aspect, the present invention provides a method for the treatment or prevention of diseases and disorders associated with MAGL, comprising administering to a mammal an effective amount of a compound of formula (I) as described herein.

[0167] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prevention of diseases and disorders associated with MAGL.

[0168] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein in the preparation of a medicament for the treatment or prevention of diseases and disorders associated with MAGL.

[0169] In one embodiment, the diseases and disorders associated with MAGL are selected from neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or renal disease.

[0170] In one embodiment, said diseases and disorders associated with MAGL are selected from neuroinflammation, neurodegenerative diseases, pain, cancer and / or psychiatric disorders.

[0171] In one embodiment, the diseases and disorders associated with MAGL are selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, rheumatoid arthritis, osteoarthritis, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, and / or renal disease.

[0172] In preferred embodiments, said diseases and disorders associated with MAGL are selected from inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, visceral pain, fibromyalgia, endometriosis, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or renal disease.

[0173] In preferred embodiments, said diseases and disorders associated with MAGL are selected from inflammatory bowel disease, symptoms associated with inflammatory bowel disease, intestinal motility, abdominal pain, and / or abdominal pain associated with irritable bowel syndrome.

[0174] In a preferred embodiment, said diseases and disorders associated with MAGL are selected from visceral pain, endometriosis, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.

[0175] In a preferred embodiment, said diseases and disorders associated with MAGL are selected from endometriosis, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.

[0176] In a particularly preferred embodiment, said disease or disorder associated with MAGL is endometriosis.

[0177] In a particularly preferred embodiment, said disease or disorder associated with MAGL is pain associated with rheumatoid arthritis.

[0178] In a particularly preferred embodiment, said disease or disorder associated with MAGL is pain associated with osteoarthritis.

[0179] In a particularly preferred embodiment, said disease or disorder associated with MAGL is inflammatory bowel disease.

[0180] In a particularly preferred embodiment, said diseases and disorders associated with MAGL are symptoms associated with inflammatory bowel disease.

[0181] In a particularly preferred embodiment, said diseases and disorders associated with MAGL are intestinal motility.

[0182] In a particularly preferred embodiment, said disease or disorder associated with MAGL is abdominal pain.

[0183] In a particularly preferred embodiment, said disease or disorder associated with MAGL is abdominal pain associated with irritable bowel syndrome.

[0184] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein and a therapeutically inert carrier.

[0185] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as pharmaceuticals (e.g., in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard 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 can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0186] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed 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 its derivatives, talc, stearic acid or its salts, etc. can be used as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0187] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols etc.

[0188] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0189] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0190] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0191] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants, and they may further contain other therapeutically valuable substances.

[0192] The dosage can vary widely and can, of course, be adapted to the individual requirements of each particular case. Generally, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (for example, about 300 mg / person), preferably divided into 1 to 3 individual doses of equal amounts, may be appropriate. However, it is clear that the upper limit given herein may be exceeded in indicated cases.

[0193] Tablet formulation (wet granulation) Item Ingredients mg / tablet 1. Compound of formula (I) 5 25 100 500 2.Anhydrous lactose DTG 125 105 30 150 3.Sta-Rx 1500 6 6 6 30 4. Microcrystalline cellulose 30 30 30 150 5. Magnesium stearate 1 1 1 1 Total 167 167 167 831

[0194] Manufacturing Procedure 1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50°C. 3. Pass the granules through a suitable grinding device. 4. Add ingredient 5 and mix for 3 minutes; compress in a suitable press.

[0195] Capsule formulation Item Ingredients mg / capsule 1. Compound of formula (I) 5 25 100 500 2. Hydrous lactose 159 123 148 --- 3. Cornstarch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium stearate 1 2 2 5 Total 200 200 300 600

[0196] Manufacturing Procedure 1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add ingredients 4 and 5 and mix for 3 minutes. 3. Fill into suitable capsules. [Example]

[0197] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims to the examples.

[0198] Where preparations are obtained as mixtures of enantiomers, the pure enantiomers may 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.

[0199] Unless otherwise noted, all reactions and intermediates were prepared under an argon atmosphere.

[0200] The examples were generated using urea coupling between building blocks AX and PX. Building blocks A.1 and A.2 can be used interchangeably as the free base or as a suitable salt (e.g., hydrochloride, tartrate), as shown by the following representative examples.

[0201] Example 1 (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka] To a solution of (4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-6-ium-3-one; (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid; (2S,3S)-4-hydroxy-2,3-bis[(4-methylbenzoyl)oxy]-4-oxo-butanoate; hydrate (building block A.1; 56 mg, 0.06 mmol, 1 equiv., CAS 2624363-49-9) and DIEA (54 mg, 0.42 mmol, 7 equiv.) in acetonitrile (1 mL) was added bis(1,2,4-triazol-1-yl)methanone (13 mg, 0.078 mmol, 1.3 equiv., CAS 41864-22-6) was added. The reaction mixture was stirred at 30° C. for 2 hours. After the addition of tosylic acid; 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane (building block P.1; 36 mg, 0.06 mmol, 1 equiv.), stirring was continued overnight at 50° C. The crude material was purified by preparative HPLC (YMC-Triart C18, 12 nm, 5 μm, 100 × 30 mm, ACN / water + 0.1% HCOOH). The product was concentrated in vacuo to give (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (11 mg, 100% purity, 41% yield) as a colorless gum. MS (ESI): m / z = 440.2 [M+H] + .

[0202] Example 12 (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka] To a solution of (4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (10 mg, 64 μmol, 1 equiv., CAS 2377107-31-6) and DIEA (24 mg, 33 μL, 192 μmol, 3 equiv.) in DMF (500 μL) was added bis(1,2,4-triazol-1-yl)methanone (10 mg, 64 μmol, 1 equiv., CAS 41864-22-6). The mixture was stirred at 35 °C for 1 h. DIEA (24 mg, 33 μL, 192 μmol, 3 equiv.) and tosylic acid; 6-[(5-triflyl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane (31 mg, 64 μmol, 1 equiv.) were added. The reaction mixture was stirred at 70° C. for 15 hours. The crude material was purified by preparative HPLC (YMC-Triart C18, 12 nm, 5 μm, 100×30 mm, ACN / water + 0.1% TEA). The product was concentrated in vacuo to give (4aR,8aS)-6-[6-[(5-triflyl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (12 mg, 35%) as a white solid. MS(ESI): m / z = 503.2 [M+H] + .

[0203] Example 35 (4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka] To a solution of (4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (10 mg, 64 μmol, 1 equiv., CAS 2377107-31-6) and DIEA (24 mg, 33 μL, 192 μmol, 3 equiv.) in DMF (500 μL) was added bis(1,2,4-triazol-1-yl)methanone (10 mg, 64 μmol, 1 equiv., CAS 41864-22-6). The mixture was stirred at 35 °C for 1 h. DIEA (24 mg, 33 μL, 192 μmol, 3 equiv.) and 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; tosylic acid (27 mg, 64 μmol, 1 equiv.) were added. The reaction mixture was stirred at 70° C. for 15 hours. The crude material was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100×30 mm, ACN / water + 0.1% HCOOH). The product was concentrated in vacuo to give (4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (21 mg, 70%) as a colorless amorphous oil. MS(ESI): m / z = 442.3 [M+H] + .

[0204] Example 113 ((4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka] To a solution of (4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one hydrochloride (35 mg, 149 μmol, 1 equiv., CAS 2411577-59-6) in DMF (836 μL) was added DIEA (134 mg, 181 μL, 1.04 mmol, 7 equiv.) and bis(1,2,4-triazol-1-yl)methanone (27 mg, 163 μmol, 1.1 equiv., CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30 min. 6-(2-Azaspiro[3.3]heptan-6-ylmethyl)-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine; 2,2,2-trifluoroacetic acid (134 mg, 163 μmol, 1.1 equiv.) was added. The reaction mixture was stirred at 50° C. for 18 hours. The reaction mixture was purified by SFC to give (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (62 mg, 78% yield) as a white solid. MS (ESI): m / z = 479.2 [M+H] + .

[0205] Example 114 (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka] To a solution of (4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one hydrochloride (35 mg, 149 μmol, 1 equiv., CAS 2411577-59-6) in DMF (836 μL) was added DIEA (134 mg, 182 μL, 1.04 mmol, 7 equiv.) and bis(1,2,4-triazol-1-yl)methanone (27 mg, 163 μmol, 1.1 equiv., CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30 min. 6-(2-Azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine; tosylic acid (105 mg, 163 μmol, 1.1 equiv.) was added. The reaction mixture was stirred at 50° C. for 18 hours. The reaction mixture was purified by reverse-phase HPLC to give (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (37 mg, 49% yield) as a white solid. MS (ESI): m / z = 479.2 [M+H] + .

[0206] Example 118 (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka] To a solution of (4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one hydrochloride (35 mg, 149 μmol, 1 equiv., CAS 2411577-59-6) in DMF (836 μL) was added DIEA (134 mg, 182 μL, 1.04 mmol, 7 equiv.) and bis(1,2,4-triazol-1-yl)methanone (27 mg, 163 μmol, 1.1 equiv., CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30 min. 5-(2-Azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine; tosylic acid (76 mg, 163 μmol, 1.1 equiv.) was added. The reaction mixture was stirred at 50° C. for 18 hours. The reaction mixture was purified by reverse-phase HPLC to give (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (29 mg, 39% yield) as a white solid. MS (ESI): m / z = 479.2 [M+H] + .

[0207] Example 133 (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one [ka] To a solution of (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (85 mg, 180 μmol, 1 equiv., CAS 2624363-49-9) in DMF (1 mL) was added DIEA (148 mg, 200 μL, 1.15 mmol, 7 equiv.) and bis(1,2,4-triazol-1-yl)methanone (29.58 mg, 180 μmol, 1.1 equiv., CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30 min. 6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane (105 mg, 163 μmol, 1 equiv.) was added. The reaction mixture was stirred at 50° C. for 18 h. The reaction mixture was purified by reverse-phase SFC to give (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one as a colorless gum. MS (ESI): m / z = 479.1 [M+H] + .

[0208] As with the examples above, the examples in the table below were generated using the respective building blocks AX and PX. [Table 4] TIFF2025530639000113.tif248170 TIFF2025530639000114.tif250170 TIFF2025530639000115.tif251170 TIFF2025530639000116.tif249170 TIFF2025530639000117.tif250170 TIFF2025530639000118.tif250170 TIFF2025530639000119.tif230170 TIFF2025530639000120.tif230170 TIFF2025530639000121.tif250170 TIFF2025530639000122.tif237170 TIFF2025530639000123.tif241170 TIFF2025530639000124.tif250170 TIFF2025530639000125.tif237170 TIFF2025530639000126.tif237170 TIFF2025530639000127.tif249170 TIFF2025530639000128.tif241170 TIFF2025530639000129.tif251170 TIFF2025530639000130.tif230170 TIFF2025530639000131.tif248170 TIFF2025530639000132.tif232170 TIFF2025530639000133.tif252170 TIFF2025530639000134.tif248170 TIFF2025530639000135.tif250170 TIFF2025530639000136.tif249170 TIFF2025530639000137.tif249170 TIFF2025530639000138.tif249170 TIFF2025530639000139.tif252170 TIFF2025530639000140.tif250170 TIFF2025530639000141.tif241170 TIFF2025530639000142.tif250170 TIFF2025530639000143.tif249170 TIFF2025530639000144.tif250170 TIFF2025530639000145.tif237170 TIFF2025530639000146.tif250170 TIFF2025530639000147.tif250170 TIFF2025530639000148.tif250170 TIFF2025530639000149.tif249170 TIFF2025530639000150.tif241170 TIFF2025530639000151.tif250170 TIFF2025530639000152.tif249170 TIFF2025530639000153.tif249170 TIFF2025530639000154.tif130170

[0209] Building Block Synthesis Building Blocks A.1 and A.2 The building blocks A.1 and A.2 are commercially available or reported in the scientific literature as, for example, the free base (A.1 free base: CAS 2377107-31-6; A.2 free base: CAS 1821824-68-3), hydrochloride (A.1 HCl: CAS 2411577-59-6; A.2 HCl: CAS 2361608-82-2), or tartrate (A.1 tartrate: CAS 2624363-49-9), which can be used interchangeably. In some cases, racemic commercial products were purchased and separated into their respective stereoisomers. (+)-(4aR,8aS)-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one and (-)-(4aS,8aR)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one [ka]

[0210] The enantiomers of rac-(4aR,8aS)-hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one dihydrochloride (500 mg, 2.18 mmol, CAS 2629166-65-8, ChemBridge Corporation) were separated by preparative chiral HPLC (ReprosilChiral NR column) using an isocratic mixture of EtOH (containing 0.05% NHOAc):n-heptane (30:70).

[0211] First eluting enantiomer: (+)-(4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (A.1). Yellow solid (0.150 g, 44.0%). MS (ESI): m / z = 157.1 [M+H] + .

[0212] Second eluting enantiomer: (-)-(4aS,8aR)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (A.2). Yellow solid (0.152 g, 44.6%). MS (ESI): m / z = 157.1 [M+H] + .

[0213] Building block P.1: 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane; tosylic acid [ka] Step 1: tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate A mixture of 2,2,6,6-tetramethylpiperidine (95.9 mL, 568 mmol) in THF (750 mL) was cooled to -30 °C under a N atmosphere. n-BuLi (227 mL, 568 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 30 min. The reaction mixture was then cooled to -60 °C, and a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (136 g, 506 mmol) in THF (750 mL) was added dropwise. After stirring for 30 min, a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (100 g, 473 mmol) in THF (300 mL) was added dropwise at -60 °C. The reaction mixture was slowly warmed to 25° C. and stirred at 25° C. for 12 h. HO (80 mL) was slowly added to the mixture, which was then purified together with an additional batch of equal size by silica gel column (PE / EA=1:0 to 3:1 gradient) to give the title compound (220 g, 656 mmol, approximately 69% yield per batch) as a white solid, which was 1 Confirmed by H NMR (400 MHz, CHLOROFORM-d) δ = 5.21-5.16 (m, 1H), 3.99-3.89 (m, 4H), 3.13-2.90 (m, 4H), 1.46-1.41 (m, 9H), 1.26-1.20 ppm (m, 13H).

[0214] Step 2: 6-[[5-(trifluoromethyl)pyrazin-2-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ka] A solution of 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1 g, 3 mmol, 1 equiv., CAS 2763647-64-7), 2-bromo-5-(trifluoromethyl)pyrazine (812 mg, 3.6 mmol, 1.2 equiv., CAS 1196152-38-1), and potassium phosphate tribasic (1.27 g, 6 mmol, 2 equiv.) in 1,4-dioxane (20 mL), water (2 mL) was degassed with argon. Chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (59 mg, 0.15 mmol, 0.05 equiv., CAS 1334497-00-5) was added. The mixture was stirred at 70 °C for 4 hours. The reaction mixture was poured into EtOAc and washed with water and saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 30% EtOAc in heptane) to give 6-[[5-(trifluoromethyl)pyrazin-2-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (593 mg, 97% purity, 54% yield) as a white solid. MS (ESI): m / z = [M-C4H8+H] + .

[0215] Step 3: 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ka] A solution of 6-[[5-(trifluoromethyl)pyrazin-2-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (0.59 g, 1.66 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and methanol (30 mL) was degassed with argon. Pd / C 10% (176 mg, 0.166 mmol, 0.1 equiv.) was added. The mixture was stirred at room temperature under a H2 balloon for 30 minutes. The reaction mixture was filtered and concentrated in vacuo to give 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (588 mg, 95% purity, 94% yield) as an off-white solid. MS (ESI): m / z = [M-C4H8+H] + .

[0216] Step 4: 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane; tosylic acid [ka] To a solution of 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (183 mg, 0.51 mmol, 1 equiv.) in ethyl acetate (1.2 mL) was added 4-methylbenzenesulfonic acid monohydrate (102 mg, 0.54 mmol, 1.05 equiv.). The mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo to give 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane; tosylate (228 mg, 94% purity, 98% yield) as a light brown solid. MS (ESI): m / z = 258.2 [M+H] + .

[0217] Similar to building block P.1, the following building blocks were generated using the related (hetero)aryl bromide, (hetero)aryl chloride, or (hetero)aryl iodide building blocks for Suzuki coupling in step 2. In some cases, alternative salts (e.g., trifluoroacetate, ditosylate, hydrochloride) were also used. To introduce different spiro ring systems, alternative building blocks were used in step 2 instead of 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester. For example, tert-butyl 7-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.5]nonane-2-carboxylate (CAS 2763648-39-9) for P.84, tert-butyl (6Z)-6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.4]octane-2-carboxylate (CAS 2763648-54-8) for P.92, or tert-butyl 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylate (C.184) for P.184. [Table 5] TIFF2025530639000161.tif232170 TIFF2025530639000162.tif250170 TIFF2025530639000163.tif230170 TIFF2025530639000164.tif245170 TIFF2025530639000165.tif230170 TIFF2025530639000166.tif249170 TIFF2025530639000167.tif248170 TIFF2025530639000168.tif250170 TIFF2025530639000169.tif236170 TIFF2025530639000170.tif233170 TIFF2025530639000171.tif249170 TIFF2025530639000172.tif236170 TIFF2025530639000173.tif228170 TIFF2025530639000174.tif228170 TIFF2025530639000175.tif250170 TIFF2025530639000176.tif237170 TIFF2025530639000177.tif250170 TIFF2025530639000178.tif237170 TIFF2025530639000179.tif245170 TIFF2025530639000180.tif233170 TIFF2025530639000181.tif222170 TIFF2025530639000182.tif218170 TIFF2025530639000183.tif250170 TIFF2025530639000184.tif250170 TIFF2025530639000185.tif232170 TIFF2025530639000186.tif250170 TIFF2025530639000187.tif23170

[0218] Building block P.14: [6-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-pyridyl]-imino-oxo-(trifluoromethyl)-λ 6 -Sulfane; 4-Methylbenzenesulfonic acid [ka] Step 1: 2-Bromo-5-(trifluoromethylsulfanyl)pyridine [ka] To a solution of 2-bromo-5-iodopyridine (0.5 g, 1.76 mmol, 1 equiv.) in ACN (10 mL) was added 2,2'-bipyridine (275 mg, 1.76 mmol, 1 equiv., CAS 366-18-7), silver(I) trifluoromethanethiolate (441 mg, 2.1 mmol, 1.2 equiv., CAS 811-68-7), and CuI (335 mg, 1.76 mmol, 1 equiv.) at 20 °C. The mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered to give 2-bromo-5-(trifluoromethylsulfanyl)pyridine (400 mg, 1.55 mmol, 88% yield). The crude product was used directly in the next step.

