Heterocyclic Compounds

Abstract

The present invention relates to a compound represented by the general formula (I) TIFF2024540874000289.tif35165 The present invention provides new MAGL inhibitors having the formula:

Description

[Technical field]

[0001] The present invention relates to organic compounds useful for the treatment or prevention in mammals, in particular monoacylglycerol lipase (MAGL) inhibitors useful for the treatment or prevention of diseases or conditions associated with MAGL, 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, inflammatory bowel syndrome, intestinal motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, and / or visceral pain. [Background technology]

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

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

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

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

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

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

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

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

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

[0011] In a first aspect, the present invention provides a compound of formula (I) [ka] where the variables are as defined herein.

[0012] In a further aspect, the present invention provides methods of preparing compounds of formula (I) described herein.

[0013] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, when prepared according to the processes described herein.

[0014] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0015] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, and a therapeutically inert carrier.

[0016] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment or prophylaxis of a disease or condition associated with MAGL. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0018] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, linear or branched saturated hydrocarbon group having 1 to 12 carbon atoms. In some preferred embodiments, an alkyl group is a group having 1 to 6 carbon atoms ("C 1~6 In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, but non-limiting, examples of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl.

[0019] The term "thiadiazolyl" includes thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl.

[0020] The term "triazolyl" includes 2H-triazolyl and 1H-1,2,4-triazolyl, as well as 4H-1,2,4-triazolyl.

[0021] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. An alkoxy group contains 1 to 12 carbon atoms, unless otherwise specified. In some preferred embodiments, an alkoxy group contains 1 to 6 carbon atoms ("C 1~6 In other embodiments, alkoxy groups contain 1-4 carbon atoms. In yet other embodiments, alkoxy groups contain 1-3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0022] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0023] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C 3-10"Cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbocyclic rings having two common carbon atoms, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and a spirocyclic moiety, i.e., the two rings are joined through one common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. A particularly preferred, but non-limiting example of cycloalkyl is cyclopropyl.

[0024] The term "aryl" refers to a group having 6 to 14 total ring members ("C6-C 14 Aryl) is preferably a monocyclic, bicyclic, or tricyclic carbocyclic ring system having 6 to 12 ring members, more preferably 6 to 10 ring members, in which at least one ring of the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred, but non-limiting example of aryl is phenyl.

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

[0026] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.

[0027] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced by a halogen atom, most preferably fluoro. Particularly preferred, but non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, (1,1,1-trifluoropropan-2-yl)oxy, and 2,2,2-trifluoroethoxy.

[0028] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, especially hydrochloric acid, as well as organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. Furthermore, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, and the like.

[0029] The compounds of formula (I) may contain several asymmetric centers and may exist as optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereomeric racemates or mixtures of diastereomeric racemates.

[0030] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom may be of the "R" or "S" configuration.

[0031] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

[0032] The term "treatment" as used herein includes: (1) suppressing a condition, disorder or symptom (e.g., in the case of maintenance treatment, arresting, reducing or delaying the onset or recurrence of at least one clinical symptom or subclinical disease thereof); and / or (2) alleviating symptoms (i.e., causing regression of the condition, disorder or symptom, or at least one of its clinical symptoms or subclinical symptoms). The benefit to the treated patient is either statistically significant or at least perceptible to the patient or the physician. However, it will be understood that when a pharmaceutical agent is administered to a patient to treat a disease, the outcome may not necessarily be an effective treatment.

[0033] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition developing in a mammal, particularly a human suffering from or susceptible to the condition, disorder or condition, but who has not yet experienced or exhibited clinical symptoms or asymptomatic symptoms of the condition, disorder or condition.

[0034] The term "neuroinflammation" as used herein refers to acute and chronic inflammation of nervous tissue, which is the main tissue component of two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branching peripheral nerves of the peripheral nervous system (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Acute neuroinflammation usually occurs immediately after injury to the central nervous system, for example as a result of traumatic brain injury (TBI).

[0035] The term "traumatic brain injury" ("TBI", also known as "intracranial injury") relates to damage to the brain due to an external mechanical force, such as rapid acceleration or deceleration, impact, blast, or penetration by a projectile.

[0036] The term "neurodegenerative disease" refers to diseases associated with the progressive loss of neuronal structure or function, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0037] The term "mental disorder" (also called mental illness or mental disorder) refers to a behavior or mental pattern that can cause distress or impaired functioning in life. Such characteristics may occur as persistent, relapsing, and remitting, or as a single episode. Examples of mental disorders include, but are not limited to, anxiety and depression.

[0038] The term "pain" refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy-induced neuropathy, phantom limb pain, and psychogenic pain. A particular example of pain is neuropathic pain, which is caused by injury or disease affecting any part of the nervous system involved in bodily sensations (i.e., the somatosensory system). In one embodiment, the "pain" is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, the "pain" is chemotherapy-induced neuropathy.

[0039] The term "neurotoxicity" refers to toxicity in the nervous system. It occurs when exposure to natural or man-made toxic substances (neurotoxins) alters the normal activity of the nervous system, causing damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, exposure to substances used in chemotherapy, radiation treatment, drug therapy, drug abuse, and organ transplantation, as well as neurotoxicity resulting from exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some naturally occurring substances.

[0040] The term "cancer" refers to a disease characterized by the presence of a neoplasm or tumor, resulting from the abnormal and uncontrolled proliferation of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, colon carcinoma, and ovarian cancer.

[0041] The term "mammal" as used herein includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term "mammal" refers to humans.

[0042] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, wherein X 1 , X 2 , X 3 , and X 4 are each independently selected from CH and N; W is selected from O and NH; Z is selected from CH2, CH2CH2, NH, CH2O, and OCH2; L is a covalent bond, CH2, NR 4 , NHCH2, CH2NH, NHCO, CONH, CH2O, OCH2, O, NHSO2, SO2, SO2NH, [ka] and CHNHSO, A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, [1,2,4]triazolo[1,5-a]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1,2-dihydropyridyl, and bicyclo[1.1.1]pentanyl; B is, [ka] is selected from R 1 is hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkyl-NHC(O)-, carbamoyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, (C1-C6-alkyl)2PO-, and groups [ka] C3 to C 10 -cycloalkyl may be optionally substituted with one halo-C1-C6-alkyl substituent, R 2 and R 3 is independently selected from hydrogen, halogen, cyano, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy; R 4 is selected from hydrogen and C1-C6-alkyl, R 5 is C3~C 10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl.

[0043] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X 1, X 2 , X 3 , and X 4 are each independently selected from CH and N; W is selected from O and NH; Z is selected from CH2, CH2CH2, NH, CH2O, and OCH2; L is a covalent bond, CH2, NR 4 , NHCH2, CH2NH, NHCO, CONH, CH2O, OCH2, O, NHSO2, SO2, SO2NH, [ka] and CHNHSO, A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, [1,2,4]triazolo[1,5-a]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1,2-dihydropyridyl, and bicyclo[1.1.1]pentanyl; B is, [ka] is selected from R 1 is hydrogen, cyano, C1-C6-alkyl, C1-C6-alkyl-NHC(O)-, carbamoyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, and groups [ka] C3 to C 10 -cycloalkyl may be optionally substituted with one halo-C1-C6-alkyl substituent, R 2 and R 3is independently selected from hydrogen, halogen, cyano, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy; R 4 is selected from hydrogen and C1-C6-alkyl, R 5 is C3~C 10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl.

[0044] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is selected from CH and N; W is selected from O and NH; Z is selected from O, CH2, NH, CH2O, and OCH2; L is a covalent bond, CH2, NR 4 , NHCH2, CH2NH, NHCO, CONH, CH2O, OCH2, O, NHSO2, and SO2NH; A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, and oxazolyl; B is, [ka] is selected from R 1 is halogen, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, and groups [ka] is selected from R 2 and R 3 is independently selected from hydrogen, halogen, cyano, and halo-C1-C6-alkyl; R 4is selected from hydrogen and C1-C6-alkyl, R 5 is selected from C1-C6-alkyl and halo-C1-C6-alkyl.

[0045] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein X is N.

[0046] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein X is CH.

[0047] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein B is [ka] is selected from.

[0048] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein B is [ka] It is.

[0049] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is CH; B is, [ka] is selected from.

[0050] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is CH; B is, [ka] is selected from.

[0051] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is CH; B is, [ka] It is.

[0052] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: B is, [ka] is selected from X 2 and X 3 are both CH X 4 is selected from CH and N.

[0053] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: B is, [ka] and X 3 is CH.

[0054] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: B is, [ka] and X 4 is selected from CH and N.

[0055] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein Z is selected from O, CH2, and NH.

[0056] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein Z is selected from O, CH2, CH2CH2, CH2O, and NH.

[0057] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein Z is CH2.

[0058] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein Z is CH2CH2.

[0059] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein Z is CHO.

[0060] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein Z is O.

[0061] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein Z is NH.

[0062] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: B is, [ka] and X is CH; Z is selected from O, CH2, and NH.

[0063] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: B is, [ka] and X is CH; Z is CH2.

[0064] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: L is a covalent bond, CH2, NR 4 , NHCH2, CH2NH, NHCO, CH2O, O, and SO2NH; R 4 is selected from hydrogen and C1-C6-alkyl.

[0065] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: L is CH2, NR 4 , NHCH2, CH2NH, NHCO, CH2O, O, and SO2NH; R 4 is selected from hydrogen and C1-C6-alkyl.

[0066] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein L is a covalent bond.

[0067] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: L is CH2, NR 4 , and O; R 4 is hydrogen.

[0068] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein L is CH2.

[0069] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: L is a covalent bond, CH2, NR 4 , NHCH2, CH2NH, NHCO, CH2O, O, SO2NH, NHSO2, SO2, [ka] and CH2NHSO2; R 4 is selected from hydrogen and C1-C6-alkyl.

[0070] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: L is CH2, SO2, NR 4 and O; R 4 is hydrogen.

[0071] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: W is selected from O and NH; A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, and oxazolyl; R1 is halogen, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, and groups [ka] is selected from R 2 is selected from hydrogen, halogen, cyano and halo-C1-C6-alkyl, R 3 is hydrogen, R 5 is selected from C1-C6-alkyl and halo-C1-C6-alkyl.

[0072] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: W is selected from O and NH; A is selected from pyridyl, phenyl, pyrimidinyl, and pyridazinyl; R 1 is halo-C1-C6-alkyl and groups [ka] is selected from R 2 is selected from hydrogen and cyano; R 3 is hydrogen, R 5 is selected from C1-C6-alkyl and halo-C1-C6-alkyl.

[0073] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: W is selected from O and NH; A is selected from pyridyl, phenyl, pyrimidinyl, and pyridazinyl; R 1 is CF3 and the group [ka] is selected from R 2 is selected from hydrogen and cyano; R 3 is hydrogen, R 5 is selected from methyl and CF3.

[0074] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: A is C6~C 14 -aryl, R 1 is halo-C1-C6-alkyl, R 2 is cyano, R 3 is hydrogen.

[0075] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: A is phenyl; R 1 is halo-C1-C6-alkyl, R 2 is cyano, R 3 is hydrogen.

[0076] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: A is phenyl; R 1 is CF3, R 2 is cyano, R 3 is hydrogen.

[0077] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: W is selected from O and NH; A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, [1,2,4]triazolo[1,5-a]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1,2-dihydropyridyl, and bicyclo[1.1.1]pentanyl; R 1 is hydrogen, cyano, C1-C6-alkyl, C1-C6-alkyl-NHC(O)-, carbamoyl, halogen, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, and groups [ka] C3 to C 10 -cycloalkyl may be optionally substituted with one halo-C1-C6-alkyl substituent, R 2 is selected from hydrogen, halogen, cyano, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy, R 3 is selected from hydrogen and C1-C6-alkyl, R 5 is C3~C 10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl.

[0078] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: W is selected from O and NH; A is selected from pyridyl, phenyl, triazolyl, pyrazolyl, pyrimidinyl, and pyridazinyl; R 1is halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and the group [ka] is selected from R 2 is selected from hydrogen, halogen, C1-C6-alkyl and cyano; R 3 is hydrogen, R 5 is selected from C1-C6-alkyl and halo-C1-C6-alkyl.

[0079] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: W is selected from O and NH; A is selected from pyridyl, phenyl, pyrimidinyl, triazolyl, pyrazolyl, and pyridazinyl; R 1 is CF3, CF3O and the group [ka] is selected from R 2 is selected from hydrogen, fluoro, methyl and cyano; R 3 is hydrogen, R 5 is selected from methyl and CF3.

[0080] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is selected from CH and N; W is selected from O and NH; Z is selected from O, CH2, NH, CH2O, and OCH2; L is a covalent bond, CH2, NR 4, NHCH2, CH2NH, NHCO, CH2O, O, and SO2NH; A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, and oxazolyl; B is, [ka] is selected from R 1 is halogen, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, and groups" [ka] is selected from R 2 is selected from hydrogen, halogen, cyano and halo-C1-C6-alkyl, R 3 is hydrogen, R 4 is selected from hydrogen and C1-C6-alkyl, R 5 is selected from C1-C6-alkyl and halo-C1-C6-alkyl.

[0081] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is CH; W is selected from O and NH; Z is selected from O, CH2, and NH; L is CH2, NR 4 , and O; A is selected from pyridyl, phenyl, pyrimidinyl, and pyridazinyl; B is, [ka] is selected from R 1 is halo-C1-C6-alkyl and groups [ka] is selected from R 2 is selected from hydrogen and cyano; R 3 is hydrogen, R 4 is hydrogen, R 5 is selected from C1-C6-alkyl and halo-C1-C6-alkyl.

[0082] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is CH; W is selected from O and NH; Z is selected from O, CH2, and NH; L is CH2, NR 4 , and O; A is selected from pyridyl, phenyl, pyrimidinyl, and pyridazinyl; B is, [ka] is selected from R 1 is CF3 and the group [ka] is selected from R 2 is selected from hydrogen and cyano; R 3 is hydrogen, R 4 is hydrogen, R 5 is selected from methyl and CF3.

[0083] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is CH; Z is CH2; L is CH2, A is C6~C 14 -aryl, B is, [ka] and R 1 is halo-C1-C6-alkyl, R 2 is cyano, R 3 is hydrogen.

[0084] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is CH; Z is CH2; L is CH2, A is phenyl; B is, [ka] and R 1 is halo-C1-C6-alkyl, R 2 is cyano, R 3 is hydrogen.

[0085] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X is CH; Z is CH2; L is CH2, A is phenyl; B is, [ka] and R 1 is CF3, R 2 is cyano, R 3 is hydrogen.

[0086] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X 1 , X 2 , X 3 , and X 4 are each independently selected from CH and N; W is selected from O and NH; Z is selected from CH2, CH2CH2, NH, CH2O, and OCH2; L is a covalent bond, CH2, NR 4 , NHCH2, CH2NH, NHCO, CH2O, O, SO2NH, NHSO2, SO2, [ka] and CH2NHSO2; A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, [1,2,4]triazolo[1,5-a]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1,2-dihydropyridyl, and bicyclo[1.1.1]pentanyl; B is, [ka] is selected from R 1is hydrogen, halogen, cyano, C1-C6-alkyl, C1-C6-alkyl-NHC(O)-, carbamoyl, halogen, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, (C1-C6-alkyl)2PO-, and groups [ka] C3 to C 10 -cycloalkyl may be optionally substituted with one halo-C1-C6-alkyl substituent, R 2 is selected from hydrogen, halogen, cyano, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy, R 3 is selected from hydrogen and C1-C6 alkyl; R 4 is selected from hydrogen and C1-C6-alkyl, R 5 is C3~C 10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl.

[0087] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X 1 , X 2 , X 3 , and X 4 are each independently selected from CH and N; W is selected from O and NH; Z is selected from CH2, CH2CH2, NH, CH2O, and OCH2; L is a covalent bond, CH2, NR 4 , NHCH2, CH2NH, NHCO, CH2O, O, SO2NH, NHSO2, SO2, [ka] and CH2NHSO2; A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, [1,2,4]triazolo[1,5-a]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1,2-dihydropyridyl, and bicyclo[1.1.1]pentanyl; B is, [ka] is selected from R 1 is hydrogen, cyano, C1-C6-alkyl, C1-C6-alkyl-NHC(O)-, carbamoyl, halogen, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C 10 -cycloalkyl, and groups [ka] C3 to C 10 -cycloalkyl may be optionally substituted with one halo-C1-C6-alkyl substituent, R 2 is selected from hydrogen, halogen, cyano, oxo, C1-C6-alkyl, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy, R 3 is selected from hydrogen and C1-C6 alkyl; R 4 is selected from hydrogen and C1-C6-alkyl, R 5 is C3~C 10 -cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl.

[0088] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X 2and X 3 are both CH X 4 is selected from CH and N; W is selected from O and NH; Z is selected from O, CH2CH2, CH2O, CH2, and NH; L is CH2, SO2, NR 4 , and O; A is selected from pyridyl, phenyl, triazolyl, pyrazolyl, pyrimidinyl, and pyridazinyl; B is, [ka] is selected from R 1 is halo-C1-C6-alkyl, halo-C1-C6-alkoxy, and the group [ka] is selected from R 2 is selected from hydrogen, halogen, C1-C6-alkyl and cyano; R 3 is hydrogen, R 4 is hydrogen, R 5 is selected from C1-C6-alkyl and halo-C1-C6-alkyl.

[0089] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein: X 2 and X 3 are both CH X4 is selected from CH and N; W is selected from O, CH2CH2, CHO, and NH; Z is selected from O, CH2, and NH; L is CH2, SO2, NR4 , and O; A is selected from pyridyl, phenyl, triazolyl, pyrazolyl, pyrimidinyl, and pyridazinyl; B is, [ka] is selected from R 1 is CF3, CF3O, and the group [ka] is selected from R 2 is selected from hydrogen, fluoro, methyl and cyano; R 3 is hydrogen, R 4 is hydrogen, R 5 is selected from methyl and CF3.

