Arylpiperidines as monoacylglycerol lipase modulators

Abstract

Arylpiperidine compounds of Formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing same, and methods of using same for treating disease states, disorders, and conditions associated with MGL modulation, such as disease states, disorders, and conditions associated with pain, psychiatric disorders, neurological disorders (including, but not limited to, major depressive disorder, treatment-resistant depression, anxiety-related depression, autism spectrum disorder, Asperger's syndrome, and bipolar disorder), cancer, and ophthalmic conditions. [Formula 1] TIFF2023518515000275.tif27128 (in the formula, X, R 2a , R 2b , R 3 , R 4 , R 5a , and R 5b is as defined herein).

Description

[Technical Field]

[0001] The present invention relates to certain arylpiperidine chemical compounds having MGL modulating properties, pharmaceutical compositions containing these chemical compounds, chemical processes for preparing these chemical compounds, and their use in treating diseases, disorders or conditions associated with MGL receptor activity in subjects, particularly humans. [Background technology]

[0002] Asa and Δ 9 Analogs of -tetrahydrocannabinol have been used for therapeutic purposes since the days of folk medicine. The endocannabinoid system consists of two G protein-coupled receptors, cannabinoid receptor type 1 (CB1) (Matsuda et al., Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB2) (Munro et al., Nature, 1993, 365, 61-5). The CB1 receptor is one of the most abundant G protein-coupled receptors expressed in the brain (Herkenam et al., Proc. Nat. Acad. Sci., 1990, 87(5), 1932-1936). CB1 is also expressed peripherally in the liver, gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle (Di Marzo et al., Curr Opin Lipidol, 2007, 18, 129-140). CB2 is primarily expressed in immune cells such as monocytes (Pacher et al., Amer J Physiol, 2008, 294, H1133-H1134), and under certain conditions (inflammation) in the brain (Benito et al., Brit J Pharmacol, 2008, 153, 277-285), skeletal muscle (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364, 105-110), and cardiac muscle (Hajrasouliha et al., Eur J Pharmacol, 2008, 579, 246-252).

[0003] In 1992, N-arachidonoylethanolamine (AEA, or anandamide) was identified as an endogenous ligand for cannabinoid receptors (Devane et al., Science, 1992, 258, 1946-9). Subsequently, 2-arachidonoylglycerol (2-AG) was also identified as an additional endogenous ligand for cannabinoid receptors (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995, 215, 89-97). It was reported that the concentration of 2-AG in rat brain was at least 100-fold higher than that of anandamide (Buczynski and Parsons, Brit J Pharmacol, 2010, 160(3), 423-42). Therefore, 2-AG may play a more important physiological role in the brain endocannabinoid system than anandamide (Sugiura et al., Prostaglandins Leukot Essent Fatty Acids., 2002, Feb-Mar, 66(2-3):173-92). The endocannabinoid 2-AG is a full agonist at CB1 and CB2 receptors, whereas anandamide is a partial agonist at both receptors (Suguira et al., Prog Lipid Res., 2006, 45(5):405-46). Unlike many classical neurotransmitters, endocannabinoids signal via a retrograde mechanism. They are synthesized on demand in postsynaptic neurons and then rapidly degraded after binding to presynaptic cannabinoid receptors (Ahn et al., Chem Rev. 2008, 108(5):1687-707).Monoacylglycerol lipase (MGLL, also known as MAG lipase and MGL) is a serine hydrolase involved in the degradation of 2-AG to arachidonic acid and glycerol in the central nervous system (Mechoulam et al., Biochem Pharmacol, 1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995, 215, 89-97; Long et al., Nat Chem Biol. 2009 Jan; 5(1): 37-44; Schlosburg et al., Nat Neurosci., 2010, Sep; 13(9): 1113-9) and peripheral tissues (Long et al., Chem Biol., 2009 Jul 31; 16(7): 744-53). Anandamide is hydrolyzed by fatty acid amide hydrolase (FAAH) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884). MGL exists in both soluble and membrane-bound forms (Dinh et al., Proc Natl Acad Sci U S A., 2002, Aug 6;99(16):10819-24). In the brain, MGL is located in presynaptic neurons (Straiker et al., Mol Pharmacol., 2009, Dec;76(6):1220-7) and astrocytes (Walter et al., J Neurosci., 2004, Sep 15;24(37):8068-74) in areas associated with high CB1 receptor density. Compared to wild-type controls, genetic disruption of MGL expression results in a 10-fold increase in brain 2-AG levels without affecting anandamide concentrations (Schlosburg et al., Nat Neurosci., 2010, Sep;13(9):1113-9).

[0004] Therefore, MGL modulation offers an interesting strategy for enhancing the cannabinoid system. A major advantage of this approach is that only brain regions where endocannabinoids are actively produced are modulated, potentially minimizing the side effects associated with exogenous CB1 agonists. Pharmacological inactivation of MGL with covalent inhibitors in animals has been found to increase 2-AG content in brain and peripheral tissues, producing analgesic, anxiolytic, and anti-inflammatory effects that depend on CB1 and / or CB2 receptors (Long et al., Nat Chem Biol., 2009, Jan, 5(1):37-44; Ghosh et al., Life Sci., 2013, Mar 19, 92(8-9):498-505; Bedse et al., Biol Psychiatry., 2017, Oct 1, 82(7):488-499; Bernal-Chico et al., Glia., 2015, Jan, 63(1):163-76; Patel et al. Neurosci Biobehav Rev., 2017, May, 76(Pt A):56-66; Bedse et al., Transl Psychiatry., 2018, Apr 26, 8(1):92). In addition to MGL's role in terminating 2-AG signaling, MGL modulation, including MGL inhibition, also promotes CB1 / 2-independent effects on neuroinflammation (Nomura et al., Science., 2011, Nov 11;334(6057):809-13).MGL regulation, including MGL inhibition, has been shown to be beneficial in a variety of conditions, including traumatic brain injury (Katz et al., J Neurotrauma., 2015, Mar 1;32(5):297-306; Zhang et al., J Cereb Blood Flow Metab., 2015, Mar 31;35(4):443-453), neurodegeneration including Alzheimer's disease (Piro et al., Cell Rep., 2012, Jun 28,1(6):617-23; Wenzel et al., Life Sci., 2018, Aug 15,207:314-322; Chen et al., Cell Rep., 2012, Nov 29,2(5):1329-39), and Parkinson's disease (Nomura et al., Science, 2011, Nov 11,334(6057),809-13; Pasquarelli et al., Neurochem Int.,2017,Nov,110:14-24), amyotrophic lateral sclerosis (Pasquarelli et al., Neuropharmacology,2017,Sep 15,124:157-169), multiple sclerosis (Hernadez-Torres et al., Angew Chem Int Ed Engl.,2014,Dec 8,53(50):13765-70; Bernal-Chico et al., Glia.,2015,Jan,63(1):163-76), Huntington's disease (Covey et al., Neuropsychopharmacology,2018,43,2056-2063), Tourette's syndrome and status epilepticus (Terrone et al. al.,Epilepsia.,2018,Jan,59(1),79-91; von Ruden et al.,Neurobiol Dis.,2015,May;77:238-45), resulting in a reduction in pro-inflammatory prostanoid signaling in animal models.

[0005] Therefore, by enhancing the cannabinoid system and attenuating the pro-inflammatory cascade, MGL modulation, including MGL inhibition, offers a compelling therapeutic approach for the treatment of a vast number of complex diseases. Importantly, MGL modulation, including MGL inhibition, in animals has been shown to improve Δ9 -Does not produce the full range of neurobehavioral effects observed with tetrahydrocannabinol and other CB1 agonists (Tuo et al., J Med Chem., 2017, Jan 12, 60(1), 4-46; Mulvihill et al., Life Sci., 2013, Mar 19, 92(8-9), 492-7).

[0006] Decreased endocannabinoid activity is a risk factor for depression, anxiety, and post-traumatic stress disorder. Human cannabis use for thousands of years and short-term human treatment with the endocannabinoid antagonist rimonabant support this hypothesis. 2-AG concentrations are decreased in individuals with major depression (Hill et al., Pharmacopsychiatry., 2008, Mar;41(2):48-53; Hill et al., Psychoneuroendocrinology., 2009, Sep;34(8):1257-1262). Low circulating 2-AG concentrations can predict the prevalence of depression (Hauer et al., Rev Neurosci., 2012, 23(5-6):681-90). Decreased circulating levels of 2-AG have previously been found in patients with post-traumatic stress disorder (PTSD) (Hill et al., Psychoneuroendocrinology, 2013, 38(12), 2952-2961). Healthy volunteers exposed to chronic stressors showed a progressive decrease in circulating levels of 2-AG, which correlated with the onset of a decline in positive affect (Yi et al., Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 67(3), 92-97). Rimonabant, a CB1 receptor inverse agonist / antagonist, was withdrawn from the market due to a high incidence of severe depression and suicidal ideation (Christensen et al., The Lancet, 2007, 370, 1706-1713). Therefore, MGL modulators are potentially useful for mood disorders, anxiety, PTSD, autism spectrum disorders, and Asperger's syndrome (Folkes et al., J Clin Invest. 2020; 130(4): 1728-1742, Jung et al., Nature Communications, 2012, 3, 1080; Wang et al., Mol Psychiatry, 2018 August, 23(8): 1798-1806).

[0007] Cannabinoid receptor agonists are used clinically to treat pain, spasticity, emesis, and anorexia (Di Marzo, et al., Annu Rev Med., 2006, 57:553-74; Ligresti et al., Curr Opin Chem Biol., 2009, Jun;13(3):321-31). Therefore, MGL modulators, including MGL inhibitors, are also useful for these indications. MGL exerts CB1-dependent analgesic effects in animal models of noxious chemical, inflammatory, thermal, and neuropathic pain (Guindon et al., Br J Pharmacol., 2011, Aug;163(7):1464-78; Kinsey et al., J Pharmacol Exp Ther., 2009, Sep;330(3):902-10; Long et al., Nat Chem Biol., 2009, Jan;5(1):37-44). MGL blockade reduces mechanical and acetone-induced cold allodynia in mice subjected to chronic sciatic nerve constriction injury (Kinsey et al., J Pharmacol Exp Ther., 2009, Sep;330(3):902-10). MGL inhibition results in an opiate-sparing event accompanied by decreased tolerance, constipation, and cannabis-like side effects (Wilkerson et al., J Pharmacol Exp Ther., 2016, Apr;357(1):145-56). MGL blockade is protective in models of inflammatory bowel disease (Alhouayek et al., FASEB J., 2011, Aug;25(8):2711-21). MGL inhibition also reverses paclitaxel-induced nociceptive behavior and proinflammatory markers in a mouse model of chemotherapy-induced neuropathy (Curry et al., J Pharmacol Exp Ther., 2018, Jul;366(1):169-18). MGL inhibitors are also potentially useful for treating chronic bladder inflammatory conditions, such as interstitial cystitis (Chinnadurai et al., 2019, Oct;131:109-321).

[0008] Inhibition of 2-AG hydrolysis exerts antiproliferative activity and reduces prostate cancer cell invasiveness (Nithipatikom et al., Cancer Res., 2004, December 15, 64(24):8826-30; Nithipatikom et al., Biochem Biophys Res Commun., 2005, July 15, 332(4):1028-33; Nithipatikom et al., Prostaglandins Other Lipid Mediat., 2011, February 94(1-2):34-43). MGL is upregulated in invasive human cancer cells and primary tumors and has the unique role of providing a lipolytic source of free fatty acids for the synthesis of oncogenic signaling lipids that promote cancer invasiveness. Thus, beyond the physiological role of MGL in mediated endocannabinoid signaling, MGL in cancer plays a distinct role in regulating the fatty acid precursor pool for the synthesis of pro-tumorigenic signaling lipids in human malignant cancer cells.

[0009] MGL blockade exhibits antiemetic and antiemetic effects in the lithium chloride model of emesis in shrews (Sticht et al., Br J Pharmacol., 2012, Apr, 165(8):2425-35).

[0010] MGL modulators, including MGL inhibitors, may be useful in regulating opiate drug dependence. MGL blockade reduces the intensity of naloxone-induced morphine withdrawal symptoms in mice. MGL blockade also attenuated symptoms during spontaneous withdrawal in morphine-dependent mice (Ramesh et al., J Pharmacol Exp Ther., 2011, Oct., 339(1):173-85).

[0011] MGL modulators are also potentially useful in treating ocular conditions, including but not limited to glaucoma and disease states resulting from elevated intraocular pressure (Miller et al., Pharmaceuticals, 2018, 11, 50). Summary of the Invention [Means for solving the problem]

[0012] Embodiments of the present invention relate to chemical entities, pharmaceutical compositions comprising them, methods for making and purifying them, and methods for their use in the treatment of pathologies, diseases, and conditions associated with MGL modulation. A further embodiment of the present invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or condition associated with MGL modulation using at least one chemical entity of the present invention.

[0013] Additional embodiments, features, and advantages of the invention will become apparent from the following detailed description as well as by practice of the invention.

[0014] As used herein, compounds of formula (I):

[0015] [ka] (In the formula, X is CH or O; R 2a and R 2b are each independently H and C 1~4 alkyl, R 3 teeth, (i) phenyl, benzyl, or monocyclic heteroaryl, each of which is selected from the group consisting of halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, SC 1~6 Alkyl, SF5, Si(CH3)3, NR a R b , C 3~6 Cycloalkyl, OC 3~6 Phenyl, benzyl, or monocyclic heteroaryl optionally substituted with 1, 2, or 3 substituents selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl is selected from 1 or 2 C1~4 Alkyl, C 1~4 optionally substituted with haloalkyl or halo groups; or two adjacent ring substituents on a phenyl, benzyl, or monocyclic heteroaryl, taken together with the atoms to which they are attached, form a fused monocyclic C 5~6 Forming a cycloalkyl or heterocycloalkyl ring, each ring having one or two C 1~4 Alkyl, C 1~4 optionally substituted with haloalkyl or halo groups; R a and R b are each independently H or C 1~4 alkyl), (ii) C 1~4 bicyclic heteroaryl optionally substituted with alkyl or halo, and (iii)C 1~4 Alkyl, C 1~4 C optionally substituted with haloalkyl or halo 3~6 Alkyl or C 3~6 cycloalkyl; R 4 H, F, and C 1~3 alkyl, R 5a and R 5b are each independently selected from H and CH and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof are described.

[0016] In some embodiments, a compound of formula (I):

[0017] [ka] (In the formula, X is CH or O; R 2a and R 2b are each independently H and C 1~4 alkyl, R 3 teeth, (a) Phenyl; Halo, C1~6 Alkyl, C 1~6 Haloalkyl, C(CH3)2OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, SCH3, SF5, Si(CH3)3, N(CH3)2, C 3~6 Cycloalkyl, OC 3~6 Cycloalkyl, phenyl, O-phenyl, O-pyridyl, and C substituted with CH 3~6 phenyl substituted with 1, 2, or 3 members each independently selected from cycloalkyl; and (b)C 1~6 Alkyl-substituted pyridyl; naphthyl;

[0018] [ka] is selected from R 4 H, F, and C 1~3 alkyl, R 5a and R 5b are each independently selected from H and CH and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof are described. DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, the terms "comprise," "contain," and "include" are used in their open, non-limiting sense.

[0020] Unless specifically limited in a particular use, the term "alkyl" refers to a straight- or branched-chain alkyl group having 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that are deemed equivalent to any one of the above examples in light of ordinary skill in the art and the teachings provided herein. "C1~6 "Alkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain. 1~4 "Alkyl" refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain. 1~3 "Alkyl" refers to a straight- or branched-chain alkyl group having 1 to 3 carbon atoms in the chain.

[0021] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic, or spiropolycyclic carbocycle having 3 to 12 ring atoms per carbocycle. Illustrative cycloalkyl groups include the following entities in the form of appropriately bonded moieties:

[0022] [ka]

[0023] The term "halogen" or "halo" refers to chlorine, fluorine, bromine, or iodine.

[0024] The term "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. 1~6 The term "haloalkyl," as used herein, refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. 1~4The term "haloalkyl," as used herein, refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF), difluoromethyl (CFH), monofluoromethyl (CHF), pentafluoroethyl (CFCF), tetrafluoroethyl (CHFCF), monofluoroethyl (CHCHF), trifluoroethyl (CHCF), tetrafluorotrifluoromethylethyl (CF(CF)), as well as groups deemed equivalent to any one of the foregoing examples given ordinary skill in the art and the teachings provided herein.

[0025] The term "aryl" refers to a monocyclic aromatic carbocycle (a ring structure having ring atoms that are all carbon) having six atoms per ring (the carbon atoms of an aryl group are sp2 hybridized).

[0026] The term "phenyl" refers to the following moiety:

[0027] [ka]

[0028] The term "pyridinyl" or "pyridyl" refers to the moiety:

[0029] [ka]

[0030] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system containing 5 to 14 ring atoms, wherein 1 to 4 ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms and at least one nitrogen ring atom. A heteroaryl group is bonded via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, fused to a benzene ring.