[0219] Step 2: tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (4.2 g, 12.5 mmol, 1 equiv., CAS 2763647-64-7), 2-chloro-5-(trifluoromethylsulfanyl)pyridine (2.67 g, 12.5 mmol, 1 equiv., CAS 1204234-94-5), and potassium carbonate (3.46 g, 25 mmol, 2 equiv.) in 1,4-dioxane (25 mL) and water (5 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.02 g, 1.25 mmol, 0.1 equiv., CAS 95464-05-4) was added. The mixture was stirred at 80 °C under N2 atmosphere for 12 h. The crude material was purified by chromatography on silica gel (heptane / EtOAc 3:1) to give tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.8 g, 37% yield) as a brown solid. MS (ESI): m / z = 331.0 [M+H] + .

[0220] Step 3: tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.7 g, 4.4 mmol, 1 equiv.) in EtOAc (20 mL) was added wet Pd / C 10% (1.7 mg, 0.44 mmol, 0.1 equiv.) under N at 20 °C, and the mixture was then stirred under an H atmosphere (balloon) at 20 °C for 6 h. The mixture was filtered and concentrated in vacuo to give tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 3.86 mmol, 87% yield) as an off-white oil. MS (ESI): m / z = [M+H] + .

[0221] Step 4: tert-butyl 6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 2.57 mmol, 1 equiv.) in hexafluoroisopropanol (15 mL) was added PhI(OAc) (3.48 g, 10.8 mmol, 4.2 equiv., CAS 3240-34-4) and ammonium carbamate (602 mg, 7.72 mmol, 3 equiv.). The reaction mixture was stirred at 20 °C for 12 h and concentrated in vacuo. The residue was purified by preparative HPLC (Phenomenex luna C18 150*40mm*15um, water (FA)-ACN) and lyophilized to give tert-butyl 6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.48 mmol, 18% yield) as a brown oil. MS(ESI): m / z=333.0 [M+H] + .

[0222] Step 5: [6-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-pyridyl]-imino-oxo-(trifluoromethyl)-λ6-sulfane; 4-methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 0.55 mmol, 1 equiv.) in EtOAc (3 mL) was added p-toluenesulfonic acid (113 mg, 0.66 mmol, 1.2 equiv.). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo, followed by the addition of deionized water and lyophilization to give [6-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-pyridyl]-imino-oxo-(trifluoromethyl)-λ6-sulfane; 4-methylbenzenesulfonic acid (244 mg, 0.5 mmol, 85% yield) as a brown solid. MS (ESI): m / z = 320.0 [M+H] + .

[0223] Analogous to building block P.14, the following building blocks were generated using (hetero)aryl bromo or iodo compounds involved in the cross-coupling reaction of step 1. [Table 6]

[0224] Building Block P.15: 2-(2-Azaspiro[3.3]heptan-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazole; 4-Methylbenzenesulfonic acid [ka] Step 1: 6-(2-hydrazino-2-keto-ethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ka] To a solution of 2-(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)acetic acid (2.5 g, 9.8 mmol, 1 equiv., CAS 1251002-39-7) in tetrahydrofuran (30 mL) was added CDI (1.75 g, 10.7 mmol, 1 equiv.). The mixture was stirred at 70° C. for 1.5 hours and cooled to 0° C. Hydrazine monohydrate (1.47 g, 29.4 mmol, 3 equiv.) was added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into 2:1 EtOAc / THF, washed with saturated NaCl, HO, dried over NaSO, and concentrated in vacuo to give 6-(2-hydrazino-2-keto-ethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.85 g, 68% purity, 99% yield) as a white solid. MS (ESI): m / z = 214.1 [M-CH + H] + .

[0225] Step 2: 6-[2-keto-2-[N'-[1-(trifluoromethyl)cyclopropanecarbonyl]hydrazino]ethyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ka] To a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (1.5 g, 9.7 mmol, 1 equiv., CAS 277756-46-4) in dichloromethane (30 mL) was added 1-chloro-N,N,2-trimethylpropenamine (1.56 g, 11.6 mmol, 1.2 equiv., CAS 26189-59-3). The mixture was stirred at room temperature for 2 hours. This carboxylic acid chloride solution was added dropwise to a solution of 6-(2-hydrazino-2-keto-ethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.85 g, 9.7 mmol, 1 equiv.) and DIPEA (2.51 g, 19.4 mmol, 2 equiv.) in tetrahydrofuran (20 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 2:1 EtOAc / THF and washed with water and saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 5% methanol in CHCl2) to give 6-[2-keto-2-[N'-[1-(trifluoromethyl)cyclopropanecarbonyl]hydrazino]ethyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.49 g, 95% purity, 84% yield) as a white solid. MS (ESI): m / z = 350.1 [M-C4H8+H] + .

[0226] Step 3: 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester [ka] To a solution of 6-[2-keto-2-[N'-[1-(trifluoromethyl)cyclopropanecarbonyl]hydrazino]ethyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.49 g, 8.61 mmol, 1 equiv.) in tetrahydrofuran (40 mL) was added Burgess reagent (4.1 g, 17.2 mmol, 2 equiv., CAS 29684-56-8). The mixture was stirred at 60 °C for 1 h. The reaction mixture was poured into 3:1 EtOAc / THF and washed with water and saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 80 g, 0% to 5% methanol in CHCl) to give 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.22 g, 95% purity, 91% yield) as a white solid. MS (ESI): m / z = 388.2 [M+H] + .

[0227] Step 4: 2-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazole; 4-methylbenzenesulfonic acid [ka] To a solution of 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.22 g, 8.31 mmol, 1 equiv.) in isopropyl acetate (160 mL) was added p-toluenesulfonic acid monohydrate (1.9 g, 9.97 mmol, 1.2 equiv.). The mixture was stirred at 85 °C for 4 h and concentrated in vacuo to give 2-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazole. 4-Methylbenzenesulfonic acid (4.25 g, 40% purity, 44% yield) was obtained as a white solid. MS (ESI): m / z = 288.0 [M+H] + .

[0228] Building Block P.16: 4-Methylbenzenesulfonic acid; 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] Step 1: tert-butyl 6-[(3-bromo-1,2,4-triazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of 3-bromo-1H-1,2,4-triazole (2 g, 13.5 mmol, 1 equiv., CAS 7343-33-1) in DCE (40 mL) was added tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (6.8 g, 20.2 mmol, 1.5 equiv., CAS 2763647-64-7), pyridine (2.2 mL, 27 mmol, 2 equiv.), boric acid (835 mg, 13.5 mmol, 1 equiv.), and Cu(OAc) (3.64 g, 18.2 mmol, 1.35 equiv.). The mixture was stirred at 70 °C for 12 h. The reaction mixture was poured into EtOAc and washed with water and saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% EtOAc in heptane) to give tert-butyl 6-[(3-bromo-1,2,4-triazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.7 g, 35% yield) as a yellow solid. MS (ESI): m / z = 354.9 [M+H] + .

[0229] Step 2: tert-butyl 6-[[3-[1-(trifluoromethyl)vinyl]-1,2,4 triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-[(3-bromo-1,2,4-triazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 1.4 mmol, 1 equiv.) in THF (5 mL) was added 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (374 mg, 1.7 mmol, 1.2 equiv., CAS 1011460-68-6), 1.5 M aqueous KPO (2.8 mL, 4.2 mmol, 3 equiv.), and Ad2nBuP-Pd-G3 (162 mg, 0.14 mmol, 0.1 equiv., CAS 1651823-59-4). The mixture was stirred at 100 °C for 16 h and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 45% EtOAc in heptane) to give tert-butyl 6-[[3-[1-(trifluoromethyl)vinyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (450 mg, 85% yield) as an off-white solid. MS (ESI): m / z = 317.1 [M-C4H8+H] + .

[0230] Step 3: tert-butyl 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-[[3-[1-(trifluoromethyl)vinyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.1 g, 3 mmol, 1 equiv.) in THF (11 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (851 mg, 3 mmol, 1 equiv., CAS 10504-60-6). The suspension was cooled to 0 °C, and NaHMDS 1 M in THF (4.7 mL, 4.7 mmol, 1.6 equiv.) was added dropwise. The reaction mixture was stirred at 20 °C for 12 h. The crude product was purified by preparative HPLC (Shim-pack C18 150*25*10 um, water (0.225% FA)-ACN) to give tert-butyl 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (440 mg, 1.14 mmol, 38% yield). MS (ESI): m / z = [M-C4H8+H] + .

[0231] Step 4: 4-Methylbenzenesulfonic acid; 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] A solution of p-toluenesulfonic acid (256 mg, 1.5 mmol, 1.2 equiv.) and tert-butyl 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (480 mg, 1.24 mmol, 1 equiv.) in EtOAc (5 mL) was stirred at 80 °C for 12 h. The mixture was concentrated in vacuo. Deionized water was added to the residue, which was then lyophilized to give 4-methylbenzenesulfonic acid; 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane (551 mg, 96% yield) as a yellow oil. MS (ESI): m / z = 287.0 [M+H] + .

[0232] Similar to building block P.16, heteroaryl compounds involved in the Chan Lam-type coupling in step 1 were used to generate the following building blocks. [Table 7]

[0233] Building Block P.19: 4-Methylbenzenesulfonic acid; 6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.82 mmol, 1 equiv.) in EtOAc (14 mL) was added p-toluenesulfonic acid monohydrate (1036 mg, 5.45 mmol, 3 equiv.). The reaction mixture was stirred at 30 °C for 72 h, concentrated in vacuo, and purified by FC to give 4-methylbenzenesulfonic acid; 6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane (563 mg, 0.89 mmol, 46% yield) as a yellow solid. MS (ESI): m / z = 286.2 [M+H] + FC conditions: Interchim, SiO2 80g, MTBE / methanol (0-66-100%), flow rate = 60ml / min, 13.8-14.9 CV.

[0234] Step 1: tert-butyl 6-[(4-bromoimidazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 4-bromo-1H-imidazole (1443 mg, 9.82 mmol, 1.5 equiv., CAS 2302-25-2) in NMP (20 mL) was added NaH (471 mg, 11.79 mmol, 1.8 equiv.) under nitrogen at 0 °C. The resulting yellow solution was stirred at 0 °C for 30 min. tert-Butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 6.55 mmol, 1 equiv., CAS 2740574-92-7) was added and stirred at 50 °C for 12 h. The mixture was diluted with 20 mL of saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse HPLC (0.01% FA:ACN in water = 100% to 0%, 220 and 254 nm) and lyophilized to give tert-butyl 6-[(4-bromoimidazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.1 g, 3.09 mmol, 47% yield) as a yellow solid. MS (ESI): m / z = 358.1 [M+H] + .

[0235] Step 2: tert-butyl 6-[[4-[1-(trifluoromethyl)vinyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4-bromoimidazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 14.03 mmol, 1 equiv.) and 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (3.74 g, 16.84 mmol, 1.2 equiv., CAS 1011460-68-6), KPO (8.93 g, 42.1 mmol, 3 equiv.) in THF (165 mL) and water (33 mL) was added APhos-Pd-G (891.35 mg, 1.4 mmol, 0.1 equiv., CAS 1820817-64-8). The mixture was degassed with N and stirred at 60 °C under N atmosphere for 12 h. The crude material was purified by column chromatography on silica (petroleum ether:ethyl acetate = 1:1 to 0:1) and concentrated in vacuo to give tert-butyl 6-[[4-[1-(trifluoromethyl)vinyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.2 g, 8.62 mmol, 61% yield) as a yellow oil. MS (ESI): m / z = 372.2 [M+H] + .

[0236] Step 3: tert-butyl 6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[4-[1-(trifluoromethyl)vinyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 5.39 mmol, 1 equiv.) in THF (40 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (1.86 g, 6.46 mmol, 1.2 equiv., CAS 10504-60-6) at 20 °C. The suspension was cooled to 0 °C, and NaHMDS / THF (8.62 mL, 8.62 mmol, 1.6 equiv.) was added dropwise under N2. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether:ethyl acetate = 0.0:1) to give the crude product. The crude product was purified by preparative HPLC (column, [Phenomenex luna C18 150*40mm*15um]; mobile phase: [ACN] and [HO] (conditions: [water (0.225% FA)-ACN], B%: 50%-80%; detector, UV 254nm. RT: [15min]) and lyophilized to give tert-butyl 6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (644mg, 1.67mmol, 31% yield) as a yellow oil. MS(ESI): m / z=386.2 [M+H] + .

[0237] Building Block P.23: 1-(2-Azaspiro[3.3]heptan-6-ylmethyl)-4-(trifluoromethyl)pyridin-2-one; 4-Methylbenzenesulfonic acid [ka] Step 1: tert-butyl 6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] 4-(Trifluoromethyl)-1H-pyridin-2-one (5.34 g, 32.75 mmol, 1 equiv., CAS 50650-59-4) was added portionwise to a suspension of 60% sodium hydride in oil (2.14 g, 49.1 mmol, 1.5 equiv.) in DMF (100 mL) under argon at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 30 minutes. The reaction mixture was cooled to 0° C., and tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 32.7 mmol, 1 equiv., CAS 2740574-92-7) and sodium iodide (4.91 g, 32.7 mmol, 1 equiv.) were added. The mixture was stirred at 0° C. for 1 hour and then at 80° C. for 18 hours. The reaction mixture was poured into EtOAc and washed with water and saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 100% tert-butyl methyl ether in heptane) to give tert-butyl 6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.6 g, 29% yield) as a yellow solid. MS (ESI): m / z = 273.0 [M+H] + .

[0238] Step 2: 1-(2-azaspiro[3.3]heptan-6-ylmethyl)-4-(trifluoromethyl)pyridin-2-one; 4-methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 13.43 mmol, 1 equiv.) in ethyl acetate (150 mL), p-toluenesulfonic acid monohydrate (5.1 g, 26.8 mmol, 2 equiv.) was added and stirred at 25 °C for 72 h. The reaction mixture was filtered and washed with diethyl ether to give 1-(2-azaspiro[3.3]heptan-6-ylmethyl)-4-(trifluoromethyl)pyridin-2-one; 4-methylbenzenesulfonic acid (5.34 mg, 85% yield) as a pale yellow solid. MS (ESI): m / z = 273.0 [M+H] + .

[0239] Building Block P.24: 1-(2-Azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)pyridin-2-one; 4-Methylbenzenesulfonic acid [ka] Similar to building block P.23, 5-(trifluoromethyl)-1H-pyridin-2-one (CAS 33252-63-0) was treated with sodium hydride, tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (CAS 2740574-92-7), and sodium iodide in DMF. The resulting product was treated with p-toluenesulfonic acid monohydrate to give 1-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)pyridin-2-one; 4-methylbenzenesulfonic acid as a white solid. MS (ESI): m / z = 273.0 [M+H] + .

[0240] Building Block P.33: 4-Methylbenzenesulfonic acid; 6-[[4-(2,2,2-trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] Step 1: tert-butyl 6-[[4-(2,2,2 trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a mixture of 4-(2,2,2-trifluoroethyl)-1H-pyrazole (737 mg, 4.9 mmol, 1 equiv., CAS 1211529-61-1), sodium iodide (1.47 g, 9.8 mmol, 2 equiv.), and cesium carbonate (3.2 g, 9.8 mmol, 2 equiv.) in acetonitrile (68 mL) was added tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 4.9 mmol, 1 equiv., CAS 2740574-92-7) at room temperature. The reaction mixture was stirred at 80 °C for 18 h, filtered, and concentrated in vacuo. The crude material was purified by HPLC to give tert-butyl 6-[[4-(2,2,2 trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (223 mg, 12% yield) as a pale yellow solid. MS (ESI): m / z = 360 [M+H] + .

[0241] Step 2: 4-Methylbenzenesulfonic acid; 6-[[4-(2,2,2-trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-[[4-(2,2,2 trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 0.7 mmol, 1 equiv.) in EtOAc (7.5 mL) was added p-toluenesulfonic acid monohydrate (330 mg, 1.74 mmol, 2.5 equiv.) and stirred at 25 °C for 18 h. The reaction mixture was concentrated in vacuo and purified by HPLC to give 4-methylbenzenesulfonic acid. 6-[[4-(2,2,2 trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (198 mg, 0.46 mmol, 62% yield) was obtained as a light brown gum. MS (ESI): m / z = 260 [M+H] + .