[0090] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, selected from: 2-[6-(4-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-fluoro-2-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[7-[methyl-[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-keto-2,5,7-triazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[7-[2-(trifluoromethyl)pyrimidin-4-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[7-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(4-fluoro-2-mesyl-phenoxy)-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-triflylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(2,5-dichlorophenoxy)-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-fluoro-2-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-mesyl-3-(trifluoromethyl)benzyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-mesyl-3-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-fluoro-5-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.5]nonan-7-yl]-3-(trifluoromethoxy)benzenesulfonamide; 2-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]-3-(trifluoromethyl)benzenesulfonamide; 2-[6-(3-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-mesylbenzyl)-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-fluorophenyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-fluoro-2-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrazin-2-yl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.5]nonan-7-yl]-3-(trifluoromethoxy)benzenesulfonamide; 2-[6-[[1-(trifluoromethyl)cyclopropyl]amino]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-fluoro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-mesyl-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-(trifluoromethyl)pyrimidin-5-yl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[4-mesyl-3-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-[4-mesyl-3-(trifluoromethyl)phenoxy]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-(trifluoromethyl)cyclopropyl]methylamino]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(5-chloro-2-mesyl-phenoxy)-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-mesylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-fluoro-2-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethyl)azetidin-1-yl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]-3-(trifluoromethyl)benzenesulfonamide; 2-[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)oxazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(5-fluoro-3-pyridyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]amino]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-fluoro-5-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6#R!)-6-[(4-methylsulfonylphenyl)methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6#S!)-6-[(4-methylsulfonylphenyl)methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-N-[1-(trifluoromethyl)cyclopropyl]-2-azaspiro[3.3]heptane-6-carboxamide; 2-[6-(4-mesylbenzyl)-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.5]nonan-6-one; N-[2-(6-keto-7-oxa-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]-3-(trifluoromethyl)benzenesulfonamide; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-7-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-(3-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(4-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-(3-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(4-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-(3-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-2,7-diazaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[3-fluoro-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[4-fluoro-2-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-(4-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[2-[3-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-fluoro-2-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-triflylbenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3,5-difluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(4-mesylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3,5-difluoro-2-pyridyl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(3-mesylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-mesylbenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(5-chloro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-fluoro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-methylsulfonyl-3-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-methylsulfonyl-3-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-methylsulfonyl-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-methylsulfonyl-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(2-methylsulfonylphenyl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[2-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[4-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[3-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-(1-methylcyclopropyl)-6-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2,6-diazaspiro[3.3]heptane-2-sulfonamide; 2-[7-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[[5-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 6-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-2,6-diazaspiro[3.3]heptane-2-sulfonamide; 2-[2-[3-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[4-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[2-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; N-methyl-2-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methyl]benzamide; 2-[6-[5-(trifluoromethyl)-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrazin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrimidin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-oxo-8-oxa-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]-3-(trifluoromethyl)benzenesulfonamide; 5-[[(6S)-2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]oxy]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6S)-2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6R)-2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6S)-2-(6-oxo-8-oxa-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]oxy]-2-(trifluoromethyl)pyridine-4-carbonitrile; 2-[6-[(4-cyclopropylsulfonylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 3-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; 2-[7-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 4-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-(3-triflylbenzyl)-2-azaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6S)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6S)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-methylsulfonyl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carbonitrile; 4-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethoxy)benzamide; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethoxy)benzamide; 2-[6-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 1-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]pyrazole-4-carbonitrile; 2-[6-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 6-Oxo-N-[[6-(trifluoromethyl)-3,4-diazatricyclo[7.1.1.03,7]undeca-4,6-dien-1-yl]methyl]-2,5-diazaspiro[3.4]octane-2-carboxamide; 3-Fluoro-4-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]benzonitrile; 2-[6-[[5-(trifluoromethylsulfonyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethylsulfonyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(methylsulfonimidoyl)-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(difluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-fluoro-4-(trifluoromethylsulfonyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-oxo-5-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-3-(trifluoromethyl)pyridine-2-carbonitrile; 2-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-fluoro-4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-fluoro-4-(trifluoromethylsulfonyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-methylsulfonyl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(4-cyclopropylsulfonylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 4-[[2-(6-oxo-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 5-[[2-(6-oxo-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 5-[[2-(6-oxo-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carbonitrile; 3-Fluoro-4-[[2-(6-oxo-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]benzonitrile; 2-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[3-(trifluoromethoxy)phenyl]sulfonyl-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[4-(trifluoromethyl)phenyl]sulfonyl-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[3-(trifluoromethyl)phenyl]sulfonyl-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethoxy)phenyl]sulfonimidoyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-3-pyridyl]oxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 4-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; 4-[[2-(6-oxo-8-oxa-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; 2-[6-[(5-chloro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-chloro-1,3-dimethyl-pyrazol-4-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; 2-[6-[4-(trifluoromethyl)thiazol-2-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-fluoro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3-chloro-5-fluoro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-(trifluoromethyl)thiazol-5-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(5-fluoro-3-pyridyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(1H-pyrazolo[4,3-b]pyridin-5-ylmethyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-keto-5-(trifluoromethyl)-1H-pyridin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(2-tert-butylthiazol-5-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)isothiazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(4-cyclobutylthiadiazol-5-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-(trifluoromethylsulfonimidoyl)phenoxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-dimethylphosphoryl-2-fluoro-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)isoxazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-dimethylphosphoryl-5-fluoro-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3-cyclopropyl-1,2,4-thiadiazol-5-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-methyl-4-(trifluoromethyl)thiazol-2-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-methyl-4-(trifluoromethyl)thiazol-5-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(1-methylpyrazol-4-yl)oxy-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(4-cyclopropylthiadiazol-5-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(difluoromethyl)thiazol-2-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-1,2,4-thiadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 4-[[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-(2-fluoro-4-triflyl-benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(4-tert-butyloxazol-2-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; and 2-[6-[(2-keto-1H-pyridin-3-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one.

[0091] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, selected from: 2-[6-(4-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 5-[[2-(6-keto-2,5,7-triazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 5-[[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; and 2-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one.

[0092] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound is 2-[6-(4-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one, or a pharma- ceutically acceptable salt thereof.

[0093] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the compound is 2-[7-[[5-(trifluoromethyl)-2-pyridyl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one, or a pharma- ceutically acceptable salt thereof.

[0094] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, wherein the compound is 2-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one, or a pharma- ceutically acceptable salt thereof.

[0095] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the compound is 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one, or a pharma- ceutically acceptable salt thereof.

[0096] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the compound is 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one, or a pharma- ceutically acceptable salt thereof.

[0097] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the compound is 2-[7-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one, or a pharma- ceutically acceptable salt thereof.

[0098] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the compound is 5-[[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile.

[0099] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the compound is 5-[[2-(6-keto-2,5,7-triazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile.

[0100] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the compound is 5-[[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile.

[0101] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, wherein the compound is 2-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one.

[0102] In certain embodiments, the present invention provides pharma- ceutically acceptable salts of the compounds according to formula (I) described herein. In further particular embodiments, the present invention provides the compounds according to formula (I) described herein in their free form (i.e., as a free base or free acid).

[0103] In some embodiments, the compound of formula (I) is isotopically labeled by replacing one or more atoms therein with an atom having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Examples of isotopes that can be incorporated into the compound of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g. 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0104] Heavier isotopes, such as deuterium, i.e. 2Substitutions such as H may confer greater metabolic stability and may confer certain therapeutic advantages, for example through increased in vivo half-life or reduced dosage requirements.

[0105] 11 C. 18 F, 15 O and 13 Substitution with positron emitting isotopes such as N can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples set forth below, substituting the appropriate isotopically labeled reagent for the non-isotopically labeled reagent previously used.

[0106] Manufacturing method The preparation of the compounds of formula (I) of the present invention can be carried out in sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The skills required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indexes used in the following method descriptions have the meanings given herein, unless indicated to the contrary.

[0107] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (as described in "Protective Groups in Organic Chemistry", TW Greene and PG M Hutts, 5th Edition, 2014, John Wiley & Sons, NY) can be introduced prior to a critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0108] When the starting material or intermediates contain a stereocenter, the compound of formula (I) can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can be separated into their antipodes via diastereomeric salts, for example, by crystallization with optically pure acids, or by separating the antipodes by specific chromatographic methods using either chiral adsorbents or chiral eluents. It is also possible to separate starting materials and intermediates containing stereocenters to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (I) generally results in the respective diastereomerically / enantiomerically enriched compound of formula (I).

[0109] Those skilled in the art will recognize that in the synthesis of compounds of formula (I), unless otherwise desired, an "orthogonal protecting group strategy" can be applied to cleave some protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany and RB Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0110] One skilled in the art will recognize that the reaction sequence may be varied depending on the reactivity and nature of the intermediates.

[0111] More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. Also, for reaction conditions described in the literature that affect the described reactions, see, for example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). The reaction could be easily carried out with or without a solvent. There is no particular restriction regarding the nature of the solvent used, provided that it does not adversely affect the reaction or the reagents involved, and that it is capable of dissolving the reagents at least to some extent. The described reactions can take place over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the described reactions at temperatures ranging from -78°C to reflux. The time required for the reaction can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to obtain the intermediates and compounds described. The reaction sequence is not limited to the sequence shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0112] In cases where starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared analogously to existing procedures for similar analogs or as outlined in the experimental section.

[0113] The following abbreviations are used herein: AcOH = acetic acid, ACN = acetonitrile, Bn = benzyl, BINAP = (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), Boc = tert-butyloxycarbonyl, CAS RN = Chemical Abstracts Registry Number, Cbz = benzyloxycarbonyl, Cs2CO3 = cesium carbonate, CO = carbon monoxide, CuCl = copper(I) chloride, CuCN = copper(I) cyanide, CuI = copper(I) iodide, DABCO = 1,4-diazabicyclo[2.2.2]octane; triethylenediamine, DAST = (diethylamino)sulfur trifluoride, DBU = 1,8-diazabicyclo[5,4,0]undec-7-ene, 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 = hours, FA = formic acid, H2O = water, H2SO4 = sulfuric acid, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N',N'-Tetramethyl-uronium-hexafluoro-phosphate, HCl = hydrogen chloride, HOBt = 1-hydroxy-1H-benzotriazole, HPLC = high performance liquid chromatography, iPrMgCl = isopropyl magnesium chloride, I2 = iodine, IPA = 2-propanol, ISP = positive ion spray (mode), ISN = negative ion spray (mode), K2CO3 = potassium carbonate, KHCO3 = potassium bicarbonate, KI = potassium iodide, KOH = potassium hydroxide, K3PO4 = tripotassium phosphate, LiAlH4 or L AH = lithium aluminum hydride, LiHMDS = lithium bis(trimethylsilyl)amide, LiOH = lithium hydroxide, mCPBA = meta-chloroperbenzoic acid, MgSO4 = magnesium sulfate, min = minute, mL = milliliter, MPLC = medium pressure liquid chromatography, MS = mass spectrum, nBuLi = n-butyllithium, NaBH3CN = sodium cyanoborohydride, NaH = sodium hydride, NBS = N-bromosuccinimide, NaHCO3 = sodium bicarbonate, NaNO2 = sodium nitrite, NaBH( OAc)3 = sodium triacetoxyborohydride, NaOH = sodium hydroxide, Na2CO3 = sodium carbonate, Na2SO4 = sodium sulfate, Na2S2O3 = sodium thiosulfate, NEt3 = triethylamine (TEA), NH4Cl = ammonium chloride, NMP = N-methyl-2-pyrrolidone, OAc = acetoxy, T3P = propylphosphonic anhydride, PE = petroleum ether, PG = protecting group, Pd-C = palladium on activated carbon, PdCl2(dppf)-CH2Cl2 = 1,1'-bis(diphenylphosphino)ferrocene- Palladium(II) dichloride dichloromethane complex, Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0), Pd(OAc)2 = palladium(II) acetate, Pd(OH)2 = palladium hydroxide, Pd(PPh3)4 = tetrakis(triphenylphosphine)palladium(0), PMP = 1,2,2,6,6-pentamethylpiperidine, PTSA = p-toluenesulfonic acid, R = any group, RP = reversed phase, RT = room temperature, SFC = supercritical fluid chromatography, S-PHOS = 2-dicyclohexylphosphino-2',6'-Dimethoxybiphenyl, TBAI = tetrabutylammonium iodine, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMEDA = N,N,N',N'-tetramethylethylenediamine, TS-TPP = triphenylphosphine-polymer bound, ZnCl2 = zinc chloride, Hal = halogen, prep-TLC = preparative thin layer chromatography.

[0114] The present compounds of formula I can be prepared by reacting an activated intermediate of formula 2 with a nucleophilic spirocyclic amine 1 by heating in a solvent such as DMF or CH3CN in the presence of a base such as DIPEA (Scheme 1). In some cases, an alternative activated intermediate bearing a 4-nitrophenyl group instead of the 1,2,4-triazole was used. Alternatively, the activated intermediate can be formed on other coupling partners (1) to generate the ureas of formula I. [ka] Scheme 1

[0115] The activated intermediate 2 can be generated by reacting amine 3 with a coupling agent such as di(1H-1,2,4 triazol-1-yl)methanone in a solvent such as CH2Cl2, either transiently in the reaction mixture or in the presence of a base such as DIPEA (Scheme 2). The related 4-nitrophenyl carbonate intermediate can be generated in a similar manner using 4-nitrophenylcarbonochloridate. Alternatively, the same strategy as in Schemes 1 and 2 can be used, but the activated intermediate is first built on the spirocyclic amine 1 before coupling with amine 3. [ka] Scheme 2

[0116] Building blocks of formula 4 where L=CH2 can be generated by Suzuki reaction (e.g., (Pd(dppf)Cl2, K2CO3, dioxane / HO), (X=Br, I), followed by hydrogenation (e.g., Pd / C, H2). The requisite boronate intermediate 5 can be generated by reacting the ketone with 4,4,5,5-tetramethyl-2-[(tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (LiTMP, THF, -78 °C). (Scheme 3) When A=N-linked heteroaryl, a Chan-Lam type coupling can be used instead of the Suzuki reaction, followed by hydrogenation / deprotection. [ka] Scheme 3

[0117] Building blocks of formula 8, where L=bond and A=C-linked (hetero)aryl, can be generated by coupling suitably protected boronic acid derivatives 9 (X=B(OR)2) with iodides 10 under nickel or palladium catalysis. Alternatively, bromides 9 (X=Br) can be directly coupled with 10 in a photochemical reaction using Ir[dF(CF3)ppy]2(dtbbpy)PF6, NiCl2.DME, dtbbpy and (TMS)3SiH. (Scheme 4) Alternatively, C-linked heteroaryl rings A can be introduced using standard heterocyclic ring syntheses, typically starting from acid or cyano derivatives of spirocyclic amines. [ka] Scheme 4

[0118] Alternatively, the building blocks of formula 11, where L=oxygen and A is (hetero)aryl (X is S N Ar substitution), in the presence of a base such as NaOtBu, 12 (X is a leaving group such as Cl, Br, etc., typically S NAr adjacent to the aromatic N for the reaction) with an appropriately protected alcohol building block 13, followed by deprotection under standard conditions (e.g., with TsOH for PG=Boc). (Scheme 5) S of the leaving group X (typically OMs, Br or I) using a base such as NaH. N A similar scheme can be used to introduce small aliphatic units such as cyclopropyl or aliphatic (hetero)cycles as the A ring via disubstitution. [ka] Scheme 5

[0119] Alternatively, building blocks of formula 14 with L = NHCO can be prepared by reacting a suitably protected carboxylic acid 15 with an amine 16 to generate amide 17 using standard amide coupling techniques (e.g., HATU, Et3N) followed by deprotection. Amide 17 can also be reduced (e.g., using borane-methylsulfide complex) prior to deprotection to give amine building blocks of formula 18. (Scheme 6) [ka] Scheme 6

[0120] Alternatively, building blocks of formula 19 where L = SO2NH can be prepared by reaction of sulfonyl chloride 20 with an appropriately protected amine building block 13 in the presence of a base such as DIPEA, followed by deprotection under standard conditions (e.g., with TsOH or TFA when PG = Boc) (Scheme 7). [ka] Scheme 7

[0121] Alternatively, the building block of formula 22, where L=N and A is (hetero)aryl (X is S N Ar substitution) is 12 (X is a leaving group such as Cl or Br, and S N Ar (often adjacent to an aromatic N for reaction) can be prepared by reaction with an appropriately protected amine building block 21 in the presence of a base such as DIPEA, followed by deprotection under standard conditions (e.g., with TsOH when PG=Boc) (Scheme 8). [ka] Scheme 8

[0122] Alternatively, building blocks of formula 22 where L=bond and A is an N-linked heterocycle can be prepared by reaction of the nucleophilic heterocycle A (24) with a suitably protected building block 25 (X=OMs, leaving group such as I, Br, etc.) in the presence of a base such as Cs2CO3, followed by deprotection under standard conditions (e.g., with TsOH when PG=Boc). (Scheme 9) Typically, a mesylate building block 25 is used (X=OMs), which can be conveniently generated from the hydroxyl analogue by reaction with MsCl in the presence of a mild base such as Et3N. [ka] Scheme 9

[0123] Alternatively, building blocks of formula 22 where L=bond and A is an N-linked heterocycle can be prepared by reductive amination reaction of heterocycle A (24) with an appropriately protected ketone building block 26 in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, followed by deprotection under standard conditions (e.g., with TsOH when PG=Boc) (Scheme 10). [ka] Scheme 10

[0124] Alternatively, building blocks of formula 27 where L = CH2N can be introduced by reductive amination reaction of amine 28 with appropriately protected ketone building block 26 in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, followed by deprotection under standard conditions (e.g., with TsOH when PG = Boc) (Scheme 11). [ka] Scheme 11

[0125] Alternatively, building blocks of formula 28 where L=CH2 and B is N-linked can be prepared by reductive amination reaction of aldehyde 29 with appropriately protected heterocycle B (30) in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, followed by deprotection under standard conditions (e.g., with TsOH when PG=Boc) (Scheme 12). [ka] Scheme 12

[0126] Alternatively, building blocks of formula 31 where L=SO2 and B is N-linked can be prepared from sulfonyl chloride 32 and appropriately protected heterocycle B (30) in the presence of a base such as DIPEA, followed by deprotection under standard conditions (e.g., with TsOH when PG=Boc) (Scheme 13). [ka] Scheme 13

[0127] Alternatively, building blocks of formula 28 where L = CH2 and A is N-linked can be prepared by reductive amination reaction of appropriately protected heterocycle B (30) with (hetero)arylmethyl halides (X = Br, I, Cl) 33 in the presence of a base such as K2CO3 in a solvent such as ACN, followed by deprotection under standard conditions (e.g., with TsOH when PG = Boc) (Scheme 14). [ka] Scheme 14

[0128] Alternatively, sulfonylurea building blocks of formula 34, where L = -NHSO2- or -CH2NHSO2, can be prepared by activation of 2-methyl-1-(2-methylimidazol-1-yl)sulfonyl-imidazole by methylation with methyl trifluoromethanesulfonate, followed by reaction with appropriately protected amine 30, a further activation sequence by methylation with methyl trifluoromethanesulfonate followed by reaction with amine 52, and finally deprotection under standard conditions (e.g., with TsOH or TFA when PG = Boc). (Scheme 15) Alternatively, sulfonylurea building block 34 can be generated from sulfuryl chloride, followed by sequential addition of 30 and 52 in the presence of a base such as Et3N or DIPEA, and finally deprotection under standard conditions. [ka] Scheme 15

[0129] Alternatively, building blocks of formula 36 with L=bond, B is an N-bond and A is a (hetero)aryl can be prepared using a metal-catalyzed cross-coupling reaction (e.g., Buchwald reaction, Pd catalyzed) between a suitably protected heterocycle B (30) and a (hetero)aryl halide (X=Br, I, Cl), followed by deprotection under standard conditions (e.g., with TsOH or TFA when PG=Boc). (Scheme 16) In certain cases, the (hetero)aryl 37 is S N When suitable for Ar reaction (X=F), the building blocks of formula 37 can be reacted with the (spiro)cycle B30 and the S of 37 in the presence of a base (e.g., K2CO3 or Et3N, DMSO, heat). N It can be produced by the Ar reaction. [ka] Scheme 16

[0130] Alternatively, building blocks of formula 38 can be prepared by Mitsunobu-type reaction of heterocycle A (24) with hydroxyl building block 39 (e.g., using diisopropyl azodicarboxylate and triphenylphosphine, or Tsunoda's reagent (cyanomethylene trimethylphosphorane)), followed by deprotection under standard conditions (e.g., with TsOH when PG=Boc). (Scheme 17) Alternatively, building blocks of formula 38 can be prepared by conversion of hydroxyl building block 39 to a mesylate (e.g., using MsCl, Et3N), followed by S-coupling with heterocycle A (24) in the presence of a base such as NaH. N It can be prepared by two reactions. [ka] Scheme 17

[0131] Alternatively, building blocks of formula 40 where L=oxygen and A is (hetero)aryl can be prepared by reacting a suitably protected (spiro)cyclic amine (42) bearing a hydroxyl group with a nucleophilic (hetero)aryl alcohol (41) under Mitsunobu-type conditions (e.g., using Tsunoda's reagent, (tributylphosphoranylidene)acetonitrile or PPh3 / DIAD) followed by deprotection (Scheme 18). [ka] Scheme 18

[0132] Alternatively, the building blocks of formula 43, where B is a C bond and L=-SO2-, can be prepared by the synthesis of thiols 44 with (spiro)cyclic amines 45 (Y=leaving group, e.g., OMs) under basic conditions (e.g., K2CO3). N 2 reaction, followed by oxidation of the thioether to the sulfone (e.g., mCPBA) and deprotection under standard conditions (e.g., with TsOH when PG=Boc). (Scheme 19) The same sequence can be used to generate the sulfoxime (L=-SNO-) using a modified oxidation step (e.g., using iodobenzene diacetate and ammonium carbamate) to introduce the sulfoximine from the thioether. [ka] Scheme 19

[0133] Alternatively, building blocks of formula 4 where A is a C-linked heteroaryl and L = -CH2- can be generated using standard heterocyclic synthesis techniques starting from the appropriate carboxylic acid (47) or nitrile (48) derivatives. The nitrile derivatives can be prepared from the hydroxyl derivatives (46) by conversion to the mesylate (e.g., using MsCl, Et3N) followed by S-reaction of the mesylate group with cyanide (e.g., using KCN). N It can be generated by 2-substitution (Scheme 20). [ka] Scheme 20

[0134] The (hetero)aryl trifluoromethylcyclopropyl building block 49 is not commonly available and was instead generated from the halide building block 50 ((X=I, Br) by Suzuki reaction with 1-(trifluoromethyl)vinylboronic acid to give 51. Cyclopropanation with diphenyl(methyl)sulfonium tetrafluoroborate and LiHMDS afforded the required building block 49 (Scheme 21). This sequence can also be carried out in other synthetic schemes, for example between steps of the N-linked heteroaryl ring A, and these functionalization steps are often carried out after the Suzuki / hydrogenation sequence but before the final deprotection while preparing the building block of formula 4 (see Scheme 3). [ka] Scheme 21

[0135] In some cases, compounds of formula I can be further functionalized to give other compounds of formula I. For example, compounds of formula I bearing (hetero)aryl bromides or iodides can be further functionalized with other groups, e.g., small amines, small alkyls, using metal-catalyzed cross-coupling conditions such as the Buchwald or Suzuki reactions.

