Heterocyclic inhibitors of monoacylglycerol lipase (MAGL)

Abstract

The invention provides new heterocyclic compounds having the general formula (I) wherein A, B, L, R1, and R2 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

Description

[0001] HETEROCYCLIC INHIBITORS OF MONOACYLGLYCEROL LIPASE (MAGL)

[0002] Field of the Invention

[0003] The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to monoacylglycerol lipase (MAGL) inhibitors for the treatment or prophylaxis of diseases and disorders that are associated with MAGL, such as neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, gut motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or renal disease in a mammal.

[0004] Background of the Invention

[0005] Endocannabinoids (ECs) are signaling lipids that exert their biological actions by interacting with cannabinoid receptors (CBRs), CB1 and CB2. They modulate multiple physiological processes including neuroinflammation, neurodegeneration and tissue regeneration (lannotti, F.A., et aL, Progress in lipid research 2016, 62, 107-28.). In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacyglycerol lipases (DAGL) and hydrolyzed by the monoacylglycerol lipase, MAGL. MAGL hydrolyses 85% of 2-AG; the remaining 15% being hydrolysed by ABHD6 and ABDH12 (Nomura, D.K., etal., Science 2011, 334, 809.). MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes and microglia cells (Chanda, P.K., et al. , Molecular pharmacology 2010, 78, 996; Viader, A., et al, Cell reports 2015, 12, 798.). 2-AG hydrolysis results in the formation of arachidonic acid (AA), the precursor of prostaglandins (PGs) and leukotrienes (LTs). Oxidative metabolism of AA is increased in inflamed tissues. There are two principal enzyme pathways of arachidonic acid oxygenation involved in inflammatory processes, the cyclo-oxygenase which produces PGs and the 5 -lipoxygenase which produces LTs. Of the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important. These products have been detected at sites of inflammation, e.g. in the cerebrospinal fluid of patients suffering from neurodegenerative disorders and are believed to contribute to inflammatory response and disease progression. Mice lacking MAGL (Mgll- / -) exhibit dramatically reduced 2-AG hydrolase activity and elevated 2-AG levels in the nervous system while other arachidonoyl-containing phospho- and neutral lipid species including anandamide (AEA), as well as other free fatty acids, are unaltered. Conversely, levels of AA and AA-derived prostaglandins and other eicosanoids, including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2), and thromboxane B2 (TXB2), are strongly decreased. Phospholipase A2 (PLA2) enzymes have been viewed as the principal source of AA, but cPLA2-deficient mice have unaltered AA levels in their brain, reinforcing the key role of MAGL in the brain for AA production and regulation of the brain inflammatory process.

[0006] Neuroinflammation is a common pathological change characteristic of diseases of the brain including, but not restricted to, neurodegenerative diseases (e.g. multiple sclerosis, Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy and mental disorders such as anxiety and migraine). In the brain, production of eicosanoids and prostaglandins controls the neuroinflammation process. The pro-inflammatory agent lipopolysaccharide (LPS) produces a robust, time-dependent increase in brain eicosanoids that is markedly blunted in Mgll- / - mice. LPS treatment also induces a widespread elevation in pro-inflammatory cytokines including interleukin- 1 -a (IL-l-a), IL-lb, IL-6, and tumor necrosis factor-a (TNF-a) that is prevented in Mgll- / - mice.

[0007] Neuroinflammation is characterized by the activation of the innate immune cells of the central nervous system, the microglia and the astrocytes. It has been reported that anti-inflammatory drugs can suppress in preclinical models the activation of glia cells and the progression of disease including Alzheimer’s disease and mutiple sclerosis (Lleo A., Cell Mol Life Sci. 2007, 64, 1403.). Importantly, genetic and / or pharmacological disruption of MAGL activity also blocks LPS-induced activation of microglial cells in the brain (Nomura, D.K., et al, Science 2011, 334, 809.).

[0008] In addition, genetic and / or pharmacological disruption of MAGL activity was shown to be protective in several animal models of neurodegeneration including, but not restricted to, Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. For example, an irreversible MAGL inhibitor has been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, J.Z., el al.. Nature chemical biology 2009, 5, 37.). Systemic injection of such inhibitor recapitulates the Mgll- / - mice phenotype in the brain, including an increase in 2- AG levels, a reduction in AA levels and related eicosanoids production, as well as the prevention of cytokines production and microglia activation following LPS-induced neuroinflammation (Nomura, D.K., et al., Science 2011, 334, 809.), altogether confirming that MAGL is a druggable target.

[0009] Consecutive to the genetic and / or pharmacological disruption of MAGL activity, the endogenous levels of the MAGL natural substrate in the brain, 2- AG, are increased. 2-AG has been reported to show beneficial effects on pain with, for example, anti-nociceptive effects in mice (Ignat owska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015, 353, 424.) and on mental disorders, such as depression in chronic stress models (Zhong P. et al, Neuropsychopharmacology 2014, 39, 1763.).

[0010] Furthermore, oligodendrocytes (OLs), the myelinating cells of the central nervous system, and their precursors (OPCs) express the cannabinoid receptor 2 (CB2) on their membrane. 2-AG is the endogenous ligand of CB1 and CB2 receptors. It has been reported that both cannabinoids and pharmacological inhibition of MAGL attenuate OLs’s and OPCs’s vulnerability to excitotoxic insults and therefore may be neuroprotective (Bernal-Chico, A., et al, Glia 2015, 63, 163.). Additionally, pharmacological inhibition of MAGL increases the number of myelinating OLs in the brain of mice, suggesting that MAGL inhibition may promote differentiation of OPCs in myelinating OLs in vivo (Alpar, A., et al, Nature communications 2014, 5, 4421.). Inhibition of MAGL was also 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.).

[0011] In recent years, metabolism is talked highly important in cancer research, especially the lipid metabolism. Researchers believe that the de novo fatty acid synthesis plays an important role in tumor development. Many studies illustrated that endocannabinoids have anti-tumorigenic actions, including anti-proliferation, apoptosis induction and anti-metastatic effects. MAGL as an important decomposing enzyme for both lipid metabolism and the endocannabinoids system, additionally as a part of a gene expression signature, contributes to different aspects of tumourigenesis (Qin, FL, et al, Cell Biochem. Biophys. 2014, 70, 33; Nomura DK et al., Cell 2009, 740(1), 49-61; Nomura DK et al., Chem. Biol. 2011, 18(fT), 846-856; Jinlong Yin et al, Nature Communications 2020, 11, 2978). The endocannabinoid system is also invlolved in many gastrointestinal physiological and physiopathological actions (Marquez, Suarez et al. 2009). All these effects are driven mainly via cannabinoid receptors (CBRs), CB1 and CB2. CB1 receptors are present throughout the GI tract of animals and healthy humans, especially in the enteric nervous system (ENS) and the epithelial lining, as well as smooth muscle cells of blood vessels in the colonic wall (Wright, Rooney et al. 2005), (Duncan, Davison et al. 2005). Activation of CB1 produces anti-emetic, anti-motility, and anti-inflammatory effect, and help to modulate pain (Perisetti, Rimu et al. 2020). CB2 receptors are expressed in immune cells such as plasma cells and macrophages, in the lamina propria of the GI tract (Wright, Rooney et al. 2005), and primarily on the epithelium of human colonic tissue associated with inflammatory bowel disease (IBD). Activation of CB2 exerts antiinflammatory effect by reducing pro-inflammatory cytokines. Expression of MAGL is increased in colonic tissue in UC patients (Marquez, Suarez et al. 2009) and 2- AG levels are increased in plasma of IBD patients (Grill, Hogenauer et al. 2019). Several animal studies have demonstrated the potential of MAGL inhibitors for symptomatic treatment of IBD. MAGL inhibition prevents TNBS-induced mouse colitis and decreases local and circulating inflammatory markers via a CB1 / CB2 MoA (Marquez, Suarez et al. 2009). Furthermore, MAGL inhibition improves gut wall integrity and intestinal permeability via a CB1 driven MoA (Wang, Zhang et al. 2020).

[0012] In conclusion, suppressing the action and / or the activation of MAGL is a promising new therapeutic strategy for the treatment or prevention of various diseases and disorders.

[0013] W02020104494 discloses certain MAGL inhibitors. However, it was found that, while those MAGL inhibitors have properties that make them particularly suitable for the treatment of CNS indications, such as multiple sclerosis, some properties (e.g. high permeability) means that they are less suitable if a differential exposure across tissues is required. This could make them less suitable for the treatment of certain disorders, which may benefit from achieving higher exposure in target tissues than in the rest of the body.

[0014] Accordingly, there continues to be a high unmet medical need for new MAGL inhibitors, especially for new MAGL inhibitors with distinct properties such that different exposures can be achieved in different tissues.

[0015] Summary of the Invention

[0016] Surprisingly, starting from the compounds disclosed in W02020104494, a number of chemical modifications enabled a marked reduction in passive permeability (Papp) and an increase in P-gp efflux ratio, while maintaining cellular potency and excellent overall drug-like properties. The compounds of the present invention were found to be particularly useful for indications benefitting from differential levels of MAGL inhibition in different tissues, in particular indications benefitting from a higher level of MAGL inhibition in the periphery than in the brain, such as inflammatory bowel disease.

[0017] In a first aspect, the present invention provides a compound of formula (I) wherein A, B, L, R1, and R2are as described herein.

[0018] In further aspects, the present invention provides processes for manufacturing the compounds of formula (I), pharmaceutical compositions comprising the compounds of formula (I), as well as methods of using the compounds of formula (I) in the treatment or prophylaxis of diseases and disorders that are associated with MAGL.

[0019] Detailed Description of the Invention

[0020] Definitions

[0021] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (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 where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0022] The term “alkyl” refers to a linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“Ci-Ce-alkyl”), e.g., of 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, yet non-limiting example of alkyl is methyl.

[0023] The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“Ci-Ce-alkoxy”). In some preferred embodiments, the alkoxy group contains contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non-limiting example of alkoxy is methoxy.

[0024] 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, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl).

[0025] The term "aryl" refers to a monocyclic or bicyclic carbocyclic ring system having a total of 6 to 10 ring members (“Ce-io-aryl”), preferably, 6 to 9 ring members, and more preferably 6 to 8 ring members, and wherein at least one ring in the system is aromatic. A particularly preferred, yet non-limiting example of aryl is phenyl.

[0026] The term “cycloalkyl” as used herein refers to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“Cs-io-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A preferred, yet non-limiting example of cycloalkyl is cyclopropyl.

[0027] The term “heterocyclyl” as used herein refers to a saturated or partly unsaturated mono- or bicyclic ring system having a total of 3 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, more preferably 5 to 8 ring members, more preferably 5 to 6 ring members, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. “Bicyclic heterocyclyl” refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom. Some non-limiting examples of heterocyclyl groups include azetidine, pyrrolidine, piperidine, piperazinyl, morpholine, 1,2-dihydropyridine, and l,5-dihydroimidazo[l,2-a]pyrimidine. Preferred, yet nonlimiting examples of heterocyclyl are azetidine, 1,2-dihydropyridine, and 1,5- dihydroimidazof 1 ,2-a]pyrimidine.

[0028] The term “bicyclic spirocycle” refers to a 7-11 membered, preferably a 7-9 membered bicyclic chemical entity consisting of two heterocyclyl moieties as defined herein, or to a combination of one heterocyclyl and one cycloalkyl moiety as defined herein, having one ring atom in common, i.e., the two rings being connected via one common ring atom. Some preferred, yet non-limiting examples of bicyclic spirocycles include:

[0029] The term "heteroaryl" refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, more preferably 5 to 8 ring members, more preferably 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. More preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4- thiadiazolyl, 1,2,4-triazolyl, 2H-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, pyridazinyl, pyrazolyl, oxazolyl, [l,2,4]triazolo[4,3-a]pyridine, [l,2,4]triazolo[l,5-a]pyridine, lH-pyrrolo[2,3-b]pyridine, imidazo[l,5-a]pyridine, imidazo[l,2-a]pyridine, 2H-pyrazolo[3,4- b]pyridine, 2H-pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[3,4-b]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 2H-pyrazolo[3,4-d]pyrimidine, [l,2,4]triazolo[l,5-a]pyrimidine, imidazo[l,2-a]pyrazine, 1,2-benzoxazole, IH-indazole, 1H- imidazo[l,2-c]pyrimidin-5-one, lH-pyrrolo[2,3-b]pyridine, imidazo[l,2-a]pyrimidine, 2H- pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [l,2,4]triazolo[l,5-b]pyrimidine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, lH-imidazo[4,5-b]pyridine, 3H- imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine, lH-pyrazolo[3,4- b]pyridine, lH-imidazo[l,2-a]pyrimidin-5-one, and 2H-indazole.

[0030] The term “cyano” refers to a -CN (nitrile) group.

[0031] The term “oxo” refers to an oxygen atom bound to the parent molecule through a double bond (=0).

[0032] The term “haloalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl (CF3) and 2,2,2-trifluoroethyl.

[0033] The term “haloalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet nonlimiting examples of haloalkoxy are trifluoromethoxy (-OCF3) and 2,2,2-trifluoroethoxy.

[0034] The term “haloalkylcycloalkyl” refers to a cycloalkyl group, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a haloalkyl group, preferably CF3 or 2,2,2-trifluoroethyl. Preferably, “haloalkylcycloalkyl” refers to a cycloalkyl group wherein one hydrogen atom of the cycloalkyl group has been replaced by a haloalkyl group, most preferably CF3. A particularly preferred, yet non-limiting example of haloalkylcycloalkyl is trifluoromethylcyclopropyl .

[0035] The term “haloalkylheterocyclyl” refers to a heterocyclyl group, wherein at least one of the hydrogen atoms of the heterocyclyl group has been replaced by a haloalkyl group, preferably CF3 or 2,2,2-trifluoroethyl. Preferably, “haloalkylheterocyclyl” refers to a heterocyclyl group wherein one hydrogen atom of the heterocyclyl group has been replaced by a haloalkyl group, most preferably CF3. A particularly preferred, yet non-limiting example of haloalkylheterocyclyl is trifluoromethylazetidinyl.

[0036] The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition, these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, 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. Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride salts.

[0037] The term “protective group” (PG) denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Protective groups can be removed at the appropriate point. Exemplary protective groups are amino-protective groups, carboxy-protective groups or hydroxy-protective groups. Particular protective groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Further particular protective groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protective group is the tert-butoxycarbonyl (Boc). Exemplary protective groups and their application in organic synthesis are described, for example, in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.

[0038] The term “urea forming reagent” refers to a chemical compound that is able to render a first amine to a species that will react with a second amine, thereby forming an urea derivative. Nonlimiting examples of urea forming reagents include bi s(trichloro methyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, 1,1’ -carbonyldiimidazole and 1,1’- carbonyl-di-(l,2,4-triazole) (“CDT”). A preferred, yet non-limiting example of a urea forming reagent includes CDT. The urea forming reagents described in G. Sartori et al., Green Chemistry 2000, 2, 140 are incorporated herein by reference.

[0039] The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. In a preferred embodiment, the compound of formula (I) according to the invention is a cv.s-enantiomer of formula (la) or (lb), respectively, as described herein.

[0040] According to the Cahn-Ingold-Prelog Convention, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0041] The abbreviation “MAGL” refers to the enzyme monoacylglycerol lipase. The terms “MAGL” and “monoacylglycerol lipase” are used herein interchangeably.

[0042] The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.

[0043] The term “prophylaxis” as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.

[0044] The term “neuroinflammation” as used herein relates to acute and chronic inflammation of the nervous tissue, which is the main tissue component of the 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 follows injury to the central nervous system immediately, e.g., as a result of traumatic brain injury (TBI).

[0045] The term “traumatic brain injury” (“TBI”, also known as “intracranial injury”), relates to damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile.

[0046] The term “neurodegenerative diseases” relates to diseases that are related to the progressive loss of structure or function of neurons, including death of neurons. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.

[0047] The term “mental disorders” (also called mental illnesses or psychiatric disorders) relates to behavioral or mental patterns that may cause suffering or a poor ability to function in life. Such features may be persistent, relapsing and remitting, or occur as a single episode. Examples of mental disorders include, but are not limited to, anxiety and depression.

[0048] The term “pain” relates to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy induced neuropathy, phantom pain and phsychogenic pain. A particular example of pain is neuropathic pain, which is caused by damage or disease affecting any part of the nervous system involved in bodily feelings (i.e., the somatosensory system). In one embodiment, “pain” is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, “pain” is chemotherapy induced neuropathy.

[0049] The term “neurotoxicity” relates to toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances (neurotoxins) alter the normal activity of the nervous system in such a way as to cause damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, neurotoxicity resulting from exposure to substances used in chemotherapy, radiation treatment, drug therapies, drug abuse, and organ transplants, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some naturally occurring substances.

[0050] The term “cancer” refers to a disease characterized by the presence of a neoplasm or tumor resulting from abnormal uncontrolled growth of cells (such cells being "cancer cells"). As used herein, the term cancer explicitly includes, but is not limited to, hepatocellular carcinoma, colon carcinogenesis and ovarian cancer.

[0051] The term “mammal” as used herein includes both humans and non-humans and includes but is 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. of the Invention

[0052] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0053] L is selected from -CR3aR3b-, -O-, *-0CH2-, and *-CH20-, wherein the asterisk marks the connection of L to ring A;

[0054] A is selected from Ce-io-aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered hetero cyclyl;

[0055] R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,

[0056] O Y

[0057] \\ / / (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-, and a group ;

[0058] R2is selected from hydrogen, halogen, oxo, cyano, Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-

[0059] O A

[0060] \\ / /

[0061] R4b / s>y alkoxy, C3-6-cycloalkyl-, and a groupz;

[0062] R3aand R3bare each independently selected from hydrogen, halogen, and Ci-6-alkyl;

[0063] R4ais selected from halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-;

[0064] R4bis selected from Ci-6-alkyl, halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-;

[0065] Y is selected from O and NH; and

[0066] B is a 7-11 membered bicyclic spirocycle comprising 1-2 nitrogen atoms, the remaining ring atoms being carbon. In one embodiment, the compound of formula (I) according to the present invention is a compound of formula (la) or a pharmaceutically acceptable salt thereof, wherein A, B, L, R1, and R2are as described herein.

[0067] In one embodiment, the compound of formula (I) according to the present invention is a compound of formula (lb) or a pharmaceutically acceptable salt thereof, wherein A, B, L, R1, and R2are as described herein.

[0068] In one embodiment, the compound of formula (I) according to the present invention is a compound of formula (Ic) or a pharmaceutically acceptable salt thereof, wherein A, B, L, R1, and R2are as described herein.

[0069] In one embodiment, the compound of formula (I) according to the present invention is a compound of formula (Id) or a pharmaceutically acceptable salt thereof, wherein A, B, L, R1, and R2are as described herein.

[0070] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from:

[0071] (i) Ce-9-aryl;

[0072] (ii) 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon; and

[0073] (iii) 3- to 9-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon.

[0074] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl and 5- to 9-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining ring atoms being carbon.

[0075] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, 1,2,4- oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, 2H-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, 1,2-dihydropyridine, pyridazinyl, pyrazolyl, oxazolyl, [l,2,4]triazolo[4,3-a]pyridine, [l,2,4]triazolo[l,5-a]pyridine, lH-pyrrolo[2,3- b]pyridine, imidazo[l,5-a]pyridine, imidazo[l,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H- pyrazolo[4,3-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, pyrazolo[l,5-a]pyrimidine, 2H- pyrazolo[3,4-b]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 2H-pyrazolo[3,4-d]pyrimidine,

[0076] [1.2.4]triazolo[l,5-a]pyrimidine, imidazo[l,2-a]pyrazine, 1,2-benzoxazole, IH-indazole, 1H- imidazo[l,2-c]pyrimidin-5-one, lH-pyrrolo[2,3-b]pyridine, imidazo[l,2-a]pyrimidine, 1,5- dihydroimidazo[l,2-a]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine,

[0077] [1.2.4]triazolo[l,5-b]pyrimidine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, 1H- imidazo[4,5-b]pyridine, 3H-imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[l,5- a]pyrimidine, lH-pyrazolo[3,4-b]pyridine, lH-imidazo[l,2-a]pyrimidin-5-one, and 2H-indazole. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, 1,2,4- triazolyl, 2H-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, 1,2- dihydropyridine, pyridazinyl, pyrazolyl, [l,2,4]triazolo[4,3-a]pyridine, [l,2,4]triazolo[l,5- a]pyridine, lH-pyrrolo[2,3-b]pyridine, imidazo[l,5-a]pyridine, imidazo[l,2-a]pyridine, 2H- pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, 2H-pyrazolo[3,4-b]pyrimidine, 2H- pyrazolo[3,4-c]pyridine, 2H-pyrazolo[3,4-d]pyrimidine, imidazo[l,2-a]pyrazine, 1,2- benzoxazole, IH-indazole, lH-pyrrolo[2,3-b]pyridine, imidazo[l,2-a] pyrimidine, 1,5- dihydroimidazo[l,2-a]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, pyrazolo[l,5-a]pyrimidine, 2H- pyrazolo[4,3-b]pyridine, and 2H-indazole.

[0078] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, pyrazinyl, pyridyl, pyrazolyl, lH-pyrrolo[2,3-b]pyridine, and 2H-indazole.

[0079] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl.

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

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

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

[0083] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is lH-pyrrolo[2,3-b]pyridine.

[0084] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is 2H-indazole.

[0085] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from:

[0086] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein

[0087] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CR3aR3b-, -O-, and *-0CH2-, wherein: the asterisk marks the connection of L to ring A;

[0088] R3ais selected from hydrogen, halogen, and Ci-6-alkyl; and

[0089] R3bis selected from hydrogen, and halogen.

[0090] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CR3aR3b-, -O-, and *-0CH2-, wherein: the asterisk marks the connection of L to ring A;

[0091] R3ais selected from hydrogen, fluoro, and methyl; and

[0092] R3bis selected from hydrogen, and fluoro.

[0093] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.

[0094] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,

[0095] (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-, and a group

[0096] R2is selected from hydrogen, halogen, oxo, cyano, Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6- alkoxy, C3-6-cycloalkyl-, and a group

[0097] R4ais selected from halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-;

[0098] R4bis Ci-6-alkyl; and

[0099] Y is selected from O and NH.

[0100] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0101] R1is selected from CF3, 2,2,2-trifluoroethyl, CF3O, 2,2,2-trifluoroethoxy, trifluoromethylcyclopropyl, trifluoromethylazetidinyl, and a group

[0102] R2is selected from hydrogen, fluoro, oxo, cyano, methyl, CF3, methoxy, cyclopropyl, and a group

[0103] R4ais selected from CF3 and trifluoromethylazetidinyl;

[0104] R4bis methyl; and

[0105] Y is selected from O and NH.

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

[0107] R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-, and a group

[0108] R2is selected from hydrogen, halogen, cyano, and Ci-6-alkyl;

[0109] R4ais halo-Ci-6-alkyl; and

[0110] Y is O. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0111] R1is selected from CF3, CF3O, trifluoromethylcyclopropyl, and a group

[0112] R2is selected from hydrogen, fluoro, cyano, and methyl;

[0113] R4ais CF3; and

[0114] Y is O.

[0115] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0116] L is selected from -CR3aR3b-, -O-, and *-OCH2-, wherein the asterisk marks the connection of L to ring A;

[0117] A is selected from:

[0118] (i) Ce-9-aryl;

[0119] (ii) 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon; and

[0120] (iii) 3- to 9-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon;

[0121] B is selected from:

[0122] R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,

[0123] (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-, and a group R2is selected from hydrogen, halogen, oxo, cyano, Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-

[0124] O

[0125] \\ / P /

[0126] R4b / S>y alkoxy, Cs-e-cycloalkyl-, and a group ' ;

[0127] R3ais selected from hydrogen, halogen, and Ci-6-alkyl;

[0128] R3bis selected from hydrogen, and halogen;

[0129] R4ais selected from halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-;

[0130] R4bis Ci-6-alkyl; and

[0131] Y is selected from O and NH.