[0242] Building Blocks P.35 and P.36: 4-Methylbenzenesulfonic acid; 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (P.35) [ka] 4-Methylbenzenesulfonic acid; 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (P.36) [ka] Step 1: tert-butyl 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 26.4 mmol, 1 equiv., CAS 1363381-93-4), triphenylphosphine (8.65 g, 33 mmol, 1.25 equiv.), and 5-methyl-3-(trifluoromethyl)-1H-pyrazole (3.96 g, 26.4 mmol, 1 equiv.) in THF (120 mL) was added diisopropyl azodicarboxylate (6.24 mL, 31.7 mmol, 1.2 equiv.) dropwise. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 330 g, 0% to 35% MTBE in heptane). tert-Butyl 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.3 g, 24% yield) was obtained as a white solid. MS (ESI): m / z = 360.0 [M+H] + and tert-butyl 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.8 g, 40% yield) were obtained as a colorless oil. MS (ESI): m / z = 360.0 [M+H] + .

[0243] Step 2: 4-Methylbenzenesulfonic acid; 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (P.35) [ka] To a solution of tert-butyl 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.05 g, 2.9 mmol, 1 equiv.) in EtOAc (10 mL) was added p-toluenesulfonic acid monohydrate (603 mg, 3.51 mmol, 1.2 equiv.). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo and lyophilized to give 4-methylbenzenesulfonic acid; 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (1.16 g, 89% yield) as a light brown powder. MS (ESI): m / z = 260.0 [M+H] + .

[0244] Step 2: 4-Methylbenzenesulfonic acid; 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (P.36) [ka] To a solution of tert-butyl 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.95 mmol, 1 equiv.) in EtOAc (7 mL) was added p-toluenesulfonic acid monohydrate (402 mg, 2.34 mmol, 1.2 equiv.). The mixture was stirred at 80 °C for 2.5 h. The reaction mixture was concentrated in vacuo and lyophilized to give 4-methylbenzenesulfonic acid; 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (840 mg, 97% yield) as a light brown powder. MS (ESI): m / z = 260.0 [M+H] + .

[0245] Building Block P.47: 5-(2-Azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole; 4-Methylbenzenesulfonic acid [ka]

[0246] Step 1: tert-butyl 6-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-(2-ethoxy-2-oxo-ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.06 mmol, 1 equiv., CAS 2122433-35-4) in methanol (3 mL), sodium methoxide 5 M (0.42 mL, 2.1 mmol, 2 equiv.) and 2,2,2-trifluoro-N'-hydroxy-acetamidine (271 mg, 2.1 mmol, 2 equiv., CAS 4314-35-6) were added. The mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc, and washed with water. The residue was purified by preparative HPLC (Shim-pack C18 150*25*10um, water (FA)-ACN, 25ml / min) and lyophilized to give tert-butyl 6-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (120mg, 32% yield) as a yellow oil. MS(ESI): m / z=292.0[M-C4H8+H] + .

[0247] Step 2: 5-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (118 mg, 0.34 mmol, 1 equiv.) in EtOAc (2 mL) was added p-toluenesulfonic acid (70 mg, 0.41 mmol, 1.2 equiv.). The reaction mixture was stirred at 80 °C for 12 h and concentrated in vacuo. The residue was added with deionized water and lyophilized to give 5-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid (125 mg, 0.3 mmol, 84% yield) as a white solid. MS (ESI): m / z = 248.1 [M+H] + .

[0248] Building Block P.48: 3-(2-Azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)-1,2,4-oxadiazole; 4-Methylbenzenesulfonic acid [ka] Step 1: tert-Butyl 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a mixture of hydroxylamine; hydrochloride (2.35 g, 33.8 mmol, 2 equiv.) in ethanol (25 mL) was added TEA (3.42 g, 33.8 mmol, 2 equiv.) at 25 °C. After 1 h, tert-butyl 6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate (4 g, 16.9 mmol, 1 equiv., CAS 1374658-94-2) was added. The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc, and washed with water. The organic layer was dried over Na SO and concentrated in vacuo to give tert-butyl 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (4.5 g, 98% yield) as a colorless oil. MS (ESI): m / z = 270.1 [M+H] + .

[0249] Step 2: tert-butyl 6-[[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (800 mg, 2.97 mmol, 1 equiv.) in methanol (20 mL) was added sodium methoxide 5 M (1.19 mL, 5.94 mmol, 2 equiv.) and ethyl trifluoroacetate (2.11 g, 14.85 mmol, 5 equiv.) at 30° C. The mixture was stirred at 50° C. for 12 h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc, and washed with water. The residue was purified by preparative HPLC (Shim-pack C18 150*25*10um, water (FA)-ACN, 25ml / min) and lyophilized to give tert-butyl 6-[[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (360mg, 36% yield) as a colorless oil. MS(ESI): m / z=292.0[M+H]+ .

[0250] Step 3: 3-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid [ka] A mixture of tert-butyl 6-[[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (350 mg, 1 mmol, 1 equiv) and p-toluenesulfonic acid (208 mg, 1.2 mmol, 1.2 equiv) in EtOAc (10 mL) was stirred at 80° C. for 12 h.

[0251] The reaction mixture was concentrated in vacuo. The residue was dissolved in ACN (2 mL) and water (20 mL) and lyophilized to give 3-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid (410 mg, 90% yield) as a white solid. MS (ESI): m / z = 248.0 [M+H] + .

[0252] Building Block P.50: 4-Methylbenzenesulfonic acid; 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane [ka] Step 1: tert-butyl 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a mixture of 4-(trifluoromethyl)-1H-triazole (2.69 g, 19.65 mmol, 1 equiv., CAS 1267573-04-5) and lithium bromide (3.41 g, 39.3 mmol, 2 equiv.) in acetonitrile (300 mL) was added tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 19.65 mmol, 1 equiv., CAS 2740574-92-7). The reaction mixture was stirred at 50° C. for 18 h, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 100% MTBE in heptane) to give tert-butyl 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g, 36% yield) as a pale yellow solid. MS (ESI): m / z = 247.0 [M-C4H8+H] + .

[0253] Step 2: 4-Methylbenzenesulfonic acid; 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g, 7.2 mmol, 1 equiv.) in EtOAc (100 mL) was added p-toluenesulfonic acid monohydrate (4.12 g, 21.6 mmol, 3 equiv.). The reaction mixture was stirred at 25 °C for 18 h, filtered, and washed with diethyl ether to give 4-methylbenzenesulfonic acid; 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane (3.63 g, 81% yield) as a white powder. MS (ESI): m / z = 247.2 [M+H] + .

[0254] During the synthesis of building block P.50, the regioisomeric compound tert-butyl 6-[[4-(trifluoromethyl)triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate was formed as a minor by-product in step 1 and was subsequently converted to the 4-methylbenzenesulfonate salt of 6-[[4-(trifluoromethyl)triazol-1-yl]methyl]-2-azaspiro[3.3]heptane according to the procedure described in step 2 of the synthesis of building block P.50. [Table 8]

[0255] Building Block P.51: 4-Methylbenzenesulfonic acid; 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] Step 1: 4-Methylbenzenesulfonic acid; 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] To a solution of 3-(trifluoromethyl)-1H-1,2,4-triazole (417 mg, 3 mmol, 1.5 equiv., CAS 60406-75-9) in NMP (6 mL) was added 60% sodium hydride in oil (146 mg, 3.65 mmol, 1.8 equiv.) at 0° C. The mixture was stirred at 0° C. for 0.5 h. tert-Butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (620 mg, 2 mmol, 1 equiv., CAS 2740574-92-7) was added at 20° C. The reaction mixture was stirred at 50° C. for 12 h. The crude product was purified by HPLC (Welch Ultimate XB-SiOH 250*50*10um, hexane-EtOH) and concentrated in vacuo to give 4-methylbenzenesulfonic acid; 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane (55 mg, 8% yield) as a pale yellow oil. MS(ESI): m / z=291.1 [M-C4H8+H] + .

[0256] Step 2: 4-Methylbenzenesulfonic acid; 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (45 mg, 0.13 mmol, 1 equiv.) in EtOAc (0.5 mL) was added p-toluenesulfonic acid (29 mg, 0.17 mmol, 1.3 equiv.). The reaction mixture was stirred at 80 °C for 12 h and concentrated in vacuo. Water was added to the residue, which was then lyophilized to give 4-methylbenzenesulfonic acid; 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane (47 mg, 86% yield) as an off-white solid. MS (ESI): m / z = 247.2 [M+H] + .

[0257] As with Building Block P.51, S in Step 1 N The following building blocks were generated using relevant commercially available building blocks for the 2 reactions. In some cases, the alternative salt trifluoroacetate was also used. [Table 9]

[0258] Building Block P.54: 6-[[4-(Trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] Step 1: tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of 4-(trifluoromethyl)-1H-pyrazole (2.43 g, 18 mmol, 3 equiv.), tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 6 mmol, 1 equiv., CAS 2763647-64-7), and pyridine (1.45 mL, 18 mmol, 3 equiv.) in DMSO (80 mL) was added copper diacetate (2.38 g, 12 mmol, 2 equiv.) under an O2 atmosphere, followed by stirring at 100 °C for 12 h under O2 (balloon) conditions. The aqueous phase was extracted with EtOAc (200 mL × 3). The combined organic phase was washed with brine (200 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse-phase HPLC (0.1% FA condition) to give tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (640 mg, 31% yield) as a brown solid. MS (ESI): m / z = 288.1 [M-C4H8+H] + .

[0259] Step 2: tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka]

[0260] To a solution of tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (690 mg, 2 mmol) in EtOAc (7 mL) was added wet Pd / C 10% (230 mg, 0.2 mmol). The reaction mixture was stirred under a H atmosphere (balloon) at 25 °C for 2 h. The mixture was filtered and concentrated in vacuo to give tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (690 mg, 99% yield) as a yellow solid. MS (ESI): m / z = 346.1 [M+H] + .

[0261] Step 3: 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid [ka] A solution of tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (675 mg, 1.95 mmol) and p-toluenesulfonic acid (404 mg, 2.35 mmol) in EtOAc (6 mL) was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. Deionized water was added to the residue, and the mixture was lyophilized to give 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (794 mg, 96% yield) as a white solid. MS (ESI): m / z = 246.2 [M+H] + .

[0262] Analogously to Example P.54, heteroaryl compounds involved in the Chan Lam-type coupling in step 1 were used to generate the following building blocks: [Table 10]

[0263] Building Blocks P.58 and P.59: 6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (P.58) [ka] 6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (P.59) [ka] Step 1: tert-butyl 6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 26.4 mmol, 1 eq., CAS 1363381-93-4) in toluene (100 mL) was added 5-(difluoromethyl)-3-methyl-1H-pyrazole (4.18 g, 31.7 mmol, 1.2 eq., CAS 934759-09-8) and 2-(tributylphosphoranylidene)acetonitrile (9.56 g, 39.6 mmol, 1.5 eq., CAS 157141-27-0). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (neutral conditions, Welch Ultimate XB-CN 250*50*10 um, hexane-EtOH) and concentrated in vacuo to give the desired product. tert-Butyl 6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.7 g, 7.91 mmol, 30% yield) was obtained as a pale yellow powder. MS(ESI): m / z=286.0 [M-C4H8+H] + and tert-butyl 6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.6 g, 10.54 mmol, 40% yield) as a pale yellow oil. MS (ESI): m / z = 286.0 [M-C4H8+H] + .

[0264] Step 2: 6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (P.58) [ka] To a solution of tert-butyl 6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.85 g, 8.35 mmol, 1 equiv.) in EtOAc (15 mL) was added p-toluenesulfonic acid (1.72 g, 10 mmol, 1.2 equiv.). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated in vacuo to give 6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (3.45 g, 98% yield) as a pale yellow solid. MS (ESI): m / z = 242.1 [M+H] + .

[0265] Step 2: 6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (P.59) [ka] To a solution of tert-butyl 6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.88 g, 11.3 mmol, 1 equiv.) in ethyl acetate (20 mL) was added p-toluenesulfonic acid (2.32 g, 13.5 mmol, 1.2 equiv.). The mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated in vacuo to give 6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (4.31 g, 90% yield) as a pale yellow oil. MS (ESI): m / z = 242.1 [M+H] + .

[0266] Building Block P.62: 6-[[3-(Difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane; 2,2,2-Trifluoroacetic acid [ka] Step 1: tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate [ka] 2-[[5-Bromo-3-(difluoromethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (5.3 g, 16.2 mmol, 1 equiv., CAS 2416163-95-4), tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (5.97 g, 17.8 mmol, 1.1 equiv., CAS 2416163-95-4) in 1,4-dioxane (50 mL) and water (5 mL). To a mixture of 2,4-dien-1-yl(diphenyl)phosphane (2763647-64-7) and potassium carbonate (4.47 g, 32.4 mmol, 2 equiv.) was added cyclopenta-2,4-dien-1-yl(diphenyl)phosphane; dichloromethane; dichloropalladium; and iron(2+) (1.32 g, 1.62 mmol, 0.1 equiv., CAS 95464-05-4) under N2. The mixture was stirred at 100 °C under N2 atmosphere for 2 h. The reaction mixture was poured into water (500 mL). The aqueous layer was extracted with EtOAc. The organic phase was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (6.1 g, 13.39 mmol, 79% yield) as a pale yellow solid. MS (ESI): m / z = 456.3 [M+H] + .

[0267] Step 2: tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a solution of tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (7 g, 15.36 mmol, 1 equiv.) in EtOAc (100 mL) was added Pd / C 10% (2 g, 4.61 mmol, 0.3 equiv.) under a N atmosphere. The mixture was stirred at 25 °C under a H atmosphere (15 PSI) for 0.5 h. The reaction mixture was filtered and concentrated in vacuo to afford tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 85% yield) as a colorless oil.

[0268] Step 3: 6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane; 2,2,2-trifluoroacetic acid [ka] To a solution of tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 13.1 mmol, 1 equiv.) in dichloromethane (40 mL) was added 2,2,2-trifluoroacetic acid (20 mL) at 0° C. The mixture was stirred at 20° C. for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*80mm*10um; mobile phase: [water (TFA)-ACN]; B%: 1%-30%, 20 min) to give 6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane; 2,2,2-trifluoroacetic acid (3.94 g, 87% yield) as a white solid. MS(ESI): m / z=228.2 [M+H] + .

[0269] Similarly to building block P.62, the heteroaryl bromides involved in the reaction of step 1 were used to generate the following building blocks: [Table 11]

[0270] Building Block P.69: [4-(2-Azaspiro[3.3]heptan-6-ylmethyl)-3-fluoro-phenyl]-imino-oxo- (trifluoromethyl)-λ 6 -Sulfane; 4-Methylbenzenesulfonic acid [ka] Step 1: 1-Bromo-2-methylsulfinyl-4-(trifluoromethyl)benzene [ka] 1-Bromo-2-methylsulfanyl-4-(trifluoromethyl)benzene (3.7 g, 13.6 mmol, 1 equiv., CAS 142994-07-8) was dissolved in trifluoroacetic acid (37 mL, 480 mmol, 35 equiv.). Hydrogen peroxide (1.15 mL, 13.6 mmol, 1 equiv.) in water (1.2 mL) was added at 0 °C. The mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and diluted between DCM and aqueous NaHCO3. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 1-bromo-2-methylsulfinyl-4-(trifluoromethyl)benzene (3.3 g, 11.49 mmol, 75% yield) as a pale yellow oil. MS (ESI): m / z = 288.9 [M+H] + .

[0271] Step 2: [2-Bromo-5-(trifluoromethyl)phenyl]-imino-methyl-oxo-λ 6 -Sulfane [ka] A 30 mL sealed tube was charged with 1-bromo-2-methylsulfinyl-4-(trifluoromethyl)benzene (2.5 g, 8.7 mmol, 1 equiv.), amino 4-nitrobenzoate; trifluoromethanesulfonic acid (7.23 g, 21.7 mmol, 2.5 equiv., CAS 2055895-59-3), ferrous sulfate (264 mg, 1.74 mmol, 0.2 equiv., CAS 7720-78-7), and 1,10-phenanthroline (627 mg, 3.48 mmol, 0.4 equiv., CAS 66-71-7) in ACN (20 mL). The reaction mixture was stirred at 30 °C for 48 h. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO solution (5 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 120 g, 0% to 50% acetonitrile in chloroform) to give [2-bromo-5-(trifluoromethyl)phenyl]-imino-methyl-oxo-λ6-sulfane (900 mg, 3 mmol, 30% yield) as a pale yellow solid. MS (ESI): m / z = 302 / 304 [M+H] + .

[0272] Step 3: tert-butyl 6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a stirred suspension of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (998 mg, 3 mmol, 1 equiv., CAS 2763647-64-7), [2-bromo-5-(trifluoromethyl)phenyl]-imino-methyl-oxo-λ-sulfane (900 mg, 3 mmol, 1 equiv.), and potassium carbonate (823 mg, 6 mmol, 2 equiv.) in 1,4-dioxane (30 mL) and water (6 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (364 mg, 0.45 mmol, 0.15 equiv., CAS 95408-45-0). The reaction mixture was stirred at 110° C. for 48 hours. The reaction mixture was concentrated in vacuo and diluted between EtOAc and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 80 g, hexane / tert-butyl methyl ether / methanol) to give tert-butyl 6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (450 mg, 32% yield) as a white solid. MS (ESI): m / z=375.2 [M-C4H8+H] + .