[0136] In some cases, standard functional group interconversion techniques (e.g., conversion of halides to other groups, e.g., small amines, small alkyls using metal-catalyzed cross-coupling conditions (e.g., Buchwald or Suzuki reactions), conversion of boron-containing groups to hydroxyls using alkaline peroxide conditions, S NBuilding blocks can be generated from commercially available fragments using techniques such as alkylation of hydroxyl or amine groups via the 2 reaction or reductive amination, acylation using activated carbonyl derivatives, or introduction of -SO2Me or -SO2CF3 groups using literature techniques. Such techniques can also be used to elaborate commercially available fragments before, after, or during the synthetic sequences described above.

[0137] In one aspect, the present invention provides a method of preparing a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, comprising the steps of: (a) Nucleophilic spirocyclic amine 1 [ka] where the variables are as defined herein, formula 2 [ka] wherein Z is as described herein, in a solvent and in the presence of a base to form said compound of formula (I); or (b) Nucleophilic spirocyclic amine 1 [ka] where the variables are as defined herein, formula 2a [ka] wherein Z is as described herein, reacting in a solvent and in the presence of a base to form said compound of formula (I); and optionally (c) contacting said compound of formula (I) with an acid to form a pharma- ceutically acceptable salt thereof.

[0138] In one embodiment, the process is carried out at a temperature between room temperature and the reflux of the solvent mixture, for example about 30°C to about 80°C, in particular about 30°C, about 40°C, about 50°C, about 60°C, about 70°C or about 80°C.

[0139] In one embodiment, the base used in the method is DIPEA.

[0140] In one embodiment, the solvent used in the process is DMF or CH3CN.

[0141] In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof, prepared according to any one of the methods described herein.

[0142] MAGL inhibitory activity The compounds of the present invention are MAGL inhibitors. Thus, in one aspect, the present invention provides the use of a compound of formula (I) as described herein for inhibiting MAGL in a mammal.

[0143] In a further aspect, the invention provides a compound of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.

[0144] In a further aspect, the invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal.

[0145] In a further aspect, the present invention provides a method for inhibiting MAGL in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0146] Compounds of formula (I) may be profiled for MAGL inhibitory activity by determining the enzymatic activity following hydrolysis of the natural substrate 2-arachidonoylglycerol (2-AG) to yield arachidonic acid, followed by mass spectrometry. This assay is hereinafter abbreviated as "2-AG assay."

[0147] Compounds of formula (I) may be profiled for MAGL inhibitory activity by determining the enzymatic activity following hydrolysis of the natural substrate 2-arachidonoylglycerol (2-AG) to yield arachidonic acid, followed by mass spectrometry. This assay is hereafter abbreviated as "2-AG assay". The 2-AG assay was performed in 384-well polypropylene assay plates. Compound dilutions were made in 3-fold dilution steps in 100% DMSO in polypropylene plates to give a final concentration range in the assay of 12.5 μM to 0.8 pM. Compound dilutions were added to MAGL protein in assay buffer (50 mM TRIS, 1 mM EDTA, 0.01% (v / v) Tween-20, 2.5% (v / v) DMSO). After shaking, the plate was incubated at room temperature for 15 minutes. To initiate the reaction, 2-arachidonoylglycerol in assay buffer was added. The final concentrations in the assay were 50 pM for MAGL protein and 8 μM for 2-arachidonoyl glycerol. After shaking and incubation at room temperature for 30 min, the reaction was stopped by adding 2 assay volumes of acetonitrile containing 4 μM d8-arachidonic acid. The amount of arachidonic acid formed was followed by an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer. A C18 SPE cartridge (Agilent G9205A) was used in an acetonitrile / water liquid setup. The mass spectrometer was operated in negative electrospray mode, following the mass transitions 303.1 → 259.1 for arachidonic acid and 311.1 → 267.0 for d8-arachidonic acid. The activity of the compounds was calculated based on the intensity ratio [arachidonic acid / d8-arachidonic acid].

[0148] [Table 1] TIFF2024540874000074.tif245170 TIFF2024540874000075.tif244170 TIFF2024540874000076.tif245170 TIFF2024540874000077.tif245170 TIFF2024540874000078.tif246170 TIFF2024540874000079.tif245170

[0149] In one aspect, the present invention provides compounds of formula (I) and their pharma- ceutically acceptable salts or esters as described herein, which have an IC50 value for MAGL inhibition as measured in the MAGL assay as described herein. 50 is less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM.

[0150] In one embodiment, the compounds of formula (I) described herein and their pharma- ceutically acceptable salts or esters have an IC 50 (MAGL inhibition) values ​​range from 0.000001 μM to 25 μM, and certain compounds have IC 50 The IC value is between 0.000005 μM and 10 μM, and certain compounds have IC 50 The values ​​are between 0.00005μM and 5μM.

[0151] Uses of the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I), as described herein, or a pharma- ceutically acceptable salt thereof, for use as a therapeutically active substance.

[0152] In one embodiment, the compounds of the invention are "peripherally" active, ie, they do not penetrate the blood-brain barrier.

[0153] In a further aspect, the present invention provides a method for treating or preventing a disease or condition associated with MAGL in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein, or a pharma- ceutically acceptable salt thereof.

[0154] In one embodiment, the disease or condition associated with MAGL is selected from neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and inflammatory bowel disease.

[0155] In one embodiment, the disease or condition associated with MAGL is selected from neuroinflammatory and neurodegenerative diseases.

[0156] In one embodiment, the disease or condition associated with MAGL is a neurodegenerative disease.

[0157] In one embodiment, the disease or condition associated with MAGL is cancer.

[0158] In a particularly preferred embodiment, the disease or condition associated with MAGL is inflammatory bowel disease.

[0159] In one embodiment, the disease or condition associated with MAGL is pain.

[0160] In one embodiment, the disease or condition associated with MAGL is selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain, abdominal pain associated with irritable bowel syndrome, and visceral pain.

[0161] In one embodiment, the disease or condition associated with MAGL is selected from multiple sclerosis, Alzheimer's disease, and Parkinson's disease.

[0162] In one embodiment, the disease or condition associated with MAGL is selected from inflammatory bowel disease, inflammatory bowel syndrome, intestinal motility, visceral pain, fibromyalgia, endometriosis, COPD and asthma.

[0163] In one aspect, the invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the above methods.

[0164] In one aspect, the invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the above method.

[0165] In one aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or condition associated with MAGL as described herein.

[0166] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0167] In one embodiment, a pharmaceutical composition according to Example 376 or Example 377 is provided.

[0168] The compounds of formula (I) and their pharma- ceutically acceptable salts and esters can be used as medicines (e.g., in the form of pharmaceutical preparations).The pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, sugar-coated tablets, hard and soft gelatin capsules, liquids, emulsions or suspensions), nasally (e.g., in the form of nasal sprays), or rectally (e.g., in the form of suppositories).However, administration can also be parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0169] The compounds of formula (I) and their pharma- ceutically acceptable salts and esters can be treated with pharma- ceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules.Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc., can be used as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0170] Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols etc.

[0171] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose etc.

[0172] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0173] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols etc.

[0174] In addition, pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. Pharmaceutical preparations may also contain other therapeutically valuable substances.

[0175] The dosage can vary widely and is of course adapted to the individual requirements in each particular case. In general, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person) will be appropriate, preferably divided into 1 to 3 individual doses, which may be composed of, for example, the same amount. However, it is clear that the upper limit given in this specification can be exceeded in indicated cases. EXAMPLES

[0176] The present invention will be more fully understood by reference to the following examples, which should not, however, be construed as limiting the scope of the claims.

[0177] Where the preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0178] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0179] Building Block Synthesis Example A.5 8-Oxa-2,5-diazaspiro[3.5]nonan-6-one; Trifluoroacetic acid [ka] To a solution of 6-keto-8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (625 mg, 2.58 mmol) in dichloromethane (14 mL) was added TFA (2.94 g, 1.99 mL, 25.8 mmol) and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed in vacuo to give 955 mg of the crude title compound, which was used without further purification. MS (ESI): m / z=143.1 [M-TFA+H] +

[0180] Example A.6 2,5-Diazaspiro[3.5]nonan-6-one; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-oxo-2,5-diazaspiro[3.5]nonane-2-carboxylate (1275 mg, 5.31 mmol) in ethyl acetate (50 mL) was added p-toluenesulfonic acid monohydrate (2520 mg, 13.3 mmol). The mixture was stirred at 20° C. for 15 h. The precipitated solid was filtered, washed with ACN, and dried to give the title compound (1655 mg, 3.42 mmol, 61% yield) as a light brown solid. MS (ESI): m / z=141.0 [M-TsOH+H] +

[0181] Step a) tert-Butyl 3-allyl-3-(prop-2-enoylamino)azetidine-1-carboxylate To a solution of tert-butyl 3-allyl-3-amino-azetidine-1-carboxylate (CAS: 1440962-19-5) (6.0 g, 28.3 mmol) in DCM (150 mL) was added triethylamine (4.73 mL, 33.9 mmol). The mixture was cooled to -30 °C and acryloyl chloride (2.4 mL, 29.7 mmol) was added dropwise. The mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was washed with water and the organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography (1:1 EtOAc / Hexanes) to give the title compound (4.55 g, 17.1 mmol, 58.6% yield) as a yellow oil. MS (ESI): m / z = 211.0 [M-C4H8+H] +

[0182] Step b) tert-Butyl 6-oxo-2,5-diazaspiro[3.5]non-7-ene-2-carboxylate A solution of tert-butyl 3-allyl-3-(prop-2-enoylamino)azetidine-1-carboxylate (4.45 g, 16.7 mmol) in toluene (500 mL) was degassed with Ar. (1,3-bis(2,4,6 trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (709 mg, 0.84 mmol) was added and the mixture was heated at 90° C. for 10 h. After cooling, the solvent was evaporated and the residue was purified by column chromatography (100% EtOAc) to give the title compound (1.35 g, 5.67 mmol, 33% yield) as a brown solid. MS (ESI): m / z=183.2 [M-C4H8+H] +

[0183] Step c) tert-Butyl 6-oxo-2,5-diazaspiro[3.5]nonane-2-carboxylate A suspension of tert-butyl 6-oxo-2,5-diazaspiro[3.5]non-7-ene-2-carboxylate (1350.0 mg, 5.67 mmol, 1.0 equiv.), Pd / C 10% (301.41 mg, 0.28 mmol, 0.05 equiv.) in ethanol (30 mL) was stirred under hydrogen atmosphere for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was dried to give tert-butyl 6-oxo-2,5-diazaspiro[3.5]nonane-2-carboxylate (1360.0 mg, 5.66 mmol, 98.6% yield) as a light brown solid. MS (ESI): m / z=185.0 [M-C4H8+H] +

[0184] Example B.1 [3-(2-azaspiro[3.3]heptan-6-ylmethyl)phenyl]-imino-oxo-(trifluoromethyl)-λ 6 -Sulfane; 4-Methylbenzenesulfonic acid [ka] A mixture of p-toluenesulfonic acid (1.18 g, 6.83 mmol) and tert-butyl 6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g, 3.11 mmol) in ethyl acetate (30 mL) was stirred at 40° C. for 24 hours. After completion of the reaction, the reaction mixture was concentrated and purified by HPLC to give the title compound (339 mg, 0.690 mmol, 15.6% yield) as a brown viscous oil. MS (ESI): m / z=319.0 [M-TsOH+H] +

[0185] Step a) tert-Butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate A mixture of 2,2,6,6-tetramethylpiperidine (95.9 mL, 568 mmol) in THF (750 mL) was cooled to -30 °C under N2 atmosphere. n-BuLi (227 mL, 568 mmol) was added dropwise and the reaction mixture was stirred at the same temperature for 30 min. The reaction was then cooled to -60 °C and a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolane (136 g, 506 mmol) in THF (750 mL) was added dropwise. After stirring for 30 min, a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (100 g, 473 mmol) in THF (300 mL) was added dropwise at -60 °C. The reaction mixture was slowly warmed to 25 °C and stirred at 25 °C for 12 h. HO (80 mL) was slowly added to the mixture, which was then purified together with an additional batch of equal size by silica gel column (PE / EA = 1:0 to 3:1 gradient) to give the title compound (220 g, 656 mmol, approx. 69% yield per batch) as a white solid, which was 1Confirmed by H NMR (400 MHz, CHLOROFORM-d) δ = 5.21-5.16 (m, 1H), 3.99-3.89 (m, 4H), 3.13-2.90 (m, 4H), 1.46-1.41 (m, 9H), 1.26-1.20 ppm (m, 13H).

[0186] Step b) tert-Butyl 6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (3-Bromophenyl)-imino-oxo-(trifluoromethyl)-λ6-sulfane (2.47 g, 8.59 mmol), tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2.4 g, 7.16 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.17 g, 1.43 mmol) and potassium carbonate (1.98 g, 14.3 mmol) were dissolved in 1,4-dioxane (40 mL) and water (8 mL). The reaction mixture was heated to 120° C. under argon for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The extract was dried over sodium sulfate, filtered through a thin layer of silica gel and evaporated. The crude product was purified by column chromatography to give the title compound (1 g, 2.4 mmol, 31.9% yield) as a pale yellow solid. MS (ESI): m / z = 361.0 [M-tBu+H] + .

[0187] Step c) tert-Butyl 6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate A mixture of tert-butyl 6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1.3 g, 3.12 mmol) and palladium on carbon (10%) (0.16 mL, 1.56 mmol) in EtOAc (35 mL) was stirred in an autoclave under 30 bar of H2 for 24 h. The reaction mixture was then filtered and concentrated to give the title compound (1.3 g, 3.11 mmol, 96.5% yield) as a grey oil. MS (ESI): m / z=319.0 [M-Boc+H] + .

[0188] Analogously to Example B.1, the relevant (hetero)aryl bromide or iodide building blocks in the Suzuki coupling of step b were used to generate the following building blocks. In some cases, alternative salts (e.g. trifluoroacetate, ditosylate, hydrochloride) were also used. Further building block substitutions can be made to introduce different spiro ring systems, for example Example B.25 used tert-butyl 7-oxo-2-azaspiro[3.3]nonane-2-carboxylate (CAS: 1363381-22-9) instead of tert-butyl 6-oxo-2-azaspiro[3.5]heptane-2-carboxylate in step a), and Examples B.26 and B.47 used tert-butyl 6-oxo-2-azaspiro[3.3]octane-2-carboxylate (CAS: 1363382-39-1) instead of tert-butyl 6-oxo-2-azaspiro[3.4]heptane-2-carboxylate in step a). [Table 2] TIFF2024540874000084.tif235165 TIFF2024540874000085.tif228165 TIFF2024540874000086.tif250165 TIFF2024540874000087.tif239165 TIFF2024540874000088.tif238165 TIFF2024540874000089.tif224165 TIFF2024540874000090.tif224165 TIFF2024540874000091.tif218165 TIFF2024540874000092.tif234165 TIFF2024540874000093.tif246165 TIFF2024540874000094.tif234165 TIFF2024540874000095.tif235165 TIFF2024540874000096.tif230165 TIFF2024540874000097.tif234165 TIFF2024540874000098.tif207165 TIFF2024540874000099.tif235165 TIFF2024540874000100.tif203165

[0189] Example B.27 7-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.5]nonane; 4-Methylbenzenesulfonic acid [ka] To a suspension of 7-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (350 mg, 0.903 mmol) in isopropyl acetate (4 mL) was added p-toluenesulfonic acid monohydrate (258 mg, 1.36 mmol). The mixture was stirred at 100 °C for 6 h. The reaction mixture was concentrated in vacuo. Et2O was added and the mixture was filtered through sintered glass. The white solid was washed with Et2O (2x) and dried in vacuo to give the title compound (0.420 g, 88%) as a white solid. MS (ESI): m / z = 288.0 [M-TsOH+H] +

[0190] Step a) 7-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester To a solution of 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (CAS: 1363383-18-9) (350 mg, 1.45 mmol) and potassium t-butoxide (195 mg, 1.74 mmol) in N,N-dimethylformamide (3.5 mL) was added 3-fluoro-6-(trifluoromethyl)pyridazine (248 mg, 1.49 mmol). The mixture was stirred at 80° C. for 15 h. The reaction mixture was poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (eluted with 0% to 40% EtOAc in heptane) to give the title compound (353 mg, 59.69%) as a white solid. MS (ESI): m / z=332.1 [M-tBu+H] +

[0191] Analogously to Example B.27, the following building blocks were generated using related (hetero)halogenated aryl and hydroxy-spirocyclic building blocks. In some cases, alternative solvents and bases were used in S N Ar was used in the reaction and in step a) a solvent such as DMSO or NaH in DMF was used.

[0192] [Table 3] TIFF2024540874000103.tif204170 TIFF2024540874000104.tif176170 TIFF2024540874000105.tif177170 TIFF2024540874000106.tif210170 TIFF2024540874000107.tif220170 TIFF2024540874000108.tif53170

[0193] Example B.28 6-[4-(trifluoromethylsulfonyl)phenyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A solution of 6-(4-triflylphenyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (313 mg, 0.772 mmol) and p-toluenesulfonic acid monohydrate (162 mg, 0.849 mmol) was refluxed with stirring in ethyl acetate (4.26 mL) for 4 h. The crude product was filtered and the solid phase was washed with EtOAc and diethyl ether to give the title compound as a white solid (estimated purity 95%), which was used directly without further purification. MS (ESI): m / z=306.2 [M-TsOH+H] +

[0194] Step a) 6-(4-triflylphenyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester In a 25 mL Radley tube equipped with a stir bar and flushed with argon, tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 2059140-61-1) (500 mg, 1.55 mmol), (IR[DF(CF3)PPY]2(DTBPY))PF6 (17.4 mg, 0.015 mmol) photocatalyst, tris(trimethylsilyl)silane (403 mg, 500 µL, 1.62 mmol), anhydrous sodium carbonate (328 mg, 3.09 mmol) and 1-bromo-4-[(trifluoromethyl)sulfonyl]benzene (CAS: 312-20-9) (492 mg, 1.7 mmol) were added. DME (14.7 mL) was added and the mixture was stirred for 5 min while bubbling argon through the mixture. The vial was sealed.

