Novel heterocyclic compounds

Abstract

The present invention provides novel heterocyclic compounds having the general formula (I) wherein A, B, R1, R2, R4 and R5 are as described herein; comprising the compound; methods of making the compounds; and methods of using the compounds. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to organic compounds useful for the treatment or prevention of mammals, and in particular to monoacylglycerol lipase (MAGL) inhibitors for the treatment or prevention of diseases and conditions associated with 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 kidney disease. Background Art

[0002] Endocannabinoids (ECs) are lipid signals that exert their biological effects by interacting with cannabinoid receptors (CBRs), CB1, and CB2. They regulate a variety of physiological processes, including neuroinflammation, neurodegenerative diseases, 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 can hydrolyze 85% of 2-AG; 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 microglia (Chanda, PK et al., Molecular pharmacology 2010, 78, 996; Viader, A. et al., Cell reports 2015, 12, 798.). 2-AG is hydrolyzed to form arachidonic acid (AA), a precursor of prostaglandins (PG) and leukotrienes (LT). AA oxidative metabolism is increased in inflamed tissues. The inflammatory process involves two major enzyme reaction pathways for arachidonic acid oxidation, namely cyclooxygenases that produce PG and 5-lipoxygenases that produce LT. Among the various cyclooxygenase products formed during the inflammatory process, PGE2 is one of the most important products. These products have been detected at sites of inflammation (e.g., in the cerebrospinal fluid of patients with neurodegenerative diseases) and are believed to contribute to inflammatory responses and disease progression. The activity of 2-AG hydrolase in the nervous system of mice lacking MAGL (Mgll- / -) was significantly reduced, while the level of 2-AG was increased, while other arachidonic acid-containing phospholipids and neutral lipids (including anandamide (AEA) and other free fatty acids) remained unchanged. In contrast, the levels of AA-derived and AA-derived prostaglandins and other eicosanoids (including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2), and thromboxane B2 (TXB2)) were greatly reduced. Phospholipase A2 (PLA2) has been regarded as the main source of AA, but the level of AA in the brain of cPLA2-deficient mice is unchanged, thus enhancing the key role of MAGL in the brain in the regulation of AA production and brain inflammatory processes.

[0003] Neuroinflammation is a common pathological change characteristic 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 mental disorders such as anxiety and migraine). In the brain, the production of eicosanoids and prostaglandins controls the neuroinflammatory process. The proinflammatory agent lipopolysaccharide (LPS) causes a stable time-dependent increase in brain eicosanoid production, which is significantly reduced in Mgll- / - mice. LPS treatment also causes a general increase in proinflammatory cytokines (including interleukin-1-a (IL-1-a), IL-1b, IL-6) and tumor necrosis factor-a (TNF-a) (suppressed in Mgll- / - mice).

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

[0005] In addition, in animal models of various neurodegenerative diseases (including but not limited to Alzheimer's disease, Parkinson's disease and multiple sclerosis), it has been demonstrated that genetic and / or pharmacological disruption of MAGL activity has a protective effect. For example, irreversible MAGL inhibitors have been widely used in preclinical models of neuroinflammation and neurodegenerative diseases (Long, JZ et al., Nature chemical biology 2009, 5, 37.). Systemic injection of such inhibitors can reproduce the phenotype of Mgll- / - mice in the brain, including increased 2-AG levels, decreased AA levels and related eicosanoid production, and prevent cytokine production and microglial activation after LPS-induced neuroinflammation (Nomura, DK et al., Science 2011, 334, 809.), fully confirming that MAGL is a drug target.

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

[0007] In addition, oligodendrocytes (OL), myelinating cells of the central nervous system and their precursors (OPC) express cannabinoid receptor 2 (CB2) on their membranes. 2-AG is an endogenous ligand for CB1 and CB2 receptors. It is reported that the pharmacological inhibition of cannabinoids and MAGL weakens the excitotoxicity of OL and OPC, and therefore may have a neuroprotective effect (Bernal-Chico, A. et al., Glia 2015, 63, 163.). In addition, the pharmacological inhibition of MAGL increases the number of myelinating OLs in the mouse brain, indicating that MAGL inhibition can promote the differentiation of OPCs in myelinating OLs in vivo (Alpar, A. et al., Nature communications 2014, 5, 4421.). In a mouse model of progressive multiple sclerosis, the inhibition of MAGL can also promote myelin regeneration and functional recovery (Feliu A. et al., Journal of Neuroscience 2017, 37 (35), 8385.).

[0008] In recent years, metabolism, especially lipid metabolism, has received great attention in cancer research. Researchers believe that de novo synthesis of fatty acids plays an important role in tumor development. Many studies have shown that endocannabinoids have anti-tumor effects, including anti-proliferation, induction of apoptosis and anti-metastasis. MAGL is an important degrading enzyme in lipid metabolism and endocannabinoid systems, and as a component of gene expression characteristics, it affects different aspects of tumorigenesis (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 physiological and pathological effects (Marquez, Suarez et al. 2009). All these effects are mainly driven by cannabinoid receptors (CBR), CB1 and CB2. CB1 receptors are present in the entire GI tract of animals and healthy humans, especially in the enteric nervous system (ENS) and epithelial lining and smooth muscle cells of blood vessels in the colon wall (Wright, Rooney et al. 2005), (Duncan, Davison et al. 2005). CB1 activation produces antiemetic, antiperistaltic and anti-inflammatory effects, and helps regulate pain (Perisetti, Rimu et al. 2020). CB2 receptors are expressed in immune cells (such as plasma cells and macrophages) in the GI tract lamina propria (Wright, Rooney et al. 2005), and mainly act on the human colon tissue epithelium related to inflammatory bowel disease (IBD). CB2 activation exerts anti-inflammatory effects by reducing proinflammatory cytokines. MAGL expression is increased in colonic tissue of UC patients (Marquez, Suarez et al. 2009), and 2-AG levels are increased in 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 colitis in mice and reduces local circulating inflammatory markers via CB1 / CB2 MoA (Marquez, Suarez et al. 2009). In addition, 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 novel therapeutic strategy for treating or preventing various diseases and disorders.

[0011] WO2020104494 discloses certain MAGL inhibitors. However, it has been found that while those MAGL inhibitors have properties that make them particularly suitable for treating CNS indications (such as multiple sclerosis), some properties (such as high permeability) mean that they are less suitable if different exposures across tissues are required. This may make them less suitable for treating certain conditions that may benefit from achieving higher exposures in the target tissue than in other parts of the body.

[0012] Therefore, there remains a high unmet medical need for novel MAGL inhibitors, especially for novel MAGL inhibitors with unique properties that can achieve differential exposure in different tissues. Summary of the invention

[0013] Surprisingly, starting from the compounds disclosed in WO2020104494, many chemical modifications have resulted in passive permeability (P app ) while maintaining high cellular potency and excellent overall drug-like properties. 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 indications 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)

[0015]

[0016] Among them, A, B, R 1 , R 2 , R 4 and R 5 As described in this article.

[0017] In one aspect, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, the method comprising:

[0018] (a) an amine of formula 1b, wherein R 1 , R 2 , R 4 , R 5 , A and B are as described herein,

[0019]

[0020] With 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2),

[0021]

[0022] react in the presence of a base; or

[0023] (b) 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (2b)

[0024]

[0025] and a compound of formula 1c, wherein R 1 , R 2 , R 4 , R 5 , A and B are as described herein,

[0026]

[0027] In the presence of a base,

[0028] To form the compound of formula (I).

[0029] In another aspect, the present invention provides a compound of formula (I) as described herein, manufactured according to a method described herein.

[0030] In another aspect, the present invention provides a compound of formula (I) as described herein for use as a therapeutically active substance.

[0031] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0032] In another aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of diseases and disorders associated with MAGL. DETAILED DESCRIPTION

[0033] definition

[0034] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings) and / or all steps of any method or process disclosed thereby may be combined in any combination, except for combinations in which at least some of these features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel step or any novel combination of steps of any method or process disclosed thereby.

[0035] The term "alkyl" refers to a monovalent or polyvalent (e.g., monovalent or divalent) straight 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, the alkyl group contains 1 to 3 carbon atoms, such as 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, isobutyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred but non-limiting example of an alkyl is methyl.

[0036] The term "alkoxy" refers to an alkyl group as defined above that is connected to the parent molecular moiety via an oxygen atom. Unless otherwise indicated, an alkoxy group contains 1 to 6 carbon atoms ("C1-C6-alkoxy"). In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred but non-limiting example of alkoxy is methoxy.

[0037] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Preferably, the term "halogen" or "halo" refers to fluorine (F), chlorine (Cl) or bromine (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluorine (F) and chlorine (Cl).

[0038] As used herein, the term "cycloalkyl" refers to a ring of 3 to 10 carbon atoms ("C 3-10 In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms (e.g., 3, 4, 5 or 6 carbon atoms). Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A preferred but non-limiting example of cycloalkyl is cyclopropyl.

[0039] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic ring system with 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 heterocyclyl is azetidine.

[0040] The term "cyano" refers to a -CN (nitrile) group.

[0041] The term "oxo" refers to an oxygen atom (=0) bound to the parent molecule by a double bond.

[0042] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group in which 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluorine. A particularly preferred but non-limiting example of a haloalkyl group is trifluoromethyl (CF3).

[0043] The term "haloalkylcycloalkyl" refers to a cycloalkyl group in which at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a haloalkyl group, preferably by CF3. Preferably, "haloalkylcycloalkyl" refers to a cycloalkyl group in which 1, 2 or 3 hydrogen atoms (particularly 1 hydrogen atom) of the cycloalkyl group have been replaced by a haloalkyl group, most preferably CF3. A particularly preferred but non-limiting example of haloalkylcycloalkyl is trifluoromethylcyclopropyl.

[0044] The term "haloalkylheterocyclyl" refers to a heterocyclyl group in which at least one of the hydrogen atoms of the heterocyclyl group has been replaced by a haloalkyl group, preferably by CF3. Preferably, "haloalkylheterocyclyl" refers to a heterocyclyl group in which 1, 2 or 3 hydrogen atoms (particularly 1 hydrogen atom) of the heterocyclyl group have been replaced by a haloalkyl group, most preferably CF3. A particularly preferred but non-limiting example of a haloalkylheterocyclyl group is 3-(trifluoromethyl)azetidine.

[0045] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group has been replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluorine. A particularly preferred but non-limiting example of a haloalkoxy group is trifluoromethoxy (-OCF3).

[0046] The term "pharmaceutical salt" refers to those salts that retain the biological effect and properties of free alkali or free acid, which are not undesirable in biology or other aspects. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. (particularly 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, methylsulfonic acid, ethylsulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. In addition, these salts can be prepared by adding inorganic bases or organic bases to free acids. Salts derived from inorganic bases include but are not limited to sodium, potassium, lithium, ammonium, calcium, magnesium salts, etc. 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, and the like). A particular pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

[0047] As used herein, the term "protecting group" (PG) represents a group that selectively blocks a reactive site in a multifunctional compound so that a chemical reaction selectively occurs on another unprotected reactive site that is usually associated therewith in synthetic chemistry. The protecting group can be removed at an appropriate point. Exemplary protecting groups are amino protecting groups, carboxyl protecting groups, or hydroxy protecting groups. Specific protecting groups are tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butyloxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butyloxycarbonyl (Boc). Exemplary protecting groups and their use in organic synthesis are described in, for example, TW Greene and PGM Wutts, Protective Groups in Organic Chemistry, 5th edition, 2014, John Wiley & Sons, NY.

[0048] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers (e.g. racemates), optically pure diastereomers, mixtures of diastereomers, 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) as described herein, respectively.

[0049] According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom can be in either the "R" or "S" configuration.

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

[0051] As used herein, the term "treating" includes: (1) inhibiting a state, disorder or condition of at least one clinical or subclinical symptom of a disease (e.g., in the case of maintenance therapy, arresting, alleviating or delaying the development of a disease or its recurrence); and / or (2) relieving a condition (i.e., causing a state, disorder or condition of a disease or at least one clinical or subclinical symptom to subside). The benefit to the patient being treated is statistically significant or at least perceptible to the patient or physician. However, it should be understood that when a drug is administered to a patient to treat a disease, the result may not always be an effective treatment.

[0052] As used herein, the term "preventing" or "treatment" includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition that develops in a mammal, particularly a human, that may have or is susceptible to the condition, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the condition, disorder or condition.

[0053] As used herein, the term "neuroinflammation" refers to acute and chronic inflammation of nervous tissue, which is the main tissue component of two parts of the nervous system; the brain and spinal cord of the central nervous system (CNS) and the peripheral nerves of the peripheral nervous system (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis. Acute neuroinflammation usually occurs immediately after injury to the central nervous system, for example, caused by traumatic brain injury (TBI).

[0054] As used herein, the term "traumatic brain injury" ("TBI", also referred to as "intracranial injury") refers to damage to the brain caused by external mechanical forces such as rapid acceleration or deceleration, impact, shock waves, or projectile penetration.

[0055] As used herein, the term "neurodegenerative disease" relates to diseases associated with progressive loss of structure or function of neurons, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0056] As used herein, the term "mental disorder" (also referred to as psychosis or mental illness) refers to a pattern of behavior or mind that may cause distress or poor functioning. Such features may be persistent, recurring, or remitted, or may be a single event. Examples of mental disorders include, but are not limited to, anxiety disorders and depression.

[0057] As used herein, the term "pain" refers to unpleasant sensory and emotional experiences 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 pain, and psychogenic pain. A specific example of pain is neuropathic pain, which is caused by damage or disease affecting any part of the nervous system involved in body sensation (i.e., the somatosensory system). In one embodiment, "pain" is neuropathic pain due to amputation or thoracotomy. In one embodiment, "pain" is chemotherapy-induced neuropathy.

[0058] As used herein, the term "neurotoxicity" refers to toxicity to the nervous system. This occurs when exposed to natural or artificial toxic substances (neurotoxins) that alter the normal activity of the nervous system, thereby causing damage to neural tissue. Examples of neurotoxicity include, but are not limited to, neurotoxicity caused by exposure to substances used in chemotherapy, radiation therapy, drug therapy, drug abuse, and organ transplantation, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some natural substances.

[0059] As used herein, the term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor due to abnormal, uncontrolled growth of cells (such cells are "cancer cells"). As used herein, the term cancer specifically includes, but is not limited to, hepatocellular carcinoma, colon carcinoma, and ovarian cancer.

[0060] As used herein, the term "mammal" includes humans and non-humans, and includes, but is not limited to, humans, non-human primates, dogs, cats, mice, cows, horses, and pigs. In particularly preferred embodiments, the term "mammal" refers to humans.

[0061] Compounds of the present invention

[0062] In a first aspect, the present invention provides a compound of formula (I)

[0063]

[0064] or a pharmaceutically acceptable salt thereof, wherein:

[0065] (i) 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, 1,2-dihydropyridinyl, [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;

[0066] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halogenated-C 1-6 -alkyl)-(3- to 6-membered heterocyclic)-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0067] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0068] R 3 Selected from C 1-6 -alkyl, halo-C 1-6-alkyl and 4- to 6-membered heterocyclic groups, wherein the 4- to 6-membered heterocyclic groups are optionally halogenated 1-6 - substituted with alkyl substituents;

[0069] X is selected from O and NH; or

[0070] (ii) A is pyridyl;

[0071] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0072] R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0073] R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and 4- to 6-membered heterocyclic groups, wherein the 4- to 6-membered heterocyclic groups are optionally halogenated 1-6 - substituted with an alkyl substituent; and

[0074] X is selected from O and NH; or

[0075] (iii) A is phenyl;

[0076] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0077] R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0078] R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and 4- to 6-membered heterocyclic groups, wherein the 4- to 6-membered heterocyclic groups are optionally halogenated 1-6 - substituted with an alkyl substituent; and

[0079] X is selected from O and NH;

[0080] R 4 and R 5 are each independently selected from hydrogen, halogen and C 1-6 -alkyl; and

[0081] B is selected from:

[0082]

[0083] In another aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0084] A is a 9-membered bicyclic heteroaryl group containing 1 to 5 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon;

[0085] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0086] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0087] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0088] X is selected from O and NH; or

[0089] R 4 and R 5 are each independently selected from hydrogen, halogen and C 1-6 -alkyl; and

[0090] B is selected from:

[0091]

[0092] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0093] (i) A is phenyl;

[0094] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0095] R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0096] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0097] X is selected from O and NH; or

[0098] (ii) A is pyridyl;

[0099] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0100] R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0101] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0102] X is selected from O and NH; or

[0103] (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, 1,2-dihydropyridinyl, [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;

[0104] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0105] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0106] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0107] X is selected from O and NH;

[0108] R 4 and R 5 are each independently selected from hydrogen, halogen and C 1-6 -alkyl; and

[0109] B is selected from:

[0110]

[0111] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia)

[0112]

[0113] in:

[0114] (i) A is phenyl;

[0115] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0116] R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0117] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0118] X is selected from O and NH; or

[0119] (ii) A is pyridyl;

[0120] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0121] R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0122] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0123] X is selected from O and NH; or

[0124] (iii) A is selected from the group consisting of 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-dihydropyridinyl;

[0125] R 1Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0126] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0127] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0128] X is selected from O and NH; and

[0129] B is selected from:

[0130]

[0131] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0132] (i) A is phenyl;

[0133] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0134] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0135] R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and (halo-C 1-6 -alkyl)-(4- to 6-membered heterocyclyl); and

[0136] X is selected from O and NH; or

[0137] (ii) A is pyridyl;

[0138] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6-alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0139] R 2 Selected from hydrogen, halogen, halo-C 1-6 - alkyl and cyano;

[0140] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0141] X is selected from O and NH; or

[0142] (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, 1,2-dihydropyridinyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 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;

[0143] R 1 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halogenated-C1-6 -alkyl)-(3- to 6-membered heterocyclic)-, halo-C 1-6 -Alkoxy and groups

[0144] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0145] R 3 For halogenated-C 1-6 -alkyl; and

[0146] X is selected from O and NH.

[0147] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0148] (i) A is phenyl;

[0149] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0150] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0151] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0152] X is selected from O and NH; or

[0153] (ii) A is pyridyl;

[0154] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0155] R 2 Selected from hydrogen, halogen, halo-C 1-6 - alkyl and cyano;

[0156] R 3 Selected from C 1-6 -alkyl and halo-C1-6 -alkyl; and

[0157] X is selected from O and NH; or

[0158] (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, 1,2-dihydropyridinyl, [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;

[0159] R 1 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl- and groups

[0160] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0161] R 3 For halogenated-C 1-6 -alkyl; and

[0162] X is selected from O and NH.

[0163] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0164] (i) A is phenyl;

[0165] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0166] R 2 is selected from hydrogen, halogen and halo-C 1-6-alkyl;

[0167] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0168] X is selected from O and NH; or

[0169] (ii) A is pyridyl;

[0170] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0171] R 2 Selected from hydrogen, halogen, halo-C 1-6 - alkyl and cyano;

[0172] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0173] X is selected from O and NH; or

[0174] (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, 1,2-dihydropyridinyl, [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;

[0175] R 1 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6-cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl- and groups

[0176] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0177] R 3 For halogenated-C 1-6 -alkyl; and

[0178] X is selected from O and NH.

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

[0180] (i) A is phenyl;

[0181] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0182] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0183] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0184] X is selected from O and NH; or

[0185] (ii) A is pyridyl;

[0186] R 1 Selected from halogen, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO-, and the group

[0187] R 2 is selected from hydrogen, halogen and cyano;

[0188] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0189] X is selected from O and NH; or

[0190] (iii) A is selected from the group consisting of 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-dihydropyridinyl;

[0191] R 1 Selected from halogenated-C 1-6 -alkyl and halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-; and

[0192] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl.

[0193] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0194] (i) A is phenyl;

[0195] R 1 Selected from (C 1-6 -alkyl)2PO-, group and Group

[0196] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0197] R 3a For halogenated-C 1-6 -alkyl; and

[0198] R 3b Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; or

[0199] (ii) A is pyridyl;

[0200] R 1 Selected from halogen, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO-, group and Group

[0201] R 2 is selected from hydrogen, halogen and cyano;

[0202] R 3a For halogenated-C 1-6 -alkyl; and

[0203] R 3b Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; or

[0204] (iii) A is selected from the group consisting of 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-dihydropyridinyl;

[0205] R 1 Selected from halogenated-C 1-6 -alkyl and halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-; and

[0206] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl.

[0207] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0208] (i) A is phenyl;

[0209] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0210] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0211] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0212] X is O; or

[0213] (ii) A is pyridyl;

[0214] R 1 Selected from halogen and halo-C 1-6 -alkyl;

[0215] R 2 is selected from hydrogen and halogen; or

[0216] (iii) A is selected from pyrazinyl and pyrazolyl;

[0217] R 1 For halogenated-C1-6 -alkyl; and

[0218] R 2 For hydrogen.