[0273] Step 4: tert-butyl 6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate [ka] tert-Butyl 6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (320 mg, 0.74 mmol, 1 equiv.) was dissolved in 30 mL of EtOAc and hydrogenated over palladium / C (79 mg, 0.07 mmol, 0.1 equiv.) at 22,800 mmHg for 10 h. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 86% yield) as a colorless oil. MS (ESI): m / z = 333.2 [M-C4H8+H] + .

[0274] Step 5: [4-(2-Azaspiro[3.3]heptan-6-ylmethyl)-3-fluoro-phenyl]-imino-oxo-(trifluoromethyl)-λ 6 -Sulfane; 4-Methylbenzenesulfonic acid [ka] p-Toluenesulfonic acid monohydrate (158 mg, 0.83 mmol, 1.2 equiv.) was added to a stirred solution of tert-butyl 6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.69 mmol, 1 equiv.) in EtOAc (30 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was purified by HPLC to give [2-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)phenyl]-imino-methyl-oxo-λ6-sulfane; 4-methylbenzenesulfonic acid (137 mg, 37% yield) as a white solid. MS (ESI): m / z = 333.0 [M+H] + .

[0275] Similar to building block P.69, the bromo-methylsulfanylbenzene compound involved in the reaction of step 1 was used to generate the following building blocks: [Table 12]

[0276] Building Block P.113: 2,2,2-Trifluoroacetic acid; 6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane [ka] To a solution of 6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (180 mg, 452 μmol, 1 equiv.) in dichloromethane (1.5 mL) was added TFA (516 mg, 348 μL, 4.53 mmol, 10 equiv.). The reaction mixture was stirred at room temperature for 18 hours.

[0277] The reaction mixture was concentrated in vacuo to give 365 mg of the crude desired product as a brownish viscous oil (approximately 50% purity). MS (ESI): m / z=298.2 [M+H] + .

[0278] Step 1: tert-butyl 6-[(5-bromopyrimidin-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (5.88 g, 17.55 mmol, 1 equiv., CAS 2763647-64-7), 5-bromo-2-iodopyrimidine (5 g, 17.55 mmol, 1 equiv.) in 1,4-dioxane (75 mL) and water (15 mL) was added potassium carbonate (4.85 g, 35.1 mmol, 2 equiv.) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.43 g, 1.76 mmol, 0.1 equiv., CAS 95464-05-4) at 20° C. The mixture was stirred at 100°C under a N2 atmosphere for 2 h. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (5:1) to give tert-butyl 6-[(5-bromopyrimidin-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (4.6 g, 12.56 mmol, 71% yield) as a white solid. MS (ESI): m / z = 312.0 [M-C4H8+H] + .

[0279] Step 2: tert-butyl 6-[(5-bromopyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(5-bromopyrimidin-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (4.8 g, 13.11 mmol, 1 equiv) in EtOAc (48 mL) was added PtO (1.63 g, 7.19 mmol, 0.55 equiv) under N at 25° C. The mixture was stirred under an atmosphere of H (15 PSI) at 25° C. for 2.5 h.

[0280] The reaction mixture was filtered, and the residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (3:1) to give tert-butyl 6-[(5-bromopyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.87 g, 5.08 mmol, 38% yield) as a white solid. MS (ESI): m / z = 314.0 [M-C4H8+H] + .

[0281] Step 3: tert-butyl 6-[[5-[1-(trifluoromethyl)vinyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (1.52 g, 6.84 mmol, 1.2 equiv., CAS 1011460-68-6) and tert-butyl 6-[(5-bromopyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.1 g, 5.7 mmol, 1 equiv.), potassium carbonate (1.58 g, 11.4 mmol, 2 equiv.) in 1,4-dioxane (20 mL) and water (4 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (465 mg, 0.57 mmol, 0.1 equiv., CAS 95464-05-4). The mixture was stirred at 80° C. under a N atmosphere for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (3:1) to give tert-butyl 6-[[5-[1-(trifluoromethyl)vinyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.05 g, 5.35 mmol, 93% yield) as a white solid. MS (ESI): m / z=328.0 [M-C4H8+H] + .

[0282] Step 4: tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[5-[1-(trifluoromethyl)vinyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.05 g, 5.35 mmol, 1 equiv.) in THF (35 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (2 g, 6.95 mmol, 1.3 equiv., CAS 10504-60-6). NaHMDS / THF (8.55 mL, 8.55 mmol, 1.6 equiv.) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl (80 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (2:1) to give the crude product. The crude product was purified by preparative HPLC (column, [Phenomenex luna C18 250*50mm*10um]; mobile phase: [ACN] and [HO] (conditions: [water (0.225% FA)-ACN], B%: 65%-90%; detector, UV 254nm. RT: [22min]) to give tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.1g, 2.78mmol, 52% yield) as a white solid. MS(ESI): m / z=342.1 [M-CH+H] + .

[0283] Similar to building block P.113, the following building blocks were generated using the relevant heteroaryl bromides or heteroaryl chlorides. [Table 13]

[0284] Building Block P.119: 6-[[4-(trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane 4-methylbenzenesulfonic acid [ka] A mixture of tert-butyl 6-[[4-(trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (630 mg, 1.54 mmol) and p-toluenesulfonic acid (317 mg, 1.85 mmol, 1.2 equiv.) in EtOAc (20 mL) was stirred at 80 °C under a N balloon for 12 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in HO (30 mL). The solution was lyophilized to afford 6-[[4-(trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-4-methylbenzenesulfonic acid (738 mg, 1.53 mmol, 97% yield) as a pale yellow solid. MS (ESI): m / z = 310.1 [M+H] + .

[0285] Step 1: tert-butyl 6-[(4-iodopyrazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (45.6 g, 136 mmol, CAS 2763647-64-7), 4-iodopyrazole (24.0 g, 123 mmol), boric acid (7.65 g, 123 mmol), and pyridine (30 mL, 371 mmol) in DCE (230 mL) was added copper diacetate (49.4 g, 247 mmol) under an O atmosphere. The mixture was stirred at 70 °C under an O atmosphere for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (4:1) to give the crude product, which was purified by preparative HPLC (water (FA)-ACN 55%-75%) to give the title compound (17.7 g, 44.1 mmol, 35.6% yield) as a white solid. MS (ESI): m / z = 346.0 [M-C4H8+H] + .

[0286] Step 2: tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4-iodopyrazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (30 mg, 0.07 mmol) in ACN (3 mL) was added silver(I) trifluoromethanethiolate (46.9 mg, 0.22 mmol, CAS 811-68-7), CuI (28.5 mg, 0.15 mmol), and 2-pyridin-2-ylpyridine (23.4 mg, 0.15 mmol) in a sealed tube. The reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (water (FA)-ACN) 52% to 82% yield) to afford the title compound (13.0 mg, 0.03 mmol, 46% yield) as a yellow solid. MS (ESI): m / z = 320.1 [M-C4H8+H] + .

[0287] Step 3: tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2.8 g, 7.46 mmol) in EtOAc (50 mL) was added Pd / C (1 g, 0.75 mmol) at 25 °C and stirred under a H balloon (760 mmHg) for 1 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound (2.8 g, 7.42 mmol, 99% yield) as a white solid. MS (ESI): m / z = 322.2 [M-CH + H] + .

[0288] Step 4: tert-butyl 6-[[4-(trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 2.65 mmol) in 1,2-dichloroethane (4 mL), ACN (4 mL), and water (8 mL) were added sodium periodate (1.13 g, 5.3 mmol, CAS 811-68-7) and ruthenium(III) chloride hydrate (59.7 mg, 0.26 mmol, CAS 14898-67-0) at 0 °C, and the mixture was then stirred at 25 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (water (FA)-ACN 50%-80%) to afford the title compound (630 mg, 1.54 mmol, 58% yield) as a gray solid. MS (ESI): m / z = 354.3 [M-C4H8+H] + .

[0289] Building Block P.123: 6-[[1-Cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] To a mixture of tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (790 mg, 2.05 mmol) in EtOAc (8 mL) was added p-toluenesulfonic acid (388 mg, 2.25 mmol) at 25 °C. The reaction mixture was stirred at 80 °C for 12 h and concentrated in vacuo. 20 mL of deionized water and 2 mL of ACN were added to the residue, which was lyophilized to give the title compound (811 mg, 1.77 mmol, 85% yield) as a yellow oil. MS (ESI): m / z = 286.1 [M-TsOH+H] + .

[0290] Step 1: tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 14.9 mmol, CAS 2763647-64-7), 4-bromo-5-(trifluoromethyl)-1H-pyrazole (2.92 g, 13.6 mmol) in 1,4-dioxane (73 mL), water (14.6 mL), potassium carbonate (3.75 g, 27.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (554 mg, 0.68 mmol) were added at 20° C. The reaction mixture was stirred at 100° C. under N for 12 h. The reaction mixture was filtered and concentrated in vacuo to give a residue that was purified by flash silica gel chromatography (eluent: 0-40% ethyl acetate / petroleum ether) to give the crude product, which was further purified by flash silica gel chromatography (eluent: 0-40% ethyl acetate / petroleum ether) to give the title compound (790 mg, 2.3 mmol, 17% yield) as a yellow oil. MS (ESI): m / z = 288.0 [M-C4H8+H] + .

[0291] Step 2: tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.75 mmol), cyclopropylboronic acid (600 mg, 6.99 mmol) in DCE (6 mL) was added pyridine (0.42 mL, 5.24 mmol), boric acid (108 mg, 1.75 mmol), and copper diacetate (698 mg, 3.5 mmol) at 20 °C. The reaction mixture was stirred at 100 °C under O (balloon) for 16 h. The reaction mixture was filtered, diluted with 50 mL of water, and extracted with 150 mL of EtOAc (50 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography (0-28% ethyl acetate / petroleum ether) to give the title compound (350 mg, 0.91 mmol, 52%) as a colorless oil. MS (ESI): m / z = 328.0 [M-C4H8+H] + .

[0292] Step 3: tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (720 mg, 1.88 mmol) in EtOAc (15 mL) was added Pd / C (wet, 216 mg, 10%) at 25 °C. The reaction mixture was stirred under H (15 Psi) at 25 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (640 mg, 1.66 mmol, 88% yield) as a colorless oil. MS (ESI): m / z = 330.0 [M-CH + H] + .

[0293] Building Block P.126: [1-(2-Azaspiro[3.3]heptan-6-ylmethyl)pyrazol-4-yl]-imino-oxo-(trifluoromethyl)-λ 6-Sulfane; 4-Methylbenzenesulfonic acid [ka] A mixture of tert-butyl 6-[[4-(trifluoromethylsulfonimidoyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (650 mg, 1.59 mmol) and p-toluenesulfonic acid (329 mg, 1.91 mmol) in EtOAc (10 mL) was stirred at 80 °C under a N balloon for 12 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in HO (30 mL). The solution was lyophilized to afford the title compound (623 mg, 1.3 mmol, 77% yield) as a pale yellow oil. MS (ESI): m / z = 309.1 [M+H] + .

[0294] Step 1: tert-butyl 6-[[4-(trifluoromethylsulfonimidoyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate A mixture of tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (P.119, Step 3) (1.8 g, 4.77 mmol), PhI(OAc) (6.14 g, 19.1 mmol), and ammonium carbamate (1.49 g, 19.1 mmol) in trifluoroethanol was stirred at 30 °C for 12 h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (water (FA)-ACN, 60%-80%) to give the title compound (650 mg, 1.59 mmol, 33% yield) as a gray solid. MS (ESI): m / z = 353.1 [M-C4H8+H] + .

[0295] Building blocks P.132 and P.156: 4-Methylbenzenesulfonic acid; 6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane and 4-methylbenzenesulfonic acid; 6-[[1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane [ka] A solution of p-toluenesulfonic acid (247 mg, 1.43 mmol) and tert-butyl 6-[[2-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (510 mg, 1.19 mmol) in EtOAc (5 mL) was stirred at 80 °C for 12 hours. The mixture was concentrated in vacuo. Deionized water was added to the residue, which was then lyophilized to give the title compound (550 mg, 1.1 mmol, 92% yield) as a colorless oil. MS (ESI): m / z = 328.0 [M+H] + .

[0296] Step 1: tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 3-bromo-5-(trifluoromethyl)-1H-pyrazole (9 g, 41.87 mmol, 1 equiv., CAS 93608-11-8), tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (14 g, 41.8 mmol, 1 equiv., CAS 2763647-64-7), potassium carbonate (11.57 g, 83.7 mmol, 2 equiv.), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (3.42 g, 4.19 mmol, 0.1 equiv., CAS 95464-05-4) was added at 25 °C. The reaction mixture was stirred at 80 °C under N2 for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Silica Flash Column, 0-46% ethyl acetate / petroleum ether gradient eluent) (petroleum:ethyl acetate = 1:1, Rf = 0.6) to give tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (7.0 g, 20.3 mmol, 48% yield) as a white solid. MS (ESI): m / z = 288.0 [M-C4H8+H] + .

[0297] Step 2: tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.26 g, 3.67 mmol, 1 equiv.) in EtOAc (20 mL) under N was added wet Pd / C (505 mg, 0.65 mmol, 0.18 equiv.). The suspension was degassed under vacuum and purged with H. The reaction was stirred under H (15 psi) at 25 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to afford tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.26 g, 3.65 mmol, 99% yield) as a colorless oil. MS (ESI): m / z = 290.0 [M-C4H8+H] + .

[0298] Step 3: tert-butyl 6-[[2-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-[[1-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (13.7 g, 39.67 mmol, 1 equiv.) in THF (278 mL) was added NaH (2.38 g, 59.5 mmol, 1.5 equiv.) at 0 °C for 0.5 h. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (18.41 g, 79.3 mmol, 2 equiv., CAS 6226-25-1) was added at 20 °C. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was slowly quenched with ice and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Welch Ultimate XB-SiOH 250*50*10 um, hexane-EtOH (0.1% NH3·H2O)) and concentrated in vacuo to give tert-butyl 6-[[1-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 4.68 mmol, 11% yield) as a colorless oil. MS(ESI): m / z=372.1 [M-C4H8+H] + and tert-butyl 6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (8.74 g, 20.45 mmol, 51% yield) as a white solid. MS (ESI): m / z = 372.1 [M-C4H8+H] + .

[0299] Step 4: 4-Methylbenzenesulfonic acid; 6-[[2-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane (P.132) and 6-[[1-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane (P.156). Analogous to building block P.1, step 3, tert-butyl 6-[[2-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-[[1-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate were treated with 4-methylbenzenesulfonic acid monohydrate in EtOAc at 80 °C for 12 hours to give 4-methylbenzenesulfonic acid; 6-[[2-(2,2,2 trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane (586 mg, 1.17 mmol, 98% yield) as a colorless oil. MS (ESI): m / z = 328.0 [M+H] + (P.132) and 4-methylbenzenesulfonic acid; 6-[[1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane (2.06 g, 4.13 mmol, 88% yield) was obtained as an off-white solid. MS (ESI): m / z = 328.0 [M+H] + .(P.156).

[0300] Building Block P.136: 4-Methylbenzenesulfonic acid; 6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane [ka] To a mixture of tert-butyl 6-[[1-(2,2,2 trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.05 g, 2.46 mmol, 1 equiv.) in EtOAc (10 mL) was added p-toluenesulfonic acid (465 mg, 2.7 mmol, 1.1 equiv.) at 20 °C. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. 20 mL of deionized water and 2 mL of acetonitrile were added, followed by lyophilization to give 4-methylbenzenesulfonic acid; 6-[[1-(2,2,2 trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane (1.22 g, 2.45 mmol, 99% yield) as a pale yellow oil. MS (ESI): m / z = 328.0 [M+H] + .

[0301] Step 1: tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 4-bromo-5-(trifluoromethyl)-1H-pyrazole (8.35 g, 38.84 mmol, 1 equiv., CAS 19968-17-3), tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (14.32 g, 42.73 mmol, 1.1 equiv., CAS 2763647-64-7), and CsCO (77.69 mL, 116.53 mmol, 3 equiv.) in 2-methylbutan-2-ol (90 mL, 821 mmol, 21 equiv.) was added Ad2nBuP-Pd-G3 (2.82 g, 3.88 mmol, 0.1 equiv., CAS 1651823-59-4) was added under a N2 atmosphere. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (400 mL). The organic phase was washed with brine (800 mL), dried over Na2SO4, and purified by column chromatography (SiO2, PE / AcOEt = 1 / 0 to 1 / 1, PE / AcOEt = 1 / 1, Rf = 0.3 for the desired product) to give tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (9 g, 26.2 mmol, 67% yield) as a yellow oil. MS (ESI): m / z = 288.1 [M-C4H8+H] + .

[0302] Step 2: 6-[[1-(2,2,2 trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2 g, 5.83 mmol, 1 equiv.), cesium carbonate (5.69 g, 17.48 mmol, 3 equiv.) in DMF (20 mL) was added a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.7 g, 11.65 mmol, 2 equiv., CAS 6226-25-1) in DMF (2 mL) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with 50 mL of saturated aqueous NaCl solution (50 mL), dried over a2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash@Silica Flash Column, eluent 0-28% EtOAc / PE gradient @ 60 mL / min, Rf = 0.45) to give tert-butyl 6-[[1-(2,2,2 trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.1 g, 2.59 mmol, 44% yield) as a white solid. MS (ESI): m / z = 370.0 [M-C4H8+H] + .