[0031] [ka]

[0032] The term "heterocycloalkyl," as used herein, refers to a ring system that is non-aromatic, in which 1 to 4 ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms, and which may optionally be fused to another ring (aromatic or heteroaromatic). Non-limiting examples of heterocycloalkyls include:

[0033] [ka]

[0034] Those of ordinary skill in the art will understand that the species of heteroaryl, heterocycloalkyl, cycloalkyl, and aryl groups listed or illustrated above are not exhaustive and that additional species may be selected within the scope of these defined terms.

[0035] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any position in the system where valency is allowed.

[0036] The term "variable point of attachment" means that a group may be attached at two or more alternative positions within a structure. The bond always replaces a hydrogen atom on one of the ring atoms. In other words, all permutations of the bond, as shown in the diagram below, are represented by a single diagram.

[0037] [ka]

[0038] Those skilled in the art will understand that when more than one such substituent is present on a given ring, the binding of each substituent is independent of all others. The groups listed or exemplified above are not exhaustive.

[0039] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any position in the system where valency is allowed.

[0040] Any formula given herein is intended to represent the compound having the structure depicted by that structural formula, as well as specific variations or forms. Specifically, compounds of any formula given herein may have asymmetric centers and therefore may exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula, as well as mixtures thereof, are considered to be within the scope of such formulas. Because compounds of the present invention may have one or more asymmetric centers, such compounds may be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Thus, any formula given herein is intended to represent a racemate, one or more of its enantiomeric forms, one or more of its diastereomeric forms, and mixtures thereof. Furthermore, any formula given herein is intended to refer to any one of hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof, even if such forms are not explicitly enumerated.

[0041] The term "R" at a stereocenter indicates that the stereocenter is in the R-configuration only, as defined in the art. Similarly, the term "S" means that the stereocenter is in the S-configuration only. As used herein, the term "RS" refers to a stereocenter that exists as a mixture of R- and S-configurations.

[0042] A compound containing one stereocenter depicted without a stereochemical bond designation is a mixture of two enantiomers. A compound containing two stereocenters depicted without a stereochemical bond designation is a mixture of four diastereomers. A compound containing two stereocenters labeled "RS" and depicted with a stereochemical bond designation is a binary mixture with the relative stereochemistry as depicted. An unlabeled stereocenter depicted without a stereochemical bond designation is a mixture of R- and S-configurations. For an unlabeled stereocenter depicted with a stereochemical bond designation, the absolute stereochemistry is as depicted.

[0043] Reference to a compound described herein refers to either (a) the actual stated form of the compound, or (b) any one of the forms of the compound in the medium in which the compound is believed to exist when named. For example, a reference to a compound such as R-COOH herein includes a reference to any one of R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R-COOH(s) refers to the solid compound as it may be present, for example, in a tablet or some other solid pharmaceutical composition or preparation, R-COOH(sol) refers to the undissociated form of the compound in the solvent, and R-COO-(sol) refers to the dissociated form of the compound in the solvent, for example, the dissociated form of the compound in an aqueous environment, regardless of whether such dissociated form is derived from R-COOH, its salt, or any other entity that generates R-COO- when believed to have dissociated in the medium. In another example, a phrase such as "exposing an entity to a compound of formula R-COOH" refers to exposing such entity to the form of the compound R-COOH present in the medium in which such exposure occurs. In yet another example, a phrase such as "reacting an entity with a compound of formula R-COOH" refers to (a) a chemically related form of such entity present in the medium in which such reaction occurs reacting with (b) a chemically related form of the compound R-COOH present in the medium in which such reaction occurs. In this context, when such an entity is present, for example, in an aqueous environment, it is understood that the entity is exposed to species such as R-COOH(aq) and / or R-COO-(aq) (the subscript "(aq)" denotes "aqueous solution" in accordance with its conventional meaning in chemistry and biochemistry), since the compound R-COOH is present in such same medium. In these nomenclature examples, a carboxylic acid functional group has been selected, but this selection is not intended to be limiting and is merely illustrative. It is understood that similar examples can be provided for other functional groups, including, but not limited to, hydroxyl, basic nitrogen members, e.g., nitrogen members in amines, and any other group that interacts or transforms in a known manner in a medium containing the compound.Such interactions and transformations include, but are not limited to, dissociation, association, tautomerization, solvolysis (including hydrolysis), solvation (including hydration), protonation, and deprotonation. Further examples in this regard are not provided herein, as these interactions and transformations that occur in a given medium are known to those skilled in the art.

[0044] Any formula given herein is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted in the formula given herein except that one or more atoms are replaced in enriched form with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention in excess of natural abundance include, respectively: 2 H (or chemical symbol D), 3 H (or chemical symbol T), 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Such isotopically labeled compounds are useful in metabolic studies, preferably 14 C), reaction kinetic studies (e.g., 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F or 11 C labeled compounds may be particularly preferred for PET or SPECT studies. Additionally, heavier isotopes, such as deuterium (i.e., 2Substitution with, for example, H, or D, may confer certain therapeutic advantages as a result of greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by practicing the schemes described below or the procedures disclosed in the Examples and Preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0045] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same selection of that species for the variable elsewhere. In other words, when a variable appears more than once, the selection of a species from a specified list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise indicated.

[0046] Term C n~m Alkyl refers to an aliphatic chain, whether straight or branched, where the total number of carbon members in the chain, N, satisfies n≦N≦m (m>n).

[0047] When the same substituents are assigned to various groups, the assignment of each specific individual substituent to each such group is meant to be made independently of the assignment of each specific individual substituent to the remaining groups. By way of example, and not by way of limitation, when each of the Q and R groups can be H or F, the selection of H or F for the Q group is made independently of the selection of H or F for the R group, and therefore the selection of the assignment for the Q group does not determine or condition the selection of the assignment for the R group, unless expressly indicated otherwise, and vice versa. In this regard, the exemplary claim language will be interpreted as "each of the Q and R groups is independently H or F" or "each of the Q and R groups is independently selected from the group consisting of H and F."

[0048] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both its individual enantiomers and mixtures, racemic or otherwise. Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0049] In another example, zwitterionic compounds are encompassed herein by reference to compounds known to form zwitterions, even if not explicitly named in their zwitterionic form. Terms such as zwitterion and its synonyms, zwitterionic compound, are well-known and standard names recognized by IUPAC that are part of the standard set of defined scientific names. In this context, the name zwitterion has been assigned the identifier CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As is generally known, zwitterions or zwitterionic compounds are neutral compounds with formal unit charges of opposite signs. These compounds are sometimes referred to by the term "inner salt." While other sources refer to these compounds as "zwitterions," this latter term is a misnomer in still other sources. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula HNCHCOOH and, in some media (in this case, neutral media), forms a zwitterionic form. + H3NCH2COO - Zwitterions, zwitterionic compounds, inner salts, and dipolar ions, in the known and well-established meanings of these terms, are within the scope of the present invention in all cases, as recognized by those skilled in the art. Since it is not necessary to name every embodiment that will be recognized by those skilled in the art, structures of zwitterionic compounds related to the compounds of the present invention are not explicitly shown herein. However, these are also part of the embodiments of the present invention. Because interactions and transformations in a given medium that lead to various forms of a given compound are known to those skilled in the art, further examples related thereto are not provided herein.

[0050] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a named variable is not intended to define the same selection of that species for that variable appearing elsewhere. In other words, when a variable appears more than once, the selection of the species from a named list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise indicated.

[0051] As a first example in the terminology of substituents, the substituent S 1 例 is one of S1 and S2, and the substituent S 2 例 If is one of S3 and S4, then these assignments are 1 例 is S1 and S 2 例 is S3;S 1 例 is S1 and S 2 例 is S4;S 1 例 is S2 and S 2 例 is S3;S 1 例 is S2 and S 2 例 is S4; and refers to embodiments of the invention provided according to the equivalents of each of such alternatives. Therefore, the shorter term "S 1 例 is one of S1 and S2, and S 2 例 is one of S3 and S4" is used for purposes of brevity and not as a limitation. The first example above of substituent terminology written in generic terms is meant to illustrate the various substituent assignments described herein.

[0052] Furthermore, when more than one assignment is given for any member or substituent, embodiments of the invention include the various groupings that can be made from the listed assignments and their equivalents when taken independently. As a second example in substituent terminology, the substituent S 例 When is described herein as being one of S1, S2, and S3, this list is 例 is S1;S 例 is S2;S 例 is S3;S 例 is one of S1 and S2; S 例 is one of S1 and S3; S 例 is one of S2 and S3; S 例 is one of S1, S2, and S3; and any equivalents of each of these alternatives. Therefore, the shorter term "S" is used herein. 例 is one of S1, S2, and S3" is used for purposes of brevity and not as a limitation. The second example above of substituent terminology stated in generic terms is intended to illustrate the various substituent assignments described herein.

[0053] Nomenclature “C i ~C j " (j>i) when applied herein to a class of substituents is meant to refer to embodiments of the invention in which each and every number of carbon members from i to j, inclusive, is independently realized. By way of example, the terms C1-C3 independently refer to embodiments having one carbon member (C1), embodiments having two carbon members (C2), and embodiments having three carbon members (C3).

[0054] "Pharmaceutically acceptable salt" is intended to mean an acid or base salt of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with a patient's tissues without undue toxicity, irritation, or allergic response.

[0055] The compounds of formula (I) may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and thus may react with many inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

[0056] Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, hydrogen sulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexaphosphate ... These include syn-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate salts.

[0057] Since the compounds of formula (I) may contain at least one nitrogen with basic character, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by cleavage with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc.), or an organic acid (e.g., acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranolic acid, etc.). They can be prepared by treating the free base with any compatible mixture of acids such as sidylic acids (e.g., glucuronic acid or galacturonic acid), alpha-hydroxy acids (e.g., mandelic acid, citric acid, or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid), sulfonic acids (e.g., laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any other acid and mixture thereof that is considered equivalent.

[0058] The compound of formula (I) may contain a carboxylic acid moiety, and the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, any compatible mixture of bases such as those provided herein as examples, and any other base and mixture thereof that is considered equivalent or acceptable substitute in light of the ordinary level of skill in the art. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines such as benzylamine, pyrrolidine, piperidine, morpholine, piperazine, N-methyl-glucamine, and tromethamine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0059] The compounds of the present invention (collectively "active agent(s)"), including the pharmaceutically acceptable salts thereof, whether alone or in combination, are useful as MGL modulators in the methods of the present invention. Such methods of modulating MGL include the use of a therapeutically effective amount of at least one chemical entity of the present invention.

[0060] In some embodiments, the MGL modulator is an inhibitor and is used in subjects diagnosed with or suffering from a disease, disorder, or condition associated with MGL receptor activity, such as those described herein. Symptoms or disease states are intended to be included within the scope of "disease, disorder, or condition."

[0061] Thus, the present invention relates to a method of treating a subject diagnosed with or suffering from a disease, disorder, or condition associated with MGL receptor activity using the active agents described herein. As used herein, the term "treat" or "treatment" is intended to refer to the administration of an active agent or composition of the present invention to a subject for the purpose of providing a therapeutic or prophylactic benefit through modulation of MGL receptor activity. Treatment includes reversing, ameliorating, alleviating, arresting the progression of, reducing the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such a disease, disorder, or condition associated with MGL modulation. The term "subject" refers to a mammalian patient, e.g., a human, in need of such treatment.

[0062] The term "composition" refers to a product containing therapeutically effective amounts of specified ingredients, as well as any product that results directly or indirectly from the combination of specified ingredients in specified amounts.

[0063] The term "MGL inhibitor" is intended to encompass compounds that interact with MGL and substantially reduce or eliminate the catalytic activity of MGL, thereby increasing the concentration of MGL substrate(s). The term "modulated by MGL" is used to refer to conditions affected by modulation of the MGL enzyme, including conditions affected by inhibition of the MGL enzyme. The present disclosure relates to methods for treating, ameliorating, and / or preventing pain-related diseases, conditions, or disorders (including inflammatory pain), as well as psychiatric disorders, neurological disorders, cancer, and ophthalmic conditions, by administering a therapeutically effective amount of an MGL modulator to a subject in need thereof.

[0064] The term "modulator" includes both inhibitors and activators, where an "inhibitor" refers to a compound that decreases, blocks, inactivates, desensitizes or downregulates the expression or activity of MGL, and an "activator" is a compound that increases, activates, promotes, sensitizes or upregulates the expression or activity of MGL.

[0065] As used herein, unless otherwise noted, the terms "affect" or "affected" (when referring to a disease, condition, or disorder affected by inhibition of MGL) include reducing the frequency and / or severity of one or more symptoms or manifestations of the disease, condition, or disorder, and / or preventing the progression of one or more symptoms or manifestations of the disease, condition, or disorder, or the progression of the disease, condition, or disorder.

[0066] In the treatment methods of the present invention, a therapeutically effective amount of at least one active agent according to the present invention is administered to a subject suffering from or diagnosed with such a disease, disorder, or condition. A "therapeutically effective amount" refers to an amount or dose sufficient to generally provide the desired therapeutic or prophylactic benefit in a subject in need of such treatment for a specified disease, disorder, or condition. Effective amounts or doses of the active agents of the present invention can be determined by routine methods, such as modeling, dose escalation studies, or clinical trials, and by taking into account routine factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, previous or current treatments the subject has received, the subject's health status and response to the agent, and the judgment of the physician administering the treatment. For a 70 kg human, an exemplary range of suitable doses is about 1 to 1000 mg / day, in single or multiple dose units (e.g., BID, TID, QID, or as required by the modality).

[0067] Once the improvement of the target disease, disorder or condition occurs, the dosage can be adjusted for prevention or maintenance treatment.For example, dosage or administration frequency, or both, can be reduced according to the function of symptoms to the level that maintains the desired treatment or prevention effect.Of course, when the symptom is alleviated to an appropriate level, treatment can be stopped.However, if the symptom recurs, the target may need long-term intermittent treatment.

[0068] In addition, it is contemplated that the compounds of the present invention may be used alone, in combination with one or more other compounds of the present invention, or in combination with additional active ingredients in the treatment of the conditions described below. The additional active ingredients may be separately co-administered with at least one compound of the present invention, separately co-administered with an active agent of the present invention, or may be included in a pharmaceutical composition according to the present invention together with such an agent. In exemplary embodiments, the additional active ingredient is one known or discovered to be effective in treating a condition, disorder, or disease associated with MGL modulation, such as another MGL inhibitor or a compound active against another target associated with a particular condition, disorder, or disease. Such combinations may provide improved efficacy (e.g., by including a compound in the combination that enhances the efficacy or effectiveness of an agent according to the present invention), reduced one or more side effects, or reduced amounts of the active agent according to the present invention may be required.

[0069] When referring to inhibiting a target, "effective amount" means an amount sufficient to affect MGL regulation.

[0070] It is contemplated that pharmaceutical compositions of the invention may be formulated using the active agents of the invention, alone or in combination with one or more additional active ingredients, and include a therapeutically effective amount of at least one active agent according to the invention.

[0071] Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are substances, e.g., inert substances, added to pharmacological compositions or otherwise used as vehicles, carriers, or diluents, that facilitate administration of a drug and are compatible with the drug, non-toxic, biologically acceptable, and otherwise biologically suitable for administration to a subject. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0072] A pharmaceutical composition delivery form containing one or more dosage units of an active agent can be prepared using pharmaceutically acceptable excipients and compounding techniques known or available to those skilled in the art, and the composition may be administered in the methods of the invention by a suitable delivery route, for example, oral, parenteral, rectal, topical, or ocular routes, or by inhalation.

[0073] The preparations may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. The compositions may be formulated for any one of several routes of administration, such as intravenous infusion, topical administration, or oral administration. Preferably, the compositions may be formulated for oral administration.

[0074] For oral administration, the active agents of the present invention may be provided in tablet or capsule form, or as a solution, emulsion, or suspension. To prepare an oral composition, the active agent may be formulated to obtain a dosage for, for example, a 70 kg human; an exemplary range for a suitable dosage is about 1 to 1000 mg / day in single or multiple dosage units.

[0075] Oral tablets may contain the active ingredient(s) and may be mixed with compatible pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary oral liquid excipients include ethanol, glycerol, water, and the like. Exemplary disintegrants include starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid. Binders may include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0076] Capsules for oral administration include hard and soft gelatin or (hydroxypropyl)methylcellulose capsules. For hard gelatin capsules, the active ingredient(s) may be mixed with a solid, semisolid, or liquid diluent. Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid); wetting agents such as lecithin; and, optionally, flavorings or coloring agents.