[0132] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0133] L is selected from -CR3aR3b-, -O-, and *-0CH2-, wherein the asterisk marks the connection of L to ring A;

[0134] A is selected from phenyl, 1,2,4-triazolyl, 2H-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, 1,2-dihydropyridine, pyridazinyl, pyrazolyl, [ 1 ,2,4]triazolo [4,3 -a]pyridine, [ 1 ,2,4]triazolo [ 1 , 5 -a]pyridine, 1 H-pyrrolo [2,3 - b]pyridine, imidazo[l,5-a]pyridine, imidazo[l,2-a]pyridine, 2H-pyrazolo[3,4- b]pyridine, 2H-pyrazolo[4,3-c]pyridine, 2H-pyrazolo[3,4-b]pyrimidine, 2H- pyrazolo[3,4-c]pyridine, 2H-pyrazolo[3,4-d]pyrimidine, imidazo[l,2-a]pyrazine, 1,2-benzoxazole, IH-indazole, lH-pyrrolo[2,3-b]pyridine, imidazo[l,2- a]pyrimidine, l,5-dihydroimidazo[l,2-a]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, and 2H-indazole;

[0135] B is selected from: R1is selected from CF3, 2,2,2-trifluoroethyl, CF3O, 2,2,2-trifluoroethoxy, trifluoromethylcyclopropyl, trifluoromethylazetidinyl, and a group

[0136] R2is selected from hydrogen, fluoro, oxo, cyano, methyl, CF3, methoxy, cyclopropyl, and a group

[0137] R3ais selected from hydrogen, fluoro, and methyl; and

[0138] R3bis selected from hydrogen, and fluoro;

[0139] R4ais selected from CF3 and trifluoromethylazetidinyl;

[0140] R4bis methyl; and

[0141] Y is selected from O and NH.

[0142] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0143] L is -CH2-;

[0144] A is selected from phenyl and 5- to 9-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining ring atoms being carbon;

[0145] R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-, and a group

[0146] R2is selected from hydrogen, halogen, cyano, and Ci-6-alkyl;

[0147] R4ais halo-Ci-6-alkyl; and

[0148] Y is O.

[0149] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0150] L is -CH2-;

[0151] A is selected from phenyl, pyrazinyl, pyridyl, pyrazolyl, lH-pyrrolo[2,3-b]pyridine, and 2H-indazole;

[0152] R1is selected from CF3, CF3O, trifluoromethylcyclopropyl, and a group

[0153] R2is selected from hydrogen, fluoro, cyano, and methyl;

[0154] R4ais CF3; and

[0155] Y is O.

[0156] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0157] L is -CH2-;

[0158] A is a 6-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining ring atoms being carbon;

[0159] R1is halo-Ci-6-alkoxy; and

[0160] R2is hydrogen.

[0161] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0162] L is -CH2-;

[0163] A is pyridyl;

[0164] R2is hydrogen.

[0165] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from:

[0166] (i) Ce-9-aryl;

[0167] (ii) 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon; and

[0168] (iii) 3- to 9-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N,

[0169] O, and S, the remaining ring atoms being carbon;

[0170] R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,

[0171] (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-, and a group

[0172] R2is selected from hydrogen, halogen, oxo, cyano, Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6- alkoxy, C3-6-cycloalkyl-, and a group

[0173] R4ais selected from halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-;

[0174] R4bis Ci-6-alkyl; and

[0175] Y is selected from O and NH.

[0176] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0177] A is selected from phenyl, 1,2,4-triazolyl, 2H-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, 1,2-dihydropyridine, pyridazinyl, pyrazolyl, [ 1 ,2,4]triazolo [4,3 -a]pyridine, [ 1 ,2,4]triazolo [ 1 , 5 -a]pyridine, 1 H-pyrrolo [2,3 - b]pyridine, imidazo[l,5-a]pyridine, imidazo[l,2-a]pyridine, 2H-pyrazolo[3,4- b]pyridine, 2H-pyrazolo[4,3-c]pyridine, 2H-pyrazolo[3,4-b]pyrimidine, 2H- pyrazolo[3,4-c]pyridine, 2H-pyrazolo[3,4-d]pyrimidine, imidazo[l,2-a]pyrazine, 1,2-benzoxazole, IH-indazole, lH-pyrrolo[2,3-b]pyridine, imidazo[l,2- a]pyrimidine, l,5-dihydroimidazo[l,2-a]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, and 2H-indazole;

[0178] R1is selected from CF3, 2,2,2-trifluoroethyl, CF3O, 2,2,2-trifluoroethoxy, trifluoromethylcyclopropyl, trifluoromethylazetidinyl, and a group R2is selected from hydrogen, fluoro, oxo, cyano, methyl, CF3, methoxy, cyclopropyl, and a group

[0179] R4ais selected from CF3 and trifhioromethylazetidinyl;

[0180] R4bis methyl; and

[0181] Y is selected from O and NH.

[0182] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0183] A is selected from phenyl and 5- to 9-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining ring atoms being carbon;

[0184] R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,

[0185] R2is selected from hydrogen, halogen, cyano, and Ci-6-alkyl;

[0186] R4ais halo-Ci-6-alkyl; and

[0187] Y is O.

[0188] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0189] A is selected from phenyl, pyrazinyl, pyridyl, pyrazolyl, lH-pyrrolo[2,3-b]pyridine, and 2H-indazole;

[0190] R1is selected from CF3, CF3O, trifluoromethylcyclopropyl, and a group

[0191] R2is selected from hydrogen, fluoro, cyano, and methyl;

[0192] R4ais CF3; and is O.

[0193] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,

[0194] °W / /

[0195] R4a / S" (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-, and a group

[0196] R4ais selected from halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-; and is selected from O and NH.

[0197] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0198] R1is selected from CF3, 2,2,2-trifluoroethyl, CF3O, 2,2,2-trifluoroethoxy, trifluoromethylcyclopropyl, trifluoromethylazetidinyl, and a group

[0199] R4ais selected from CF3 and trifluoromethylazetidinyl; and is selected from O and NH.

[0200] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0201] R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-, and a group

[0202] R4ais halo-Ci-6-alkyl; and is O.

[0203] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0204] °W >

[0205] R1is selected from CF3, CF3O, trifluoromethylcyclopropyl, and a group

[0206] R4ais CF3; and is O.

[0207] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is CF3. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is CF3O.

[0208] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is trifluoromethylcyclopropyl.

[0209] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is a group

[0210] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R1is a group

[0211] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:

[0212] R2is selected from hydrogen, halogen, oxo, cyano, Ci-6-alkyl, halo-Ci-6-alkyl, C1-6- alkoxy, C3-6-cycloalkyl-, and a group wherein

[0213] R4bis Ci-6-alkyl.

[0214] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen,

[0215] O,

[0216] \\ / / fluoro, oxo, cyano, methyl, CF3, methoxy, cyclopropyl, and a group .

[0217] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halogen, cyano, and Ci-6-alkyl.

[0218] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, fluoro, cyano, and methyl. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is hydrogen.

[0219] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is fluoro.

[0220] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is cyano.

[0221] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

[0222] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

[0223] (4aR,8aS)-6-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0224] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0225] (4aR,8aS)-6-[6-[4-(trifluoromethoxy)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0226] (4aR, 8aS)-6- [6- [ [ 1 -methyl-3 -(trifhroromethyl)pyrrolo [2,3 -b]pyridin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0227] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0228] 2-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro [3.3 ]heptan-6-yl] methyl] -5 -(trifl uoromethy 1 Jbenzonitri 1 e;

[0229] (4aR,8aS)-6-[6-[difhioro-[2-methoxy-6-(trifhroromethyl)-3-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0230] (4aR,8aS)-6-[6-[4-fluoro-2-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0231] (4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)indoxazen-6-yl] methyl] -2-azaspiro [3.3 ]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0232] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-indazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; (4aR,8aS)-6-[6-(4-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;

[0233] (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0234] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0235] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0236] (4aR,8aS)-6-[6-(3-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;

[0237] (4aR,8aS)-6-[6-(3-fluoro-5-triflyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;

[0238] (4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)indoxazen-5 -y 1 ] methyl] -2-azaspiro [3.3 ]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0239] (4aR,8aS)-6-[6-[(lS)-l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0240] 5-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile;

[0241] (4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0242] (4aR,8aS)-6-[6-[[5-[l-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0243] (4aR,8aS)-6-[6-[[5-[l-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0244] (4aR,8aS)-6-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0245] (4aR,8aS)-6-[6-[2-fluoro-4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0246] 4-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile;

[0247] (4aR,8aS)-6-[6-[[l-(trifluoromethyl)indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0248] (4aR, 8aS)-6- [6- [ [2-methyl-4-(trifluoromethyl)pyrazol-3 -yl] methyl] -2-azaspiro [3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; (4aS,8aR)-6-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0249] (4aR,8aS)-6-[6-[[l-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0250] (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0251] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0252] (4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0253] (4aR,8aS)-6-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0254] (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[l,2-a]pyridin-7-yl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0255] (4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0256] (4aR,8aS)-6-[(6R)-6-(3-triflylbenzyl)-2-azaspiro[3.4]octane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;

[0257] (4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl] - 1 H-pyrazol-3 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0258] (4aR,8aS)-6-[6-[[3-methyl-5-(trifluoromethyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0259] (4aR,8aS)-6-[6-[[2-[l-(trifluoromethyl)cyclopropyl]-4-pyridyl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0260] (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0261] (4aR, 8aS)-6- [6- [ [ 1 -(2,2,2-trifluoroethyl)-3 -(trifluoromethyl)pyrazol-4-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0262] (4aR,8aS)-6-[6-[[l-methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0263] (4aR,8aS)-6-[6-[[5-[3-(trifluoromethyl)azetidin-l-yl]pyrazin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0264] (4aR,8aS)-6-[6-[[l-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[3,4-c]pyridin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0265] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0266] 3-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro [3.3 ]heptan-6-yl] methyl] -5 -(trifluoromethyl)benzonitrile;

[0267] (4aR,8aS)-6-[6-[(lR)-l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0268] (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0269] (4aR,8aS)-6-[6-[[4-[l-(trifluoromethyl)cyclopropyl]pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0270] (4aR,8aS)-6-[6-[[4-[l-(trifluoromethyl)cyclopropyl]pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0271] (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0272] (4aR,8aS)-6-[6-[[4-[l-(trifluoromethyl)cyclopropyl]-2-pyridyl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0273] (4aR,8aS)-6-[6-[[5-[l-(trifluoromethyl)cyclopropyl]-2-pyridyl]oxy]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0274] (4aR,8aS)-6-[6-[difluoro-[2-methoxy-5-(trifluoromethyl)-3-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0275] (4aR,8aS)-6-[6-[3-mesyl-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0276] (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[l,2-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0277] (4aR,8aS)-6-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0278] (4aR,8aS)-6-[6-[3-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0279] (4aR, 8aS)-6- [6- [ [2-keto-4-[ 1 -(trifluoromethyl)cyclopropyl] - 1 -pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0280] (4aR,8aS)-6-[8-(3-triflylbenzyl)-2-azaspiro[4.4]nonane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one; (4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl]pyrazin-2-yl] methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0281] (4aR,8aS)-6-[6-[4-[3-(trifluoromethyl)azetidin-l-yl]sulfonylbenzyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0282] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)imidazo[l,5-a]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0283] (4aR,8aS)-6-[6-[[5-[l-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0284] (4aR,8aS)-6-[6-[(4-triflylpyrazol-l-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0285] (4aR,8aS)-6-[6-[(5-triflyl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0286] (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-7-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0287] (4aR, 8aS)-6- [6- [ [2-(trifluoromethyl)pyrazolo [ 1 , 5 -a]pyrimidin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0288] (4aR,8aS)-6-[6-[[2-[l-(trifluoromethyl)cyclopropyl]pyrimidin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0289] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[4,3-c]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0290] (4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl] imidazol- 1 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0291] (4aR,8aS)-6-[6-[[4-(trifluoromethyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0292] (4aR,8aS)-6-[6-[[2-methyl-5-(trifluoromethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0293] (4aR, 8aS)-6- [6- [ [2-(2,2,2-trifluoroethyl)-5 -(trifluoromethyl)pyrazol-3 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0294] (4aR,8aS)-6-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0295] (4aR,8aS)-6-[7-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0296] (4aR, 8aS)-6- [6- [ [4 - [ 1 -(trifluoromethyl)cyclopropyl] imidazol- 1 -yl] methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; (4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0297] (4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)- 1 H-pyrazolo [4,3 -b]pyridin-5 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0298] (4aR,8aS)-6-[6-[[l-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0299] (4aR,8aS)-6-[6-[[5-(trifluoromethyl)-2-pyridyl]oxymethyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0300] (4aR,8aS)-6-[6-[[5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0301] (4aR,8aS)-6-[6-[[3-methoxy-5-(trifluoromethyl)pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0302] (4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]-3-pyridyl]oxy]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0303] (4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[l,2-a]pyrazin-6-yl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0304] (4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)pyrazolo [ 1 , 5 -a]pyrimidin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0305] (4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)imidazo [ 1 ,2-a]pyrimidin-7-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0306] (4aR,8aS)-6-[6-[[l-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0307] (4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0308] (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0309] (4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)-4-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0310] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-7-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0311] (4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0312] (4aR,8aS)-6-[6-[2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-6-yl]oxy-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; (4aR,8aS)-6-[6-[difluoro-[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0313] (4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonimidoyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0314] (4aR,8aS)-6-[6-[[2-(2,2,2-trifluoroethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0315] (4aR, 8aS)-6- [6- [ [6-(2,2,2-trifluoroethoxy)-3 -pyridyl] methyl] -2, 6-diazaspiro [3.3 ]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0316] (4aR,8aS)-6-[6-[2-[l-(trifluoromethyl)cyclopropyl]pyrimidin-5-yl]oxy-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0317] (4aR,8aS)-6-[7-[[3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl]methyl]-2-azaspiro[3.5]nonane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0318] (4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]-2-pyridyl]oxy]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0319] (4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0320] (4aR,8aS)-6-[6-[[2-[l-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0321] (4aR,8aS)-6-[6-[6-[l-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]oxy-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0322] (4aR, 8aS)-6- [6- [ [ 1 -(2,2,2-trifluoroethyl)-5 -(trifluoromethyl)pyrazol-3 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0323] (4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0324] (4aR,8aS)-6-[6-[[5-[l-(trifluoromethyl)cyclopropyl]-3-pyridyl]oxy]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0325] (4aR,8aS)-6-[6-[2-[l-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]oxy-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0326] (4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0327] (4aR,8aS)-6-[6-[[4-[l-(trifluoromethyl)cyclopropyl]-2-pyridyl]oxy]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0328] (4aR,8aS)-6-[6-[[2-keto-5-[l-(trifluoromethyl)cyclopropyl]-l-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; (4aR, 8aS)-6- [6- [ [2-(trifluoromethyl)imidazo [ 1 ,2-a]pyrimidin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0329] (4aR, 8aS)-6- [6- [ [5 -keto- 1 -(2,2, 2-trifluoroethyl)imidazo [ 1 ,2-a]pyrimidin-7-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; and

[0330] (4aR,8aS)-6-[6-[[2-[l-(trifluoromethyl)cyclopropyl]-4-pyridyl]oxy]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one.

[0331] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from:

[0332] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0333] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0334] (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-indazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0335] (4aR,8aS)-6-[6-(4-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;

[0336] (4aR,8aS)-6-[6-(3-fluoro-5-triflyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;

[0337] 5-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile;

[0338] (4aR,8aS)-6-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0339] 4-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile;

[0340] (4aR,8aS)-6-[6-[[l-methyl-5-(trifhroromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0341] (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0342] (4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;

[0343] (4aR,8aS)-6-[6-[[6-[l-(trifhroromethyl)cyclopropyl]-3-pyridyl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; and (4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one; or a pharmaceutically acceptable salt thereof.

[0344] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[3-(trifhroromethyl)-lH- indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4- b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0345] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH- pyrrolo[2,3-b]pyridin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0346] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH- indazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4- b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0347] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-(4-triflylbenzyl)-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0348] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-(3-fluoro-5-triflyl-benzyl)-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0349] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is 5-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-2- (trifluoromethyl)benzonitrile or a pharmaceutically acceptable salt thereof.

[0350] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[5-(trifluoromethoxy)-2- pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4- b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0351] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is 4-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-2- (trifluoromethyl)benzonitrile or a pharmaceutically acceptable salt thereof.

[0352] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[l-methyl-5- (trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0353] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethyl)-2- pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4- b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0354] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3- pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4- b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0355] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[6-[l-

[0356] (trifl uoromethy 1 Jcyclopropy 1] -3 -pyridyl] methyl] -2-azaspiro[3.3 ]heptane-2-carbonyl] - l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0357] In one embodiment, the present invention provides a compound of formula (I) as described herein, wherein the compound of formula (I) is (4aR,8aS)-6-[6-[[6-[l- (trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one or a pharmaceutically acceptable salt thereof.

[0358] In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein, especially hydrochloride salts. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein.

[0359] In some embodiments, the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to,2H,3H,nC,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36C1,123I, and125I, respectively. 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 isotopes tritium, i.e.3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.

[0360] Substitution with heavier isotopes such as deuterium, i.e.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Thus, deuterated variants of the presently disclosed compounds are to be understood within the scope of the present invention. In one embodiment, the present invention provides compounds of formula (I) as described herein, wherein one or more hydrogen atoms are replaced by deuterium, preferably wherein 1-4 hydrogen atoms are replaced by deuterium, more prefereably wherein 1-3 hydrogen atoms are replaced by deuterium.

[0361] Substitution with positron emitting isotopes, such asnC,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the nonlabeled reagent previously employed.

[0362] Processes of Manufacturing

[0363] The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.

[0364] If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0365] If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (I).

[0366] A person skilled in the art will acknowledge that in the synthesis of compounds of formula (I) - insofar not desired otherwise - an “orthogonal protection group strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, J. Am. Chem. Soc. 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0367] A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates.

[0368] In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered.

[0369] If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.

[0370] The following abbreviations are used in the present text:

[0371] Ac = acetyl, ACN = acetonitrile , Bn = benzyl, BINAP = (2,2'-bis(diphenylphosphino)-l,T- binaphthyl), Boc = tert-butyloxycarbonyl, CAS RN = chemical abstracts registration number, Cbz = benzyloxycarbonyl, CDT = l,r-carbonyl-di-(l,2,4-triazole), CMBP = (Cyanomethylene)tributylphosphorane, 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, dba = dibenzylideneacetone, DBU = l,8-diazabicyclo[5,4,0]undec-7-ene, DCE = 1,2-dichloroethane, DCM = dichloromethane, DEAD = diethyl azodicarboxylate, DIAD = diisopropyl azodicarboxylate, DIBAL-H = diisobutyl aluminium hydride, DMAP = 4- dimethylaminopyridine, DME = dimethoxy ethane , DMEDA = N,N’ -dimethylethylenediamine, DMF = N,N-dimethylformamide, DMF-DMA = N,N-Dimethylformamide dimethyl acetal, DMSO = dimethylsulfoxide, DIPEA (or DIEA) = N,N-diisopropylethylamine, dppf = 1,1 bis(diphenyl phosphino)ferrocene, EDC HC1 = N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride, El = electron impact, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour(s), FA = formic acid, H2O = water, H2SO4 = sulfuric acid, HATU = l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro- phosphate, HC1 = hydrogen chloride, HOBt = 1 -hydroxy- IH-benzotriazole; HPLC = high performance liquid chromatography, iPrMgCl = isopropylmagnesium chloride, 12 = iodine, IPA = 2-propanol, ISP = ion spray positive (mode), ISN = ion spray negative (mode), K2CO3 = potassium carbonate, KHCO3 = potassium bicarbonate, KI = potassium iodide, KOH = potassium hydroxide, K3PO4 = potassium phosphate tribasic, LiAlEU or LAH = lithium aluminium hydride, LiHMDS = lithium bis(trimethylsilyl)amide, LiOH = lithium hydroxide, mCPB A = meta-chloroperoxybenzoic acid, MgSO4 = magnesium sulfate, min = minute(s), mL = milliliter, MPLC = medium pressure liquid chromatography, Ms = mesyl, MS = mass spectrum, MTBE = methyl tert-butyl ether, nBuLi = n-butyllithium, NaBHsCN = sodium cyanoborohydride, NaH = sodium hydride, NaHMDS = sodium bis(trimethylsilyl)amide NBS = N-bromosuccinimide, NaHCOs = sodium hydrogen carbonate, NaNCE = sodium nitrite, NaBH(OAc)3 = sodium triacetoxyborohydride, NaOH = sodium hydroxide, Na2CO3 = sodium carbonate, Na2SO4 = sodium sulfate, Na2S20s = sodium thiosulfate, NEt3 = triethylamine (TEA), NH4C1 = ammonium chloride, NMP = N-methyl-2-pyrrolidone, OAc = Acetoxy, T3P = propylphosphonic anhydride, PE = petroleum ether, PG = protective group, Pd-C = palladium on activated carbon, PdC12(dppf)-CH2C12 = l,l'-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, PTS A = p-toluenesulfonic acid, R = any group, RP = reverse phase, RT = room temperature, SFC = Supercritical Fluid Chromatography, S-PHOS = 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl, TBAI = tetra butyl ammonium iodine, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, TMEDA = N,N,N',N'- tetramethylethylenediamine, Ts = tosyl, TS-TPP = triphenylphospine - polymer bound, ZnCh = zinc chloride, prep-TLC = preparative thin layer chromatography.

[0372] The present compounds of formula I can be prepared by reacting nucleophilic amine 1 (building block A.l) with acoupling agent such as l,r-carbonyl-di-(l,2,4-triazole) (CDT) by heating in a solvent such as DMF or CH3CN in the presence of a base such as DIPEA to transiently generate an activated intermediate, which then can be reacted with spirocyclic amine 2 (building block B.X) to yield Boc-protected derivative 3. Deprotection under standard conditions (e.g. using an acid such as TFA or TsOH) yields the final compound of formula I. This deprotection step can either be carried out on a purified and isolated intermediate 3, or on the crude material. (Scheme 1)

[0373] 1

[0374] Scheme 1

[0375] Building blocks of formula 4 where L = CH2, and the B ring is C-linked, can be generated by Suzuki reaction (e.g. (Pd(dppf)C12, K2CO3, dioxane / ftO), between a boronate 5 and a (hetero)aryl halide 6 (X = Br, I) followed by hydrogenation (e.g. Pd / C, H2) (Scheme 2). The required boronate intermediate 5 can be generated by reacting a ketone with 4,4,5,5-tetramethyl- 2-[(tetramethyl-l,3,2-dioxaborolan-2-yl)methyl]-l,3,2-dioxaborolane (LiTMP, THF, - 78 °C). Where A = N-linked heteroaryl, a Chan-Lam type coupling can be used in place of the Suzuki reaction, followed by the hydrogenation / deprotection. A similar sequence could also be used to generate building blocks where e.g. L = -CH(Me), starting from a suitably functionalized boronate 5, with an additional Me group on the alkene carbon bearing the boronate. In some cases, where A = heteroaryl with a free N-H group (e.g. N-H pyrazole or a fused N-H pyrazole) it was beneficial to use an additional protecting group on the N-H group (e.g. SEM protection, which could be introduced using standard techniques, and typically could be deprotected in the final deprotection step under acidic conditions).

[0376] Scheme 2

[0377] Alternatively, building blocks of formula 8 with L = CH2, and the B-ring is N-linked, can be prepared by a reductive amination reaction of aldehyde 9 with suitably protected spirocycle (10) 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 3)

[0378] Scheme 3

[0379] Alternatively, building blocks of formula 11 with L = CH2, the A-ring is N-linked, and the firing is C-linked, can be prepared by a Mitsunobu type reaction of heterocycle A (12) with a hydroxyl building block 13 (e.g. using diisopropyl azodicarboxylate and triphenylphosphine, or Tsunoda reagent (cyanomethylenetrimethylphosphorane)), followed by deprotection under standard conditions (e.g. with TsOH when PG = Boc). (Scheme 4) Alternatively, building blocks of formula 11 can be prepared by conversion of hydroxyl building block 13 to a mesylate (e.g. using MsCl, EtsN) followed by an SN2 reaction with the heterocycle A (12) in the presence of a base such as NaH.