[0219] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0220] (i) A is phenyl;

[0221] R 1 Selected from (CH3)2PO- and groups

[0222] R 2 is selected from hydrogen, fluorine and CF3;

[0223] R 3 is selected from methyl and CF3; and

[0224] X is O; or

[0225] (ii) A is pyridyl;

[0226] R 1 Selected from fluorine and CF3;

[0227] R 2 is selected from hydrogen and fluorine; or

[0228] (iii) A is selected from pyrazinyl and pyrazolyl;

[0229] R 1 is CF3; and

[0230] R 2 For hydrogen.

[0231] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0232] (i) A is phenyl;

[0233] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0234] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0235] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0236] X is O; or

[0237] (ii) A is pyridyl;

[0238] R 1 Selected from halogen and halo-C 1-6 -alkyl;

[0239] R 2 is selected from hydrogen and halogen; or

[0240] (iii) A is selected from pyrazinyl and pyrazolyl;

[0241] R 1 For halogenated-C 1-6 -alkyl; and

[0242] R 2 is hydrogen; and

[0243] B is selected from:

[0244]

[0245] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0246] (i) A is phenyl;

[0247] R 1 Selected from (CH3)2PO- and groups

[0248] R 2 is selected from hydrogen, fluorine and CF3;

[0249] R 3 is selected from methyl and CF3; and

[0250] X is O; or

[0251] (ii) A is pyridyl;

[0252] R 1 Selected from fluorine and CF3;

[0253] R 2 is selected from hydrogen and fluorine; or

[0254] (iii) A is selected from pyrazinyl and pyrazolyl;

[0255] R 1 is CF3; and

[0256] R 2 is hydrogen; and

[0257] B is selected from:

[0258]

[0259] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0260] A is phenyl;

[0261] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0262] R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0263] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0264] X is selected from O and NH.

[0265] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0266] A is pyridyl;

[0267] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0268]

[0269] R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0270] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0271] X is selected from O and NH.

[0272] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0273] A is pyridyl;

[0274] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0275]

[0276] R 2 Selected from hydrogen, halogen, halo-C 1-6 - alkyl and cyano;

[0277] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0278] X is selected from O and NH.

[0279] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0280] 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, 1,2-dihydropyridinyl, [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;

[0281] R 1 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halogenated-C 1-6 -alkyl)-(3- to 6-membered heterocyclic)-, halo-C 1-6 -Alkoxy and groups

[0282] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0283] R 3 For halogenated-C 1-6 -alkyl; and

[0284] X is selected from O and NH.

[0285] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0286] A is selected from the group consisting of 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-dihydropyridinyl, [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;

[0287] R 1 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl- and groups

[0288] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0289] R 3 For halogenated-C 1-6 -alkyl; and

[0290] X is selected from O and NH.

[0291] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0292] A is selected from the group consisting of 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-dihydropyridinyl;

[0293] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0294]

[0295] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0296] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0297] X is selected from O and NH.

[0298] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0299] A is phenyl;

[0300] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0301] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0302] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0303] X is selected from O and NH.

[0304] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0305] A is pyridyl;

[0306] R 1 Selected from halogen, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO-,

[0307] and Group

[0308] R 2is selected from hydrogen, halogen and cyano;

[0309] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0310] X is selected from O and NH.

[0311] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0312] A is selected from the group consisting of 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-dihydropyridinyl;

[0313] R 1 Selected from halogenated-C 1-6 -alkyl and halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-; and

[0314] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl.

[0315] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0316] A is phenyl;

[0317] R 1 Selected from (C 1-6 -alkyl)2PO-, group and Group

[0318] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0319] R 3a For halogenated-C 1-6 -alkyl; and

[0320] R 3b Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl.

[0321] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0322] A is pyridyl;

[0323] R 1 Selected from halogen, halogen-C 1-6 -alkyl, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO-, group and Group

[0324] R 2 is selected from hydrogen, halogen and cyano;

[0325] R 3a For halogenated-C 1-6 -alkyl; and

[0326] R 3b Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl.

[0327] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0328] A is phenyl;

[0329] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0330] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0331] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0332] X is O.

[0333] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0334] A is pyridyl;

[0335] R 1 Selected from halogen and halo-C 1-6 -alkyl; and

[0336] R 2 Selected from hydrogen and halogen.

[0337] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0338] A is selected from pyrazinyl and pyrazolyl;

[0339] R 1 For halogenated-C 1-6 -alkyl; and

[0340] R 2 For hydrogen.

[0341] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0342] A is phenyl;

[0343] R 1 Selected from (CH3)2PO- and groups

[0344] R 2 is selected from hydrogen, fluorine and CF3;

[0345] R 3 is selected from methyl and CF3; and

[0346] X is O.

[0347] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0348] A is pyridyl;

[0349] R 1 is selected from fluorine and CF3; and

[0350] R 2 Selected from hydrogen and fluorine.

[0351] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0352] A is selected from pyrazinyl and pyrazolyl;

[0353] R 1 is CF3; and

[0354] R 2 For hydrogen.

[0355] 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 a 9-membered bicyclic heteroaryl group containing 1 to 5 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon.

[0356] 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 a 9-membered bicyclic heteroaryl group containing 1 to 5 nitrogen atoms, and the remaining ring atoms are carbon.

[0357] 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 a 9-membered bicyclic heteroaryl group containing 1 to 5 nitrogen atoms, and the remaining ring atoms are carbon.

[0358] 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 [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.

[0359] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from:

[0360]

[0361] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from:

[0362]

[0363] 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

[0364] 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

[0365] 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

[0366] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0367] R 4 is selected from hydrogen, halogen and C 1-6 -alkyl; and

[0368] R 5 Selected from hydrogen and halogen.

[0369] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0370] R 4 and R 5 both are hydrogen; or

[0371] R 4 and R 5 Both are halogens; or

[0372] R 4 C 1-6 -alkyl and R 5 For hydrogen.

[0373] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0374] R 4 and R 5 both are hydrogen; or

[0375] R 4 and R 5 Both are fluorine; or

[0376] R 4 is methyl and R 5 For hydrogen.

[0377] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein R 4 and R 5 Both are hydrogen.

[0378] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Both are fluorine.

[0379] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl and R 5 For hydrogen.

[0380] In one embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, wherein:

[0381] (i) A is phenyl;

[0382] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0383] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0384] R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and (halo-C 1-6 -alkyl)-(4- to 6-membered heterocyclyl); and

[0385] X is selected from O and NH; or

[0386] (ii) A is pyridyl;

[0387] R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group

[0388] R 2 Selected from hydrogen, halogen, halo-C 1-6 - alkyl and cyano;

[0389] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0390] X is selected from O and NH; or

[0391] (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, 1,2-dihydropyridinyl, [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, 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;

[0392] R 1 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halogenated-C 1-6 -alkyl)-(3- to 6-membered heterocyclic)-, halo-C 1-6 -Alkoxy and groups

[0393] R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl;

[0394] R 3 For halogenated-C 1-6 -alkyl;

[0395] X is selected from O and NH;

[0396] R 4 and R5 both are hydrogen; or

[0397] R 4 and R 5 Both are halogens; or

[0398] R 4 C 1-6 -alkyl and R 5 is hydrogen; and

[0399] B is selected from:

[0400]

[0401] In a preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0402] (i) A is phenyl;

[0403] R 1 Selected from (C 1-6 -alkyl)2PO- and group

[0404] R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl;

[0405] R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and

[0406] X is O; or

[0407] (ii) A is pyridyl;

[0408] R 1 Selected from halogen and halo-C 1-6 -alkyl;

[0409] R 2 is selected from hydrogen and halogen; or

[0410] (iii) A is selected from pyrazinyl and pyrazolyl;

[0411] R 1 For halogenated-C 1-6 -alkyl; and

[0412] R 2 is hydrogen;

[0413] R 4 and R 5 both are hydrogen; and

[0414] B is selected from:

[0415]

[0416] In a particularly preferred embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, wherein:

[0417] (i) A is phenyl;

[0418] R 1 Selected from (CH3)2PO- and groups

[0419] R 2 is selected from hydrogen, fluorine and CF3;

[0420] R 3 is selected from methyl and CF3; and

[0421] X is O; or

[0422] (ii) A is pyridyl;

[0423] R 1 Selected from fluorine and CF3;

[0424] R 2 is selected from hydrogen and fluorine; or

[0425] (iii) A is selected from pyrazinyl and pyrazolyl;

[0426] R 1 is CF3; and

[0427] R 2 is hydrogen;

[0428] R 4 and R 5 both are hydrogen; and

[0429] B is selected from:

[0430]

[0431] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0432] (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;

[0433] (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0434] (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;

[0435] (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;

[0436] (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;

[0437] (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;

[0438] (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0439] (4aR,8aS)-6-[6-[(3,5-difluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0440] (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0441] (4aR,8aS)-6-[6-[(5-fluoro-3-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0442] (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;

[0443] (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;

[0444] (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;

[0445] (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;

[0446] (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;

[0447] 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;

[0448] 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;

[0449] (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0450] (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0451] rac-(4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonamidoyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0452] (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;

[0453] (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;

[0454] (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;

[0455] (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;

[0456] (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;

[0457] (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0458] (4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0459] (4aR,8aS)-6-[6-[[5-(trifluoromethoxy)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0460] (4aR,8aS)-6-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0461] (4aR,8aS)-6-[6-[[2-oxo-5-(trifluoromethyl)-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0462] (4aR,8aS)-6-[6-[(5-methylsulfonyl-3-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0463] (4aR,8aS)-6-[6-[(5-methylsulfonyl-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0464] (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;

[0465] (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;

[0466] (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;

[0467] (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;

[0468] (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;

[0469] (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;

[0470] (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;

[0471] (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;

[0472] (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;

[0473] (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;

[0474] (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;

[0475] (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;

[0476] (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;

[0477] (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;

[0478] (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;

[0479] (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;

[0480] (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;

[0481] (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0482] (4aR,8aS)-6-[6-[[4-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0483] (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0484] (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;

[0485] (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;

[0486] (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;

[0487] (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;

[0488] (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;

[0489] (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;

[0490] (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;

[0491] (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;

[0492] (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;

[0493] (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;

[0494] (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;

[0495] (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;

[0496] (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;

[0497] (4aR,8aS)-6-[6-[(5-chloro-3-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0498] (4aR,8aS)-6-[6-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0499] (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;

[0500] (4aR,8aS)-6-[6-[(5-chloro-3-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0501] (4aR,8aS)-6-[6-[(5-chloro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0502] (4aR,8aS)-6-[6-[(5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0503] (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;

[0504] rac-(4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0505] rac-(4aR,8aS)-6-[6-[[2-fluoro-4-(trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0506] 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;

[0507] 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;

[0508] 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;

[0509] (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;

[0510] (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;

[0511] (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;

[0512] (4aR,8aS)-6-[6-[[4-([S(R)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0513] (4aR,8aS)-6-[6-[[4-([S(S)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0514] (4aR,8aS)-6-[6-[[4-([S(S)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0515] (4aR,8aS)-6-[6-[[4-([S(R)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0516] (4aR,8aS)-6-[6-[[3-([S(R)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0517] (4aR,8aS)-6-[6-[[3-([S(S)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0518] (4aR,8aS)-6-[6-[[3-([S(S)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0519] (4aR,8aS)-6-[6-[[3-([S(R)]-trifluoromethylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0520] rac-(4aR,8aS)-6-[6-[[4-fluoro-2-(methylsulfonamidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0521] (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;

[0522] 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;

[0523] 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;

[0524] (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;

[0525] (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;

[0526] (4aR,8aS)-6-[7-[[5-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0527] (4aR,8aS)-6-[7-[(3,5-difluoro-2-pyridinyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0528] (4aR,8aS)-6-[7-[(5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0529] (4aR,8aS)-6-[7-[[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0530] (4aR,8aS)-6-[7-[[6-(difluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0531] 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;

[0532] 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;

[0533] (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;

[0534] (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;

[0535] (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0536] (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;

[0537] (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;

[0538] (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;

[0539] (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;

[0540] (4aS,8aR)-6-[6-[[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0541] (4aS,8aR)-6-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0542] (4aS,8aR)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0543] (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;

[0544] (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;

[0545] (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;

[0546] (4aS,8aR)-6-[6-[(3-chloro-5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0547] (4aS,8aR)-6-[6-[(5-chloro-3-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0548] (4aS,8aR)-6-[7-[(5-fluoro-2-pyridinyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0549] (4aS,8aR)-6-[7-[[5-(trifluoromethyl)-2-pyridinyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0550] (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;

[0551] (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;

[0552] (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;

[0553] (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;

[0554] (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;

[0555] (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;

[0556] (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;

[0557] (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;

[0558] (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;

[0559] (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;

[0560] (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;

[0561] (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;

[0562] (4aR,8aS)-6-[6-[[3-(Trifluoromethyl)benzo[d]isoxazol-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;

[0563] (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;

[0564] (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;

[0565] (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;

[0566] (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;

[0567] (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;

[0568] (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0569] (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;

[0570] (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;

[0571] (4aR,8aS)-6-[6-[(4-trifluoromethanesulfonylpyrazol-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;

[0572] (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;

[0573] (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0574] (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;

[0575] (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;

[0576] (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;

[0577] (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;

[0578] rac-(4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonamidoyl)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;

[0579] (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;

[0580] (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;

[0581] (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;

[0582] (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;

[0583] (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;

[0584] (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;

[0585] (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;

[0586] (4aR,8aS)-6-[6-[3-methylsulfonyl-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;

[0587] (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;

[0588] (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;

[0589] (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;

[0590] (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;

[0591] (4aR,8aS)-6-[6-[difluoro-[2-methoxy-6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0592] (4aR,8aS)-6-[6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0593] (4aR,8aS)-6-[6-[(1S)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0594] (4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)-4-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0595] (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;

[0596] (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0597] (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;

[0598] (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;

[0599] (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;

[0600] (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;

[0601] (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;

[0602] (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;

[0603] (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0604] (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;

[0605] (4aR,8aS)-6-[6-[[4-[1-(trifluoromethyl)cyclopropyl]-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0606] (4aR,8aS)-6-[6-[[5-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0607] (4aR,8aS)-6-[6-[[2-[1-(trifluoromethyl)cyclopropyl]-4-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0608] (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethoxy)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0609] (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;

[0610] (4aR,8aS)-6-[6-[3-methylsulfonyl-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;

[0611] (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;

[0612] (4aR,8aS)-6-[6-[difluoro-[2-methoxy-5-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0613] (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;

[0614] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)benzo[d]isoxazol-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;

[0615] (4aR,8aS)-6-[6-[[2-keto-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0616] (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;

[0617] (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;

[0618] (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;

[0619] (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;

[0620] (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;

[0621] (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;

[0622] (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;

[0623] (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;

[0624] (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;

[0625] (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;

[0626] (4aR,8aS)-6-[6-[[2-oxo-5-[1-(trifluoromethyl)cyclopropyl]-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0627] (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;

[0628] (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;

[0629] (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;

[0630] (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;

[0631] (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;

[0632] (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;

[0633] (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;

[0634] (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;

[0635] (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;

[0636] (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;

[0637] (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;

[0638] (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;

[0639] (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;

[0640] (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;

[0641] (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;

[0642] (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;

[0643] (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;

[0644] (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;

[0645] 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

[0646] (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.

[0647] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of:

[0648] (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;

[0649] (4aR,8aS)-6-[6-[(3,5-difluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0650] (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one;

[0651] (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;

[0652] (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;

[0653] (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;

[0654] (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;

[0655] (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;

[0656] (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

[0657] (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.

[0658] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (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.

[0659] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[(3,5-difluoro-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0660] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one.

[0661] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (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.

[0662] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (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.

[0663] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (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.

[0664] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (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.

[0665] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (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.

[0666] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (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.

[0667] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is (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.

[0668] In a particular embodiment, the present invention provides a pharmaceutically acceptable salt, especially a hydrochloride salt, of a compound of formula (I) as described herein. In another particular embodiment, the present invention provides a compound of formula (I) as described herein.

[0669] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms 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 can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as but not limited to 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125 I. Certain isotopically-labeled compounds of formula (I) (e.g., those containing a radioactive isotope) are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and detection means are readily available. For example, compounds of formula (I) may be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95 or 99% of a given isotope.

[0670] Using heavier isotopes (such as deuterium, 2 H) substitutions may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0671] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 N) substitution can be used to examine positron emission tomography (PET) studies of 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 using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used.

[0672] Preparation process

[0673] The preparation of the compound of formula (I) of the present invention can be carried out according to sequential or concurrent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required for performing the reaction and purifying the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and indices used in the following method descriptions have the meanings provided herein.

[0674] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction steps, appropriate protecting groups can be introduced before the key steps by methods well known in the art (such as "Protective Groups in Organic Chemistry" by TW Greene and PGM Wutts, 5th edition, 2014, John Wiley & Sons, NY). Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0675] If the starting material or intermediate contains a stereogenic center, the compound of formula (I) can be obtained in the form of a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art (e.g., chiral HPLC, chiral SFC or chiral crystallization). Racemic compounds can be separated into corresponding enantiomers, for example, by diastereomeric salts, which are crystallized with optically pure acids, or by specific chromatography separations of enantiomers using chiral adsorbents or chiral eluents. Starting materials and intermediates containing stereogenic centers can also be separated to provide starting materials and intermediates enriched in diastereomers / enantiomers. Using such diastereomer / enantiomer-enriched starting materials and intermediates in the synthesis of compounds of formula (I) will generally produce diastereomers / enantiomer-enriched compounds of the corresponding formula (I).

[0676] Those skilled in the art will recognize that in the synthesis of compounds of formula (I) (if not desired), an "orthogonal protecting group strategy" will be applied, which allows multiple protecting groups to be cleaved each time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has also been reported in the literature (e.g., Barany and RB Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0677] Those skilled in the art will recognize that the order of reactions may vary depending on the reactivity and nature of the intermediates.

[0678] In more detail, the compound of formula (I) can be manufactured by the method given below, by the method given in the examples or by similar methods. The appropriate reaction conditions for each reaction step are known to those skilled in the art. Similarly, the reaction conditions affecting the reaction reported in the relevant literature are described, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999. It is convenient to react in the presence or absence of a solvent. There are no particular restrictions on the nature of the solvent used, as long as it has no adverse effect on the reaction or the reagents involved and can dissolve the reagents at least to a certain extent. The described reaction can occur over a wide temperature range, and the precise reaction temperature is not critical to the present invention. The above reaction can be conveniently performed in a temperature range of -78°C to reflux. The time required for the reaction can also vary over a wide range, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, it usually takes 0.5 hours to several days to obtain the intermediates and compounds. The reaction sequence is not limited to the one shown in the schemes, but, depending on the starting materials and their respective reactivity, the order of the reaction steps can be freely varied.

[0679] If starting materials or intermediates were not commercially available or their synthesis was not reported in the literature, they could be prepared by analogy to existing preparations of close analogs or as outlined in the experimental section.

[0680] The following abbreviations are used in this text:

[0681] 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 = cuprous chloride (I), CuCN = cuprous cyanide (I), CuI = cuprous iodide (I), 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, DMEDA = N,N'-dimethylethylenediamine, DMF = N,N-dimethylformamide, DIPEA = N,N-diisopropylethylamine, dppf = 1,1-bis(diphenylphosphino)ferrocene, EDC.HCl = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, EI = electron impact, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour, FA = formic acid, H2O = water, H2SO4 = sulfuric acid, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-1H-benzotriazole; HPLC = high performance liquid chromatography, iPrMgCl = isopropylmagnesium chloride, I2 = iodine, IPA = 2- propanol, ISP = ion spray positive (mode), ISN = ion spray negative (mode), K2CO3 = potassium carbonate, KHCO3 = potassium bicarbonate, KI = potassium iodide, KOH = potassium hydroxide, K3PO4 = tripotassium phosphate, LiAlH4 or LAH = lithium aluminum hydride, LiHMDS = lithium bis(trimethylsilyl)amide, LiOH = lithium hydroxide, mCPBA = meta-chloroperbenzoic acid, MgSO4 = magnesium sulfate, min = minutes, mL = milliliters, MPLC = medium pressure liquid chromatography, MS = mass spectrometry, MTBE = tert-butyl methyl ether, nBuLi = n-butyl lithium, NaBH3CN = sodium cyanoborohydride, NaH = sodium hydride, NBS = N-bromosuccinimide, NaHCO3 = carbon =Sodium hydrogen phosphate, NaNO2 = sodium nitrite, 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-dichloropalladium(II) 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 = reverse 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 bonded, ZnCl2 = zinc chloride, Hal = halogen, preparative TLC = preparative thin layer chromatography. .

[0682] The compounds of formula I of the present invention can be prepared by reacting an activated intermediate of formula 2 with a nucleophilic spirocyclic amine 1 in the presence of a base such as DIPEA in a solvent such as DMF or CH3CN with heating. (Scheme 1). Alternatively, the activated intermediate can be formed on another coupling partner (1), which will produce a urea of ​​formula I.

[0683]

[0684] Solution 1

[0685] Activated intermediate 2 can be generated instantaneously in the reaction mixture or by reacting amine 3 with a coupling agent such as di(1H-1,2,4-triazol-1-yl)methanone (4) in the presence of a base such as DIPEA in a solvent such as acetonitrile (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.