[0303] Step 3: tert-butyl 6-[[1-(2,2,2 trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-[[1-(2,2,2 trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 2.35 mmol, 1 equiv.) in EtOAc (10 mL) was added Pd / C (300 mg, 10%, wet) at 20 °C. The reaction mixture was stirred under H at 20 °C for 1 h. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6-[[1-(2,2,2 trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.05 g, 2.46 mmol, 104% yield) as a colorless oil. MS (ESI): m / z = 372.0 [M-CH + H] + .

[0304] Similar to building block P.136, heteroaryl halides involved in the cross-coupling in step 1 were used to generate the following building blocks. [Table 14]

[0305] Building Block P.137: 2-[6-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-1-yl]ethanol; 4-Methylbenzenesulfonic acid [ka] A solution of 6-[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (80 mg, 144.47 μmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (56 mg, 296 μmol, 2.05 equiv.) in ethyl acetate (0.5 mL) was refluxed with stirring for 20 minutes in a sealed vial. The suspension was cooled to room temperature and then filtered. The filter cake was washed with ethyl acetate to give 2-[6-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-1-yl]ethanol; 4-methylbenzenesulfonic acid (82 mg, 78% yield) as a colorless solid. MS (ESI): m / z = 340.2 [M+H] + .

[0306] Step 1: tert-butyl 6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate 6-Bromo-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (565 mg, 2.13 mmol, 1.1 equiv., CAS 1934574-07-8), 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (650 mg, 1.94 mmol, 1 equiv., CAS 2763647-64-7), chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (38 mg, 96.94 μmol, 0.05 equiv., CAS 2763647-64-7) in 1,4-dioxane (13 mL) and water (1.3 mL). A mixture of (1334497-00-5) and tripotassium phosphate (823 mg, 3.88 mmol, 2 equiv.) was degassed with argon. The solution was stirred in a sealed vial at 70 °C overnight. The reaction mixture was poured into water and ethyl acetate, and the layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by silica gel chromatography on a 25 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to afford tert-butyl 6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (0.323 g, 40% yield) as a pale yellow solid. MS (ESI): m / z = 394.2 [M+H] + .

[0307] Step 2: tert-butyl 6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 1.27 mmol, 1 equiv.) in EtOAc (8 mL) was added wet Pd / C (175 mg, 0.22 mmol, 0.18 equiv.) under N2. The suspension was degassed under vacuum and HCl was added. 2でパージした。The reaction mixture was stirred under H (15 psi) at 25° C. for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl 6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (440 mg, 1.11 mmol, 85% yield) as a light brown solid. MS (ESI): m / z = 340.0 [M-C4H8+H] + .

[0308] Step 3: 6-[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester To an ice-cold solution of 6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (186 mg, 470 μmol, 1 equiv.) in DMF (1.5 mL) was added NaH (20 mg, 517.42 μmol, 1.1 equiv.), and the mixture was stirred at this temperature for 30 minutes. After adding (2-bromoethoxy)-tert-butyldimethylsilane (123 mg, 111.52 μL, 517.42 μmol, 1 equiv.), stirring was continued at room temperature overnight. The mixture was poured into half-saturated aqueous NH4Cl and ethyl acetate, and the layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layer was washed twice with water, dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by silica gel chromatography on a 4 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:ethyl acetate (100:0 to 65:35) to give 6-[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester as a colorless oil (208 mg, 79% yield). MS (ESI): m / z = 554.4 [M+H] + .

[0309] Building Block P.143: 6-[Difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] To a solution of 6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (77 mg, 196 μmol) in isopropyl acetate (3 mL) was added p-toluenesulfonic acid monohydrate (82 mg, 432 μmol). The mixture was stirred at 80° C. for 3 hours. The reaction mixture was concentrated in vacuo to give 6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (163 mg, 99% yield) as a colorless oil. MS (ESI): m / z = 293.0 [M+H] + .

[0310] Step 1: tert-butyl 6-[6-(trifluoromethyl)pyridine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[methoxy(methyl)carbamoyl]-2-azaspiro[3.3]heptane-2-carboxylate (4.3 g, 15.1 mmol, CAS 2428601-18-5) and 5-bromo-2-(trifluoromethyl)pyridine (6.83 g, 30.2 mmol, CAS 436799-32-5) in THF (100 mL) was added n-BuLi (18.2 mL, 45.4 mmol) at −78° C. for 1 h. The reaction mixture was stirred at 30° C. for 12 h. The reaction mixture was poured into saturated aqueous NH4Cl (500 mL) and extracted with ethyl acetate. The organic layer was washed with brine. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (2:1) to give the title compound (1400 mg, 3.78 mmol, 25% yield) as a brown solid. MS (ESI): m / z = 315.1 [M-C4H8+H] + . 1H NMR (400MHz, methanol-d4) δ=9.17(s,1H), 8.49(dd,J=1.5,8.3Hz,1H), 7.95(d,J =8.3Hz,1H), 4.11-3.99(m, 3H), 3.84(s,2H), 2.65-2.48(m, 4H), 1.43(s,9H).

[0311] Note that the regioisomer: tert-butyl 6-[2-(trifluoromethyl)pyridine-4-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate (1100 mg, 2.97 mmol, 20% yield) was co-produced as a brown oil. 1 H NMR(400MHz,METHANOL-d4)δ=8.92(d,J=5.0Hz,1H),8.15(s,1H),8.04(dd,J=1.1,4.9Hz,1H),4.03(s,3H),3.83(s,2H),2.55(br dd,J=8.3,12.1Hz,4H),1.43(s,9H).

[0312] Step 2: 6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester To a solution of tert-butyl 6-[6-(trifluoromethyl)pyridine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate (750 mg, 2.03 mmol) in DCM (5 mL) was added dropwise at 0 °C under a N atmosphere. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was added dropwise to saturated aqueous NaHCO (200 mL) and extracted with DCM (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (water (FA)-ACN, 58%-88%) to give the title compound (510 mg, 1.3 mmol, 64% yield) as a pale yellow solid. MS (ESI): m / z = 337.0 [M-C H + H] + ; 1H NMR(400MHz,METHANOL-d4)δ=8.87(s,1H),8.26-8.13(m,1H),7.94(d,J=8.3H z,1H),4.03-3.83(m,4H),3.18-2.96(m,1H),2.47-2.27(m,4H),1.44(s,9H).

[0313] Similar to building block P.143, the following building blocks were prepared using related heteroaryl bromides. In some cases, alternative salts (e.g., trifluoroacetate, ditosylate, hydrochloride) were also used. [Table 15]

[0314] Building blocks P.139 and P.140: 6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid and 6-[(1S)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (arbitrary assignment of enantiomers) [ka] and [ka] A solution of tert-butyl 6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 0.65 mmol) and p-toluenesulfonic acid monohydrate (309 mg, 1.63 mmol) in EtOAc (10 mL) was stirred at 60 °C for 3 h. After cooling to room temperature, the resulting precipitate was filtered, washed with EtOAc, and dried in vacuo to give the title compound P.139 (237 mg, 0.38 mmol, 55% yield) as a white solid. MS (ESI): m / z = 285.2 [M+H] + The other enantiomer was deprotected in the same manner to give the title compound P.140 (241 mg, 0.38 mmol, 58% yield) as a white solid. MS (ESI): m / z = 285.2 [M+H] + .

[0315] Step 1: tert-butyl 6-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethylidene]-2-azaspiro[3.3]heptane-2-carboxylate To a stirred solution of 2,2,6,6-tetramethylpiperidine (4.31 mL, 25.6 mmol) in THF (75 mL) under Ar at −30° C., n-BuLi (2.5 M in hexanes) (10.2 mL, 25.6 mmol) was added. The solution was stirred at −30° C. for 30 min and cooled to −78° C. A solution of 4,4,5,5-tetramethyl-2-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]-1,3,2-dioxaborolane (6.61 g, 23.4 mmol, CAS 1227056-25-8) in 10 mL of anhydrous THF was added dropwise, and the reaction mixture was stirred at −78° C. for 30 min. A solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (4.5 g, 21.3 mmol) in 15 mL of anhydrous THF was added dropwise at −78° C., and the reaction mixture was warmed and stirred at room temperature overnight. The reaction was quenched with water, and the mixture was concentrated in vacuo. The residue was partitioned between water and DCM. The organic layer was washed with citric acid, water, brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (1:4 TBME / hexane) to give the title compound (3.1 g, 8.88 mmol, 41% yield) as a white solid. MS (ESI): m / z=294.2 [M-C4H8+H] + .

[0316] Step 2: tert-butyl 6-[1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethylidene]-2-azaspiro[3.3]heptane-2-carboxylate To a stirred suspension of 2-chloro-4-methyl-5-(trifluoromethyl)pyridine (1.36 g, 6.93 mmol, CAS 780802-36-0), tert-butyl 6-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethylidene]-2-azaspiro[3.3]heptane-2-carboxylate (2.2 g, 6.3 mmol), and cesium carbonate (4.1 g, 12.6 mmol) in anhydrous 1,4-dioxane (110 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (771 mg, 0.94 mmol, CAS 95464-05-4) was added. The mixture was stirred at 80 °C under argon for 48 h. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The resulting residue was partitioned between EtOAc and brine. The organic layer was dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (hexane / MTBE 10-23%) to give the title compound (700 mg, 1.83 mmol, 28% yield) as a pale yellow solid. MS (ESI): m / z = 327.2 [M-C4H8+H] + .

[0317] Step 3: tert-butyl 6-[1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate A stirred mixture of tert-butyl 6-[1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethylidene]-2-azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.83 mmol) and Pd / C (5%) (200 mg) in 50 mL of EtOAc was hydrogenated in an autoclave at 20 bar (15,200 mm Hg) for 24 h at 25 °C. The reaction mixture was filtered and concentrated in vacuo to give the title compound (680 mg, 1.77 mmol, 92% yield) as an orange gum; MS (ESI): m / z = 329.0 [M-CH+H] +The mixture of enantiomers tert-butyl 6-[1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (680 mg, 1.77 mmol) was separated by chiral chromatography to give tert-butyl 6-[(1S)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate. -carboxylate (270 mg, 0.7 mmol, 40% yield) (or enantiomer) RetTime (min): 11.2 and tert-butyl 6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 0.65 mmol, 37% yield) (or enantiomer) RetTime (min): 13.9.

[0318] Building Block P.146: 2-(2-Azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (48 mg, 1.1 mmol, 1 equiv.) in EtOAc (9.8 mL) was added p-toluenesulfonic acid monohydrate (749 mg, 4 mmol, 3.5 equiv.). The mixture was stirred at 25 °C for 18 h. The reaction mixture was concentrated in vacuo, and the residue was treated with MTBE. The formed precipitate was filtered to give 2-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine; 4-methylbenzenesulfonic acid (729 mg, 1.14 mmol, 99% yield) as a pale yellow solid. MS (ESI): m / z = 297.2 [M+H] + .

[0319] Step 1: tert-Butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethylene)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2.2 g, 6.6 mmol, 1.01 equiv., CAS 2763647-64-7) and 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.51 mmol, 1 equiv., CAS 335654-06-3), KCO (2.7 g, 19.54 mmol, 3 equiv.) in 1,4-dioxane (10 mL) and water (2 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (531 mg, 0.65 mmol, 0.1 equiv., CAS 95464-05-4) was added. The mixture was stirred at 80 °C for 12 h under a N balloon (760 mmHg). The reaction mixture was concentrated in vacuo and purified by column chromatography (SiO, petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to give tert-butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethylene)-2-azaspiro[3.3]heptane-2-carboxylate (650 mg, 1.99 mmol, 27% yield) as a pink solid. MS (ESI): m / z = 327.2 [M+H] + .

[0320] Step 2: tert-Butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethylene)-2-azaspiro[3.3]heptane-2-carboxylate (650 mg, 1.99 mmol, 1 equiv.) in EtOAc (10 mL) was added wet Pd / C (100 mg, 0.6 mmol, 0.3 equiv.) under N. The suspension was degassed under vacuum and purged with H. The reaction was stirred under H (15 psi) at 25 °C for 1 h to give a black suspension. The precipitate was filtered off, and the filtrate was dried in vacuo to give tert-butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate (450 mg, 1.37 mmol, 68% yield) as a yellow solid. MS (ESI): m / z = 329.3 [M+H] + .

[0321] Step 3: tert-butyl 6-[(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate (650 mg, 1.98 mmol, 1 equiv.) in ACN (20 mL) was added NIS (534 mg, 2.38 mmol, 1.2 equiv.), and the reaction mixture was stirred at 25 °C for 2 h to give a yellow suspension. The reaction mixture was added to water (20 mL), and the mixture was filtered. The cake was concentrated in vacuo to give tert-butyl 6-[(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.54 mmol, 75% yield) as a yellow solid. MS (ESI): m / z = 455.1 [M+H] + .

[0322] Step 4: tert-butyl 6-[[5-iodo-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.54 mmol, 1 equiv.) in THF (5 mL) was added NaH (74 mg, 1.85 mmol, 1.2 equiv.) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. 4-Methylbenzenesulfonyl chloride (587 mg, 3.08 mmol, 2 equiv.) was added. The mixture was stirred at 25 °C for 12 h to give a gray suspension. The reaction mixture was quenched at 0 °C by the addition of 10 mL of saturated aqueous NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluted with PE / EtOAc (PE / EtOAc=3:1) to give tert-butyl 6-[[5-iodo-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (900 mg, 1.48 mmol, 96% yield) as a pale yellow solid. MS (ESI): m / z=455.1 [M+H] + .

[0323] Step 5: tert-butyl 6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of benzyl tert-butyl 6-[[5-iodo-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (900 mg, 1.48 mmol, 1 equiv.) and copper (282 mg, 4.44 mmol, 3 equiv.) in DMF (1 mL) was added diphenyl(trifluoromethyl)sulfonium; trifluoromethanesulfonate (1.2 g, 2.96 mmol, 2 equiv., CAS 147531-11-1). The reaction mixture was stirred at 80 °C for 12 h and concentrated in vacuo. The residue was poured into water (10 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The crude material was purified by column chromatography on silica gel eluting with PE / EtOAc = 3:1 to give tert-butyl 6-[[7-(p-tolylsulfonyl)-5-(trifluoromethyl)pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.54 mmol, 36% yield) as a pale red oil and tert-butyl 6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (260 mg, 0.66 mmol, 44% yield) as a pale brown oil. MS (ESI): m / z = 397.1 [M + H] + .

[0324] Building Block P.161: 6-(2-Azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1,2-benzoxazole; 4-Methylbenzenesulfonic acid [ka] A mixture of tert-butyl 6-[[3-(trifluoromethyl)-1,2-benzoxazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.4 g, 3.53 mmol, 1 equiv.) and p-toluenesulfonic acid monohydrate (1 g, 5.26 mmol, 1.49 equiv.) in EtOAc (100 mL) was stirred at 50 °C for 3 h. The reaction mixture was concentrated in vacuo, and the resulting residue was stirred with TBME (100 mL) for 3 h. The precipitate was filtered and dried to give 6-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1,2-benzoxazole; 4-methylbenzenesulfonic acid (1.31 g, 2.8 mmol, 75.21% yield) as a white solid. MS (ESI): m / z = 297.0 [M+H] + .

[0325] Step 1: tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (3.72 g, 11.1 mmol, 1 equiv., CAS 2763647-64-7), 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoroethanone (3.01 g, 11.1 mmol, 1 equiv., CAS 2763647-64-7) in 1,4-dioxane (70 mL) and water (7 mL). To a stirred suspension of 617706-18-0) and potassium carbonate (3.07 g, 22.19 mmol, 2 equiv.), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.36 g, 1.66 mmol, 0.15 equiv., CAS 95464-05-4) was added. The mixture was stirred at 80 °C for 18 h. The reaction mixture was concentrated in vacuo. The residue was stirred with EtOAc (200 mL) and Na SO . The mixture was filtered and concentrated in vacuo. The crude product was purified by FC to give tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2.8 g, 7.01 mmol, 58% yield) as a pale red solid. MS (ESI): m / z = 300.0 [M+H] + . FC conditions: column Interchim, SiO2 (120 g), hexane / ethyl acetate (0–27%), flow rate = 80 mL / min.

[0326] Step 2: tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (3 g, 7.51 mmol, 1 equivalent) and EtOAc (150 mL) was added Pd / C (10%) (300 mg). The mixture was hydrogenated at 3800 mmHg (in an autoclave) and then stirred at room temperature for 36 hours. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.0 g, 7.47 mmol, 90% yield) as a light brown oil. MS (ESI): m / z = 346.0 [M-C4H8+H] + .

[0327] Step 3: tert-butyl 6-[[3-fluoro-4-[N-hydroxy-C-(trifluoromethyl)carbonimidoyl]phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3 g, 7.47 mmol, 1 equiv.) in pyridine (40 mL) was added hydroxylamine hydrochloride (0.93 g, 13.45 mmol, 1.8 equiv.). The mixture was stirred at 50° C. for 18 hours. The mixture was concentrated in vacuo. The residue was stirred with water (50 mL) for 2 hours. The aqueous layer was decanted, and the resulting residue was partitioned between TBME (100 mL) and water (15 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo with toluene to give tert-butyl 6-[[3-fluoro-4-[N-hydroxy-C-(trifluoromethyl)carbonimidoyl]phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.8 g, 6.72 mmol, 80% yield). MS (ESI): m / z = 361.2 [M-C4H8+H] + .