[0077] The active agents of the present invention may also be administered parenterally. For example, compositions may be formulated as suppositories, enemas, or foams for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the present invention may be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose forms, such as ampoules or disposable injection devices; in multi-dose forms, such as vials from which the appropriate dose can be dispensed; or in solid or pre-concentrated forms that can be used to prepare injectable formulations. Exemplary infusion dosages are those in which the agent, mixed with a pharmaceutical carrier, is infused at a rate of about 1 to 1,000 μg / kg / min over a period ranging from several minutes to several days.

[0078] For topical administration, the drug may be mixed with a pharmaceutical carrier at a concentration of about 0.01% to about 20%, preferably 0.1% to 10%, of drug relative to vehicle. Another mode of administering the drugs of the present invention may utilize a patch formulation for transdermal delivery.

[0079] In the methods of the present invention, the active agent may alternatively be administered by inhalation, nasal or oral routes, such as in a spray formulation (also containing a suitable carrier).

[0080] In a further embodiment, the present invention relates to a method for treating a subject suffering from or diagnosed with a disease, disorder, or condition associated with MGL modulation, comprising administering to a subject in need of such treatment a therapeutically effective amount of an active agent.

[0081] The compounds of formula (I) are useful for the treatment, amelioration, and / or prevention of diseases, conditions, or disorders affected by the inhibition of MGL. Such methods comprise administering to a subject, including animals, mammals, and humans, in need of such treatment, amelioration, and / or prevention, a therapeutically effective amount of a compound of formula (I), or an enantiomer, diastereomer, solvate, or pharmaceutically acceptable salt thereof.

[0082] In particular, the compounds of formula (I), or their pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers, are useful for treating, ameliorating, and / or preventing pain, psychiatric disorders, neurological disorders, cancer, and ophthalmic conditions. More specifically, the compounds of formula (I), or their pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers, are useful for treating, ameliorating, and / or preventing inflammatory pain, major depressive disorder, treatment-resistant depression, anxiety-related depression, or bipolar disorder by administering a therapeutically effective amount of the compound of formula (I), or its pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers, to a subject in need thereof.

[0083] 1) Pain Examples of inflammatory pain include, but are not limited to, pain due to a disease, condition, syndrome, disorder, or painful state including inflammatory bowel disease, visceral pain, migraine, post-operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor pains, musculoskeletal disorders, skin disorders, toothache, fever, burns, sunburn, snake bites, venomous snake bites, spider bites, insect stings, irritable bladder, interstitial cystitis, urinary tract infections, rhinitis, contact dermatitis / hypersensitivity, pruritus, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, post-mastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.

[0084] Inflammatory hyperalgesia / hypersensitivity is a type of inflammatory pain. Examples of inflammatory hyperalgesia include diseases, conditions, disorders, or painful conditions such as inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal disorders, skin disorders, post-operative pain, headache, toothache, burns, sunburn, insect bites, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis / hypersensitivity and / or skin allergies, pruritus, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, benign prostatic hyperplasia cough, and nasal hypersensitivity.

[0085] In one embodiment, the present invention relates to a method for treating, ameliorating, and / or preventing inflammatory visceral hyperalgesia in which enhanced visceral irritability is present, the method comprising, consisting of, and / or consisting essentially of administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. In a further embodiment, the present invention relates to a method for treating inflammatory somatic hyperalgesia in which hypersensitivity to thermal, mechanical, and / or chemical stimuli is present, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0086] Further embodiments of the present invention are directed to methods for treating, ameliorating, and / or preventing neuropathic pain, including but not limited to, cancer, neuropathy, spinal and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndromes, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatica, temporomandibular joint neuralgia, peripheral neuritis, polyneuropathy, stump pain, phantom limb pain, fractures, oral neuropathic pain, Charcot pain, and complex regional pain syndrome I and II (CRPSI / II). The pain may be caused by a disease, condition, disorder, or painful state including radiculopathy, Guillain-Barré syndrome, dysesthesias, femoral neuralgia, burning mouth syndrome, optic neuritis, post-febrile neuritis, migratory neuritis, segmental neuritis, Gombort neuritis, neuronal injury, cervicobachial neuralgia, cranial neuralgia, genu neuralgia, glossopharyngeal neuralgia, cluster headache, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, post-herpetic neuralgia, burning mouth syndrome, erythroderma, splendid neuralgia, pterygopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian neuralgia.

[0087] One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of a neuropathy-related allodynic state in which hypersensitivity to cold stimuli is present. Examples of neuropathic cold allodynia include allodynia due to diseases, conditions, disorders, or pain states, including neuropathic pain (neuralgia), pain caused by spinal cord and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, post-herpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuropathy, complex regional pain syndrome I and II (CRPSI / II), and radiculopathy.

[0088] In a further embodiment, the present invention relates to a method for treating, ameliorating, and / or preventing neuropathic cold allodynia in which hypersensitivity to cold stimuli is present, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0089] 2) Mental disorders Examples of mental disorders include anxiety disorders such as social anxiety disorder, post-traumatic stress disorder, phobias, social phobia, specific phobias, panic disorder, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression, major depression, bipolar disorder, seasonal affective disorder, postpartum depression, manic depression, bipolar depression, mood disorders and mood-affective disorders that can be treated according to the present invention, including, but not limited to, bipolar disorder type I with depression, hypomania, mania, and mixed forms; bipolar disorder type II; depressive disorders such as single depressive episode or recurrent major depressive disorder, minor depressive disorder, treatment-resistant depression, anxious depression, bipolar disorder, depressive disorder with postpartum onset, depressive disorder with psychotic symptoms; persistent mood disorders such as cyclothymia, dysthymia, manic-depressive remission; premenstrual dysphoric disorder; psychosis; and developmental disorders such as autism spectrum disorders, and Asperger's syndrome.

[0090] 3) Neurological disorders Examples of neurological disorders include, but are not limited to, tremors, dyskinesia, dystonia, spasticity, Tourette's syndrome; neuromyelitis, Parkinson's disease, Alzheimer's disease, senile dementia; Huntington's disease; epilepsy / seizure disorders, and sleep disorders.

[0091] 4) Cancer Examples of cancer include, but are not limited to, benign skin tumors, prostate tumors, ovarian tumors, brain tumors (glioblastoma, medulloepithelioma, medulloblastoma, neuroblastoma, embryonal tumor, astrocytoma, astroblastoma, ependymoma, oligodendroglioma, neuroepithelioma, epiphyseal adenoma, ependymoblastoma, malignant meningioma, sarcoma, malignant melanoma, schwannoma).

[0092] 5) Eye condition Examples of ocular conditions include, but are not limited to, ocular hypertension, glaucoma, degeneration and apoptosis of retinal ganglion cells and neuroretinal cells.

[0093] Another embodiment of the present invention provides a method for modulating MGL receptor activity, including when such receptor is present in a subject, comprising exposing the MGL receptor to a therapeutically effective amount of at least one compound selected from the compounds of the present invention.

[0094] In some embodiments of Formula (I), X is CH. In some embodiments, X is O.

[0095] In some embodiments, R 2a and R 2b are each H. In some embodiments, R 2a and R 2b are each CH. In some embodiments, R 2a is H and R 2b is CH3.

[0096] In some embodiments, R 3 is phenyl; or Cl, F, C 1~6 Alkyl, C 1~6 Haloalkyl, C(CH3)2OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, SCH3, Si(CH3)3, SF5, N(CH3)2, C 3~6 Cycloalkyl, C substituted with CH 3~6 Cycloalkyl, OC 3~6 and phenyl substituted with 1, 2, or 3 members each independently selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl.

[0097] In some embodiments, R 3 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 Alkyl, OC 1~6haloalkyl, SCH3, SF5, or Si(CH3)3; and phenyl substituted with 1, 2, or 3 members each independently selected from SCH3, SF5, or Si(CH3)3.

[0098] In some embodiments, R 3 teeth,

[0099] [ka] is.

[0100] In some embodiments, R 3 is 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-(1-methylcyclopropyl)phenyl.

[0101] In some embodiments, R 3 is benzyl; tert-butyl; cyclohexyl; phenyl substituted with 1-methylcyclopropyl or 1-trifluoromethylcyclopropyl or fused to a cyclobutenyl or cyclohexenyl ring; pyridyl optionally substituted with trifluoromethyl, fluoro, or methyl; pyrimidinyl optionally substituted with tert-butyl; or oxazolyl optionally substituted with tert-butyl. In some embodiments, R 3 is an optionally substituted bicyclic heteroaryl as described herein. In some embodiments, R 3 is optionally substituted phenyl as described herein.

[0102] In some embodiments, R 4 is H, F, CH, or CHCH. In some embodiments, R 4 is H.

[0103] In some embodiments, R 5a and R 5b are each H. In some embodiments, R5a is CH3 and R 5b is H. In some embodiments, R 5a is H and R 5b is CH3.

[0104] In some embodiments of Formula (I),

[0105] [ka] is.

[0106] In some embodiments of Formula (I),

[0107] [ka] is.

[0108] In some embodiments of Formula (I),

[0109] [ka] is.

[0110] In some embodiments of Formula (I),

[0111] [ka] is.

[0112] In some embodiments of Formula (I),

[0113] [ka] is.

[0114] Further embodiments of the present invention are compounds as shown in Table 1 below.

[0115] [Table 1-1]

[0116] [Table 1-2]

[0117] [Table 1-3]

[0118] [Table 1-4]

[0119] [Table 1-5]

[0120] [Table 1-6] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0121] A further embodiment of the present invention comprises: (2s,4s)-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, and (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0122] A further embodiment of the present invention is a compound of formula (IA):

[0123] [ka] (In the formula, R 3 teeth, (a) Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 Haloalkyl, Si(CH3)3, C 3~6 Cycloalkyl, phenyl, O-phenyl, and CH3-substituted C 3~6 phenyl substituted with one or two members each independently selected from cycloalkyl; and (b)

[0124] [ka] is selected from R 5b is H or CH3, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0125] A further embodiment of the present invention is a compound of formula (IB):

[0126] [ka] (In the formula, R 2a and R 2b are each independently selected from H and CH3; R 3 teeth, (a) Phenyl; Cl, ​​F, C 1~6 Alkyl, C 1~6 Haloalkyl, C(CH3)2OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, SCH3, SF5, Si(CH3)3, N(CH3)2, cyclopropyl, cyclobutyl, O-cyclopropyl, phenyl, O-phenyl, O-pyridyl, and

[0127] [ka] phenyl substituted with 1, 2, or 3 members each independently selected from (b)

[0128] [ka] is selected from R 4 is selected from H, F, CH3, and CH2CH3; R 5a is H or CH3, R 5b is H or CH3, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0129] A further embodiment of the present invention is a compound of formula (IC):

[0130] [ka] (In the formula, X is CH or O; Ring A is

[0131] [ka] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0132] A further embodiment of the present invention is a compound of formula (ID):

[0133] [ka] (In the formula, X is CH or O; R 2a and R 2b are each independently selected from H and CH3; R b are Cl, F, C 1~6 Alkyl, C 1~6 Haloalkyl, C(CH3)2OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, SCH3, SF5, Si(CH3)3, N(CH3)2, cyclopropyl, cyclobutyl, O-cyclopropyl, phenyl, O-phenyl, O-pyridyl, and

[0134] [ka] is selected from n is 0, 1, 2, or 3; R 4 is selected from H, F, CH3, and CH2CH3; R 5a is H or CH3, R 5b is H or CH3, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0135] A further embodiment of the present invention comprises: (A) a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; (B) at least one pharmaceutically acceptable excipient.

[0136] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the compounds in Table 1, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutically acceptable prodrugs of the compounds of Table 1, and pharmaceutically active metabolites of the compounds of Table 1, and at least one pharmaceutically acceptable excipient.

[0137] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from a compound of formula (IA), a pharmaceutically acceptable salt, N-oxide, or solvate of a compound of formula (IA), a pharmaceutically acceptable prodrug of a compound of formula (IA), and a pharmaceutically active metabolite of formula (IA), and at least one pharmaceutically acceptable excipient.

[0138] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from a compound of formula (IB), a pharmaceutically acceptable salt, N-oxide, or solvate of a compound of formula (IB), a pharmaceutically acceptable prodrug of a compound of formula (IB), and a pharmaceutically active metabolite of formula (IB), and at least one pharmaceutically acceptable excipient.

[0139] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from a compound of formula (IC), a pharmaceutically acceptable salt, N-oxide, or solvate of a compound of formula (IC), a pharmaceutically acceptable prodrug of a compound of formula (IC), and a pharmaceutically active metabolite of formula (IC), and at least one pharmaceutically acceptable excipient.

[0140] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the compound of formula (ID), pharmaceutically acceptable salts, N-oxides and solvates of the compound of formula (ID), pharmaceutically acceptable prodrugs of the compound of formula (ID), and pharmaceutically active metabolites of formula (ID), and at least one pharmaceutically acceptable excipient.

[0141] Also within the scope of the present invention are enantiomers and diastereomers of the compounds of formula (I) (and formulas (IA), (IB), (IC), and (ID)). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of the compounds of formula (I) (and formulas (IA), (IB), (IC), and (ID)), including combinations thereof. Also within the scope of the present invention are pharmaceutically acceptable prodrugs of the compounds of formula (I) (and formulas (IA), (IB), (IC), and (ID)), and pharmaceutically active metabolites of the compounds of formula (I) (and formulas (IA), (IB), (IC), and (ID)).

[0142] Also within the scope of the present invention are isotopic variations of the compounds of Formula (I) (and Formulas (IA), (IB), (IC), and (ID)), e.g., deuterated compounds of Formula (I). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates (or combinations thereof) of isotopic variations of the compounds of Formula (I) (and Formulas (IA), (IB), (IC), and (ID)). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of isotopic variations of the compounds of Formula (I) (and Formulas (IA), (IB), (IC), and (ID)), and pharmaceutically active metabolites of isotopic variations of the compounds of Formula (I) (and Formulas (IA), (IB), (IC), and (ID)).

[0143] A further embodiment of the present invention is a method for treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound selected from the compounds of formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof. Also described herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, in the preparation of a medicament. In some embodiments, the medicament is for the treatment of a disease, disorder, or condition mediated by MGL receptor activity. Also described herein is a compound of formula (I), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, for use in a method for treating a disease, disorder, or condition mediated by MGL receptor activity.

[0144] A further embodiment of the present invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound selected from the compounds of formula (I) (and formulas (IA), (IB), (IC), and (ID)), the enantiomers and diastereomers of the compounds of formula (I) (and formulas (IA), (IB), (IC), and (ID)), isotopic variants of the compounds of formula (I) (and formulas (IA), (IB), (IC), and (ID)), and pharmaceutically acceptable salts of all of the above. Also described herein is the use of a compound of formula (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, in the preparation of a medicament. In some embodiments, the medicament is for the treatment of a disease, disorder, or condition mediated by MGL receptor activity. Also described herein are compounds of formula (IA), (IB), (IC), and (ID), or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof, for use in methods for treating a disease, disorder, or condition mediated by MGL receptor activity.

[0145] Exemplary compounds useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation, followed by specific examples. To obtain the various compounds herein, those skilled in the art will understand that starting materials can be suitably selected so that the ultimately desired substituents are retained throughout the reaction scheme, with or without appropriate protection, to yield the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is retained throughout the reaction scheme and can be appropriately substituted with the desired substituent. Unless otherwise specified, variables are as defined above with reference to Formula (I). The reaction can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0° C. and the reflux temperature of the solvent. The reaction can be carried out under heating using conventional or microwave heating. The reaction can also be carried out in a sealed pressure vessel at a temperature higher than the normal reflux temperature of the solvent.

[0146] Abbreviations and acronyms used herein are as follows:

[0147] [Table 2-1]

[0148] [Table 2-2]

[0149] Preparation example Exemplary compounds useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation and the following specific examples.

[0150] [ka]

[0151] According to Scheme 1, R a But C 1~4The compound of formula (V), which is alkyl, is treated with hydroxylamine in a suitable solvent such as ethanol (EtOH) using an additive such as sodium acetate (NaOAc) to give the compound of formula (VI).

[0152] Compounds of formula (VII) are prepared from compounds of formula (VI) using an oxidizing agent such as hydrogen peroxide, urea hydrogen peroxide, in the presence of a base, such as disodium hydrogen phosphate, in the presence of an activating agent such as trifluoroacetic anhydride (TFAA) in a solvent such as acetonitrile (ACN).

[0153] [ka]

[0154] According to Scheme 2, compounds of formula (VIIIa) and (VIIIb) are prepared by reacting a compound of formula (VII) with formaldehyde in the presence of a base such as triethylamine (TEA) in a solvent such as ACN. Compounds of formula (IX) are prepared by hydrogenolysis of a compound of formula (VIIIb) in the presence of a catalyst such as palladium on carbon (Pd / C) under an atmosphere of hydrogen gas (H).

[0155] Compounds of formula (X) are prepared by reaction of compounds of formula (IX) with triphosgene in the presence of a base such as TEA in a solvent such as tetrahydrofuran (THF). Compounds of formula (XI) (wherein X is O) are prepared by acidic deprotection of compounds of formula (X) using an acid such as trifluoroacetic acid (TFA), HCl in dioxane.