[0686]

[0687] Solution 2

[0688] The structural unit of formula 1 can be generated by the following method: Suzuki reaction (e.g., Pd(dppf)Cl2, K2CO3, dioxane / H2O), (X=Br, I), followed by hydrogenation (e.g., Pd / C, H2) and deprotection (e.g., when PG=Boc, using TsOH or TFA) (Scheme 3). The required 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-dioxaborolan (LiTMP, THF, -78°C). In the case of A=N-linked heteroaryl groups, a Chan-Lam type coupling can be used instead of the Suzuki reaction (e.g., using Cu(OAc)2 under an oxygen atmosphere), followed by hydrogenation / deprotection. A similar sequence can also be used starting from appropriately functionalized boronates 5 with an additional Me group on the olefinic carbon bearing the boronate to generate building blocks where, for example, R4 = Me and R5 = H. In some cases, where A = heteroaryl with a free NH group (e.g., NH pyrazole or fused NH pyrazole), it is beneficial to use an additional protecting group on the NH group (e.g., SEM protection, which can be introduced using standard techniques and can typically be deprotected in a final deprotection step under acidic conditions).

[0689]

[0690] Solution 3

[0691] Alternatively, building blocks of formula 1 (where A = N-linked heteroaryl) can be prepared by reacting a nucleophilic heterocycle A (8) with an appropriately protected building block 9 (X = leaving group, such as OMs, I, Br) in the presence of a base such as Cs2CO3, followed by deprotection under standard conditions (e.g., when PG = Boc, using TsOH) (Scheme 4). Mesylate building blocks 9 (X = OMs) are commonly used, which can be conveniently generated from hydroxy analogs by reaction with MsCl in the presence of a weak base such as Et3N.

[0692]

[0693] Solution 4

[0694] Alternatively, the building blocks of formula 1 (where A = N-linked heteroaryl) can be prepared by subjecting heterocycle A (8) to a Mitsunobu-type reaction with hydroxy building blocks 10 (e.g., using diisopropyl azodicarboxylate and triphenylphosphine, or Tsunoda reagent (cyanomethylenetributylphosphine)), followed by deprotection under standard conditions (e.g., using TsOH when PG = Boc). (Scheme 5) Alternatively, the building blocks of formula 1 can be prepared by converting hydroxy building blocks 10 to a mesylate (e.g., using MsCl, Et3N), followed by S-reaction with heterocycle A (8) in the presence of a base such as NaH. N 2 reactions were used to prepare.

[0695]

[0696] Solution 5

[0697] Alternatively, the structural unit of formula 1 (where A is a C-linked heteroaryl) can be generated using standard heterocyclic synthesis techniques starting from, for example, a suitable carboxylic acid (11) or ester, nitrile (12) or diketone (13) derivative. The nitrile derivative can be generated from the hydroxy derivative (10) via conversion to a mesylate (e.g., using MsCl, Et3N), followed by S-treatment of the mesylate group with cyanide. N 2 displacement (e.g., using KCN). Diketone derivatives can be generated from ester derivatives (14). (Scheme 6)

[0698]

[0699] Solution 6

[0700] (Hetero)aryl trifluoromethylcyclopropyl building blocks 15 are generally not accessible, but are generated from halide building blocks 16 (X = I, Br) via Suzuki reaction with 1-(trifluoromethyl)vinylboronic acid to give 17. Cyclopropanation using diphenyl(methyl)sulfonium tetrafluoroborate with LiHMDS gives the desired building blocks 15. (Scheme 7) This sequence can also be performed between steps of other synthetic schemes, for example for N-linked heteroaryl ring A, these functionalization steps can also be performed while preparing the building blocks of Formula 1 after the Chan-Lam coupling / hydrogenation sequence but before the final deprotection (see Scheme 3). Alternatively, (hetero)aryl trifluoromethylcyclopropyl building blocks can be generated from commercial building blocks via standard heterocycle synthesis techniques.

[0701]

[0702] Solution 7

[0703] The structural unit of formula 18, wherein R4 = R5 = F, can be generated via deoxyfluorination of a suitable ketone 20, e.g. using DAST (diethylaminosulfur trifluoride), followed by a suitable deprotection, e.g. using TsOH or TFA, wherein PG = Boc. The ketone can be generated using oxidation of the benzyl CH2 group on a suitable intermediate 19 (generated in Scheme 3), e.g. using SeO2, or alternatively via nucleophilic attack of a Weinreb amine 23 by a metallated anionic derivative of a suitable (hetero)aryl 22. Intermediate 22 can be generated from a suitable halogenated (hetero)aryl derivative 21 (X = Br, I, Cl) via metalation, e.g. using nBuLi.

[0704] (Scheme 8)

[0705]

[0706] Solution 8

[0707] In some cases, where A = fused (hetero)aryl, an appropriately substituted monocyclic A-ring is introduced as detailed above (e.g., Scheme 3), followed by the introduction of the fused (hetero)aryl ring using standard heterocycle 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 group typically occurs in the middle of an existing synthetic step, most commonly prior to deprotection of building block 1.

[0708] In some cases, compounds of formula I may be further functionalized to provide other compounds of formula I. For example, compounds of formula I bearing (hetero)aryl bromides or iodides may be further functionalized with other groups (e.g., amines, or alkyl groups) using metal-catalyzed cross-coupling conditions such as the Buchwald or Suzuki reactions.

[0709] In some cases, building blocks can be generated from commercially available fragments using standard functional group interconversion techniques (e.g., installation of halides (e.g., using NIS or NBS); removal of halides (e.g., under hydrogenation conditions); conversion of halides to other groups (e.g., small amines, small alkyl groups) using metal-catalyzed cross-coupling conditions such as Buchwald or Suzuki reactions; conversion of iodides to trifluoromethyl groups using trifluoromethylating agents (e.g., diphenyl(trifluoromethyl)sulfonium triflate); installation and removal of protecting groups; hydrolysis of esters to acids; generation of amides from acids and small amines; conversion of boron-containing groups to hydroxyls using basic peroxide conditions; cycloaddition of azidotrimethylsilane to nitriles to generate tetrazoles; Sandmeyer reaction of anilines to give bromides; oxidation of thioethers to sulfones; oxidation of thioethers to sulfoximines using PhI(OAc)2 and NH2COONH4; oxidation of thioethers to sulfoximines via S N 2 reaction or reductive amination to alkylate hydroxyl or amine groups; acylation using activated carbonyl derivatives; or installation of –SO2Me or –SO2CF3 from iodinated or brominated building blocks using literature techniques; using S N 2-alkylation or Chan-Lam type conditions, installation of small alkyl groups or rings such as cyclopropyl onto heteroaromatic nitrogens with alkyl borate esters; cyclopropanation of olefins; or installation of dimethylphosphine groups in place of (hetero)aromatic halides (X=Br, I) groups via Pd-catalyzed cross-coupling with dimethylphosphine oxide in the presence of a base such as Et3N. Such techniques can also be used to elaborate commercially available fragments before, after or in the middle of the above synthetic sequence reactions.

[0710] In one aspect, the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein, the method comprising:

[0711] (a) an amine of formula 1b, wherein R 1 , R 2 , R 4 , R 5 , A and B are as described herein,

[0712]

[0713] With 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2),

[0714]

[0715] react in the presence of a base; or

[0716] (b) 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (2b)

[0717]

[0718] and a compound of formula 1c, wherein R 1 , R 2 , R 4 , R 5 , A and B are as described herein,

[0719]

[0720] In the presence of a base,

[0721] To form the compound of formula (I).

[0722] In one embodiment, the present invention provides a method for preparing a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, comprising:

[0723] (a) an amine of formula 1, wherein R 1 , R 2 , A and B are as described herein,

[0724]

[0725] With 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2),

[0726]

[0727] react in the presence of a base; or

[0728] (b) 4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (2a)

[0729]

[0730] A compound of formula 1a, wherein R 1 , R 2, A and B are as described herein,

[0731]

[0732] In the presence of a base,

[0733] To form the compound of formula (I).

[0734] In one embodiment, the base is DIPEA.

[0735] In one embodiment, the step (a) or (b) is carried out in a solvent, preferably DMF or CH3CN.

[0736] In one embodiment, the amine of formula 1 is obtained by

[0737] (c) making a compound of formula 6, wherein R 1 , R 2 and A is as defined herein, and wherein X is bromine or iodine;

[0738]

[0739] and a borate of formula 5, wherein B is as defined herein and R is C 1-6 -alkyl;

[0740]

[0741] Suzuki coupling is carried out in the presence of a base and a palladium catalyst to form a compound of formula (7) wherein R 1 , R 2 , A and B are as defined herein, and PG is a suitable amino protecting group,

[0742]

[0743] Then:

[0744] (d) hydrogenating the compound of formula 7 to obtain a compound of formula 7a,

[0745] and

[0746] (e) removing the amino protecting group PG from the compound of formula 7a to obtain the compound of formula 1.

[0747] In one embodiment, the palladium catalyst in step (c) is selected from PdCl(crotyl) (PtBu3) and Pd(dppf)Cl2.

[0748] In one embodiment, the base in step (c) is K2CO3.

[0749] In one embodiment, the Suzuki coupling of step (c) is performed in a solvent mixture comprising dioxane and water.

[0750] In one embodiment, the suitable amino protecting group is tert-butoxycarbonyl (BOC).

[0751] In one embodiment, the hydrogenation in step (d) is performed under hydrogen atmosphere using palladium / carbon as a catalyst.

[0752] In one embodiment, the hydrogenation in step (d) is performed under elevated hydrogen pressure, preferably about 22800 mmHg.

[0753] In one embodiment, the hydrogenation in step (d) is performed in ethyl acetate.

[0754] In one embodiment, the suitable amino protecting group PG is BOC and is removed in step (e) using p-toluenesulfonic acid.

[0755] In one embodiment, the amine of formula 1 is obtained by

[0756] (c1) an amine of formula 8

[0757]

[0758] and an alcohol of formula 9, wherein PG is a suitable amino protecting group

[0759]

[0760] A Mitsunobu-type reaction is carried out in the presence of a phosphine and a dialkyl azodicarboxylate;

[0761] To form a compound of formula 10, wherein PG is a suitable amino protecting group;

[0762] and

[0763] (d1) removing the amino protecting group PG from the compound of formula 10 to obtain the compound of formula 1.

[0764] In one embodiment, the phosphine is triphenylphosphine.

[0765] In one embodiment, the dialkyl azodicarboxylate is selected from DEAD and DIAD.

[0766] In one embodiment, the Mitsunobu-type reaction is carried out in a solvent, preferably THF.

[0767] In one embodiment, the suitable amino protecting group PG is BOC and is removed in step (d1) using p-toluenesulfonic acid.

[0768] In one aspect, the present invention provides a compound of formula (I) as described herein, manufactured according to any one of the methods described herein.

[0769] MAGL inhibitory activity

[0770] 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.

[0771] In another aspect, the invention provides a compound of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.

[0772] In another 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.

[0773] In another aspect, the present invention provides a method for inhibiting MAGL in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0774] The inhibitory activity of the compounds of formula (I) according to the invention on MAGL is analyzed by determining the enzymatic activity after hydrolysis of the natural substrate 2-arachidonoylglycerol to give arachidonic acid, which can be followed by mass spectrometry analysis. This assay is hereinafter abbreviated as "2-AG assay".

[0775] The 2-AG assay was performed in a 384-well assay plate (PP, Greiner catalog number 784201) with a total volume of 20 μL. Compound dilutions were prepared in 100% DMSO (VWR Chemicals 23500.297) using a 3-fold dilution step in a polypropylene plate to allow the final concentration range of the assay to be 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, 03690-100 ml), 0.01% (v / v) Tween). After shaking, the plate was incubated at RT for 15 min. 10 μL of 2-arachidonoylglycerol in assay buffer was added to start the reaction. The final concentration in this assay is 50pM MAGL and 8μM 2-arachidonoylglycerol. After shaking and incubating at RT for 30 minutes, 40μL of acetonitrile containing 4μM d8-arachidonic acid is added to quench the reaction. The content of arachidonic acid is tracked using an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer (Agilent6460). In the acetonitrile / water liquid position, a C18SPE cartridge (G9205A) is used. The mass spectrometer is operated in negative electrospray mode, and the mass ion pair of arachidonic acid is 303.1→259.1, and the mass ion pair of d8-arachidonic acid is 311.1→267.0. The activity of the compound is calculated based on the intensity ratio of [arachidonic acid / d8-arachidonic acid].

[0776] Table 1

[0777]

[0778]

[0779] In one aspect, the present invention provides a compound of formula (I) as described herein and a pharmaceutically acceptable salt or ester thereof, wherein the compound of formula (I) and a pharmaceutically acceptable salt or ester thereof has a MAGL inhibition IC of less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM. 50 , as measured in the MAGL assay described herein.

[0780] In one embodiment, the compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have an IC between 0.000001 μM and 25 μM. 50 (MAGL inhibition) values, with specific compounds having IC between 0.000005 μM and 10 μM 50 values, further specific compounds have IC values ​​between 0.00005 μM and 5 μM 50Value as measured in the MAGL assay described herein.

[0781] P app (Passive permeability measurement) obtained as part of a one-way P-gp screen

[0782] Experimental Description

[0783] The general assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human or mouse P-gp, cultured on 96-well semipermeable filter plates where they form a polarized monolayer with tight junctions and serve as a barrier between the apical and basolateral compartments.

[0784] P-gp is expressed in the apical membrane of the monolayer.

[0785] The compactness of the cell monolayer and the functional activity of P-gp were confirmed by adding the cell-impermeable marker Lucifer Yellow and the reference P-gp substrate Edoxaban, respectively.

[0786] The assay was fully automated on a Tecan liquid handling robot.

[0787] Data analysis and interpretation

[0788] For substrate testing, the assay determines the unidirectional permeability (P) of test compounds by dosing the apical (i.e., donor compartment) side of the cell monolayer in the absence and presence of app A>B Equation 1), and the movement of compounds into the basolateral (i.e., receptor) compartment was measured in the presence and absence of the specific P-gp inhibitor zosuquidar and incubated at 37°C for 3 h. The effect of P-gp was measured by expressing the apical efflux rate (AP-ER, Equation 2). The average permeability (P app ) was determined by zosuquidar conditions in the absence of P-gp. AP-ER and average P app The compounds were classified according to their efflux extent and permeability properties (Table 2).

[0789]

[0790] Reaction formula 1. app , A, C0 and dQ / dt represent the apparent permeability, filter surface area, initial concentration and transport volume per time period, respectively. app Values ​​are calculated based on a single point in time.

[0791]

[0792] Equation 2. Calculation of the apical efflux rate (AP-ER). Papp,inh(A>B) is the permeability value from the apical to basolateral direction in the presence of the inhibitor, and Papp(A>B) is the permeability value from the apical to basolateral direction in the absence of the inhibitor.

[0793] result

[0794] Compared to the compounds disclosed in WO2020104494, the compounds of the present invention surprisingly exhibit reduced P app , while retaining overall drug-like properties. Therefore, the passive permeability (P app ) are typically in the range of 250 nm / s to 350 nm / s (Table 2), at which point setting an exposure gradient across tissue becomes extremely challenging. In contrast, the passive permeability of the compounds of the present invention is typically in the range of 30 nm / s to 250 nm / s (Table 3), more preferably in the range of 50 nm / s to 200 nm / s, which, when combined with other suitable properties, enables setting an exposure gradient across tissue.

[0795] Table 2

[0796] WO2020104494 <![CDATA[P app (nm / s)]]> Example 49 253 Example 51 258 Example 72 262 Example 50 267 Example 53 274 Example 71 300 Example 25 293 Example 23 265

[0797] Table 3

[0798]

[0799]

[0800] Compared with the heteroaryl analogs disclosed in WO2020104494 (wherein L=O), due to the heteroaryl group and CR 4 R 5 Novel combinations of linkers, also observed P app The reduction of R 4 and R 5 As defined herein. Comparison of Example 25 of WO2020104494 and Example 3 of the present invention, P app A surprising reduction from 293 nm / s to 133 nm / s.

[0801] Use of the Compounds of the Invention

[0802] In one aspect, the invention provides a compound of formula (I) as described herein for use as therapeutically active substance.

[0803] In another aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment or prevention of diseases and disorders associated with MAGL.

[0804] In another aspect, the present invention provides a method for treating or preventing diseases and disorders associated with MAGL, the method comprising administering to a mammal an effective amount of a compound of formula (I) as described herein.

[0805] In another aspect, the present invention provides the use of a compound of formula (I) as described herein for treating or preventing diseases and disorders associated with MAGL.

[0806] In another 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.

[0807] In one embodiment, the diseases and conditions 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 kidney disease.

[0808] In one embodiment, the diseases and conditions associated with MAGL are selected from neuroinflammation, neurodegenerative diseases, pain, cancer and / or psychiatric disorders.

[0809] In one embodiment, the diseases and conditions 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 kidney disease.

[0810] In a preferred embodiment, the diseases and conditions 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 kidney disease.

[0811] In a preferred embodiment, the 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.

[0812] In a preferred embodiment, the diseases and disorders associated with MAGL are selected from visceral pain, endometriosis, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.

[0813] In a preferred embodiment, the diseases and conditions associated with MAGL are selected from endometriosis, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.

[0814] In a particularly preferred embodiment, the disease and condition associated with MAGL is endometriosis.

[0815] In a particularly preferred embodiment, the disease and condition associated with MAGL is pain associated with rheumatoid arthritis.

[0816] In a particularly preferred embodiment, the diseases and disorders associated with MAGL are pain associated with osteoarthritis.

[0817] In a particularly preferred embodiment, the diseases and disorders associated with MAGL are inflammatory bowel disease.

[0818] In a particularly preferred embodiment, the diseases and disorders associated with MAGL are symptoms associated with inflammatory bowel disease.

[0819] In a particularly preferred embodiment, the diseases and disorders associated with MAGL are intestinal motility.

[0820] In a particularly preferred embodiment, the diseases and disorders associated with MAGL are abdominal pain.

[0821] In a particularly preferred embodiment, the disease and disorder associated with MAGL is abdominal pain associated with irritable bowel syndrome.

[0822] Pharmaceutical compositions and administration

[0823] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0824] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered internally, such as orally (e.g., in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions or suspensions), intranasally (e.g., in the form of nasal sprays) or rectally (e.g., in the form of suppositories). However, they can also be administered parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0825] The compound of formula (I) and its pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants to form tablets, coated tablets, dragees and hard gelatin capsules. For example, lactose, corn starch or its derivatives (talc, stearic acid or its salts, etc.) can be used as such adjuvants for tablets, dragees and hard gelatin capsules.

[0826] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols and the like.

[0827] Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

[0828] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0829] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

[0830] In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying the osmotic pressure, buffer masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0831] The dosage can vary within a wide range and will of course be adapted to the various requirements in each particular case. In general, a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person) for oral administration should be suitable, preferably divided into 1-3 separate doses (which may consist of, for example, the same amount). However, it is apparent that, when indicated as indicated, the upper limit given herein may be exceeded.

[0832] Tablet preparation (wet granulation)

[0833]

[0834] Preparation Procedure

[0835] 1. Mix items 1, 2, 3 and 4 and granulate with purified water.

[0836] 2. Dry the granules at 50°C.

[0837] 3. Pass the particles through suitable grinding equipment.

[0838] 4. Add item 5 and mix for three minutes; press on a suitable press.

[0839] Capsule preparation

[0840]

[0841] Preparation Procedure

[0842] 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

[0843] 2. Add items 4 and 5 and mix for 3 minutes.

[0844] 3. Fill into suitable capsules.

[0845] Examples

[0846] The present invention will be more fully understood by reference to the following examples. However, the claims should not be interpreted as being limited to the scope of the examples.

[0847] Where the preparation examples are obtained as mixtures of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to those skilled in the art such as chiral chromatography (eg chiral SFC) or crystallization.

[0848] If not stated otherwise, all reaction examples and intermediates were prepared under argon atmosphere.

[0849] Examples were generated using urea coupling between building blocks AX and PX. Building blocks A.1 and A.2 can be used interchangeably as free bases or suitable salts (eg hydrochloride, tartrate) as shown in the representative examples below.

[0850] Example 1

[0851] (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

[0852]

[0853] 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]succinic acid; (2S,3S)-4-hydroxy-2,3-bis[(4-methylbenzoyl)oxy]-4-oxo-butyrate; hydrate (structural unit A.1; 56 mg, 0.06 mmol, 1 eq, CAS 2624363-49-9) and DIEA (54 mg, 0.42 mmol, 7 eq) in acetonitrile (1 mL) was added bis(1,2,4-triazol-1-yl)methanone (13 mg, 0.078 mmol, 1.3 eq, CAS 41864-22-6). The reaction mixture was stirred at 30° C. for 2 h. After addition of p-toluenesulfonic acid; 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane (building block P.1; 36 mg, 0.06 mmol, 1 eq), stirring was continued at 50° C. overnight. The crude material was purified by preparative HPLC (YMC-Triart C18, 12 nm, 5 μm, 100 x 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] + .