[0380] Scheme 4

[0381] Building blocks of formula 14, where L = CF2, and both the A and B rings are C-linked, can be generated via deoxyfluorination of a suitable ketone 16 (e.g. using DAST, diethylaminosulfur trifluoride), followed by a suitable deprotection (e.g. using TsOH or TFA, where PG = Boc). The ketone can be generated using oxidation of a benzylic CH2 group on a suitable intermediate 15 (e.g. generated in Scheme 2), e.g. using SeCh, or alternatively via nucleophilic attack of a metallated-anion derivative of a suitable (hetero)aryl 17 onto a Weinreb amide 18. The intermediate 17 can be generated from a suitable halogenated (hetero)aryl derivate 6 (X = Br, I, Cl) via metallation (e.g. using nBuLi). (Scheme 5).

[0382] 6 17

[0383] Scheme 5

[0384] Alternatively, building blocks of formula 19 with L = oxygen and A is (hetero)aryl (where X is in a position suitable for SNAT displacement) can be prepared by reacting 6 (X is a leaving group such as Cl, Br, F typically adjacent to aromatic N for SNAT reaction), with a suitably protected alcohol building block 20 in the presence of a base such as NaOtBu, followed by deprotection under standard conditions (e.g. with TsOH when PG = Boc). (Scheme 6)

[0385] Scheme 6 Alternatively, building blocks of formula 19 with L = oxygen and A is (hetero)aryl can be prepared by reacting a suitably protected spirocyclic amine bearing a hydroxyl group (20) with a nucleophilic (hetero)aryl alcohol (21) under Mitsunobu-type conditions (e.g. using Tsunoda reagent, (tributylphosphoranylidene)acetonitrile or PPI DI AD), followed by deprotection. (Scheme 7) 1 . Mitsunobu type conditions

[0386] 2. deprotection

[0387] 21 20

[0388] Scheme 7

[0389] (Hetero)aryl trifluoromethylcyclopropyl building blocks 22 were not always available, and in these cases were generated from halide building block 23 (X = I, Br) via Suzuki reaction with 1- (trifluoromethyl)vinylboronic acid to give 24. Cyclopropanation using dip henyl(methyl) sulfonium tetrafluoroborate and LiHMDS gave the required building block 22. (Scheme 8) This synthetic sequence could also be carried out inbetween steps in other synthetic schemes, e.g. while making building blocks of formula 4 this sequence could be carried out after the Suzuki or Chan-Lam / hydrogenation sequence, but prior to final deprotection (see Scheme 2). Alternatively the (hetero)aryl trifluoromethylcyclopropyl building blocks could be generated from commercial building blocks via standard heterocyclic synthesis techniques.

[0390] Scheme 8

[0391] In some cases, compounds of formula I could be further functionalized to give other compounds of formula I. For example, a compound of formula I bearing a (hetero)aryl bromide or iodide can be further functionalized with other groups e.g. small amine, small alkyl using metal catalyzed cross-coupling conditions such as Buchwald or Suzuki reactions. Building blocks 2 can also be subjected to further functionalization reactions (e.g. formation of an amide under standard conditions, alkylation of an alcohol (e.g. using NaH and an alkylating agent in DMF), alkylation of a 5-membered heteroaryl such as pyrazole or triazole, conversion of boron-containing groups to hydroxyl using alkaline peroxide conditions, oxidation of thioethers to sulfones, or installation of small alkyl groups in place of Br or I groups using metal catalyzed cross-coupling conditions such as Buchwald or Suzuki reactions) before or after deprotection of the nucleophilic amine, to yield other building blocks of formula 2.

[0392] In some cases, building blocks could be generated from commercially available fragments using standard functional group interconversion techniques (e.g. installation of a halide (e.g. using NIS or NBS, removal of a halide (e.g. under hydrogenation conditions), conversion of halides to other groups (e.g. small amine, small alkyl using metal catalyzed cross-coupling conditions such as Buchwald or Suzuki reactions, boronates using Miyaura conditions), conversion of iodide to a trifluoromethyl group using a trifluoromethylating reagent (e.g. diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate), installation and removal of protecting groups, hydrolysis of an ester to an acid, generation of an amide from an acid and a small amine, conversion of boron-containing groups to hydroxyl using alkaline peroxide conditions, cycloaddition of azidotrimethylsilane with a nitrile to generate a tetrazole, Sandmeyer reaction of an aniline to a bromide, oxidation of thioethers to sulfones, oxidation of thioethers to sulfoximines using PhI(O Ac)? and NH2COONH4, alkylation of hydroxyl or amine groups via SN2 reaction or reductive amination, acylation using an activated carbonyl derivative, installation of-SChMe or -SO2CF3 groups from a iodo- or bromo- building block using literature techniques, or installation of small alkyl groups or rings such as cyclopropyl onto heteroaromatic nitrogen using a boronate derivative under Chan-Lam type conditions). Such techniques may also be used to elaborate commercially available fragments before, after, or intermediate within the synthetic sequences described above. In some cases, building blocks could be generated from commercially available fragments using standard heterocyclic synthesis techniques (e.g. synthesis of pyrazoles, oxadiazoles, imidazoles), or by using standard heterocyclic synthesis techniques for further elaboration of intermediates generated in the syntheses described above. For example, in Scheme 2 which described the synthetic procedure to generate building blocks 4, a simplified precursor A-ring could be installed via Suzuki coupling / hydrogenation, followed by conversion of the precusor A-ring into the required complex (hetero)aryl, prior to the final deprotection step.

[0393] In one aspect, the present invention provides a process of manufacturing a compound of formula (I), wherein A, B, L, R1and R2are as defined herein, or a pharmaceutically acceptable salt thereof, comprising:

[0394] (a) reacting a compound of formula 1, wherein PG is an amino protective group, with an amine of Formula 2, wherein A, B, L, R1and R2are as defined herein, in the presence of a urea forming reagent and a base to form a compound of formula 3, wherein A, B, L, R1and R2are as defined herein and PG is an amino protective group, followed by

[0395] (b) removing said amino protective group PG to form said compound of formula (I).

[0396] In one embodiment, said amino protective group is tert-butyloxycarbonyl (“BOC”).

[0397] In one embodiment, said urea forming reagent is l,r-carbonyl-di-(l,2,4-triazole) (“CDT”).

[0398] In one embodiment, said base is selected from diethyl amine (“DIEA”) and diisopropylamine (“DIPEA”).

[0399] In one embodiment, said protective group PG is removed by addition of an acid, for example 2,2,2-trifluoroacetic acid (“TFA”), phosphoric acid (H3PO4) or hydrochloric acid (HC1). In one embodiment, said amino protective group is tert-butyloxycarbonyl (“BOC”), said urea forming reagent is l,r-carbonyl-di-(l,2,4-triazole) (“CDT”), said base is selected from diethyl amine (“DIEA”) and diisopropylamine (“DIPEA”), and said protective group PG is removed by addition of 2,2,2-trifluoroacetic acid (“TFA”).

[0400] In one aspect, the present invention provides a compound of formula (I) as described herein, when manufactured according to any one of the processes described herein.

[0401] MAGL Inhibitory Activity

[0402] Compounds of the present invention are MAGL inhibitors. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for inhibiting MAGL in a mammal.

[0403] In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.

[0404] In a further aspect, the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal.

[0405] In a further aspect, the present invention provides a method for inhibiting MAGL in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.

[0406] Compounds of formula (I) according to the invention were profiled for MAGL inhibitory activity by determining the enzymatic activity by following the hydrolysis of the natural substrate 2-arachidonoylglycerol resulting in arachidonic acid, which can be followed by mass spectrometry. This assay is hereinafter abbreviated “2-AG assay”.

[0407] The 2-AG assay was carried out in 384 well assay plates (PP, Greiner Cat# 784201) in a total volume of 20 pL. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in a polypropylene plate in 3-fold dilution steps to give a final concentration range in the assay from 12.5 pM to 0.8 pM. 0.25pL compound dilutions (100% DMSO) were added to 9 pL MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690- 100ml), 0.01% (v / v) Tween. After shaking, the plate was incubated for 15 min at RT. To start the reaction, 10 pL 2-arachidonoylglycerol in assay buffer was added. The final concentrations in the assay was 50 pM MAGL and 8 pM 2-arachidonoylglyerol. After shaking and 30 min incubation at RT, the reaction was quenched by the addition of 40 pL of acetonitrile containing 4pM of d8-arachidonic acid. The amount of arachidonic acid was traced by an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer (Agilent 6460). A Cl 8 SPE cartridge (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 ratio of intensities [arachidonic acid / d8-arachidonic acid].

[0408] Table 1

[0409] In one aspect, the present invention provides compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein, wherein said compounds of formula (I) and their pharmaceutically acceptable salts or esters have ICso’s for MAGL inhibition below 25 pM, preferably below 10 pM, more preferably below 5 pM as measured in the MAGL assays described herein.

[0410] In one embodiment, compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have IC50 (MAGL inhibition) values between 0.000001 pM and 25 pM, particular compounds have IC50 values between 0.000005 pM and 10 pM, further particular compounds have IC50 values between 0.00005 pM and 5 pM, as measured in the MAGL assays described herein.

[0411] Papp (passive permeability measurements) obtained as part of Unidirectional P-gp Screen

[0412] Experiment Description The general assay uses transfected LLC-PK1 cells (porcine kidney epithelial cells) overexpressing human or mouse P-gp, cultured on 96 well semi-permeable filter membrane plates, where they form a polarized monolayer with tight junctions, and act as a barrier between the apical and basolateral compartment.

[0413] P-gp is expressed in the apical-facing membrane of the monolayer. The tightness of the cell monolayer and functional activity of P-gp are confirmed by addition of a cell-impermeable marker, Lucifer yellow, and a reference P-gp substrate, edoxaban, respectively.

[0414] The assay is fully automated on a Tecan liquid handling robot.

[0415] Data analysis and interpretation

[0416] For substrate testing the assay determines the unidirectional permeability (PappA>B Equation 1) of a test compound by dosing to the apical (i.e. donor compartment) side of the cell monolayer, in the absence and presence of specific P-gp inhibitor, zosuquidar, and measuring the movement of the compound into the basolateral (i.e. receiver) compartment over a 3 hour incubation at 37°C. The effect of P-gp is measured by expressing the apical efflux ratio (AP-ER, Equation 2). The mean permeability (Papp) is determined in the absence of P-gp via the zosuquidar condition. The AP-ER and mean Pappare then used to categorize compound properties for degree of efflux and permeability (Table 2).

[0417] Equation 1. Papp, A, CO, and dQ / dt represent the apparent permeability, the filter surface area, the initial concentration, and the amount transported per time period, respectively. Pappvalues are calculated on the basis of a single time point.

[0418] Equation 2. Calculation of the apical efflux ratio (AP-ER). Papp,inh (A>B) is the permeability value in the apical to basolateral direction in the presence of the inhibitor, and Papp(A>B)the permeability value in the apical-to-basolateral direction in the absence of the inhibitor.

[0419] Results

[0420] The compounds of the present invention surprisingly exhibit a reduced Pappcompared to similar compounds disclosed in W02020104494, while retaining the overall drug-like properties. Thus, the passive permeability of the compounds (Papp) disclosed in W02020104494 typically came in the 250-350 nm / s range (Table 2), at which point setting up an exposure gradient across tissues becomes extremely challenging. In contrast, the passive permeability of the compounds of the present invention typically come in the 10-200 nm / s range (Table 3), more preferably in the 50- 180 nm / s range which, when in combination with other suitable properties, enables an exposure gradient to be set up across tissues.

[0421] Table 2 Table 3

[0422] Comparing matched pairs Ex. 49 of W02020104494 and present Example 1, Pappis surprsingly reduced from 253 nm / s to 167 nm / s, while P-gp AP-ER (mouse) is surprisingly increased from 2.2 to 6.2. Similarly, the present Example 8 surprisingly shows a reduction in Papp from 243 nm / s to 134 nm / s and an increase in P-gp AP-ER (mouse) from 2.6 to 7.5, when compared to its matched pair of formula 25.

[0423] Using the Compounds of the Invention

[0424] In one aspect, the present invention provides a compound of formula (I) as described herein for use as therapeutically active substance.

[0425] In a further aspect, the present invention provides a compound of formula (I) as described herein for use in the treatment or prophylaxis of diseases and disorders that are associated with MAGL. In a further aspect, the present invention provides a method for the treatment or prophylaxis of diseases and disorders that are associated with MAGL, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.

[0426] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for the treatment or prophylaxis of diseases and disorders that are associated with MAGL.

[0427] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein in the preparation of a medicament for the treatment or prophylaxis of diseases and disorders that are associated with MAGL.

[0428] In one embodiment, said diseases and disorders that are associated with MAGL are selected from neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, gut motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or renal disease.

[0429] In one embodiment, said diseases and disorders that are associated with MAGL are selected from neuroinflammation, neurodegenerative diseases, pain, cancer and / or mental disorders.

[0430] In one embodiment, said diseases and disorders that are associated with MAGL are selected from multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, symptoms associated with inflammatory bowel disease, gut motility, visceral pain, fibromyalgia, endometriosis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, rheumatoid arthritis, osteoarthritis, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, and / or renal disease.

[0431] In a preferred embodiment, said diseases and disorders that are associated with MAGL are selected from inflammatory bowel disease, symptoms associated with inflammatory bowel disease, gut motility, visceral pain, fibromyalgia, endometriosis, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, abdominal pain, abdominal pain associated with irritable bowel syndrome, asthma, COPD, visceral pain, and / or renal disease. In a preferred embodiment, said diseases and disorders that are associated with MAGL are selected from inflammatory bowel disease, symptoms associated with inflammatory bowel disease, gut motility, abdominal pain, and / or abdominal pain associated with irritable bowel syndrome.

[0432] In a preferred embodiment, said diseases and disorders that are associated with MAGL are selected from visceral pain, endometriosis, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.

[0433] In a preferred embodiment, said diseases and disorders that are associated with MAGL are selected from endometriosis, pain associated with rheumatoid arthritis, and pain associated with osteoarthritis.

[0434] In a particularly preferred embodiment, said diseases and disorders that are associated with MAGL are endometriosis.

[0435] In a particularly preferred embodiment, said diseases and disorders that are associated with MAGL are pain associated with rheumatoid arthritis.

[0436] In a particularly preferred embodiment, said diseases and disorders that are associated with MAGL are pain associated with osteoarthritis.

[0437] In a particularly preferred embodiment, said diseases and disorders that are associated with MAGL are inflammatory bowel disease.

[0438] In a particularly preferred embodiment, said diseases and disorders that are associated with MAGL are symptoms associated with inflammatory bowel disease.

[0439] In a particularly preferred embodiment, said diseases and disorders that are associated with MAGL are gut motility.

[0440] In a particularly preferred embodiment, said diseases and disorders that are associated with MAGL are abdominal pain.

[0441] In a particularly preferred embodiment, said diseases and disorders that are associated with MAGL are abdominal pain associated with irritable bowel syndrome. Pharmaceutical Compositions and Administration

[0442] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0443] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).

[0444] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, com starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragees and hard gelatin capsules.

[0445] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances and liquid polyols, etc.

[0446] Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.

[0447] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

[0448] Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semisolid or liquid polyols, etc.

[0449] Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosityincreasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0450] The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated.

[0451] Tablet Formulation (Wet Granulation)

[0452] Item Ingredients mg / tablet

[0453] 1. Compound of formula (I) 5 25 100 500

[0454] 2. Lactose Anhydrous DTG 125 105 30 150

[0455] 3. Sta-Rx 1500 6 6 6 30

[0456] 4. Microcrystalline Cellulose 30 30 30 150

[0457] 5. Magnesium Stearate 1 1 1 1

[0458] Total 167 167 167 831

[0459] Manufacturing Procedure

[0460] 1. Mix items 1, 2, 3 and 4 and granulate with purified water.

[0461] 2. Dry the granules at 50°C.

[0462] 3. Pass the granules through suitable milling equipment.

[0463] 4. Add item 5 and mix for three minutes; compress on a suitable press.

[0464] Capsule Formulation

[0465] Item Ingredients mg / capsule

[0466] 1. Compound of formula (I) 5 25 100 500

[0467] 2. Hydrous Lactose 159 123 148

[0468] 3. Com Starch 25 35 40 70

[0469] 4. Talc 10 15 10 25

[0470] 5. Magnesium Stearate 1 2 2 5

[0471] Total 200 200 300 600

[0472] Manufacturing Procedure

[0473] 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

[0474] 2. Add items 4 and 5 and mix for 3 minutes.

[0475] 3. Fill into a suitable capsule. Examples

[0476] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0477] In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization.

[0478] All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.

[0479] Example 1

[0480] (4aR,8aS)-6-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one

[0481] To a solution of (4aR,8aS)-6-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2- carbonyl]-3-keto-4,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4-b]pyrazine-l-carboxylic acid tert-butyl ester (62 mg, 112 pmol) in chloroform (800 pL) was added TFA (128 mg, 86.1 pL, 1. 12 mmol) and the solution was stirred at RT for 48 h. The reaction solution was evaporated. The residue was taken up in DCM and a small volume of saturated aqueous NaHCCh solution and the layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were dried over MgSCh, filtered and evaporated. The product was purified on a preparative HPLC (YMC Triart C18 column) using a gradient of MeCN: water +0. 1% TEA. The combined fractions were evaporated to get the title compound as a colorless solid (27 mg, 63.1%). MS (ESI): m / z = 455.2 [M+H]+.

[0482] Step a) ( 4aR, 8aS)-6-[ 6-[ 2-fluoro-4-( trifluoromethyl)benzyl ]-2-azaspiro[ 3.3 ]heptane-2- carbonyl]-3-keto-4,4a,5, 7, 8, 8a-hexahydro-2H-pyrido[ 3, 4-b] pyrazine- 1 -carboxylic acid tertbutyl ester

[0483] To an ice-cold suspension of (4aR,8aS)-3-keto-2,4,4a,5,6,7,8,8a-octahydropyrido[3,4- b]pyrazine-l -carboxylic acid tert-butyl ester (A.l) (40 mg, 157 pmol) in acetonitrile (600 pL) was added l, r-carbonyl-di-(l,2,4-triazole) (CDT) (25.7 mg, 157 pmol) followed by DIEA (162 mg, 219 pL, 1.25 mmol) and the solution was stirred in an ice-bath for 30 minutes. To the solution was added 6-[[2-fluoro-4-(trifluoromethyl)phenyl]methyl]-2-azaspiro[3.3]heptane; 4- methylbenzenesulfonic acid (B.19) (69.8 mg, 157 pmol) and the mixture was stirred overnight at 50 °C. The crude was purified by preparative HPLC using a gradient MeCN: water + 0.1% HCOOH to get the title compound as a colorless solid (0.062 g, 71.4%). MS (ESI): m / z = 555.2 [M+H]+.

[0484] Example 16

[0485] (4aR,8aS)-6-[6-(3-fluoro-5-triflyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonylJ- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one

[0486] To a solution of (4aR,8aS)-3-keto-2,4,4a,5,6,7,8,8a-octahydropyrido[3,4-b]pyrazine-l- carboxylic acid tert-butyl ester (A.l) (35 mg, 137 pmol) in N,N-dimethylformamide (719 pL) cooled down to 0 °C was added DIPEA (124 mg, 167 pL, 959 pmol) followed by addition of CDT (23.6 mg, 144 pmol) after which the reaction mixture was stirred at 0 °C for 30 min. 6-[[3- Fluoro-5-(trifluoromethylsulfonyl)phenyl]methyl]-2-azaspiro[3 ,3]heptane; 4- methylbenzenesulfonic acid (P.66) (80.33 mg, 157.65 pmol) was added to the reaction mixture, which was then stirred at 50 °C for 18 h. Volatiles were removed in vacuo, the crude residue was dissolved in dichloromethane (0.500 mL), TFA (234 mg, 158 pL, 2.06 mmol) was added, and the reaction mixture was stirred at RT for 18 h. Volatiles were removed in vacuo, the crude

[0487] material was dissolved in DMF and directly purified by reversed-phase HPLC and SFC to give the title compound (6.9 mg) as a colorless gum. MS (ESI): m / z = 519.4 [M+H]+.

[0488] Example 30 (4aR,8aS)-6-[6-[[l-methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one

[0489] To a solution of (4aR,8aS)-3-keto-2,4,4a,5,6,7,8,8a-octahydropyrido[3,4-b]pyrazine-l- carboxylic acid tert-butyl ester (A.l) (300 mg, 1.18 mmol) in acetonitrile (7 mL) cooled down to 0 °C was added DIPEA (1.06 g, 1.44 mL, 8.23 mmol) followed by addition of CDT (202 mg, 1.23 mmol) after which the reaction mixture was stirred at 0 °C for 30 min. 6-[[l-methyl-5- (trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3 ,3]heptane; 4-methylbenzenesulfonic acid (B.308) (608 mg, 1.41 mmol) was added to the reaction mixture which was then stirred at 50 °C for 18 h. Volatiles were removed in vacuo, the crude residue was partitioned between ethyl acetate and 1 M aq. NaHCCL 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 down to dryness to give a residue which was purified by flash chromatography (eluent mixture of heptane and a solution of (EtOAc:EtOH 3: 1) (5% to 80%)) to yield the intermediate, (4aR,8aS)-3-keto-6-[6-[[l-methyl-5-(trifluoromethyl)pyrazol-4- yl]methyl]-2-azaspiro[3.3]heptane-2-carbonyl]-4,4a,5,7,8,8a-hexahydro-2H-pyrido[3,4- b]pyrazine-l -carboxylic acid tert-butyl ester (677 mg) as a white solid, which was used directly without further purification. MS (ESI): m / z = 541.3 [M+H]+.

[0490] The intermediate, (4aR, 8aS)-3 -keto-6- [6- [ [ 1 -methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-4, 4a, 5,7,8, 8a-hexahydro-2H-pyrido[3,4-b]pyrazine-l- carboxylic acid tert-butyl ester was dissolved in dichloromethane (5 mL) and TFA (1.34 g, 905 pL, 11.8 mmol) was added, after which the reaction mixture was stirred at RT for 18 h. Volatiles were removed in vacuo, the crude residue was then partitioned between ethyl acetate and sat. aq. Na2CC>3 solution. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulfate and evaporated down to dryness to give a residue which was purified by SFC, and again purified by FC (eluent mixture of dichloromethane and a solution (MeOH: 25 % aq. NH3 solution 97:3) (0% to 15%)) to give the title compound as a white solid (331 mg). MS (ESI): m / z = 441.4 [M+H]+.

[0491] Example 33 (4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one

[0492] To a solution of (4aR,8aS)-3-keto-2,4,4a,5,6,7,8,8a-octahydropyrido[3,4-b]pyrazine-l- carboxylic acid tert-butyl ester (A.l) (300 mg, 1.18 mmol) in acetonitrile (7 mL) was added DIPEA (759 mg, 1.03 mL, 5.88 mmol), CDT (212 mg, 1.29 mmol) after which the reaction mixture was stirred at room temperature for 30 min. 6-[[6-(Trifluoromethoxy)-3- pyridyl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid (B.302) (797 mg, 1.29 mmol) was added to the reaction mixture which was then stirred at 50 °C for 18 h. The reaction mixture was poured into a separating funnel containing ethyl acetate and 1 M aq. ISfeCCL solution for 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 down to dryness. The crude material was purified by flash chromatography (eluent mixture of heptane and a solution (EtOAc:EtOH 3:1) (10% to 70%)) to give 545 mg of the intermediate product, (4aR,8aS)-3-keto-6-[6-[[6-(trifhioromethoxy)-3-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-4, 4a, 5,7,8, 8a-hexahydro-2H-pyrido[3,4-b]pyrazine-l- carboxylic acid tert-butyl ester, as a colorless gum, which was used directly without further purification. MS (ESI): m / z = 554.2 [M+H]+.

[0493] The intermediate, (4aR,8aS)-3-keto-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-4, 4a, 5,7,8, 8a-hexahydro-2H-pyrido[3,4-b]pyrazine-l- carboxylic acid tert-butyl ester, was dissolved in 5 mL CH2CI2, followed by addition of 2,2,2- trifhioroacetic acid (1.34 g, 899 pL, 11.8 mmol) and the reaction mixture was stirred at RT for 18 h. Volatiles were removed in vacuo, the crude residue was partitioned between ethyl acetate and sat. aq. ISfeCCL 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 down to dryness to give a residue which was purified by SFC to yield the title compound (303 mg) as a white solid. MS (ESI): m / z = 454.2 [M+H]+.

[0494] In analogy to Examples 1, 16, 30, and 33 the following compounds were made using the indicated building block as the B.X building block. In some cases alternative salts were used, e.g. trifluoroacetic acid, 4-methylbenzene sulfonic acid.