[0195] To a separate vial (flushed with argon) was added 4,4'-di-tert-butyl-2,2'-bipyridine (4.15 mg, 0.015 mmol) and nickel(II) chloride ethylene glycol dimer ether complex (3.4 mg, 0.015 mmol) followed by DME (737 μL). The precatalyst vial was sealed and purged again with argon. The precatalyst vial was sonicated for 5 min and then poured into the reaction vessel. The reaction was stirred and irradiated with a 465 nm lamp under argon for 14 h. The sodium carbonate was filtered off, washed with ethyl acetate and the filtrate was evaporated. The crude product was absorbed on Isolute HM-N, dried and purified by flash chromatography eluting with heptane / EtOAc 0-30% to give the title compound as a white solid (313 mg, 47.4%, 95% pure) which was used directly in the next step without further purification. MS(ESI):m / z=350.0 [M-tBu+H] +

[0196] Analogously to Example B.28, the following building blocks were generated using the relevant (hetero)aryl bromide building blocks for photochemical coupling in step a. In some cases, alternative salts (e.g. trifluoroacetate, ditosylate, hydrochloride) were also used. [Table 4] TIFF2024540874000111.tif47170

[0197] Example B.325 6-(5-fluoro-3-pyridyl)-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A solution of tert-butyl 6-(5-fluoro-3-pyridyl)-2-azaspiro[3.3]heptane-2-carboxylate (4.0 g, 13.68 mmol) and p-toluenesulfonic acid monohydrate (6.51 g, 34.21 mmol) in EtOAc (150 mL) was stirred at 25° C. for 18 h. The RM was then evaporated and the resulting residue (as an oil) was stirred with TBME (150 mL) for 6 h. The resulting precipitate was filtered, washed with TBME and dried to give the title compound (5.66 g, 10.6 mmol, 73.2% yield) as a white solid. MS (ESI): m / z=193.2 [M-TsOH+H] +

[0198] Step a) tert-Butyl 6-(5-fluoro-3-pyridyl)-2-azaspiro[3.3]heptane-2-carboxylate To a stirred mixture of 5-fluoropyridine-3-boronic acid (CAS: 872041-86-6) (6.1 g, 43.3 mmol), (1S,2S)-2-aminocyclohexanol (249 mg, 2.17 mmol), nickel(II) iodide (677 mg, 2.17 mmol) in iPrOH (140 mL) under argon atmosphere, 2 M sodium bis(trimethylsilyl)amide solution in THF (21.7 mL, 43.3 mmol) was added via syringe at room temperature. The RM was then stirred at ambient temperature for 10 min, followed by the addition of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 2059140-61-1) (7.0 g, 21.7 mmol). The reaction mixture was refluxed for 4 h and then stirred at room temperature overnight. The resulting mixture was filtered through SiO2 and the filter cake was washed with IPA. The filtrate was evaporated and the residue was partitioned between TBME and water. The organic layer was dried over Na2SO4 and evaporated in vacuo. The resulting crude product was purified by flash column chromatography to give the title compound (3.95 g, 13.5 mmol, 59.3% yield) as a white solid. MS (ESI): m / z=293.2 [M-TsOH+H] +

[0199] Example B.29 N-(2-azaspiro[3.3]heptan-6-ylmethyl)-1-(trifluoromethyl)cyclopropanamine; 4-Methylbenzenesulfonic acid [ka] p-Toluenesulfonic acid monohydrate (1024 mg, 5.38 mmol) was added to a stirred solution of tert-butyl 6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.79 mmol) in acetonitrile (20 mL). The reaction mixture was stirred for 16 h. The solvent was evaporated under reduced pressure and the residue was triturated with MTBE to give the title compound (668 mg, 1.15 mmol, 64% yield) as a white solid. MS (ESI): m / z=235.2 [M-TsOH+H] +

[0200] Step a) tert-Butyl 6-[[1-(trifluoromethyl)cyclopropyl]carbamoyl]-2-azaspiro[3.3]heptane-2-carboxylate To a stirred solution of 2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid (CAS: 1211526-53-2) (2.0 g, 8.29 mmol) and 1-(trifluoromethyl)cyclopropanamine hydrochloride (CAS: 112738-67-7) (1340 mg, 8.29 mmol) in DMF (5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3782 mg, 9.95 mmol) and N,N-diisopropylethylamine (5.05 mL, 29.0 mmol). The mixture was stirred at room temperature overnight. It was then poured into water and extracted with EtOAc (2 x 50 mL). The combined organic fractions were washed three times with water, dried under anhydrous sodium sulfate, and the solvent was removed under vacuum. The residue was triturated with 25 ml of MTBE to give the title compound (1.7 g, 4.88 mmol, 59% yield) as a white solid. MS (ESI): m / z = 347.2 [MH] -

[0201] Step b) tert-Butyl 6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-[[1-(trifluoromethyl)cyclopropyl]carbamoyl]-2-azaspiro[3.3]heptane-2-carboxylate (1.1 g, 3.16 mmol) was dissolved in THF (30 mL). Borane-methylsulfide complex (0.48 g, 6.32 mmol) was added at 0° C. The reaction mixture was stirred at reflux for 6 h, then cooled to 0° C., quenched by dropwise addition of methanol (5 mL), and then concentrated in vacuo. The residue was diluted with brine and then extracted with EtOAc (3 times). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (600 mg, 1.79 mmol, 57% yield) as a colorless oil. MS (ESI): m / z=279.0 [M-tBu+H] +

[0202] Example B.30 N-(2-azaspiro[3.3]heptan-6-yl)-3-(trifluoromethyl)benzenesulfonamide; Trifluoroacetic acid [ka] To a solution of 6-[[3-(trifluoromethyl)phenyl]sulfonylamino]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1245 mg, 2.96 mmol) in dichloromethane (8 mL) was added TFA (3.38 g, 2.28 mL, 29.6 mmol) and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed in vacuo to give 1910 mg of the crude title compound (approximately 65% ​​purity and major contaminant excess TFA) which was used without further purification. MS (ESI): m / z=321.1 [M-TFA+H] +

[0203] Step a) 6-[[3-(trifluoromethyl)phenyl]sulfonylamino]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester To a solution of 6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (750 mg, 3.53 mmol) in dichloromethane (15 mL) cooled to 0 °C, DIPEA (685 mg, 926 μL, 5.3 mmol) and 3-(trifluoromethyl)benzenesulfonyl chloride (907 mg, 3.71 mmol) were added, after which the reaction mixture was stirred at 0 °C for 30 min and at room temperature for 1 h. The reaction mixture was poured into a separatory funnel containing dichloromethane and aqueous Na2CO3 1M. The organic phase was collected and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography using an eluent mixture of heptane and ethyl acetate (10%-90%) to give 775 mg of the title compound. MS(ESI):m / z=365.1 [M-tBu+H] +

[0204] Example B.31 N-[6-(trifluoromethyl)pyridazin-3-yl]-2-azaspiro[3.3]heptan-6-amine; Trifluoroacetic acid [ka] To a solution of 6-[[6-(trifluoromethyl)pyridazin-3-yl]amino]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (708 mg, 1.94 mmol) in dichloromethane (8 mL) was added TFA (2.21 g, 1.49 mL, 19.4 mmol) and the reaction mixture was stirred at room temperature for 18 h. Volatiles were removed in vacuo to give 1310 mg of the crude title compound, approximately 55% pure with the major contaminant excess TFA, which was used without further purification. MS (ESI): m / z=259.1 [M-TFA+H] +

[0205] Step a) 6-[[6-(trifluoromethyl)pyridazin-3-yl]amino]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester To a solution of 6-amino-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (832 mg, 3.92 mmol) in N,N-dimethylformamide (12 mL) was added DIPEA (690 mg, 932 μL, 5.34 mmol) and 3-chloro-6-(trifluoromethyl)pyridazine (650 mg, 3.56 mmol), after which the reaction mixture was stirred at 80° C. for 18 h. The volatiles were removed in vacuo and the crude residue was partitioned between ethyl acetate and saturated NH4Cl solution. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography using eluent mixtures of dichloromethane and methanol (0%-10%) to give 708 mg of the title compound. MS (ESI): m / z=359.2 [M+H] +

[0206] Example B.32 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A solution of tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (675 mg, 1.95 mmol) and p-toluenesulfonic acid (404 mg, 2.35 mmol) in EtOAc (6 mL) was stirred at 80° C. for 12 h. The reaction mixture was concentrated under vacuum to give a residue. Deionized water was added to the residue and the mixture was lyophilized to give the title compound (794 mg, 96% yield) as a white solid. MS (ESI): m / z=246.2 [M-TsOH+H] +

[0207] Step a) tert-Butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 4-(trifluoromethyl)-1H-pyrazole (2435 mg, 17.9 mmol), tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (Example B.1, step a)) (2000 mg, 5.97 mmol) and pyridine (1.45 mL, 17.9 mmol) in DMSO (80 mL), copper diacetate (2380 mg, 11.9 mmol) was added under O2 atmosphere, and then stirred at 100° C. for 12 h under O2 (balloon) conditions. The aqueous phase was extracted with ethyl acetate (200 mL×3). The combined organic phase was washed with brine (200 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (eluent 0-30% ethyl acetate / petroleum ether) to give a crude product, which was purified by reverse-phase HPLC (0.1% FA condition) to give the title compound (640 mg, 31% yield) as a brown solid. MS (ESI): m / z=288.1 [M-tBu+H] +

[0208] Step b) tert-Butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (690 mg, 2.01 mmol) in EtOAc (7 mL) was added wet Pd / C (230 mg, 0.200 mmol) and the mixture was stirred at 25° C. under H2 atmosphere (balloon) for 2 h. The mixture was then filtered and the filtrate was concentrated to give the title compound (690 mg, 99% yield) as a yellow solid. MS (ESI): m / z=346.1 [M+H] +

[0209] Analogously to Example B.32, the (hetero)aryl building blocks involved in the Chan Lam-type coupling in step 1 were used to generate the following building blocks. In some cases, alternative salts (e.g. trifluoroacetate, ditosylate, hydrochloride) were also used. [Table 5]

[0210] Example B.33 6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane; Trifluoroacetic acid [ka] To a solution of tert-butyl 6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (6.00 g, 19.7 mmol) in DCM (120 mL) was added TFA (46.2 g, 405 mmol, 30 mL) at 25° C. The mixture was stirred at 30° C. for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. The title compound (14.0 g, crude) was used in the next step without further purification. MS (ESI): m / z=205.2 [M+H] +

[0211] Step a) tert-Butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1147557-97-8) (10.0 g, 46.9 mmol) in DCM (200 mL), TEA (7.12 g, 70.3 mmol, 9.79 mL) and MsCl (6.90 g, 60.2 mmol, 4.66 mL) were added dropwise at 0 °C, and the mixture was stirred at 30 °C for 2 h. The reaction mixture was quenched by the addition of aqueous NaHCO3 (200 mL) and then extracted with DCM (300 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue (crude product 13.5 g, 46.3 mmol, 98.8% yield), which was used in the next step without further purification. MS (ESI): m / z = 236.2 [M + H] +

[0212] Step b) tert-Butyl 6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate (12.0 g, 41.2 mmol, 90.0% purity) in ACN (200 mL) was added 3-cyclopropyl-1H-1,2,4-triazole (CAS: 1211390-33-8) (4.50 g, 41.2 mmol) and Cs2CO3 (26.8 g, 82.4 mmol) at 25 °C. The mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was further separated by SFC to give the title compound (6.77 g, 22.2 mmol, 54.0% yield) as a brown solid. MS (ESI): m / z = 305.2 [M + H] +

[0213] Example B.37 7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane; 4-Methylbenzenesulfonic acid [ka] To a solution of 7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (675 mg, 1.86 mmol) in isopropyl acetate (14 mL) was added p-toluenesulfonic acid monohydrate (424 mg, 2.23 mmol). The mixture was stirred at 80° C. for 5 h. The reaction mixture was concentrated in vacuo. Et2O was added and the mixture was filtered through sintered glass. The white solid was washed twice with Et2O and dried in vacuo to give the title compound (752 mg, 88%) as a white solid. MS (ESI): m / z=264.4 [M+H] +

[0214] Step a) 7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester To a solution of 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (CAS: 1363383-18-9) (0.600 g, 2.49 mmol) in N,N-dimethylformamide, extra dry (6 mL), sodium hydride (114 mg, 2.86 mmol) was added. The mixture was stirred at room temperature for 1 hour. 1-(Bromomethyl)-1-(trifluoromethyl)cyclopropane (505 mg, 2.49 mmol) was added. The mixture was stirred at 80° C. for 16 hours.

[0215] The reaction mixture was poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (eluted with 0% to 40% AcOEt in heptane) to give the title compound (681 mg, 68%). MS (ESI): m / z = 308.1 [M-tBu + H] + Example B.39 6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A solution of 6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (633 mg, 1.89 mmol) in ethyl acetate (20 mL) was treated with p-toluenesulfonic acid monohydrate (366 mg, 1.93 mmol) at 23° C. The mixture was then heated to 80° C. for 18 h before being cooled to 23° C. and evaporated to give 6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-4-methylbenzenesulfonate (769 mg, 95.0%) as a pale yellow solid. MS (ESI): m / z=236.2 [M-C7H8O3S+H] +

[0216] Step a) 6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester A solution of 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) in N,N-dimethylformamide, ultra-dry (10 mL) was treated with 1-(bromomethyl)-1-(trifluoromethyl)cyclopropane (476 mg, 2.34 mmol) under Ar at 23 °C. The mixture was stirred at this temperature for an additional 30 min before being heated to 80 °C and stirred for 21.5 h. The mixture was then cooled to 23 °C, diluted with EtOAc, and the organic layer was washed with 1M NaHCO3 solution (1x), water (2x), and brine (1x). The organic layer was then dried over Na2SO4, filtered, and evaporated to give the title compound (633 mg, 73%) as a crude colorless oil, which was used directly without further purification. MS (ESI): m / z = 280.2 [M+H-tBu] +

[0217] Example B.40 N-[1-(trifluoromethyl)cyclopropyl]-2-azaspiro[3.3]heptan-6-amine; 4-Methylbenzenesulfonic acid [ka] A solution of tert-butyl 6-[[1-(trifluoromethyl)cyclopropyl]amino]-2-azaspiro[3.3]heptane-2-carboxylate (880 mg, 2.75 mmol) and p-toluenesulfonic acid monohydrate (1568 mg, 8.24 mmol) in EtOAc (30 mL) was heated at reflux for 3 h and then cooled to room temperature. Stirred for an additional 16 h. The resulting precipitate was collected by filtration, washed with EtOAc (15 mL) and dried under vacuum to give the title compound (1335 mg, 84% yield) as a white solid. MS (ESI): m / z=221.2 [M-TsOH+H] +

[0218] Step a) tert-Butyl 6-[[1-(trifluoromethyl)cyclopropyl]amino]-2-azaspiro[3.3]heptane-2-carboxylate To a stirred solution of 1-(trifluoromethyl)cyclopropanamine hydrochloride (918 mg, 5.68 mmol) and tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1181816-12-5) (1.2 g, 5.68 mmol) in DCM (70 mL) was added triethylamine (2.38 mL, 17.0 mmol). The reaction mixture was stirred at room temperature for 20 min. Sodium triacetoxyborohydride (2410 mg, 11.4 mmol) was then added to the solution in one portion and the resulting mixture was stirred at 23 °C for 18 h. The reaction mixture was then diluted with DCM (50 mL) and 5% NaHCO3(aq) (80 mL) was added. The organic phase was separated and the aqueous layer was extracted with DCM (50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and evaporated. Purification by FC (SiO2; PE / MTBE) afforded the title compound (70 mg, 3.7% yield) as a white solid. MS (ESI): m / z=321.2 [M+H] +

[0219] Example B.42 N-[1-(trifluoromethyl)cyclopropyl]-2-azaspiro[3.3]heptane-6-carboxamide; hydrochloride [ka] To a solution of benzyl 6-[[1-(trifluoromethyl)cyclopropyl]carbamoyl]-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.520 mmol) in methanol (10 mL) was added palladium (10% on carbon) (0.02 mL, 0.190 mmol). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 24 h. The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was then dissolved in THF (10 mL), treated with 4N HCl in dioxane and stirred at 23° C. for 10 min. The precipitate was collected by filtration to give the title compound (60 mg, 40% yield) as a white solid. MS (ESI): m / z=249.2 [M+H] +

[0220] Step a) Benzyl 6-[[1-(trifluoromethyl)cyclopropyl]carbamoyl]-2-azaspiro[3.3]heptane-2-carboxylate 2-Benzyloxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid (CAS: To a stirred solution of 1291487-33-6) (1.3 g, 4.72 mmol) and 1-(trifluoromethyl)cyclopropanamine hydrochloride (0.76 g, 4.72 mmol) was added HATU (2.33 g, 6.14 mmol) and TEA (2.3 mL, 16.5 mmol). The mixture was stirred overnight at 23° C., then poured into water and extracted with EtOAc (2×100 mL). The combined organic fractions were washed three times with water, dried under anhydrous sodium sulfate, and the solvent was removed under vacuum. The residue was triturated with 50 mL of MTBE to give the title compound (1 g, 55% yield) as a white solid. MS (ESI): m / z=383.2 [M+H] +

[0221] Example B.50 6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A mixture of tert-butyl 6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane-2-carboxylate (1450 mg, 4.24 mmol) and p-toluenesulfonic acid (1605 mg, 9.32 mmol) in ethyl acetate (10 mL) was stirred at 80° C. for 16 h. The reaction mixture was filtered and the cake was concentrated to give the title compound (2110 mg, 3.6 mmol, 84% yield) as an off-white solid. MS (ESI): m / z=243.3 [M-TsOH+H] +

[0222] Step a) tert-Butyl 6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane-2-carboxylate Two batches were set up in parallel. tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 3.09 mmol), 2-trifluoromethylpyridine-5-boronic acid (1180 mg, 6.19 mmol), sodium bis(trimethylsilyl)amide in THF (6.19 mL, 6.19 mmol), trans-2-aminocyclohexanol hydrochloride (28.2 mg, 0.190 mmol) and nickel(II) iodide (58.0 mg, 0.190 mmol) were placed in a microwave tube in 2-propanol (10 mL). The sealed tube was heated at 110° C. in a microwave for 2.5 h. The reaction was slowly quenched with H2O. The residue was purified by flash silica gel chromatography (0-20% ethyl acetate / petroleum ether gradient eluent) to give the title compound (1.5 g, 4.38 mmol, 71% yield) as a yellow solid. MS (ESI): m / z=287.2 [M-tBu+H] +

[0223] Example B.51 6-[3-(trifluoromethyl)azetidin-1-yl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A solution of tert-butyl 6-[3-(trifluoromethyl)azetidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate (550 mg, 1.72 mmol) and p-toluenesulfonic acid monohydrate (980 mg, 5.15 mmol) in EtOAc (50 mL) was heated at reflux for 2 h, then cooled to room temperature and stirred for an additional 16 h. The precipitate was collected by filtration, washed with ethyl acetate (20 mL) and dried under vacuum to give the title compound (486 mg, 49% yield) as a white solid. MS (ESI): m / z=221.2 [M-TsOH+H] +

[0224] Step a) tert-Butyl 6-[3-(trifluoromethyl)azetidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1181816-12-5) (800 mg, 3.79 mmol), 3-(trifluoromethyl)azetidine; hydrochloride (CAS: 1221272-90-7) (612 mg, 3.79 mmol) and triethylamine (1.58 mL, 11.4 mmol) were mixed in DCM (40 mL) and stirred at room temperature for 10 min. Sodium triacetoxyborohydride (1.61 g, 7.57 mmol) was then added in one portion and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with DCM (50 mL) and 5% aqueous NaHCO3 (80 mL) was added. The organic phase was separated and the aqueous layer was extracted with DCM (50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and evaporated. The cured product was purified by HPLC to give the title compound (550 mg, 44% yield) as a pale yellow solid. MS (ESI): m / z=321.0 [M+H] +

[0225] Analogously to Example B.51, the following building blocks were prepared using the relevant amine building blocks in step a): [Table 6]

[0226] Example B.53 7-[[4-(Trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.5]nonane;Trifluoroacetic acid [ka] To a solution of 7-(4-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (360 mg, 0.803 mmol) in isopropyl acetate (6 mL) was added p-toluenesulfonic acid monohydrate (336 mg, 1.77 mmol). The mixture was stirred at 80° C. for 5 h. Et2O was added and the mixture was filtered through sintered glass. The white solid was washed twice with Et2O and dried in vacuum to give the title compound (537 mg, 92%) as a white solid. MS (ESI): m / z=349.1 [M-TFA+H] +

[0227] Step a) 7-(4-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester To a solution of 4-triflylbenzaldehyde (CAS: 650-89-5) (316 mg, 1.33 mmol) and 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (CAS: 236406-55-6) (0.300 g, 1.33 mmol) in 1,2-dichloroethane (2.5 mL) was added sodium triacetoxyborohydride (309 mg, 1.46 mmol) and acetic acid (159 mg, 152 μL, 2.65 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into EtOAc:THF 2:1 and washed with saturated aqueous NaHCO3, water and brine. The organic layer was dried over Na2SO4 and evaporated. Purification by FC (SiO2; DCM / MeOH) afforded the title compound (364 mg, 58%) as a white solid. MS(ESI): m / z=449.5[M+H] +