[0854] Example 12

[0855] (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

[0856]

[0857] 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 eq, CAS 2377107-31-6) and DIEA (24 mg, 33 uL, 192 μmol, 3 eq) in DMF (500 uL) was added bis(1,2,4-triazol-1-yl)methanone (10 mg, 64 μmol, 1 eq, CAS 41864-22-6). The mixture was stirred at 35 °C for 1 h. DIEA (24 mg, 33 uL, 192 μmol, 3 eq) and p-toluenesulfonic acid; 6-[(5-trifluoromethanesulfonyl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane (31 mg, 64 μmol, 1 eq) were added. The reaction mixture was stirred at 70 ° C for 15h. The crude material was purified by preparative HPLC (YMC-Triart C18, 12nm, 5μm, 100x 30mm, ACN / water+0.1% TEA). The product was concentrated in vacuo to give (4aR, 8aS)-6-[6-[(5-trifluoromethanesulfonyl-2-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazine-3-one (12mg, 35%) as a white solid. MS (ESI): m / z=503.2[M+H] + .

[0858] Example 35

[0859] (4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-yl]

[0860] [carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

[0861]

[0862] 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 eq, CAS 2377107-31-6) and DIEA (24 mg, 33 uL, 192 μmol, 3 eq) in DMF (500 uL) was added bis(1,2,4-triazol-1-yl)methanone (10 mg, 64 μmol, 1 eq, CAS 41864-22-6). The mixture was stirred at 35 °C for 1 h. DIEA (24 mg, 33 uL, 192 μmol, 3 eq) and 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; p-toluenesulfonic acid (27 mg, 64 μmol, 1 eq) were added. The reaction mixture was stirred at 70 °C for 15 h. The crude material was purified by preparative HPLC (Gemini NX, 12 nm, 5 μm, 100 x 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] + .

[0863] Example 113

[0864] (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

[0865]

[0866] 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 eq, CAS 2411577-59-6) in DMF (836 uL) was added DIEA (134 mg, 181 uL, 1.04 mmol, 7 eq) and bis(1,2,4-triazol-1-yl)methanone (27 mg, 163 μmol, 1.1 eq, CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30 min. 6-(2-azaspiro[3.3]heptane-6-ylmethyl)-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine; 2,2,2-trifluoroacetic acid (134 mg, 163 μmol, 1.1 eq) was added. The reaction mixture was stirred at 50° C. for 18 h. 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, yield 78%) as a white solid. MS (ESI): m / z=479.2[M+H] + .

[0867] Example 114

[0868] (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

[0869]

[0870] 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 eq, CAS 2411577-59-6) in DMF (836 uL) was added DIEA (134 mg, 182 uL, 1.04 mmol, 7 eq) and bis(1,2,4-triazol-1-yl)methanone (27 mg, 163 μmol, 1.1 eq, CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30 min. 6-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine; p-toluenesulfonic acid (105 mg, 163 μmol, 1.1 eq) was added. The reaction mixture was stirred at 50° C. for 18 h. 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] + .

[0871] Example 118

[0872] (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

[0873]

[0874] 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 eq, CAS 2411577-59-6) in DMF (836 uL) was added DIEA (134 mg, 182 uL, 1.04 mmol, 7 eq) and bis(1,2,4-triazol-1-yl)methanone (27 mg, 163 μmol, 1.1 eq, CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30 min. 5-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine; p-toluenesulfonic acid (76 mg, 163 μmol, 1.1 eq) was added. The reaction mixture was stirred at 50° C. for 18 h. 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] + .

[0875] Example 133

[0876] (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one

[0877]

[0878] To a solution of (4aR,8aS)-6-[6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]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 eq, CAS 2624363-49-9) in DMF (1 mL) was added DIEA (148 mg, 200 uL, 1.15 mmol, 7 eq) and bis(1,2,4-triazol-1-yl)methanone (29.58 mg, 180 μmol, 1.1 eq, CAS 41864-22-6). The reaction mixture was stirred at room temperature for 30 min. p-Toluenesulfonic acid; 6-[[6-[1-(trifluoromethyl)cyclopropyl]-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane (105 mg, 163 μmol, 1 eq) were 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-pyridinyl]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] + .

[0879] Similar to the above examples, the examples in the following table are generated using the corresponding structural units AX and PX.

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920] Synthesis of building blocks

[0921] Structural units A.1 and A.2

[0922] The building blocks A.1 and A.2 are commercially available or have been reported in the scientific literature, for example as 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) salts, and can be used interchangeably. In some cases, racemic commercial products were purchased and separated into the corresponding stereoisomers.

[0923] (+)-(4aR,8aS)-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

[0924] and

[0925] (-)-(4aS,8aR)-4a,5,6,7,8,8a-Hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one

[0926]

[0927] The enantiomers of racemic-(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% NH4OAc):n-heptane (30:70).

[0928] The 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] + .

[0929] The 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] + .

[0930] Structural unit P.1: 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane; p-toluenesulfonic acid

[0931]

[0932] Step 1: tert-Butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[0933] The mixture of 2,2,6,6-tetramethylpiperidine (95.9mL, 568mmol) in THF (750mL) is cooled to -30 ° C under N2 atmosphere. n-BuLi (227mL, 568mmol) is added dropwise, and the reaction mixture is stirred at the same temperature for 30min. Next, the reaction is cooled to -60 ° C, and a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)methyl]-1,3,2-dioxaborolane (136g, 506mmol) in THF (750mL) is added dropwise. After stirring for 30min, a solution of 6-oxo-2-azaspiro [3.3] heptane-2-tert-butyl formate (100g, 473mmol) in THF (300mL) is added dropwise at -60 ° C. The reaction mixture was slowly warmed to 25° C. and stirred at 25° C. for 12 h. H O (80 mL) was slowly added to the mixture, and then purified by silica gel column (PE / EA=1:0 to 3:1 gradient) together with another batch of the same size to give the title compound (220 g, 656 mmol, approximately 69% yield per batch) as a white solid, confirmed by: 1H 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).

[0934] Step 2: tert-Butyl 6-[[5-(trifluoromethyl)pyrazin-2-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate ester

[0935]

[0936] 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 eq, CAS 2763647-64-7), 2-bromo-5-(trifluoromethyl)pyrazine (812 mg, 3.6 mmol, 1.2 eq, CAS 1196152-38-1) and tripotassium phosphate (1.27 g, 6 mmol, 2 eq) in 1,4-dioxane (20 mL) and water (2 mL) was degassed with argon. Chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (59 mg, 0.15 mmol, 0.05 eq, CAS 1334497-00-5) was added. The mixture was stirred at 70 ° C for 4 h. The reaction mixture was poured into EtOAc and washed with water, 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, EtOAc in heptane 0% to 30%) to give tert-butyl 6-[[5-(trifluoromethyl)pyrazin-2-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (593 mg, 97% purity, 54% yield) as a white solid. MS (ESI): m / z = [M-C4H8+H] + .

[0937] Step 3: tert-Butyl 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[0938]

[0939] A solution of tert-butyl 6-[[5-(trifluoromethyl)pyrazine-2-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (0.59 g, 1.66 mmol, 1 eq) in tetrahydrofuran (10 mL), methanol (30 mL) was degassed with argon. Pd / C 10% (176 mg, 0.166 mmol, 0.1 eq) was added. The mixture was stirred at room temperature for 30 min under a balloon of H2. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6-[[5-(trifluoromethyl)pyrazine-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (588 mg, 95% purity, 94% yield) as an off-white solid. MS (ESI): m / z = [M-C4H8+H] + .

[0940] Step 4: 6-[[5-(Trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane; p-toluenesulfonic acid

[0941]

[0942] To a solution of tert-butyl 6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (183 mg, 0.51 mmol, 1 eq) in ethyl acetate (1.2 mL) was added 4-methylbenzenesulfonic acid monohydrate (102 mg, 0.54 mmol, 1.05 eq). 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; p-toluenesulfonic acid (228 mg, 94% purity, 98% yield) as a light brown solid. MS (ESI): m / z=258.2 [M+H] + .

[0943] Analogously to building block P.1, the following building blocks were generated in step 2 using the relevant (hetero)aryl bromide, chloride or iodide building blocks for Suzuki coupling. In some cases, alternative salts (e.g. trifluoroacetate, xylenesulfonate, hydrochloride) were also used. To introduce different spirocyclic systems, alternative building blocks were used in step 2 instead of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate, e.g. 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, (6Z)-6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (CAS2763648-54-8) for P.92, or 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (C.184) for P.184.

[0944]

[0945]

[0946]

[0947]

[0948]

[0949]

[0950]

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969] Structural unit P.14: [6-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-pyridyl]-imino-oxo-(trifluoromethyl)-λ 6 -sulfane; 4-methylbenzenesulfonic acid

[0970]

[0971] Step 1: 2-Bromo-5-(trifluoromethylthio)pyridine

[0972]

[0973] To a solution of 2-bromo-5-iodopyridine (0.5 g, 1.76 mmol, 1 eq) in ACN (10 mL) was added 2,2'-bipyridine (275 mg, 1.76 mmol, 1 eq, CAS 366-18-7), silver (I) trifluoromethanethiol (441 mg, 2.1 mmol, 1.2 eq, CAS 811-68-7) and CuI (335 mg, 1.76 mmol, 1 eq) at 20 °C. The mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered to give 2-bromo-5-(trifluoromethylthio)pyridine (400 mg, 1.55 mmol, 88% yield). The crude product was used directly in the next step.

[0974] Step 2: 6-[[5-(Trifluoromethylthio)-2-pyridinyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[0975]

[0976] 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 eq, CAS 2763647-64-7), 2-chloro-5-(trifluoromethylsulfanyl)pyridine (2.67 g, 12.5 mmol, 1 eq, CAS 1204234-94-5) and potassium carbonate (3.46 g, 25 mmol, 2 eq) in 1,4-dioxane (25 mL) and water (5 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (1.02 g, 1.25 mmol, 0.1 eq, CAS 95464-05-4). Under N2 atmosphere, the mixture was stirred at 80°C for 12 h. The crude material was purified by silica gel chromatography (heptane / EtOAc 3:1) to give tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridinyl]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] + .

[0977] Step 3: tert-6-[[5-(trifluoromethylthio)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Butyl Ester

[0978]

[0979] To a solution of tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridinyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.7 g, 4.4 mmol, 1 eq) in EtOAc (20 mL) at 20° C. under N2 was added wet Pd / C 10% (1.7 mg, 0.44 mmol, 0.1 eq), and then the mixture was stirred at 20° C. for 6 h under H2 atmosphere (balloon). The mixture was filtered and concentrated in vacuo to give tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridinyl]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] + .

[0980] Step 4: 6-[[5-(trifluoromethylsulfonamidoyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-yl]- Tert-Butyl Formate

[0981]

[0982] To a solution of tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1 g, 2.57 mmol, 1 eq) in hexafluoroisopropanol (15 mL) was added PhI(OAc)2 (3.48 g, 10.8 mmol, 4.2 eq, CAS 3240-34-4) and ammonium carbamate (602 mg, 7.72 mmol, 3 eq). 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-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.48 mmol, yield 18%) as a brown oil. MS (ESI): m / z=333.0[M+H] + .

[0983] Step 5: [6-(2-Azaspiro[3.3]heptane-6-ylmethyl)-3-pyridinyl]-imino-oxo-(trifluoromethyl)- 4-Methylbenzenesulfonic acid

[0984]

[0985] To a solution of tert-butyl 6-[[5-(trifluoromethylsulfonyl)-2-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 0.55 mmol, 1 eq) in EtOAc (3 mL) was added p-toluenesulfonic acid (113 mg, 0.66 mmol, 1.2 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo, then deionized water was added and lyophilized to give [6-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-pyridinyl]-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] + .

[0986] Analogously to building block P.14, the following building blocks were generated in step 1 using the relevant (hetero)aryl bromide or iodide compounds for the cross-coupling reaction.

[0987]

[0988]

[0989] Structural unit P.15: 2-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazole; 4-methylbenzenesulfonic acid

[0990]

[0991] Step 1: 6-(2-Hydrazino-2-oxo-ethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0992]

[0993] To a solution of 2-(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-yl)acetic acid (2.5 g, 9.8 mmol, 1 eq, CAS 1251002-39-7) in tetrahydrofuran (30 mL) was added CDI (1.75 g, 10.7 mmol, 1 eq). The mixture was stirred at 70 ° C for 1.5 h and cooled to 0 ° C. Hydrazine monohydrate (1.47 g, 29.4 mmol, 3 eq) was added. The mixture was stirred at room temperature for 30 min. The reaction mixture was poured into EtOAc / THF 2: 1, washed with H2O, saturated NaCl, dried over Na2SO4 and concentrated in vacuo to give tert-butyl 6-(2-hydrazine-2-keto-ethyl)-2-azaspiro[3.3]heptane-2-carboxylate (3.85 g, 68% purity, 99% yield) as a white solid. MS(ESI): m / z=214.1[M-C4H8+H] + .

[0994] Step 2: 6-[2-keto-2-[N'-[1-(trifluoromethyl)cyclopropanecarbonyl]hydrazine]ethyl]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[0995]

[0996] 1- chloro-N, N, 2- trimethylpropyleneamine (1.56g, 11.6mmol, 1.2eq, CAS26189-59-3) was added to a solution of 1- (trifluoromethyl) cyclopropanecarboxylic acid (1.5g, 9.7mmol, 1eq, CAS277756-46-4) in dichloromethane (30mL). The mixture was stirred at room temperature for 2h. At room temperature, the formyl chloride solution was added dropwise to a solution of 6- (2- hydrazine-2- keto-ethyl) -2- azaspiro [3.3] heptane -2- tert-butyl formate (3.85g, 9.7mmol, 1eq) and DIPEA (2.51g, 19.4mmol, 2eq) in tetrahydrofuran (20mL). The mixture was stirred at room temperature for 2h. The reaction mixture was poured into EtOAc / THF 2: 1 and washed with water, 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, methanol in CH2Cl2 0% to 5%) to give tert-butyl 6-[2-keto-2-[N'-[1-(trifluoromethyl)cyclopropanecarbonyl]hydrazine]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.49 g, 95% purity, 84% yield) as a white solid. MS (ESI): m / z=350.1 [M-C4H8+H] + .

[0997] Step 3: 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[0998]

[0999] To a solution of tert-butyl 6-[2-keto-2-[N'-[1-(trifluoromethyl)cyclopropanecarbonyl]hydrazine]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.49 g, 8.61 mmol, 1 eq) in tetrahydrofuran (40 mL) was added Burgess reagent (4.1 g, 17.2 mmol, 2 eq, CAS 29684-56-8). The mixture was stirred at 60 ° C for 1 h. The reaction mixture was poured into EtOAc / THF 3:1 and washed with water, 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, methanol in CH2Cl2 0% to 5%) to give tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.22 g, 95% purity, 91% yield) as a white solid. MS (ESI): m / z=388.2 [M+H] + .

[1000] Step 4: 2-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazole Oxadiazole; 4-Methylbenzenesulfonic acid

[1001]

[1002] To a solution of tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.22 g, 8.31 mmol, 1 eq) in isopropyl acetate (160 mL) was added p-toluenesulfonic acid monohydrate (1.9 g, 9.97 mmol, 1.2 eq). The mixture was stirred at 85 °C for 4 h and concentrated in vacuo to give 2-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazole; 4-methylbenzenesulfonic acid (4.25 g, 40% purity, 44% yield) as a white solid. MS (ESI): m / z=288.0 [M+H] + .

[1003] Structural unit P.16: 4-methylbenzenesulfonic acid; 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane

[1004]

[1005] Step 1: tert-Butyl 6-[(3-bromo-1,2,4-triazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[1006]

[1007] To a solution of 3-bromo-1H-1,2,4-triazole (2 g, 13.5 mmol, 1 eq, CAS 7343-33-1) in DCE (40 mL) was added 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6.8 g, 20.2 mmol, 1.5 eq, CAS 2763647-64-7), pyridine (2.2 mL, 27 mmol, 2 eq), boric acid (835 mg, 13.5 mmol, 1 eq) and Cu(OAc)2 (3.64 g, 18.2 mmol, 1.35 eq). The mixture was stirred at 70 ° C for 12 h. The reaction mixture was poured into EtOAc and washed with water, 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, EtOAc in heptane 0% to 50%) 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] + .

[1008] Step 2: 6-[[3-[1-(trifluoromethyl)vinyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3] Heptane-2-carboxylic acid tert-butyl ester

[1009]

[1010] 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 eq) 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 eq, CAS 1011460-68-6), 1.5 M aqueous K3PO4 solution (2.8 mL, 4.2 mmol, 3 eq) and Ad2nBuP-Pd-G3 (162 mg, 0.14 mmol, 0.1 eq, CAS1651823-59-4). The mixture was stirred at 100 ° C for 16 h and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, EtOAc in heptane 0% to 45%) 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] + .

[1011] Step 3: 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3] Heptane-2-carboxylic acid tert-butyl ester

[1012]

[1013] 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 eq) in THF (11 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (851 mg, 3 mmol, 1 eq, CAS 10504-60-6). The suspension was cooled to 0 °C, and a solution of NaHMDS 1M in THF (4.7 mL, 4.7 mmol, 1.6 eq) 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*10um, 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, yield 38%). MS (ESI): m / z=[M-C4H8+H] + .

[1014] Step 4: 4-methylbenzenesulfonic acid; 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]- 2-Azaspiro[3.3]heptane

[1015]

[1016] A solution of p-toluenesulfonic acid (256 mg, 1.5 mmol, 1.2 eq) 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 eq) 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 and 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, yield 96%) as a yellow oil. MS (ESI): m / z=287.0[M+H] + .

[1017] Similar to building block P.16, the following building blocks were generated in step 1 using the relevant heteroaryl compounds for Chan Lam type couplings.

[1018]

[1019]

[1020] Structural unit P.19: 4-methylbenzenesulfonic acid; 6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane

[1021]

[1022] 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 eq) in EtOAc (14 mL) was added p-toluenesulfonic acid monohydrate (1036 mg, 5.45 mmol, 3 eq). 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, 80 g SiO2, MTBE / methanol (0% to 66% to 100%), flow rate = 60 ml / min, 13,8-14,9 CV.

[1023] Step 1: tert-Butyl 6-[(4-bromoimidazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1024] At 0 ℃ under nitrogen, NaH (471mg, 11.79mmol, 1.8eq) was added to a solution of 4-bromo-1H-imidazole (1443mg, 9.82mmol, 1.5eq, CAS2302-25-2) in NMP (20mL). The resulting yellow solution was stirred for 30min at 0 ℃. 6-(methylsulfonyloxymethyl)-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (2g, 6.55mmol, 1eq, CAS 2740574-92-7) was added and stirred for 12h at 50 ℃. The mixture was diluted with 20ml saturated NH4Cl aqueous solution 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 phase HPLC (0.01% FA:ACN in water = 100% to 0%, 220 nm 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] + .

[1025] Step 2: 6-[[4-[1-(trifluoromethyl)vinyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] Tert-Butyl Formate

[1026] APhos-Pd-G3 (891.35 mg, 1.4 mmol, 0.1 eq, CAS1820817-64-8) was added 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 eq) and 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (3.74 g, 16.84 mmol, 1.2 eq, CAS1011460-68-6), K3PO4 (8.93 g, 42.1 mmol, 3 eq) in THF (165 mL) and water (33 mL). The mixture was degassed with N2 and stirred at 60°C for 12 h under N2 atmosphere. The crude material was purified by silica gel column (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] + .

[1027] Step 3: 6-[[4-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-yl] Tert-Butyl Formate

[1028] At 20 ° C, diphenyl (methyl) sulfonium tetrafluoroborate (1.86 g, 6.46 mmol, 1.2 eq, CAS10504-60-6) was added to a solution of 6-[[4-[1-(trifluoromethyl) vinyl] imidazole-1-yl] methyl]-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (2 g, 5.39 mmol, 1 eq) in THF (40 mL). The suspension was cooled to 0 ° C, and NaHMDS / THF (8.62 mL, 8.62 mmol, 1.6 eq) was added dropwise under N2. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was poured into a saturated NH4Cl aqueous solution 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: 1) to obtain a crude product. The crude product was purified by preparative HPLC (column, [Phenomenex luna C18 150*40mm*15um]; mobile phase: [ACN] and [H2O] (conditions: [water (0.225% FA)-ACN], B%: 50% to 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, yield 31%) as a yellow oil. MS (ESI): m / z=386.2[M+H] + .

[1029] Structural unit P.23: 1-(2-azaspiro[3.3]heptane-6-ylmethyl)-4-(trifluoromethyl)pyridin-2-one; 4-methylbenzenesulfonic acid

[1030]

[1031] Step 1: 6-[[2-Oxo-4-(trifluoromethyl)-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[1032]

[1033] At 0 ℃ under argon, 4-(trifluoromethyl)-1H-pyridin-2-one (5.34g, 32.75mmol, 1eq, CAS50650-59-4) was added to a suspension of sodium hydride (60% in oil) (2.14g, 49.1mmol, 1.5eq) in DMF (100mL) in small portions. The mixture was stirred at 0 ℃ for 10 minutes and at room temperature for 30 minutes. The reaction mixture was cooled to 0 ℃, and 6-(methylsulfonyloxymethyl)-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (10g, 32.7mmol, 1eq, CAS2740574-92-7), sodium iodide (4.91g, 32.7mmol, 1eq) were added. The mixture was stirred at 0 ℃ for 1h and then at 80 ℃ for 18h. The reaction mixture was poured into EtOAc and washed with water, 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, tert-butyl methyl ether in heptane 0% to 100%) to give tert-butyl 6-[[2-oxo-4-(trifluoromethyl)-1-pyridinyl]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] + .