[0495] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0496] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0497] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0498] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0499] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0500] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0501] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0502] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0503] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0504] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0505] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0506] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0507]

[0508] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0509] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0510] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0511] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0512] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0513] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0514] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0515]

[0516] SHEET INCORPORATED BY REFERENCE (RULE 20.6)

[0517] SHEET INCORPORATED BY REFERENCE (RULE 20.6) evaporated down to dryness to give a residue which was purified by SFC to yield the title compound (303 mg) as a white solid. MS (ESI): m / z = 454.2 [M+H]+.

[0518] In analogy to Examples 1, 16, 30, and 33 the following compounds were made using the indicated building block as the B.X building block. In some cases alternative salts were used, e.g. trifluoroacetic acid, 4-methylbenzene sulfonic acid.

[0519] -70- -72-

[0520]

[0521] -79- - 82 -

[0522] Synthesis of Building Blocks

[0523] Example A.l

[0524] ( 4aR, 8aS)-3-keto-2, 4, 4a, 5, 6, 7, 8, 8a-octahydropyrido[ 3, 4-b ]pyrazine-l -carboxylic acid tert-butyl ester

[0525] Racemate rac-tert-butyl (4aR,8aS)-3-oxo-decahydropyrido[3,4-b]piperazine-l-carboxylate (CAS: 2307777-24-6) was separated by chiral SFC (Chiral cellulose-4, 20% MeOH) to yield the title compound (5.15 g, first eluted enantiomer) as a white solid. MS (ESI): m / z = 256.2 [M+H]+

[0526] Note: The second eluted enantiomer (5.34 g) also yielded a white solid (5.34 g). MS (ESI): m / z = 256.2 [M+H]+

[0527] Example B.l

[0528] [ 3-(2-azaspiro[ 3.3 ]heptan-6-ylmethyl)phenyl ]-imino-oxo-( trifluoromethyl) -26-sulfane; 4- methylbenzenesulfonic acid

[0529] 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 h. After the completion of the reaction, the reaction mixture was concentrated and purified by HPLC to afford the title compound (339 mg, 0.690 mmol, 15.6 % yield) as brown viscous oil. MS (ESI): m / z = 319.0 [M-TsOH+H]+

[0530] Step a) tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0531] A mixture of 2,2,6, 6-tetramethylpiperidine (95.9 mL, 568 mmol) in THF (750 mL) was cooled to -30 °C under a N2 atmosphere. n-BuLi (227 mL, 568 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 30 min. Next, the reaction was cooled to - 83 -

[0532] -60 °C, and a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methyl]-l,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 in dropwise at -60 °C. The reaction mixture was allowed to slowly warm up to 25 °C and stirred at 25 °C for 12 h. The mixture was added H2O (8 OmL) slowly and then purified together with an additional batch of equal size by silica gel column (PE / EA=l :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 confirmed by1H NMR (400 MHz, CHLOROFORM- d) 5 = 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).

[0533] Step b) tert-butyl 6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methylene]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0534] (3-bromophenyl)-imino-oxo-(trifluoromethyl)-Z6-sulfane (2.47 g, 8.59 mmol), tert-butyl 6- [(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (2.4 g, 7.16 mmol), l, r-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.

[0535] 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 FC (SiCL) to afford the title compound (1 g, 2.4 mmol, 31.9% yield) as light yellow solid. MS (ESI): m / z = 361.0 [M-tBu+H]+.

[0536] Step c) tert-butyl 6-[[3-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2-azaspiro[3.3]heptane-2- carboxylate

[0537] 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 for 24 h under 30 bar of H2. Then the reaction mixture was filtered and concentrated to afford the title compound (1.3 g, 3.11 mmol, 96.5 % yield) a as grey oil. MS (ESI): m / z = 319.0 [M-Boc+H]+.

[0538] In analogy to Example B.l, the following building blocks were generated using the relevant (hetero)aryl bromide or iodide building block for the Suzuki coupling in Step b. In some cases, alternative salts (e.g. trifluoroacetate, ditosylate, hydrochloride) were also used. To introduce - 84 - different spiro-ring systems further building block substitutions can be made, for example Example B.353 used tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (CAS: 1363381-22- 9) in place of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate in Step a), and Example B.560 used 8-keto-2-azaspiro[4.4]nonane-2-carboxylic acid tert-butyl ester (CAS: 2227204-72- 8). In some cases the synthesis was planned to include removal of an additional Br group in the hydrogenation step, or additional protecting groups such as SEM during the Boc deprotection step.

[0539]

[0540] -97- - 100 -

[0541] Example B.32

[0542] 6-[[4-(trifluoromethyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[0543] A solution of tert-butyl 6-[[4-(trifluoromethyl)pyrazol-l-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 mixture was concentrated under vacuum to give a residue. To the residue was added deionized water 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]+

[0544] Step a) tert-butyl 6-[[4-(trifluoromethyl)pyrazol-l-yl]methylene]-2-azaspiro[3.3]heptane-2- carboxylate - 101 -

[0545] To a solution of 4-(trifluoromethyl)-lH-pyrazole (2435 mg, 17.9 mmol), tert-butyl 6-[(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (Example B. l, Step a)) (2000 mg, 5.97 mmol) and pyridine (1.45 mL, 17.9 mmol) in DMSO (80 mL) was added copper diacetate (2380 mg, 11.9 mmol) under O2 atmosphere, then stirred at 100 °C for 12 h under O2 (balloon) condition. The aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (eluent of 0 to 30% ethyl acetate / petroleum ether) to give a crude product which was purified by reversed-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]+

[0546] Step b) tert-butyl 6-[[4-(trifluoromethyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane-2- carboxylate

[0547] To a solution of tert-butyl 6-[[4-(trifluoromethyl)pyrazol-l-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), 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 yellow solid. MS (ESI): m / z = 346.1 [M+H]+

[0548] Example B.117

[0549] 7-[[ 2-fluoro-4-(trifluorome thyl)phenyl methyl -2, 7-diazaspiro[ 3.5 ] nonane ; 4- methylbenzenesulfonic acid

[0550] To a solution of 7-[2-fluoro-4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (1.23 g, 2.9 mmol ) in isopropyl acetate (10 mL) was added tosic acid monohydrate (1.1 g, 5.81 mmol). The mixture was stirred at 80 °C for 3 h to give a white suspension. The suspension was filtered through sintered glass, the filter cake washed twice with Et2O, and dried in vauo to give the title compound (1.75 g, 88 %) as white solid. MS (ESI): m / z = 303.1 [M+H]+.

[0551] Step a) 7-[2-fluoro-4-(trifluoromethyl)benzyl]-2, 7 -diazaspiro [3.5]nonane-2-carboxylic acid tertbutyl ester - 102 -

[0552] To a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (1.0 g, 5.21 mmol) and 2,7- diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester (CAS: 236406-55-6) (1.18 g, 5.21 mmol ) in dichloromethane (10 mL) was added sodium triacetoxy borohydride (1.21 g, 5.73 mmol) and acetic acid (625 mg, 596 pL, 10.4 mmol). The mixture was stirred at RT for 4 h.The reaction mixture was poured into EtOAc / THF 2: 1 and washed with sat. aq. NaHCCh solution, water and brine. The organic layer was dried over ISfeSCU and concentrated in vacuo. The crude material was purified by flash chromatography (eluting with 0% to 30% EtOAc in heptane) to give the title compound (1.23 g, 56 %) as white solid. MS (ESI): m / z = 403.4 [M+H]+.

[0553] Example B.509

[0554] 6-[ [5-[l -(trifluoromethyl)cyclopropyl ]imidazol-l-yl methyl ]-2-azaspiro[ 3.3 ] heptane; 4- methylbenzenesulfonic acid

[0555] To a solution of tert-butyl 6-[[5-[l-(trifhioromethyl)cyclopropyl]imidazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.78 mmol) in EtOAc (6 mL) was added p- toluenesulfonic acid monohydrate (444 mg, 2.34 mmol). The mixture was stirred at 30 °C for 72 h, evaporated and the residue was purified by HPLC to give the title compound (81.5 mg, 0.13 mmol, 15.8% yield) as a yellow gum. MS (ESI): m / z = 286.2 [M-TsOH+H]+.

[0556] Step a) tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0557] 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), cooled the reaction mixture to 0 °C followed by dropwise addition of methanesulfonyl chloride (6.1 mL, 78.9 mmol) then reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM, washed with water, brine, dried over anhydrous sodium sulphate and evaporate under reduced pressure to give the title compound (19.8 g, 64.8 mmol, 93.7% yield) as a light yellow solid. MS (ESI): m / z = 250.0 [M-Bu+H]+.

[0558] Step b) tert-butyl 6-[ [5-[ l-(trtfhioromethyl)cyclopropyl]imidazol-l-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate - 103 - tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (1040 mg, 3.41 mmol) was added at room temperature to a mixture of 4-[l-(trifluoromethyl)cyclopropyl]-lH- imidazole (C.18) (800 mg, 3.41 mmol), cesium carbonate (2220 mg, 6.81 mmol) in DMF (15 mL). The reaction mixture was stirred at 50 °C for 18 h, then it was taken up in EtOAc (100 mL) and the organics were washed with water (2 x 200 mL) and brine (100 mL). The organics were separated, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to give the title compound (300 mg, 0.78 mmol, 23 % yield) as a light yellow solid. MS (ESI): m / z = 386.2 [M+H]+.

[0559] Note: tert-butyl 6-[[4-[l-(trifluoromethyl)cyclopropyl]imidazol-l-yl]methyl]-2- azaspiro [3.3]heptane-2-carboxylate (800 mg, 2.07 mmol, 61 % yield) was also isolated as a yellow solid.

[0560] In analogy to Example B.509, the following building block was generated using the relevant commercial building block in Step b).

[0561] Example B.497

[0562] [ 4-(2-azaspiro[ 3.3 ]heptan-6-ylmethyl)-3-fluoro-phenyl ]-imino-oxo-( irifluoromelhyl)- / .6-sulfane; 4-methylbenzenesulfonic acid - 104 -

[0563] To a mixture of tert-butyl 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. Then the mixture was stirred at 80 °C for 12 h. The mixture was concentrated to remove the solvent. Deionized water was added and the mixture was lyophilized to give the title compound (2.05 g, 4.03 mmol, 83% yield) as a yellow gum. MS (ESI): m / z = 337.1 [M-TsOH+H]+’;

[0564] 'H NMR (400 MHz, DMSO-d6) 5 = 8.46 (br d, J = 3.8 Hz, 2H), 7.83 (dd, J = 8.5, 17.0 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 7.01 (br s, 1H), 3.95 (t, J = 6.1 Hz, 2H), 3.86 (t, J = 6.1 Hz, 2H), 3.71 - 3.46 (m, 2H), 2.79 (d, J = 7.5 Hz, 2H), 2.40 (td, J = 7.7, 15.3 Hz, 1H), 2.33 - 2.22 (m, 5H), 1.98 - 1.88 (m, 2H).

[0565] Step a) tert-butyl 6-[[2-fluoro-4-(trifluoromethylsulfanyl)phenyl]methylene]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0566] To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2- azaspiro[3.3]heptane-2-carboxylate (3291 mg, 9.82 mmol), l-bromo-2-fluoro-4- (trifluoromethylsulfanyl)benzene (CAS: 1520947-39-0) (2700 mg, 9.82 mmol) and K2CO3 (2713 mg, 19.6 mmol) in 1,4-Dioxane (30 mL) and water (6 mL) was added 1, 1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (801 mg, 0.98 mmol) at 25°C, then the mixture was stirred at 80 °C under a N2 atmosphere for 12 h. The mixture was purified by chromatography (PE:EtOAc=5: 1) and concentrated under vacuum to give product, which was further purified by prep-HPLC (water(FA)-ACN) to give the title compound (870 mg, 2.16 mmol, 22% yield) as colorless oil. MS (ESI): m / z = 348.0 [M- C4H8+H]+; 'H NMR (400 MHz, CHLOROFORM-d) 5 = 7.41 - 7.34 (m, 2H), 7.28 - 7.24 (m, 1H), 6.39 - 6.35 (m, 1H), 4.01 (s, 4H), 3.20 (br s, 2H), 3.10 (br s, 2H), 1.46 (s, 9H).

[0567] Step b) tert-butyl 6-[[2-fluoro-4-(trifluoromethylsulfanyl)phenyl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0568] 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) at 25°C under N2, the mixture was stirred at 25 °C under H2 atmosphere (balloon) 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% yield) as colorless oil. MS (ESI): m / z = 350.0 [M- C4H8+H]+;1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.38 - 7.31 (m, 2H), 7.17 (t, J = 7.7 Hz, - 105 -

[0569] 1H), 3.91 (s, 2H), 3.83 (s, 2H), 2.73 (d, J = 7.5 Hz, 2H), 2.49 - 2.38 (m, 1H), 2.33 - 2.21 (m, 2H), 1.95 - 1.84 (m, 2H)

[0570] Step c) tert-butyl 6-[[2-fluoro-4-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate

[0571] To a soution 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 mL) was added PhI(OAc)2(17.7 g, 54.9 mmol) and NH2COONH4(3.06 g, 39.2 mmol) at 25 °C. Then the mixture was stirred at 60 °C for 12 h, then was purified by PREP-HPLC (water(FA)-ACN) to give (2.03 g, 4.65 mmol, 36% yield) as a yellow oil. MS (ESI): m / z = 381.1 [M-C4Hs+H]+.

[0572] 1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.89 - 7.77 (m, 2H), 7.39 (t, J = 7.4 Hz, 1H), 3.92 (s, 2H), 3.84 (s, 2H), 3.66 (br s, 1H), 2.82 (d, J = 7.5 Hz, 2H), 2.46 (td, J = 7.8, 15.6 Hz, 1H), 2.34 - 2.24 (m, 2H), 1.97 - 1.86 (m, 2H), 1.66 (br s, 1H), 1.43 (s, 9H)

[0573] Example B.377

[0574] 6-[[4-[ l-(trifluoromethyl)cyclopropyl]pyrazol-l-yl]methyl]-2-azaspiro[3.3 ]heptane; 4- methylbenzenesulfonic acid

[0575] A solution of tert-butyl 6-[[4-[l-(trifhioromethyl)cyclopropyl]pyrazol-l-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]+

[0576] Step a) tert-butyl 6-[(4-bromopyrazol-l-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[0577] To a solution of 4-bromopyrazole (2000 mg, 13.6 mmol) in DCE (40 mL) were added tert-butyl 6- [(4,4, 5,5 -tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)methylene] -2-azaspiro [3.3 ]heptane-2- carboxylate (6840 mg, 20.4 mmol), pyridine (2153 mg, 27.2 mmol), boric acid (841 mg, 13.6 mmol) and Cu(OAc)2(3670 mg, 18.4 mmol). The mixture was stirred at 70 °C for 12 h under O2. The reaction mixture was purified by prep-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 - 106 - the title compound (2867 mg, 8.09 mmol, 59% yield) as an off-white solid. MS (ESI): m / z =

[0578] 298.1 [M+H]+

[0579] Step b) tert-butyl 6-[(4-bromopyrazol-l-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[0580] To a solution of tert-butyl 6-[(4-bromopyrazol-l-yl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (2300 mg, 6.49 mmol) in EtOAc (25 mL) was added PtO? (920 mg, 4.05 mmol) at 20 °C under N2, then the mixture was stirred at 20 °C under H2 atmosphere (balloon) for 1 h. The precipitate was filtered off and the filtrate was dried in vacuo. The residue was purified by FC (SiO2; hexane / EtOAc 1 : 1) to give the title compound (2200 mg, 6.18 mmol, 95% yield) as a light yellow solid.

[0581] MS (ESI): m / z = 302.0 [M-C4H8+H]+

[0582] Step c) tert-butyl 6-[[4-[l-(trifluoromethyl)vinyl]pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane- 2-carboxylate

[0583] To a solution of tert-butyl 6-[(4-bromopyrazol-l-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 for 12 h under N2 atmosphere. The precipitate was filtered off and the filtrate was dried in vacuo. The residue was purified by FC (SiO2; PEZEA, 0-60%). The reaction mixture was purified by prep-HPLC, and lyophilized to give the title compound (1134.0 mg, 3.05 mmol, 64 % yield) as light brown solid. MS (ESI): m / z = 372. 1 [M+H]+

[0584] Step d) tert-butyl 6-[[4-[l-(trifluoromethyl)cyclopropyl]pyrazol-l-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0585] To a solution of tert-butyl 6-[[4-[l-(trifhioromethyl)vinyl]pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (1000 mg, 2.69 mmol) in THF (20 mL) was added dip henyl(methyl) sulfonium tetrafluoroborate (1008 mg, 3.5 mmol). The suspension was cooled to 0 °C and NaHMDS / THF (1 M) (10.8 mL, 10.8 mmol) was added dropwise. The reaction mixture was warmed to 20 °C for and stirred for 12 h. The reaction mixture was purified by prep-HPLC and lyophilized to give the title compound (432 mg, 1.12 mmol, 42 % yield) as light yellow solid. MS (ESI): m / z = 386.1 [M+H]+ - 107 -

[0586] Example B.379

[0587] 6-[ [ I -cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl methyl ]-2-azaspiro[ 3.3 ]heptane; 4- methylbenzenesulfonic acid

[0588] To the mixture of tert-butyl 6-[[l-cyclopropyl-3-(trifhioromethyl)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, then the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. 20 mL deionized water and 2 mL ACN was 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]+

[0589] Step a) tert-butyl 6-[[5-(trifluoromethyl)-lH-pyrazol-4-yl]methylene]-2-azaspiro[3.3]heptane-2- carboxylate

[0590] To the solution of tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2- azaspiro[3.3]heptane-2-carboxylate (5009 mg, 14.9 mmol), 4-bromo-5-(trifluoromethyl)-lH- 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), l, T-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (554 mg, 0.68 mmol) at 20 °C, then the reaction was stirred at 100 °C for 12 h under N2. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (eluent of 0-40% ethyl acetate / petroleum ether) to give a crude product which was further purified by FC (SiCL; eluent of 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]+.

[0591] Step b) tert-butyl 6-[[l-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0592] To a mixture of tert-butyl 6-[[5-(trifhioromethyl)-lH-pyrazol-4-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate (600 mg, 1.75 mmol), cyclopropylboronic acid (600 mg, 6.99 mmol) in DCE (6 mL) was added pyridine (0.42 mL, 5.24 mmol), boric acid (108 mg, 1.75 mmol), copper diacetate (698 mg, 3.5 mmol) at 20 °C, then the reaction mixture was stirred at - 108 -

[0593] 100 °C for 16 h under O2 (balloon). The reaction mixture was filtered and then diluted with water 50 mL and extracted with EtOAc 150 mL (50 mL x 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 FC (SiCL; 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]+.

[0594] Step c) tert-butyl 6-[ [ l-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0595] To the mixture of tert-butyl 6-[[l-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, then the reaction mixture was stirred at 25 °C for 0.5 h under H2 (15 Psi (103’421 Pa)). The reaction mixture was filtered and the filter liquor 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]+.

[0596] Example B.382

[0597] 6-[[3-methyl-5-( trifluoromethyl)pyrazol-l-yl methyl ]-2-azaspiro[ 3.3 ] heptane; 4- methylbenzenesulfonic acid

[0598] A mixture of tert-butyl 6-[[3-methyl-5-(trifluoromethyl)pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (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. Then the reaction mixture was 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]+

[0599] Step a) tert-butyl 6-[[3-methyl-5-(trifluoromethyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane- 2-carboxylate

[0600] 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)-lH-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 for 12 h under N2 atmosphere. The reaction - 109 - mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC and lyophilized to give the title compound (735 mg, 2.05 mmol, 46.5 % yield) as a dark brown oil. MS (ESI): m / z = 304.0 [M+H]+

[0601] Note: Regioisomer tert-butyl 6-[[5-methyl-3-(trifluoromethyl)pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (485 mg, 1.35 mmol, 31% yield) was also generated as a dark brown powder. MS (ESI): m / z = 304.0 [M+H]+

[0602] Example B.408

[0603] 6-[[l -(2, 2, 2-trifluoroethyl)-3-( trifluoromethyl)pyrazol-4-yl Jmethyl ]-2-azaspiro[ 3.3 ]heptane; 4- methylbenzenesulfonic acid

[0604] To the mixture of tert-butyl 6-[[l-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]- 2-azaspiro[3.3]heptane-2-carboxylate (1.05 g, 2.46 mmol) in EtOAc (10 mL) was added p- toluenesulfonic acid (465 mg, 2.7 mmol) at 20 °C, then the reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. Then to the residue was added 20 mL deionized water and 2 mL CH3CN. The mixture was lyophilized to give the title compound (1224 mg, 2.45 mmol, 99 % yield) as a light yellow oil. MS (ESI): m / z = 328.0 [M+H]+.

[0605] Step a) tert-butyl 6-[[l-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0606] To the mixture of tert-butyl 6-[[5-(trifluoromethyl)-lH-pyrazol-4-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate (B.379, Step a) (2000 mg, 5.83 mmol), cesium carbonate (5694 mg, 17.5 mmol) in DMF (20 mL) was added a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (2704 mg, 11.7 mmol) in DMF (2 mL) at 0 °C, and the mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brince (50 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by FC (SiCL; Eluent of 0-28% Ethyl acetate / Petroleum ether) to give the title compound (1.1 g, 2.59 mmol, 44 % yield) as a white solid. MS (ESI): m / z = 370.0 [M-C4H8+H]+. - 110 -

[0607] Step b) tert-butyl 6-[[l-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0608] To the mixture of tert-butyl 6-[[l-(2,2,2-trifhioroethyl)-3-(trifhroromethyl)pyrazol-4- yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate (1000 mg, 2.35 mmol) in EtOAc (10 mL) was added Pd / C (300 mg, 10 %, wet.) at 20 °C, then the reaction mixture was stirred at 20 °C for 1 h under H2. The reaction mixture was concentrated under reduced pressure to give the title compound (1.05 g, 2.46 mmol, 104% yield) as a colorless oil. MS (ESI): m / z = 372.0 [M- C4H8+H]+.

[0609] In analogy to the sequence in Building Block B.379 / B.408, the following building block was generated using the relevant heteroarylhalide for Suzuki coupling, followed by alkylation and reduction.