[0156] [ka]

[0157] According to Scheme 3, compounds of formula (XIa) and formula (XIb) are prepared by a Michael-type reaction between a compound of formula (VII) and methyl acrylate in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a solvent such as ACN. Compounds of formula (XIa) are reductively ring-closed using a reducing agent such as sodium borohydride (NaBH), an additive such as nickel(II) chloride hexahydrate in a suitable solvent such as methanol (MeOH) to give compounds of formula (XI) where X is CH.

[0158] [ka]

[0159] According to Scheme 4, compounds of formula (XII) can be prepared by reacting acetaldehyde with R a C 1~4 Using the conditions described above, compounds of formula (XII) can be hydrogenolyzed to give compounds of formula (XIIIa) and (XIIIb).

[0160] [ka]

[0161] According to Scheme 5, a compound of formula (XIIIa) (wherein R a is tert-butyl) is subjected to ring closure conditions with triphosgene using the conditions previously described to give a compound of formula (XIV). Compound of formula (XIV) is subjected to acidic deprotection conditions previously described to give a compound of formula (XV) (wherein R 2a is H and R 2b is CH3).

[0162] [ka]

[0163] According to Scheme 6, compounds of formula (XVI) are prepared in two steps from compounds of formula (XIIIa). In the first step, a compound of formula (XIIIa) (wherein R a Protection of the compound of formula (XVI) (where PG is BOC and R is tert-butyl) is achieved by reaction with di-tert-butyl dicarbonate in the presence of a base such as TEA in a suitable solvent such as dichloromethane (DCM). In a second step, oxidation to the ketone compound of formula (XVI) (where PG is BOC and R is tert-butyl) is achieved using conditions known to those skilled in the art, such as DMP (Dess-Martin periodinane), SO3-pyridine, Swern oxidation conditions [(COCl)2, DMSO, Et3N], PCC, etc., in solvents such as EtOAc, DMSO, DCM, at temperatures ranging from about -78 °C to room temperature (about 23 °C). a (wherein the aryl group is tert-butyl) to give a compound of formula (XVI). In a preferred method, oxidation to a compound of formula (XVI) is achieved using Dess-Martin periodinane in DCM at 20°C for 4 hours. Compound of formula (XVI) is reacted in the presence of an organomagnesium halide, such as methylmagnesium bromide, under conventional Grignard reaction conditions, e.g., in a suitable solvent such as EtO, THF, or a mixture thereof, at temperatures ranging from -40°C to room temperature, to give a compound of formula (XVII). Deprotection of the BOC protecting group is achieved according to methods known to those skilled in the art. For example, acidic conditions such as TFA / DCM or HCl / dioxane are used to provide a compound of formula (XVIII). (2s,4s)-8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid is prepared from compound of formula (XVIII) in two steps. In the first step, ring closure is achieved using triphosgene conditions as previously described, followed by deprotection of the tert-butyl ester using conditions previously described.

[0164] [ka]

[0165] According to Scheme 7, tert-butyl 4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate is prepared from commercially available or synthetically available tert-butyl 4-bromopiperidine-1-carboxylate using a suitable commercially available or synthetically available bromobenzene, such as 5-bromo-2-methylphenol; a catalyst, such as nickel(II) chloride ethylene glycol dimethyl ether complex (NiClDME); a ligand, such as 1,10-phenanthroline; and additives, such as sodium tetrafluoroborate (NaBF), manganese powder (Mn), and 4-ethylpyridine, in a solvent, such as MeOH, at a temperature of about 60 °C for 16-20 hours. tert-Butyl 4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate is prepared from tert-butyl 4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate using dibromodifluoromethane (CBrF) with a suitable base such as sodium hydride (NaH) or potassium tert-butoxide (KOtBu) in a suitable solvent such as N,N-dimethylacetamide (DMA). 4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine is prepared from tert-butyl 4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate) using silver tetrafluoroborate (AgBF) in a solvent such as DCM at temperatures ranging from −78° C. to room temperature for 16 hours.

[0166] [ka]

[0167] According to Scheme 8, tert-butyl 4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylate is prepared via a Sonogashira coupling reaction of commercially available or synthetically available tert-butyl 4-ethynylpiperidine-1-carboxylate and 2-amino-3-bromopyridine; with cuprous iodide; with a catalyst such as bis(triphenylphosphine)palladium(II) dichloride; and with a base such as TEA in a solvent such as N,N-dimethylformamide (DMF) at a temperature of about 100° C. for 15 hours. tert-Butyl 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate is prepared from tert-butyl 4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylate using a suitable base such as KOtBu in a suitable solvent such as N-methyl-2-pyrrolidone (NMP) at a temperature of about 70° C. for 16 hours.

[0168] [ka]

[0169] According to Scheme 9, cleavage of the BOC protecting group on tert-butyl 4-bromopiperidine-1-carboxylate is accomplished according to previously described methods to give 4-bromopiperidine. 2a and R 2b is H or CH3 and X is CH2 or O), are prepared by conventional amide bond forming techniques such as coupling reactions known to those skilled in the art (e.g., HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), or conversion of an acid to an acid chloride). For example, synthetically available, suitably substituted compounds of formula (XXII) (including compounds of formula (XI) and formula (XV)) (wherein R 2a and R 2bis H or CH3, and X is CH2 or O), the reaction of 4-bromopiperidine with the acid is carried out by activating the 4-bromopiperidine with a suitable activating agent, such as a carbodiimide (e.g., N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)), optionally with a catalyst such as hydroxybenzotriazole (HOBt) and / or 4-dimethylaminopyridine (DMAP); BOP or bromotripyrrolidinophosphonium hexafluorophosphate (PyB The coupling is carried out under activating conditions in the presence of a halotrisaminophosphonium salt such as roP®; a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or other suitable coupling agents such as N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), HATU, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®). The coupling reaction is carried out in a suitable solvent such as DCM, THF, DMF, and the like, optionally in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethylamine (DIPEA), or TEA, at a temperature ranging from 0° C. to room temperature to give (2s,4s)-2-(4-bromopiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one of formula (XIX), where R 2a and R 2b is H and X is O) is a compound of formula R 3 -Br(wherein, R 3 Ha, Hello, OC 1~6 Haloalkyl, and C 1~6 and (II) a bromobenzene compound of formula (I), wherein R is phenyl substituted with 1, 2, or 3 members independently selected from haloalkyl, to produce a bromobenzene compound of formula (I), wherein R is phenyl substituted with 1, 2, or 3 members independently selected from haloalkyl. 5a and R 5b is H).

[0170] [ka]

[0171] According to Scheme 10, tert-butyl 4-bromopiperidine-1-carboxylate can be prepared according to the formula R 3 -Br(wherein, R 3 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Cycloalkyl, OC 1~6 Haloalkyl, phenyl, Ophenyl, Opyridyl, Si(CH3)3, SF5, OC 1~4 Cycloalkyl, C(CH3)2OH, or OC 1~6 The compound of formula (XXI) can be obtained by subjecting a compound of formula (XXII) (including compounds of formula (XI) and formula (XV)) (wherein R is a phenyl or pyridyl substituted with 1, 2, or 3 members selected from the group consisting of alkyl, phenyl, phenyl, phenyl, pyridyl ... 2a and R 2b is H or CH3 and X is CH2 or O) using the amide bond coupling method described above to give a compound of formula (I), 4 , R 5a , and R 5b is H).

[0172] [ka]

[0173] According to Scheme 11, a compound of formula (XXIV) (wherein R 5a and R 5bare each independently H or CH3), can be reacted in a metal-mediated cross-coupling reaction with a suitably substituted aryl or heteroaryl boronic acid, boronate ester, or the like under Suzuki reaction conditions known to those skilled in the art using a palladium catalyst such as (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos-Pd-G3), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)), or tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), in the presence of K3PO4, K2CO 3、 Reaction of the compound of formula (XXV) with a base such as Na2CO3 or Cs2CO3 and potassium fluoride in a suitable solvent such as 1,4-dioxane, DMF, ethanol, water, or a mixture thereof at a temperature ranging from 60 to 150 °C using conventional or microwave heating methods provides a compound of formula (XXV). Treatment of the compound of formula (XXV) with benzyl bromide in a solvent such as ACN provides a compound of formula (XXVI). Treatment of the compound of formula (XXVI) with a reducing agent such as NaBH4 in a solvent such as MeOH provides a compound of formula (XXVII). Reaction of the compound of formula (XXVII) with H2 in the presence of a catalyst such as Pd / C in a suitable solvent such as MeOH provides a compound of formula (XXVIII). Reaction of the compound of formula (XXVIII) with a compound of formula (XXII) (including compounds of formula (XI) and formula (XV)) (wherein R 2a and R 2b is H or CH3 and X is CH2 or O) under the amide bond coupling conditions described above to give a compound of formula (I), 4 is H).

[0174] [ka]

[0175] According to Scheme 12, 4-bromo-3-methylpyridine is alkylated with benzyl bromide using the conditions previously described to give 1-benzyl-4-bromo-3-methylpyridin-1-ium bromide. 1-benzyl-4-bromo-3-methylpyridin-1-ium bromide is reduced using the conditions previously described to give 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine. 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine is reacted with a suitably substituted aryl or heteroaryl boronic acid of formula (XXIII) using the Suzuki coupling conditions previously described to give a compound of formula (XXVII). Compound (XXVII) is subjected to the hydrogenation conditions previously described to give a compound of formula (XXVIII). The compound of formula (XXVIII) is converted under the above-mentioned amide bonding conditions to a compound of formula (XXII) (including compounds of formula (XI) and formula (XV)) (wherein R 2a and R 2b is H or CH3 and X is CH2 or O) to give a compound of formula (I), 4 is H and R 5a is H and R 5b is CH3).

[0176] [ka]

[0177] According to Scheme 13, an appropriately substituted aryl bromide, such as 2-bromo-6-tert-butylpyridine, is treated with n-BuLi and 1-boc-4-piperidone in a suitable solvent, such as THF, at temperatures ranging from −78° C. to room temperature for 1 to 3 hours to afford tert-butyl 4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate. Reaction of tert-butyl 4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate with a halogenating agent, such as thionyl chloride (SOCl) and a catalyst, such as 4-(dimethylamino)pyridine (DMAP), in a suitable solvent, such as pyridine, affords tert-butyl 6-(tert-butyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate. tert-butyl 6-(tert-butyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate is reacted under the hydrogenation conditions described above to give a compound of formula (XX), where R 3 is C 1~6 Cleavage of the BOC protecting group on the compound of formula (XX) is accomplished according to methods known to those skilled in the art or as described above to give a compound of formula (XXI). The compound of formula (XXI) can be converted to a compound of formula (XXII) (including compounds of formula (XI) and formula (XV)) (wherein R 2a and R 2b is H or CH3 and X is CH2 or O) under the amide bond coupling conditions described above to give a compound of formula (I), 4 is H).

[0178] The compound of formula (I) may be converted into its corresponding salt using methods known to those skilled in the art. For example, the amine of formula (I) may be treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as EtO, CHCl, THF, MeOH, chloroform, or isopropanol to obtain the corresponding salt form. Alternatively, reverse-phase HPLC purification conditions may result in the trifluoroacetate salt or formate salt. The crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) may be obtained in crystalline form by recrystallization from a polar solvent (including a mixture of polar solvents and an aqueous mixture of polar solvents) or a nonpolar solvent (including a mixture of nonpolar solvents).

[0179] When the compounds according to the present invention have at least one chiral center, they may consequently exist as enantiomers. When the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0180] The compounds prepared according to the above schemes can be obtained in a single form, such as a single enantiomer, by form-specific synthesis or by resolution. Alternatively, the compounds prepared according to the above schemes can be obtained as a mixture of various forms, such as a racemic (1:1) mixture or a non-racemic (non-1:1) mixture. When racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers can be isolated using conventional isolation methods known to those skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts, biotransformation, or enzymatic conversion. When regioisomeric or diastereomeric mixtures are obtained, single isomers can be separated, as appropriate, using conventional methods, such as chromatography or crystallization.

[0181] The following specific examples are provided to further illustrate the invention and various preferred embodiments. [Example]

[0182] In obtaining the compounds described in the Examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0183] Unless otherwise noted, reaction mixtures were magnetically stirred under a nitrogen atmosphere at room temperature (rt). Solutions were generally dried over a drying agent such as NaSO or MgSO. Mixtures, solutions, and extracts were typically concentrated under reduced pressure on a rotary evaporator. Reactions under microwave irradiation conditions were performed in a Biotage Initiator or CEM (Microwave Reactor) Discover instrument.

[0184] For reactions conducted under continuous flow conditions, "flowing through an LTF-VS mixer" refers to the use of a Chemyx Fusion 100 touch syringe pump in series with an LTF-VS mixer (Little Things Factory GmbH (http: / / www.ltf-gmbh.com) via 1 / 16 inch PTFE tubing, unless otherwise specified.

[0185] Normal phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using pre-packed cartridges.

[0186] Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed by one of the following methods. Method A. Agilent HPLC using an Xterra Prep RP18 column (5 μM, 30 × 100 or 50 × 150 mm) or an XBridge C18 OBD column (5 μM, 30 × 100 or 50 × 150 mm) at a flow rate of 40 or 80 mL / min, with a mobile phase of 5% ACN in 20 mM NH4OH, held for 2 min, followed by a gradient of 5 to 99% ACN over 15 min, then held at 99% ACN for 5 min, or or Method B. Performed on a Shimadzu LC-8A series HPLC using an Inertsil ODS-3 column (3 μm, 30 × 100 mm, T = 45 °C) at a flow rate of 80 mL / min with a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) held for 1 min, followed by a gradient of 5–99% ACN over 6 min, followed by a 3 min hold at 99% ACN. or Method C. Shimadzu LC-8A series HPLC was used with an XBridge C18 OBD column (5 μm, 50 × 100 mm) at a flow rate of 80 mL / min. The mobile phase was 5% ACN in H2O (both containing 0.05% TFA) with a 1-minute hold, followed by a 5-99% ACN gradient over 14 minutes, followed by a 10-minute hold at 99% ACN. or Method D. Performed on a Gilson HPLC using an XBridge C18 column (5 μm, 100 × 50 mm) at a flow rate of 80 mL / min with a mobile phase change of 5 to 99% ACN in 20 mM NH4OH over 10 min, followed by a 2 min hold at 99% ACN. or Method E. An ACCQ Prep HPLC equipped with an XBridge C18OBD column (5 μM, 50 × 100) was run at a flow rate of 80 mL / min with a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) held for 1 min, followed by a gradient of 5–95% ACN over 12 min, followed by a 2 min hold at 95% ACN.

[0187] Preparative supercritical fluid high-performance liquid chromatography (SFC) was performed on either a Jasco preparative SFC system, a Berger Instruments APS 1010 system, or an SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Separations were performed at 100–150 bar with flow rates ranging from 40–60 mL / min. The column was heated to 35–40 °C.

[0188] Mass spectra (MS) were obtained on an Agilent Series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated mass values ​​(calcd.) correspond to exact masses.

[0189] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker DRX spectrometer. Multiplicity definitions are as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hept = heptet, dd = doublet of doublets, dt = triplet of triplets, pd = pentet of doublets, ddd = doublet of doublet of doublets, tp = triplet of pentets, td = triplet of doublets, qd = quartet of doublets, dq = doublet of quartets, tt = triplet of triplets, td = triplet of doublets, m = multiplet, br = broad. It will be understood that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectrum and the concentration of the compound in solution.

[0190] Compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0191] R * or S * Compounds designated as are enantiomerically pure compounds for which the absolute configuration has not been determined.

[0192] Intermediate 1: tert-butyl 3-nitrocyclobutanecarboxylate.

[0193] [ka]

[0194] Step A: tert-Butyl 3-hydroxyiminocyclobutanecarboxylate. To a solution of tert-butyl 3-oxocyclobutane-1-carboxylate (100 g, 588 mmol) in EtOH (1.8 L) was added NaOAc (192 g, 2340 mmol) and hydroxylamine hydrochloride (81 g, 1166 mmol). The reaction mixture was stirred at reflux for 4 hours and then filtered through a pad of Celite®, which was washed with EtOH. The combined filtrate was evaporated under reduced pressure, and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give the title compound (108 g, 99% yield) as a white solid. MS (ESI): CH 15 Calculated mass for NO3: 185.1; observed m / z: 186.2 [M+H] + .