[1034] Step 2: 1-(2-azaspiro[3.3]heptane-6-ylmethyl)-4-(trifluoromethyl)pyridin-2-one; 4-methylbenzenesulfonate acid

[1035]

[1036] To a solution of tert-butyl 6-[[2-oxo-4-(trifluoromethyl)-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 13.43 mmol, 1 eq) in ethyl acetate (150 mL) was added p-toluenesulfonic acid monohydrate (5.1 g, 26.8 mmol, 2 eq) 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]heptane-6-ylmethyl)-4-(trifluoromethyl)pyridin-2-one; 4-methylbenzenesulfonic acid (5.34 mg, 85% yield) as a light yellow solid. MS (ESI): m / z=273.0[M+H] + .

[1037] Structural unit P.24: 1-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-(trifluoromethyl)pyridin-2-one; 4-methylbenzenesulfonic acid

[1038]

[1039] Analogously 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]heptane-6-ylmethyl)-5-(trifluoromethyl)pyridin-2-one; 4-methylbenzenesulfonic acid as a white solid. MS (ESI): m / z=273.0 [M+H] + .

[1040] Structural unit P.33: 4-methylbenzenesulfonic acid; 6-[[4-(2,2,2-trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane

[1041]

[1042] Step 1: 6-[[4-(2,2,2-trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[1043]

[1044] To a mixture of 4-(2,2,2-trifluoroethyl)-1H-pyrazole (737 mg, 4.9 mmol, 1 eq, CAS1211529-61-1), sodium iodide (1.47 g, 9.8 mmol, 2 eq) and cesium carbonate (3.2 g, 9.8 mmol, 2 eq) in acetonitrile (68 mL) was added tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1.5 g, 4.9 mmol, 1 eq, CAS2740574-92-7) 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 light yellow solid. MS (ESI): m / z=360 [M+H] + .

[1045] Step 2: 4-Methylbenzenesulfonic acid; 6-[[4-(2,2,2-trifluoroethyl)pyrazol-1-yl]methyl]-2-azaspiro [3.3] Heptane

[1046]

[1047] 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 eq) in EtOAc (7.5 mL) was added p-toluenesulfonic acid monohydrate (330 mg, 1.74 mmol, 2.5 eq) 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) as a light brown gum. MS (ESI): m / z=260 [M+H] + .

[1048] Structural units P.35 and P.36:

[1049] 4-Methylbenzenesulfonic acid; 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (P.35)

[1050]

[1051] 4-Methylbenzenesulfonic acid; 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane (P.36)

[1052]

[1053] Step 1: 6-[[3-Methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[1054] and tert-butyl 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate ester

[1055]

[1056] 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), triphenylphosphine (8.65 g, 33 mmol, 1.25 eq) and 5-methyl-3-(trifluoromethyl)-1H-pyrazole (3.96 g, 26.4 mmol, 1 eq) in THF (120 mL) was added diisopropyl azodicarboxylate (6.24 mL, 31.7 mmol, 1.2 eq) dropwise. The mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 330 g, MTBE in heptane 0% to 35%) to give

[1057] tert-Butyl 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.3 g, yield 24%) as a white solid. MS (ESI): m / z=360.0 [M+H] +

[1058] and tert-butyl 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.8 g, yield 40%), which is a colorless oil. MS (ESI): m / z=360.0[M+H] + .

[1059] Step 2: 4-Methylbenzenesulfonic acid; 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro [3.3] Heptane (P.35)

[1060]

[1061] 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 eq) in EtOAc (10 mL) was added p-toluenesulfonic acid monohydrate (603 mg, 3.51 mmol, 1.2 eq). 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] + .

[1062] Step 2: 4-Methylbenzenesulfonic acid; 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro [3.3] Heptane (P.36)

[1063]

[1064] 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 eq) in EtOAc (7 mL) was added p-toluenesulfonic acid monohydrate (402 mg, 2.34 mmol, 1.2 eq). 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] + .

[1065] Structural unit P.47: 5-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid

[1066]

[1067] Step 1: 6-[[3-(Trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate Tert-butyl ester

[1068]

[1069] To a solution of 6-(2-ethoxy-2-oxo-ethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (300 mg, 1.06 mmol, 1 eq, CAS 2122433-35-4) in methanol (3 mL) was added sodium methoxide 5M (0.42 mL, 2.1 mmol, 2 eq) and 2,2,2-trifluoro-N'-hydroxy-acetamidine (271 mg, 2.1 mmol, 2 eq, CAS 4314-35-6). The mixture was stirred at 60 ° C for 12 h. The reaction mixture was concentrated in a vacuum, 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, yield 32%) as a yellow oil. MS (ESI): m / z=292.0[M-C4H8+H] + .

[1070] Step 2: 5-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole; 4-methyl Benzenesulfonic acid

[1071]

[1072] 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 eq) in EtOAc (2 mL) was added p-toluenesulfonic acid (70 mg, 0.41 mmol, 1.2 eq). The reaction mixture was stirred at 80 °C for 12 h and concentrated in vacuo. Deionized water was added to the residue and lyophilized to give 5-(2-azaspiro[3.3]heptane-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]+ .

[1073] Structural unit P.48: 3-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-(trifluoromethyl)-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid

[1074]

[1075] Step 1: tert-Butyl 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate ester

[1076]

[1077] At 25 ° C, to a mixture of hydroxylamine; hydrochloride (2.35g, 33.8mmol, 2eq) in ethanol (25mL) TEA (3.42g, 33.8mmol, 2eq) was added. After 1h, 6-(cyanomethyl)-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (4g, 16.9mmol, 1eq, CAS 1374658-94-2) was added. The mixture was stirred at 50 ° C for 12h. The reaction mixture was concentrated in vacuo, dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to obtain 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (4.5g, yield 98%), which was a colorless oil. MS (ESI): m / z = 270.1 [M+H] + .

[1078] Step 2: 6-[[5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate Tert-butyl ester

[1079]

[1080] 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 eq) in methanol (20 mL) was added sodium methoxide 5M (1.19 mL, 5.94 mmol, 2 eq) and ethyl trifluoroacetate (2.11 g, 14.85 mmol, 5 eq) 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 C18150*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, yield 36%) as a colorless oil. MS (ESI): m / z=292.0[M+H] + .

[1081] Step 3: 3-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-(trifluoromethyl)-1,2,4-oxadiazole; 4-methyl Benzenesulfonic acid

[1082]

[1083] 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 eq) and p-toluenesulfonic acid (208 mg, 1.2 mmol, 1.2 eq) in EtOAc (10 mL) was stirred at 80 °C for 12 h.

[1084] The reaction mixture was concentrated in vacuo. The residue was dissolved in ACN (2 mL), water (20 mL) and lyophilized to give 3-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-(trifluoromethyl)-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid (410 mg, yield 90%) as a white solid. MS (ESI): m / z=248.0 [M+H] + .

[1085] Structural unit P.50: 4-methylbenzenesulfonic acid; 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane

[1086]

[1087] Step 1: tert-Butyl 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1088]

[1089] 6-(methylsulfonyloxymethyl)-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (6g, 19.65mmol, 1eq, CAS2740574-92-7) is added to a mixture of 4-(trifluoromethyl)-1H-triazole (2.69g, 19.65mmol, 1eq, CAS1267573-04-5), lithium bromide (3.41g, 39.3mmol, 2eq) in acetonitrile (300mL). The reaction mixture is stirred at 50°C for 18h, filtered, and concentrated in a vacuum. The crude material is purified by flash chromatography (silica gel, 220g, MTBE in heptane 0% to 100%) to obtain 6-[[4-(trifluoromethyl) triazole-2-yl] methyl]-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (2.5g, 36% yield), which is a light yellow solid. MS(ESI): m / z=247.0[M-C4H8+H] + .

[1090] Step 2: 4-Methylbenzenesulfonic acid; 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane

[1091]

[1092] 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 eq) in EtOAc (100 mL) was added p-toluenesulfonic acid monohydrate (4.12 g, 21.6 mmol, 3 eq). 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] + .

[1093] During the synthesis of building block P.50, the positionally isomeric compound tert-butyl 6-[[4-(trifluoromethyl)triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1094] Formed as a minor by-product in step 1, it was subsequently converted to the 4-methylbenzenesulfonate salt of 6-[[4-(trifluoromethyl)triazol-1-yl]methyl]-2-azaspiro[3.3]heptane following the procedure described in step 2 of the synthesis of building block P.50.

[1095]

[1096]

[1097] Structural unit P.51: 4-methylbenzenesulfonic acid; 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane

[1098]

[1099] Step 1: 4-Methylbenzenesulfonic acid; 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro [3.3] Heptane

[1100]

[1101] To a solution of 3-(trifluoromethyl)-1H-1,2,4-triazole (417 mg, 3 mmol, 1.5 eq, CAS 60406-75-9) in NMP (6 mL) was added sodium hydride (60% in oil) (146 mg, 3.65 mmol, 1.8 eq) at 0°C. The mixture was stirred at 0°C for 0.5 h. 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (620 mg, 2 mmol, 1 eq, 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, yield 8%) as a light yellow oil. MS (ESI): m / z=291.1 [M-C4H8+H] + .

[1102] Step 2: 4-Methylbenzenesulfonic acid; 6-[[5-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro [3.3] Heptane

[1103]

[1104] 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 eq) in EtOAc (0.5 mL) was added p-toluenesulfonic acid (29 mg, 0.17 mmol, 1.3 eq). The reaction mixture was stirred at 80 ° C for 12 h and concentrated in vacuo. Water was added to the residue and 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] + .

[1105] Similar to structure unit P.51, the following structure unit is used in step 1 for S N 2 were generated from related commercial building blocks. In some cases, the alternative salt trifluoroacetate was also used.

[1106]

[1107] Structural unit P.54: 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[1108]

[1109] Step 1: tert-Butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate ester

[1110]

[1111] Under O2 atmosphere, to a solution of 4-(trifluoromethyl)-1H-pyrazole (2.43 g, 18 mmol, 3 eq), 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2 g, 6 mmol, 1 eq, CAS2763647-64-7) and pyridine (1.45 mL, 18 mmol, 3 eq) in DMSO (80 mL) was added copper diacetate (2.38 g, 12 mmol, 2 eq), then stirred at 100 ° C for 12 h under O2 (balloon) conditions. The aqueous phase was extracted with EtOAc (200 mL×3). The combined organic phases were 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 conditions) 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] + .

[1112] Step 2: tert-Butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1113]

[1114] 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 at 25 °C for 2 h under H2 atmosphere (balloon). 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] + .

[1115] Step 3: 6-[[4-(Trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[1116]

[1117] 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, yield 96%) as a white solid. MS (ESI): m / z=246.2[M+H] + .

[1118] Similar to building block P.54, the following building blocks were generated in step 1 using the relevant heteroaryl compounds for Chan Lam type coupling.

[1119]

[1120] Structural units P.58 and P.59:

[1121] 6-[[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (P.58)

[1122]

[1123] 6-[[5-(Difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (P.59)

[1124]

[1125] Step 1: 6-[[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate Tert-butyl ester

[1126] and 6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert- Butyl Ester

[1127]

[1128] To a solution of 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6 g, 26.4 mmol, 1 eq, CAS1363381-93-4) 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, CAS157141-27-0). The mixture was stirred at 100 ° C for 12 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (neutral conditions, Welch Ultimate XB-CN 250*50*10um, hexane-EtOH) and concentrated in vacuo to give 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) as a light yellow powder. MS (ESI): m / z=286.0 [M-C4H8+H] +

[1129] and 6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.6 g, 10.54 mmol, yield 40%), which is a light yellow oil. MS (ESI): m / z = 286.0 [M-C4H8+H] + .

[1130] Step 2: 6-[[3-(Difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methyl Benzenesulfonic acid (P.58)

[1131]

[1132] 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 eq) in EtOAc (15 mL) was added p-toluenesulfonic acid (1.72 g, 10 mmol, 1.2 eq). 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 light yellow solid. MS (ESI): m / z=242.1 [M+H] + .

[1133] Step 2: 6-[[5-(Difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-methyl Benzenesulfonic acid (P.59)

[1134]

[1135] 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 eq) in ethyl acetate (20 mL) was added p-toluenesulfonic acid (2.32 g, 13.5 mmol, 1.2 eq). 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 light yellow oil. MS (ESI): m / z=242.1 [M+H] + .

[1136] Structural unit P.62: 6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane; 2,2,2-trifluoroacetic acid

[1137]

[1138] Step 1: 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methylene tert-Butyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1139]

[1140] Under N2, 2-[[5-bromo-3-(difluoromethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (5.3 g, 16.2 mmol, 1 eq, CAS 2416163-95-4), 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (5.97 g, 17.8 mmol, 1 eq, CAS 2416163-95-4) were added. 1,1.1eq, CAS2763647-64-7) and potassium carbonate (4.47g, 32.4mmol, 2eq) in 1,4-dioxane (50mL) and water (5mL) were added cyclopentadien-2,4-diene-1-yl (diphenyl) phosphine; dichloromethane; palladium dichloride; iron (2+) (1.32g, 1.62mmol, 0.1eq, CAS95464-05-4). The mixture was stirred at 100 ° C for 2h under N2 atmosphere. The reaction mixture was poured into water (500mL). The aqueous phase was extracted with EtOAc. The organic phase was washed with brine (600mL), 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 light yellow solid. MS (ESI): m / z = 456.3 [M+H] + .

[1141] Step 2: 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]- tert-Butyl 2-azaspiro[3.3]heptane-2-carboxylate

[1142]

[1143] Under N2 atmosphere, to a solution of 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (7 g, 15.36 mmol, 1 eq) in EtOAc (100 mL) was added Pd / C 10% (2 g, 4.61 mmol, 0.3 eq). The mixture was stirred at 25 ° C for 0.5 h under H2 (15 PSI) atmosphere. The reaction mixture was filtered and concentrated in vacuo to give 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (6 g, 85% yield) as a colorless oil.

[1144] Step 3: 6-[[3-(Difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane; 2,2,2-trifluoromethyl Fluoroacetic acid

[1145]

[1146] 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 eq) 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 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 250*80mm*10um; mobile phase: [water (TFA)-ACN]; B%: 1% to 30%, 20min) to give 6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane; 2,2,2-trifluoroacetic acid (3.94 g, yield 87%) as a white solid. MS (ESI): m / z=228.2[M+H] + .

[1147] The following building blocks were generated analogously to building block P.62 using the relevant heteroaryl bromide for reaction in step 1.

[1148]

[1149] Structural unit P.69: [4-(2-Azaspiro[3.3]heptane-6-ylmethyl)-3-fluoro-phenyl]-imino-oxo-(trifluoromethyl)-λ 6 -sulfane; 4-methylbenzenesulfonic acid

[1150]

[1151] Step 1: 1-Bromo-2-methylsulfinyl-4-(trifluoromethyl)benzene

[1152]

[1153] 1-Bromo-2-methylsulfanyl-4-(trifluoromethyl)benzene (3.7 g, 13.6 mmol, 1 eq, CAS 142994-07-8) was dissolved in trifluoroacetic acid (37 mL, 480 mmol, 35 eq). A solution of hydrogen peroxide (1.15 mL, 13.6 mmol, 1 eq) 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 NaHCO3 aqueous solution. 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 light yellow oil. MS (ESI): m / z=288.9[M+H] + .

[1154] Step 2: [2-Bromo-5-(trifluoromethyl)phenyl]-imino-methyl-oxy-λ 6 -Sulfane

[1155]

[1156] 1-Bromo-2-methylsulfinyl-4-(trifluoromethyl)benzene (2.5 g, 8.7 mmol, 1 eq), amino 4-nitrobenzoate; trifluoromethanesulfonic acid (7.23 g, 21.7 mmol, 2.5 eq, CAS 2055895-59-3), ferrous sulfate (264 mg, 1.74 mmol, 0.2 eq, CAS 7720-78-7) and 1,10-phenanthroline (627 mg, 3.48 mmol, 0.4 eq, CAS 66-71-7) in ACN (20 mL) were loaded into a 30 mL sealed tube. 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 Na SO and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 120 g, acetonitrile in chloroform 0% to 50%) to give [2-bromo-5-(trifluoromethyl)phenyl]-imino-methyl-oxo-λ6-sulfane (900 mg, 3 mmol, 30% yield) as a light yellow solid. MS (ESI): m / z=302 / 304 [M+H] + .

[1157] Step 3: 6-[[2-(Methylsulfonylamino)-4-(trifluoromethyl)phenyl]methylene]-2-azaspiro[3.3]heptyl tert-Butyl 2-oxanecarboxylate

[1158]

[1159] To a stirred suspension 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 (998 mg, 3 mmol, 1 eq, CAS 2763647-64-7), [2-bromo-5-(trifluoromethyl)phenyl]-imino-methyl-oxo-λ6-sulfane (900 mg, 3 mmol, 1 eq) and potassium carbonate (823 mg, 6 mmol, 2 eq) in 1,4-dioxane (30 mL) and water (6 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (364 mg, 0.45 mmol, 0.15 eq, CAS 95408-45-0). The reaction mixture was stirred at 110°C for 48 h. 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 6-[[2-(methylsulfonylamino)-4-(trifluoromethyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (450 mg, 32% yield) as a white solid. MS (ESI): m / z=375.2[M-C4H8+H] + .

[1160] Step 4: 6-[[2-(Methylsulfonimide)-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptyl tert-Butyl 2-oxanecarboxylate

[1161]

[1162] 6-[[2-(Methylsulfonylamino)-4-(trifluoromethyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (320 mg, 0.74 mmol, 1 eq) was dissolved in EtOAc (30 mL) and hydrogenated over palladium / C (79 mg, 0.07 mmol, 0.1 eq) at 22800 mmHg for 10 h. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6-[[2-(methylsulfonylamino)-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] + .

[1163] Step 5: [4-(2-Azaspiro[3.3]heptane-6-ylmethyl)-3-fluoro-phenyl]-imino-oxo-(trifluoromethyl)- Basis)-λ 6 -sulfane; 4-methylbenzenesulfonic acid

[1164]

[1165] p-Toluenesulfonic acid monohydrate (158 mg, 0.83 mmol, 1.2 eq) was added to a stirred solution of tert-butyl 6-[[2-(methylsulfoiminoyl)-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.69 mmol, 1 eq) in EtOAc (30 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by HPLC to give [2-(2-azaspiro[3.3]heptane-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] + .

[1166] Similar to building block P.69, the following building blocks were generated in step 1 using the related bromo-methylthiobenzene compound for reaction.

[1167]

[1168]

[1169] Structural unit P.113: 2,2,2-trifluoroacetic acid; 6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane

[1170]

[1171] To a solution of tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (180 mg, 452 μmol, 1 eq) in dichloromethane (1.5 mL) was added TFA (516 mg, 348 uL, 4.53 mmol, 10 eq). The reaction mixture was stirred at RT for 18 h.

[1172] The reaction mixture was concentrated in vacuo to give 365 mg of the crude desired product as a nearly brown viscous oil with a purity of about 50%. MS (ESI): m / z = 298.2 [M+H] + .

[1173] Step 1: tert-Butyl 6-[(5-bromopyrimidin-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[1174] Potassium carbonate (4.85 g, 35.1 mmol, 2 eq) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1.43 g, 1.76 mmol, 0.1 eq, CAS 95464-05-4) were added 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 eq, CAS 2763647-64-7), 5-bromo-2-iodopyrimidine (5 g, 17.55 mmol, 1 eq) in 1,4-dioxane (75 mL) and water (15 mL) at 20° C. The mixture was stirred at 80° C. for 12 h under N2 atmosphere. 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] + .

[1175] Step 2: tert-Butyl 6-[(5-bromopyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1176] 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 eq) in EtOAc (48 mL) was added PtO (1.63 g, 7.19 mmol, 0.55 eq) at 25° C. under N2. The mixture was stirred at 25° C. for 2.5 h under H2 atmosphere (15 PSI).

[1177] 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] + .

[1178] Step 3: 6-[[5-[1-(trifluoromethyl)vinyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl Tert-Butyl Formate

[1179] To a solution of 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (1.52 g, 6.84 mmol, 1.2 eq, 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 eq), potassium carbonate (1.58 g, 11.4 mmol, 2 eq) in 1,4-dioxane (20 mL) and water (4 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (465 mg, 0.57 mmol, 0.1 eq, CAS 95464-05-4). The mixture was stirred at 80°C for 12 h under N2 atmosphere. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (15 mL x 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, eluted 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] + .