[0610] Example B.415

[0611] 6-[ [2 -(2, 2, 2-trifluoroethyl) -5-( trifluor ome thyl)pyrazol-3-yl ]me thy I ]-2-azaspiro[ 3.3 ] heptane ; 4- methylbenzenesulfonic acid - I l l -

[0612] A solution of p-toluenesulfonic acid (247 mg, 1.43 mmol) and tert-butyl 6-[[2-(2,2,2- trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (510 mg, 1.19 mmol) in EtOAc (5 mL) was stirred at 80 °C for 12 h. The mixture was concentrated under reduced pressure to give residue. To the residue was added deionized water and lyophilized to give the title compound (550 mg, 92.3% yield) as a colorless oil. MS (ESI): m / z =328.0 [M-TsOH+H]+

[0613] Step a) tert-butyl 6-[[2-(2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0614] To a solution of tert-butyl 6-[[5-(trifluoromethyl)-lH-pyrazol-3-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (generated in the synthesis ofP.7, Step c)) (1.5 g, 4.34 mmol) in THF (15 mL) was added NaH (261 mg, 6.51 mmol) at 0°C for 0.5 h. Then 2,2,2- trifluoroethyl trifluoromethanesulfonate (2016 mg, 8.69 mmol) was added at 20 °C, and the reaction stirred for 12 h. The reaction was quenched by ice slowly and then extracted with EtOAc (20 mL><3).The combined organic phase was washed with brine (20mL><3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC and lyophilized to give regioisomer tert-butyl 6-[[l-(2,2,2-trifhioroethyl)-5- (trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (240.0 mg, 0.56 mmol, 12.93% yield) (crude) and tert-butyl 6-[[2-(2,2,2-trifhioroethyl)-5- (trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (800 mg, 1.87 mmol, 43.1% yield) (crude) as yellow solid. The residue was purified by prep-HPLC to give the title compound (530 mg, 1.24 mmol, 66 % yield) as a colorless oil. MS (ESI): m / z =372.0 [M- C4H8+H]+

[0615] Example B.416

[0616] 6-[[l -(2, 2, 2-trifluoroethyl)-5-( trifluoromethyl)pyrazol-3-yl methyl ]-2-azaspiro[ 3.3 ]heptane; 4- methylbenzenesulfonic acid

[0617] A solution of p-toluenesulfonic acid (43.5 mg, 0.25 mmol) and tert-butyl 6-[[l-(2,2,2- trifhioroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (regioisomeric product from B.415, Step a)) (90.0 mg, 0.21 mmol) in EtOAc (2 mL) was stirred at 80 °C for 12 h. The mixture was concentrated under reduced pressure to give residue. The - 112 - residue was added deionized water and lyophilized to give 4-methylbenzenesulfonic acid;6-[[l- (2,2,2-trifluoroethyl)-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptane (95.4 mg, 0.19 mmol, 88.31% yield) as a off-white solid. MS (ESI): m / z =328.0 [M-TsOH+H]+; 'HNMR (400 MHz, DMSO-d6) 5 = 8.56 - 8.34 (m, 1H), 7.47 (d, J = 8.1 Hz, 3H), 7.11 (d, J = 7.9 Hz, 3H), 6.85 (s, 1H), 5.16 (q, J = 8.8 Hz, 2H), 4.00 - 3.92 (m, 2H), 3.87 - 3.79 (m, 2H), 2.64 (d, J = 7.3 Hz, 2H), 2.48 - 2.35 (m, 2H), 2.34 - 2.30 (m, 1H), 2.29 (s, 4H), 1.95 - 1.86 (m, 2H)

[0618] Example B.504

[0619] [6-(2-azaspiro[ 3.3 ]heptan-6-ylmethyl)-3-pyridyl]-imino-oxo-(trifluoromethyl)- 6-sulfane;4- methylbenzenesulfonic acid

[0620] To a solution of tert-butyl 6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (4.8 g, 11.4 mmol) in EtOAc (48 mL) was added p- toluenesulfonic acid (2.36 g, 13.7 mmol) at 20 °C. Then the mixture was stirred at 80 °C for 12 h. The mixture was concentrated to remove the solvent , then deionized water was added and mixture was lyophilized to give the title compound (5608 mg, 11.4 mmol, 93.8% yield) as a brown solid. MS (ESI): m / z = 320.0 [M-TsOH+H]+

[0621] Step a) tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methylene]-2-azaspiro[3.3]heptane- 2-carboxylate

[0622] To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2- azaspiro[3.3]heptane-2-carboxylate (58.8 g, 175 mmol) , 2-chloro-5- (trifluoromethylsulfanyl)pyridine (CAS: 1204234-95-6) (37.5 g, 175 mmol) and K^CCE (48.5 g, 351 mmol) in 1,4-Dioxane (400 mL) and water (80 mL) was added Pd(dppf)C12*DCM (14.3 g, 17.5 mmol) at 20 °C, the mixture was stirred at 80 °C under N2 atmosphere for 12 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give a crude product which was purified by FC (SiCE; eluent of 0-30% EtOAc / PE) and evaporated to give the title compound (28500 mg, 73.8 mmol, 42.1% yield) as an off-white solid. MS (ESI): m / z = 331.0 [M-C4H8+H]+

[0623] Step b) tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carboxylate - 113 -

[0624] To a solution of tert-butyl 6-[[5-(trifhioromethylsulfanyl)-2-pyridyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate (28.0 g, 72.5 mmol) in EtOAc (280 mL) was added wet Pd / C (28.0 g) at 30 °C, then the mixture was stirred at 30 °C for 12 h. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl 6-[[5- (trifluoromethylsulfanyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (27.0 g, 69.5 mmol, 96 % yield) as a yellow solid. MS (ESI): m / z = 333.0 [M-C4Hs+H]+

[0625] Step c) tert-butyl 6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0626] To a solution of tert-butyl 6-[[5-(trifluoromethylsulfanyl)-2-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (20.0 g, 51.5 mmol) in HTTP (300 mL) was added PhI(OAc)2 (69.7 g, 216 mmol) and NH2COONH4 (12.1 g, 154 mmol) at 20 °C. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under vacuum to give residue. The residue was purified by prep-HPLC (water (FA)-ACN) and lyophilized to give the title compund (4.0 g, 9.54 mmol, 18.5% yield) as a dark brown oil. MS (ESI): m / z = 364.1 [M-C4Hs+H]+

[0627] In analogy to Example B.504, the following building block was generated using the relevant commercial building blocks.

[0628] Example B.520

[0629] 2- [6-(2, 2, 2-trifluoroethoxy)-3-pyridyl methyl -2, 6-diazaspiro[ 3.3 ] heptane; 4- methylbenzenesulfonic acid - 114 -

[0630] The mixture of tert-butyl 6-[[6-(2,2,2-trifhioroethoxy)-3-pyridyl]methyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (800.0 mg, 2.07 mmol) and p-toluenesulfonic acid monohydrate (1.3 g, 6.81 mmol) in EtOAc (60 mL) was stirred at 55 °C for 2 h. After cooling to RT, the obtained precipitate was filtered, washed with EtOAc and dried to give the title compound (1.1 g, 1.74 mmol, 80.1% yield) as a white solid. MS (ESI): m / z = 288.2 [M+H]+.

[0631] Step a) tert-butyl 6-[ ( 6-oxo-lH-pyridin-3-yl)methyl -2, 6-diazaspiro[ 3.3 ]heptane-2-carboxylate

[0632] To the stirred mixture of 6-oxo-lH-pyridine-3-carbaldehyde (2. 1 g, 17.0 mmol) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hydrochloride (4.0 g, 17.0 mmol) in dry DCM (150 mL), triethylamine (7.13 mL, 51.1 mmol) was added and the reaction was stirred for 20 min at RT. Then sodium triacetoxyborohydride (7.22 g, 34.1 mmol) was added in one portion, and the reaction mixture was stirred for 18 h at 25 °C. Then reaction mixture was diluted with DCM (150 mL), and 5% aq. NaHCCL solution (100 mL) was added. After stirring for 10 min the organic phase was separated, and the aqueous layer was extracted with DCM (100 mL). The organic layers were combined, washed with brine (50 mL), dried over ISfeSCL and concentrated in vacuo. The crude product was stirred with EtOAc (100 mL) and obtained precipitate was filtered. The filtrate was evaporated in vacuum to the title compound (4.6 g, 15.1 mmol, 80 % yield) as light yellow semisolid. MS (ESI): m / z = 306.2 [M+H]+.

[0633] Step b) tert-butyl 6-[[6-(2, 2, 2-trifluoroethoxy)-3-pyridyl methyl -2, 6-diazaspiro[ 3.3 ]heptane-2- carboxylate

[0634] To a stirred suspension of tert-butyl 6-[(6-oxo-lH-pyridin-3-yl)methyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (2.7 g, 8.84 mmol) and potassium carbonate (4.89 g, 35.4 mmol) in DMF (50 mL), 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.08 g, 13.3 mmol) was added. Then RM was stirred at RT for 18 h The precipitate was filtered-off and filtrate was partitioned between water (150 mL) and TBME (250 mL). The organic layer was washed with brine, dried over ISfeSCU and evaporated in vacuum. The crude product was purified by FC (SiCL; hexane / MTBE (50-100%) / MeOH (0-100%)) to give two regioisomers: tert-butyl 6-[[6- oxo-l-(2,2,2-trifluoroethyl)-3-pyridyl]methyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (750 - 115 - mg, 1.94 mmol, 20.8% yield, not used further for this building block); MS (ESI): m / z =388.2 [M+H]+) and tert-butyl 6-[[6-(2,2,2-trifluoroethoxy)-3-pyridyl]methyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate (1.1 g, 2.84 mmol, 30.51% yield); MS (ESI): m / z = 388.0 [M+H]+).

[0635] Example B.529

[0636] 6-[[4-(trifluoromethylsulfonyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane 4- methylbenzenesulfonic acid

[0637] A mixture of tert-butyl 6-[[4-(trifluoromethylsulfonyl)pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (630 mg, 1.54 mmol) and p-toluenesulfonic acid (317.97 mg, 1.85 mmol, 1.2 eq) in EtOAc (20 mL) was stirred at 80 °C for 12 h under N2 balloon. The reaction was concentrated and the residue was dissolved in H2O (30 mL).The solution was lyophilized to afford the title compound (738 mg, 1.53 mmol, 97 % yield) as a light yellow solid. MS (ESI): m / z = 310. 1 [M+H]+

[0638] Step a) tert-butyl 6-[(4-iodopyrazol-l-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[0639] To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2- azaspiro[3.3]heptane-2-carboxylate (45.6 g, 136 mmol), 4-iodopyrazole (24.0 g, 123 mmol), boric acid (7.65 g, 123 mmol) and pyridine (30 mL, 371 mmol) in DCE (230 mL) was added copper diacetate (49.4 g, 247 mmol) under O2 atmosphere. The mixture was stirred at 70 °C for 12 h under O2 atmosphere. The reaction was concentrated. The residue was purified by flash chromatography on silica gel eluting with PE / EtOAc (4: 1) to afford the crude product, which was purified by prep-HPLC (water(FA)-ACN 55%-75%) to afford the title compound (17.7 g, 44.1 mmol, 35.6 % yield) as a white solid. MS (ESI): m / z = 346.0 [M-C4H8+H]+

[0640] Step b) tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-l-yl]methylene]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0641] To a solution of tert-butyl 6-[(4-iodopyrazol-l-yl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (30.0 mg, 0.07 mmol) in ACN (3 mL) was added silver(I) Trifluoromethanethiolate (46.9 mg, 0.22 mmol) , Cui (28.5 mg, 0.15 mmol) and 2-pyridin-2-ylpyridine (23.4 mg, 0.15 - 116 - mmol) in a sealed tube at 90 °C for 12 h. The reaction was concentrated. The residue was purified by prep-HPLC (water (FA)-ACN] 52%-82%); to afford the title compound (13.0 mg, 0.03 mmol, 46 % yield) as a yellow solid. MS (ESI): m / z = 320.1 [M-C4H8+H]+

[0642] Step c) tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane-2- carboxylate

[0643] To a solution of tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-l-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate (2.8 g, 7.46 mmol) in EtOAc (50 mL) was added Pd / C (1.0 g, 0.75 mmol) at 25 °C and stirred for 1 h under EE balloon (760 mm Hg). The reaction was filtered and concentrated to afford the title compound (2.8 g, 7.42 mmol, 99 % yield) as a white solid. MS (ESI): m / z = 322.2 [M-C4H8+H]+

[0644] Step d) tert-butyl 6-[[4-(trifluoromethylsulfonyl)pyrazol-l-yl]methyl]-2-azaspiro[3.3]heptane-2- carboxylate

[0645] To a solution of tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (1.0 g, 2.65 mmol) in 1,2-dichloroethane (4 mL), ACN (4 mL) and water (8 mL) was added sodium periodate (1. 13 g, 5.3 mmol) and ruthenium(III) chloride hydrate (59.7 mg, 0.26 mmol) at 0 °C, then the mixture was stirred at 25 °C for 12 h. The reaction was concentrated. The residue was purified by prep-HPLC (water(FA)-ACN 50%- 80%) to afford the title compound (630 mg, 1.54 mmol, 58 % yield) as a grey solid. MS (ESI): m / z = 354.3 [M-C4H8+H]+

[0646] Example B.530

[0647] [ 1 -(2-azaspiro[ 3.3 ]heptan-6-ylmethyl)pyrazol-4-yl]-imino-oxo-(trifluoromethyl)-6-sulfane; 4- methylbenzenesulfonic acid

[0648] A mixture of tert-butyl 6-[[4-(trifluoromethylsulfonimidoyl)pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (650 mg, 1.59 mmol) and p-toluenesulfonic acid (329 mg, 1.91 mmol) in EtOAc (10 mL) was stirred at 80 °C for 12 h under N2 balloon.The reaction was concentrated and the residue was dissolved in H2O (30 mL).The solution was lyophilized to the title compound (623 mg, 1.3 mmol, 77 % yield) as a light yellow oil. MS (ESI): m / z = 309.1 [M+H]+ - 117 -

[0649] Step a) tert-butyl 6-[[4-(trifluoromethylsulfonimidoyl)pyrazol-l-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0650] A mixture of tert-butyl 6-[[4-(trifluoromethylsulfanyl)pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (B.529, Step b) (1.8 g, 4.77 mmol), PhI(OAc)2 (6.14 g, 19.1 mmol) and NH2COONH4 (1.49 g, 19.1 mmol) in TFE was stirred at 30 °C for 12 h. The reaction was concentrated. The residue was purified by prep-HPLC (water (FA)-ACN, 60%-80%) to afford the title compound (650 mg, 1.59 mmol, 33 % yield) as a grey solid. MS (ESI): m / z = 353.1 [M-C4H8+H]+

[0651] Example B.533

[0652] 6-[difluoro-[ 6-(trifluoromethyl)-3-pyridyl methyl ]-2-azaspiro[ 3.3 ] heptane; 4- methylbenzenesulfonic acid

[0653] To a solution of 6-[difluoro-[6-(trifhioromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carboxylic acid tert-butyl ester (77 mg, 196 pmol ) in isopropyl acetate (3 mL) was added p- toluenesulfonic acid monohydrate (82.1 mg, 432 pmol). The mixture was stirred at 80 °C for 3 h. The reaction mixture was concentrated in vacuo to afford the title compound (163 mg, 99 %) as a colorless oil. MS (ESI): m / z = 293.0 [M+H]+

[0654] Step a) tert-butyl 6-[6-(trifluoromethyl)pyridine-3-carbonyl]-2-azaspiro[3.3]heptane-2- carboxylate

[0655] To a solution of tert-butyl 6-[methoxy(methyl)carbamoyl]-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 2428601-18-5) (4.3 g, 15.1 mmol), and 5-bromo-2-(trifhioromethyl)pyridine (6.83 g, 30.2 mmol) in THF (100 mL) was added n-BuLi (18.2 mL, 45.4 mmol) at -78 °C for 1 h. Then the reaction mixture was stirred at 30 °C for 12 h. The reaction mixture was poured into saturated NH4CI aqueous solution (500 mL) and then extracted with ethyl acetate (60 mL x 3). The organic layer was washed with brine. The residue was purified by flash chromatography on silica gel eluting with PEZEtOAc (2: 1) to afford the title compound (1400 mg, 3.78 mmol, 25 % yield) as a brown solid.1H NMR (400 MHz, METHANOL-d4) 5 = 9.17 (s, 1H), 8.49 (dd, J = 1.5, 8.3 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 4.11 - 3.99 (m, 3H), 3.84 (s, 2H), 2.65 - 2.48 (m, 4H), 1.43 (s, 9H). - 118 -

[0656] Note that regioisomer was generated concurrently: tert-butyl 6-[2-(trifluoromethyl)pyridine-4- carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate (1100 mg, 2.97 mmol, 20 % yield) as a brown oil. 'H NMR (400 MHz, METHANOL-d4) 5 = 8.92 (d, J = 5.0 Hz, 1H), 8.15 (s, 1H), 8.04 (dd, J = 1.1, 4.9 Hz, 1H), 4.03 (s, 3H), 3.83 (s, 2H), 2.55 (br dd, J = 8.3, 12.1 Hz, 4H), 1.43 (s, 9H) Step b) 6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0657] To a solution of tert-butyl 6-[6-(trifluoromethyl)pyridine-3-carbonyl]-2-azaspiro[3.3]heptane-2- carboxylate (750 mg, 2.03 mmol) in DCM (5 mL) was added DAST (5.0 mL, 37.8 mmol) dropwise at 0 °C under N2 atmosphere. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was added into saturated NaHCCL aqueous solution (200 mL) dropwise and then extracted with DCM (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (water(FA)-ACN, 58%-88%); to afford the title compound (510 mg, 1.3 mmol, 64 % yield) as a light yellow solid. MS (ESI): m / z = 337.0 [M-C4H8+H]+;XH NMR (400 MHz, METHANOL-d4) 5 = 8.87 (s, 1H), 8.26 - 8.13 (m, 1H), 7.94 (d, J = 8.3 Hz, 1H), 4.03 - 3.83 (m, 4H), 3.18 - 2.96 (m, 1H), 2.47 - 2.27 (m, 4H), 1.44 (s, 9H)

[0658] In analogy to Building Block P. 143, the following building blocks were generated using the relevant heteroarylbromide. In some cases, alternative salts (e.g. trifluoroacetate, ditosylate, hydrochloride) were also used. - 119 -

[0659] Example B.542 and B.543

[0660] 6-[ ( 1R)-1~[ 4-methyl-5-(trifluoromethyl)-2-pyridyl ethyl ]-2-azaspiro[ 3.3 ] heptane; 4- methylbenzene sulfonic acid and 6-[(lS)-l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2- azaspiro [3.3] heptane; 4-methylbenzenesulfonic acid

[0661] (arbitrary assignment of enantiomers) - 120 -

[0662] The solution of tert-butyl 6-[(lR)-l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2- azaspiro[3.3]heptane-2-carboxylate (250 mg, 0.65 mmol) and p-toluenesulfonic acid monohydrate (309 mg, 1.63 mmol) in EtOAc (10 mL) was stirred at 60 °C for 3 h. After cooling to RT, the obtained precipitate was filtered, washed with EtOAc and dried in vacuum to give the title compound B.542 (237 mg, 0.38 mmol, 55% yield) as white solid. MS (ESI): m / z =285.2 [M+H]+. Deprotection of the other enantiomer carried out in analogy to yield title compound B.543 (241 mg, 0.38 mmol, 58 % yield) as white solid. MS (ESI): m / z =285.2 [M+H]+

[0663] Step a) tert-butyl 6-[l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ethylidene]-2- azaspiro[3.3]heptane-2-carboxylate

[0664] To a stirred -30 °C solution of 2,2,6, 6-tetramethylpiperidine (4.31 mL, 25.6 mmol) in THF (75 mL) under Ar, butyllithium solution (2.5 M in hexane) (10.2 mL, 25.6 mmol) was added. The solution was stirred at -30 °C for 30 min and cooled to -78 °C. The solution of 4,4, 5, 5- tetramethyl-2-[l-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)ethyl]-l,3,2-dioxaborolane (CAS: 1227056-25-8) (6.61 g, 23.4 mmol) in 10 mL of dry THF was added dropwise and reaction mixture was stirred at -78 °C for 30 min. The solution of tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (4500 mg, 21.3 mmol) in 15 mL of dry THF was added dropwise at -78 °C and reaction mixture was allowed to warm and stirred overnight at room temperature. The reaction was quenched with water; the mixture was vacuum-concentrated, and the residue was separated between water and DCM. The organic layer was washed with citric acid, water, brine, dried over sodium sulfate and concentrated to give residue which was purified by FC (SiCL; 1 :4 TBME / hexane) to give the title compound (3.1 g, 8.88 mmol, 41% yield) as a white solid. MS (ESI): m / z =294.2 [M-C4H8+H]+

[0665] Step b) tert-butyl 6-[l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethylidene]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0666] To a stirred suspension of 2-chloro-4-methyl-5-(trifluoromethyl)pyridine (1.36 g, 6.93 mmol), tert-butyl 6- [ 1 -(4,4, 5 , 5 -tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)ethylidene] -2-azaspiro [3.3 ]heptane- 2-carboxylate (2.2 g, 6.3 mmol) and cesium carbonate (4. 1 g, 12.6 mmol) in dry 1,4-Dioxane (110 mL), flushed with Argon for 3 minutes, l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (771 mg, 0.94 mmol) was added. The mixture was stirred at 80 °C for 48 h under Argon atmosphere. After cooling to RT, the reaction mixture was filtered and filtrate was concentrated. The obtained residue was partitioned between EtOAc and brine. The organic layer was dried over Na2SO4and concentrated to give crude product, - 121 - which was purified by FC (SiCL; hexane / MTBE 10-23%) to obtain the title compound (700 mg, 1.83 mmol, 28% yield) as light yellow solid. MS (ESI): m / z =327.2 [M-C4H8+H]+

[0667] Step c) tert-butyl 6-[l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2-azaspiro[3.3]heptane-2- carboxylate

[0668] The stirred mixture of tert-butyl 6-[l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethylidene]-2- azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.83 mmol) and Pd / C (5%) (200 mg) in EtOAc (50 mL) was hydrogenated in autoclave at 15200 mmHg (20 bar) for 24 h at 25 °C. The reaction mixture was filtered and concentrated in vacuum to give the title compound (680 mg, 1.77 mmol, 92% yield) as orange gum; MS (ESI): m / z =329.0 [M-C4Hs+H]+. A mixture of enantiomers tert-butyl 6-[l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2- azaspiro[3.3]heptane-2-carboxylate (680 mg, 1.77 mmol) was separated by chiral chromatography to give tert-butyl 6-[(lS)-l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2- azaspiro[3.3]heptane-2-carboxylate (270 mg, 0.7 mmol, 40% yield) (or enantiomer) RetTime (min): 11.2 and tert-butyl 6-[(lR)-l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2- azaspiro[3.3]heptane-2-carboxylate (250 mg, 0.65 mmol, 37% yield) (or enantiomer) RetTime(min): 13.9.

[0669] Example B.552

[0670] 6-[[5-(trifluoromethyl)-2-pyridyl]oxymethyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid

[0671] To a solution of tert-butyl 6-[[5-(trifluoromethyl)-2-pyridyl]oxymethyl]-2-azaspiro[3.3]heptane- 2-carboxylate (1299 mg, 3.49 mmol) in EtOAc (21.7 mL) p-toluenesulfonic acid monohydrate (1991 mg, 10.5 mmol) was added. Reaction mixture was stirred at 25 °C for 72 h, then filtered and washed with ether to give the title compound (1538 mg, 3.46 mmol, 94 % yield) as white solid. MS (ESI): m / z = 273.0 [M+H]+.

[0672] Step a) tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0673] To a stirred solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate

[0674] (CAS: 1363381-93-4) (14.9 g, 65.7 mmol) in DCM (299 mL) was added triethylamine (13.7 - 122 - mL, 98.6 mmol), cooled the reaction mixture to 0 °C followed by dropwise addition of methanesulfonyl chloride (6.1 mL, 78.9 mmol) then reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with water and extracted with DCM, washed with water, brine, dried over anhydrous sodium sulphate and evaporate under reduced pressure to give the title compound (19.8 g, 64.8 mmol, 93.7% yield) as a light yellow solid. MS (ESI): m / z = 250.0 [M-Bu+H]+.

[0675] Step b) tert-butyl 6-[[5-(trifluoromethyl)-2-pyridyl]oxymethyl]-2-azaspiro[3.3]heptane-2- carboxylate

[0676] To a solution of 5-(trifluoromethyl)-2-pyridone (294 mg, 1.8 mmol) in dry N,N- dimethylformamide (7.5 mL) cooled down to 0 °C under an inert atmosphere was added NaH (60% in mineral oil) (72 mg, 1.8 mmol) and the reaction mixture was stirred at 0 °C for 10 min and 15 min at RT followed by addition of tert-butyl 6-(methylsulfonyloxymethyl)-2- azaspiro[3.3]heptane-2-carboxylate (500 mg, 1.64 mmol) after which the reaction mixture was stirred at RT for 18 h. Volatiles were removed in vacuo, the crude residue was partitioned between ethyl acetate and aq. Na2COs 1 M (aq.). 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 down to dryness to give a residue. The crude material was purified by FC (SiCL; 5% to 80% EtOAc in heptane) to give the title compound (227 mg) as a white solid. MS (ESI): m / z = 317.2 [M-C4H8+H]+. Also isolated was regioisomeric side product 6-[[2-keto-5-(trifluoromethyl)-l-pyridyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylic acid tertbutyl ester (266 mg); MS (ESI): m / z = 317.2 [M-C4H8+H]+.

[0677] Example P.113

[0678] 6-[ [5-[l -(trifluorome thyl)cyclopropyl ]pyrimidin-2-yl ]me thy I ]-2-azaspiro[ 3.3 ] heptane ; 2,2,2- tr i fluor oacetic acid

[0679] To a solution of 6-[[5-[l-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (180 mg, 452 pmol) in dichloromethane (1.5 mL) was added TFA (516 mg, 348 pL, 4.53 mmol). The reaction mixture was stirred at RT - 123 - for 18 h. The reaction mixture was concentrated in vacuo to give 365 mg of the crude title compound as a brownish viscous oil, purity -50%. MS (ESI): m / z = 298.2 [M+H]+.