[0195] Step B: tert-Butyl 3-nitrocyclobutanecarboxylate. To a suspension of urea hydrogen peroxide (164 g, 1.74 mol) in ACN (1 L) was added dropwise a solution of TFAA (245 mL, 1.75 mol) in ACN (500 mL) at −10° C. over 1 h. The reaction mixture was stirred at room temperature for 1 h. This was added dropwise to a solution of tert-butyl 3-hydroxyiminocyclobutanecarboxylate (108 g, 0.584 mol) and disodium hydrogen phosphate (911 g, 6.42 mol) in ACN (1 L) over 30 min at 80° C. The reaction mixture was stirred at 80° C. for 30 min and then filtered through a pad of Celite®, which was washed with ACN. The combined filtrate was diluted with EtOAc, and the mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography (FCC) on silica (0-20% EtOAc in heptane) to give the title compound (89.6 g, 76% yield) as a yellow oil as a 1.3:1 mixture of cis / trans isomers. + Does not ionize by LCMS.

[0196] Intermediate 2: Ethyl 3-nitrocyclobutanecarboxylate.

[0197] [ka]

[0198] The title compound was prepared in a similar manner to Intermediate 1, using ethyl 3-oxocyclobutane-1-carboxylate instead of tert-butyl 3-oxocyclobutane-1-carboxylate in Step A. The compound is shown in ESI + Does not ionize by LCMS. 1 H NMR (300MHz, CDCl3) δ 5.02~4.70 (m, 1H), 4.20 (q, J=7.2Hz, 2H), 3.04~2.71 (m, 5H), 1.29 (t, J=7.0Hz, 3H).

[0199] Intermediate 3: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0200] [ka]

[0201] Step A: tert-Butyl (1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate. To a solution of tert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 1, 89.6 g, 445 mmol) in MeCN (1 L) was added formaldehyde (37 wt% in water, 73 mL, 971 mmol). Triethylamine (TEA) (62 mL, 444 mmol) was added dropwise to the reaction mixture at 0 °C, and the reaction was stirred at room temperature for 2 h. The reaction mixture was evaporated, and the residue was purified by FCC on silica (0-25% EtOAc in heptane) to give the title compound (38.2 g, 165 mmol, 37% yield) as a white powder. MS (ESI): C 10 H 17 Calculated mass for NO5: 231.2; observed m / z: 254.1 [M+Na] +trans-tert-butyl 3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate was formed but not isolated.

[0202] Step B: tert-Butyl (1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate. To a solution of tert-butyl (1s,3s)-3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate (38 g, 165 mmol) in 600 mL of EtOAc was added 1.9 g of 10% palladium on carbon (Pd / C). The reaction mixture was stirred under 10 bar of hydrogen (H) at 50° C. for 1 hour. The mixture was filtered through a pad of Celite®. To the filtrate was added 1.9 g of 10% Pd / C. The reaction mixture was stirred under 10 bar of H at 50° C. for 2 hours. The reaction mixture was filtered through a pad of Celite®, and the Celite® was washed with EtOAc. The combined filtrates were evaporated and the residue was triturated with diethyl ether (EtO) to give the title compound (18.6 g, 92.4 mmol, 55% yield) as a white powder. MS (ESI): C 10 H 19 Calculated mass for NO3: 201.1; observed m / z: 202.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ 5.26~3.98 (m, 1H), 3.74~2.94 (m, 4H), 2.70~2.57 (m, 1H), 2.20~2.07 (m, 2H), 1.97~1.82 (m, 2H), 1.39 (s, 9H).

[0203] Step C: tert-Butyl (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solution of tert-butyl (1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate (18.6 g, 92.4 mmol) in tetrahydrofuran (THF) (300 mL) was added TEA (26 mL, 186 mmol). A solution of triphosgene (9.6 g, 32.4 mmol) in THF (200 mL) was added dropwise at −10° C. and stirred at room temperature for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate (600 mL), and the mixture was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was triturated with EtO to give the title compound (17.7 g, 77.9 mmol, 84% yield) as a white powder. MS (ESI): C 11 H 17 Calculated mass for NO4: 227.1; observed m / z: 228.2 [M+H] + .

[0204] Step D: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. To trifluoroacetic acid (TFA) (180 mL, 235 mmol) was added tert-butyl (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (17.7 g, 77.9 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated, and the residue was triturated with EtO to give the title compound (12.9 g, 75.4 mmol, 96% yield) as a white powder. MS (ESI): mass calculated for C7H9NO3 171.0; m / z found 172.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ 12.26 (br s, 1H), 8.08 (s, 1H), 4.34 (s, 2H), 2.79~2.66 (m, 1H), 2.43~2.29 (m, 4H).

[0205] Intermediate 4: (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid.

[0206] [ka]

[0207] Step A: Ethyl (1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate. To a solution of ethyl 3-nitrocyclobutanecarboxylate (Intermediate 2, 16.6 g, 95.6 mmol) in MeCN (145 mL) was added methyl acrylate (10.3 mL, 114 mmol). 1,8-Diazabicyclo[5.4.0]undec-7-ene (7.1 mL, 47.6 mmol) was added dropwise to the reaction mixture at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with saturated ammonium chloride and EtOAc, and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by FCC on silica (0-15% EtOAc in heptane) to give the title compound (13.6 g, 52.6 mmol, 55% yield) as a colorless liquid. MS (ESI): C 11 H 17 Calculated mass for NO6: 259.1; observed m / z: 282.1 [M+Na] + . 1 H NMR (300 MHz, chloroform-d) δ 4.17 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 3.12–2.79 (m, 3H), 2.69–2.49 (m, 2H), 2.48–2.21 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H).

[0208] Step B: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic acid. To a solution of ethyl (1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate (13.6 g, 52.5 mmol) in methanol (MeOH) (133 mL) was added nickel(II) chloride hexahydrate (12.5 g, 52.6 mmol). Sodium borohydride (NaBH) (10 g, 264 mmol) was added portionwise to the reaction mixture at -10 °C, and the reaction mixture was stirred at 0 °C for 1 hour. Aqueous potassium carbonate solution (47 mL, 141 mmol, 3 M) was added dropwise to the reaction mixture at 0 °C (pH 10), and the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was filtered through a pad of Celite®, and the pad was washed with EtOH. The combined filtrates were evaporated. The residue was purified by FCC on silica eluting with chloroform:methanol:acetic acid (100:0:0 to 9:1:1) to give the title compound (4.8 g, 28.2 mmol, 53% yield) as an off-white powder. MS (ESI): CH 11 Calculated mass for NO3: 169.1; observed m / z: 170.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ 7.97 (br s, 1H), 4.01~2.94 (m, 1H), 2.82~2.65 (m, 1H), 2.36~2.01 (m, 8H).

[0209] Intermediate 5: cis-tert-butyl 3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate.

[0210] [ka]

[0211] Step A: tert-Butyl 3-(1-hydroxyethyl)-3-nitrocyclobutanecarboxylate. To a solution of tert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 1, 11.7 g, 58.1 mmol) in ACN (120 mL) was added acetaldehyde (19.6 mL, 349 mmol). TEA (8.1 mL, 58 mmol) was added dropwise to the reaction mixture at 0° C., and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure, and the residue was purified by FCC on silica (0-20% EtOAc in heptane) to give the title compound (10.5 g) as a colorless oil as a mixture of cis and trans isomers. MS (ESI): C 11 H 19 Calculated mass for NO5: 245.1; observed m / z: 263.2 [M+H+NH3] + .

[0212] Step B: tert-Butyl (1s,3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate. To a solution of tert-butyl 3-(1-hydroxyethyl)-3-nitro-cyclobutanecarboxylate (10.5 g, 42.8 mmol) in 110 mL of EtOAc was added 1 g of 10% Pd / C. The reaction mixture was stirred at 50° C. under 10 bar of H2 for 1 h. The reaction mixture was filtered through a pad of Celite®. To the filtrate was added 500 mg of 10% Pd / C, and the reaction mixture was stirred at 50° C. under 10 bar of H2 for 2 h. The reaction mixture was filtered through a pad of Celite®, and the pad was washed with EtOAc. The combined filtrates were evaporated and the residue was purified by FCC on silica eluting with chloroform:methanol:ammonium hydroxide (1:0:0 to 9:1:0.05) to give the title compound (3.6 g, 16.7 mmol, 39% yield) as a yellow oil. MS (ESI): C 11 H 21 Calculated mass for NO3: 215.2; observed m / z: 216.3 [M+H] + . 1H NMR (300 MHz, chloroform-d) δ 3.83–3.64 (m, 1H), 2.80–2.61 (m, 1H), 2.54 (br s, 2H), 2.52–2.27 (m, 3H), 2.14–1.93 (m, 2H), 1.45 (s, 9H), 1.22–1.13 (m, 3H). Additional fractions from the same purification were collected to give tert-butyl (1r,3r)-3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate (550 mg) as a yellow oil.

[0213] Intermediate 6: (2s,4s)-8-Methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0214] [ka]

[0215] Step A: cis-tert-butyl 8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solution of tert-butyl (1s,3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate (Intermediate 5, 15.2 g, 70.4 mmol) in THF (240 mL) was added TEA (20 mL, 143 mmol). To the mixture was added a solution of triphosgene (7.3 g, 24.6 mmol) in THF (170 mL) dropwise at -10 °C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica (0-35% EtOAc in heptane) to give the title compound (9.0 g, 52% yield) as a white powder. MS (ESI): 12 H 19 Calculated mass for NO4: 241.1; observed m / z: 242.2 [M+H] + .

[0216] Step B: (2s,4s)-8-Methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. To TFA (60 mL, 784 mmol) was added cis-tert-butyl 8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (6.1 g, 25.3 mmol) in portions at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the residue was triturated with EtO to give the title compound as a white powder (4.3 g, 91% yield). MS (ESI): CH 11 Calculated mass for NO4: 185.1; observed m / z: 186.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6)δ 12.23(br s, 1H), 7.94(s, 1H), 4.50(q, J=6.4Hz, 1H), 2.68~2.59(m, 1H), 2.53~2.46(m, 1H), 2.41 ~2.35(m, 1H), 2.32~2.24(m, 1H), 2.17(dd, J=12.0, 10.1Hz, 1H), 1.30(d, J=6.5Hz, 3H).

[0217] Intermediate 7: (2s,4s)-8,8-Dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0218] [ka]

[0219] Step A: cis-tert-butyl 3-(tert-butoxycarbonylamino)-3-(1-hydroxyethyl)cyclobutanecarboxylate. To a solution of cis-tert-butyl 3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate (Intermediate 5, 3.1 g, 14.4 mmol) in DCM (60 mL) was added di-tert-butyl dicarbonate (3.5 g, 16 mmol) and TEA (4 mL, 28.7 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water and DCM were added to the reaction mixture. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified by FCC on silica (25% EtOAc in heptane) to give the title compound (3.0 g, 66% yield) as a white powder. MS (ESI): C 16 H 29 Calculated mass for NO5: 315.2; observed m / z: 338.2 [M+Na] + . 1 H NMR (500MHz, CDCl3)δ 4.89(s, 1H), 3.88(q, J=6.3Hz, 1H), 3.36~2.93(m, 1H), 2.91~2.74(m, 2H), 2.30~ 2.18(m, 2H), 2.18~2.09(m, 1H), 1.44(s, 9H), 1.42(s, 9H), 1.13(d, J=6.3Hz, 3H).

[0220] Step B: cis-tert-butyl 3-acetyl-3-(tert-butoxycarbonylamino)cyclobutanecarboxylate. To a solution of cis-tert-butyl 3-(tert-butoxycarbonylamino)-3-(1-hydroxyethyl)cyclobutanecarboxylate (3.0 g, 9.51 mmol) in DCM (60 mL) was added DMP (4.8 g, 11.4 mmol) at 10° C. The reaction mixture was stirred at room temperature for 3 hours. Saturated NaHCO and DCM were added to the reaction mixture. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica (0-25% EtOAc in heptane) to give the title compound (2.6 g, 8.17 mmol, 85% yield) as a white powder. MS (ESI): C 16 H27 Calculated mass for NO5: 313.19; observed m / z: 336.2 [M+Na] + . 1 H NMR (500MHz, CDCl3)δ 5.29(s, 1H), 2.93~2.81(m, 1H), 2.80~2.69(m, 2H), 2.16(s, 3H), 2.25~2.09(m, 2H), 1.43(s, 9H), 1.42~1.36(m, 9H).

[0221] Step C: cis-tert-butyl 3-(tert-butoxycarbonylamino)-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate. To a solution of cis-tert-butyl 3-acetyl-3-(tert-butoxycarbonylamino)cyclobutanecarboxylate (2.5 g, 7.98 mmol) in THF (50 mL) was added dropwise methylmagnesium bromide (8 mL, 24 mmol, 3 M in EtO) at −40° C. The reaction mixture was stirred at −40° C. for 1 hour. The reaction mixture was diluted with ammonium chloride and extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica (0-20% EtOAc in heptane) to give the title compound (650 mg, 24% yield) as a white powder. MS (ESI): C 17 H 31 Calculated mass for NO5: 329.2; observed m / z: 174.2 [M+H-tBu-Boc] + . 1 H NMR(500MHz, CDCl3)δ 4.91(br s, 1H), 4.11~2.93(m, 1H), 2.88~2.78(m, 1H), 2.64~2.55(m, 2H), 2.30~2.18(m, 2H), 1.44(s, 9H), 1.42(s, 9H), 1.21(s, 6H).

[0222] Step D: cis-tert-butyl 3-amino-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate. To a solution of cis-tert-butyl 3-(tert-butoxycarbonylamino)-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate (650 mg, 1.97 mmol) in DCM (13 mL) was added TFA (1.2 mL, 15.7 mmol), and the reaction mixture was stirred at room temperature for 1 hour. Saturated sodium carbonate and DCM were added to the reaction mixture. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound (430 mg, 95% yield) as a yellow oil. MS (ESI): C 12 H 23 Calculated mass for NO3: 229.2; observed m / z: 230.4 [M+H] + .

[0223] Step E: cis-tert-Butyl 8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solution of cis-tert-butyl 3-amino-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate (630 mg, 2.75 mmol) in THF (10 mL) was added TEA (770 μL, 5.52 mmol). A solution of triphosgene (285 mg, 0.96 mmol) in THF (7.5 mL) was added dropwise to the mixture at −10° C., and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica (0–35% EtOAc in heptane) to give the title compound (520 mg, 74% yield) as a white powder. MS(ESI):C 13 H 21 Calculated mass for NO4: 255.2; observed m / z: 256.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ 6.06 (br s, 1H), 2.73~2.63 (m, 3H), 2.28~2.17 (m, 2H), 1.45 (s, 9H), 1.39 (s, 6H).

[0224] Step F: (2s,4s)-8,8-Dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. To TFA (5.2 mL, 67.9 mmol) was added cis-tert-butyl 8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (520 mg, 2.04 mmol) in portions at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, and the residue was triturated with EtO to give the title compound as a white powder (330 mg, 81% yield). MS (ESI): CH 13 Calculated mass for NO4: 199.1; observed m / z: 200.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ 12.25(s, 1H), 7.84(s, 1H), 2.76~2.41(m, 3H), 2.33~2.17(m, 2H), 1.38(s, 6H).

[0225] Intermediate 8: 4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine.

[0226] [ka]

[0227] Step A: tert-Butyl 4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate. In an oven-dried pressure-resistant vial, N-boc-4-bromopiperidine (200 mg, 0.742 mmol) was combined with 5-bromo-2-methylphenol (146 mg, 0.742 mmol), NiCl(DME) (33 mg, 0.148 mmol), 1,10-phenanthroline (55 mg, 0.297 mmol), NaBF (42 mg, 0.371 mmol), and Mn (81 mg, 1.48 mmol). This was added to anhydrous MeOH (3.7 mL) and 4-ethylpyridine (43 μL, 0.371 mmol) was added. The vial was capped, purged with nitrogen (N), and heated at 60 °C for 18 h. The mixture was diluted with EtOAc, filtered through Celite®, and concentrated under reduced pressure. FCC of silica (0-30% EtOAc in hexanes) gave the title compound (116 mg, 54% yield). MS (ESI): C 17 H 25 Calculated mass for NO3: 291.2; observed m / z: 236.1 [M+2H-tBu] + .

[0228] Step B: tert-Butyl 4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate. In an oven-dried flask under N, tert-butyl 4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate (108 mg, 0.371 mmol) was dissolved in DMA (0.75 mL) and cooled to 0 °C. To this was added NaH (71 mg, 1.85 mmol), and the mixture was warmed to room temperature and stirred for 1.5 h. After cooling to 0 °C, a solution of CBrF (0.29 mL, 2.96 mmol) in DMA (0.75 mL) was added dropwise, and this was stirred at room temperature for 3 h. The mixture was cooled again to 0 °C and KOtBu (127 mg, 1.11 mmol) was added, followed by heating to 80 °C for 24 h. The reaction was cooled, water was added, extracted with EtOAc, dried over sodium sulfate (NaSO), and concentrated under reduced pressure. The resulting residue was purified by FCC on silica (0-50% EtOAc in hexanes) to give the title compound (36 mg, 23% yield).