[0328] Step 4: tert-butyl 6-[[3-(trifluoromethyl)-1,2-benzoxazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate A mixture of tert-butyl 6-[[3-fluoro-4-[N-hydroxy-C-(trifluoromethyl)carbonimidoyl]phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.8 g, 6.72 mmol, 1 equiv.) and potassium carbonate (1.39 g, 10.09 mmol, 1.5 equiv.) in dry DMF (60 mL) was stirred at 80 °C for 18 h. The reaction mixture was poured into water (300 mL) and extracted with EtOAc / TBME (100 mL / 100 mL). The organic layer was washed with brine, dried over Na SO , and concentrated in vacuo to give tert-butyl 6-[[3-(trifluoromethyl)-1,2-benzoxazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 3.78 mmol, 53% yield). MS (ESI): m / z = 341.0 [M-C4H8+H] + .

[0329] Building Block P.162: 1-(2-Azaspiro[3.3]heptan-6-ylmethyl)-4-[1-(trifluoromethyl)cyclopropyl]pyridin-2-one; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 0.56 mmol, 1 equiv.) in EtOAc (3 mL) was added p-toluenesulfonic acid (115 mg, 0.67 mmol, 1.2 equiv.). The reaction was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. Deionized water (3 mL) was added to the residue, which was then lyophilized to give 1-(2-azaspiro[3.3]heptan-6-ylmethyl)-4-[1-(trifluoromethyl)cyclopropyl]pyridin-2-one; 4-methylbenzenesulfonic acid (236 mg, 0.49 mmol, 81% yield) as a yellow solid. MS (ESI): m / z = 313.1 [M+H] + .

[0330] Step 1: tert-butyl 6-[(4-bromo-2-oxo-1-pyridyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 4-bromo-1H-pyridin-2-one (5 g, 28.74 mmol, 1 equiv.) in DCE (100 mL) was added tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (11.56 g, 34.48 mmol, 1.2 equiv., CAS 2763647-64-7), pyridine (4.55 g, 57.47 mmol, 2 equiv.), boronic acid (1.78 g, 28.74 mmol, 1 equiv.), and Cu(OAc) (7.75 g, 38.79 mmol, 1.35 equiv.). The mixture was stirred at 70 °C under O for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 0:1, Rf = 0.4) and concentrated in vacuo to give tert-butyl 6-[(4-bromo-2-oxo-1-pyridyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2.74 g, 7.19 mmol, 25% yield) as a white solid. MS (ESI): m / z = 325.0 [M-C4H8+H] + .

[0331] Step 2: tert-butyl 6-[(4-bromo-2-oxo-1-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4-bromo-2-oxo-1-pyridyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (629 mg, 1.65 mmol, 1 equiv.) in EtOAc (6 mL) was added PtO (112 mg, 0.49 mmol, 0.3 equiv.) under N. The suspension was degassed under vacuum and purged with H. The reaction was stirred under H (15 psi) at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc 60%) (petroleum ether / EtOAc 1:1, Rf = 0.4) and concentrated in vacuo to give tert-butyl 6-[(4-bromo-2-oxo-1-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (370 mg, 0.97 mmol, 58% yield) as a yellow oil. MS (ESI): m / z = 327.0 [M-C4H8+H] + .

[0332] Step 3: tert-butyl 6-[[2-oxo-4-[1-(trifluoromethyl)vinyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4-bromo-2-oxo-1-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.78 mmol, 1 equiv.) and 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (208 mg, 0.94 mmol, 1.2 equiv., CAS 1011460-68-6), KCO (324 mg, 2.35 mmol, 3 equiv.) in 1,4-dioxane (3 mL) and water (0.600 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (63.87 mg, 0.08 mmol, 0.1 equiv., CAS 95464-05-4) was added. The mixture was degassed with N2 and stirred at 80 °C under N2 atmosphere for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 60%) (petroleum ether / EtOAc = 1:1, Rf = 0.4) and concentrated in vacuo to give tert-butyl 6-[[2-oxo-4-[1-(trifluoromethyl)vinyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (360 mg, 0.9 mmol, 115% yield) as a yellow oil. MS (ESI): m / z = 343.1 [M-C4H8+H] + .

[0333] Step 4: tert-butyl 6-[[2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[2-oxo-4-[1-(trifluoromethyl)vinyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (320 mg, 0.8 mmol, 1 equiv.) in THF (3 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (323 mg, 1.12 mmol, 1.4 equiv., CAS 10504-60-6). NaHMDS / THF (1.36 mL, 1.36 mmol, 1.69 equiv.) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C under a N atmosphere for 1 h. The reaction mixture was slowly added to 6 mL of saturated aqueous NH4Cl. The mixture was added to 6 mL of water and extracted with EtOAc (4 mL × 3). The organic phase was concentrated in vacuo. The crude product was purified by silica gel chromatography (PE: EtOAc = 0:1) to give tert-butyl 6-[[2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (250.0 mg, 0.61 mmol, 75% yield) as a yellow solid. MS (ESI): m / z = 357.1 [M-C4H8+H] + .

[0334] Similar to building block P.162, heteroaryl compounds involved in the Chan Lam-type coupling in step 1 were used to generate the following building blocks. [Table 16]

[0335] Building Block P.164: 5-(2-Azaspiro[3.3]heptan-6-ylmethyl)-3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole; 2,2,2-Trifluoroacetic acid [ka] To a solution of 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (130 mg, 335 μmol, 1 equiv.) in dichloromethane (1 mL), TFA (382 mg, 258.53 μL, 3.36 mmol, 10 equiv.) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give 5-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole; 2,2,2-trifluoroacetic acid (324 mg, 241% yield). MS (ESI): m / z = 288.2 [M+H] + .

[0336] Step 1: tert-butyl 6-[2-[(Z)-[amino-[1-(trifluoromethyl)cyclopropyl]methylene]amino]oxy-2-oxo-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate A solution of 2-(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)acetic acid (2.5 g, 9.79 mmol, 1 equiv., CAS 1251002-39-7) and CDI (1905 mg, 11.75 mmol, 1.2 equiv.) in DMF (30 mL) was stirred at room temperature for 3 h. N'-hydroxy-1-(trifluoromethyl)cyclopropanecarboxamidine (1.64 g, 9.79 mmol, 1 equiv., CAS 2172624-76-7) was added. The solution was stirred at 25 °C for 2 h. The reaction mixture was purified by reverse-phase HPLC (conditions: water (0.02% FA), ACN) to give tert-butyl 6-[2-[(Z)-[amino-[1-(trifluoromethyl)cyclopropyl]methylene]amino]oxy-2-oxo-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 3.7 mmol, 37% yield) as a white solid. MS (ESI): m / z = 350.1 [M-C4H8+H] + .

[0337] Step 2: tert-butyl 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate A mixture of tert-butyl 6-[2-[(Z)-[amino-[1-(trifluoromethyl)cyclopropyl]methylene]amino]oxy-2-oxo-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 3.7 mmol, 1 equiv.) and tetrabutylammonium fluoride / THF (1.85 mL, 1.85 mmol, 0.5 equiv.) in THF (20 mL) was stirred at 70° C. for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (FA conditions: water (FA)-ACN, Phenomenex luna C18 150*40mm*15um) and lyophilized to give tert-butyl 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (807 mg, 2.08 mmol, 56.3% yield) as a pale yellow solid. MS (ESI): m / z = 388.1 [M+H] + .

[0338] Building Block P.165: 3-(2-Azaspiro[3.3]heptan-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (370 mg, 0.96 mmol, 1 equiv.) in EtOAc (4 mL) was added p-toluenesulfonic acid (197 mg, 1.15 mmol, 1.2 equiv.). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. Deionized water (3 mL) was added to the residue, which was then lyophilized to give 3-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole. 4-Methylbenzenesulfonic acid (406 mg, 0.88 mmol, 82% yield) was obtained as a white solid. MS (ESI): m / z = 288.1 [M+H] + .

[0339] Step 1: tert-Butyl 6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-(cyanomethylene)-2-azaspiro[3.3]heptane-2-carboxylate (2.66 g, 11.35 mmol, 1 equiv., CAS 1428726-12-8) in methanol (26 mL) was added Pd / C (wet) (886 mg, 1.14 mmol, 0.1 equiv.) at 25 °C. The reaction was stirred under a H atmosphere (H balloon) at 25 °C for 0.5 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl 6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate (2.6 g, 11.0 mmol, 96% yield) as a white solid. MS (ESI): m / z = 181.0 [M-CH + H] + .

[0340] Step 2: tert-Butyl 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of hydroxylamine hydrochloride (588 mg, 8.46 mmol, 2 equiv.) in ethanol (10 mL) was added triethylamine (856 mg, 8.46 mmol, 2 equiv.) at 25 °C. After 0.5 h, tert-butyl 6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 4.23 mmol, 1 equiv.) was added. The reaction was stirred at 50 °C for 2 h. The reaction was concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted with ethyl acetate (5 mL × 3). The combined extracts were concentrated in vacuo to give tert-butyl 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.03 g, 3.82 mmol, 90% yield) as a colorless oil. MS (ESI): m / z = 270.2 [M+H] + .

[0341] Step 3: tert-butyl 6-[(2Z)-2-amino-2-[1-(trifluoromethyl)cyclopropanecarbonyl]oximino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate A solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (589 mg, 3.82 mmol, 1 equiv., CAS 277756-46-4) and CDI (744 mg, 4.59 mmol, 1.2 equiv.) in DMF (10 mL) was stirred at room temperature for 2 h. tert-Butyl 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.03 g, 3.82 mmol, 1 equiv.) was added to the solution and stirred at 25 °C for 1 h. The reaction mixture was purified by reverse-phase HPLC (conditions: water (0.02% FA), ACN) to give tert-butyl 6-[(2Z)-2-amino-2-[1-(trifluoromethyl)cyclopropanecarbonyl]oximino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (130 mg, 0.32 mmol, 8.4% yield) as a white solid. MS (ESI): m / z = 350.1 [M-CH+H] + .

[0342] Step 4: tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate A solution of tert-butyl 6-[2-[(Z)-[amino-[1-(trifluoromethyl)cyclopropyl]methylene]amino]oxy-2-oxo-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (210 mg, 0.52 mmol, 1 equiv.) and tetrabutylammonium fluoride / THF (0.13 mL, 0.13 mmol, 0.25 equiv.) in THF (2 mL) was stirred at 70° C. for 1 h. The mixture was added to 2 mL of water and extracted with EtOAc (15 mL × 3). The organic phase was concentrated in vacuo. The mixture was purified by PREP-HPLC to give tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (220 mg, 0.57 mmol, 109% yield) as a yellow solid. MS (ESI): m / z = 332.1 [M-C4H8+H] + .

[0343] Building Block P.167: 4-Methylbenzenesulfonic acid; 6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane [ka] To a solution of tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.78 mmol, 1 equiv.) in EtOAc (6 mL) was added p-toluenesulfonic acid monohydrate (444 mg, 2.34 mmol, 3 equiv.). The mixture was stirred at 30 °C for 72 h. The reaction mixture was concentrated in vacuo. The residue was purified by HPLC to give 4-methylbenzenesulfonic acid; 6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane (81 mg, 0.13 mmol, 15% yield) as a yellow gum. MS (ESI): m / z = 286.2 [M+H] + HPLC conditions: Apparatus (mobile phase, column): SYSTEM 0-2-9 min 0-70% H2O / MEOH / 0.1NH4OH Flow rate 30 ml / min ((loading pump 4 ml MEOH) Target mass 337 Column: XBridge BEH C18 100*19 mm, 5 microM.

[0344] Step 1: 4-[1-(trifluoromethyl)cyclopropyl]-1H-imidazole 2-Bromo-1-[1-(trifluoromethyl)cyclopropyl]ethanone (0.5 g, 2.16 mmol, 1 eq., CAS 1382999-80-5) was added to methanamide (5 mL, 125 mmol, 58 eq.). The reaction mixture was stirred at 180 °C for 2 h. After the reaction was complete, 50 mL of water was added. The mixture was washed three times with dichloromethane, and then the aqueous phase was adjusted to pH 8 with 1 M aqueous NaOH. The aqueous phase was extracted twice with dichloromethane. The organic phase was dried, concentrated in vacuo, and purified by HPLC to give 4-[1-(trifluoromethyl)cyclopropyl]-1H-imidazole (110 mg, 0.62 mmol, 28% yield) as a brown solid. MS (ESI): m / z = 177.2 [M+H] +HPLC conditions: Apparatus (mobile phase, column): SYSTEM 0-2~10 min 0~75% H2O / ACN, flow rate 30 ml / min (loading pump 4 mACN), target mass 177. Column: Chromatorex C18 SMB100-5T 100*19 mm, 5 microns.

[0345] Step 2: tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of 4-[1-(trifluoromethyl)cyclopropyl]-1H-imidazole (800 mg, 3.41 mmol, 1 equiv.) and cesium carbonate (2.21 g, 6.81 mmol, 2 equiv.) in DMF (15 mL) was added tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.04 g, 3.41 mmol, 1 equiv., CAS 2740574-92-7) at room temperature. The reaction mixture was stirred at 50° C. for 18 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (2×200 mL) and brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by FC to give tert-butyl 6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (800 mg, 2.07 mmol, 60% yield) and tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.78 mmol, 22% yield) as pale yellow solids. MS (ESI): m / z = 286.2 [M+H] + . FC conditions: Interchim; 40 g SiO2, petroleum ether / MtBE with MtBE from 15-100%, plus MtBE / methanol with methanol from 0-10%. Flow rate = 40 mL / min, Rv = 21-23 CV.

[0346] Building Block P.168: 6-[Difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.38 g, 8.59 mmol, 1 equiv.) in EtOAc (34 mL) was added p-toluenesulfonic acid (1.77 g, 10.3 mmol, 1.2 equiv.). The reaction was stirred at 80 °C for 4 h. The reaction mixture was concentrated in vacuo. Deionized water (30 mL) was added to the residue and lyophilized to give 6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (3.96 g, 8.51 mmol, 97% yield) as a yellow solid. MS (ESI): m / z = 294.3 [M+H] + .

[0347] Step 1: tert-butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 3-chloro-6-(trifluoromethyl)pyridazine (30 g, 164 mmol, 1 equiv., CAS 258506-68-2) in 1,4-dioxane (500 mL) and water (50 mL) was added tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (55.1 g, 164 mmol, 1 equiv., CAS 2763647-64-7), potassium carbonate (45.43 g, 328 mmol, 2 equiv.), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (13.41 g, 16.44 mmol, 0.1 equiv., CAS 95464-05-4) was added. The reaction mixture was stirred at 100° C. under a N atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (3:1) (TLC, PE:EtOAc = 3:1, Rf = 0.40) to give the crude product. The crude product was washed with PE (300 mL). After filtration, the solid was collected and concentrated in vacuo to give tert-butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (46 g, 121 mmol, 73% yield) as a yellow solid. MS (ESI): m / z = 300.3 [M-C4H8+H] + .

[0348] Step 2: tert-butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (19 g, 53.47 mmol, 1 equiv.) in EtOAc (600 mL) was added Pd / C (wet) (6.33 g, 5.95 mmol, 0.11 equiv.) at 25 °C. The reaction was stirred under a H atmosphere (H balloon) at 25 °C for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give tert-butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (19 g, 53.17 mmol, 99% yield) as a yellow solid. MS (ESI): m / z = 358.2 [M+H] + .

[0349] Step 3: tert-Butyl 6-[6-(trifluoromethyl)pyridazine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (15 g, 41.9 mmol, 1 equiv.) in 1,4-dioxane (300 mL) was added SeO (27.94 g, 251.8 mmol, 6 equiv.). The reaction mixture was stirred at 90 °C under a N atmosphere for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0-30% AcOEt / petroleum ether, petroleum ether / AcOEt=1 / 1, Rf=0.5) and concentrated in vacuo to give tert-butyl 6-[6-(trifluoromethyl)pyridazine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate (4.3 g, 11.58 mmol, 27% yield) as a yellow solid. MS (ESI): m / z=316.0 [M-C4H8+H] + .

[0350] Step 4: tert-Butyl 6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[6-(trifluoromethyl)pyridazine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate (3 g, 8.08 mmol, 1 equiv.) in DCM (30 mL) was added DAST (30 mL, 227 mmol, 28 equiv.) dropwise at 0° C. under a N atmosphere. The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was added dropwise to saturated aqueous NaHCO (500 mL) and extracted with EtOAc (200 mL×3). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (5:1) (TLC, PE:EtOAc = 3:1, Rf = 0.40) to give tert-butyl 6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.6 g, 6.61 mmol, 81.82% yield) as a yellow solid. MS (ESI): m / z = 394.0 [M+H] + .

[0351] Similar to building block P.168, the following building blocks were generated using heteroaryl bromides or heteroaryl chlorides involved in the cross-coupling in step 1. [Table 17]

[0352] Building Block P.178: 6-(2-Azaspiro[3.3]heptan-6-ylmethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine; 4-Methylbenzenesulfonic acid [ka] A mixture of p-toluenesulfonic acid (364 mg, 2.12 mmol, 3 equiv.) and tert-butyl 6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (280 mg, 0.71 mmol, 1 equiv.) in EtOAc (30 mL) was stirred at 50 °C for 24 h. The mixture was concentrated in vacuo and purified by FC to give 6-(2-azaspiro[3.3]heptan-6-ylmethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine; 4-methylbenzenesulfonic acid (178 mg, 0.38 mmol, 53% yield) as a light brown solid. MS (ESI): m / z = 297.0 [M+H] + . FC conditions: Interchim, SiO2 40g, MTBE / methanol (0-60%), flow rate = 40ml / min, 16.1-18.3 CV.