[0680] Step a) tert-butyl 6-[(5-bromopyrimidin-2-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[0681] To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2- azaspiro[3.3]heptane-2-carboxylate (5.88 g, 17.6 mmol, CAS 2763647-64-7), 5-bromo-2- iodopyrimidine (5 g, 17.6 mmol) in 1,4-dioxane (75 mL) and water (15 mL), was added potassium carbonate (4.85 g, 35.1 mmol) and l, l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (1.43 g, 1.76 mmol, CAS 95464-05-4 ) at 20 °C. The mixture was stirred at 80 °C under N2 atmosphere for 12 h. The residue was purified by FC (SiCh; PE / EtOAc 5: 1) to afford the title compound (4.6 g, 12.6 mmol, 71% yield) as white solid. MS (ESI): m / z = 312.0 [M-C4H8+H]+.

[0682] Step b) tert-butyl 6-[(5-bromopyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[0683] To a solution of tert-butyl 6-[(5-bromopyrimidin-2-yl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (4.8 g, 13.1 mmol) in EtOAc (48 mL) was added PtCL (1.63 g, 7.19 mmol) at 25 °C under N2. The mixture was stirred at 25 °C under H2 atmosphere (15 PSI (103’421 Pa)) for 2.5 h. The reaction mixture was filtered and the residue was purified by FC (SiCL; PE / EtOAc 3: 1) to afford the title compound (1.87 g, 5.08 mmol, 38% yield) as white solid. MS (ESI): m / z = 314.0 [M-C4H8+H]+.

[0684] Step c) tert-butyl 6-[[5-[l-(trifluoromethyl)vinyl]pyrimidin-2-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0685] To a solution of 4,4,6-trimethyl-2-[l-(trifluoromethyl)vinyl]-l,3,2-dioxaborinane (1.52 g, 6.84 mmol, CAS 1011460-68-6) and tert-butyl 6-[(5-bromopyrimidin-2-yl)methyl]-2- azaspiro[3.3]heptane-2-carboxylate (2.1 g, 5.7 mmol), potassium carbonate (1.58 g, 11.4 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was added l, l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (465 mg, 0.57 mmol, CAS 95464-05-4). The mixture was stirred at 80 °C under N2 atmosphere for 12 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (15mL x 3). The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with FC (SiCL; PE / EtOAc 3: 1) to afford the title compound (2.05 g, 5.35 mmol, 93% yield) as a white solid. MS (ESI): m / z = 328.0 [M- C4H8+H]+. - 124 -

[0686] Step d) tert-butyl 6-[[5-[l-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0687] To a solution of tert-butyl 6-[[5-[l-(trifluoromethyl)vinyl]pyrimidin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (2.05 g, 5.35 mmol) in THF (35 mL) was added dip henyl(methyl) sulfonium tetrafluoroborate (2 g, 6.95 mmol, CAS 10504-60-6). NaHMDS 1 M in THF (8.55 mL, 8.55 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into saturated NH4CI aqueous solution (80 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was washed with brine and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by FC (SiCL; PE / EtOAc 2: 1) to afford a residue which was purified by prep-HPLC to yield the title compound (1.1 g, 2.78 mmol, 52% yield) as white solid. MS (ESI): m / z = 342.1 [M-C4Hs+H]+.

[0688] In analogy to Building Block P. 113, the following building blocks were generated using the relevant heteroarylbromide or heteroarylchloride. - 125 -

[0689] Example P.146

[0690] 2-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine;4- methylbenzenesulfonic acid - 126 -

[0691] To a solution of tert-butyl 6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (48 mg, 1.1 mmol) in EtOAc (9.8 mL), p-toluenesulfonic acid monohydrate (749 mg, 4.0 mmol) was added. The mixture was stirred at 25 °C for 18 h. The reaction mixture concentrated in vacuo and residue was treated with MTBE. The formed precipitate was filtered to give the title compound (729 mg, 1.14 mmol) as a light yellow solid. MS (ESI): m / z = 297.2 [M+H]+.

[0692] Step a) tert-butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethylene)-2-azaspiro[3.3]heptane-2- carboxylate

[0693] To a solution of tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2- azaspiro[3.3]heptane-2-carboxylate (2.2 g, 6.6 mmol, CAS 2763647-64-7) and 2-chloro-7H- pyrrolo[2,3-d]pyrimidine (1.0 g, 6.51 mmol, CAS 335654-06-3), K2CO3 (2.7g, 19.6 mmol, 3 eq) in 1,4-dioxane (10 mL) and water (2 mL) was added l, l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (531 mg, 0.65 mmol, CAS 95464-05-4). The mixture was stirred at 80 °C under N2 balloon (760 mmHg) for 12 h. The reaction mixture was concentrated in vacuo and purified by FC (SiCL, PEZEtOAc 2: 1 to 1 : 1) to afford the title compound (650mg, 1.99 mmol, 27% yield) as a pink solid. MS (ESI): m / z = 327.2 [M+H]+.

[0694] Step b) tert-butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethyl)-2-azaspiro[3.3]heptane-2- carboxylate

[0695] To a solution of tert-butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethylene)-2- azaspiro[3.3]heptane-2-carboxylate (650 mg, 1.99 mmol) in EtOAc (10 mL) was added wet Pd / C (100 mg, 0.6 mmol) under N2. The suspension was degassed under vacuum and purged with H2. The reaction was stirred under H2 (15 psi (103’421 Pa)) at 25 °C for 1 h, filtered and evaporated to afford the title compound (450 mg, 1.37 mmol, 68% yield) as yellow solid. MS (ESI): m / z = 329.3 [M+H]+.

[0696] Step c) tert-butyl 6-[(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methyl]-2-azaspiro[3.3]heptane- 2-carboxylate

[0697] To a solution of tert-butyl 6-(7H-pyrrolo[2,3-d]pyrimidin-2-ylmethyl)-2-azaspiro[3.3]heptane-2- carboxylate (650 mg, 1.98 mmol) in ACN (20 mL) was added NIS (534 mg, 2.38 mmol) and the reaction mixture was stirred at 25 °C for 2 h to give a yellow suspension. The reaction mixture was added to water (20 mL) and the mixture was filtered. The cake was dried under vacuum to - 127 - give the the title compound (700 mg, 1.54 mmol, 75% yield) as a yellow solid. MS (ESI): m / z = 455.1 [M+H]+.

[0698] Step d) tert-butyl 6-[[5-iodo-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0699] To a solution of tert-butyl 6-[(5-iodo-7H-pyrrolo[2,3-d]pyrimidin-2-yl)methyl]-2- azaspiro[3.3]heptane-2-carboxylate (700 mg, 1.54 mmol) in THF (5 mL) was added NaH (74 mg, 1.85 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. 4-methylbenzenesulfonyl chloride (587 mg, 3.08 mmol) was added. The mixture was stirred at 25 °C for 12 h to give a grey suspension. The reaction mixture was quenched by addition sat. aq. NH4CI (10 mL) at 0 °C and extracted with EtOAc. The organic layer was washed with brine, dried over ISfeSCU, filtered and evaporated. Purification by FC (SiCE; eluted with PEZEtOAc = 3: 1) gave the title compound (900 mg, 1.48 mmol, 96% yield) as a light yellow solid. MS (ESI): m / z = 455.1 [M+H]+.

[0700] Step e) tert-butyl 6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0701] To a solution of benzyl tert-butyl 6-[[5-iodo-7-(p-tolylsulfonyl)pyrrolo[2,3-d]pyrimidin-2- yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (900 mg, 1.48 mmol) and copper (282 mg, 4.44 mmol) in DMF (1 mL) was added diphenyl(trifluoromethyl)sulfonium; trifluoromethanesulfonate (1.2 g, 2.96 mmol, CAS 147531-11-1). The reaction mixture was stirred at 80 °C for 12 h and concentrated in vacuo. The residue was poured into water (10 mL), extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (eluted with PE / EtOAc = 3: 1) to afford tert-butyl 6-[[5-(trifhioromethyl)-7H-pyrrolo[2,3- d]pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (260 mg, 0.66 mmol, 44% yield) as a light brown oil. MS (ESI): m / z = 397. 1 [M+H]+.

[0702] Note: tert-butyl 6-[[7-(p-tolylsulfonyl)-5-(trifluoromethyl)pyrrolo[2, 3-d]pyrimidin-2-yl]methyl]- 2 -azaspiro [3.3]heptane-2-carboxylate (300 mg, 0.54 mmol, 36% yield) was also isolated as a light red oil.

[0703] Example P.161

[0704] 6-(2-azaspiro[ 3.3 ]heptan-6-ylmethyl)-3-(trifhioromethyl)-l, 2-benzoxazole; 4- methylbenzenesulfonic acid - 128 -

[0705] A mixture of tert-butyl 6-[[3-(trifluoromethyl)-l,2-benzoxazol-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (1.4 g, 3.53 mmol) and p-toluenesulfonic acid monohydrate (1 g, 5.26 mmol) in EtOAc (100 mL) was stirred at 50 °C for 3 h. The reaction mixture was concentrated in vacuo and the resulting residue was stirred with TBME (100 mL) for 3 h. The precipitate was filtered and dried to give the title compound (1.31 g, 2.8 mmol, 75 % yield) as a white solid. MS (ESI): m / z = 297.0 [M+H]+.

[0706] Step a) tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methylene]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0707] To a stirred suspension of tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]- 2-azaspiro[3.3]heptane-2-carboxylate (3.72 g, 11.1 mmol, CAS 2763647-64-7), l-(4-bromo-2- fhioro-phenyl)-2,2,2-trifhioro-ethanone (3.01 g, 11.1 mmol, CAS 617706-18-0) and potassium carbonate (3.07 g, 22.2 mmol) in 1,4-dioxane (70 mL) and water (7 mL), 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.36 g, 1.66 mmol, CAS 95464-05-4) was added. The mixture was stirred at 80 °C for 18 h. The reaction mixture was concentrated in vacuo. The residue was stirred with EtOAc (200 mL) and dried with Na2SO4. The mixture was filtered and concentrated in vacuo. The crude product was purified by FC (SiO?; hexane / ethyl acetate (0-27%)) to obtain the title compound (2.8 g, 7.01 mmol, 58% yield) as a light red solid. MS (ESI): m / z = 300.0 [M+H]+.

[0708] Step b) tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methyl]-2-azaspiro[3.3]heptane- 2-carboxylate

[0709] To a solution of tert-butyl 6-[[3-fluoro-4-(2,2,2-trifluoroacetyl)phenyl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate (3 g, 7.51 mmol) and in EtOAc (150 mL), Pd / C (10%) (300 mg) was added. The mixture was hydrogenated at 3800 mmHg (in autoclave) and then allowed to stir at RT for 36 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo to give the title compound (3.0 g, 7.47 mmol, 90% yield) as a light brown oil. MS (ESI): m / z =346.0 [M-C4H8+H]+. - 129 -

[0710] Step 3) tert-butyl 6-[[3-fluoro-4-[N-hydroxy-C-(trifluoromethyl)carbonimidoyl]phenyl]methyl]- 2-azaspiro[3.3 ]heptane-2-carboxylate

[0711] To a solution of tert-butyl 6-[[3-fhioro-4-(2,2,2-trifluoroacetyl)phenyl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (3 g, 7.47 mmol) in pyridine (40 mL), hydroxylamine;hydrochloride (0.93 g, 13.45 mmol) was added. The mixture was stirred at 50 °C for 18 h. The mixture was concentrated in vacuo. The residue was stirred with water (50 mL) for 2 h. The aqueous layer was decanted and the obtained residue was partitioned between TBME (100 mL) and water (15 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo with toluene to give the title compound (2.8 g, 6.72 mmol, 80% yield). MS (ESI): m / z =361.2 [M-C4H8+H]+.

[0712] Step 4) tert-butyl 6-[[3-(trifluoromethyl)-l,2-benzoxazol-6-yl]methyl]-2-azaspiro[3.3]heptane- 2-carboxylate

[0713] The mixture of tert-butyl 6-[[3-fluoro-4-[N-hydroxy-C- (trifluoromethyl)carbonimidoyl]phenyl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (2.8 g, 6.72 mmol) and potassium carbonate (1.39 g, 10. 1 mmol) in dry DMF (60 mL) was stirred at 80 °C for 18 h. The reaction mixture was poured into water (300 mL) and extracted with EtOAc / TBME (lOOmL / lOOmL). The organic layer was washed with brine, dried over Na2SO4and concentrated in vacuo to give the title compound (1.5 g, 3.78 mmol, 53% yield). MS (ESI): m / z =341.0 [M-C4H8+H]+.

[0714] Example P.162 l-(2-azaspiro[3.3]heptan-6-ylmethyl)-4-[l-(trifluoromethyl)cyclopropyl]pyridin-2-one; 4- methylbenzenesulfonic acid

[0715] To a solution of tert-butyl 6-[[2-oxo-4-[l-(trifluoromethyl)cyclopropyl]-l-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (230 mg, 0.56 mmol) in EtOAc (3 mL) was added p- toluenesulfonic acid (115 mg, 0.67 mmol). The reaction was stirred at 80 °C for 12 h. The reaction mixture was concentrated in vacuo. To the residue was added deionized water (3 mL) - 130 - and then lyophilized to afford the title compound (236 mg, 0.49 mmol, 81% yield) as a yellow solid. MS (ESI): m / z = 313.1 [M+H]+.

[0716] Step a) tert-butyl 6-[(4-bromo-2-oxo-l-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate

[0717] To a solution of 4-bromo-lH-pyridin-2-one (5 g, 28.7 mmol) in DCE (100 mL) was added tertbutyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (11.6 g, 34.48 mmol, CAS 2763647-64-7), pyridine (4.55 g, 57.5 mmol), boric acid (1.78 g, 28.7 mmol) and Cu(OAc)2 (7.75 g, 38.8 mmol). The mixture was stirred at 70 °C for 16 h under O2. The reaction mixture was concentrated in vacuo. The residue was purified by FC (SiCh; petroleum ether / EtOAc=0: l, Rf=0.4) and concentrated in vacuo to give the title compound (2.74 g, 7.19 mmol, 25% yield) as a white solid. MS (ESI): m / z = 325.0 [M- C4H8+H]+.

[0718] Step 2) tert-butyl 6-[(4-bromo-2-oxo-l-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[0719] To a solution of tert-butyl 6-[(4-bromo-2-oxo-l-pyridyl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (629 mg, 1.65 mmol, 1 eq) in EtOAc (6 mL) was added PtCL (112 mg, 0.49 mmol, 0.3 eq) under N2. The suspension was degassed under vacuum and purged with H2. The reaction was stirred under H2 (15 psi (103’421 Pa)) at 25 °C for 0.5 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / EtOAc=60 to 50 %) and concentrated in vacuo to give the title compound (370 mg, 0.97 mmol, 58% yield) as a yellow oil. MS (ESI): m / z = 327.0 [M-C4H8+H]+.

[0720] Step 3) tert-butyl 6-[[2-oxo-4-[l-(trifluoromethyl)vinyl]-l-pyridyl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0721] To a solution of tert-butyl 6-[(4-bromo-2-oxo-l-pyridyl)methyl]-2-azaspiro[3.3]heptane-2- carboxylate (300 mg, 0.78 mmol) and 4,4,6-trimethyl-2-[l-(trifluoromethyl)vinyl]-l,3,2- dioxaborinane (208 mg, 0.94 mmol, CAS 1011460-68-6), K2CO3 (324 mg, 2.35 mmol) in 1,4- dioxane (3 mL) and water (0.600 mL) was added l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (63.9 mg, 0.08 mmol, CAS 95464-05-4). The mixture was degassed with lSh and stirred at 80 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by FC (SiCL; PE / EtOAc=60 - 50%) and concentrated in vacuo to give the title compound (360 mg, 0.9 mmol) as a yellow oil. MS (ESI): m / z = 343.1 [M-C4H8+H]+. - 131 -

[0722] Step 4) tert-butyl 6- [[2-oxo-4-[l -(trifluoromethyl) cyclopropyl]- l-pyridyl]methyl] -2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0723] To a solution of tert-butyl 6-[[2-oxo-4-[l-(trifluoromethyl)vinyl]-l-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (320 mg, 0.8 mmol) in THF (3 mL) was added dip henyl(methyl) sulfonium tetrafluoroborate (323 mg, 1.12 mmol, CAS 10504-60-6).

[0724] NaHMDS / THF (1.36 mL, 1.36 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 1 h under N2 atmosphere. The reaction mixture was slowly added to 6 mL sat. aq NH4CI. The mixture was added to 6 mL water and extracted with EtOAc (4 mL x 3). The organic phases were concentrated in vacuo. The crude product was purified by FC (SiCL; PE:EtOAc=0: 1) to give the title compound (250 mg, 75% yield) as a yellow solid. MS (ESI): m / z = 357.1 [M-C4H8+H]+.

[0725] In analogy to Building Block P. 162, the following building blocks were generated using the relevant heteroaryl compound for the Chan Lam-type coupling in Step 1.

[0726] Example P.178

[0727] 6-(2-azaspiro[ 3.3 ]heptan-6-ylmethyl)-2-(trifluoromethyl)imidazo[ 1, 2-a]pyrimidine;4- methylbenzenesulfonic acid - 132 -

[0728] A mixture of p-toluenesulfonic acid (364 mg, 2.12 mmol) and tert-butyl 6-[[2- (trifluoromethyl)imidazo[l,2-a]pyrimidin-6-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (280 mg, 0.71 mmol) in EtOAc (30 mL) was stirred at 50 °C for 24 h. The mixture was concentrated in vacuo and purificated by FC to afford the title compound (178 mg, 0.38 mmol, 53% yield) as a light brown solid. MS (ESI): m / z = 297.0 [M+H]+.

[0729] Step 1 ) tert-butyl 6-[ ( 2-aminopyrimidin-5-yl)methylene ]-2-azaspiro[ 3.3 ]heptane-2-carboxylate l,r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.87 g, 2.3 mmol, CAS 95408-45-0), potassium carbonate (3.17 g, 23.0 mmol), 2-amino-5- bromopyrimidine (2 g, 11.5 mmol) and tert-butyl 6-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (3.85 g, 11.5 mmol, CAS 2763647-64-7) were added to a mixture of 1,4-dioxane (61 mL) and water (13 mL). The reaction mixture was stirred at 90 °C for 24 h. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by to give the title compound (1.5 g, 4.96 mmol, 43% yield) as a light yellow solid. MS (ESI): m / z = 303.2 [M+H]+.

[0730] Step 2) tert-butyl 6-[(2-aminopyrimidin-5-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[0731] A mixture of tert-butyl 6-[(2-aminopyrimidin-5-yl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (1.5 g, 4.96 mmol, 1 eq) and Pd / C, 10% (158 mg, 0.15 mmol, 0.03 eq) in EtOAc (80 mL) was hydrogenated at 19000 mmHg and stirred at 25 °C for 18 h. The reaction mixture was filtered and concentrated in vacuo to afford the title compound (1.5 g, 4.93 mmol, 96% yield) as a white solid. MS (ESI): m / z = 249.2 [M-C4H8+H]+.

[0732] Step 3) tert-butyl 6-[[2-(trifluoromethyl)imidazo[l,2-a]pyrimidin-6-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0733] A solution of tert-butyl 6-[(2-aminopyrimidin-5-yl)methyl]-2-azaspiro[3.3]heptane-2- carboxylate (1.5 g, 4.93 mmol) and 3 -bro mo- 1,1,1 -trifluoroacetone (940 mg, 4.93 mmol) in ACN (9 mL) and toluene (1.5 mL) was stirred at 100 °C for 24 h. The reaction mixture concentrated in vacuo and diluted between DCM and NaHCCL (10% aq solution). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by FC (SiCL) gave the title compound (340 mg, 0.86 mmol, 17% yield) as yellow solid. MS (ESI): m / z = 397.2 [M+H]+. - 133 -

[0734] Example P.169

[0735] 6-[ difluoro- [ 5-( trifluor ome thyl)pyrimidin-2-yl [methyl ]-2-azaspiro[ 3.3 [heptane ; 4- methylbenzenesulfonic acid

[0736] A mixture of p-toluenesulfonic acid (223 mg, 1.3 mmol) and tert-butyl 6- [difluoro- [5- (trifluoromethyl)pyrimidin-2-yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (170 mg, 0.43 mmol) in EtOAc (10 mL) was stirred at 50 °C for 12 h. Then it was concentrated and crystallized from Et2O to afford the title compound (190 mg, 0.41 mmol, 94 % yield) as a light brown solid. MS (ESI): m / z = 294.2 [M+H]+.

[0737] Step a) tert-butyl 6- [ [5-(trifluor omethyl)pyrimidin-2-yl] methylene] -2-azaspir o[ 3.3 ]heptane-2- carboxylate

[0738] To a solution of 2-chloro-5-(trifluromethyl)pyrimidine (8000 mg, 43.8 mmol, CAS: 69034-12-4) and tert-butyl 6- [(4, 4, 5 , 5-tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)methylene] -2- azaspiro[3.3]heptane-2-carboxylate (14693 mg, 43.8 mmol), K2CO3 (12115 mg, 87.7 mmol) in 1,4-dioxane (80 mL) and water (16 mL) was added l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (1788 mg, 2.19 mmol), and the mixture was stirred at 100 °C under N2 atmosphere for 16 h. The crude was purified by silica gel column (PE:EA = 5: 1) to give a residue which was triturated with Petroleum ether at 20 °C for 30 min. The mixture was filtered and the cake was dried under vaccum to give the title compound (4.9 g, 13.8 mmol, 66 % yield) as a white solid. MS (ESI): m / z = 300.1 [M-C4H8+H]+; *HNMR (400 MHz, CHLOROFORM-d) 5 = 8.87 (s, 2H), 6.46 (br s, 1H), 4.02 (s, 4H), 3.46 (br s, 2H), 3.16 (s, 2H), 1.45 (s, 9H).

[0739] Step b) tert-butyl 6- [ [5-(trifluor omethyl)pyrimidin-2-yl] methyl] -2 -azaspiro [3.3] heptane-2- carboxylate

[0740] To a solution of tert-butyl 6-[[5-(trifluoromethyl)pyrimidin-2-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate (4.96 g, 14.0 mmol) in EtOAc (50 mL) was added Pd / C (1.65 g, 1.4 mmol) at 25 °C and stirred for 1 h under hydrogen balloon (15 Psi (103’421 Pa)) . The mixture filtered through celite. The filtrate was concentrated in vacuo to give the title compound (4.9 g, 13.7 mmol, 98 % yield) as yellow solid. MS (ESI): m / z = 358.2 [M+H]+. 'H - 134 -

[0741] NMR (400 MHz, CHLOROFORM-d) 5 = 8.89 (s, 2H), 3.94 (s, 2H), 3.84 (s, 2H), 3.11 (d, J = 7.6 Hz, 2H), 2.74 (td, J = 7.9, 15.8 Hz, 1H), 2.38 - 2.27 (m, 2H), 2.03 - 1.93 (m, 2H), 1.43 (s, 9H)

[0742] Step c) tert-butyl 6-[5-(trifluoromethyl)pyrimidine-2-carbonyl]-2-azaspiro[3.3]heptane-2- carboxylate

[0743] To a solution of tert-butyl 6-[[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate (2.5 g, 7.0 mmol) in 1,4-Dioxane (2 mL) was added SeCL (7.76 g, 70.0 mmol). The reaction mixture was stirred at 105 °C for 4 h under N2 atmosphere. The reaction was concentrated under reduced pressire and the residue was purified by prep- HPLC (water(FA)-CHsCN 55%-85%) to afford the crude title compound (200 mg, 0.54 mmol, 7.7% yield) as a yellow solid. MS (ESI): m / z = 316.2 [M-C4Hs+H]+.

[0744] Step d) tert-butyl 6-[difluoro-[5-(trifluoromethyl)pyrimidin-2-yl]methyl]-2- azaspiro[ 3.3 ]heptane-2-carboxylate tert-butyl 6-[5-(trifluoromethyl)pyrimidine-2-carbonyl]-2-azaspiro[3.3]heptane-2-carboxylate (350 mg, 0.94 mmol) was dissolved in DCM (30 mL) and bis(2-methoxyethyl)aminosulfur trifluoride (626 mg, 2.83 mmol) was added in one portion and the reaction mixture was stirred at 25 °C for 48 h. Then it was washed by NaHCCh (10% aq. solution) and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by FC (SiCL) to give the title compound (150 mg, 0.38 mmol, 38% yield) as a light yellow solid. MS (ESI): m / z = 338.2 [M-tBu+H]+.