[0229] Step C: 4-(4-Methyl-3-(trifluoromethoxy)phenyl)piperidine. To a solution of tert-butyl 4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate (50 mg, 0.119 mmol) in DCM (1.2 mL) at −78° C. was added AgBF (52 mg, 0.262 mmol). The reaction was allowed to warm to room temperature and stirred for 16 hours. The resulting mixture was filtered through a PTFE filter with MeOH and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS (ESI): C 13 H 16 Calculated mass for FNO: 259.1; observed m / z: 260.1 [M+H] + .

[0230] Intermediate 9: tert-butyl 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate.

[0231] [ka]

[0232] Step A: tert-Butyl 4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylate. A solution of 2-amino-3-bromopyridine (200 mg, 1.156 mmol), bis(triphenylphosphine)palladium(II) dichloride (42 mg, 0.060 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (240 mg, 1.147 mmol), cuprous iodide (22 mg, 0.116 mmol), and TEA (1 mL, 7.194 mmol) in DMF (2 mL, previously sparged with N) was heated to 100 °C under N in a sealed pressure-resistant vial. After 15 h, the reaction was cooled to room temperature, and the mixture was filtered through Celite® using EtOAc as the eluent. The filtrate was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification on silica via FCC (0-100% EtOAc in hexanes) afforded the title compound as a brown oil (209 mg, 60% yield). MS (ESI): C 17 H 23 Calculated mass for N3O2: 301.2; observed m / z: 302.2 [M+H] + .

[0233] Step B: tert-Butyl 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate. To a solution of tert-butyl 4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylate (183 mg, 0.607 mmol) in NMP (1.8 mL) was added dropwise via syringe KOtBu (1.8 mL, 1 M in THF) at room temperature under N. The resulting solution was heated to 70 °C for 16 h. It was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (NaSO), filtered, and concentrated under reduced pressure. Purification via FCC on silica (0-100% EtOAc in hexanes) afforded the title compound as an off-white solid (93 mg, 51% yield). MS (ESI): C 17 H 23 Calculated mass for N3O2: 301.2; observed m / z: 302.2 [M+H] + .

[0234] Intermediate 10: (racemic)-(cis)-3-methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine.

[0235] [ka]

[0236] The title compound was prepared analogously to cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28) using 4-methyl-3-(trifluoromethyl)phenylboronic acid instead of 3-(trifluoromethoxy)phenylboronic acid.

[0237] Intermediate 11: (2s,4s)-2-(4-Bromopiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0238] [ka]

[0239] To N-boc-4-bromopiperidine (210 mg, 0.795 mmol) in MeOH (1 mL) was added hydrochloric acid (HCl) in 1,4-dioxane (4 M, 1.5 mL), which was heated to 45° C. for 1 h and then concentrated under reduced pressure. The residue was redissolved in DMF (2 mL) and to this was added (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 179 mg, 1.05 mmol), DIPEA (0.32 mL, 1.85 mmol), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (410 mg, 1.05 mmol). This was stirred at room temperature for 2 hours. The reaction mixture was filtered through a PTFE filter with MeOH and purified via reverse-phase HPLC (5-95% ACN in 20 mM NH4OH in water) to give the title compound (117 mg, 46% yield). MS (ESI): C 12 H 17 Calculated mass for BrN2O3: 316.0; observed m / z: 317.0 [M+H] + .

[0240] Intermediate 12: 1-Benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine.

[0241] [ka]

[0242] Step A: 1-benzyl-4-bromo-3-methylpyridin-1-ium bromide. 4-Bromo-3-methylpyridine (500 mg, 2.9 mmol) and benzyl bromide (0.41 mL, 3.5 mmol) were dissolved in ACN (5 mL) and stirred overnight at 70° C. The reaction mixture was washed with hexane, concentrated under reduced pressure, and used directly in the next step without purification. MS (ESI): C 13 H 13 Calculated mass for BrN: 262.0; observed m / z: 262.0 [M] + .

[0243] Step B: 1-Benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine. 1-Benzyl-4-bromo-3-methylpyridin-1-ium bromide from Step A was dissolved in MeOH (10 mL) and the reaction mixture was cooled to 0 °C. NaBH (330 mg, 8.7 mmol) was added slowly with stirring. The reaction mixture was stirred at 0 °C for 30 min, concentrated under reduced pressure, and partitioned between DCM and water. The organic layer was concentrated under reduced pressure and purified by FCC on silica (0-50% EtOAc in hexanes) to give the title compound (381 mg, 49% yield). MS (ESI): C 13 H 16 Calculated mass for BrN: 265.0; observed m / z: 266.0 [M+H] + .

[0244] Intermediate 13: 4-(3-(tert-butyl)phenyl)-3-methylpyridine.

[0245] [ka]

[0246] 4-Bromo-3-methylpyridine (1.0 g, 5.8 mmol), 4-(tert-butyl)phenylboronic acid (1.2 g, 7.0 mmol), cesium carbonate (5.7 g, 17 mmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhos Pd G3) (243 mg, 0.29 mmol) were added to 1,4-dioxane (40 mL), and the reaction mixture was stirred overnight at 100° C. under N. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were concentrated under reduced pressure and purified by FCC on silica (0-100% EtOAc in hexanes) to give the title compound (805 mg, 61% yield). MS (ESI): C 16 H 19 Calculated mass for N: 225.2; observed m / z: 226.2 [M+H]+ .

[0247] Intermediate 14: 4-(4-(tert-butyl)phenyl)-2-methylpyridine.

[0248] [ka]

[0249] The title compound was prepared analogously to 4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13), using 4-(tert-butyl)phenylboronic acid instead of 3-(tert-butyl)phenylboronic acid and 4-bromo-2-methylpyridine instead of 4-bromo-3-methylpyridine. MS (ESI): C 16 H 19 Calculated mass for N: 225.2; observed m / z: 226.2 [M+H] + .

[0250] Intermediate 15: 4-(4-(trifluoromethyl)phenyl)-2-methylpyridine.

[0251] [ka]

[0252] The title compound was prepared analogously to 4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13), using 4-(trifluoromethyl)phenylboronic acid instead of 3-(tert-butyl)phenylboronic acid and 4-bromo-2-methylpyridine instead of 4-bromo-3-methylpyridine. MS (ESI): C 13 H 10 Calculated mass for F3N: 237.1; observed m / z: 238.1 [M+H] + .

[0253] Intermediate 16: 4-(3-(tert-butyl)phenyl)-2-methylpyridine.

[0254] [ka]

[0255] The title compound was prepared analogously to 4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13), using 4-bromo-2-methylpyridine instead of 4-bromo-3-methylpyridine. MS (ESI): C 16 H 19 Calculated mass for N: 225.2; observed m / z: 226.2 [M+H] + .

[0256] Intermediate 17: 4-([1,1'-biphenyl]-3-yl)-3-methylpyridine.

[0257] [ka]

[0258] The title compound was prepared analogously to 4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13) using biphenyl-3-boronic acid instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 18 H 15 Calculated mass for N: 245.1; observed m / z: 246.0 [M+H] + .

[0259] Intermediate 18: 1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine.

[0260] [ka]

[0261] The title compound was prepared analogously to 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12), using 4-(3-(tert-butyl)phenyl)-3-methylpyridine (Intermediate 13) instead of 4-bromo-3-methylpyridine. MS (ESI): C 23 H 29 Calculated mass for N: 319.2; observed m / z: 320.3 [M+H] + .

[0262] Intermediate 19: 1-benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine.

[0263] [ka]

[0264] The title compound was prepared analogously to 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12) using 4-(4-(tert-butyl)phenyl)-2-methylpyridine (Intermediate 14) instead of 4-bromo-3-methylpyridine. MS (ESI): C 23 H 29 Calculated mass for N: 319.2; observed m / z: 320.3 [M+H] + The alkene isomer was not determined unambiguously.

[0265] Intermediate 20: 1-benzyl-6-methyl-4-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine.

[0266] [ka]

[0267] The title compound was prepared analogously to 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12) using 4-(4-(trifluoromethyl)phenyl)-2-methylpyridine (Intermediate 15) instead of 4-bromo-3-methylpyridine. MS (ESI): C 20 H 20 Calculated mass for F3N: 331.2; observed m / z: 332.1 [M+H] + The alkene isomer was not determined unambiguously.

[0268] Intermediate 21: 1-benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine.

[0269] [ka]

[0270] The title compound was prepared analogously to 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12) using 4-(3-(tert-butyl)phenyl)-2-methylpyridine (Intermediate 16) instead of 4-bromo-3-methylpyridine. MS (ESI): C 23 H 29 Calculated mass for N: 319.2; observed m / z: 320.1 [M+H] + The alkene isomer was not determined unambiguously.

[0271] Intermediate 22: 4-([1,1'-biphenyl]-3-yl)-1-benzyl-5-methyl-1,2,3,6-tetrahydropyridine.

[0272] [ka]

[0273] The title compound was prepared analogously to 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12), using 4-([1,1'-biphenyl]-3-yl)-3-methylpyridine (Intermediate 17) instead of 4-bromo-3-methylpyridine. MS (ESI): C 25 H 25 Calculated mass for N: 339.2; observed m / z: 340.3 [M+H] + .

[0274] Intermediate 23: (racemic)-(cis)-3-methyl-4-(4-(tert-butyl)phenyl)piperidine.

[0275] [ka]

[0276] 1-Benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 18, 270 mg, 0.845 mmol) and 10% Pd / C (500 mg) were added in 20 mL of EtOAc. The reaction vessel was degassed and filled with H. The reaction mixture was stirred at room temperature for 3 h, filtered through Celite®, concentrated under reduced pressure, and used directly in the subsequent transformation without further purification (183 mg, 0.791 mmol, 94% yield). MS (ESI): C 16 H 25 Calculated mass for N: 231.2; observed m / z: 232.2 [M+H] + .

[0277] Intermediate 24: (racemic)-(cis)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine.

[0278] [ka]

[0279] The title compound was prepared analogously to racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) using 4-([1,1'-biphenyl]-3-yl)-1-benzyl-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 19) instead of 1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 18). MS (ESI): C 18 H 21 Calculated mass for N: 215.2; observed m / z: 252.1 [M+H] + .

[0280] Intermediate 25: 4-(4-(tert-butyl)phenyl)-2-methylpiperidine.

[0281] [ka]

[0282] The title compound (mixture of four diastereomers) was prepared analogously to racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) using 1-benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine (Intermediate 19) instead of 1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 18). MS (ESI): C 18 H 21 Calculated mass for N: 215.2; observed m / z: 252.1 [M+H] + .

[0283] Intermediate 26: 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine.

[0284] [ka]

[0285] The title compound (mixture of four diastereomers) was prepared analogously to racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) using 1-benzyl-6-methyl-4-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine (Intermediate 20) instead of 1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 18). MS (ESI): C 13 H 16 Calculated mass for F3N: 243.1; observed m / z: 244.1 [M+H] + .

[0286] Intermediate 27: 4-(3-(tert-butyl)phenyl)-2-methylpiperidine.

[0287] [ka]

[0288] The title compound (mixture of four diastereomers) was prepared analogously to racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) using 1-benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine (Intermediate 21) instead of 1-benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 18). MS (ESI): C 18 H 21 Calculated mass for N: 215.2; observed m / z: 252.1 [M+H] + .

[0289] Intermediate 28: (racemic)-(cis)-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine.

[0290] [ka]

[0291] Step A: 1-benzyl-5-methyl-4-(3-(trifluoromethoxy)phenyl)-1,2,3,6-tetrahydropyridine. 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine (Intermediate 12, 100 mg, 0.38 mmol), 3-(trifluoromethoxy)phenylboronic acid (95 mg, 0.45 mmol), cesium carbonate (367 mg, 1.13 mmol), and RuPhos Pd G3 (16 mg, 0.019 mmol) was added in dioxane, and the reaction mixture was stirred overnight at 100° C. under N. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was partitioned between DCM and water. The aqueous layer was extracted with DCM, and the combined organic layers were concentrated under reduced pressure and purified by FCC on silica (0-100% EtOAc in hexanes) to give the title compound (70 mg, 0.20 mmol, 54% yield). MS (ESI): C 20 H 20 Calculated mass for FNO: 347.2; observed m / z: 348.1 [M+H] + .

[0292] Step B: (racemic)-(cis)-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine. 1-Benzyl-5-methyl-4-(3-(trifluoromethoxy)phenyl)-1,2,3,6-tetrahydropyridine (70 mg, 0.20 mmol) and 10% Pd / C (50 mg) were added in EtOAc. The reaction vessel was degassed and filled with H2, and the reaction mixture was stirred at room temperature overnight. The mixture was filtered through Celite® and concentrated under reduced pressure to give the title compound (56 mg, 0.22 mmol, 107% yield). MS (ESI): C 13 H 16 Calculated mass for FNO: 259.1; observed m / z: 260.1 [M+H] + .

[0293] Intermediate 29: (racemic)-(cis)-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidine.

[0294] [ka]

[0295] The title compound was prepared analogously to cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28) using 3-(trifluoromethyl)phenylboronic acid instead of 3-(trifluoromethoxy)phenylboronic acid. MS (ESI): C 13 H 16 Calculated mass for F3N: 243.1; observed m / z: 244.1 [M+H] + .

[0296] Intermediate 30: (racemic)-(cis)-3-methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine.

[0297] [ka]

[0298] The title compound was prepared analogously to cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28) using 3-methyl-4-(trifluoromethoxy)phenylboronic acid instead of 3-(trifluoromethoxy)phenylboronic acid. MS(ESI): C 14 H 18 Calculated mass for FNO: 273.1; observed m / z: 274.2 [M+H] + .

[0299] Intermediate 31: (racemic)-(cis)-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidine.

[0300] [ka]

[0301] The title compound was prepared analogously to cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28), using 4-(trifluoromethoxy)phenylboronic acid instead of 3-(trifluoromethoxy)phenylboronic acid and stirring for 48 hours instead of overnight. MS (ESI): C 13 H 16 Calculated mass for FNO: 259.1; observed m / z: 260.0 [M+H] + .

[0302] Intermediate 32: (racemic)-(cis)-3-methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine.

[0303] [ka]

[0304] The title compound was prepared analogously to cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28), using 3-fluoro-4-(trifluoromethoxy)phenylboronic acid instead of 3-(trifluoromethoxy)phenylboronic acid and stirring for 48 hours instead of overnight. MS (ESI): C 13 H 15 Calculated mass for FNO: 277.1; observed m / z: 278.2 [M+H] + .

[0305] Intermediate 33: (racemic)-(cis)-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine.

[0306] [ka]

[0307] The title compound was prepared analogously to cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28), using 4-(trifluoromethyl)phenylboronic acid instead of 3-(trifluoromethoxy)phenylboronic acid in Step B and stirring the reaction mixture for 5 days. MS (ESI): C 13 H 16 Calculated mass for F3N: 243.1; observed m / z: 244.1 [M+H] + .

[0308] Intermediate 34: (racemic)-(cis)-3-methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine.

[0309] [ka]

[0310] The title compound was prepared analogously to cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28), using 3-methyl-4-(trifluoromethyl)phenylboronic acid instead of 3-(trifluoromethoxy)phenylboronic acid in Step B and stirring the reaction mixture for 5 days.

[0311] Example 1: (2s,4s)-2-(4-(3-(2,2,2-trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0312] [ka]

[0313] In an oven-dried pressure-resistant vial, (2s,4s)-2-(4-bromopiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Intermediate 11, 31.5 mg, 0.099 mmol) was combined with 1-bromo-3-(2,2,2-trifluoroethyl)benzene (25 mg, 0.099 mmol), NiCl(DME) (4.5 mg, 0.020 mmol), 1,10-phenanthroline (7.3 mg, 0.040 mmol), NaBF (5.6 mg, 0.050 mmol), and Mn (11 mg, 0.200 mmol). This mixture was added to anhydrous MeOH (0.5 mL) and 4-ethylpyridine (5.7 μL, 0.050 mmol). The vial was capped, purged with N2, and heated at 60 °C for 18 h. The reaction was diluted with EtOAc, filtered through Celite®, and concentrated under reduced pressure. Purification via reverse-phase HPLC (5-95% ACN in 20 mM NH4OH in water) afforded the title compound (23 mg, 58% yield). MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.30(t, J=7.6Hz, 1H), 7.16(dd, J=7.6, 1.7Hz, 2H), 7.10(s, 1H), 6.22(s, 1H), 4.81~4.71(m, 1H), 4.38(s, 2H), 3.89~3.78(m, 1H), 3.34(q, J=1 0.9Hz, 2H), 3.12(td, J=13.1, 2.5Hz, 1H), 3.03(p, J=8.1Hz, 1H), 2.81~2.62(m, 4H), 2.56~2.41(m, 2H), 1.96~1.87(m, 2H), 1.70~1.51(m, 2H).