[0353] Step 1: tert-butyl 6-[(2-aminopyrimidin-5-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.87 g, 2.3 mmol, 0.2 equiv., CAS 95408-45-0), potassium carbonate (3.17 g, 22.99 mmol, 2.0 equiv.), 2-amino-5-bromopyrimidine (2 g, 11.49 mmol, 1 equiv.), and tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (3.85 g, 11.49 mmol, 1 equiv., CAS 2763647-64-7) were added to a mixture of 1,4-dioxane (61 mL) and water (13 mL). The reaction mixture was stirred at 90° C. for 24 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by FC to give tert-butyl 6-[(2-aminopyrimidin-5-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 4.96 mmol, 43% yield) as a pale yellow solid. MS (ESI): m / z=303.2 [M+H] + . FC conditions: Interchim, SiO2 120 g, chloroform / acetonitrile (0–100%), flow rate = 80 ml / min, 22.6–28.3 CV.

[0354] Step 2: tert-butyl 6-[(2-aminopyrimidin-5-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate A mixture of tert-butyl 6-[(2-aminopyrimidin-5-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 4.96 mmol, 1 equiv.) and Pd / C 10% (158 mg, 0.15 mmol, 0.03 equiv.) in EtOAc (80 mL) was hydrogenated at 19,000 mmHg and stirred at 25 °C for 18 h. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6-[(2-aminopyrimidin-5-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 4.93 mmol, 96% yield) as a white solid. MS (ESI): m / z = 249.2 [M-CH + H] + .

[0355] Step 3: tert-butyl 6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate A solution of tert-butyl 6-[(2-aminopyrimidin-5-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 4.93 mmol, 1 equiv.) and 3-bromo-1,1,1-trifluoroacetone (940 mg, 4.93 mmol, 1 equiv.) in ACN (9 mL) and toluene (1.5 mL) was stirred at 100° C. for 24 h. The reaction mixture was concentrated in vacuo and diluted with DCM and NaHCO (10% aqueous solution). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by FC to give tert-butyl 6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (340.0 mg, 0.86 mmol, 17% yield) as a yellow solid. MS (ESI): m / z = 397.2 [M+H] + . FC conditions: Interchim: 40 g SiO2, chloroform / ACN with ACN from 0-40%, flow rate = 40 mL / min, Rv = 10-12 CV.

[0356] Synthesis of non-commercial building blocks: C.184 tert-Butyl 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylate [ka] 2,2,6,6-Tetramethylpiperidine (16 mL, 100 mmol, 1.2 equiv., CAS 768-66-1) was dissolved in THF (100 ml) and cooled to -30 °C under Ar atmosphere. Butyllithium solution (2.5 M) (40.12 mL, 100 mmol, 1.2 equiv.) was added dropwise, and the reaction mixture was stirred at the same temperature for 30 min. The reaction mixture was cooled to -78 °C. A solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (24.63 g, 91.93 mmol, 1.1 equiv., CAS 78782-17-9) in THF (20 ml) was added dropwise. After stirring for 30 min, a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (20 g, 83.57 mmol, 1 equiv., CAS 203661-69-2) in THF (30 ml) was added dropwise at −78° C. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was cooled to 0° C., and aqueous NH4Cl (30 mL) was added dropwise. After stirring for an additional 1 h, the resulting mixture was filtered, and the solvent was concentrated in vacuo. H2O (100 mL) was added to the residue, and the aqueous layer was extracted with EtOAc (250 mL). The organic phase was washed with brine (250 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography (Interchim, 330 g SiO, hexane / MTBE (0–15–100%), flow rate = 100 ml / min, 5–9 CV) to give tert-butyl 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylate (20.4 g, 56.15 mmol, 63% yield) as a white solid. MS (ESI): m / z = 308.2 [M-C4H8+H]+ .

[0357] C.9 1-Bromo-3-dimethylphosphoryl-5-(trifluoromethyl)benzene To a solution of methylphosphonoylmethane (2.22 g, 28.5 mmol, CAS 150765-29-0), 1-bromo-3-iodo-5-(trifluoromethyl)benzene (5 g, 14.3 mmol, CAS 481075-59-6), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (206 mg, 0.36 mmol, CAS 161265-03-8), and triethylamine (2.98 mL, 21.4 mmol) in 1,4-dioxane (50 mL) was added tris(dibenzylideneacetone)dipalladium(0) (130 mg, 0.14 mmol, CAS 51364-51-3). The reaction mixture was stirred under argon at 25 °C for 48 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The extract was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to give the title compound (1.9 g, 6.31 mmol, 42% yield) as an orange solid. MS (ESI): m / z = 301.0 [M+H] + .

[0358] C.17 3-Bromo-5-[1-(trifluoromethyl)cyclopropyl]-4H-1,2,4 triazole To a solution of 3-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4-triazole (5.07 g, 27 mmol, 1 equiv.) in DMF (25 mL) was added NBS (10.65 g, 59.82 mmol, 2.2 equiv.). The mixture was stirred at 60 °C for 15 h. The reaction mixture was poured into EtOAc and washed with water and saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in heptane) to give 5-bromo-3-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4-triazole (3.08 g, 42% yield) as a white solid. MS: (ESI): m / z = 255.9 [{79Br}M+H] + ,257.9[{81Br}M+H] + .

[0359] Step 1: (NE)-N-(dimethylaminomethylene)-1-(trifluoromethyl)cyclopropanecarboxamide 1-(Trifluoromethyl)cyclopropanecarboxamide (5 g, 32 mmol, 1 equiv., CAS 1628184-67-7) was dissolved in N,N-dimethylformamide dimethyl acetal (27.24 g, 228 mmol, 7 equiv.). The mixture was stirred at room temperature for 6 h. The reaction mixture was poured into EtOAc and washed with water and saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo to give (NE)-N-(dimethylaminomethylene)-1-(trifluoromethyl)cyclopropanecarboxamide (6.5 g, 90% yield) as a yellow amorphous oil. MS (ESI): m / z = 209.1 [M+H] + .

[0360] Step 2: 3-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4 triazole To an ice-cold solution of (NE)-N-(dimethylaminomethylene)-1-(trifluoromethyl)cyclopropanecarboxamide (6.5 g, 28 mmol, 1 equiv.) in acetic acid (18 mL) was added hydrazine hydrate (1.55 g, 30.9 mmol, 1.1 equiv.). The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. NaOH 1N was added (pH 7-8). The mixture was washed with water and saturated NaCl. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 3-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4-triazole (5.07 g, 96% yield) as a yellow solid. MS (ESI): m / z = 178.1 [M+H] + .

[0361] C.72 1-Bromo-4-dimethylphosphoryl-2-(trifluoromethyl)benzene To a solution of methylphosphonoylmethane (1.85 g, 23.7 mmol, CAS 7211-39-4), 1-bromo-4-iodo-2-(trifluoromethyl)benzene (8.3 g, 23.7 mmol, CAS 364-11-4), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (137 mg, 0.24 mmol, CAS 161265-03-8), and triethylamine (3.86 mL, 27.7 mmol) in 1,4-dioxane (80 mL) was added tris(dibenzylideneacetone)dipalladium(0) (108 mg, 0.12 mmol, CAS 51364-51-3). The mixture was stirred at room temperature under Ar for 24 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by FC (eluting with 0-100% MtBE in petroleum ether / MtBE, then 0-25% MtBE / methanol) to give 1-bromo-4-dimethylphosphoryl-2-(trifluoromethyl)benzene (50 mg, 0.170 mmol, 18.5% yield) as a white semisolid. MS (ESI): m / z = 301.0 [{79Br}M+H] + ,303.0[{81Br}M+H] + .

[0362] C.115 2-Bromo-3-methoxy-5-(trifluoromethyl)pyrazine To a mixture of 3-methoxy-5-(trifluoromethyl)pyrazin-2-amine (1.6 g, 8.28 mmol, CAS 1823377-58-7) and CuBr (1.42 g, 9.94 mmol) in ACN (15 mL) was added a solution of tert-butyl nitrite (1.28 g, 12.4 mmol) in ACN (5 mL) at 25 °C. The reaction mixture was stirred at 70 °C under a N atmosphere for 12 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo at room temperature. The residue was purified by column chromatography (ethyl acetate:petroleum ether 0-10%) and concentrated in vacuo at room temperature to give the title compound (800 mg, 3.11 mmol, 38% yield) as a colorless oil. MS (ESI): m / z = 256.9 [M+H] + NOTE: The product was volatile.

[0363] C.122 3-Bromo-5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazole To a solution of 5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazol-3-amine (2.3 g, 12 mmol, CAS 1001354-47-7) in ACN (40 mL) was added dropwise a solution of isopentyl nitrite (1.55 g, 13.2 mmol) in ACN (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. CuBr (1.61 g, 7.22 mmol) was added to the mixture at 0 °C, and the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by reverse-phase HPLC (water (0.1% FA)-ACN). The purified solution was lyophilized to give the title compound (740 mg, 2.9 mmol, 24.1% yield) as a pale green solid. MS (ESI): m / z = 257.2 [M+H] + .

[0364] C.124 2-chloro-5-[1-(trifluoromethyl)cyclopropyl]pyrazine To a solution of 2-chloro-5-[1-(trifluoromethyl)vinyl]pyrazine (1.6 g, 7.67 mmol) in THF (60 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (2.87 g, 9.97 mmol, CAS 10504-60-6). The suspension was stirred at 0 °C for 0.5 h. A NaHMDS solution (12.3 mL, 12.3 mmol, 1 M in THF) was added dropwise. The reaction mixture was heated at 25 °C for 1 h. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted twice with EtOAc (40 mL). The organic layers were combined, washed with brine, dried over Na SO , and concentrated in vacuo. Purification by FC (SiO ; PE / EtOAc) afforded the title compound (1.5 g, 63% yield) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ = 8.53 (s, 1H), 8.43 (d, J = 1.2Hz, 1H), 1.48-1.42 (m, 2H), 1.36ppm (brs, 2H).

[0365] Step 1: 2-chloro-5-[1-(trifluoromethyl)vinyl]pyrazine To a solution of 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (3.44 g, 15.5 mmol, CAS 1011460-68-6), 2-bromo-5-chloropyrazine (3 g, 15.5 mmol), and potassium carbonate (4.29 g, 31 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1266 mg, 1.55 mmol, CAS 95464-05-4). The mixture was stirred at 80 °C under N atmosphere for 12 h, filtered, and concentrated in vacuo. Purification by FC (SiO; PE) afforded the title compound (1.6 g, 49% yield) as a yellow solid. MS (ESI): m / z = 209.3 [M+H] +

[0366] C.125 3-Bromo-6-[1-(trifluoromethyl)cyclopropyl]pyridazine To a solution of 3-bromo-6-[1-(trifluoromethyl)vinyl]pyridazine (340 mg, 1.34 mmol) in THF (10 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (503 mg, 1.75 mmol, CAS 10504-60-6). The suspension was stirred at 0° C. for 0.5 h. A solution of NaHMDS (2.15 mL, 2.15 mmol, 1 M in THF) was added dropwise. The reaction mixture was stirred at 25° C. for 1 h. The mixture was quenched with 6 mL of methanol. The reaction mixture was partitioned between EtOAc (20 mL) and water (40 mL). The organic phase was concentrated in vacuo. Purification by preparative HPLC afforded the title compound (280 mg, 78% yield) as a white solid. MS (ESI): m / z=267.3 [M+H] + .

[0367] Step 1: 3-Bromo-6-[1-(trifluoromethyl)vinyl]pyridazine To a solution of 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (560 mg, 2.52 mmol, CAS 1011460-68-6) and 3,6-dibromopyridazine (500 mg, 2.1 mmol), potassium carbonate (581 mg, 4.2 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (172 mg, 0.210 mmol, CAS 95464-05-4). The mixture was stirred at 80 °C under a N atmosphere for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL × 3). The combined organic phase was washed with brine, dried over NaSO, and concentrated in vacuo. Purification by FC (SiO2; PE) gave the title compound (300 mg, 56% yield) as a white crystalline solid. MS (ESI): m / z = 253.3 [M+H] + .

[0368] C.128 4,5-Dibromo-2-(2,2,2-trifluoroethyl)triazole To a solution of 4,5-dibromo-2H-triazole (5 g, 22 mmol, CAS 22300-52-3) in ACN (50 mL) was added cesium carbonate (7.18 g, 22 mmol). 2,2,2-Trifluoroethyl trifluoromethanesulfonate (5.12 g, 22.0 mmol, CAS 6226-25-1) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured into water. EtOAc was added, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, PE / EtOAc 0-7%). Fractions containing pure product were combined and concentrated in vacuo to give 4,5-dibromo-2-(2,2,2 trifluoroethyl)triazole (5.3 g, 17.2 mmol, 77% yield) as a yellow oil. 1 H NMR(400MHz,chloroform-d)δ=4.95(q,J=7.9Hz,2H).

[0369] C.145 2-[[5-Bromo-3-(trifluoromethyl)pyrazolo[3,4-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane A mixture of 2-[(5-bromo-3-iodo-pyrazolo[3,4-c]pyridin-1-yl)methoxy]ethyl-trimethyl-silane (5.6 g, 12 mmol, 1 equiv., CAS 2097610-93-8), copper(I) iodide (11.74 g, 61 mmol, 5 equiv.), potassium fluoride (3.58 g, 61 mmol, 5 equiv.), and trifluoromethyltrimethylsilane (8.77 g, 61 mmol, 5 equiv.) in NMP (113 mL) was stirred at 100 °C for 18 h. The reaction mixture was quenched by adding 1 L of water and filtered from the inorganic precipitate. The filtrate was extracted with ethyl acetate, and the organic phase was washed with water, saturated NaCl solution, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by FC to give 2-[[5-bromo-3-(trifluoromethyl)pyrazolo[3,4-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (1.4 g, 3.5 mmol, 28% yield) as a pale yellow viscous oil. MS (ESI): m / z = 396.0 [M+H] + . FC conditions: Interchim, 120 SiO2, hexane / ethyl acetate (0–22%), flow rate = 80 ml / min.

[0370] C.149 1-(4-Bromophenyl)sulfonyl-3-(trifluoromethyl)azetidine To a solution of 4-bromobenzenesulfonyl chloride (1.33 g, 5.2 mmol, 1.3 equiv.) and 3-(trifluoromethyl)azetidine (500 mg, 4 mmol, 1 equiv., CAS 1221349-18-3) in DMF (5 mL) was added DIEA (3.46 mL, 20 mmol, 5 equiv.) at 25 °C. The mixture was shaken at 100 °C for 2 h. The crude material was purified by flash column (PE to PE: EtOAc = 3:1; UV) and concentrated in vacuo to give 1-(4-bromophenyl)sulfonyl-3-(trifluoromethyl)azetidine (980 mg, 2.85 mmol, 71% yield) as a white solid. MS (ESI): m / z = 344.0 [{79Br}M+H] + ,346.0[{81Br}M+H] + .

[0371] C.157 4-Chloro-2-methylsulfonyl-1-(trifluoromethyl)benzene To a solution of 4-chloro-2-methylsulfanyl-1-(trifluoromethyl)benzene (1.95 g, 8.6 mmol, 1 equiv., CAS 1428234-60-9) in 1,2-dichloroethane (20 mL)-ACN (20 mL)-water (40 mL) was added sodium periodate (3.68 g, 17.21 mmol, 2 equiv.) and ruthenium(III) chloride hydrate (19.4 mg, 0.09 mmol, 0.01 equiv.) at 0° C. The mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with water (40 ml) and extracted with 50 mL of DCM and 2×50 mL of EtOAc. The combined organic layers were washed with 75 mL of brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:ethyl acetate = 0.3:1) to give 4-chloro-2-methylsulfonyl-1-(trifluoromethyl)benzene (1.8 g, 6.96 mmol, 72% yield) as a white solid. H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.32 (d, J = 1.96 Hz, 1H), 7.87 (d, J = 8.44 Hz, 1H), 7.76 (dd, J = 8.44, 1.22 Hz, 1H), 3.22 (s, 3H).

[0372] C.158 7-chloro-3-(trifluoromethyl)imidazo[1,2-a]pyrimidine Lithium fluoride (7.45 mL, 368.53 mmol, 30 equiv.) in a pre-cooled (liquid N2) autoclave was charged with 7-chloroimidazo[1,2-a]pyrimidine-3-carboxylate (2.5 g, 12.28 mmol, 1 equiv., CAS 2839138-71-3). Tetrafluoro-λ4-sulfane (2.65 g, 24.57 mmol, 2 equiv., CAS 7783-60-0) was then pressurized into the vessel. The reaction mixture was then stirred at 65 °C for 72 h. The reaction mixture was carefully diluted with saturated K2CO3 (150 ml). The aqueous layer was extracted with MTBE. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated in vacuo and purified by FC to give 7-chloro-3-(trifluoromethyl)imidazo[1,2-a]pyrimidine (500 mg, 2.25 mmol, 16.3% yield) as a white solid. MS (ESI): m / z = 222.0 [M+H] + . FC conditions: 1) Interchim, 12 g SiO2, chloroform / acetonitrile (0–10%), flow rate = 80 ml / min, 6.2–9.6 CV; 2) Interchim, 40 g SiO2, hexane / isopropanol (5–100%), flow rate = 40 ml / min, RV = 7.8–31.1 CV.