[0745] Example B.561

[0746] 6-[ [5-[l -(trifluorome thyl)cyclopropyl / -2 -pyridyl oxy ]-2-azaspiro[ 3.3 ] heptane ; 4- methylbenzenesulfonic acid p-toluenesulfonic acid monohydrate (945 mg, 4.97 mmol) was added to a stirred solution of tertbutyl 6- [ [5 - [ 1 -(trifluoromethyl)cy clopropy 1] -2-pyridyl] oxy] -2-azaspiro [3.3 ]heptane-2- carboxylate (900 mg, 2.26 mmol) in EtOAc (50 mL). The reaction mixture was stirred at 50 °C for 24 h. The reaction mixture was then concentrated under vacuum. The residue was triturated - 135 - with Et20 to provide the title compound (939 mg, 1.46 mmol, 61% yield) as a white solid. MS (ESI): m / z = 299.0 [M+H]+

[0747] Step a) tert-butyl 6-[[5-[l-(trifluoromethyl)cyclopropyl]-2-pyridyl]oxy]-2-azaspiro[3.3]heptane- 2-carboxylate To a mixture of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1147557-97- 8) (728 mg, 3.41 mmol) and 2-fluoro-5-[l-(trifluoromethyl)cyclopropyl]pyridine (CAS: 69045- 82-5) (0.7 g, 3.41 mmol) in THF (50 mL) was added potassium tert-butoxide (498 mg, 4.44 mmol) at 0 °C. Then the mixture was stirred at 25 °C for 16 h. Then the reaction mixture was quenched with sat. NEUCl (10 mL), and the mixture was extracted with EtOAc (60 mL x 2). The combined organic phase was washed with brine (30 mL), dried over ISfeSCU, filtered and concentrated to give a residue. The residue was combined with that from another equivalent batch (starting from 0. 1 g of 2-fhioro-5-[l-(trifhioromethyl)cyclopropyl]pyridine) and purified by FC to afford the title compound (1.0 g, 2.51 mmol, 74% yield) as a white solid. MS (ESI): m / z = 343.2 [M-C4H8+H]+In analogy to Building Block B.561, the following building blocks were generated using the relevant heteroaryl building block for the SNAT reaction in Step a. - 136 -

[0748] Example B.562

[0749] 6-[[6-[ 1 -(trifluoromethyl)cyclopropyl ]-3-pyridyl oxy] -2-azaspiro [ 3.3 ]heptane; 4- methylbenzenesulfonic acid p-toluenesulfonic acid monohydrate (525 mg, 2.76 mmol) was added to a stirred solution of tertbutyl 6- [ [6- [ 1 -(trifl uoromethy I )cy clopropy 1] -3 -pyridyl] oxy] -2-azaspiro [3.3 ]heptane-2- carboxylate (500 mg, 1.25 mmol) in EtOAc (15 mL). The reaction mixture was stirred at 50 °C for 16 h. The reaction mixture was then concentrated under vacuum. The residue was triturated with MTBE to provide the title compound (577 mg, 0.9 mmol, 68% yield) as a white solid. MS (ESI): m / z =299.2 [M+H]+

[0750] Step a) tert-butyl 6-[(6-bromo-3-pyridyl)oxy] -2-azaspiro [3.3]heptane-2-carboxylate

[0751] Cyanomethylenetributylphosphorane (4.79 g, 19.8 mmol) was added to a mixture of tert-butyl 6- hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (2.54 g, 11.9 mmol) and 2-bromo-5- hydroxypyridine (2.3 g, 13.2 mmol, 1.0 eq) in Toluene (90 mL), and the resulting mixture was heated at 100 °C and stirred for 48 h. The reaction solution was concentrated and the residue was - 137 - purified by FC (SiCL; hexane / ethyl acetate (0-35%)) to give the title compound (2.8 g, 7.58 mmol, 57% yield) as a white solid. MS (ESI): m / z = 371.0 / 369.0 [M+H]+

[0752] Step b) tert-butyl 6-[[6-[l-(trifluoromethyl)vinyl]-3-pyridyl]oxy]-2-azaspiro[3.3]heptane-2- carboxylate

[0753] A stirred suspension of tert-butyl 6-[(6-bromo-3-pyridyl)oxy]-2-azaspiro[3.3]heptane-2- carboxylate (2.8 g, 7.58 mmol), 4,4,5,5-tetramethyl-2-[l-(trifluoromethyl)vinyl]-l,3,2- dioxaborolane (1.68 g, 7.58 mmol) and sodium carbonate (1206 mg, 11.4 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was flushed with Argon for 5 min. 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (928 mg, 1.14 mmol) was added to the mixture. Then the reaction mixture was stirred at 90 °C (the temperature of oil bath) for 48 h in Argon atmosphere. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue was purified by FC (SiCL; hexane / ethyl acetate (0- 30%)) to give the title compound (1.4 g, 3.64 mmol, 45% yield) as a light yellow solid. MS (ESI): m / z = 385.2 [M+H]+

[0754] Step c) tert-butyl 6-[[6-[l-(trifluoromethyl)cyclopropyl]-3-pyridyl]oxy]-2-azaspiro[3.3]heptane- 2-carboxylate

[0755] A solution of sodium bis(trimethylsilyl)amide 40% in THF (3.14 mL, 7.28 mmol) was added to a cooled 0 °C solution of tert-butyl 6-[[6-[l-(trifluoromethyl)vinyl]-3-pyridyl]oxy]-2- azaspiro[3.3]heptane-2-carboxylate (1.4 g, 3.64 mmol) and diphenyl(methyl)sulfonium tetrafluoroborate (1574 mg, 5.46 mmol) in THF (50 mL). The resulting mixture was stirred at 0 °C for 30 minutes, and was then allowed to warm to 20 °C over 2 h. The reaction mixture was then cooled to 0 °C, quenched with aqueous NH4CI (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (chloroform / aceto nitrile (0-20%)) to afford the title compound (500 mg, 1.25 mmol, 34 % yield) as a white solid. MS (ESI): m / z =399.0 [M+H]+

[0756] In analogy to Building Block B.562, the following building blocks were generated using the relevant heteroaryl building block for the Mitsunobu-type reaction in Step a.

[0757] Example B.565

[0758] 6-[ 6-[ I -(trifluoromethyl) cyclopropyl pyrazin-2-yl ]oxy-2-azaspiro[ 3.3 ] heptane; 4- methylbenzenesulfonic acid

[0759] A mixture of p-toluenesulfonic acid (970 mg, 5.63 mmol) and tert-butyl 6-[6-[l- (trifluoromethyl)cyclopropyl]pyrazin-2-yl]oxy-2-azaspiro[3 ,3]heptane-2-carboxylate (0.75 g, 1.88 mmol) in EtOAc (50 mL) was stirred at 50 °C for 24 h. Then it was evaporated and purified by FC (SiO?; MtBE / methanol 0-50%) to obtain the title compound (541 mg, 1.15 mmol, 61% yield) as a white solid. MS (ESI): m / z = 300.2 [M+H]+.

[0760] Step a) tert-butyl 6-(6-bromopyrazin-2-yl)oxy-2-azaspiro[3.3]heptane-2 -carboxy late

[0761] A solution of 2-bromo-6-fluoro-pyrazine (1.49 g, 8.44 mmol) and tert-butyl 6-hydroxy-2- azaspiro[3.3]heptane-2-carboxylate (1.5 g, 7.03 mmol) in THF (120 mL) was cooled to 0 °C and potassium tert-butoxide (1026 mg, 9.14 mmol) was added in one portion. Then the reaction mixture was allowed to warm to rt and was stirred for 24 h. Then NH4CI (10% aq. solution) was added and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over ISfeSCU and concentrated. The crude product was purified by flash chromatography (SiCh; petroleum ether / EtOAc 4: 1) to give the title compound (2.54 g, 6.86 mmol, 96% yield) as a colorless oil. MS (ESI): m / z = 314.0 / 316.0 [M-C4H8+H]+. - 139 -

[0762] Step b) tert-butyl 6-[ 6-[ l-( trifluoromethyl)vinyl ]pyrazin-2-yl ]oxy-2-azaspiro[ 3.3 ]heptane-2- carboxylate

[0763] 4,4,5,5-tetramethyl-2-[l-(trifluoromethyl)vinyl]-l,3,2-dioxaborolane (CAS: 1055881-27-0) (1523 mg, 6.86 mmol), tert-butyl 6-(6-bromopyrazin-2-yl)oxy-2-azaspiro[3.3]heptane-2- carboxylate (2.54 g, 6.86 mmol), l, r-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (840 mg, 1.03 mmol) and sodium carbonate (1454 mg, 13.7 mmol) were added to a mixture of 1,4-Dioxane (46 mL) and water (11 mL). The reaction mixture was heated to 90 °C under Ar for 24 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 and evaporated. The crude product was purified by FC (SiCL; hexane / ethyl acetate (0-40%)) to give the title compound (1.6 g, 4.15 mmol, 61% yield) as a colorless solid. MS (ESI): m / z = 330.2 [M-tBu+H]+.

[0764] Step c) tert-butyl 6- [6- [1 -(trifluor omethyl)cyclopr opyl]pyr azin-2 -yl]oxy-2- azaspiro[ 3.3 ]heptane-2-carboxylate tert-butyl 6-[6-[l-(trifluoromethyl)vinyl]pyrazin-2-yl]oxy-2-azaspiro[3.3]heptane-2-carboxylate (1.4 g, 3.63 mmol) was dissolved in THF (85 mL) and diphenyl(methyl)sulfonium tetrafluoroborate (1256 mg, 4.36 mmol) was added. The resulting mixture was cooled to -5 °C and sodium bis(trimethylsilyl)amide (2 M in THF) (3.63 mL, 7.27 mmol) was added dropwise. The resulting mixture was allowed to warm to rt and stirred for 24 h. Then NH4CI (10% aq solution) was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. Purification by FC (SiCL; hexane / ethyl acetate (0-40%)) gave the title compound (850 mg, 2. 13 mmol, 57% yield) as a white solid. MS (ESI): m / z = 344.0 [M-C4H8+H]+

[0765] In analogy to Building Block B.565, the following building blocks were generated using the relevant heteroaryl building block for the SNAT reaction in Step a. - 140 -

[0766] Example B.566

[0767] 6-[[5-[l-(trifluoromethyl)cyclopropyl]-3-pyridyl]oxy]-2-azaspiro[3.3]heptane; 4- methylbenzenesulfonic acid

[0768] To a solution of tert-butyl 6-[[5-[l-(trifluoromethyl)cyclopropyl]-3-pyridyl]oxy]-2- azaspiro[3.3]heptane-2-carboxylate (1100 mg, 2.76 mmol) in ethyl acetate (37 mL) p- toluenesulfonic acid monohydrate (1838 mg, 9.66 mmol) was added. The mixture was stirred at 25 °C for 48 h, then evaporated and the residue was purified by flash chromatography (MTBE / methanol (0-70%)) to give the title compound (781 mg, 1.22 mmol, 42% yield) as a yellow solid. MS (ESI): m / z = 299.2 [M+H]+.

[0769] Step a) 3-bromo-5-[l-(trijluoromethyl)cyclopropyl]pyridine

[0770] In pre-cooled (liquid N2) l-(5-bromo-3-pyridyl)cyclopropanecarboxylic acid (CAS: 1256038- 40-0) (4.0 g, 16.5 mmol) in an autoclave hydrogen fluoride (10.0 mL, 496 mmol) was placed. Then tetrafluoro-M-sulfane (3571 mg, 33.1 mmol) was pressurized into the vessel. Then the reaction mixture was stirred at 85 °C for 18 h. After that it was carefully diluted with sat. aq. K2CO3 (150 mL). The aqueous layer was extracted with MTBE (2 x 100 mL). The combined organic layers were washed with brine (300mL), dried over ISfeSCU, filtered, and concentrated in vacuo to afford the title compound (4.1 g, 15.4 mmol, 93% yield) as a brown liquid. MS (ESI): m / z = 266.0 [M+H]+.

[0771] Step b) 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-[l-

[0772] ( trifluoromethyl) cyclopropyl pyridine - 141 -

[0773] To a stirred solution of 3-bromo-5-[l-(trifluoromethyl)cyclopropyl]pyridine (2.18 g, 8.19 mmol) in 1,4-Dioxane (31.5mL) at room temperature bis(pinacolato)diboron (2.29 g, 9.01 mmol), potassium acetate (2.41 g, 24.6 mmol) and l, l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.67 g, 0.82 mmol) were added and degassed with argon for 5 min. The resulting mixture was sealed and stirred at 80 °C for 18 h. Then the reaction mixture was diluted with 300 mL of hexane, filtered through SiCL and the filtrate was concentrated under reduced pressure to obtain the title compound (3000 mg, 9.58 mmol, 96 % yield) as a light brown solid. GC-MS m / z = 313.2 [M+H]+.

[0774] Step c) 5-[l-(trifluoromethyl)cyclopropyl]pyridin-3-ol

[0775] To a stirred solution of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5-[l- (trifluoromethyl)cyclopropyl]pyridine (3000 mg, 9.58 mmol) in THF (60 mL) at 25 °C was added sodium hydrogencarbonate (805 mg, 9.58 mmol) solution in water (10.4 mL, 575 mmol), followed by slow addition of 30% aqueous hydrogen peroxide (8.24 mL, 95.8 mmol). After 2 h of stirring the reaction mixture was quenched with water (500 mL) and the aqueous layer was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (0.9 g, 4.43 mmol, 43% yield) as a brown solid. MS (ESI): m / z = 204.2 [M+H]+.

[0776] Step d) tert-butyl 6-[[5-[l-(trifluoromethyl)cyclopropyl]-3-pyridyl]oxy]-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0777] To a mixture of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.05 g, 4.92 mmol) and 5-[l-(trifluoromethyl)cyclopropyl]pyridin-3-ol (1000 mg, 4.92 mmol) in toluene (30 mL) cyanomethylenetributylphosphorane (1782 mg, 7.39 mmol) was added and the resulting mixture was heated at 100 °C and stirred for 48 h. The reaction solution was concentrated and the residue was purified by FC (SiCL; chloroform / aceto nitrile (0-40%)) to afford the title compound (1100 mg, 2.76 mmol, 56% yield) as a light brown solid. MS (ESI): m / z = 399.2 [M+H]+.

[0778] Example B.570

[0779] 6-(2-azaspiro[ 3.3 ]heptan-6-yloxy)-2-(trifluoromethyl)pyrazolo[ 1, 5-a]pyrimidine;4- methylbenzenesulfonic acid - 142 -

[0780] To a solution of tert-butyl 6-[2-(trifhioromethyl)pyrazolo[l,5-a]pyrimidin-6-yl]oxy-2- azaspiro[3.3]heptane-2-carboxylate (1200 mg, 3.01 mmol) in Ethyl acetate (24 mL) p- toluenesulfonic acid monohydrate (2005 mg, 10.5 mmol) was added. The mixture was stirred at 25 °C for 18 h, then evaporated and residue was treated with MTBE, the formed precipitate was filtered to give the title compound (1037 mg, 2.2 mmol, 70 % yield) as a light yellow solid. MS (ESI): m / z = 299.0 [M+H]+.

[0781] Step a) 6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2-( trifluoromethyl)pyrazolo[ 1, 5- a] pyrimidine

[0782] To a stirred solution of 6-bromo-2-(trifhioromethyl)pyrazolo[l,5-a]pyrimidine (CAS: 1379358- 08-3) (6.2 g, 23.3 mmol) 1,4-Dioxane (97.6 mL) at room temperature bis(pinacolato)diboron (6.51 g, 25.6 mmol), potassium acetate (6.86 g, 69.92 mmol) and 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.9 g, 2.33 mmol) were added and degassed with Argon for 5 min. The resulting mixture was sealed and stirred at 80 °C for 18 h. Then the reaction mixture was diluted with hexane (250 mL), filtered through SiCL and the filtrate was concentrated under reduced pressure to obtain the title compound (7.0 g, 22.4 mmol, 48% yield) as a light brown oil. GC-MS m / z = 313.1 [M+H]+.

[0783] Step b) 2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-6-ol

[0784] To a stirred solution of 6-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2- (trifluoromethyl)pyrazolo[l,5-a]pyrimidine (7000 mg, 11.2 mmol) in THF (140 mL) at 25 °C was added sodium hydrogencarbonate (939 mg, 11.2 mmol) solution in water (12.1 mL, 671 mmol), followed by slow addition of 30% aqueous hydrogen peroxide solution (9.61 mL, 112 mmol). After 2 h of stirring the reaction mixture was quenched with water (500 mL) and the aqueous layer was extracted with EtOAc (2 x 250 mL). The combined organic layers were washed with brine (250 mL), dried over ISfeSCL, filtered, and concentrated in vacuo to give the title compound (1.5 g, 7.38 mmol, 57% yield) as a light brown solid MS (ESI): m / z = 204.0 [M+H]+.

[0785] Step c) tert-butyl 6-[2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-6-yl]oxy-2- azaspiro[ 3.3 ]heptane-2-carboxylate

[0786] To a mixture of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.4 g, 6.56 mmol) and 2-(trifhioromethyl)pyrazolo[l,5-a]pyrimidin-6-ol (1333 mg, 6.56 mmol) was added cyanomethylenetributylphosphorane (2376 mg, 9.85 mmol) in toluene (45 mL), and the resulting - 143 - mixture was heated at 100 °C and stirred for 16 h. The reaction mixture was concentrated. The obtained crude was purified by flash chromatography (hexane / ethyl acetate (0-36%)), to afford the title compound (1200 mg, 3.01 mmol, 45% yield) as a light yellow solid. MS (ESI): m / z = 343.2 [M-C4H8+H]+.

[0787] Example C.l 4-bromo-2-methylsulfonyl-l-(trifluoromethyl) benzene

[0788] To a solution of 4-chloro-2-methylsulfanyl-l-(trifluoromethyl)benzene (1950 mg, 8.6 mmol) in 1,2-dichloroethane (20 mL), CH3CN (20 mL) and water (40 mL) cooled with a water bath was added sodium periodate (3680 mg, 17.2 mmol) and ruthenium(III) chloride hydrate (19.4 mg, 0.090 mmol) 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 2x50mL EtOAc. The combined organic layers were washed with 75 mL brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiCL; PEZEtOAc) gave the title compound (1800 mg, 73% yield) as a white solid. 'H NMR (400 MHz, CHLOROFORM-d) 5 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).

[0789] Step a) 4-chloro-2-methylsulfanyl-l-(trifluoromethyl)benzene

[0790] A mixture of 4-chloro-2-fhioro-l-(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, extracted with 2 x 75mL EtOAc. The combined organic layers were washed with 100 mL brine, dried over Na2SO4, filtered, and evaporated. Purification by FC (SiO2; PEZEtOAc) gave the title compound (2 g, 31.5% yield) as a yellow solid. 'HNMR (400 MHz, CHLOROFORM-d) 5 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).

[0791] Example C.ll

[0792] 4, 5-dibromo-2-(2, 2, 2-trifluoroethyl) triazole

[0793] To a solution of 4,5-dibromo-2H-triazole (5.0 g, 22.0 mmol) in ACN (50 mL) was added cesium carbonate (7.18 g, 22.0 mmol). Then, 2, 2, 2-trifluoroethyl trifluoromethanesulfonate (5.12 g, 22.0 mmol) was added dropwise at 0°C. The reactional mixture was stirred for 16h at RT. The reaction mixture was poured into water, EtOAc was added and the aqueous layer was extracted three times with EtOAc. Then, the combined organic layers were washed with water and brine, dried over Na2SO4, filtered off and evaporated. Purification by FC (SiO2; PEZEtOAc 0-7%) gave - 144 - the title compound (5.3 g, 17.2 mmol, 77.9% yield) as a yellow oil. 'H NMR (400 MHz, CHLOROFORM-d) 5 = 4.95 (q, J = 7.9 Hz, 2H)

[0794] Example C.17

[0795] 3-bromo-5-[l-(trifluoromethyl)cyclopropyl]-lH-pyrazole

[0796] To a solution of 5-[l-(trifluoromethyl)cyclopropyl]-lH-pyrazol-3-amine (2.3 g, 12.0 mmol) in ACN (40 mL) was added a solution of isopentyl nitrite (1.55 g, 13.2 mmol) in ACN (5 mL) dropwise at 0 °C. The reaction was stirred at 0 °C for 1 h. Then CuBr2 (1.61 g, 7.22 mmol) was added into the mixture at 0 °C and the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (water(0. 1%FA)-ACN). The purified solution was lyophilized to afford the title compound (740 mg, 2.9 mmol, 24.1% yield) as a light green solid. MS (ESI): m / z = 257.2 [M+H]+.

[0797] Example C.18

[0798] 4-[l-(trifluoromethyl)cyclopropyl]-lH-imidazole

[0799] 2-Bromo-l-[l-(trifhioromethyl)cyclopropyl]ethanone (5.0 g, 21.6 mmol) was added to methanamide (50.0 mL, 1259 mmol) and the mixture was stirred at 180 °C for 2 h. After the reaction was completed, 500mL of water was added, and the mixture was washed three times with dichloromethane (100 mL><3), then the aqueous phase was adjusted to pH 8 with a 1 M aqueous NaOH solution, and the aqueous phase was extracted twice with dichloromethane (50 mL><2). The organic phase was dried and evaporated to give the title compound (800 mg, 4.54 mmol, 15.5% yield) as a brown solid. MS (ESI): m / z = 177.2 [M+H]+.

[0800] Example C.24 l-bromo-3-fluoro-5-(trifluoromethylsulfanyl)benzene

[0801] To a solution of l-bromo-3-fluoro-5-iodo-benzene (2000 mg, 6.65 mmol) in ACN (10 mL) were added 2,2'-bipyridine (1038 mg, 6.65 mmol), Cui (1266 mg, 6.65 mmol) and trifluoromethylsulfanylsilver (1667 mg, 7.98 mmol). The mixture was stirred at 90 °C for 12 h under N2 balloon.The reaction mixture was filtered to get l-bromo-3-fluoro-5- (trifluoromethylsulfanyl)benzene (1.8 g, 6.54 mmol, 98.45% yield) as a green liquid solution. The filtrate was used in the next step of the reaction directly. (NMR of solution concentrated in vacuo to give crude product:1H NMR (400 MHz, CHLOROFORM-d) 5 = 7.69 (d, J = 0.6 Hz, 1H), 7.48 - 7.37 (m, 1H), 7.32 - 7.21 (m, 1H)) - 145 -

[0802] Example C.25

[0803] 2-bromo-3-methoxy-5-(trifluoromethyl)pyrazine

[0804] To a mixture of 3-methoxy-5-(trifluoromethyl)pyrazin-2-amine (1.6 g, 8.28 mmol) and CuBr (1.42 g, 9.94 mmol) in MeCN (15 mL) was added a solution of tert-butyl nitrite (1.28 g, 12.4 mmol) 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, the filtrate was concentrated under reduced pressure at room temperature to give a residue. The residue was purified by column chromatography (ethyl acetate: petroleum ether 0-10%) and concentrated under reduced pressure at room temperature to give the title compound (800 mg, 3.11 mmol, 38% yield) as a colorless oil. MS (ESI): m / z = 256.9 [M+H]+. NOTE:The product was volatile.

[0805] Example C.124

[0806] 2-chloro-5-[l-(trifluoromethyl)cyclopropyl]pyrazine

[0807] To a solution of 2-chloro-5-[l-(trifluoromethyl)vinyl]pyrazine (1.6 g, 7.67 mmol) in THF (60 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (2.87 g, 9.97 mmol, CAS 10504- 60-6). The suspension was stirred at 0 °C for 0.5 h. A solution ofNaHMDS (12.3 mL, 12.3 mmol, 1 M in THF) was added dropwise. The reaction mixture was heated at 25 °C for 1 h. Water (50 mL) was added to the reaction mixture and the aqueous phase was extracted with EtOAc (40 mL) twice. The organic layers were combined, washed with brine, dried over Na2SO4 and concantrated in vacuo. Purification by FC (SiCL; PE / EtOAc) gave the title compound (1.5 g, 63% yield) as a yellow oil. 'H NMR (400 MHz, chloroform-d) 5 = 8.53 (s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 1.48 - 1.42 (m, 2H), 1.36 ppm (br s, 2H).