[1180] Step 4: 6-[[5-[1-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-yl Tert-Butyl Formate

[1181] To a solution of 6-[[5-[1-(trifluoromethyl)vinyl]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.05g, 5.35mmol, 1eq) in THF (35mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (2g, 6.95mmol, 1.3eq, CAS10504-60-6). NaHMDS / THF (8.55mL, 8.55mmol, 1.6eq) was added dropwise at 0°C. The reaction mixture was stirred for 1h at 25°C. The reaction mixture was poured into a saturated NH4Cl aqueous solution (80mL) and extracted with ethyl acetate (20mL x 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, eluted with PE / EtOAc (2:1) to obtain a crude product. The crude product was purified by preparative HPLC (column, [Phenomenex luna C18 250*50mm*10um]; mobile phase: [ACN] and [H2O] (conditions: [water (0.225% FA)-ACN], B%: 65% to 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 (1.1 g, 2.78 mmol, yield 52%) as a white solid. MS (ESI): m / z=342.1 [M-C4H8+H] + .

[1182] Similar to building block P.113, the following building blocks were generated using the relevant heteroaryl bromides or heteroaryl chlorides.

[1183]

[1184]

[1185] Structural unit P.119: 6-[[4-(Trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane 4-methylbenzenesulfonic acid

[1186]

[1187] A mixture of 6-[[4-(trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (630 mg, 1.54 mmol) and p-toluenesulfonic acid (317 mg, 1.85 mmol, 1.2 eq) in EtOAc (20 mL) was stirred at 80 ° C for 12 h under a N2 balloon. The reaction mixture was concentrated in vacuo, and the residue was dissolved in H2O (30 mL). The solution was lyophilized to give 6-[[4-(trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane 4-methylbenzenesulfonic acid (738 mg, 1.53 mmol, 97% yield) as a light yellow solid. MS (ESI): m / z=310.1[M+H] + .

[1188] Step 1: tert-Butyl 6-[(4-iodopyrazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[1189] Under O2 atmosphere, 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), boronic 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 O2 atmosphere, the mixture was stirred at 70 ° C 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 a crude product which was purified by preparative HPLC (water (FA)-ACN 55% to 75%) to give the title compound as a white solid (17.7 g, 44.1 mmol, 35.6% yield). MS (ESI): m / z=346.0 [M-C4H8+H] + .

[1190] Step 2: 6-[[4-(Trifluoromethylthio)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[1191] In a sealed tube, 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 trifluoromethanethiol silver (I) (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). 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%) to give the title compound (13.0 mg, 0.03 mmol, 46% yield) as a yellow solid. MS (ESI): m / z=320.1 [M-C4H8+H] + .

[1192] Step 3: tert-6-[[4-(Trifluoromethylsulfanyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Butyl Ester

[1193] 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 H2 balloon (760 mm Hg) 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-C4H8+H] + .

[1194] Step 4: 6-[[4-(Trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[1195] At 0 ° C, sodium periodate (1.13 g, 5.3 mmol, CAS 811-68-7) and ruthenium (III) chloride hydrate (59.7 mg, 0.26 mmol, CAS14898-67-0) were added to a solution of 6-[[4-(trifluoromethylsulfanyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1 g, 2.65 mmol) in 1,2-dichloroethane (4 mL), ACN (4 mL) and water (8 mL), and the mixture was stirred at 25 ° C for 12 h. The reaction was concentrated in vacuo. The residue was purified by preparative HPLC (water (FA)-ACN 50% to 80%) to obtain the title compound (630 mg, 1.54 mmol, 58% yield) as a gray solid. MS(ESI): m / z=354.3[M-C4H8+H] +.

[1196] Structural unit P.123: 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[1197]

[1198] 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) at 25°C was added p-toluenesulfonic acid (388 mg, 2.25 mmol), 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] + .

[1199] Step 1: 6-[[5-(Trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[1200] Potassium carbonate (3.75 g, 27.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (554 mg, 0.68 mmol) were added 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) at 20° C. The reaction mixture was stirred at 100° C. for 12 h under N2. The reaction mixture was filtered and concentrated in vacuo to give a residue which was purified by flash silica gel chromatography (0% to 40% ethyl acetate / petroleum ether eluent) to give a crude product which was further purified by flash silica gel chromatography (0% to 40% ethyl acetate / petroleum ether eluent) 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] + .

[1201] Step 2: 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-yl]- Tert-Butyl Formate

[1202] At 20°C, pyridine (0.42mL, 5.24mmol), boric acid (108mg, 1.75mmol), cupric diacetate (698mg, 3.5mmol) were added to a mixture of 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (600mg, 1.75mmol), cyclopropylboronic acid (600mg, 6.99mmol) in DCE (6mL). The reaction mixture was stirred at 100°C for 16h under O2 (balloon). The reaction mixture was filtered and diluted with water 50mL and extracted with EtOAc150mL (50mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography (0% to 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] + .

[1203] Step 3: 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate Tert-butyl ester

[1204] 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) at 25° C. was added Pd / C (wet, 216 mg, 10%). The reaction mixture was stirred at 25° C. for 0.5 h under H2 (15 Psi). 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-C4H8+H] + .

[1205] Structural unit P.126: [1-(2-azaspiro[3.3]heptane-6-ylmethyl)pyrazol-4-yl]-imino-oxo-(trifluoromethyl)-λ 6 -sulfane; 4-methylbenzenesulfonic acid

[1206]

[1207] Under N2 balloon, a mixture of 6-[[4-(trifluoromethylsulfonyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (650 mg, 1.59 mmol) and p-toluenesulfonic acid (329 mg, 1.91 mmol) in EtOAc (10 mL) was stirred at 80 ° C for 12 h. The reaction mixture was concentrated in vacuo, and the residue was dissolved in H2O (30 mL). The solution was lyophilized to give the title compound (623 mg, 1.3 mmol, 77% yield) as a light yellow oil. MS (ESI): m / z=309.1[M+H] + .

[1208] Step 1: 6-[[4-(trifluoromethylsulfonamidoyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-yl]- Tert-Butyl Formate

[1209] 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)2 (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% to 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] + .

[1210] Structural units 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

[1211]

[1212] A solution of p-toluenesulfonic acid (247 mg, 1.43 mmol) and 6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (510 mg, 1.19 mmol) 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 and lyophilized to give the title compound (550 mg, 1.1 mmol, yield 92%) as a colorless oil. MS (ESI): m / z=328.0[M+H] + .

[1213] Step 1: 6-[[5-(Trifluoromethyl)-1H-pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[1214] To a solution of 3-bromo-5-(trifluoromethyl)-1H-pyrazole (9 g, 41.87 mmol, 1 eq, 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 eq CAS 2763647-64-7), potassium carbonate (11.57 g, 83.7 mmol, 2 eq) in 1,4-dioxane (10 mL) and water (2 mL) at 25 °C was added 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (3.42 g, 4.19 mmol, 0.1 eq, CAS 95464-05-4). Under N2, the reaction mixture was stirred at 80 ° C for 12h. 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 ether: ethyl acetate = 1: 1, Rf = 0.6) to obtain 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (7.0g, 20.3mmol, yield 48%), which is a white solid. MS (ESI): m / z = 288.0 [M-C4H8+H] + .

[1215] Step 2: tert-6-[[5-(Trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Butyl Ester

[1216] To a solution of 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.26 g, 3.67 mmol, 1 eq) in EtOAc (20 mL) was added wet Pd / C (505 mg, 0.65 mmol, 0.18 eq) under N2. The suspension was degassed under vacuum and purged with H2. The reaction was stirred at 25 °C for 0.5 h under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.26 g, 3.65 mmol, 99% yield) as a colorless oil. MS(ESI): m / z=290.0[M-C4H8+H] + .

[1217] Step 3: 6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro [3.3] tert-butyl heptane-2-carboxylate and 6-[[1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2- Azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[1218] At 0 ° C, NaH (2.38 g, 59.5 mmol, 1.5 eq) was added to a solution of 6-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (13.7 g, 39.67 mmol, 1 eq) in THF (278 mL) for 0.5 h. At 20 ° C, 2,2,2-trifluoroethyl trifluoromethanesulfonate (18.41 g, 79.3 mmol, 2 eq, CAS 6226-25-1) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was slowly quenched by 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*10um, 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, yield 11%) 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, yield 51%) as a white solid. MS (ESI): m / z=372.1 [M-C4H8+H] + .

[1219] Step 4: 4-Methylbenzenesulfonic acid; 6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methanesulfonic acid 1-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methane 1-Azaspiro[3.3]heptane (P.156).

[1220] Analogously 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 a solution of 4-methylbenzenesulfonic acid monohydrate in EtOAc at 80 °C for 12 h 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, yield 88%), which is an off-white solid. MS (ESI): m / z=328.0 [M+H] + . (P.156).

[1221] Structural unit P.136: 4-methylbenzenesulfonic acid; 6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane

[1222]

[1223] 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 eq) in EtOAc (10 mL) at 20 ° C, p-toluenesulfonic acid (465 mg, 2.7 mmol, 1.1 eq) was added. 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 and then freeze-dried to obtain 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 light yellow oil. MS (ESI): m / z = 328.0 [M+H] + .

[1224] Step 1: 6-[[5-(Trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

[1225] Under N2 atmosphere, a solution of 4-bromo-5-(trifluoromethyl)-1H-pyrazole (8.35 g, 38.84 mmol, 1 eq, CAS19968-17-3), 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 eq, CAS 2763647-64-7), and Cs2CO3 (77.69 mL, 116.53 mmol, 3 eq) in 2-methylbutan-2-ol (90 mL, 821 mmol, 21 eq) was added Ad2nBuP-Pd-G3 (2.82 g, 3.88 mmol, 0.1 eq, CAS1651823-59-4). 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, desired product Rf=0.3) to obtain 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (9 g, 26.2 mmol, 67% yield) as a yellow oil. MS (ESI): m / z=288.1[M-C4H8+H] + .

[1226] Step 2: 6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[1227] At 0 ° C, to 6- [ [5- (trifluoromethyl) -1H- pyrazole -4- bases] methylene] -2- azaspiro [3.3] heptane -2- carboxylic acid tert-butyl ester (2g, 5.83mmol, 1eq), cesium carbonate (5.69g, 17.48mmol, 3eq) in DMF (20mL) mixture was added trifluoromethanesulfonic acid 2,2,2- trifluoroethyl ester (2.7g, 11.65mmol, 2eq, CAS 6226-25-1) in DMF (2mL) solution. The mixture was stirred at 20 ° C for 12h. The reaction mixture was diluted with water (100mL), and extracted with EtOAc (100mL x3). The combined organic layer was washed with saturated NaCl aqueous solution 50mL (50mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash@Silica Flash Column, 0-28% EtOAc / PE gradient eluent, at 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] + .

[1228] Step 3: 6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[1229] 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 eq) in EtOAc (10 mL) at 20°C was added Pd / C (300 mg, 10%, wet). The reaction mixture was stirred at 20°C for 1 h under H2. 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-C4H8+H] + .

[1230] The following building blocks were generated in analogy to building block P.136 using the relevant heteroaryl halides for cross coupling in step 1.

[1231]

[1232] Structural unit P.137: 2-[6-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-1-yl]ethanol; 4-methylbenzenesulfonic acid

[1233]

[1234] In a sealed vial, 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 eq) and p-toluenesulfonic acid monohydrate (56 mg, 296 μmol, 2.05 eq) in ethyl acetate (0.5 mL) was stirred at reflux for 20 minutes. The suspension was allowed to cool to room temperature and then filtered. The filter cake was washed with ethyl acetate to obtain 2-[6-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-1-yl]ethanol; 4-methylbenzenesulfonic acid as a colorless solid (82 mg, 78% yield). MS (ESI): m / z = 340.2 [M+H] + .

[1235] Step 1: 6-[[3-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methylene]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[1236] A mixture of 6-bromo-3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (565 mg, 2.13 mmol, 1.1 eq, CAS 1934574-07-8), tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (650 mg, 1.94 mmol, 1 eq, CAS 2763647-64-7), chloro(crotyl)(tri-tert-butylphosphine)palladium(II) (38 mg, 96.94 μmol, 0.05 eq, CAS 1334497-00-5) and tripotassium phosphate (823 mg, 3.88 mmol, 2 eq) in 1,4-dioxane (13 mL) and water (1.3 mL) was degassed with argon. The solution was stirred overnight in a sealed vial at 70 ° C. The reaction mixture was poured on 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, which was separated on a 25g column using an MPLC (ISCO) system, eluted with a gradient of n-heptane: ethyl acetate (100: 0 to 0: 100) to obtain 6- [[3- (trifluoromethyl) -1H- pyrrolo [2,3-b] pyridin-6-yl] methylene] -2- azaspiro [3.3] heptane -2- carboxylic acid tert-butyl ester, which was a light yellow solid (0.323 g, 40% yield). MS (ESI): m / z = 394.2 [M + H] + .

[1237] Step 2: 6-[[3-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3] Heptane-2-carboxylic acid tert-butyl ester

[1238] Under N2, wet Pd / C (175 mg, 0.22 mmol, 0.18 eq) was added to a solution of 6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (500 mg, 1.27 mmol, 1 eq) in EtOAc (8 mL). The suspension was degassed under vacuum and purged with H2. Under H2 (15 psi), the reaction mixture was stirred at 25 ° C for 0.5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain 6-[[3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (440 mg, 1.11 mmol, 85% yield) as a light brown solid. MS(ESI): m / z=340.0[M-C4H8+H] + .

[1239] Step 3: 6-[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-(trifluoromethyl)pyrrolo[2-(tert-butyl(dimethyl)silyl)oxyethyl]- [2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[1240] 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 (186mg, 470μmol, 1eq) in DMF (1.5mL) was added NaH (20mg, 517.42μmol, 1.1eq), and the mixture was stirred at this temperature for 30 minutes. After adding (2-bromoethoxy)-tert-butyldimethylsilane (123mg, 111.52uL, 517.42μmol, 1eq), stirring was continued at room temperature overnight. The mixture was poured on a half-saturated NH4Cl aqueous solution and ethyl acetate, and the layers were separated. The water 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 using an MPLC (ISCO) system on a 4 g column, eluting with a gradient of n-heptane:ethyl acetate (100:0 to 65:35) to give tert-butyl 6-[[1-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-3-(trifluoromethyl)pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate as a colorless oil (208 mg, 79% yield). MS (ESI): m / z=554.4 [M+H] + .

[1241] Structural unit P.143: 6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[1242]

[1243] To a solution of tert-butyl 6-[difluoro-[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (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 h. The reaction mixture was concentrated in vacuo to give 6-[difluoro-[6-(trifluoromethyl)-3-pyridinyl]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] + .

[1244] Step 1: tert-Butyl 6-[6-(trifluoromethyl)pyridine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1245] At -78 ° C, to 6- [methoxy (methyl) amino formyl] -2- azaspiro [3.3] heptane -2- carboxylic acid tert-butyl ester (4.3g, 15.1mmol, CAS2428601-18-5) and 5- bromo -2- (trifluoromethyl) pyridine (6.83g, 30.2mmol, CAS436799-32-5) in THF (100mL) solution n-BuLi (18.2mL, 45.4mmol) was added for 1h. The reaction mixture was stirred at 30 ° C for 12h. The reaction mixture was poured into saturated NH4Cl aqueous solution (500mL) and extracted with ethyl acetate. The organic layer was washed with brine. The residue was purified by flash chromatography on silica gel, eluted with PE / EtOAc (2: 1), to obtain the title compound (1400mg, 3.78mmol, 25% yield), which was a brown solid. MS(ESI): m / z=315.1[M-C4H8+H] + . 1 HNMR (400 MHz, methanol-d4) δ = 9.17 (s, 1H), 8.49 (dd, J = 1.5, 8.3 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 4.11-3.99 (m, 3H), 3.84 (s, 2H), 2.65-2.48 (m, 4H), 1.43 (s, 9H).

[1246] Note that the positional isomer was also produced: tert-butyl 6-[2-(trifluoromethyl)pyridine-4-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate (1100 mg, 2.97 mmol, 20% yield) 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).

[1247] Step 2: tert-6-[difluoro-[6-(trifluoromethyl)-3-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Butyl Ester

[1248] Under N2 atmosphere, DAST (5mL, 37.8mmol) was added dropwise to a solution of 6-[6-(trifluoromethyl)pyridine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (750mg, 2.03mmol) in DCM (5mL) at 0°C. The reaction mixture was stirred at 25°C for 12h. The reaction mixture was added dropwise to a saturated NaHCO3 aqueous solution (200mL) and extracted with DCM (50mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (water (FA)-ACN 58% to 88%) to give the title compound (510mg, 1.3mmol, 64% yield) as a light yellow solid. MS (ESI): m / z=337.0[M-C4H8+H] + ; 1 H 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).

[1249] Analogously to building block P.143, the following building blocks were generated using the relevant heteroaryl bromides. In some cases, alternative salts (eg trifluoroacetate, xylenesulfonate, hydrochloride) were also used.

[1250]

[1251] Structural units P.139 and P.140: 6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid and 6-[(1S)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[1252] (Enantiomers were randomly assigned)

[1253]

[1254] A solution of tert-butyl 6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]methyl]-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 RT, the obtained precipitate was filtered, washed with EtOAc and dried in vacuo to give the title compound P.139 (237 mg, 0.38 mmol, yield 55%) as a white solid. MS (ESI): m / z=285.2[M+H] + Deprotection of the other enantiomer was carried out in a similar manner to give the title compound P.140 (241 mg, 0.38 mmol, yield 58%) as a white solid. MS (ESI): m / z=285.2 [M+H] + .

[1255] Step 1: 6-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethylidene]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[1256] To a stirred solution of 2,2,6,6-tetramethylpiperidine (4.31 mL, 25.6 mmol) in THF (75 mL) at -30°C was added n-BuLi (2.5 M in hexanes) (10.2 mL, 25.6 mmol) under Ar. 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-dioxaborolane-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 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (4.5 g, 21.3 mmol) in 15 mL of anhydrous THF was added dropwise at -78 ° C, and the reaction mixture was allowed to warm and stirred at room temperature overnight. The reaction was quenched with water, and the mixture was concentrated in vacuo. The residue was separated 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 obtain the title compound (3.1 g, 8.88 mmol, 41% yield), which was a white solid. MS (ESI): m / z = 294.2 [M-C4H8 + H] + .

[1257] Step 2: 6-[1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethylidene]-2-azaspiro[3.3]heptane-2-yl]- Tert-Butyl Formate

[1258] To a stirred suspension of 2-chloro-4-methyl-5-(trifluoromethyl)pyridine (1.36 g, 6.93 mmol, CAS 780802-36-0), 6-[1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethylidene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (2.2 g, 6.3 mmol) and cesium carbonate (4.1 g, 12.6 mmol) in anhydrous 1,4-dioxane (110 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (771 mg, 0.94 mmol, CAS 95464-05-4). Under an argon atmosphere, the mixture was stirred at 80 ° C for 48 h. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The obtained residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give a crude product, which was purified by column chromatography (hexane / MTBE 10% to 23%) to obtain the title compound (700 mg, 1.83 mmol, yield 28%) as a light yellow solid. MS (ESI): m / z=327.2 [M-C4H8+H] + .

[1259] Step 3: 6-[1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate Tert-butyl ester

[1260] In an autoclave, a stirred mixture of tert-butyl 6-[1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethylidene]-2-azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.83 mmol) and Pd / C (5%) (200 mg) in EtOAc (50 mL) was hydrogenated at 15200 mmHg (20 bar) at 25° C. for 24 h. 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-C4H8+H] +A mixture of enantiomers 6-[1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (680 mg, 1.77 mmol) was separated by chiral chromatography to give: 6-[(1S)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester ( 270 mg, 0.7 mmol, yield 40%) (or enantiomer), retention time (min): 11.2; and tert-butyl 6-[(1R)-1-[4-methyl-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 0.65 mmol, yield 37%) (or enantiomer), retention time (min): 13.9.

[1261] Structural unit P.146: 2-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine; 4-methylbenzenesulfonic acid

[1262]

[1263] 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 eq) in EtOAc (9.8 mL) was added p-toluenesulfonic acid monohydrate (749 mg, 4 mmol, 3.5 eq). 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]heptane-6-ylmethyl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine; 4-methylbenzenesulfonic acid (729 mg, 1.14 mmol, 99% yield) as a light yellow solid. MS (ESI): m / z=297.2[M+H] + .

[1264] Step 1: tert-6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethylene)-2-azaspiro[3.3]heptane-2-carboxylic acid Butyl Ester

[1265] 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 eq, CAS 2763647-64-7) and 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.51 mmol, 1 eq, CAS 335654-06-3), K2CO3 (2.7 g, 19.54 mmol, 3 eq) in 1,4-dioxane (10 mL) and water (2 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (531 mg, 0.65 mmol, 0.1 eq, CAS 95464-05-4). Under N2 balloon (760mmHg), the mixture was stirred at 80°C for 12h. The reaction mixture was concentrated in vacuo and purified by column chromatography (SiO2, 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 (650mg, 1.99mmol, 27% yield) as a pink solid. MS (ESI): m / z = 327.2 [M+H] + .