[0228] Analogously to example B.53, the following building blocks were prepared using the related building blocks in step a): [Table 7] TIFF2024540874000128.tif215170 TIFF2024540874000129.tif253170 TIFF2024540874000130.tif198170 TIFF2024540874000131.tif205170 TIFF2024540874000132.tif241170 TIFF2024540874000133.tif237170 TIFF2024540874000134.tif225170 TIFF2024540874000135.tif219170 TIFF2024540874000136.tif48170

[0229] Example B.55 2-[3-(Trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane; Trifluoroacetic acid [ka] To a solution of 2-[3-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester (1350 mg, 3.2 mmol) in dichloromethane (13.5 mL) was added TFA (3.64 g, 2.46 mL, 32.0 mmol) and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed in vacuo to give 1855 mg of the crude title compound (approximately 70% purity, major contaminant excess TFA), which was used without further purification. MS (ESI): m / z=323.1 [M-TFA+H] +

[0230] Step a) 2-[3-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester To a suspension of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (790 mg, 3.98 mmol) cooled to 0 °C in dichloromethane (18 mL) was added DIPEA (773 mg, 1.04 mL, 5.98 mmol) and 3-(trifluoromethoxy)benzenesulfonyl chloride (1.04 g, 3.98 mmol), after which the reaction mixture was stirred at 0 °C for 10 min and at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with Na2CO3 1 M solution. The organic phase was collected and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by FC (SiO2; heptane / EtOAc) to give 1350 mg of the title compound. MS (ESI): m / z = 367.1 [M-tBu + H] +

[0231] Analogously to Example B.55, the following building blocks were prepared using the relevant building blocks in step a): For Examples B.167 and B.168, 2,7-diazaspiro[3.3]nonane-2-carboxylic acid tert-butyl ester was used instead of 2,6-diazaspiro[3.5]heptane-2-carboxylic acid tert-butyl ester. [Table 8] TIFF2024540874000139.tif198170

[0232] Example B.101 2-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,6-diazaspiro[3.3]heptane;Di-4-methylbenzenesulfonic acid [ka] A mixture of p-toluenesulfonic acid (1010 mg, 5.86 mmol), tert-butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (1000 mg, 2.79 mmol) in EtOAc (10 mL) was stirred at 80° C. for 12 h. The mixture was filtered and the cake was concentrated to give the title compound (1450 mg, 86% yield). MS (ESI): m / z=259.2 [M-2TsOH+H] +

[0233] Step a) 3-(chloromethyl)-6-(trifluoromethyl)pyridazine To a mixture of 3-methyl-6-(trifluoromethyl)pyridazine (2.0 g, 12.3 mmol) in 1,2-dichloroethane (40 mL) was added trichloroisocyanuric acid (958 mg, 4.12 mmol). The mixture was heated to 80° C. and stirred for 12 h. The residue was purified by FC to give the title compound (1.3 g, 54% yield) as a white solid. MS (ESI): m / z=197.1 [M+H]+ Step b) tert-Butyl 6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate To a solution of 3-(chloromethyl)-6-(trifluoromethyl)pyridazine (1.3 g, 6.61 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate; oxalic acid (3.22 g, 6.61 mmol) in ACN (10 mL) was added K2CO3 (1.83 g, 13.2 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 h. The mixture was stirred at 50 °C for 2 h. The residue was purified by silica column (petroleum ether: ethyl acetate = 10:1 to 0:1) and concentrated under reduced pressure to give the title compound (1.7 g, 71.7% yield) as a white solid. MS (ESI): m / z = 359.3 [M+H] +

[0234] Analogously to Example B.101, the following building blocks were prepared in step b) using the relevant commercially available building blocks. In the case of 4,6 or 4,5 spiro ring systems, 2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate can be used instead of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester, respectively. In some cases, Cs2CO3 was used instead of K2CO3. [Table 9] TIFF2024540874000142.tif253170 TIFF2024540874000143.tif102170

[0235] Example B.110 2-[[4-Fluoro-2-(trifluoromethyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane;Trifluoroacetic acid [ka] To a solution of tert-butyl 6-(4-fluoro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (455 mg, 1.09 mmol) in dichloromethane (4 mL) was added TFA (843 μL, 10.9 μL) and the reaction mixture was stirred at room temperature for 18 h. The volatiles were removed in vacuo to give 685 mg of the crude title compound (approximately 80% purity), which was used without further purification. MS (ESI): m / z=275.2 [M-TFA+H] +

[0236] Step a) tert-Butyl 6-(4-fluoro-2-(trifluoromethyl)benzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (400 mg, 2.02 mmol) in CHCl (9 mL) cooled to 0° C., DIPEA (652 mg, 881 μL, 5.04 mmol) and 4-fluoro-2-(trifluoromethyl)benzoyl chloride (503 mg, 2.22 mmol) were added. The reaction mixture was stirred at 0° C. for 10 min and at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and extracted with 1M aqueous NaCO, the organic phase was collected and the aqueous phase was back-extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography using an eluent mixture of heptane and ethyl acetate (5%-80%) to give the title compound (569 mg). MS (ESI): m / z=389.3 [M+H] +

[0237] Step b) tert-Butyl 6-(4-fluoro-2-(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-(4-fluoro-2-(trifluoromethyl)benzoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (565 mg, 1.45 mmol) in dry THF (5 mL) was slowly added borane tetrahydrofuran complex 1.0 M (3.64 mL, 3.64 mmol) and the reaction mixture was then refluxed for 20 h. The reaction was cooled to 0° C. followed by the slow addition of methanol to quench the excess borane and then stirred at 23° C. for 15 min and then at 55° C. for 18 h. The volatiles were removed in vacuo and the crude residue was directly purified by flash chromatography using an eluent mixture of dichloromethane and methanol (0%-10%) to give 417 mg of the title compound. MS (ESI): m / z=375.2 [M+H] +

[0238] Example B.113 2-(2,6-diazaspiro[3.3]heptan-2-ylmethyl)-N-methyl-benzamide; 4-Methylbenzenesulfonic acid [ka] A solution of tert-butyl 6-[[2-(methylcarbamoyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (800 mg, 2.32 mmol) and p-toluenesulfonic acid monohydrate (1320 mg, 6.95 mmol) in EtOAc (60 mL) was heated at reflux for 2 h, then cooled to room temperature and stirred for an additional 16 h. The precipitate was collected by filtration, washed with ethyl acetate (20 mL) and dried under vacuum to give the title compound (1069 mg, 1.81 mmol, 77% yield) as a pale yellow solid. MS (ESI): m / z=246.2 [M+H] +

[0239] Step a) tert-Butyl 6-[[2-(methylcarbamoyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-[(2-methoxycarbonylphenyl)methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (Example B.112) (1000 mg, 2.89 mmol) was mixed in a vial with a solution of monomethylamine (43.3 mL, 866 mmol) (20% in MeOH). The vial was then sealed and heated at 70° C. for 24 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give the title compound (970 mg, 92% yield) as a pale yellow viscous oil. The product was used in the next step without further purification. MS (ESI): m / z=346.2 [M+H] +

[0240] Example B.149 N-(1-methylcyclopropyl)-2,6-diazaspiro[3.3]heptane-2-sulfonamide; 2,2,2-trifluoroacetic acid [ka] To a solution of 2-[(1-methylcyclopropyl)sulfamoyl]-2,6-diazaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester (448 mg, 1.35 mmol) in dichloromethane (5 mL) was added TFA (1.54 g, 1.04 mL, 13.52 mmol, 10 equiv.) and the reaction mixture was stirred at room temperature for 18 h. Volatiles were removed in vacuo to give the crude title compound (736 mg) in 63%, containing excess TFA as the main contaminant, which was used directly without further purification. MS (ESI): m / z=232.2 [M-TFA+H] +

[0241] Step a) 2-(2-Methylimidazol-1-yl)sulfonyl-2,6-diazaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester Methyl trifluoromethanesulfonate (1.09 g, 730 μL, 6.63 mmol) was added slowly to a solution of 2-methyl-1-(2-methylimidazol-1-yl)sulfonyl-imidazole (1.5 g, 6.63 mmol) in dichloromethane (27 mL) under an inert atmosphere cooled to 0° C. Upon complete addition of the reagent, a white precipitate began to form and the reaction mixture was stirred at 0° C. and allowed to slowly warm to room temperature overnight. The volatiles were removed in vacuo to give 2.60 g of the crude intermediate as a white solid which was used without further purification. The crude solid was dissolved in acetonitrile and dried in excess (27 mL) followed by the addition of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1.31 g, 6.63 mmol) and then the reaction mixture was stirred at 80° C. for 64 hours. The reaction mixture was diluted with ethyl acetate, poured into a separatory funnel and extracted with aqueous Na2CO3 1M. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and evaporated to dryness. The crude material was subjected to SFC purification to give 1372 mg of the title compound. MS (ESI): m / z=343.2 [M-TFA+H] +

[0242] Step b) 2-[(1-methylcyclopropyl)sulfamoyl]-2,6-diazaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester To a solution of 2-(2-methylimidazol-1-yl)sulfonyl-2,6-diazaspiro[3.3]heptane-6-carboxylic acid tert-butyl ester (778 mg, 2.27 mmol) in dichloromethane (10 mL) cooled to 0 °C, methyl trifluoromethanesulfonate (392 mg, 263 μL, 2.39 mmol) was added and the reaction mixture was stirred at 0 °C for 3 h. The volatiles were removed in vacuo and the crude white solid was redissolved in acetonitrile and dried over water (10 mL) followed by the addition of (1-methylcyclopropyl)amine (242 mg, 3.41 mmol) after which the reaction mixture was stirred at 70 °C for 18 h. The volatiles were removed in vacuo. The crude residue was dissolved in ethyl acetate, transferred to a separatory funnel and extracted with saturated aqueous Na2CO3. The organic phase was collected and the aqueous phase was back extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and evaporated to dryness. Purification by FC (SiO2; DCM / MeOH) gave the title compound (448 mg). MS (ESI): m / z=330.3 [M+H] +

[0243] Example B.152 N-[[1-(trifluoromethyl)cyclopropyl]methyl]-2,6-diazaspiro[3.3]heptane-2-sulfonamide; 4-Methylbenzenesulfonic acid [ka] A solution of tert-butyl 2-[[1-(trifluoromethyl)cyclopropyl]methylsulfamoyl]-2,6-diazaspiro[3.3]heptane-6-carboxylate (450 mg, 1.13 mmol) and p-toluenesulfonic acid monohydrate (429 mg, 2.25 mmol) in EtOAc (15 mL) was heated at reflux for 2 h, then cooled to room temperature and stirred for an additional 16 h. The precipitate was collected by filtration, washed with EtOAc (5 mL) and dried under vacuum to give the title compound (298 mg, 53% yield). MS (ESI): m / z=300.2 [M-TsOH+H] +

[0244] Step a) tert-Butyl 2-chlorosulfonyl-2,6-diazaspiro[3.3]heptane-6-carboxylate To a stirred solution of sulfuryl chloride (0.63 g, 4.69 mmol) in DCM (15 mL) at 0° C. was added a mixture of triethylamine (1.19 mL, 8.52 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hydrochloride (1.0 g, 4.26 mmol) (as a solution in 15 mL of DCM) at a rate to keep the temperature below 20° C. The reaction mixture was stirred at room temperature for 18 h and then evaporated to dryness. The crude sulfamoyl chloride (30% purity) was used directly in the next step without further purification.

[0245] Step b) tert-Butyl 2-[[1-(trifluoromethyl)cyclopropyl]methylsulfamoyl]-2,6-diazaspiro[3.3]heptane-6-carboxylate To a stirred mixture of tert-butyl 2-chlorosulfonyl-2,6-diazaspiro[3.3]heptane-6-carboxylate (310 mg, 1.04 mmol) and [1-(trifluoromethyl)cyclopropyl]methanamine; hydrochloride (238 mg, 1.36 mmol) in ACN (10 mL) was added N,N-diisopropylethylamine (0.55 mL, 3.13 mmol). The tube was then sealed and stirred at 40° C. for 18 h. The reaction mixture was then concentrated to dryness, the residue was dissolved in DCM (20 mL) and the organics were washed with water (2×5 mL) and saturated brine solution (5 mL). The organic layer was dried (Na2SO4) and then concentrated to dryness in vacuo. (290 mg, 0.730 mmol, 66% yield) was used in the next step without further purification. MS (ESI): m / z=398.2 [MH] -

[0246] Example B.153 2-[5-(trifluoromethyl)pyrazin-2-yl]-2,6-diazaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] Into a flask were added 6-[5-(trifluoromethyl)pyrazin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (312 mg, 0.906 mmol), p-toluenesulfonic acid monohydrate (361.96 mg, 1.9 mmol) in ethyl acetate (7.64 mL), and the mixture was stirred at reflux overnight. The crude residue was washed with EtOAc and diethyl ether to give the title compound as an off-white solid with an estimated purity of 95%, which was used without further purification. MS (ESI): m / z=245.1 [M-TsOH+H] +

[0247] Step a) 6-[5-(trifluoromethyl)pyrazin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester In a flask were added 2-bromo-5-(trifluoromethyl)pyrazine (280 mg, 1.23 mmol), 2-Boc-2,6-diazaspiro[3.3]heptane (269 mg, 1.36 mmol) and cesium carbonate (804 mg, 2.47 mmol) in 1,4-dioxane (6 mL). The suspension was bubbled with N2 for 5 min and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (47.9 mg, 0.062 mmol) was added. The mixture was heated at 110°C for 2 h. The mixture was diluted with EtOAc, filtered through celite and the filtrate was concentrated. Purification by FC (SiO2; heptane / EtOAc) afforded the title compound as a yellow solid, which was used directly in the next step. MS (ESI): m / z=345.1 [M+H]+

[0248] Analogously to Example B.153, the following building blocks were prepared using relevant commercially available building blocks: [Table 10]

[0249] Example B.265 N-[5-(trifluoromethyl)pyrazin-2-yl]-2-azaspiro[3.5]nonan-7-amine; 4-Methylbenzenesulfonic acid [ka] To a solution of 7-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (525 mg, 1.36 mmol) in isopropyl acetate (12 mL) was added p-toluenesulfonic acid monohydrate (568.57 mg, 2.99 mmol). The mixture was stirred at 80 °C for 5 h and then evaporated. Et2O was added and the resulting precipitate was filtered off, washed with Et2O (2x) and dried to give the title compound (755 mg, 83.7%) as a white solid. MS (ESI) m / z = 287.1 [M+H] +

[0250] Step a): tert-Butyl 7-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carboxylate To a solution of 7-amino-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (CAS RN: 1408075-19-3; 1.33 g, 5.53 mmol) and DIPEA (1.45 mL, 8.3 mmol) in DMSO (10 mL) was added 2-fluoro-5-(trifluoromethyl)pyrazine (CAS RN: 1220799-65-4; 919.06 mg, 5.53 mmol). The mixture was stirred at 60° C. for 5 h and then poured into EtOAc. The mixture was washed with water and brine. The organic layer was dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2; heptane / EtOAc) afforded the title compound (1.66 g, 73.75% yield) as a white solid. MS (ESI): m / z=331.2 [M+H-tBu] +

[0251] Analogously to Example B.265, the following building blocks were prepared in step a) using the relevant commercially available building blocks: [Table 11]

[0252] Example B.368 N-Methyl-N-[5-(trifluoromethyl)pyrazin-2-yl]-2-azaspiro[3.5]nonan-7-amine; 4-Methylbenzenesulfonic acid [ka] To a solution of 7-[methyl-[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (460 mg, 1.15 mmol) in isopropyl acetate (10 mL) was added p-toluenesulfonic acid monohydrate (481 mg, 2.53 mmol). The mixture was stirred at 80° C. for 5 h. Et2O was added and the mixture was filtered through sintered glass. The white solid was washed with Et2O (2×) and dried in vacuum to give the title compound (678 mg, 87%) as a white solid. MS (ESI): m / z=301.1 [M+H] +

[0253] Step a) 7-[methyl-[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester To a solution of tert-butyl 7-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carboxylate (B.265, step a) (0.610 g, 1.5 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (72.0 mg, 1.8 mmol). The mixture was stirred at 40° C. for 15 min. The reaction mixture was cooled to room temperature. Iodomethane (213 mg, 93.8 μL, 1.5 mmol) was added in one portion. The reaction mixture was stirred at 60° C. for 2 h, then poured into EtOac / THF 2:1 and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (eluting with 0% to 2% methanol in dichloromethane) to give the title compound (462 mg, 73.1%) as a white solid. MS (ESI): m / z=345.2 [M+H-tBu] +

[0254] Example B.311 6-[[5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.58 mmol) in EtOAc (2 mL) was added p-toluenesulfonic acid (110 mg, 0.64 mmol) and stirred at 80° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (230 mg, 0.55 mmol, 95% yield) as a yellow oil. MS (ESI): m / z=246.1 [M+H] + .

[0255] Step a) tert-Butyl 6-[[5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1363381-93-4) (10.0 g, 44.0 mmol), 5-(trifluoromethyl)-1H-pyrazole (5.99 g, 44.0 mmol), triphenylphosphine (14.4 g, 55.0 mmol) in THF (100 mL) was added diisopropyl azodicarboxylate (10.4 mL, 52.8 mmol) at 0° C., and then the reaction mixture was stirred at 20° C. under N2 for 12 h. The reaction mixture was diluted with 100 mL and extracted with 300 mL of EtOAc (100 mL×3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by normal phase preparative HPLC to give the title compound (3.7 g, 10.7 mmol, 24.4% yield) as a yellow solid. MS (ESI): m / z=346.1 [M+H] +

[0256] Analogously to Example B.311, the following building blocks were prepared in step a) using the relevant commercially available building blocks: [Table 12]

[0257] Example P.23 1-(2-Azaspiro[3.3]heptan-6-ylmethyl)-4-(trifluoromethyl)pyridin-2-one; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 13.4 mmol) in ethyl acetate (150 mL) was added p-toluenesulfonic acid monohydrate (5.1 g, 26.8 mmol) 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 pale yellow solid. MS (ESI): m / z=273.0 [M-TsOH+H] + .

[0258] Step a) tert-Butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate To a stirred solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1363381-93-4) (14.9 g, 65.7 mmol) in DCM (299 mL) was added triethylamine (13.7 mL, 98.6 mmol), the reaction mixture was cooled to 0° C., followed by dropwise addition of methanesulfonyl chloride (6.1 mL, 78.9 mmol), and the reaction mixture was then stirred at room temperature for 4 h. The reaction mixture was diluted with water, extracted with DCM, washed with water, brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound (19.8 g, 64.8 mmol, 93.7% yield) as a pale yellow solid. MS (ESI): m / z=250.0 [M-Bu+H] + .

[0259] Step b) tert-Butyl 6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate 4-(trifluoromethyl)-1H-pyridin-2-one (CAS: 50650-59-4) (5.34 g, 32.8 mmol) was added in portions to a suspension of sodium hydride 60% in oil (2.14 g, 49.1 mmol) in DMF (100 mL) at 0° C. under argon. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 30 minutes. The reaction mixture was cooled to 0° C. and tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 32.7 mmol), sodium iodide (4.91 g, 32.7 mmol) were added in one portion. The mixture was stirred at 0° C. for 1 h and then at 80° C. for 18 h. The reaction mixture was poured into EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% to 100% tert-butyl methyl ether in heptane) to give the title compound (3.6 g, 29% yield) as a yellow solid. MS (ESI): m / z=273.0 [M+H] + .

[0260] Analogously to Example P.23, the following building blocks were prepared in step b) using the relevant commercially available building blocks: [Table 13]

[0261] Example P.50 1-(2-Azaspiro[3.3]heptan-6-ylmethyl)-4-(trifluoromethyl)pyridin-2-one; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.5 g, 7.2 mmol) in EtOAc (100 mL) was added p-toluenesulfonic acid monohydrate (4.12 g, 21.6 mmol). The reaction mixture was stirred at 25° C. for 18 h, filtered, and washed with diethyl ether to give the title compound (3.63 g, 81% yield) as a white powder. MS (ESI): m / z=247.2 [M+H] + .