[0373] C.160 2-Bromo-5-[3-(trifluoromethyl)azetidin-1-yl]pyrazine. To a solution of 3-(trifluoromethyl)azetidine hydrochloride (500 mg, 3.08 mmol, 1 equiv., CAS 1221272-90-7) and DIEA (1.55 g, 15.3 mmol, 5 equiv.) in DMF (10 mL) was added 2,5-dibromopyrazine (951 mg, 4 mmol, 1.3 equiv.). The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was poured into saturated NaCl. The mixture was extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO, petroleum ether / EtOAc) and concentrated in vacuo to give 2-bromo-5-[3-(trifluoromethyl)azetidin-1-yl]pyrazine (500 mg, 1.77 mmol, 44% yield) as a yellow solid. MS (ESI): m / z = 281.9 [M+H] + .

[0374] C.171 3-Bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazole To a solution of 3-bromo-1H-1,2,4-triazole (8 g, 54 mmol, 1 equiv., CAS 7343-33-1) in THF (80 mL) was added NaH (3.89 g, 97 mmol, 1.8 equiv.) at 0 °C. After 0.5 h, 2,2,2-trifluoroethyl trifluoromethanesulfonate (25.1 g, 108.14 mmol, 2 equiv., CAS 6226-25-1) was added. The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Welch Ultimate XB-SiOH 250*70*10um, hexane-EtOH) and concentrated in vacuo to give 3-bromo-1-(2,2,2 trifluoroethyl)-1,2,4-triazole (6g, 26.09mmol, 48% yield) as a brown oil. MS(ESI):m / z=229.9[M+H] + .

[0375] C.195 2-chloro-4-[1-(trifluoromethyl)cyclopropyl]pyrimidine To a solution of 2-chloro-4-[1-(trifluoromethyl)vinyl]pyrimidine (1 g, 4.79 mmol, 1 equiv.) in THF (5 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (2.07 g, 7.19 mmol, 1.5 equiv., CAS 10504-60-6) and NaHMDS (7.67 mL, 7.67 mmol, 1.6 equiv.) at 20 °C. The mixture was stirred under N at 20 °C for 12 h. The reaction mixture was poured into H O and extracted with EtOAc. The organic layer was washed with brine, dried over Na SO , and concentrated in vacuo to give 2-chloro-4-[1-(trifluoromethyl)cyclopropyl]pyrimidine (1 g, 4.49 mmol, 93% yield) as a red oil. MS (ESI): m / z = 233.0 [M+H] + .

[0376] Step 1: 2-chloro-4-[1-(trifluoromethyl)vinyl]pyrimidine To a solution of 4-bromo-2-chloropyrimidine (2 g, 10.34 mmol, 1 equiv., CAS 885702-34-1) 4,4,6-trimethyl-2-(2.29 g, 10.34 mmol, 1 equiv., CAS 1011460-68-6)-1,3,2-dioxaborinane and KCO (2.85 g, 20.68 mmol, 2 equiv.) in 1,4-dioxane (40 mL) and water (4 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (844 mg, 1.03 mmol, 0.1 equiv., CAS 95464-05-4). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO, eluent: 0-3% ethyl acetate / petroleum ether, Rf = 0.6) and concentrated in vacuo to give 2-chloro-4-[1-(trifluoromethyl)vinyl]pyrimidine (1.36 g, 6.54 mmol, 62% yield) as a yellow oil. MS (ESI): m / z = 208.9 [M+H] + .

Claims

1. Compounds of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein (i) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5 -a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5- a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R １ is a halogen, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, hydroxy C １～６ -Alkyl, C ３～６ Cycloalkyl-, haloC １～６ Alkyl C ３～６ Cycloalkyl-, (haloC １～６ alkyl)-(3- to 6-membered heterocyclyl)-, haloC １～６ Alkoxy, (C １～６ alkyl) ２ PO-, and groups 【Chemistry 2】 Selected from: R ２ is hydrogen, halogen, cyano, oxo, C １～６ Alkyl and HaloC １～６ alkyl; R ３ is C １～６ Alkyl, haloC １～６ alkyl, and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is selected from haloC １～６ optionally substituted with alkyl substituents; X is selected from O and NH; or (ii) A is pyridyl; R １ is a halogen, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, hydroxy C １～６ Alkyl, C ３～６ Cycloalkyl-, haloC １～６ Alkyl C ３～６ Cycloalkyl-, haloC １～６ Alkoxy, (C １～ ６ alkyl) ２ PO-, and groups 【Chemistry 3】 Selected from: R ２ is hydrogen, halogen, cyano, C １～６ Alkyl and HaloC １～６ alkyl; R ３ is C １～６ Alkyl, haloC １～６ alkyl, and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is selected from haloC １～６ optionally substituted with alkyl substituents; and X is selected from O and NH; or (iii) A is phenyl; R １ is (C １～６ alkyl) ２ PO- and groups 【Chemistry 4】 Selected from: R ２ is hydrogen, halogen, cyano, C １～６ Alkyl and HaloC １～６ alkyl; R ３ is C １～６ Alkyl, haloC １～６ alkyl, and 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is selected from haloC １～６ optionally substituted with alkyl substituents; and X is selected from O and NH; R ４ and R ５ are each independently hydrogen, halogen, and C １～６ alkyl; and B is, 【Chemistry 5】 (selected from).

2. Compounds of formula (I) 【Chemistry 6】 or a pharmaceutically acceptable salt thereof, wherein A is a 9-membered bicyclic heteroaryl containing 1-5 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; R １ is a halogen, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, hydroxy C １～６ Alkyl, C ３～６ Cycloalkyl-, haloC １～６ Alkyl C ３～６ Cycloalkyl-, haloC １～６ Alkoxy, (C １～６ alkyl) ２ PO-, and groups 【Chemistry 7】 Selected from: R ２ is hydrogen, halogen, cyano, oxo, C １～６ Alkyl and HaloC １～６ alkyl; R ３ is C １～６ Alkyl and HaloC １～６ alkyl; X is selected from O and NH; or R ４ and R ５ are each independently hydrogen, halogen, and C １～６ alkyl; and B is, 【Chemistry 8】 (selected from).

3. (i) A is phenyl; R １ However, (C １～６ alkyl) ２ PO- and groups 【Chemistry 9】 Selected from: R ２ is hydrogen, halogen, and haloC １～６ alkyl; R ３ But C １～６ Alkyl, haloC １～６ Alkyl, and (haloC １～６ alkyl)-(4- to 6-membered heterocyclyl); and X is selected from O and NH; or (ii) A is pyridyl; R １ But halogen, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, haloC １～６ Alkyl C ３～６ Cycloalkyl-, haloC １～６ Alkoxy, (C １～６ alkyl) ２ PO-, and groups 【Chemistry 10】 Selected from: R ２ But hydrogen, halogen, halo C １～６ selected from alkyl and cyano; R ３ But C １～６ Alkyl and HaloC １～６ alkyl; and X is selected from O and NH; or (iii) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1 ,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5 -a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R １ But C １～６ Alkoxy, HaloC １～６ Alkyl, hydroxy C １～６ Alkyl, C ３～６ Cycloalkyl-, haloC １～６ Alkyl C ３～６ Cycloalkyl-, (haloC １～６ alkyl)-(3- to 6-membered heterocyclyl)-, haloC １～６ Alkoxy, and groups 【Chemistry 11】 Selected from: R ２ is hydrogen, halogen, cyano, oxo, C １～６ Alkyl and HaloC １～６ alkyl; R ３ But, Haro C １～６ is alkyl; and 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from O and NH.

4. (i) A is phenyl; R １ However, (C １～６ alkyl) ２ PO- and groups 【Chemistry 12】 Selected from: R ２ is hydrogen, halogen, and haloC １～６ alkyl; R ３ But C １～６ Alkyl and HaloC １～６ alkyl; and X is O; or (ii) A is pyridyl; R １ but halogen and haloC １～６ alkyl; R ２ is selected from hydrogen and halogen; or (iii) A is selected from pyrazinyl and pyrazolyl; R １ But, Haro C １～６ is alkyl; and R ２ 4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

5. (i) A is phenyl; R １ However, (CH ３ ) ２ PO- and groups 【Chemistry 13】 Selected from: R ２ is hydrogen, fluoro, and CF ３ Selected from: R ３ However, methyl and CF ３ is selected from: X is O; or (ii) A is pyridyl; R １ Fluoro and CF ３ Selected from: R ２ is selected from hydrogen and fluoro; or (iii) A is selected from pyrazinyl and pyrazolyl; R １ But CF ３ and R ２ 5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

6. A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a ]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5-a] Pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine , pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R １ But C １～６ Alkoxy, HaloC １～６ Alkyl, hydroxy C １～６ Alkyl, C ３～６ Cycloalkyl-, haloC １～６ Alkyl C ３～６ Cycloalkyl-, (haloC １～６ alkyl)-(3- to 6-membered heterocyclyl)-, haloC １～６ Alkoxy, and groups 【Chemistry 14】 Selected from: R ２ is hydrogen, halogen, cyano, oxo, C １～６ Alkyl and HaloC １～６ alkyl; R ３ But, Haro C １～６ is alkyl; and 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from O and NH.

7. B, 【Chemistry 15】 7. The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, selected from:

8. B, 【Chemistry 16】 7. The compound of formula (I) according to any one of claims 1 to 6, wherein:

9. B, 【Chemistry 17】 7. The compound of formula (I) according to any one of claims 1 to 6, wherein:

10. R ４ is hydrogen, halogen and C １～６ alkyl; and R ５ A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and halogen.

11. R ４ and R ５ are both hydrogen; or R ４ and R ５ are both halogens; or R ４ is C １～６ alkyl, and R ５ A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

12. R ４ and R ５ A compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein are both hydrogen.

13. (i) A is phenyl; R １ is (C １～６ alkyl) ２ PO- and groups 【Chemistry 18】 Selected from: R ２ is hydrogen, halogen, and haloC １～６ alkyl; R ３ is C １～６ Alkyl, haloC １～６ Alkyl, and (haloC １～６ alkyl)-(4- to 6-membered heterocyclyl); and X is selected from O and NH; or (ii) A is pyridyl; R １ is a halogen, C １～６ Alkyl, C １～６ Alkoxy, HaloC １～６ Alkyl, haloC １～６ Alkyl C ３～６ Cycloalkyl-, haloC １～６ Alkoxy, (C １～６ alkyl) ２ PO-, and groups 【Chemistry 19】 Selected from: R ２ is hydrogen, halogen, C １～６ selected from alkyl and cyano; R ３ is C １～６ Alkyl and HaloC １～６ alkyl; and X is selected from O and NH; or (iii) A is 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, 1,2-dihydropyridyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1 ,5-a]pyridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[3,4-d]pyrimidine, [1,2,4]triazolo[1,5 -a]pyrimidine, imidazo[1,2-a]pyrazine, 1,2-benzoxazole, 1H-indazole, 1H-imidazo[1,2-c]pyrimidin-5-one, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [1,2,4]triazolo[1,5-b]pyrimidine pyrazolo[1,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 1H-pyrazolo[3,4-b]pyridine, 1H-imidazo[1,2-a]pyrimidin-5-one, and 2H-indazole; R １ is C １～６ Alkoxy, HaloC １～６ Alkyl, hydroxy C １～６ Alkyl, C ３～６ Cycloalkyl-, haloC １～６ Alkyl C ３～６ Cycloalkyl-, (haloC １～６ alkyl)-(3- to 6-membered heterocyclyl)-, haloC １～６ Alkoxy, and groups 【Chemistry 20】 Selected from: R ２ is hydrogen, halogen, cyano, oxo, C １～６ Alkyl and HaloC １～６ alkyl; R ３ Halo C １～６ is alkyl; X is selected from O and NH; R ４ and R ５ are both hydrogen; or R ４ and R ５ are both halogens; or R ４ is C １～６ alkyl, and R ５ is hydrogen; and B, 【Chemical 21】 2. The compound of formula (I) according to claim 1, selected from: or a pharmaceutically acceptable salt thereof.

14. (i) A is phenyl; R １ However, (C １～６ alkyl) ２ PO- and groups 【Chemical 22】 Selected from: R ２ is hydrogen, halogen, and haloC １～６ alkyl; R ３ But C １～６ Alkyl and HaloC １～６ alkyl; and X is O; or (ii) A is pyridyl; R １ but halogen and haloC １～６ alkyl; R ２ is selected from hydrogen and halogen; or (iii) A is selected from pyrazinyl and pyrazolyl; R １ But, Haro C １～６ is alkyl; and R ２ is hydrogen; R ４ and R ５ are both hydrogen; and B, 【Chemical 23】 14. A compound of formula (I) according to claim 13, selected from: or a pharmaceutically acceptable salt thereof.

15. (i) A is phenyl; R １ However, (CH ３ ) ２ PO- and groups 【Chemistry 24】 Selected from: R ２ is hydrogen, fluoro and CF ３ Selected from: R ３ However, methyl and CF ３ is selected from: X is O; or (ii) A is pyridyl; R １ Fluoro and CF ３ Selected from: R ２ is selected from hydrogen and fluoro; or (iii) A is selected from pyrazinyl and pyrazolyl; R １ But CF ３ and R ２ is hydrogen; R ４ and R ５ are both hydrogen; and B, 【Chemistry 25】 15. The compound of formula (I) according to claim 14, selected from: or a pharmaceutically acceptable salt thereof.

16. wherein said compound of formula (I) (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-fluoro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(4-fluoro-2-methylsulfonyl-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-methylsulfonylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(2-fluoro-4-methylsulfonyl-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-dimethylphosphoryl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 5-[[2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-3-(trifluoromethyl)pyridine-2-carbonitrile; 5-[[2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carbonitrile; (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-oxo-5-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-methylsulfonyl-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-methylsulfonyl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-dimethylphosphoryl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-methyl-5-(trifluoromethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(2,2,2-trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)oxazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-chloro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[2-fluoro-4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[2-(methylsulfonimidoyl)-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[4-(methylsulfonimidoyl)-3-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[3-(methylsulfonimidoyl)-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-dimethylphosphoryl-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(R)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(S)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(S)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-([S(R)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(R)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(S)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(S)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-([S(R)]-trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[4-fluoro-2-(methylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-dimethylphosphoryl-5-fluoro-phenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[4-(methylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[3-(methylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(3-dimethylphosphorylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[(5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; 5-[[(6S)-2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6R)-2-[(4aR,8aS)-3-oxo-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-6-carbonyl]-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; (4aR,8aS)-6-[(6S)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[4-(trifluoromethyl)oxazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[4-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[3-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[(5-chloro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[7-[(5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-indazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(trifluoromethyl)indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)indoxazen-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-methoxy-5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(4-triflylpyrazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonimidoyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(2,2,2-trifluoroethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-mesyl-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2-hydroxyethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aS,8aR)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[2-methoxy-6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(1S)-1-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)-4-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-c]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[4-[3-(trifluoromethyl)azetidin-1-yl]sulfonylbenzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]-4-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[3-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)imidazo[1,2-a]pyrimidin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[2-methoxy-5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[3-(trifluoromethyl)azetidin-1-yl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)indoxazen-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-keto-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-keto-1H-imidazo[1,2-c]pyrimidin-7-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[4-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[difluoro-[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-oxo-5-[1-(trifluoromethyl)cyclopropyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-oxo-1-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyrimidin-7-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[1,2,4]triazolo[1,5-b]pyridazin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[2-(trifluoromethyl)imidazo[1,2-a]pyrazin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[7-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-5-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[2-[[2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-6-yl]methyl]-7-azaspiro[3.5]nonane-7-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-(1H-pyrazolo[4,3-b]pyridin-5-ylmethyl)-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[(5-methoxypyrrolo[2,3-c]pyridin-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; (4aR,8aS)-6-[6-[[1-methyl-3-(trifluoromethyl)pyrazolo[3,4-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; rac-(4aR,8aS)-6-[7-[[2-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one; and 16. The compound of formula (I) according to claim 15, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

17. A process for preparing a compound of formula (I) according to any one of claims 1 to 16, comprising the steps of: (a) an amine of formula 1, wherein R １ , R ２ , A and B are as defined in any one of claims 1 to 16 【Chemical Formula 26】 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2) 【Chemical 27】 reacting in the presence of a base; or (b) 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (2a) [Chemical Formula 28] A compound of formula 1a, wherein R １ , R ２ , A and B are as defined in any one of claims 1 to 16) 【Chemical 29】 Reacting in the presence of a base, forming said compound of formula (I).

18. A compound of formula (I) according to any one of claims 1 to 16 when prepared according to the process of claim 17.

19. A compound of formula (I) according to any one of claims 1 to 16 for use as a therapeutically active substance.

20. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 16 and a therapeutically inert carrier.

21. Use of a compound of formula (I) according to any one of claims 1 to 16 for the treatment or prevention of MAGL-related diseases and disorders in mammals.

22. A compound of formula (I) according to any one of claims 1 to 16 for use in the treatment or prevention of diseases and disorders associated with MAGL.

23. Use of a compound of formula (I) according to any one of claims 1 to 16 in the preparation of a medicament for the treatment or prevention of diseases and disorders associated with MAGL.

24. A method for the treatment or prevention of MAGL-related diseases and disorders in a mammal, comprising administering to said mammal an effective amount of a compound of formula (I) according to any one of claims 1 to 16.

25. 10. The invention as hereinbefore described.

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