[0808] Step 1: 2-chloro-5-[l-(trifluoromethyl)vinyl]pyrazine

[0809] To a solution of 4,4,6-trimethyl-2-[l-(trifluoromethyl)vinyl]-l,3,2-dioxaborinane (3.44 g, 15.5 mmol, CAS 1011460-68-6) and 2-bromo-5-chloropyrazine (3 g, 15.5 mmol), potassium carbonate (4.29 g, 31 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1266 mg, 1.55 mmol, CAS 95464-05-4). The mixture was stirred at 80 °C under N2 atmosphere for 12 h, filtered and concentrated in vacuo. Purification by FC (SiCL; PE) gave the title compound (1.6 g, 49 % yield) as a yellow solid. MS (ESI): m / z =209.3 [M+H]+

[0810] Example C.125

[0811] 3-bromo-6-[l-(trifluoromethyl)cyclopropyl]pyridazine - 146 -

[0812] To a solution of 3-bromo-6-[l-(trifluoromethyl)vinyl]pyridazine (340 mg, 1.34 mmol) in THF (10 mL) was added diphenyl(methyl)sulfonium tetrafluoroborate (503 mg, 1.75 mmol, CAS 10504-60-6). The suspension was stirred at 0 °C for 0.5 h. A solution of NaHMDS (2. 15 mL, 2.15 mmol, 1 M in THF) was added dropwise. The reaction mixture was stirred at 25 °C for 1 h. The mixture was quenched with 6 mL methanol. The reaction mixture was partitioned between EtOAc (20 mL) and water (40 mL). The organic phase was concentrated in vacuo. Purification by prep-HPLC gave the title compound (280 mg, 78 % yield) as a white solid. MS (ESI): m / z = 267.3 [M+H]+.

[0813] Step 1: 3-bromo-6-[l-(trifluoromethyl)vinyl]pyridazine

[0814] To a solution of 4,4,6-trimethyl-2-[l-(trifluoromethyl)vinyl]-l,3,2-dioxaborinane (560 mg, 2.52 mmol, CAS 1011460-68-6) and 3,6-dibromopyridazine (500 mg, 2.1 mmol), potassium carbonate (581 mg, 4.2 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added 1,1'- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (172 mg, 0.210 mmol, CAS 95464-05-4). The mixture was stirred at 80 °C under N2 atmosphere for 3 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by FC (SiO2; PE) gave the title compound (300 mg, 56 % yield) as a white crystalline solid. MS (ESI): m / z = 253.3 [M+H]+.

[0815] Example C.145

[0816] 2-[[5-bromo-3-(trifluoromethyl)pyrazolo[3,4-c]pyridin-l-yl]methoxy]ethyl-trimethyl-silane

[0817] A mixture of 2-[(5-bromo-3-iodo-pyrazolo[3,4-c]pyridin-l-yl)methoxy]ethyl-trimethyl-silane (5.6 g, 12 mmol, CAS 2097610-93-8), copper(I) iodide (11.74 g, 61 mmol), potassium fluoride (3.58 g, 61 mmol, 5 eq), and trifluoromethyltrimethylsilane (8.77 g, 61 mmol) in NMP (113 mL) was stirred for 18 h at 100 °C. The reaction mixture was quenched by the addition of 1 L of water and filtered from inorganic precipitate. The filtrate was extracted with ethyl acetate and the organic phase was washed with water, saturated NaCl solution, dried over ISfeSCU and concentrated in vacuo. Purification by FC (SiCL) gave the title compound (1.4 g, 3.5 mmol, 28% yield) as a light yellow viscous oil. MS (ESI): m / z = 396.0 [M+H]+.

[0818] Example C.149 l-(4-bromophenyl)sulfonyl-3-(trifluoromethyl)azetidine - 147 -

[0819] To a solution of 4-bromobenzenesulfonyl chloride (1.33 g, 5.2 mmol) and 3- (trifluoromethyl)azetidine (500 mg, 4 mmol, CAS 1221349-18-3) in DMF (5 mL) was added DIEA (3.46 mL, 20 mmol) at 25 °C. The mixture was shaken for 2 h at 100 °C. Purification by FC (SiCh; PE to PE:EtOAc=3: l;UV ) gave the title compound (980 mg, 2.85 mmol, 71% yield) as a white solid. MS (ESI): m / z = 344.0 [{79Br}M+H]+, 346.0 [{81Br}M+H]+.

[0820] Example C.160

[0821] 2-bromo-5-[ 3-(trifluoromethyl)azetidin-l-yl pyrazine

[0822] To a solution of 3-(trifluoromethyl)azetidine;hydrochloride (500 mg, 3.08 mmol, CAS 1221272- 90-7) and DIEA (1.55 g, 15.3 mmol) in DMF (10 mL) was added 2,5-dibromopyrazine (951 mg, 4 mmol). The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was poured into sat. NaCl. The mixture was extracted with EtOAc. The organic phase was dried over anhydrous ISfeSCU and concentrated in vacuo. The crude product was purified by FC (SiCL, petroleum ether / EtOAc) to give the title compound (500 mg, 1.77 mmol, 44% yield) as a yellow solid. MS (ESI): m / z = 281.9 [M+H]+.

Claims

CLAIMS1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, wherein:L is selected from -CR3aR3b-, -O-, *-OCH2-, and *-CH2O-, wherein the asterisk marks the connection of L to ring A;A is selected from Ce-io-aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered hetero cyclyl;R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,O Y \\ / / (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-, and a group;R2is selected from hydrogen, halogen, oxo, cyano, Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-O Y\\ / / R4b / S>y alkoxy, C3-6-cycloalkyl-, and a group ' ;R3aand R3bare each independently selected from hydrogen, halogen, and Ci-6-alkyl;R4ais selected from halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-;R4bis selected from Ci-6-alkyl, halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-; is selected from O and NH; andB is a 7-11 membered bicyclic spirocycle comprising 1-2 nitrogen atoms, the remaining ring atoms being carbon.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A is selected from:(i) Ce-9-aryl;(ii) 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, andS, the remaining ring atoms being carbon; and(iii) 3- to 9-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl and 5- to 9-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining ring atoms being carbon.

4. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein A is selected from: phenyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,4-triazolyl, 2H- triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, 1,2-dihydropyridine, pyridazinyl, pyrazolyl, oxazolyl, [l,2,4]triazolo[4,3-a]pyridine, [l,2,4]triazolo[l,5- a]pyridine, lH-pyrrolo[2,3-b]pyridine, imidazo[l,5-a]pyridine, imidazo[l,2-a]pyridine, 2H-pyrazolo [3 ,4-b]pyridine, 2H-pyrazolo [4,3 -b]pyridine, 2H-pyrazolo [4, 3 -c]pyridine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[3,4-b]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 2H-pyrazolo[3 ,4-d]pyrimidine, [ 1 ,2,4]triazolo[ 1 , 5-a]pyrimidine, imidazof 1 ,2-a]pyrazine,1.2-benzoxazole, IH-indazole, lH-imidazo[l,2-c]pyrimidin-5-one, lH-pyrrolo[2,3- b]pyridine, imidazof l,2-a]pyrimidine, l,5-dihydroimidazo[l,2-a]pyrimidine, 2H- pyrazolo[3,4-c]pyridine, 7H-pyrrolo[2,3-d]pyrimidine, [l,2,4]triazolo[l,5-b]pyrimidine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, lH-imidazo[4,5-b]pyridine, 3H- imidazo[4,5-b]pyridine, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyrimidine, lH-pyrazolo[3,4- b]pyridine, lH-imidazo[l,2-a]pyrimidin-5-one, and 2H-indazole.

5. The compound of formula (I) according to claim 4, or a pharmaceutically acceptable salt thereof, wherein A is selected from: phenyl, 1,2,4-triazolyl, 2H-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl,1.2-dihydropyridine, pyridazinyl, pyrazolyl, [l,2,4]triazolo[4,3-a]pyridine,[ 1 ,2,4]triazolo[ 1 ,5-a]pyridine, lH-pyrrolo[2,3-b]pyridine, imidazof 1 ,5-a]pyridine, imidazo[l,2-a]pyridine, 2H-pyrazolo[3,4-b]pyridine, 2H-pyrazolo[4,3-c]pyridine, 2H- pyrazolo[3,4-b]pyrimidine, 2H-pyrazolo[3,4-c]pyridine, 2H-pyrazolo[3,4-d]pyrimidine, imidazo[l,2-a]pyrazine, 1,2-benzoxazole, IH-indazole, lH-pyrrolo[2,3-b]pyridine, imidazo[l,2-a]pyrimidine, l,5-dihydroimidazo[l,2-a]pyrimidine, 7H-pyrrolo[2,3- d]pyrimidine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, and 2H-indazole.- 150 -6. The compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, pyrazinyl, pyridyl, pyrazolyl, lH-pyrrolo[2,3- b]pyridine, and 2H-indazole.

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

8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CR3aR3b-, -O-, and *-OCH2-, wherein: the asterisk marks the connection of L to ring A;R3ais selected from hydrogen, halogen, and Ci-6-alkyl; andR3bis selected from hydrogen, and halogen.

10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein L is selected from -CR3aR3b-, -O-, and *-OCH2-, wherein: the asterisk marks the connection of L to ring A;R3ais selected from hydrogen, fluoro, and methyl; and R3bis selected from hydrogen, and fluoro.

11. The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-.- 151 -12. The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,(halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-, and a groupR2is selected from hydrogen, halogen, oxo, cyano, Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6- alkoxy, C3-6-cycloalkyl-, and a groupR4ais selected from halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-;R4bis Ci-6-alkyl; andY is selected from O and NH.

13. The compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt thereof, wherein:R1is selected from CF3, 2,2,2-trifluoroethyl, CF3O, 2,2,2-trifluoroethoxy, trifluoromethylcyclopropyl, trifluoromethylazetidinyl, and a groupR2is selected from hydrogen, fluoro, oxo, cyano, methyl, CF3, methoxy, cyclopropyl, and a groupR4ais selected from CF3 and trifluoromethylazetidinyl;R4bis methyl; andY is selected from O and NH.

14. The compound of formula (I) according to claim 12, or a pharmaceutically acceptable salt thereof, wherein:R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-, and a groupR2is selected from hydrogen, halogen, cyano, and Ci-6-alkyl;R4ais halo-Ci-6-alkyl; andY is O.

15. The compound of formula (I) according to claim 14, or a pharmaceutically acceptable salt thereof, wherein:R1is selected from CF3, CF3O, trifluoromethylcyclopropyl, and a groupR2is selected from hydrogen, fluoro, cyano, and methyl;R4ais CF3; andY is O.

16. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:L is selected from -CR3aR3b-, -O-, and *-0CH2-, wherein the asterisk marks the connection of L to ring A;A is selected from:(i) Ce-9-aryl;(ii) 5- to 9-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon; and(iii) 3- to 9-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon;B is selected from:R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-,(halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-, and a groupR2is selected from hydrogen, halogen, oxo, cyano, Ci-6-alkyl, halo-Ci-6-alkyl, Ci-6-O \\ / P / R4b / S>y alkoxy, Cs-e-cycloalkyl-, and a group ' ;R3ais selected from hydrogen, halogen, and Ci-6-alkyl;R3bis selected from hydrogen, and halogen;R4ais selected from halo-Ci-6-alkyl and (halo-Ci-6-alkyl)-(3- to 6-membered heterocyclyl)-;R4bis Ci-6-alkyl; andY is selected from O and NH.

17. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein:L is selected from -CR3aR3b-, -O-, and *-0CH2-, wherein the asterisk marks the connection of L to ring A;A is selected from phenyl, 1,2,4-triazolyl, 2H-triazolyl, thiazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridyl, 1,2-dihydropyridine, pyridazinyl, pyrazolyl, [ 1 ,2,4]triazolo [4,3 -a]pyridine, [ 1 ,2,4]triazolo [ 1 , 5 -a]pyridine, 1 H-pyrrolo [2,3 - b]pyridine, imidazo[l,5-a]pyridine, imidazo[l,2-a]pyridine, 2H-pyrazolo[3,4- b]pyridine, 2H-pyrazolo[4,3-c]pyridine, 2H-pyrazolo[3,4-b]pyrimidine, 2H- pyrazolo[3,4-c]pyridine, 2H-pyrazolo[3,4-d]pyrimidine, imidazo[l,2-a]pyrazine, 1,2-benzoxazole, IH-indazole, lH-pyrrolo[2,3-b]pyridine, imidazo[l,2- a]pyrimidine, l,5-dihydroimidazo[l,2-a]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, pyrazolo[l,5-a]pyrimidine, 2H-pyrazolo[4,3-b]pyridine, and 2H-indazole;B is selected from:- 154 -R1is selected from CF3, 2,2,2-trifluoroethyl, CF3O, 2,2,2-trifluoroethoxy, trifluoromethylcyclopropyl, trifluoromethylazetidinyl, and a groupR2is selected from hydrogen, fluoro, oxo, cyano, methyl, CF3, methoxy, cyclopropyl, and a groupR3ais selected from hydrogen, fluoro, and methyl; andR3bis selected from hydrogen, and fluoro;R4ais selected from CF3 and trifluoromethylazetidinyl;R4bis methyl; andY is selected from O and NH.

18. The compound of formula (I) according to claim 16, or a pharmaceutically acceptable salt thereof, wherein:L is -CH2-;A is selected from phenyl and 5- to 9-membered heteroaryl comprising 1 to 2 nitrogen atoms, the remaining ring atoms being carbon;R1is selected from halo-Ci-6-alkyl, halo-Ci-6-alkoxy, halo-Ci-6-alkyl-C3-6-cycloalkyl-, and a groupR2is selected from hydrogen, halogen, cyano, and Ci-6-alkyl;R4ais halo-Ci-6-alkyl; andY is O.

19. The compound of formula (I) according to claim 18, or a pharmaceutically acceptable salt thereof, wherein:L is -CH2-;A is selected from phenyl, pyrazinyl, pyridyl, pyrazolyl, lH-pyrrolo[2,3-b]pyridine, and 2H-indazole;- 155 -R1is selected from CF3, CF3O, trifluoromethylcyclopropyl, and a groupR2is selected from hydrogen, fluoro, cyano, and methyl;R4ais CF3; andY is O.

20. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from: (4aR,8aS)-6-[6-[2-fluoro-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[4-(trifluoromethoxy)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [ 1 -methyl-3 -(trifhroromethyl)pyrrolo [2,3 -b]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrrolo[2,3-b]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;2-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro [3.3 ]heptan-6-yl] methyl] -5 -(trifl uoromethy 1 Jbenzonitri 1 e;(4aR,8aS)-6-[6-[difhioro-[2-methoxy-6-(trifhroromethyl)-3-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[4-fluoro-2-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)indoxazen-6-yl] methyl] -2-azaspiro [3.3 ]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;- 156 -(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-indazol-5-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-(4-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[3,4-b]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrrolo[2,3-b]pyridin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-(3-triflylbenzyl)-2-azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-(3-fluoro-5-triflyl-benzyl)-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)indoxazen-5 -y 1 ] methyl] -2-azaspiro [3.3 ]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[(lS)-l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;5-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile;(4aR, 8aS)-6- [6- [ [6 - [ 1 -(trifluoromethyl)cyclopropyl] -2-pyridyl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl] -3 -pyridyl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl] -2-pyridyl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;- 157 -(4aR,8aS)-6-[6-[[5-(trifluoromethoxy)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[2-fluoro-4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;4-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro[3.3]heptan-6-yl]methyl]-2-(trifluoromethyl)benzonitrile;(4aR,8aS)-6-[6-[[l-(trifluoromethyl)indazol-6-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [2-methyl-4-(trifluoromethyl)pyrazol-3 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aS,8aR)-6-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [ 1 -methyl-5 -(trifluoromethyl)pyrazol-4-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[3,4-d]pyrimidin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[6-(trifluoromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[3-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [2-(trifluoromethyl)imidazo [ 1 ,2-a]pyridin-7-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [6 - [ 1 -(trifluoromethyl)cyclopropyl] -3 -pyridyl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[(6R)-6-(3-triflylbenzyl)-2-azaspiro[3.4]octane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;- 158 -(4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl] - 1 H-pyrazol-3 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [3 -methyl-5 -(trifluoromethyl)pyrazol- 1 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [2 - [ 1 -(trifluoromethyl)cyclopropyl] -4-pyridyl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[3-fluoro-5-(trifluoromethylsulfonimidoyl)phenyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [ 1 -(2,2,2-trifluoroethyl)-3 -(trifluoromethyl)pyrazol-4-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [ 1 -methyl-5 -(trifluoromethyl)pyrazol-3 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[5-[3-(trifluoromethyl)azetidin-l-yl]pyrazin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [ 1 -cyclopropyl-3 -(trifluoromethyl)pyrazol-4-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[3,4-c]pyridin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[3,4-b]pyridin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;3-[[2-[(4aR,8aS)-3-keto-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazine-6-carbonyl]-2- azaspiro [3.3 ]heptan-6-yl] methyl] -5 -(trifluoromethyl)benzonitrile;- 159 -(4aR,8aS)-6-[6-[(lR)-l-[4-methyl-5-(trifluoromethyl)-2-pyridyl]ethyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-2-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[4-[l-(trifluoromethyl)cyclopropyl]pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[4-[l-(trifluoromethyl)cyclopropyl]pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [5 -(trifluoromethyl)-3 -pyridyl] methyl] -2-azaspiro [3.3 ]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [4 - [ 1 -(trifluoromethyl)cyclopropyl] -2-pyridyl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl] -2-pyridyl] oxy] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[difluoro-[2-methoxy-5-(trifluoromethyl)-3-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[3-mesyl-5-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [2-(trifluoromethyl)imidazo [ 1 ,2-a]pyridin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[4-(trifluoromethylsulfonimidoyl)benzyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[3-mesyl-4-(trifluoromethyl)benzyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [2-keto-4-[ 1 -(trifluoromethyl)cyclopropyl] - 1 -pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;- 160 -(4aR,8aS)-6-[8-(3-triflylbenzyl)-2-azaspiro[4.4]nonane-2-carbonyl]-l,2,4,4a,5,7,8,8a- octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl]pyrazin-2-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[4-[3-(trifluoromethyl)azetidin-l-yl]sulfonylbenzyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)imidazo [ 1 , 5-a]pyridin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[5-[l-(trifluoromethyl)cyclopropyl]pyrimidin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[(4-triflylpyrazol-l-yl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[(5-triflyl-2-pyridyl)methyl]-2-azaspiro[3.3]heptane-2-carbonyl]- l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-7-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [2-(trifluoromethyl)pyrazolo [ 1 , 5 -a]pyrimidin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[2-[l-(trifluoromethyl)cyclopropyl]pyrimidin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-lH-pyrazolo[4,3-c]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl] imidazol- 1 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;- 161 -(4aR, 8aS)-6- [6- [ [4-(trifluoromethyl)pyrazol- 1 -yl] methyl] -2-azaspiro [3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[2-methyl-5-(trifluoromethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [2-(2,2,2-trifluoroethyl)-5 -(trifluoromethyl)pyrazol-3 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[4-(trifluoromethyl)thiazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [7 - [2-fluoro-4-(trifluoromethyl)benzyl] -2, 7-diazaspiro [3.5 ]nonane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [4 - [ 1 -(trifluoromethyl)cyclopropyl] imidazol- 1 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[2-(trifluoromethyl)-[l,2,4]triazolo[l,5-a]pyridin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)- 1 H-pyrazolo [4,3 -b]pyridin-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [ 1 -(trifluoromethyl)pyrazol-4-yl] methyl] -2-azaspiro [3.3 ]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[5-(trifluoromethyl)-2-pyridyl]oxymethyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [5 -(trifluoromethyl)pyrazin-2-yl] methyl] -2-azaspiro [3.3 ]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [3 -methoxy-5 -(trifluoromethyl)pyrazin-2-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [6 - [ 1 -(trifluoromethyl)cyclopropyl] -3 -pyridyl] oxy] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;- 162 -(4aR,8aS)-6-[6-[[2-(trifluoromethyl)imidazo[l,2-a]pyrazin-6-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)pyrazolo [ 1 , 5 -a]pyrimidin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [3 -(trifluoromethyl)imidazo [ 1 ,2-a]pyrimidin-7-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[l-(2,2,2-trifluoroethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]pyridazin-3-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[difluoro-[6-(trifluoromethyl)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[difluoro-[2-(trifluoromethyl)-4-pyridyl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[[3-(trifluoromethyl)-[l,2,4]triazolo[4,3-a]pyridin-7-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[5-(trifluoromethylsulfonimidoyl)-2-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[2-(trifluoromethyl)pyrazolo[l,5-a]pyrimidin-6-yl]oxy-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [difluoro-[ 5 -(trifluoromethyl)pyrimidin-2-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[4-(trifluoromethylsulfonimidoyl)pyrazol-l-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[2-(2,2,2-trifluoroethyl)triazol-4-yl]methyl]-2-azaspiro[3.3]heptane-2- carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [6-(2,2,2-trifluoroethoxy)-3 -pyridyl] methyl] -2, 6-diazaspiro [3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR,8aS)-6-[6-[2-[l-(trifluoromethyl)cyclopropyl]pyrimidin-5-yl]oxy-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[7-[[3-(trifluoromethyl)-lH-l,2,4-triazol-5-yl]methyl]-2-azaspiro[3.5]nonane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [6 - [ 1 -(trifluoromethyl)cyclopropyl] -2-pyridyl] oxy] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[2-[l-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[6-[l-(trifluoromethyl)cyclopropyl]pyrazin-2-yl]oxy-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [ 1 -(2,2,2-trifluoroethyl)-5 -(trifluoromethyl)pyrazol-3 -yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[6-[l-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [5 -[ 1 -(trifluoromethyl)cyclopropyl] -3 -pyridyl] oxy] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[2-[l-(trifluoromethyl)cyclopropyl]pyrimidin-4-yl]oxy-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[difhioro-[6-(trifhioromethoxy)-3-pyridyl]methyl]-2-azaspiro[3.3]heptane- 2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3-one;(4aR, 8aS)-6- [6- [ [4 - [ 1 -(tri fl uoromethy I Jcyclopropyl ] -2-pyridyl] oxy] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR,8aS)-6-[6-[[2-keto-5-[l-(trifhioromethyl)cyclopropyl]-l-pyridyl]methyl]-2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [2-(trifluoromethyl)imidazo [ 1 ,2-a]pyrimidin-6-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one;(4aR, 8aS)-6- [6- [ [5 -keto- 1 -(2,2, 2-trifluoroethyl)imidazo [ 1 ,2-a]pyrimidin-7-yl] methyl] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one; and(4aR, 8aS)-6- [6- [ [2 - [ 1 -(tri fl uoromethy I Jcyclopropyl ] -4-pyridyl] oxy] -2- azaspiro[3.3]heptane-2-carbonyl]-l,2,4,4a,5,7,8,8a-octahydropyrido[3,4-b]pyrazin-3- one.

21. A process of manufacturing the compounds of formula (I) according to any one of claims1 to 20, or pharmaceutically acceptable salts thereof, comprising:(a) reacting a compound of formula 1, wherein PG is an amino protective group,with an amine of Formula 2, wherein A, B, L, R1and R2are as defined herein,in the presence of a urea forming reagent and a base to form a compound of formula3, wherein A, B, L, R1and R2are as defined herein and PG is an amino protective group,- 165 -followed by(b) removing said amino protective group PG to form said compound of formula (I).

22. A compound of formula (I) according to any one of claims 1 to 20, when manufactured according to the process of claim 21.

23. A compound of formula (I) according to any one of claims 1 to 20 for use as therapeutically active substance.

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

25. The use of a compound of formula (I) according to any one of claims 1 to 20 for the treatment or prophylaxis of diseases and disorders that are associated with MAGL in a mammal.

26. A compound of formula (I) according to any one of claims 1 to 20 for use in the treatment or prophylaxis of diseases and disorders that are associated with MAGL.

27. The use of a compound of formula (I) according to any one of claims 1 to 20 in the preparation of a medicament for the treatment or prophylaxis of diseases and disorders that are associated with MAGL.

28. A method for the treatment or prophylaxis of diseases and disorders that are associated with MAGL in a mammal, which method comprises administering an effective amount of a compound of formula (I) according to any one of claims 1 to 20 to the mammal.

29. The invention as described hereinbefore.

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