[0262] Step a) tert-Butyl 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of 4-(trifluoromethyl)-1H-triazole (2.69 g, 19.7 mmol), lithium bromide (3.41 g, 39.3 mmol) in acetonitrile (300 mL) was added tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (P.23, step a) (6.0 g, 19.65 mmol, 1 equiv., CAS2740574-92-7). The reaction mixture was stirred at 50° C. for 18 h, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 100% MTBE in heptane) to give the title compound (2.5 g, 36% yield) as a pale yellow solid. MS (ESI): m / z=247.0 [M+H-Boc] + .

[0263] Analogously to Example P.50, the following building blocks were prepared in step a) using the relevant commercially available building blocks: [Table 14]

[0264] Example P.62 6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane;2,2,2-trifluoroacetic acid [ka] To a solution of tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 13.1 mmol) 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 to give the title compound (3.94 g, 87% yield) as a white solid. MS (ESI): m / z=228.2 [M+H] + .

[0265] Step a) tert-Butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate 2-[[5-Bromo-3-(difluoromethyl)pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (5.3 g, 16.2 mmol, CAS 2416163-95-4), tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane in 1,4-dioxane (50 mL) and water (5 mL). To a mixture of tan-2-carboxylate (5.97 g, 17.8 mmol, CAS2763647-64-7) and potassium carbonate (4.47 g, 32.4 mmol) under N2, cyclopenta-2,4-dien-1-yl(diphenyl)phosphane; dichloromethane; dichloropalladium; iron(2+) (1.32 g, 1.62 mmol, 0.1 equiv., CAS95464-05-4) were added. The mixture was stirred at 100° C. under N2 atmosphere for 2 h. The reaction mixture was poured into water (500 mL). The aqueous phase was extracted with EtOAc (300 mL×2). The organic phase was washed with brine (600 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1) to give the title compound (6.1 g, 13.4 mmol, 79% yield) as a light yellow solid. MS (ESI): m / z = 456.3 [M+H] + .

[0266] Step b) tert-Butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (7 g, 15.4 mmol) in EtOAc (100 mL) was added Pd / C 10% (2 g, 4.61 mmol, 0.3 equiv.) under N2 atmosphere. The mixture was stirred at 25° C. under H2 (15 PSI) atmosphere for 0.5 h. The reaction mixture was filtered and concentrated in vacuo to give tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 85% yield) as a colorless oil.

[0267] Example B.329 [4-(2-azaspiro[3.3]heptan-6-ylmethyl)phenyl]-imino-oxo-(trifluoromethyl)-lambda 6 -Sulfane; 4-Methylbenzenesulfonic acid [ka] To a mixture of 6-[[2-fluoro-4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.03 g, 4.65 mmol) in EtOAc (20 mL) was added p-toluenesulfonic acid (0.96 g, 5.58 mmol) at 20° C. The mixture was then stirred at 80° C. for 12 h. The mixture was concentrated to remove the solvent, then deionized water was added and lyophilized to give the title compound (2.05 g, 4.03 mmol, 83.2% yield) as a yellow gum. MS (ESI): m / z=337.1 [M-TsOH+H] +

[0268] Step a) tert-Butyl 6-[[2-fluoro-4-(trifluoromethylsulfanyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (15.6 g, 46.5 mmol), 1-bromo-2-fluoro-4-(trifluoromethylsulfanyl)benzene (CAS: 1520947-39-0) (12.8 g, 46.5 mmol) and potassium carbonate (12.9 g, 93.1 mmol) in 1,4-dioxane (170 mL) and water (34 mL), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (3.8 g, 4.65 mmol) was added at 25 °C, and the mixture was then stirred at 80 °C under N2 atmosphere for 12 h. The mixture was purified by silica gel chromatography (PE:EA=5:1) and concentrated in vacuo to give the crude product, which was further purified by preparative HPLC to give the title compound (5.3 g, 13.1 mmol, 28% yield) as a yellow oil. MS(ESI): m / z=348.0 [M-C4H8+H] +

[0269] Step b) tert-Butyl 6-[[2-fluoro-4-(trifluoromethylsulfanyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[2-fluoro-4-(trifluoromethylsulfanyl)phenyl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (5.3 g, 13.1 mmol) in EtOAc (80 mL) was added wet Pd / C (1.8 g, 1.31 mmol) under N2 at 25° C., and the mixture was stirred under H2 atmosphere (balloon) at 25° C. for 12 h. The mixture was then filtered and the filtrate was concentrated to give the title compound (5.5 g, 13.6 mmol, 95.0% yield) as a colorless oil. MS (ESI): m / z=350.0 [M-C4H8+H] +

[0270] Step c) tert-Butyl 6-[[2-fluoro-4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[2-fluoro-4-(trifluoromethylsulfanyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (5.3 g, 13.1 mmol) in trifluoroethanol (55.0 mL) was added PhI(OAc)2 (17.7 g, 54.9 mmol) and NH2COONH4 (3.06 g, 39.2 mmol) at 25°C. The mixture was then stirred at 60°C for 12 hours. The mixture was purified by preparative HPLC (Phenomenex luna C18 150 x 40 mm x 15 um water (FA)-ACN) to give the title compound (2.03 g, 4.65 mmol, 36% yield) as a yellow oil. MS (ESI): m / z = 381.1 [M-C4H8+H] +

[0271] Example B.334 5-(2-Azaspiro[3.3]heptan-6-yloxy)-2-(trifluoromethyl)benzonitrile; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[3-cyano-4-(trifluoromethyl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylate (452 ​​mg, 1.18 mmol) in ethyl acetate (10 mL) was added p-toluenesulfonic acid monohydrate (292 mg, 1.54 mmol). The mixture was stirred at 20° C. for 16 h and the precipitated solid was filtered, washed with ACN and dried to give the title compound (283 mg, 0.62 mmol, 53% yield) as a white solid. MS (ESI): m / z=283.2 [M-TsOH+H] +

[0272] Step a) tert-Butyl 6-[3-cyano-4-(trifluoromethyl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylate A solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.34 mmol) and 5-hydroxy-2-(trifluoromethyl)benzonitrile (483 mg, 2.58 mmol) in toluene (10 mL) was cooled to 0° C. Triphenylphosphine (799 mg, 3.05 mmol) and diisopropyl azodicarboxylate (0.6 mL, 3.05 mmol) were added under Ar. The mixture was warmed to 20° C. and stirred for 16 h. The mixture was concentrated and the residue was triturated with TBME. The precipitated solid was filtered off and the filtrate was concentrated. The residue was purified by FC (silica, 20% EtOAc in hexane) to give the title compound (430 mg, 1.12 mmol, 48% yield) as a white solid. LCMS: no molecular peaks shown.

[0273] Analogously to Example B.334, the following building blocks were prepared in step a) using the relevant commercially available building blocks: [Table 15]

[0274] Example B.336 6-[3-(trifluoromethoxy)phenyl]sulfonyl-2-azaspiro[3.3]heptane;2,2,2-trifluoroacetic acid [ka] To a solution of 7-[3-(trifluoromethyl)phenyl]sulfonyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (267 mg, 0.585 mmol) in dichloromethane (3 mL) was added TFA (667 mg, 451 μL, 5.85 mmol) and the reaction mixture was stirred at room temperature for 18 h. Volatiles were removed in vacuo to give 431 mg of the crude title compound as a colorless viscous oil (purity approx. 60% major contaminant excess TFA) which was used without further purification. MS (ESI): m / z=322.1 [M-TsOH+H] +

[0275] Step a) tert-Butyl 6-[[2-fluoro-4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 6-methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1000 mg, 3.26 mmol) in tetrahydrofuran (15 mL) was added 3-(trifluoromethoxy)benzenethiol (696 mg, 3.59 mmol) and cesium carbonate (1.06 g, 3.26 mmol), after which the reaction mixture was stirred at 60° C. for 18 h. Further 3-(trifluoromethoxy)benzenethiol (348 mg) and cesium carbonate (503 mg) were added, after which the reaction mixture was stirred again at 60° C. for 6 h. The reaction mixture was poured into a separatory funnel containing ethyl acetate and aqueous Na2CO3 1M for extraction. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate and evaporated to dryness. The crude material was purified by flash chromatography (silica gel, ethyl acetate in heptane (5% to 25%) to give 1.11 g of the title compound. MS (ESI): m / z=334.0 [M-C4H8+H] +

[0276] Step b) 7-[3-(trifluoromethyl)phenyl]sulfonyl-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester To a suspension of 6-[[3-(trifluoromethoxy)phenyl]thio]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (250 mg, 0.629 mmol) in a mixture of methanol (3 mL) / water (3 mL), oxone (812 mg, 1.32 mmol) and sodium bicarbonate (159 mg, 1.89 mmol) were added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into a separatory funnel containing ethyl acetate and 1M aqueous NaHCO3, and after extraction, the organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated to dryness to give 265 mg of the crude title compound as a white solid. MS(ESI): m / z=366.1 [M-C4H8+H] +

[0277] Analogously to Example B.336, the following building blocks were prepared using relevant commercially available building blocks: [Table 16]

[0278] Example B.339 2-Azaspiro[3.3]heptan-6-yl-imino-oxo-[3-(trifluoromethoxy)phenyl]-lambda6-sulfane;2,2,2-trifluoroacetic acid [ka] To a solution of 6-[[3-(trifluoromethoxy)phenyl]sulfonimidoyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (225 mg, 0.508 mmol) in dichloromethane (2 mL) was added TFA (580 mg, 392 μL, 5.08 mmol) and the reaction mixture was stirred at room temperature for 18 h. Volatiles were removed in vacuo to give 440 mg of the crude title compound (approximately 50% purity, major contaminant excess TFA) as a yellow viscous oil which was used without further purification. MS (ESI): m / z=321.1 [M-TsOH+H] +

[0279] Step a) 6-[3-(trifluoromethoxy)phenyl]sulfonimidoyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester To a solution of 6-[[3-(trifluoromethoxy)phenyl]thio]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (B.336, step a) (300 mg, 0.755 mmol) in methanol (1.5 mL) was added iodobenzene diacetate (608 mg, 1.89 mmol) and ammonium carbamate (58.9 mg, 0.755 mmol), after which the reaction mixture was stirred at room temperature for 3 h. The crude reaction solution was absorbed onto H-MN isolute and dried under vacuum, followed by direct purification by flash chromatography using a SiO2 column (eluent mixture of heptane and ethyl acetate (EtOAc:EtOH 3:1) (5%-50%)) to give 228 mg of the title compound as a colorless gum. MS (ESI): m / z=421.1 [M+H] +

[0280] Example B.349 3-(2-Azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)-1,2,4-thiadiazole; 4-Methylbenzenesulfonic acid [ka] A mixture of tert-butyl 6-[[5-(trifluoromethyl)-1,2,4-thiadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (400 mg, 1.1 mmol) and TsOH (227 mg, 1.32 mmol) in EtOAc (5 mL) was stirred at 80° C. for 3 h. The reaction mixture was concentrated under reduced pressure and lyophilized to give the title compound (415 mg, 0.95 mmol, 85.3% yield) as a white solid. MS (ESI): m / z=264.0 [M-TsOH+H] +

[0281] Step a) tert-Butyl 6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (2740574-92-7) (5.0 g, 16.4 mmol) in DMSO (70 mL) was added potassium cyanide (2.45 g, 37.7 mmol) at room temperature. The resulting solution was stirred at 80° C. for 18 h. The reaction was quenched with water (50 mL) and then extracted with TBME (3×100 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (3.4 g, 14.4 mmol, 83.6% yield) as a white solid. MS (ESI): m / z=181.0 [M-C4H8+H] + .

[0282] Step b) tert-Butyl 6-[2-(hydroxyamino)-2-imino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of hydroxylamine; hydrochloride (2353 mg, 33.9 mmol) in ethanol (25 mL) was added TEA (3426 mg, 33.9 mmol) at 25° C. After 1 h, tert-butyl 6-(cyanomethyl)-2-azaspiro[3.3]heptane-2-carboxylate (4000 mg, 16.9 mmol) was added to the above reaction mixture, and then the reaction was stirred at 50° C. for another 12 h. The reaction was concentrated under reduced pressure to give a residue. The residue was dissolved in water (50.0 mL), extracted with ethyl acetate (50.0 mL×3), and the combined extracts were concentrated under reduced pressure to give the title compound (4.5 g, 16.7 mmol, 98.7% yield) as a colorless oil, which was used in the next step without further purification. MS (ESI): m / z=270.1 [M+H] +

[0283] Step c) tert-Butyl 6-(2-amino-2-imino-ethyl)-2-azaspiro[3.3]heptane-2-carboxylate; acetic acid To a solution of tert-butyl 6-[2-(hydroxyamino)-2-imino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate (4.5 g, 16.7 mmol) and Ac2O (2.56 g, 25.1 mmol) in acetic acid (20 mL) was added Pd / C (wet) (1.2 g) at 25 °C. The reaction was then stirred under H2 atmosphere (H2 balloon) at 25 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (5.2 g, 16.6 mmol, 99.3% yield) as a pale yellow oil. MS (ESI): m / z = 254.0 [M-AcOH + H] +

[0284] Step d) tert-Butyl 6-[(5-amino-1,2,4-thiadiazol-3-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-(2-amino-2-imino-ethyl)-2-azaspiro[3.3]heptane-2-carboxylate;acetic acid (3000 mg, 9.57 mmol) in water (30 mL) was added dropwise sodium hypochlorite (15.0 mL, 10.5 mmol) at 0° C., then the mixture was stirred at 20° C. for 1 h, then diluted with water and extracted with EtOAc (20 mL×3), the combined organic phase was dried over Na2SO4, concentrated, the residue was dissolved in methanol (30 mL), potassium thiocyanate (1023 mg, 10.5 mmol) was added at 0° C., then the solution was stirred at 20° C. for 11 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column on silica (ethyl acetate:petroleum ether 0-80%) and concentrated under reduced pressure to give the title compound (1400 mg, 4.51 mmol, 47.1% yield) as a brown solid. MS (ESI): m / z=311.0 [M+H] +

[0285] Step e) tert-Butyl 6-[(5-iodo-1,2,4-thiadiazol-3-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-[(5-amino-1,2,4-thiadiazol-3-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1400 mg, 4.51 mmol) and CuI (1718 mg, 9.02 mmol) in MeCN (50 mL) was added a solution of tert-butyl nitrite (930 mg, 9.02 mmol, 2.0 equiv.) in MeCN (5 mL) at 25 °C, then the reaction was stirred at 70 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column on silica (ethyl acetate:petroleum ether 0-40%) and concentrated under reduced pressure to give the title compound (900 mg, 2.14 mmol, 47.4% yield) as a yellow solid. MS (ESI): m / z=421.9 [M+H] +

[0286] Step f) tert-Butyl 6-[[5-(trifluoromethyl)-1,2,4-thiadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate A mixture of tert-butyl 6-[(5-iodo-1,2,4-thiadiazol-3-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (890 mg, 2.11 mmol), diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (1025 mg, 2.54 mmol) and Cu (1207 mg, 6.34 mmol) in DMF (8 mL) was stirred at 60 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reverse flush (FA condition; MeCN:H2O = 0-70%) and lyophilized to give a residue. The residue was purified by silica column (ethyl acetate:petroleum ether 0-30%) and concentrated under reduced pressure to give the title compound (400 mg, 1.1 mmol, 52.1% yield) as a colorless oil. MS(ESI): m / z=307.9 [M-C4H8+H] +

[0287] Example B.358 4-(2-Azaspiro[3.3]heptan-6-ylmethyl)-2-(trifluoromethoxy)benzamide; 4-Methylbenzenesulfonic acid [ka] To a solution of 6-[4-carbamoyl-3-(trifluoromethoxy)benzyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (63 mg, 0.152 mmol) in ethyl acetate (1.01 mL) was added p-toluenesulfonic acid monohydrate (30.4 mg, 0.160 mmol). The reaction mixture was stirred in an oven at reflux. The solvent was removed and the product was used in the next step without further purification. MS (ESI): m / z=315.1 [M+H] +

[0288] Step a) 6-[4-carbomethoxy-3-(trifluoromethoxy)benzylidene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 4-Bromo-2-(trifluoromethoxy)benzoic acid methyl ester (981 mg, 603 μL, 3.28 mmol) 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 (1000 mg, 2.98 mmol) were dissolved in a degassed solution of 1,4-dioxane (149 mL) and water (14.9 mL). The reaction mixture was degassed again for 5 min, after which 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium dichloride (97.2 mg, 0.149 mmol) was added, followed by tripotassium phosphate (1.27 g, 5.97 mmol). The reaction mixture was then stirred at room temperature for 3.5 h. The reaction mixture was poured into EtOAc and washed with water. The aqueous layer was extracted back twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was then purified by flash chromatography eluting with a gradient heptane / EtOAc 0-35% to give the title compound as a white solid. MS(ESI): m / z=372.1 [M-C4H8+H] +

[0289] Step b) 6-[4-carbomethoxy-3-(trifluoromethoxy)benzyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester 6-[4-Carbomethoxy-3-(trifluoromethoxy)benzylidene]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (1050 mg, 2.46 mmol) was dissolved in methanol (81.9 mL) and tetrahydrofuran (40.9 mL). The reaction mixture was degassed with argon for 10 minutes. Platinum(IV) oxide (112 mg, 0.491 mmol) was then added to the mixture under further argon. The argon atmosphere was replaced with hydrogen (via balloon) and the reaction mixture was stirred under hydrogen atmosphere for 1 hour. The reaction mixture was filtered and the resulting solution was concentrated under reduced pressure to give the crude title compound as an oil, which was used directly in the next step without further purification. MS (ESI): m / z=374.1 [M-C4H8+H]+

[0290] Step c) 4-[(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)methyl]-2-(trifluoromethoxy)benzoic acid To a solution of 6-[4-carbomethoxy-3-(trifluoromethoxy)benzyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (460 mg, 1.04 mmol) in tetrahydrofuran (2.6 mL) and methanol (2.6 mL) was added 1M aqueous NaOH (4.16 mL, 4.16 mmol) at room temperature. The mixture was then heated at 70° C. for 48 h. The organic solvent was removed under reduced pressure and the remaining crude material was then acidified to pH 2. The aqueous layer was then extracted three times with EtOAc. The organic layers were combined, dried over Na2SO4, filtered off and concentrated under reduced pressure to give the crude product, which was used directly in the next step without further purification. MS (ESI): m / z=360.1 [M-C4H8+H] +

[0291] Step d) 6-[4-carbamoyl-3-(trifluoromethoxy)benzyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester A solution of 4-[(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)methyl]-2-(trifluoromethoxy)benzoic acid (440 mg, 1.06 mmol) in dichloromethane (5.3 mL) was cooled at 0° C. CDI (177 mg, 1.06 mmol) was added and the resulting mixture was stirred for 15 min. 2M NH3 in isopropanol solution (2.65 mL, 5.3 mmol) was then added and the reaction mixture was stirred at room temperature overnight. An additional 2M NH3 in isopropanol solution (2.65 mL, 5.3 mmol) was added and the reaction was stirred for 48 h. The reaction mixture was washed twice with 1M HCl (aq) and with water. The aqueous layer was back-extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude material was then purified by flash chromatography using hexanes / EtOAc to give the title compound as a viscous oil. MS(ESI): m / z=359.1 [M-C4H8+H] +

[0292] Similar to Example B.358, the following building blocks were prepared using relevant commercially available building blocks. [Table 17]

[0293] Example B.366 2-[5-(trifluoromethyl)-2-pyridyl]-2,6-diazaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] Into a flask was added 6-[5-(trifluoromethyl)-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (285 mg, 0.830 mmol) and p-toluenesulfonic acid monohydrate (174 mg, 0.913 mmol) in ethyl acetate (7 mL) and the mixture was stirred at reflux overnight.