[0314] Example 2: (2s,4s)-2-(4-(3-fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0315] [ka]

[0316] The title compound was prepared analogously to Example 1, using 1-bromo-3-fluoro-5-(trifluoromethoxy)benzene instead of 1-bromo-3-(2,2,2-trifluoroethyl)benzene. MS (ESI): C 19 H 20 Calculated mass for F4N2O4, 416.1; observed m / z, 417.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 6.88~6.79(m, 3H), 6.03(s, 1H), 4.82~4.74(m, 1H), 4.38(s, 2H), 3.89~3.79(m, 1H), 3.17~3.07(m, 1H) ), 3.03(p, J=8.1Hz, 1H), 2.83~2.61(m, 4H), 2.55~2.42(m, 2H), 1.98~1.88(m, 2H), 1.63~1.45(m, 2H).

[0317] Example 3: (2s,4s)-2-(4-(2-fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0318] [ka]

[0319] The title compound was prepared analogously to Example 1, using 2-bromo-1-fluoro-4-(trifluoromethoxy)benzene instead of 1-bromo-3-(2,2,2-trifluoroethyl)benzene. MS (ESI): C 19 H 20 Calculated mass for F4N2O4, 416.1; observed m / z, 417.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.11~7.03(m, 2H), 7.04~6.99(m, 1H), 5.78(s, 1H), 4.85~4.73(m, 1H), 4.39(s, 2H), 3.85(d, J=13.3Hz, 1H), 3 .20~2.99(m, 3H), 2.77~2.62(m, 3H), 2.51(dd, J=12.7, 8.7Hz, 2H), 1.93(d, J=13.3Hz, 2H), 1.70~1.47(m, 2H).

[0320] Example 4: (2s,4s)-2-(4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0321] [ka]

[0322] Step A: tert-Butyl 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate. In an oven-dried pressure-resistant vial, N-boc-4-bromopiperidine (30 mg, 0.111 mmol) was combined with 1-bromo-2-methyl-4-(trifluoromethyl)benzene (27 mg, 0.111 mmol), NiCl(DME) (2.5 mg, 0.011 mmol), 1,10-phenanthroline (4 mg, 0.022 mmol), NaBF (6 mg, 0.056 mmol), and Mn (12 mg, 0.223 mmol). This was added to anhydrous MeOH (0.6 mL) and 4-ethylpyridine (6.4 μL, 0.056 mmol). The vial was capped, purged with N, and heated at 60 °C for 18 h. The mixture was diluted with EtOAc, filtered through Celite®, and concentrated under reduced pressure. Purification via FCC on silica (0-15% EtOAc in hexanes) afforded the title compound (31 mg, 81% yield). MS (ESI): C 18 H 24 Calculated mass for F3NO2: 343.2; observed m / z: 288.0 [M+2H-tBu] + .

[0323] Step B: 4-(2-Methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. To tert-butyl 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (31 mg, 0.090 mmol) in MeOH (0.2 mL) was added HCl in 1,4-dioxane (4 M, 0.23 mL). This was heated to 45° C. for 1 h and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 13 H 17 Calculated mass for ClF3N: 279.1; observed m / z: 244.1 [M-Cl] + .

[0324] Step C: (2s,4s)-2-(4-(2-Methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. 4-(2-Methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride was added to DMF (0.6 mL), and to this was added (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 15 mg, 0.089 mmol), DIPEA (47 μL, 0.268 mmol), and HATU (38 mg, 0.098 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered through a PTFE filter with MeOH and purified via reverse-phase HPLC (5-95% ACN in 20 mM NH4OH in water) to give the title compound (30 mg, 85% yield). MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.45~7.38(m, 2H), 7.22(d, J=7.9Hz, 1H), 6.22(s, 1H), 4.91~4.68(m, 1H), 4.39(s, 2H), 3.96~3.78(m, 1H), 3 .25~2.93(m, 3H), 2.82~2.59(m, 3H), 2.56~2.43(m, 2H), 2.41(s, 3H), 1.90~1.79(m, 2H), 1.68~1.48(m, 2H).

[0325] Example 5: (2s,4s)-2-(4-(4-(difluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0326] [ka]

[0327] The title compound was prepared analogously to Example 4, using 1-bromo-4-(difluoromethyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 22 Calculated mass for F2N2O3, 364.2; observed m / z, 365.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.49~7.42(m, 2H), 7.31~7.26(m, 2H), 6.78~6.46(m, 1H), 6.15(s, 1H), 4.82~4.73(m, 1H), 4.38(s, 2H), 3.89~3.78(m, 1H), 3.19~ 3.08(m, 1H), 3.08~2.97(m, 1H), 2.87~2.75(m, 1H), 2.75~2.62(m, 3H), 2.56~2.42(m, 2H), 1.98~1.87(m, 2H), 1.69~1.47(m, 2H).

[0328] Example 6: (2s,4s)-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0329] [ka]

[0330] The title compound was prepared in a similar manner to Example 4, using 1-bromo-3-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS ( ESI):C 19 H 21 Calculated mass for F3N2O4, 398.1; observed m / z, 399.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.33(t, J=7.9Hz, 1H), 7.14~7.04(m, 2H), 7.02(p, J=1.5Hz, 1H), 6.28(s, 1H), 4.81~4.73(m, 1H), 4.38(s, 2H), 3.88~3.80(m, 1H), 3.12(td, J=13.1, 2.5Hz, 1H), 3.02(p, J=8.1Hz, 1H), 2.83~2.60(m, 4H), 2.53~2.42(m, 2H), 1.98~1.88(m, 2H), 1.66~1.47(m, 2H).

[0331] Example 7: (2s,4s)-2-(4-(2-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0332] [ka]

[0333] The title compound was prepared analogously to Example 4, using 1-bromo-2-methyl-4-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.1 [M+H]+ . 1 H NMR (400MHz, CDCl3)δ 7.14~7.08(m, 1H), 7.05~6.97(m, 2H), 6.13(s, 1H), 4.83~4.73(m, 1H), 4.39(s, 2H), 3.91~3.79(m, 1H), 3.19~3.09(m, 1H), 3. 09~2.99(m, 1H), 2.99~2.88(m, 1H), 2.77~2.62(m, 3H), 2.55~2.43(m, 2H), 2.36(s, 3H), 1.89~1.77(m, 2H), 1.65~1.44(m, 2H).

[0334] Example 8: (2s,4s)-2-(4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0335] [ka]

[0336] The title compound was prepared analogously to Example 4, using 4-bromo-2-methyl-1-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.15~7.09(m, 1H), 7.07~7.02(m, 1H), 7.02~6.96(m, 1H), 6.24(s, 1H), 4.80~4.70(m, 1H), 4.38(s, 2H), 3.88~3.76( m, 1H), 3.18~2.97(m, 2H), 2.78~2.60(m, 4H), 2.53~2.43(m, 2H), 2.29(s, 3H), 1.95~1.83(m, 2H), 1.65~1.43(m, 2H).

[0337] Example 9: (2s,4s)-2-(4-(4-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0338] [ka]

[0339] The title compound was prepared analogously to Example 4, using 1-bromo-4-cyclopropylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 26 Calculated mass for N2O3, 354.2; observed m / z, 355.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.09~6.99(m, 4H), 4.78~4.68(m, 1H), 4.38(s, 2H), 3.86~3.75(m, 1H), 3.15~2.96(m, 2H), 2.79~2.60( m, 4H), 2.52~2.39(m, 2H), 1.94~1.80(m, 3H), 1.65~1.44(m, 2H), 0.98~0.88(m, 2H), 0.69~0.62(m, 2H).

[0340] Example 10: (2s,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0341] [ka]

[0342] The title compound was prepared analogously to Example 4, using 4-bromo-2-methylbenzotrifluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23Calculated mass for F3N2O3, 396.2; observed m / z, 397.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.53(d, J=8.0Hz, 1H), 7.10~7.03(m, 2H), 4.82~4.71(m, 1H), 4.38(s, 2H), 3.89~3.80(m, 1H), 3.18~3.07 (m, 1H), 3.07~2.96(m, 1H), 2.83~2.62(m, 4H), 2.53~2.40(m, 5H), 1.95~1.85(m, 2H), 1.67~1.46(m, 2H).

[0343] Example 11: (2s,4s)-2-(4-(4-isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0344] [ka]

[0345] The title compound was prepared analogously to Example 4, using 1-bromo-4-isopropylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 28 Calculated mass for N2O3, 356.2; observed m / z, 357.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.20~7.13(m, 2H), 7.12~7.06(m, 2H), 6.38(s, 1H), 4.79~4.68(m, 1H), 4.39(s, 2H), 3.87~3.73(m, 1H), 3.17~3.06(m, 1H), 3.06~2 .96(m, 1H), 2.93~2.81(m, 1H), 2.79~2.61(m, 4H), 2.53~2.40(m, 2H), 1.98~1.83(m, 2H), 1.66~1.46(m, 2H), 1.23(d, J=6.9Hz, 6H).

[0346] Example 12 (2s,4s)-2-(4-(4-(difluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0347] [ka]

[0348] The title compound was prepared analogously to Example 4, using 1-bromo-4-(difluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 22 Calculated mass for F2N2O4, 380.2; observed m / z, 381.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.20~7.13(m, 2H), 7.10~7.04(m, 2H), 6.48(t, J=74.0Hz, 1H), 5.80(s, 1H), 4.81~4.71(m, 1H), 4.38(s, 2H), 3.8 7~3.77(m, 1H), 3.17~2.98(m, 2H), 2.81~2.60(m, 4H), 2.55~2.44(m, 2H), 1.96~1.85(m, 2H), 1.65~1.45(m, 2H).

[0349] Example 13: (2s,4s)-2-(4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0350] [ka]

[0351] The title compound was prepared analogously to Example 4, using 5-bromo-2-methylbenzotrifluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23Calculated mass for F3N2O3, 396.2; observed m / z, 397.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.40(s, 1H), 7.23(d, J=1.2Hz, 2H), 6.15(s, 1H), 4.83~4.69(m, 1H), 4.38(s, 2H), 3.89~3.78(m, 1H), 3.19~3 .08(m, 1H), 3.08~2.97(m, 1H), 2.83~2.61(m, 4H), 2.53~2.40(m, 5H), 1.95~1.86(m, 2H), 1.66~1.45(m, 2H).

[0352] Example 14: (2s,4s)-2-(4-(3-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0353] [ka]

[0354] The title compound was prepared analogously to Example 4, using 1-bromo-3-tert-butylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 30 Calculated mass for N2O3, 370.2; observed m / z, 371.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.28~7.23(m, 2H), 7.21~7.18(m, 1H), 7.02~6.97(m, 1H), 5.93(s, 1H), 4.81~4.73(m, 1H), 4.39(s, 2H), 3.86~3.79(m, 1H), 3. 18~3.09(m, 1H), 3.09~2.99(m, 1H), 2.79~2.61(m, 4H), 2.54~2.45(m, 2H), 1.97~1.89(m, 2H), 1.68~1.50(m, 2H), 1.32(s, 9H).

[0355] Example 15: (2s,4s)-2-(4-(3-isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0356] [ka]

[0357] The title compound was prepared analogously to Example 4, using 1-bromo-3-isopropylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 28 Calculated mass for N2O3, 356.2; observed m / z, 357.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.26~7.21(m, 1H), 7.10(dt, J=7.6, 1.4Hz, 1H), 7.03(q, J=1.9Hz, 1H), 6.99(dt, J=7.6, 1.5Hz, 1H), 6.16(s, 1H), 4.82~4.73(m, 1H), 4.39(s, 2H), 3.83(dq, J=11.4, 2.3Hz, 1H), 3 .12(td, J=13.1, 2.5Hz, 1H), 3.03(q, J=8.1Hz, 1H), 2.88(hept, J=6.9Hz, 1H), 2.78~2.62 (m, 4H), 2.54~2.44(m, 2H), 1.96~1.87(m, 2H), 1.70~1.51(m, 2H), 1.24(d, J=6.9Hz, 6H).

[0358] Example 16: (2r,4s)-2-(4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0359] [ka]

[0360] The title compound was prepared in analogy to Example 4, using 5-bromo-2-methylbenzotrifluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 21 H 25 Calculated mass for F3N2O2, 394.2; observed m / z, 395.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.40(s, 1H), 7.25~7.19(m, 2H), 6.04(s, 1H), 4.83~4.70(m, 1H), 3.90~3.79(m, 1H), 3.16~2.97(m, 2H), 2.82~2.71(m, 1) H), 2.71~2.48(m, 3H), 2.48~2.42(m, 3H), 2.42~2.30(m, 4H), 2.28~2.18(m, 2H), 1.95~1.84(m, 2H), 1.66~1.46(m, 2H).

[0361] Example 17: (2r,4s)-2-(4-(4-cyclopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0362] [ka]

[0363] The title compound was prepared in analogy to Example 4, using 1-bromo-4-cyclopropylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 22 H 28Calculated mass for N2O2, 352.2; observed m / z, 353.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.09~7.04(m, 2H), 7.04~6.99(m, 2H), 6.13(s, 1H), 4.80~4.66(m, 1H), 3.89~3.77(m, 1H), 3.14~2.96(m, 2H), 2.76~2.48( m, 4H), 2.42~2.31(m, 4H), 2.27~2.17(m, 2H), 1.93~1.81(m, 3H), 1.67~1.44(m, 2H), 0.99~0.88(m, 2H), 0.71~0.60(m, 2H).

[0364] Example 18: (2r,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0365] [ka]

[0366] The title compound was prepared in analogy to Example 4, using 4-bromo-2-methylbenzotrifluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 21 H 25 Calculated mass for F3N2O2, 394.2; observed m / z, 395.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.53(d, J=7.9Hz, 1H), 7.10~7.03(m, 2H), 6.18(s, 1H), 4.83~4.70(m, 1H), 3.92~3.79(m, 1H), 3.17~2.95(m, 2H), 2.81~2.70 (m, 1H), 2.70~2.49(m, 3H), 2.50~2.44(m, 3H), 2.44~2.31(m, 4H), 2.27~2.19(m, 2H), 1.94~1.83(m, 2H), 1.68~1.48(m, 2H).

[0367] Example 19: (2s,4s)-2-(4-(2-fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0368] [ka]

[0369] The title compound was prepared analogously to Example 4, using 4-bromo-3-fluorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 23 Calculated mass for FN2O3, 346.2; observed m / z, 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.05~6.98(m, 1H), 6.92~6.88(m, 1H), 6.88~6.81(m, 1H), 6.04(s, 1H), 4.80~4.70(m, 1H), 4.38(s, 2H), 3.86~3.75(m, 1H), 3. 19~3.09(m, 1H), 3.09~2.95(m, 2H), 2.76~2.60(m, 3H), 2.54~2.41(m, 2H), 2.31(s, 3H), 1.94~1.81(m, 2H), 1.68~1.48(m, 2H).

[0370] Example 20: (2s,4s)-2-(4-(4-(2,2,2-trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0371] [ka]

[0372] The title compound was prepared analogously to Example 4, using 1-bromo-4-(2,2,2-trifluoroethyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.26~7.21(m, 2H), 7.19~7.14(m, 2H), 5.78(s, 1H), 4.81~4.72(m, 1H), 4.38(s, 2H), 3.88~3.78(m, 1H), 3.41~ 3.28(m, 2H), 3.17~2.99(m, 2H), 2.82~2.59(m, 4H), 2.57~2.43(m, 2H), 1.97~1.88(m, 2H), 1.68~1.47(m, 2H).

[0373] Example 21: (2s,4s)-2-(4-(3-fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0374] [ka]

[0375] The title compound was prepared analogously to Example 4, using 4-bromo-2-fluorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 23Calculated mass for FN2O3, 346.2; observed m / z, 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.14~7.07(m, 1H), 6.87~6.79(m, 2H), 4.79~4.70(m, 1H), 4.38(s, 2H), 3.86~3.76(m, 1H), 3.17~2.97(m, 2H), 2.77~2.61(m, 4H), 2.53~2.43(m, 2H), 2.23(d, J=1.9Hz, 3H), 1.94~1.85(m, 2H), 1.62~1.43(m, 2H).

[0376] Example 22: (2r,4s)-2-(4-(3-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0377] [ka]

[0378] The title compound was prepared in analogy to Example 4, using 1-bromo-3-tert-butylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 23 H 32 Calculated mass for N2O2, 368.2; observed m / z, 369.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.26~7.22(m, 2H), 7.20(p, J=1.4Hz, 1H), 7.02~6.96(m, 1H), 6.06(s, 1H), 4.81~4.70(m, 1H), 3.90~3.79(m, 1H), 3.14~2 .98(m, 2H), 2.81~2.48(m, 4H), 2.44~2.32(m, 4H), 2.28~2.19(m, 2H), 1.97~1.86(m, 2H), 1.69~1.50(m, 2H), 1.31(s, 9H).