[1266] Step 2: tert-Butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethyl)-2-azaspiro[3.3]heptane-2-carboxylate ester

[1267] Under N2, wet Pd / C (100 mg, 0.6 mmol, 0.3 eq) was added to a solution of 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethylene)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (650 mg, 1.99 mmol, 1 eq) in EtOAc (10 mL). The suspension was degassed under vacuum and purged with H2. The reaction was stirred at 25 ° C for 1 h under H2 (15 psi) to give a black suspension. The precipitate was filtered out and the filtrate was dried in a vacuum to give 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (450 mg, 1.37 mmol, 68% yield) as a yellow solid. MS (ESI): m / z = 329.3 [M+H] + .

[1268] Step 3: 6-[(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate Tert-butyl ester

[1269] 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 eq) in ACN (20 mL) was added NIS (534 mg, 2.38 mmol, 1.2 eq) 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 filter 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] + .

[1270] Step 4: 6-[[5-iodo-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-aza tert-Butyl spiro[3.3]heptane-2-carboxylate

[1271] At 0 ° C, 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 eq) in THF (5 mL) was added NaH (74 mg, 1.85 mmol, 1.2 eq). The mixture was stirred at 0 ° C for 0.5 h. 4-methylbenzenesulfonyl chloride (587 mg, 3.08 mmol, 2 eq) was added. The mixture was stirred at 25 ° C for 12 h to obtain a gray suspension. At 0 ° C, the reaction mixture was quenched by adding saturated NH4Cl aqueous solution 10 mL 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 eluting 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 light yellow solid. MS (ESI): m / z=455.1 [M+H] + .

[1272] Step 5: 6-[[5-(Trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3] Heptane-2-carboxylic acid tert-butyl ester

[1273] To a solution of 6-[[5-iodo-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid benzyl tert-butyl ester (900 mg, 1.48 mmol, 1 eq) and copper (282 mg, 4.44 mmol, 3 eq) in DMF (1 mL) was added diphenyl(trifluoromethyl)sulfonium; trifluoromethanesulfonate (1.2 g, 2.96 mmol, 2 eq, CAS147531-11-1). 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 Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography 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 light 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 light brown oil. MS (ESI): m / z=397.1 [M+H] + .

[1274] Structural unit P.161: 6-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-(trifluoromethyl)-1,2-benzoxazole; 4-methylbenzenesulfonic acid

[1275]

[1276] 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 eq) and p-toluenesulfonic acid monohydrate (1 g, 5.26 mmol, 1.49 eq) 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]heptane-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] + .

[1277] Step 1: 6-[[3-Fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-yl]- Tert-Butyl Formate

[1278] 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 (3.72 g, 11.1 mmol, 1 eq, CAS 2763647-64-7), 1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethanone (3.01 g, 11.1 mmol, 1 eq, CAS 617706-18-0) and potassium carbonate (3.07 g, 22.19 mmol, 2 eq) in 1,4-dioxane (70 mL) and water (7 mL) was added 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1.36 g, 1.66 mmol, 0.15 eq, CAS 95464-05-4). The mixture was stirred at 80 ° C for 18 h. The reaction mixture was concentrated under vacuum. The residue was stirred with EtOAc (200 mL) and Na2SO4. The mixture was filtered and concentrated in vacuo. The crude product was purified by FC to obtain 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, yield 58%) as a light red solid. MS (ESI): m / z=300.0[M+H] + .

[1279] FC conditions: column Interchim, SiO2 (120 g), hexane / ethyl acetate (0% to 27%), flow rate = 80 mL / min.

[1280] Step 2: 6-[[3-Fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate Tert-butyl ester

[1281] To a solution of 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3 g, 7.51 mmol, 1 eq) in EtOAc (150 mL) was added Pd / C (10%) (300 mg). The mixture was hydrogenated (in an autoclave) at 3800 mmHg and then allowed to stir at room temperature for 36 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.0 g, 7.47 mmol, 90% yield) as a light brown oil. MS (ESI): m / z=346.0[M-C4H8+H] + .

[1282] Step 3: 6-[[3-Fluoro-4-[N-hydroxy-C-(trifluoromethyl)carbonimidoyl]phenyl]methyl]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[1283] 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 eq) in pyridine (40 mL) was added hydroxylamine; hydrochloride (0.93 g, 13.45 mmol, 1.8 eq). The mixture was stirred at 50 ° C for 18 h. The mixture was concentrated in vacuo. The residue was stirred with water (50 mL) for 2 h. The aqueous layer was decanted and the obtained residue was partitioned between TBME (100 mL) and water (15 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo with toluene to give tert-butyl 6-[[3-fluoro-4-[N-hydroxy-C-(trifluoromethyl)carboimidoyl]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] + .

[1284] Step 4: 6-[[3-(Trifluoromethyl)-1,2-benzoxazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate Tert-butyl ester

[1285] By 6-[[3-fluoro-4-[N-hydroxy-C-(trifluoromethyl) carbonimidoyl] phenyl] methyl] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (2.8g, 6.72mmol, 1eq) and potassium carbonate (1.39g, 10.09mmol, 1.5eq) in anhydrous DMF (60mL) mixture was stirred at 80 ° C for 18h. The reaction mixture was poured into water (300mL) and extracted with EtOAc / TBME (100mL / 100mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to obtain 6-[[3-(trifluoromethyl) -1,2-benzooxazol-6-yl] methyl] -2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.5g, 3.78mmol, 53% yield). MS(ESI): m / z=341.0[M-C4H8+H] + .

[1286] Structural unit P.162: 1-(2-azaspiro[3.3]heptane-6-ylmethyl)-4-[1-(trifluoromethyl)cyclopropyl]pyridin-2-one; 4-methylbenzenesulfonic acid

[1287]

[1288] To a solution of tert-butyl 6-[[2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridinyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 0.56 mmol, 1 eq) in EtOAc (3 mL) was added p-toluenesulfonic acid (115 mg, 0.67 mmol, 1.2 eq). 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, and the residue was then lyophilized to give 1-(2-azaspiro[3.3]heptane-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] + .

[1289] Step 1: tert-Butyl 6-[(4-bromo-2-oxo-1-pyridinyl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[1290] To a solution of 4-bromo-1H-pyridin-2-one (5 g, 28.74 mmol, 1 eq) 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 eq, CAS 2763647-64-7), pyridine (4.55 g, 57.47 mmol, 2 eq), boronic acid (1.78 g, 28.74 mmol, 1 eq) and Cu(OAc)2 (7.75 g, 38.79 mmol, 1.35 eq). The mixture was stirred at 70 °C under O2 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-pyridinyl)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] + .

[1291] Step 2: tert-Butyl 6-[(4-bromo-2-oxo-1-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1292] 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 eq) in EtOAc (6 mL) was added PtO (112 mg, 0.49 mmol, 0.3 eq) under N. The suspension was degassed under vacuum and purged with H. The reaction was stirred at 25 °C for 0.5 h under H (15 psi). 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-pyridinyl)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] + .

[1293] Step 3: 6-[[2-oxo-4-[1-(trifluoromethyl)vinyl]-1-pyridinyl]methyl]-2-azaspiro[3.3] Heptane-2-carboxylic acid tert-butyl ester

[1294] To a solution of tert-butyl 6-[(4-bromo-2-oxo-1-pyridinyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.78 mmol, 1 eq) and 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (208 mg, 0.94 mmol, 1.2 eq, CAS 1011460-68-6), K2CO3 (324 mg, 2.35 mmol, 3 eq) in 1,4-dioxane (3 mL) and water (0.600 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (63.87 mg, 0.08 mmol, 0.1 eq, CAS 95464-05-4). The mixture was degassed with N2 and stirred at 80 ° C for 12h under N2 atmosphere. 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 obtain 6-[[2-oxo-4-[1-(trifluoromethyl)vinyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (360mg, 0.9mmol, yield 115%), which is a yellow oil. MS (ESI): m / z=343.1[M-C4H8+H] + .

[1295] Step 4: 6-[[2-oxo-4-[1-(trifluoromethyl)cyclopropyl]-1-pyridinyl]methyl]-2-azaspiro[3.3] Heptane-2-carboxylic acid tert-butyl ester

[1296] To a solution of 6-[[2-oxo-4-[1-(trifluoromethyl)vinyl]-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (320mg, 0.8mmol, 1eq) in THF (3mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (323mg, 1.12mmol, 1.4eq, CAS10504-60-6). At 0°C, NaHMDS / THF (1.36mL, 1.36mmol, 1.69eq) was added dropwise. Under N2 atmosphere, the reaction mixture was stirred for 1h at 25°C. The reaction mixture was slowly added to 6mL saturated NH4Cl aqueous solution. The mixture was added to 6mL water and extracted with EtOAc (4mL x 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-pyridinyl]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] + .

[1297] Similar to building block P.162, the following building blocks were generated in step 1 using the relevant heteroaryl compounds for Chan Lam type couplings.

[1298]

[1299] Structural unit P.164: 5-(2-azaspiro[3.3]heptane-6-ylmethyl)-3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole; 2,2,2-trifluoroacetic acid

[1300]

[1301] To a solution of tert-butyl 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (130 mg, 335 μmol, 1 eq) in dichloromethane (1 mL) was added TFA (382 mg, 258.53 uL, 3.36 mmol, 10 eq). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo to give 5-(2-azaspiro[3.3]heptane-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] + .

[1302] Step 1: 6-[2-[(Z)-[amino-[1-(trifluoromethyl)cyclopropyl]methylene]amino]oxy-2-oxo-ethyl tert-Butyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1303] A solution of 2-(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-yl)acetic acid (2.5 g, 9.79 mmol, 1 eq, CAS 1251002-39-7) and CDI (1905 mg, 11.75 mmol, 1.2 eq) in DMF (30 mL) was stirred at room temperature for 3 h. N'-hydroxy-1-(trifluoromethyl)cyclopropanecarboximidamide (1.64 g, 9.79 mmol, 1 eq, 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] + .

[1304] Step 2: 6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-5-yl]methyl]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[1305] 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 eq) and tetrabutylammonium fluoride / THF (1.85 mL, 1.85 mmol, 0.5 eq) 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, yield 56.3%) as a pale yellow solid. MS (ESI): m / z=388.1[M+H] + .

[1306] Structural unit P.165: 3-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid

[1307]

[1308] To a solution of tert-butyl 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (370 mg, 0.96 mmol, 1 eq) in EtOAc (4 mL) was added p-toluenesulfonic acid (197 mg, 1.15 mmol, 1.2 eq). The mixture was stirred at 80 ° C for 12 h. The reaction mixture was concentrated under vacuum. Deionized water (3 mL) was added to the residue and then lyophilized to give 3-(2-azaspiro[3.3]heptane-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole; 4-methylbenzenesulfonic acid (406 mg, 0.88 mmol, 82% yield) as a white solid. MS (ESI): m / z=288.1[M+H] + .

[1309] Step 1: tert-Butyl 6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate

[1310] To a solution of tert-butyl 6-(cyanomethylene)-2-azaspiro[3.3]heptane-2-carboxylate (2.66 g, 11.35 mmol, 1 eq, CAS 1428726-12-8) in methanol (26 mL) was added Pd / C (wet) (886 mg, 1.14 mmol, 0.1 eq) at 25°C. The reaction was stirred at 25°C for 0.5 h under an H2 atmosphere (H2 balloon). The reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl 6-(cyanomethylene)-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-C4H8+H] + .

[1311] Step 2: tert-Butyl 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate ester

[1312] At 25 ° C, triethylamine (856 mg, 8.46 mmol, 2 eq) was added to a mixture of hydroxylamine; hydrochloride (588 mg, 8.46 mmol, 2 eq) in ethanol (10 mL). After 0.5 h, 6- (cyanomethyl) -2- azaspiro [3.3] heptane -2- carboxylic acid tert-butyl ester (1 g, 4.23 mmol, 1 eq) 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 x 3). The combined extracts were concentrated in vacuo to obtain 6- [(2Z) -2- amino -2- hydroxyimino-ethyl] -2- azaspiro [3.3] heptane -2- carboxylic acid tert-butyl ester (1.03 g, 3.82 mmol, 90% yield) as a colorless oil. MS (ESI): m / z = 270.2 [M+H] + .

[1313] Step 3: 6-[(2Z)-2-amino-2-[1-(trifluoromethyl)cyclopropanecarbonyl]oxyiminoethyl]-2-nitrogen Heterospiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[1314] A solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (589 mg, 3.82 mmol, 1 eq, CAS 277756-46-4) and CDI (744 mg, 4.59 mmol, 1.2 eq) in DMF (10 mL) was stirred at room temperature for 2 h. 6-[(2Z)-2-amino-2-hydroxyimino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.03 g, 3.82 mmol, 1 eq) 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]oxyimino-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-C4H8+H] + .

[1315] Step 4: 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazol-3-yl]methyl]-2-azaspiro [3.3] tert-Butyl heptane-2-carboxylate

[1316] By 6-[2-[(Z)-[amino-[1-(trifluoromethyl)cyclopropyl]methylene]amino]oxy-2-oxo-ethyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (210mg, 0.52mmol, 1eq) and tetrabutylammonium fluoride / THF (0.13mL, 0.13mmol, 0.25eq) solution in THF (2mL) at 70 DEG C stir 1h.Mixture is added to 2mL water and extracted with EtOAc (15mL x 3).Organic phase is concentrated in vacuo.Mixture is purified by preparative HPLC, to obtain 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,2,4-oxadiazole-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (220mg, 0.57mmol, yield 109%), it is yellow solid. MS(ESI): m / z=332.1[M-C4H8+H] + .

[1317] Structural unit P.167: 4-methylbenzenesulfonic acid; 6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane

[1318]

[1319] 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 eq) in EtOAc (6 mL) was added p-toluenesulfonic acid monohydrate (444 mg, 2.34 mmol, 3 eq). The mixture was stirred at 30 ° C for 72 h. The reaction mixture was concentrated under vacuum. 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 0-2-9min 0-70% H20 / MEOH / 0.1NH4OH Flow rate 30ml / min ((loading pump 4ml MEOH) Target mass 337 Column: XBridge BEH C18 100*19mm, 5microM.

[1320] Step 1: 4-[1-(Trifluoromethyl)cyclopropyl]-1H-imidazole

[1321] 2-Bromo-1-[1-(trifluoromethyl)cyclopropyl]ethanone (0.5 g, 2.16 mmol, 1 eq, CAS 1382999-80-5) was added to formamide (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 the aqueous phase was then adjusted to pH 8 with a 1 M NaOH aqueous solution. The aqueous phase was extracted twice with dichloromethane. The organic phase was dried, concentrated in vacuo and purified by HPLC to obtain 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 0-2-10min 0-75% H20 / ACN, flow rate 30ml / min ((loading pump 4mACN) target mass 177 column: Chromatorex C18 SMB100-5T 100*19mm, 5micro.

[1322] Step 2: 6-[[5-[1-(trifluoromethyl)cyclopropyl]imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-yl]- Tert-Butyl Formate

[1323] At room temperature, to a mixture of 4-[1-(trifluoromethyl)cyclopropyl]-1H-imidazole (800mg, 3.41mmol, 1eq), cesium carbonate (2.21g, 6.81mmol, 2eq) in DMF (15mL) was added 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.04g, 3.41mmol, 1eq, CAS2740574-92-7). The reaction mixture was stirred at 50°C for 18h. The reaction mixture was diluted with EtOAc (100ml) and washed with water (2x 200ml), brine (100ml). 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] + .

[1324] FC conditions: Interchim; 40 g SiO2, petroleum ether / MtBE, wherein MtBE is 15-100%, further MtBE / methanol, wherein methanol is 0-10%, flow rate = 40 mL / min, Rv = 21-23 CV.

[1325] Structural unit P.168: 6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[1326]

[1327] 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 eq) in EtOAc (34 mL) was added p-toluenesulfonic acid (1.77 g, 10.3 mmol, 1.2 eq). 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] + .

[1328] Step 1: tert-Butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate ester

[1329] To a solution of 3-chloro-6-(trifluoromethyl)pyridazine (30 g, 164 mmol, 1 eq, CAS 258506-68-2) in 1,4-dioxane (500 mL) and water (50 mL) were 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 eq, CAS 2763647-64-7), potassium carbonate (45.43 g, 328 mmol, 2 eq) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (13.41 g, 16.44 mmol, 0.1 eq, CAS 95464-05-4). Under N2 atmosphere, the reaction mixture was stirred at 100 ° C for 12h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluted with PE / EtOAc (3: 1) (TLC, PE: EtOAc = 3: 1, Rf = 0.40) to obtain a crude product. The crude product was washed with PE (300mL). After filtration, the solid was collected and concentrated in vacuo to obtain 6- [[6- (trifluoromethyl) pyridazine -3- base] methylene] -2- azaspiro [3.3] heptane -2- carboxylic acid tert-butyl ester (46g, 121mmol, yield 73%), which is a yellow solid. MS (ESI): m / z = 300.3 [M-C4H8 + H] + .

[1330] Step 2: tert-Butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1331] 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 eq) in EtOAc (600 mL) at 25°C was added Pd / C (wet) (6.33 g, 5.95 mmol, 0.11 eq). The reaction was stirred at 25°C for 1 h under H2 atmosphere (H2 balloon). 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] + .

[1332] Step 3: tert-Butyl 6-[6-(trifluoromethyl)pyridazine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylateTo a solution of 6-[[6-(trifluoromethyl)pyridazine-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (15 g, 41.9 mmol, 1 eq) in 1,4-dioxane (300 mL) was added SeO2 (27.94 g, 251.8 mmol, 6 eq). The reaction mixture was stirred at 90 ° C for 12 h under N2 atmosphere. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-30% AcOEt / petroleum ether eluent, petroleum ether / AcOEt=1 / 1, Rf=0.5) and concentrated in vacuo to give 6-[6-(trifluoromethyl)pyridazine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (4.3 g, 11.58 mmol, 27% yield) as a yellow solid. MS(ESI): m / z=316.0[M-C4H8+H] + .

[1333] Step 4: tert-6-[difluoro-[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid Butyl Ester

[1334] At 0 ° C under N2 atmosphere, DAST (30 mL, 227 mmol, 28 eq) was added dropwise to a solution of 6-[6-(trifluoromethyl)pyridazine-3-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3 g, 8.08 mmol, 1 eq) in DCM (30 mL). The reaction mixture was stirred at 25 ° C for 12 h. The reaction mixture was added dropwise to a saturated NaHCO3 aqueous solution (500 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na2SO4, 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] + .

[1335] Analogously to building block P.168, the following building blocks were generated in step 1 using the relevant heteroaryl bromide or heteroaryl chloride for cross coupling.

[1336]

[1337]

[1338] Structural unit P.178: 6-(2-azaspiro[3.3]heptane-6-ylmethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine; 4-methylbenzenesulfonic acid

[1339]

[1340] A mixture of p-toluenesulfonic acid (364 mg, 2.12 mmol, 3 eq) 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 eq) 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]heptane-6-ylmethyl)-2-(trifluoromethyl)imidazo[1,2-a]pyrimidine; 4-methylbenzenesulfonic acid (178 mg, 0.38 mmol, yield 53%) as a light brown solid. MS (ESI): m / z=297.0[M+H] + .

[1341] FC conditions: Interchim, 40 g SiO2, MTBE / methanol (0% to 60%), flow rate = 40 ml / min, 16, 1-18, 3 CV.

[1342] Step 1: tert-Butyl 6-[(2-aminopyrimidin-5-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[1343] 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1.87 g, 2.3 mmol, 0.2 eq, CAS 95408-45-0), potassium carbonate (3.17 g, 22.99 mmol, 2.0 eq), 2-amino-5-bromopyrimidine (2 g, 11.49 mmol, 1 eq) and 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.85 g, 11.49 mmol, 1 eq, 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 h. 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 light yellow solid. MS (ESI): m / z=303.2 [M+H] + .

[1344] FC conditions: Interchim, 120 g SiO2, chloroform / acetonitrile (0% to 100%), flow rate = 80 ml / min, 22,6-28,3 CV.

[1345] Step 2: tert-Butyl 6-[(2-aminopyrimidin-5-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[1346] 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 eq) and Pd / C, 10% (158 mg, 0.15 mmol, 0.03 eq) in EtOAc (80 mL) was hydrogenated at 19000 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-C4H8+H] + .

[1347] Step 3: 6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane- 2-tert-Butyl formate

[1348] A solution of 6-[(2-aminopyrimidin-5-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.5 g, 4.93 mmol, 1 eq) and 3-bromo-1,1,1-trifluoroacetone (940 mg, 4.93 mmol, 1 eq) 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 between 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 obtain 6-[[2-(trifluoromethyl)imidazo[1,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (340.0 mg, 0.86 mmol, 17% yield) as a yellow solid. MS (ESI): m / z = 397.2 [M+H] + .

[1349] FC conditions: Interchim: 40 g SiO2, chloroform / ACN, wherein ACN is 0-40%, flow rate = 40 mL / min, Rv = 10-12 CV.