[0294] Another equivalent of p-toluenesulfonic acid monohydrate (174 mg, 0.913 mmol) was added and the reaction was stirred for an additional 6 h. The solvent was evaporated and the crude product was washed with diethyl ether to give the crude title compound as an orange solid. MS (ESI): m / z=244.1 [M+H] + Step a) 6-[5-(trifluoromethyl)-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester In a flask were added 2-bromo-5-(trifluoromethyl)pyridine (250 mg, 1.11 mmol), 2-Boc-2,6-diazaspiro[3.3]heptane (241 mg, 1.22 mmol) and cesium carbonate (721 mg, 2.21 mmol) in 1,4-dioxane (5.38 mL). The suspension was bubbled with N2 for 5 min and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (43.0 mg, 0.055 mmol) was added. The mixture was heated at 100°C for 2 h. The mixture was diluted with EtOAc, filtered through celite and the filtrate was concentrated. Purification was carried out by flash chromatography (heptane / EtOAc with a gradient of 0 to 40% EtOAc) to give the title compound as a yellow solid. MS (ESI): m / z=344.1 [M+H] +

[0295] Analogously to Example B.367, the following building blocks were prepared using relevant commercially available building blocks: In some cases, a different palladium / ligand catalyst was used in step a) (e.g., Pd2dba3 / Xantphos). [Table 18]

[0296] Example B.377 6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A solution of tert-butyl 6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (400 mg, 1.04 mmol) and p-toluenesulfonic acid (214 mg, 1.25 mmol) in EtOAc (8 mL) was stirred at 80° C. for 12 h. The reaction mixture was concentrated and lyophilized to give the title compound (467 mg, 1.02 mmol, 91% yield) as a light brown solid. MS (ESI): m / z=286.2 [M+H] +

[0297] Step a) tert-Butyl 6-[(4-bromopyrazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 4-bromopyrazole (2000 mg, 13.6 mmol) in DCE (40 mL) was added tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (6840 mg, 20.4 mmol), pyridine (2153 mg, 27.2 mmol), boronic acid (841 mg, 13.6 mmol) and Cu(OAc)2 (3670 mg, 18.4 mmol). The mixture was stirred at 70 °C under O2 for 12 h. The reaction mixture was purified by preparative HPLC and lyophilized. The residue was triturated in petroleum ether (10 mL) and stirred for 10 min. The solid was collected by filtration to give the title compound (2867 mg, 8.09 mmol, 59% yield) as an off-white solid. MS (ESI): m / z=298.1 [M+H] +

[0298] Step b) tert-Butyl 6-[(4-bromopyrazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4-bromopyrazol-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2300 mg, 6.49 mmol) in EtOAc (25 mL) was added PtO2 (920 mg, 4.05 mmol) under N2 at 20°C, and then the mixture was stirred under H2 atmosphere (balloon) at 20°C for 1 h. The precipitate was filtered off and the filtrate was dried in vacuum. The residue was purified by column chromatography (hexane / EtOAc, 1:1) to give the title compound (2200 mg, 6.18 mmol, 95% yield) as a pale yellow solid.

[0299] MS(ESI):m / z=302.0 [M-C4H8+H] + Step c) tert-Butyl 6-[[4-[1-(trifluoromethyl)vinyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4-bromopyrazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1700 mg, 4.77 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added 1-(trifluoromethyl)vinylboronic acid hexylene glycol ester (1270 mg, 5.73 mmol), K2CO3 (1980 mg, 14.3 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (390 mg, 0.48 mmol) under N2. The mixture was stirred at 80 °C under N2 atmosphere for 12 h. The precipitate was filtered off and the filtrate was dried in vacuum. The residue was purified by column chromatography (PE / EA, 0-60%). The reaction mixture was purified by preparative HPLC and lyophilized to give the title compound (1134.0 mg, 3.05 mmol, 64% yield) as a light brown solid. MS (ESI): m / z=372.1 [M+H] +

[0300] Step d) tert-Butyl 6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[[4-[1-(trifluoromethyl)vinyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (1000 mg, 2.69 mmol) in THF (20 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (1008 mg, 3.5 mmol). The suspension was cooled to 0° C. and NaHMDS / THF (1M) (10.8 mL, 10.8 mmol) was added dropwise. The reaction mixture was warmed to 20° C. and stirred for 12 h. The reaction mixture was purified by preparative HPLC and lyophilized to give the title compound (432 mg, 1.12 mmol, 42% yield) as a pale yellow solid. MS (ESI): m / z=386.1 [M+H] +

[0301] Similar to Example B.377, the following building blocks were prepared using relevant commercially available building blocks. [Table 19]

[0302] Example B.379 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] To a mixture of tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (790 mg, 2.05 mmol) in EtOAc (8 mL) was added p-toluenesulfonic acid (388 mg, 2.25 mmol) at 25° C., and the reaction mixture was then stirred at 80° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. 20 mL of deionized water and 2 mL of ACN were added to the residue, which was then 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] +

[0303] Step a) tert-Butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (5009 mg, 14.9 mmol), 4-bromo-5-(trifluoromethyl)-1H-pyrazole (2920 mg, 13.6 mmol) in 1,4-dioxane (73 mL), water (14.6 mL) was added potassium carbonate (3750 mg, 27.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (554 mg, 0.68 mmol) at 20 °C, and the reaction was then stirred at 100 °C under N for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (eluent 0-40% ethyl acetate / petroleum ether) to give the crude product which was further purified by flash silica gel chromatography (eluent 0-40% ethyl acetate / petroleum ether) to give the title compound (790 mg, 2.3 mmol, 17% yield) as a yellow oil. MS (ESI): m / z=288.0 [M-C4H8+H] + .

[0304] Step b) tert-Butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.75 mmol), cyclopropylboronic acid (600 mg, 6.99 mmol) in DCE (6 mL) was added pyridine (0.42 mL, 5.24 mmol), boronic acid (108 mg, 1.75 mmol), copper diacetate (698 mg, 3.5 mmol) at 20° C., and the reaction mixture was then stirred under O2 (balloon) at 100° C. for 16 h. The reaction mixture was filtered, then diluted with 50 mL water and extracted with 150 mL EtOAc (50 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (0-28% ethyl acetate / petroleum ether) to give the title compound (350 mg, 0.91 mmol, 52%) as a colorless oil. MS (ESI): m / z=328.0 [M-C4H8+H] + .

[0305] Step c) tert-Butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (720 mg, 1.88 mmol) in EtOAc (15 mL) was added Pd / C (wet, 216 mg, 10%) at 25° C., and the reaction mixture was then stirred under H2 (15 Psi) at 25° C. for 0.5 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (640 mg, 1.66 mmol, 88.4% yield) as a colorless oil. MS (ESI): m / z=330.0 [M-C4H8+H] + .

[0306] Example B.381 6-[[5-Methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A mixture of tert-butyl 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (3.8 g, 10.57 mmol, 1.0 equiv.) and p-toluenesulfonic acid (4.55 g, 26.43 mmol, 2.5 equiv.) in EtOAc (70 mL) was stirred at 25° C. for 24 h. The reaction mixture was then concentrated and crystallized from MTBE to give the title compound (3940 mg, 9.13 mmol, 86% yield) as a white solid. MS (ESI): m / z=260.2 [M+H] +

[0307] Step a) tert-Butyl 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate To a solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1000 mg, 4.4 mmol) in toluene (20 mL) was added 3-methyl-5-(trifluoromethyl)-1H-pyrazole (CAS: 10010-93-2) (660 mg, 4.4 mmol) and (cyanomethylene)tributylphosphorane (1590 mg, 6.6 mmol). The reaction mixture was stirred at 100° C. under N2 atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC and lyophilized to give the title compound (485 mg, 1.35 mmol, 31% yield) as a dark brown powder. MS (ESI): m / z=304.0 [M+H] +

[0308] Note: The regioisomer tert-butyl 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (735 mg, 2.05 mmol, 46.5% yield) was also produced as a dark brown oil. MS (ESI): m / z = 304.0 [M+H] + Example B.382 6-[[3-Methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4-Methylbenzenesulfonic acid [ka] A mixture of tert-butyl 6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (B.381, generated as regioisomer in step a)) (2.3 g, 6.4 mmol) and p-toluenesulfonic acid (2755 mg, 16.0 mmol) in EtOAc (50 mL) was stirred at 25° C. for 24 h. The reaction mixture was then concentrated and crystallized from MTBE to give the title compound (1468 mg, 3.4 mmol, 53% yield) as a white solid. MS (ESI): m / z=260.2 [M+H] +

[0309] Analogously to examples B.381 / B.382, the following regioisomeric pairs of building blocks were generated using related commercially available building blocks. [Table 20]

[0310] Example B.386 [4-(2-azaspiro[3.3]heptan-6-yloxy)phenyl]-imino-oxo-(trifluoromethyl)-lambda 6 -Sulfane; 4-Methylbenzenesulfonic acid [ka] To a solution of tert-butyl 6-[4-(trifluoromethylsulfonimidoyl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylate (380 mg, 0.9 mmol) in EtOAc (5 mL), p-toluenesulfonic acid monohydrate (206 mg, 1.08 mmol) was added and stirred at 25° C. for 18 h, then the reaction mixture was evaporated and purified by HPLC to give the title compound (143 mg, 0.29 mmol, 31% yield) as a yellow solid. MS (ESI): m / z=321.0 [M+H] +

[0311] Step a) 4-(trifluoromethylsulfonimidoyl)phenol To a stirred solution of imino-oxo-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-(trifluoromethyl)-λ6-sulfane (CAS: 1798336-50-1) (1.5 g, 4.48 mmol) in THF (75 mL) was added sodium bicarbonate (376 mg, 4.48 mmol) in water (7.5 mL) at 0° C. under air, followed by slow addition of hydrogen peroxide (1522 mg, 44.8 mmol). The reaction mixture was stirred at room temperature for 4 h. The resulting mixture was washed with water and aqueous sodium bisulfite, then dried and concentrated to give 4-(trifluoromethylsulfonimidoyl)phenol (1.0 g, 4.44 mmol, 94% yield) as a yellow solid. MS (ESI): m / z=226.0 [M+H] +

[0312] Step b) tert-Butyl 6-[4-(trifluoromethylsulfonimidoyl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylate To a mixture of 4-(trifluoromethylsulfonimidoyl)phenol (1.0 g, 4.44 mmol) and tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (947 mg, 4.44 mmol), cyanomethylenetributylphosphorane (2140 mg, 8.88 mmol) in toluene (30 mL) was added, and the resulting mixture was heated at 120 °C and stirred for 48 h. The reaction solution was concentrated. The residue was purified by flash chromatography (hexane / MTBE (10-100%)) to give the title compound (320 mg, 0.76 mmol, 16% yield) as a yellow solid. MS (ESI): m / z = 365.0 [M-C4H8+H] + .

[0313] Analogously to Example B.386, the following building blocks were prepared using relevant commercially available building blocks: [Table 21]

[0314] Example C.1 4-Bromo-2-methylsulfonyl-1-(trifluoromethyl)benzene To a solution of 4-chloro-2-methylsulfanyl-1-(trifluoromethyl)benzene (1950 mg, 8.6 mmol), CH3CN (20 mL) and water (40 mL) in 1,2-dichloroethane (20 mL) cooled with a water bath, sodium periodate (3680 mg, 17.2 mmol) and ruthenium(III) chloride hydrate (19.4 mg, 0.090 mmol) were added at 0 °C, then the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with 40 mL water and extracted with 50 mL DCM and 2 x 50 mL EtOAc. The combined organic layers were washed with 75 mL brine, dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2; PE / EtOAc) afforded the title compound (1800 mg, 73% yield) as a white solid. 1H NMR(400 MHz,CHLOROFORM-d)δ ppm 8.32(d,J=1.96 Hz,1 H)7.87(d,J=8.44 Hz,1 H)7.76(dd,J=8.44,1.22 Hz,1 H)3.22 ppm(s,3 H).

[0315] Step a) 4-Chloro-2-methylsulfanyl-1-(trifluoromethyl)benzene To a mixture of 4-chloro-2-fluoro-1-(trifluoromethyl)benzene (CAS: 94444-59-4) (5.0 g, 25.2 mmol) in DMF (50 mL) was added sodium methanethiolate (2.12 g, 30.2 mmol). The mixture was stirred at 50° C. for 2 h. The reaction mixture was diluted with 150 mL water and extracted with 2×75 mL EtOAc. The combined organic layers were washed with 100 mL brine, dried over Na2SO4, filtered and evaporated. Purification by FC (SiO2; PE / ) afforded the title compound (2 g, 31.5% yield) as a yellow solid. 1 H NMR(400 MHz,CHLOROFORM-d)δ ppm 7.55(d,J=8.44 Hz,1 H)7.30(s,1 H)7.20(dd,J=8.38,0.92 Hz,1 H)2.52-2.57 ppm(m,3 H).

[0316] Example C.6 [3-Bromo-5-(trifluoromethyl)phenyl]-imino-methyl-oxo-lambda6-sulfane Under argon atmosphere, a 200 mL sealed tube was charged with 1-bromo-3-methylsulfinyl-5-(trifluoromethyl)benzene (10.0 g, 34.8 mmol), amino 4-nitrobenzoate; trifluoromethanesulfonic acid (28.9 g, 87.1 mmol), ferrous sulfate (1058 mg, 6.97 mmol), 1,10-phenanthroline (2511 mg, 13.9 mmol) and ACN (80 mL). The reaction mixture was then stirred at 40 °C for 72 h. After cooling to room temperature, the reaction mixture was quenched with saturated NaHCO3 solution (100 mL). The mixture was extracted with CHCl2 (150 mL x 3). The combined organic layers were dried over anhydrous NaSO4 and concentrated in vacuum. The product was purified by column chromatography to give the title compound (2.2 g, 7.28 mmol, 19.9% ​​yield) as a pale yellow solid. MS(ESI): m / z=302.0 / 304.0 [M+H] +

[0317] Step a) 1-Bromo-3-methylsulfinyl-5-(trifluoromethyl)benzene 1-Bromo-3-methylsulfanyl-5-(trifluoromethyl)benzene (11.0 g, 40.6 mmol) was dissolved in trifluoroacetic acid (62.5 mL, 812 mmol) and cooled to 0° C. in an ice bath. Hydrogen peroxide (3.77 mL, 44.6 mmol) in water (4 mL) was then added and the mixture was stirred at room temperature for 12 h. After completion, the mixture was concentrated and partitioned between DCM and saturated aqueous NaHCO3 solution. The organic layer was dried and concentrated to give the title compound (10.0 g, 34.83 mmol, 81.55% yield) as a white solid. MS (ESI): m / z=287.0 / 289.0 [M+H]+

[0318] Example C.7 1-Chloro-4-dimethylphosphoryl-2-fluorobenzene To a solution of 4-chloro-3-fluoroiodobenzene (2000 mg, 7.8 mmol) in 1,4-dioxane (20 mL) was added TEA (2.17 mL, 15.6 mmol), dimethylphosphine oxide (CAS: 7211-39-4) (730 mg, 9.36 mmol), Xantphos (903 mg, 1.56 mmol) and Pd2(dba)3 (714 mg, 0.78 mmol) at 25 °C. The reaction mixture was stirred at 70 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by back-flushing (FA conditions; MeCN:H2O 0-30%) and lyophilized to give 1-chloro-4-dimethylphosphoryl-2-fluorobenzene (1387 mg, 6.71 mmol, 86% yield) as a pale yellow powder. MS(ESI): m / z=207.0 [M+H]+

[0319] Example C.8 1-Bromo-3-dimethylphosphoryl-5-fluoro-benzene To a solution of 1-bromo-3-fluoro-5-iodo-benzene (2.0 g, 6.65 mmol) in 1,4-dioxane (20 mL) was added TEA (2.32 mL, 16.6 mmol), dimethylphosphine oxide (CAS: 7211-39-4) (545 mg, 6.98 mmol), Xantphos (1923 mg, 3.32 mmol) and Pd2(dba)3 (609 mg, 0.66 mmol). The reaction mixture was stirred at 60 °C under N2 atmosphere for 16 h. The reaction mixture was filtered and the filter was concentrated. The crude product was purified by reverse phase HPLC (0.1% FA condition) and lyophilized to give 1-bromo-3-dimethylphosphoryl-5-fluoro-benzene (1.36 g, 5.42 mmol, 81.5% yield) as a brown solid, which was subsequently purified by HPLC. 1 Confirmed by H NMR. MS(ESI): m / z=251.1 [M+H] + ; 1 H NMR(400 MHz,CHLOROFORM-d)δ=7.68-7.62(m,1H),7.45-7.37(m,2H),1.78(s,3H),1.75(s,3H)

[0320] Example C.9 1-(Bromomethyl)-2-fluoro-4-(trifluoromethylsulfonyl)benzene To a mixture of 2-fluoro-1-methyl-4-(trifluoromethylsulfonyl)benzene (4.2 g, 17.3 mmol) in trifluoromethylbenzene (80.0 mL, 646 mmol) was added N-bromosuccinimide (6.33 g, 35.6 mmol) and 2,2-azobis(2-methylpropionitrile) (5.84 g, 35.6 mmol). The reaction mixture was stirred at 90° C. under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (9:1) to give the title compound (2.5 g, 7.79 mmol, 44.9% yield) as a yellow oil. 1 H NMR(400 MHz,CHLOROFORM-d)δ=4.55(s,2 H),7.73-7.79(m,2 H),7.85(dd,J=8.01,1.28 Hz,1 H).

[0321] Example 1 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one [ka] To a solution of 2,5-diazaspiro[3.4]octan-6-one hydrochloride (A.1; CAS: 1630906-86-3) (23 mg, 0.141 mmol) in N,N-dimethylformamide (0.746 mL) cooled to 0 ° C., DIPEA (128 mg, 173 μL, 0.990 mmol) was added, followed by bis(1,2,4 triazol-1-yl)methanone (24.4 mg, 0.149 mmol), after which the reaction mixture was stirred for 30 min at 0 ° C. [3-(2-azaspiro[3.3]heptan-6-ylmethyl)phenyl]-imino-keto-(trifluoromethyl)-λ6-sulfane; tosylic acid (B.1) (72.9 mg, 0.149 mmol) was added to the reaction mixture, which was then stirred at 50 ° C. for 18 h. The crude reaction mixture was directly subjected to reverse phase HPLC purification to give 28.9 mg of the title compound as a colorless oil. MS (ESI): m / z=471.4 [M+H] +

[0322] Similar to Example 1, the examples in the table below were generated using the respective building blocks AX and BX. [Table 22] TIFF2024540874000181.tif243170 TIFF2024540874000182.tif210170 TIFF2024540874000183.tif237170 TIFF2024540874000184.tif205170 TIFF2024540874000185.tif205170 TIFF2024540874000186.tif252170 TIFF2024540874000187.tif243170 TIFF2024540874000188.tif210170 TIFF2024540874000189.tif205170 TIFF2024540874000190.tif216170 TIFF2024540874000191.tif221170 TIFF2024540874000192.tif210170 TIFF2024540874000193.tif220170 TIFF2024540874000194.tif243170 TIFF2024540874000195.tif238170 TIFF2024540874000196.tif243170 TIFF2024540874000197.tif238170 TIFF2024540874000198.tif210170 TIFF2024540874000199.tif216170 TIFF2024540874000200.tif216170 TIFF2024540874000201.tif252170 TIFF2024540874000202.tif205170 TIFF2024540874000203.tif220170 TIFF2024540874000204.tif253170 TIFF2024540874000205.tif238170 TIFF2024540874000206.tif238170 TIFF2024540874000207.tif249170 TIFF2024540874000208.tif243170 TIFF2024540874000209.tif211170 TIFF2024540874000210.tif248170 TIFF2024540874000211.tif205170 TIFF2024540874000212.tif221170 TIFF2024540874000213.tif209170 TIFF2024540874000214.tif243170 TIFF2024540874000215.tif210170 TIFF2024540874000216.tif248170 TIFF2024540874000217.tif248170 TIFF2024540874000218.tif221170 TIFF2024540874000219.tif206170 TIFF2024540874000220.tif221170 TIFF2024540874000221.tif226170 TIFF2024540874000222.tif221170 TIFF2024540874000223.tif221170 TIFF2024540874000224.tif242170 TIFF2024540874000225.tif211170 TIFF2024540874000226.tif215170 TIFF2024540874000227.tif204170 TIFF2024540874000228.tif211170 TIFF2024540874000229.tif222170 TIFF2024540874000230.tif222170 TIFF2024540874000231.tif221170 TIFF2024540874000232.tif227170 TIFF2024540874000233.tif215170 TIFF2024540874000234.tif216170 TIFF2024540874000235.tif221170 TIFF2024540874000236.tif226170 TIFF2024540874000237.tif211170 TIFF2024540874000238.tif212170 TIFF2024540874000239.tif205170 TIFF2024540874000240.tif221170 TIFF2024540874000241.tif243170 TIFF2024540874000242.tif211170 TIFF2024540874000243.tif216170 TIFF2024540874000244.tif211170 TIFF2024540874000245.tif210170 TIFF2024540874000246.tif205170 TIFF2024540874000247.tif217170 TIFF2024540874000248.tif253170 TIFF2024540874000249.tif211170 TIFF2024540874000250.tif212170 TIFF2024540874000251.tif222170 TIFF2024540874000252.tif217170 TIFF2024540874000253.tif222170 TIFF2024540874000254.tif212170 TIFF2024540874000255.tif215170 TIFF2024540874000256.tif215170 TIFF2024540874000257.tif211170 TIFF2024540874000258.tif221170 TIFF2024540874000259.tif220170 TIFF2024540874000260.tif210170 TIFF2024540874000261.tif221170 TIFF2024540874000262.tif221170 TIFF2024540874000263.tif216170 TIFF2024540874000264.tif151170

[0323] Example 3 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one [ka] To a solution of 6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane;4-methylbenzenesulfonic acid (B.3) (79.4 mg, 0.132 mmol) in N,N-dimethylformamide (0.781 mL) was added DIPEA (109 mg, 147 μL, 0.841 mmol). 4-Nitrophenyl 6-oxo-2,5-diazaspiro[3.4]octane-2-carboxylate (35 mg, 0.120 mmol) was added to the reaction mixture, which was then stirred at 50° C. for 18 hours. The crude reaction mixture was directly subjected to reverse phase HPLC purification to give the title compound (28.7 mg). MS (ESI): m / z=409.3 [M+H] +

[0324] Step a) 4-Nitrophenyl 6-oxo-2,5-diazaspiro[3.4]octane-2-carboxylate To a solution of 2,5-diazaspiro[3.4]octan-6-one hydrochloride (A.1) (205 mg, 1.26 mmol) and TEA (383 mg, 527 μL, 3.78 mmol) in DCM (3 ml) cooled to 0° C. using an ice bath, 4-nitrophenyl carbonochloridate (280 mg, 1.39 mmol) was added in three portions and the reaction mixture was stirred at room temperature for 3.5 h. The reaction was filtered and the solid was the title compound (126 mg, 34% yield). MS (ESI): m / z=292.2 [M+H] +

[0325] Similar to Example 3, the examples in the table below were generated using the respective building blocks AX and BX. [Table 23] TIFF2024540874000267.tif248170 TIFF2024540874000268.tif167170

[0326] Example 376 The compounds of formula (I) can be used in a manner known per se as active ingredient to prepare tablets of the following composition:

[0327] Per tablet Active ingredient: 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg Example 377 The compounds of formula (I) can be used in a manner known per se as active ingredient to prepare capsules of the following composition:

[0328] Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Formula (I): 【Chemistry 117】 (In the formula, X １ , X ２ , X ３ , and X ４ are each independently selected from CH and N; W is selected from O and NH; Z is O, CH ２ , C.H. ２ CH ２ , N.H., C.H. ２ O, and OCH ２ is selected from L is shared, CH ２ NR ４ NHCH ２ , CH ２ NH, NHCO, CONH, CH ２ O, OH ２ ,O,NHSO ２ , SO ２ , SO ２ NH, 【Chemistry 118】 , and C.H. ２ NHSO ２ is selected from A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, [1,2,4]triazolo[1,5-a]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1,2-dihydropyridyl, and bicyclo[1.1.1]pentanyl; B is, 【Chemistry 119】 is selected from R １ is hydrogen, halogen, cyano, C １ ~C ６ -Alkyl, C １ ~C ６ -Alkyl-NHC(O)-, carbamoyl, C １ ~C ６ -alkoxy, halo-C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkoxy, C ３ ~C １０ -cycloalkyl, (C １ ~C ６ -alkyl) ２ PO-, and groups 【Chemistry 120】 and C is selected from ３ ~C １０ -cycloalkyl is one halo-C １ ~C ６ - optionally substituted with alkyl substituents; R ２ and R ３ is hydrogen, halogen, cyano, oxo, C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkyl, and halo-C １ ~C ６ -alkoxy; R ４ is hydrogen and C １ ~C ６ - alkyl, R ５ is C ３ ~C １０ -cycloalkyl, C １ ~C ６ -Alkyl and halo-C １ ~C ６ -alkyl) or a pharmaceutically acceptable salt thereof.

2. B, 【Chemistry 121】 is selected from: X ２ and X ３ But both are CH, X ４ 2. The compound of formula (I) according to claim 1, wherein is selected from CH and N, or a pharmaceutically acceptable salt thereof.

3. Z is O, CH ２ , C.H. ２ CH ２ , C.H. ２ 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is selected from O and NH.

4. L が、shared bond、CH ２ NR ４ NHCH ２ , CH ２ NH, NHCO, CH ２ O、O、SO ２ NH, NHSO ２ , SO ２ 、 【Chemical 122】 , and C.H. ２ NHSO ２ is selected from R ４ is hydrogen and C １ ~C ６ 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: - alkyl is selected from:

5. L is CH ２ , S.O. ２ , N.R. ４ and O; R ４ 5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

6. W is selected from O and NH; A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, [1,2,4]triazolo[1,5-a]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1,2-dihydropyridyl, and bicyclo[1.1.1]pentanyl; R １ But hydrogen, cyano, C １ ~C ６ -Alkyl, C １ ~C ６ -Alkyl-NHC(O)-, carbamoyl, halogen, halo-C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkoxy, C ３ ~C １０ -cycloalkyl, and groups 【Chemical 123】 and C is selected from ３ ~C １０ -cycloalkyl is one halo-C １ ~C ６ - optionally substituted with alkyl substituents; R ２ is hydrogen, halogen, cyano, oxo, C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkyl, and halo-C １ ~C ６ -alkoxy, R ３ is hydrogen and C １ ~C ６ - alkyl, R ５ But C ３ ~C １０ -cycloalkyl, C １ ~C ６ -Alkyl and halo-C １ ~C ６ 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: - alkyl is selected from:

7. W is selected from O and NH; A is selected from pyridyl, phenyl, triazolyl, pyrazolyl, pyrimidinyl, and pyridazinyl; R １ But, Halo-C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkoxy, and groups 【Chemical 124】 is selected from R ２ But hydrogen, halogen, C １ ~C ６ - selected from alkyl and cyano, R ３ is hydrogen, R ５ But C １ ~C ６ -Alkyl and halo-C １ ~C ６ 7. The compound of formula (I) according to claim 6, or a pharmaceutically acceptable salt thereof, wherein: - alkyl is selected from:

8. W is selected from O and NH; A is selected from pyridyl, phenyl, pyrimidinyl, triazolyl, pyrazolyl, and pyridazinyl; R １ But CF ３ , C.F. ３ O and groups 【Chemistry 125】 is selected from R ２ is selected from hydrogen, fluoro, methyl, and cyano; R ３ is hydrogen, R ５ However, methyl and CF ３ 8. The compound of formula (I) according to claim 7, selected from: or a pharmaceutically acceptable salt thereof.

9. X １ , X ２ , X ３ , and X ４ are each independently selected from CH and N; W is selected from O and NH; Z is O, CH ２ , C.H. ２ CH ２ , N.H., C.H. ２ O, and OCH ２ is selected from L が、shared bond、CH ２ NR ４ NHCH ２ , CH ２ NH, NHCO, CH ２ O、O、SO ２ NH, NHSO ２ , SO ２ 、 【Chemical 126】 , and C.H. ２ NHSO ２ is selected from A is selected from pyridyl, phenyl, azetidinyl, cyclopropyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, oxazolyl, isoxazolyl, [1,2,4]triazolo[1,5-a]pyridyl, 1H-pyrazolo[4,3-b]pyridyl, 1,2-dihydropyridyl, and bicyclo[1.1.1]pentanyl; B, 【127】 is selected from R １ But hydrogen, halogen, cyano, C １ ~C ６ -Alkyl, C １ ~C ６ -Alkyl-NHC(O)-, carbamoyl, halogen, halo-C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkoxy, C ３ ~C １０ -cycloalkyl, (C １ ~C ６ -alkyl) ２ PO-, and groups 【128】 and C is selected from ３ ~C １０ -cycloalkyl is one halo-C １ ~C ６ - optionally substituted with alkyl substituents; R ２ is hydrogen, halogen, cyano, oxo, C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkyl, and halo-C １ ~C ６ -alkoxy, R ３ is hydrogen and C １ ~C ６ alkyl, R ４ is hydrogen and C １ ~C ６ - alkyl, R ５ But C ３ ~C １０ -cycloalkyl, C １ ~C ６ -Alkyl and halo-C １ ~C ６ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: - alkyl is selected from:

10. X ２ and X ３ But both are CH, X ４ is selected from CH and N; W is selected from O and NH; Z is O, CH ２ CH ２ , C.H. ２ O, CH ２ and NH; L is CH ２ , S.O. ２ , N.R. ４ and O; A is selected from pyridyl, phenyl, triazolyl, pyrazolyl, pyrimidinyl, and pyridazinyl; B, 【129】 is selected from R １ But, Halo-C １ ~C ６ -Alkyl, halo-C １ ~C ６ -alkoxy, and groups 【Chemistry 130】 is selected from R ２ But hydrogen, halogen, C １ ~C ６ - selected from alkyl and cyano, R ３ is hydrogen, R ４ is hydrogen, R ５ But C １ ~C ６ -Alkyl and halo-C １ ~C ６ 10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein: - alkyl is selected from:

11. X ２ and X ３ But both are CH, X ４ is selected from CH and N; W is O, CH ２ CH ２ , C.H. ２ O, and NH; Z is O, CH ２ and NH; L is CH ２ , S.O. ２ , N.R. ４ and O; A is selected from pyridyl, phenyl, triazolyl, pyrazolyl, pyrimidinyl, and pyridazinyl; B, 【Chemistry 131】 is selected from R １ But CF ３ , C.F. ３ O, and groups 【Chemistry 132】 is selected from R ２ is selected from hydrogen, fluoro, methyl and cyano; R ３ is hydrogen, R ４ is hydrogen, R ５ However, methyl and CF ３ 11. The compound of formula (I) according to claim 10, selected from: or a pharmaceutically acceptable salt thereof.

12. 2. A compound of formula (I) according to claim 1, selected from the following: 2-[6-(4-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-fluoro-2-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[7-[methyl-[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-keto-2,5,7-triazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[7-[2-(trifluoromethyl)pyrimidin-4-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[7-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(4-fluoro-2-mesyl-phenoxy)-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-triflylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(2,5-dichlorophenoxy)-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-fluoro-2-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-mesyl-3-(trifluoromethyl)benzyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-mesyl-3-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-fluoro-5-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.5]nonan-7-yl]-3-(trifluoromethoxy)benzenesulfonamide; 2-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]-3-(trifluoromethyl)benzenesulfonamide; 2-[6-(3-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-mesylbenzyl)-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-fluorophenyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-fluoro-2-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrazin-2-yl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.5]nonan-7-yl]-3-(trifluoromethoxy)benzenesulfonamide; 2-[6-[[1-(trifluoromethyl)cyclopropyl]amino]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-fluoro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-mesyl-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-(trifluoromethyl)pyrimidin-5-yl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[4-mesyl-3-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-[4-mesyl-3-(trifluoromethyl)phenoxy]-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-(trifluoromethyl)cyclopropyl]methylamino]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[(5-chloro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrazin-2-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[6-(trifluoromethyl)-3-pyridyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(5-chloro-2-mesyl-phenoxy)-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[5-(trifluoromethyl)pyrimidin-2-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-mesylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-fluoro-2-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethyl)azetidin-1-yl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]-3-(trifluoromethyl)benzenesulfonamide; 2-[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)oxazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(5-fluoro-3-pyridyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]amino]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-fluoro-5-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethyl)-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)imidazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[(4-methylsulfonylphenyl)methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6S)-6-[(4-methylsulfonylphenyl)methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-N-[1-(trifluoromethyl)cyclopropyl]-2-azaspiro[3.3]heptane-6-carboxamide; 2-[6-(4-mesylbenzyl)-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.5]nonan-6-one; N-[2-(6-keto-7-oxa-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]-3-(trifluoromethyl)benzenesulfonamide; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(difluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-7-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-(3-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(4-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-(3-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(4-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[[1-(trifluoromethyl)cyclopropyl]amino]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-(2,4-difluorobenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[2-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-7-carbonyl]-2,5,7-triazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-(3-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-(trifluoromethyl)cyclopropyl]methoxy]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-2,7-diazaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[3-fluoro-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[4-fluoro-2-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-(4-triflylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[2-[3-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-fluoro-2-mesyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-triflylbenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3,5-difluorobenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(4-mesylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3,5-difluoro-2-pyridyl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-(3-mesylbenzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-mesylbenzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(5-chloro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(5-chloro-3-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3-chloro-5-fluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-fluoro-3-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-methylsulfonyl-3-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-methylsulfonyl-3-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-methylsulfonyl-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-methylsulfonyl-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(2-methylsulfonylphenyl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[2-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[4-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[3-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-(1-methylcyclopropyl)-6-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2,6-diazaspiro[3.3]heptane-2-sulfonamide; 2-[7-[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[4-fluoro-2-(trifluoromethyl)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[[5-(trifluoromethyl)-3-pyridyl]sulfonyl]-2,6-diazaspiro[3.3]heptane-6-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 6-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-N-[[1-(trifluoromethyl)cyclopropyl]methyl]-2,6-diazaspiro[3.3]heptane-2-sulfonamide; 2-[2-[3-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[4-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[2-[2-(trifluoromethoxy)phenyl]sulfonyl-2,6-diazaspiro[3.3]heptane-6-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; N-methyl-2-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2,6-diazaspiro[3.3]heptan-6-yl]methyl]benzamide; 2-[6-[5-(trifluoromethyl)-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-fluoro-5-(trifluoromethyl)-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]sulfonyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrazin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[5-(trifluoromethyl)pyrimidin-2-yl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; N-[2-(6-oxo-8-oxa-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]-3-(trifluoromethyl)benzenesulfonamide; 5-[[(6S)-2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]oxy]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6S)-2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6R)-2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]methyl]-2-(trifluoromethyl)pyridine-4-carbonitrile; 5-[[(6S)-2-(6-oxo-8-oxa-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.4]octan-6-yl]oxy]-2-(trifluoromethyl)pyridine-4-carbonitrile; 2-[6-[(4-cyclopropylsulfonylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 3-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; 2-[7-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 4-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[(6S)-6-(3-triflylbenzyl)-2-azaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)phenyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-(trifluoromethyl)pyrimidin-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6S)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6R)-6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6S)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[(6R)-6-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-methylsulfonyl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-5-(trifluoromethyl)benzonitrile; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carbonitrile; 4-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethoxy)benzamide; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethoxy)benzamide; 2-[6-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 1-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]pyrazole-4-carbonitrile; 2-[6-[[1-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-oxo-4-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 6-oxo-N-[[6-(trifluoromethyl)-3,4-diazatricyclo[7.1.1.03,7]undeca-4,6-dien-1-yl]methyl]-2,5-diazaspiro[3.4]octane-2-carboxamide; 3-fluoro-4-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]benzonitrile; 2-[6-[[5-(trifluoromethylsulfonyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethylsulfonyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(methylsulfonimidoyl)-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(difluoromethyl)-1H-pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-fluoro-4-(trifluoromethylsulfonyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-oxo-5-(trifluoromethyl)-1-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 5-[[2-(6-oxo-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-3-(trifluoromethyl)pyridine-2-carbonitrile; 2-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[5-(trifluoromethylsulfonyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-fluoro-4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[3-(trifluoromethylsulfonyl)phenyl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-fluoro-4-(trifluoromethylsulfonyl)phenyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-methylsulfonyl-5-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(4-cyclopropylsulfonylphenyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 4-[[2-(6-oxo-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 5-[[2-(6-oxo-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 5-[[2-(6-oxo-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)pyridine-3-carbonitrile; 3-fluoro-4-[[2-(6-oxo-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]benzonitrile; 2-[6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[3-(trifluoromethoxy)phenyl]sulfonyl-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[4-(trifluoromethyl)phenyl]sulfonyl-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[3-(trifluoromethyl)phenyl]sulfonyl-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethoxy)phenyl]sulfonimidoyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-3-pyridyl]oxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 4-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; 4-[[2-(6-oxo-8-oxa-2,5-diazaspiro[3.5]nonane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; 2-[6-[(5-chloro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-chloro-1,3-dimethyl-pyrazol-4-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-oxo-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]oxy]-2-(trifluoromethyl)benzonitrile; 2-[6-[4-(trifluoromethyl)thiazol-2-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(5-fluoro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]oxy-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-[1-(trifluoromethyl)cyclopropyl]pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3-chloro-5-fluoro-2-pyridyl)oxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-(trifluoromethyl)pyrimidin-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-(trifluoromethyl)thiazol-5-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[6-(trifluoromethyl)pyridazin-3-yl]methyl]-2,7-diazaspiro[3.4]octane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(5-fluoro-3-pyridyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(1H-pyrazolo[4,3-b]pyridin-5-ylmethyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-fluoro-5-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[7-[[5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-keto-5-(trifluoromethyl)-1H-pyridin-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-[1-(trifluoromethyl)cyclopropyl]-1,2,4-triazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(2-tert-butylthiazol-5-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)isothiazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-1H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(4-cyclobutylthiadiazol-5-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-(trifluoromethylsulfonimidoyl)phenoxy]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(4-dimethylphosphoryl-2-fluoro-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)isoxazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-dimethylphosphoryl-5-fluoro-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(3-cyclopropyl-1,2,4-thiadiazol-5-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-methyl-4-(trifluoromethyl)thiazol-2-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[2-methyl-4-(trifluoromethyl)thiazol-5-yl]methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(1-methylpyrazol-4-yl)oxy-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[(4-cyclopropylthiadiazol-5-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[3-(difluoromethyl)-5-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(difluoromethyl)thiazol-2-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[5-(trifluoromethyl)-1,2,4-thiadiazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-1H-pyrazol-3-yl]methyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 4-[[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 2-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-(3-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[5-(difluoromethyl)-3-methyl-pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[2-methyl-4-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(3,5-difluoro-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-(2-fluoro-4-triflyl-benzyl)-2,6-diazaspiro[3.3]heptane-2-carbonyl]-8-oxa-2,5-diazaspiro[3.5]nonan-6-one; 2-[6-[(4-tert-butyloxazol-2-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; and 2-[6-[(2-keto-1H-pyridin-3-yl)methyl]-2,6-diazaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one.

13. 12. A compound of formula (I) according to claim 11, selected from the following: or a pharmaceutically acceptable salt thereof: 2-[6-(4-mesylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[[5-(trifluoromethyl)-2-pyridyl]amino]-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one; 2-[6-[[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 2-[7-[6-(trifluoromethyl)pyridazin-3-yl]oxy-2-azaspiro[3.5]nonane-2-carbonyl]-7-oxa-2,5-diazaspiro[3.4]octan-6-one; 5-[[2-(6-keto-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 5-[[2-(6-keto-2,5,7-triazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; 5-[[2-(6-keto-7-oxa-2,5-diazaspiro[3.4]octane-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile; and 2-[6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-2,5-diazaspiro[3.4]octan-6-one.

14. A method for producing a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, comprising: (a) Nucleophilic spirocyclic amine 1 【Chemistry 133】 (In the formula, R １ ~R ３ , L, A and B are as defined in claim 1 or 2), Formula 2 【Chemistry 134】 wherein Z is as defined in claim 1 or 2, in a solvent and in the presence of a base to form said compound of formula (I); or (b) Nucleophilic spirocyclic amine 1 【Chemistry 135】 (In the formula, R １ ~R ３ , L, A and B are as defined in claim 1 or 2), Formula 2a 【Chemistry 136】 wherein Z is as defined in claim 1 or 2, in a solvent and in the presence of a base to form said compound of formula (I); and optionally (c) contacting said compound of formula (I) with an acid to form a pharmaceutically acceptable salt thereof; A method comprising:

15. 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

16. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier.

17. 17. The pharmaceutical composition of claim 16 for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, and / or inflammatory bowel disease in a mammal.

18. 10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2 for the manufacture of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, and / or inflammatory bowel disease in a mammal.

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