[1350] Synthesis of non-commercial building blocks:

[1351] C.184

[1352] tert-Butyl 2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-7-azaspiro[3.5]nonane-7-carboxylate

[1353]

[1354] 2,2,6,6-tetramethylpiperidine (16mL, 100mmol, 1.2eq, CAS 768-66-1) is dissolved in THF (100ml) and cooled to -30°C under Ar atmosphere. Butyl lithium solution (2.5M) (40.12mL, 100mmol, 1.2eq) is added dropwise, and the reaction mixture is stirred for 30min at the same temperature. The reaction mixture is cooled to -78°. A solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolan (24.63g, 91.93mmol, 1.1eq, CAS 78782-17-9) in THF (20ml) is added dropwise. After stirring for 30min, a solution of 2-oxo-7-azaspiro [3.5] nonane-7-formic acid tert-butyl ester (20g, 83.57mmol, 1eq, CAS203661-69-2) in THF (30ml) was added dropwise at -78°C. The reaction mixture was allowed to slowly warm up to room temperature and stirred overnight. The mixture was cooled to 0°C, and NH4Cl aqueous solution (30mL) was added dropwise. After stirring for 1h, the resulting mixture was filtered, and the solvent was concentrated in vacuo. H2O (100mL) was added to residue, and water layer was extracted with EtOAc (250mL). Organic phase was washed with brine (250mL), anhydrous Na2SO4 was used, and it was concentrated in vacuo. The crude product was purified by column chromatography (Interchim, 330 g SiO2, hexane / MTBE (0% to 15% to 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] + .

[1355] C.9

[1356] 1-Bromo-3-dimethylphosphoryl-5-(trifluoromethyl)benzene

[1357] To a solution of dimethylphosphine oxide (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 at 25 °C for 48 h under argon. 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] + .

[1358] C.17

[1359] 3-Bromo-5-[1-(trifluoromethyl)cyclopropyl]-4H-1,2,4-triazole

[1360] To a solution of 3-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4-triazole (5.07 g, 27 mmol, 1 eq) in DMF (25 mL) was added NBS (10.65 g, 59.82 mmol, 2.2 eq). The mixture was stirred at 60 ° C for 15 h. The reaction mixture was poured into EtOAc and washed with water, 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, EtOAc 0% to 20% 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] + .

[1361] Step 1: (NE)-N-(dimethylaminomethylene)-1-(trifluoromethyl)cyclopropanecarboxamide

[1362] 1-(Trifluoromethyl)cyclopropanecarboxamide (5 g, 32 mmol, 1 eq, CAS 1628184-67-7) was dissolved in N,N-dimethylformamide dimethyl acetal (27.24 g, 228 mmol, 7 eq). The mixture was stirred at room temperature for 6 h. The reaction mixture was poured into EtOAc and washed with water, 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] + .

[1363] Step 2: 3-[1-(Trifluoromethyl)cyclopropyl]-1H-1,2,4-triazole

[1364] To an ice-cold solution of (NE)-N-(dimethylaminomethylene)-1-(trifluoromethyl)cyclopropanecarboxamide (6.5 g, 28 mmol, 1 eq) in acetic acid (18 mL) was added hydrazine hydrate (1.55 g, 30.9 mmol, 1.1 eq). The mixture was stirred at 50 °C for 2 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. NaOH 1N (pH 7 to 8) was added. The mixture was washed with water, 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] + .

[1365] C.72

[1366] 1-Bromo-4-dimethylphosphoryl-2-(trifluoromethyl)benzene

[1367] To a solution of dimethylphosphine oxide (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 for 24 h under Ar. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by FC (eluted with petroleum ether / MtBE, wherein MtBE was 0% to 100%, further eluted with MtBE / methanol, wherein methanol was 0% to 25%) 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] + .

[1368] C.115

[1369] 2-Bromo-3-methoxy-5-(trifluoromethyl)pyrazine

[1370] At 25 ° C, to a mixture of 3-methoxy-5-(trifluoromethyl)pyrazine-2-amine (1.6 g, 8.28 mmol, CAS1823377-58-7) 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). Under N2 atmosphere, the reaction mixture was stirred at 70 ° C 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% to 10%) and concentrated in vacuo at room temperature to obtain the title compound (800 mg, 3.11 mmol, yield 38%), which was a colorless oil. MS (ESI): m / z=256.9[M+H] + . Note: The product is volatile.

[1371] C.122

[1372] 3-Bromo-5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazole

[1373] At 0°C, a solution of 5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazole-3-amine (2.3g, 12mmol, CAS1001354-47-7) in ACN (40mL) was added dropwise to a solution of isoamyl nitrite (1.55g, 13.2mmol) in ACN (5mL). The reaction mixture was stirred at 0°C for 1h. At 0°C, CuBr2 (1.61g, 7.22mmol) was added to the mixture, and the resulting mixture was stirred at 20°C for 12h. 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 (740mg, 2.9mmol, 24.1% yield) as a light green solid. MS (ESI): m / z=257.2[M+H] + .

[1374] C.124

[1375] 2-Chloro-5-[1-(trifluoromethyl)cyclopropyl]pyrazine

[1376] 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 solution of NaHMDS (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 Na2SO4, and concentrated in vacuo. Purification by FC (SiO2; PE / EtOAc) gave the title compound (1.5 g, 63% yield) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.53 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 1.48-1.42 (m, 2H), 1.36 ppm (br s, 2H).

[1377] Step 1: 2-Chloro-5-[1-(trifluoromethyl)vinyl]pyrazine

[1378] 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (1266mg, 1.55mmol, CAS 95464-05-4) was added to a solution of 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (3.44g, 15.5mmol, CAS1011460-68-6) and 2-bromo-5-chloropyrazine (3g, 15.5mmol), potassium carbonate (4.29g, 31mmol) in 1,4-dioxane (60mL) and water (6mL). Under N2 atmosphere, the mixture was stirred at 80°C for 12h, filtered and concentrated in vacuo. Purification by FC (SiO2; PE) gave the title compound (1.6g, 49% yield) as a yellow solid. MS (ESI): m / z = 209.3 [M + H] +

[1379] C.125

[1380] 3-Bromo-6-[1-(trifluoromethyl)cyclopropyl]pyridazine

[1381] 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 distributed between EtOAc (20 mL) and water (40 mL). The organic phase was concentrated in vacuo. Purification by preparative HPLC gave the title compound (280 mg, 78% yield) as a white solid. MS (ESI): m / z=267.3[M+H]+.

[1382] Step 1: 3-Bromo-6-[1-(trifluoromethyl)vinyl]pyridazine

[1383] To 4,4,6-trimethyl-2-[1-(trifluoromethyl) vinyl]-1,3,2-dioxaborinane (560mg, 2.52mmol, CAS1011460-68-6) and 3,6-dibromopyridazine (500mg, 2.1mmol), potassium carbonate (581mg, 4.2mmol) in 1,4-dioxane (10mL) and water (2mL) solution add 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (172mg, 0.210mmol, CAS 95464-05-4). Under N2 atmosphere, the mixture was stirred at 80°C for 3h. The reaction mixture was diluted with water (100mL) and extracted with EtOAc (200mL x 3). The organic phases merged were washed with salt water, dried over Na2SO4, 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] + .

[1384] C.128

[1385] 4,5-Dibromo-2-(2,2,2-trifluoroethyl)triazole

[1386] To a solution of 4,5-dibromo-2H-triazole (5g, 22mmol, CAS22300-52-3) in ACN (50mL) is added cesium carbonate (7.18g, 22mmol). At 0°C, trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (5.12g, 22.0mmol, CAS 6226-25-1) is added dropwise. The reaction mixture is stirred at room temperature for 16h. The reaction mixture is poured into water. EtOAc is added, and the water layer is extracted with EtOAc. The organic layer is washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, PE / EtOAc 0% to 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 (400 MHz, chloroform-d) δ = 4.95 (q, J = 7.9 Hz, 2H).

[1387] C.145

[1388] 2-[[5-Bromo-3-(trifluoromethyl)pyrazolo[3,4-c]pyridin-1-yl]methoxy]ethyl-trimethyl-silane

[1389] 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 eq, CAS 2097610-93-8), copper (I) iodide (11.74 g, 61 mmol, 5 eq), potassium fluoride (3.58 g, 61 mmol, 5 eq) and trifluoromethyltrimethylsilane (8.77 g, 61 mmol, 5 eq) 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 out 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 light yellow viscous oil. MS (ESI): m / z=396.0 [M+H] + FC conditions: Interchim, 120 SiO2, hexane / ethyl acetate (0% to 22%), flow rate = 80 ml / min.

[1390] C.149

[1391] 1-(4-Bromophenyl)sulfonyl-3-(trifluoromethyl)azetidine

[1392] At 25 ° C, DIEA (3.46 mL, 20 mmol, 5 eq) was added to a solution of 4-bromobenzenesulfonyl chloride (1.33 g, 5.2 mmol, 1.3 eq) and 3- (trifluoromethyl) azetidine (500 mg, 4 mmol, 1 eq, CAS1221349-18-3) in DMF (5 mL). 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] + .

[1393] C.157

[1394] 4-Chloro-2-methylsulfonyl-1-(trifluoromethyl)benzene

[1395] At 0 ° C, sodium periodate (3.68g, 17.21mmol, 2eq) and ruthenium chloride (III) hydrate (19.4mg, 0.09mmol, 0.01eq) were added to a solution of 4-chloro-2-methylsulfanyl-1-(trifluoromethyl)benzene (1.95g, 8.6mmol, 1eq, CAS1428234-60-9) in 1,2-dichloroethane (20mL)-ACN (20mL)-water (40mL). The mixture was stirred for 12h at 25 ° C. The reaction mixture was diluted with water (40ml) and extracted with 50mL DCM, 2x 50mL EtOAc. The combined organic layer was washed with 75mL brine, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = .3: 1) to give 4-chloro-2-methylsulfonyl-1-(trifluoromethyl)benzene (1.8 g, 6.96 mmol, 72% yield) as a white solid. 1H 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).

[1396] C.158

[1397] 7-Chloro-3-(trifluoromethyl)imidazo[1,2-a]pyrimidine

[1398] In an autoclave, hydrogen fluoride (7.45 mL, 368.53 mmol, 30 eq) was placed in pre-cooled (liquid N2) lithium; 7-chloroimidazo[1,2-a]pyrimidine-3-carboxylate (2.5 g, 12.28 mmol, 1 eq, CAS 2839138-71-3). Tetrafluoro-λ4-sulfane (2.65 g, 24.57 mmol, 2 eq, 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 and 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] + .

[1399] FC conditions: 1) Interchim, 12g SiO2, chloroform / acetonitrile (0% to 10%), flow rate = 80ml / min, 6,2-9,6CV; 2) Interchim, 40g SiO2, hexane / isopropanol (5% to 100%), flow rate = 40ml / min, RV = 7,8-31,1CV.

[1400] C.160

[1401] 2-bromo-5-[3-(trifluoromethyl)azetidine-1-yl]pyrazine. To a solution of 3-(trifluoromethyl)azetidine; hydrochloride (500mg, 3.08mmol, 1eq, CAS1221272-90-7) and DIEA (1.55g, 15.3mmol, 5eq) in DMF (10mL) was added 2,5-dibromopyrazine (951mg, 4mmol, 1.3eq). The resulting solution was stirred at 100 °C for 2h. 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 (SiO2, 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] + .

[1402] C.171

[1403] 3-Bromo-1-(2,2,2-trifluoroethyl)-1,2,4-triazole

[1404] At 0 ° C, NaH (3.89 g, 97 mmol, 1.8 eq) was added to a solution of 3-bromo-1H-1,2,4-triazole (8 g, 54 mmol, 1 eq, CAS 7343-33-1) in THF (80 mL). After 0.5 h, 2,2,2-trifluoroethyl trifluoromethanesulfonate (25.1 g, 108.14 mmol, 2 eq, 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 Na2SO4, 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 (6 g, 26.09 mmol, yield 48%) as a brown oil. MS (ESI): m / z=229.9 [M+H] + .

[1405] C.195

[1406] 2-Chloro-4-[1-(trifluoromethyl)cyclopropyl]pyrimidine

[1407] To a solution of 2-chloro-4-[1-(trifluoromethyl)vinyl]pyrimidine (1 g, 4.79 mmol, 1 eq) in THF (5 mL) at 20°C was added diphenyl(methyl)sulfonium tetrafluoroborate (2.07 g, 7.19 mmol, 1.5 eq, CAS 10504-60-6) and NaHMDS (7.67 mL, 7.67 mmol, 1.6 eq). The mixture was stirred at 20°C for 12 h under N2. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 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] + .

[1408] Step 1: 2-Chloro-4-[1-(trifluoromethyl)vinyl]pyrimidine

[1409] To a solution of 4-bromo-2-chloropyrimidine (2 g, 10.34 mmol, 1 eq, CAS 885702-34-1), 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (2.29 g, 10.34 mmol, 1 eq, CAS 1011460-68-6) and K2CO3 (2.85 g, 20.68 mmol, 2 eq) in 1,4-dioxane (40 mL) and water (4 mL) was added 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (844 mg, 1.03 mmol, 0.1 eq, CAS 95464-05-4). The mixture was stirred at 25°C for 12 h. The reaction mixture was concentrated under vacuum. The residue was purified by column chromatography (SiO2, 0% to 3% ethyl acetate / petroleum ether eluent, 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. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: (i) 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, 1,2-dihydropyridinyl, [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 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halogenated-C 1-6 -alkyl)-(3- to 6-membered heterocyclic)-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and groups R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and 4- to 6-membered heterocyclic groups, wherein the 4- to 6-membered heterocyclic groups are optionally halogenated 1-6 - substituted with alkyl substituents; X is selected from O and NH; or (ii) A is pyridyl; R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and groups R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl; R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and 4- to 6-membered heterocyclic groups, wherein the 4- to 6-membered heterocyclic groups are optionally halogenated 1-6 - substituted with an alkyl substituent; and X is selected from O and NH; or (iii) A is phenyl; R 1 Selected from (C 1-6 -alkyl)2PO- and group R 2 Selected from hydrogen, halogen, cyano, C 1-6 -alkyl and halo-C 1-6 -alkyl; R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and 4- to 6-membered heterocyclic groups, wherein the 4- to 6-membered heterocyclic groups are optionally halogenated 1-6 - substituted with an alkyl substituent; and X is selected from O and NH; R 4 and R 5 are each independently selected from hydrogen, halogen and C 1-6 -alkyl; and B is selected from:

2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: A is a 9-membered bicyclic heteroaryl group containing 1 to 5 heteroatoms selected from N, O and S, and the remaining ring atoms are carbon; R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and groups R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; X is selected from O and NH; or R 4 and R 5 are each independently selected from hydrogen, halogen and C 1-6 -alkyl; and B is selected from:

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: (i) A is phenyl; R 1 Selected from (C 1-6 -alkyl)2PO- and group R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl; R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and (halo-C 1-6 -alkyl)-(4- to 6-membered heterocyclyl); and X is selected from O and NH; or (ii) A is pyridyl; R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group R 2 Selected from hydrogen, halogen, halo-C 1-6 - alkyl and cyano; R 3 Selected from C 1-6 -alkyl and halo-C 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, 1,2-dihydropyridinyl, [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 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halogenated-C 1-6 -alkyl)-(3- to 6-membered heterocyclic)-, halo-C 1-6 -Alkoxy and groups R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R 3 For halogenated-C 1-6 -alkyl; and X is selected from O and NH.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 3, wherein: (i) A is phenyl; R 1 Selected from (C 1-6 -alkyl)2PO- and groups R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl; R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and X is O; or (ii) A is pyridyl; R 1 Selected from halogen and halo-C 1-6 -alkyl; R 2 is selected from hydrogen and halogen; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 For halogenated-C 1-6 -alkyl; and R 2 For hydrogen.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein: (i) A is phenyl; R 1 Selected from (CH3)2PO- and groups R 2 is selected from hydrogen, fluorine and CF3; R 3 is selected from methyl and CF3; and X is O; or (ii) A is pyridyl; R 1 Selected from fluorine and CF3; R 2 is selected from hydrogen and fluorine; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 is CF3; and R 2 For hydrogen.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, 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, 1,2-dihydropyridinyl, [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 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halogenated-C 1-6 -alkyl)-(3- to 6-membered heterocyclic)-, halo-C 1-6 -Alkoxy and groups R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R 3 For halogenated-C 1-6 -alkyl; and X is selected from O and NH.

7. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein B is selected from:

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

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

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

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: (i) A is phenyl; R 1 Selected from (C 1-6 -alkyl)2PO- and groups R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl; R 3 Selected from C 1-6 -alkyl, halo-C 1-6 -alkyl and (halo-C 1-6 -alkyl)-(4- to 6-membered heterocyclyl); and X is selected from O and NH; or (ii) A is pyridyl; R 1 Selected from halogen, C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkyl, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, halo-C 1-6 -alkoxy, (C 1-6 -alkyl)2PO- and group R 2 Selected from hydrogen, halogen, halo-C 1-6 - alkyl and cyano; R 3 Selected from C 1-6 -alkyl and halo-C 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, 1,2-dihydropyridinyl, [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 Selected from C 1-6 -alkoxy, halo-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 3-6 -cycloalkyl-, halo-C 1-6 -alkyl-C 3-6 -cycloalkyl-, (halogenated-C 1-6 -alkyl)-(3- to 6-membered heterocyclic)-, halo-C 1-6 -Alkoxy and groups R 2 Selected from hydrogen, halogen, cyano, oxo, C 1-6 -alkyl and halo-C 1-6 -alkyl; R 3 For halogenated-C 1-6 -alkyl; X is selected from O and NH; R 4 and R 5 both are hydrogen; or R 4 and R 5 Both are halogens; or R 4 C 1-6 -alkyl and R 5 is hydrogen; and B is selected from:

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein: (i) A is phenyl; R 1 Selected from (C 1-6 -alkyl)2PO- and group R 2 is selected from hydrogen, halogen and halo-C 1-6 -alkyl; R 3 Selected from C 1-6 -alkyl and halo-C 1-6 -alkyl; and X is O; or (ii) A is pyridyl; R 1 Selected from halogen and halo-C 1-6 -alkyl; R 2 is selected from hydrogen and halogen; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 For halogenated-C 1-6 -alkyl; and R 2 is hydrogen; R 4 and R 5 both are hydrogen; and B is selected from:

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 14, wherein: (i) A is phenyl; R 1 Selected from (CH3)2PO- and groups R 2 is selected from hydrogen, fluorine and CF3; R 3 is selected from methyl and CF3; and X is O; or (ii) A is pyridyl; R 1 Selected from fluorine and CF3; R 2 is selected from hydrogen and fluorine; or (iii) A is selected from pyrazinyl and pyrazolyl; R 1 is CF3; and R 2 is hydrogen; R 4 and R 5 both are hydrogen; and B is selected from:

16. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein the 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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]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-(trifluoromethylsulfonamidoyl)-2-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-pyridinyl)methyl]-2-azaspiro[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-(trifluoromethylsulfonamidoyl)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-(trifluoromethylsulfonamidoyl)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)]-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(S)]-trifluoromethylsulfonamidoyl)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)]-trifluoromethylsulfonamidoyl)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)]-trifluoromethylsulfonamidoyl)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)]-trifluoromethylsulfonamidoyl)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)]-trifluoromethylsulfonamidoyl)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)]-trifluoromethylsulfonamidoyl)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)]-trifluoromethylsulfonamidoyl)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-(methylsulfonamidoyl)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-pyridinyl]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-pyridinyl)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-pyridinyl)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-pyridinyl]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-pyridinyl]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-pyridinyl]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-pyridinyl]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-pyridinyl]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-pyridinyl]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-pyridinyl)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-pyridinyl)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-pyridinyl)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-pyridinyl]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)benzo[d]isoxazol-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-pyridinyl]methyl]-2-azaspiro[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-trifluoromethanesulfonylpyrazol-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-pyridinyl]methyl]-2-azaspiro[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-(trifluoromethylsulfonamidoyl)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-methylsulfonyl-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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]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-pyridinyl]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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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-methylsulfonyl-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-pyridinyl]methyl]-2-azaspiro[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)benzo[d]isoxazol-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-pyridinyl]methyl]-2-azaspiro[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-pyridinyl]methyl]-2-azaspiro[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.

17. A method for producing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, the method comprising: (a) an amine of formula 1, wherein R 1 , R 2 , A and B as defined in any one of claims 1 to 16, With 6-(1,2,4-triazole-1-carbonyl)-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (2), react 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) A compound of formula 1a, wherein R 1 , R 2 , A and B as defined in any one of claims 1 to 16, In the presence of a base, To form the compound of formula (I).

18. A compound of formula (I) according to any one of claims 1 to 16, which is manufactured according to the process of claim 17.

19. Compounds of formula (I) according to any one of claims 1 to 16 for use as therapeutically active substances.

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 treating or preventing diseases and disorders associated with MAGL 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 treating or preventing diseases and disorders associated with MAGL in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) according to any one of claims 1 to 16.

25. The invention as hereinbefore described.

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