[0379] Example 23: (2s,4s)-2-(4-(3-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0380] [ka]

[0381] The title compound was prepared analogously to Example 4, using 1-bromo-3-cyclopropylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 26 Calculated mass for N2O3, 354.2; observed m / z, 355.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.22~7.15(m, 1H), 6.98~6.92(m, 1H), 6.92~6.88(m, 2H), 6.28(s, 1H), 4.80~4.70(m, 1H), 4.39(s, 2H), 3.87~3.77(m, 1H), 3.17~3.06(m, 1) H), 3.06~2.97(m, 1H), 2.77~2.60(m, 4H), 2.52~2.42(m, 2H), 1.95~1.83(m, 3H), 1.68~1.46(m, 2H), 1.00~0.91(m, 2H), 0.73~0.62(m, 2H).

[0382] Example 24: (2s,4s)-2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0383] [ka]

[0384] The title compound was prepared analogously to Example 4, using 5-bromo-2,2-difluoro-1,3-benzodioxole instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 20 Calculated mass for F2N2O5, 394.1; observed m / z, 395.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.00~6.95(m, 1H), 6.90~6.83(m, 2H), 6.33(s, 1H), 4.82~4.70(m, 1H), 4.38(s, 2H), 3.89~3.78(m, 1H), 3.17~ 3.07(m, 1H), 3.07~2.95(m, 1H), 2.80~2.59(m, 4H), 2.54~2.39(m, 2H), 1.96~1.85(m, 2H), 1.62~1.42(m, 2H).

[0385] Example 25: (2s,4s)-2-(4-(4-cyclobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0386] [ka]

[0387] The title compound was prepared analogously to Example 4, using 1-bromo-4-cyclobutylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 28Calculated mass for N2O3, 368.2; observed m / z, 369.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.21~7.14(m, 2H), 7.14~7.07(m, 2H), 6.06(s, 1H), 4.80~4.69(m, 1H), 4.38(s, 2H), 3.86~3.77(m, 1H), 3.51(p, J=8.6Hz) , 1H), 3.18~2.97(m, 2H), 2.79~2.60(m, 4H), 2.55~2.41(m, 2H), 2.38~2.27(m, 2H), 2.20~1.78(m, 6H), 1.66~1.47(m, 2H).

[0388] Example 26: (2s,4s)-2-(4-(3-(1,1-difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0389] [ka]

[0390] The title compound was prepared analogously to Example 4, using 1-bromo-3-(1,1-difluoroethyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 24 Calculated mass for F2N2O3, 378.2; observed m / z, 379.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.40~7.33(m, 2H), 7.32(s, 1H), 7.26~7.20(m, 1H), 6.18(s, 1H), 4.81~4.73(m, 1H), 4.38(s, 2H), 3.88~3.80(m, 1H), 3.13( td, J=13.1, 2.5Hz, 1H), 3.03(p, J=8.1Hz, 1H), 2.85~2.62(m, 4H), 2.54~2.43(m, 2H), 1.98~1.84(m, 5H), 1.69~1.50(m, 2H).

[0391] Example 27: (2s,4s)-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0392] [ka]

[0393] The title compound was prepared analogously to Example 4, using 1-bromo-4-(1-methylcyclopropyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 28 Calculated mass for N2O3, 368.2; observed m / z, 369.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.22~7.16(m, 2H), 7.11~7.05(m, 2H), 6.12(s, 1H), 4.80~4.68(m, 1H), 4.38(s, 2H), 3.86~3.75(m, 1H), 3.17~2.98(m, 2H), 2. 77~2.61(m, 4H), 2.53~2.43(m, 2H), 1.95~1.85(m, 2H), 1.65~1.46(m, 2H), 1.39(s, 3H), 0.86~0.81(m, 2H), 0.74~0.69(m, 2H).

[0394] Example 28: (2s,4s)-2-(4-(4-(1,1-difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0395] [ka]

[0396] The title compound was prepared analogously to Example 4, using 1-bromo-4-(1,1-difluoroethyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C20 H 24 Calculated mass for F2N2O3, 378.2; observed m / z, 360.2 [M+HF] + . 1 H NMR (400MHz, CDCl3)δ 7.45(d, J=8.3Hz, 2H), 7.23(d, J=8.1Hz, 2H), 6.06(s, 1H), 4.83~4.72(m, 1H), 4.38(s, 2H), 3.88~3.79(m, 1H), 3.13(td, J=13.1, 2.5Hz, 1H), 3.04(p, J=8.1Hz, 1H), 2.84~2.61(m, 4H), 2.55~2.44(m, 2H), 1.97~1.85(m, 5H), 1.67~1.49(m, 2H).

[0397] Example 29: (2s,4s)-2-(4-(3-fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0398] [ka]

[0399] The title compound was prepared analogously to Example 4, using 3-bromo-5-fluorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 23 Calculated mass for FN2O3, 346.2; observed m / z, 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 6.79~6.73(m, 1H), 6.72(dt, J=9.6, 2.0Hz, 1H), 6.66(dt, J=9.9, 2.0Hz, 1H), 6.44(s, 1H), 4.78~4.70(m, 1H), 4.38(s, 2H), 3. 86~3.78(m, 1H), 3.16~2.95(m, 2H), 2.79~2.60(m, 4H), 2.53~2.40(m, 2H), 2.32(s, 3H), 1.97~1.84(m, 2H), 1.62~1.44(m, 2H).

[0400] Example 30: (2s,4s)-2-(4-(2,3-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0401] [ka]

[0402] The title compound was prepared analogously to Example 4, using 1-bromo-2,3-difluoro-4-methylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 22 Calculated mass for F2N2O3, 364.2; observed m / z, 365.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 6.91~6.84(m, 1H), 6.81~6.74(m, 1H), 5.96(s, 1H), 4.80~4.72(m, 1H), 4.38(s, 2H), 3.85~3.76(m, 1H), 3.19~ 2.96(m, 3H), 2.76~2.62(m, 3H), 2.55~2.43(m, 2H), 2.31~2.22(m, 3H), 1.94~1.83(m, 2H), 1.69~1.48(m, 2H).

[0403] Example 31: (2s,4s)-2-(4-(2,5-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0404] [ka]

[0405] The title compound was prepared analogously to Example 4, using 1-bromo-2,5-difluoro-4-methylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19H 22 Calculated mass for F2N2O3, 364.2; observed m / z, 365.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 6.88~6.80(m, 1H), 6.78(dd, J=10.1, 6.1Hz, 1H), 5.88(s, 1H), 4.81~4.70(m, 1H), 4.38(s, 2H), 3.86~3.76(m, 1H), 3.13(td, J=13.2) , 2.6Hz, 1H), 3.08~2.97(m, 2H), 2.76~2.58(m, 3H), 2.55~2.43(m, 2H), 2.22(d, J=1.9Hz, 3H), 1.93~1.83(m, 2H), 1.59~1.42(m, 2H).

[0406] Example 32: (2r,4s)-2-(4-(4-isopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0407] [ka]

[0408] The title compound was prepared in analogy to Example 4, using 1-bromo-4-isopropylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 22 H 30 Calculated mass for N2O2, 354.2; observed m / z, 355.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.19~7.13(m, 2H), 7.13~7.06(m, 2H), 6.04(s, 1H), 4.78~4.70(m, 1H), 3.88~3.79(m, 1H), 3.14~2.98(m, 2H), 2.89(dq, J=13.8, 6 .8Hz, 1H), 2.77~2.50(m, 4H), 2.43~2.33(m, 4H), 2.27~2.19(m, 2H), 1.95~1.84(m, 2H), 1.66~1.47(m, 2H), 1.24(d, J=6.9Hz, 6H).

[0409] Example 33: (2s,4s)-2-(4-(2-fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0410] [ka]

[0411] The title compound was prepared analogously to Example 4, using 3-bromo-4-fluorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 23 Calculated mass for FN2O3, 346.2; observed m / z, 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.01~6.85(m, 3H), 6.02(s, 1H), 4.80~4.72(m, 1H), 4.38(s, 2H), 3.86~3.77(m, 1H), 3.14(td, J=13.2, 2.6Hz, 1H ), 3.09~2.98(m, 2H), 2.74~2.63(m, 3H), 2.56~2.44(m, 2H), 2.29(s, 3H), 1.93~1.83(m, 2H), 1.71~1.49(m, 2H).

[0412] Example 34: (2s,4s)-2-(4-(3,4-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0413] [ka]

[0414] The title compound was prepared analogously to Example 4, using 4-bromo-o-xylene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 26 Calculated mass for N2O3, 342.2; observed m / z, 343.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.07(d, J=7.7Hz, 1H), 6.95(d, J=1.9Hz, 1H), 6.91(dd, J=7.7, 2.0Hz, 1H), 6.4 2(d, J=47.7Hz, 1H), 4.79~4.69(m, 1H), 4.39(s, 2H), 3.88~3.77(m, 1H), 3.10( td, J=13.9, 13.5, 2.8Hz, 1H), 3.01(q, J=8.3Hz, 1H), 2.76~2.62(m, 4H), 2.52~ 2.42(m, 2H), 2.24(s, 3H), 2.23(s, 3H), 1.93~1.84(m, 2H), 1.66~1.47(m, 2H).

[0415] Example 35: (2s,4s)-2-(4-(2,3-dihydro-1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0416] [ka]

[0417] The title compound was prepared analogously to Example 4, using 5-bromo-2,3-dihydro-1H-indene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 26Calculated mass for N2O3, 354.2; observed m / z, 355.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.16 (d. 6~2.95(m, 2H), 2.92~2.83(m, 4H), 2.77~2.62(m, 4H), 2.53~2.43(m, 2H), 2.07(p, J=7.4Hz, 2H), 1.96~1.85(m, 2H), 1.67~1.48(m, 2H).

[0418] Example 36: (2s,4s)-2-(4-(3-chloro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0419] [ka]

[0420] The title compound was prepared analogously to Example 4, using 4-bromo-2-chlorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 23 Calculated mass for ClN2O3, 362.1; observed m / z, 363.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.19~7.12(m, 2H), 6.96(dd, J=7.9, 1.8Hz, 1H), 6.06(s, 1H), 4.79~4.71(m, 1H), 4.38(s, 2H), 3.86~3.76(m, 1H) ), 3.15~2.97(m, 2H), 2.75~2.61(m, 4H), 2.53~2.42(m, 2H), 2.33(s, 3H), 1.94~1.84(m, 2H), 1.63~1.44(m, 2H).

[0421] Example 37: (2s,4s)-2-(4-(2-fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0422] [ka]

[0423] The title compound was prepared analogously to Example 4, using 1-bromo-2-fluorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 23 Calculated mass for FN2O3, 346.2; observed m / z, 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.10~7.00(m, 1H), 7.01~6.93(m, 2H), 5.98(s, 1H), 4.80~4.70(m, 1H), 4.38(s, 2H), 3.87~3.74(m, 1H), 3.20~2 .96(m, 3H), 2.75~2.61(m, 3H), 2.53~2.42(m, 2H), 2.26(d, J=2.3Hz, 3H), 1.96~1.82(m, 2H), 1.65~1.47(m, 2H).

[0424] Example 38: (2s,4s)-2-(4-(3-isopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0425] [ka]

[0426] The title compound was prepared analogously to Example 4, using 1-bromo-3-isopropoxybenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 28Calculated mass for N2O4, 372.2; observed m / z, 373.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.20(t, J=7.9Hz, 1H), 6.76~6.66(m, 3H), 6.39(s, 1H), 4.77~4.70(m, 1H), 4.53(hept, J=6.0Hz, 1H), 4.38(s, 2H), 3.85~3.77(m, 1H), 3.10(td, J=13.1, 2.5Hz, 1H), 3.01(p, J=8.2Hz, 1H), 2.78~2.58(m, 4H), 2.52~2.41(m, 2H), 1.96~1.89(m, 2H), 1.65~1.46(m, 2H), 1.32(d, J=6.1Hz, 6H).

[0427] Example 39: (2r,4s)-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0428] [ka]

[0429] The title compound was prepared in analogy to Example 4, using 1-bromo-4-(1-methylcyclopropyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 23 H 30 Calculated mass for N2O2, 366.2; observed m / z, 367.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.21~7.16(m, 2H), 7.11~7.05(m, 2H), 6.02(s, 1H), 63.14~2.98(m, 2H), 2.76~2.48(m, 4H), 2.43~2.32(m, 4H), 2.27 ~2.19(m, 2H), 1.88(dt, J=13.4, 3.3Hz, 2H), 1.65~1.46(m, 2H), 1.39(s, 3H), 0.86~0.80(m, 2H), 0.74~0.67(m, 2H).

[0430] Example 40: (2s,4s)-2-(4-(3-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0431] [ka]

[0432] The title compound was prepared analogously to Example 4, using 1-bromo-3-(1-methylcyclopropyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 28 Calculated mass for N2O3, 368.2; observed m / z, 369.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.22(t, J=7.6Hz, 1H), 7.13~7.09(m, 1H), 7.07(t, J=1.9Hz, 1H), 6.97(dt, J=7.6, 1. 5Hz, 1H), 6.19(s, 1H), 4.79~4.72(m, 1H), 4.39(s, 2H), 3.87~3.79(m, 1H), 3.11(td, J =13.3, 2.6Hz, 1H), 3.03(q, J=8.2Hz, 1H), 2.78~2.61(m, 4H), 2.54~2.42(m, 2H), 1.98 ~1.86(m, 2H), 1.67~1.48(m, 2H), 1.39(s, 3H), 0.87~0.81(m, 2H), 0.75~0.69(m, 2H).

[0433] Example 41: (2r,4s)-2-(4-(3-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0434] [ka]

[0435] The title compound was prepared in analogy to Example 4, using 1-bromo-3-(1-methylcyclopropyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 23 H 30 Calculated mass for N2O2, 366.2; observed m / z, 367.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.22(t, J=7.6Hz, 1H), 7.11(dt, J=7.7, 1.5Hz, 1H), 7.07(t, J=1.9Hz, 1H), 6.97(d t, J=7.6, 1.5Hz, 1H), 6.13~5.97(m, 1H), 4.80~4.71(m, 1H), 3.89~3.80(m, 1H), 3. 16~2.98(m, 2H), 2.78~2.47(m, 4H), 2.44~2.32(m, 4H), 2.28~2.19(m, 2H), 1.95~1 .85(m, 2H), 1.67~1.48(m, 2H), 1.39(s, 3H), 0.88~0.80(m, 2H), 0.75~0.68(m, 2H).

[0436] Example 42: (2s,4s)-2-(4-(1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0437] [ka]

[0438] The title compound was prepared analogously to Example 4, using 1-bromo-1H-indene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 24 Calculated mass for N2O3, 352.2; observed m / z, 353.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.37(dd, J=29.1, 7.7Hz, 1H), 7.27(dd, J=29.3, 1.6Hz, 1H), 7.11~6.99(m, 1H), 6. 89~6.81(m, 1H), 6.59~6.51(m, 1H), 5.91(s, 1H), 4.82~4.72(m, 1H), 4.39(s, 2H), 3.87~3.78(m, 1H), 3.40~3.34(m, 2H), 3.19~2.98(m, 2H), 2.79(td, J=12.0, 2.8Hz , 1H), 2.76~2.62(m, 3H), 2.55~2.45(m, 2H), 1.99~1.88(m, 2H), 1.74~1.50(m, 2H).

[0439] Example 43: (2s,4s)-2-(4-(2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0440] [ka]

[0441] The title compound was prepared analogously to Example 4, using 3-bromo-o-xylene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 26 Calculated mass for N2O3, 342.2; observed m / z, 343.2 [M+H] + . 1H NMR (400 MHz, CDCl) δ 7.12~7.06(m, 1H), 7.06~7.02(m, 1H), 6.99(dd, J=7.5, 1.7Hz, 1H), 5.8 9(s, 1H), 4.82~4.73(m, 1H), 4.38(s, 2H), 3.88~3.79(m, 1H), 3.15(td, J=13.1, 2.5Hz, 1H), 3.09~2.96(m, 2H), 2.75~2.61(m, 3H), 2.54~2.43( m, 2H), 2.30(s, 3H), 2.25(s, 3H), 1.90~1.79(m, 2H), 1.67~1.47(m, 2H).

[0442] Example 44: (2s,4s)-2-(4-(4-fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0443] [ka]

[0444] The title compound was prepared analogously to Example 4, using 5-bromo-2-fluorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 23 Calculated mass for FN2O3, 346.2; observed m / z, 347.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.00~6.95(m, 1H), 6.95~6.89(m, 2H), 5.97(s, 1H), 4.79~4.71(m, 1H), 4.38(s, 2H), 3.86~3.77(m, 1H), 3.16~ 2.96(m, 2H), 2.75~2.60(m, 4H), 2.54~2.44(m, 2H), 2.27~2.21(m, 3H), 1.93~1.83(m, 2H), 1.62~1.43(m, 2H).

[0445] Example 45: (2s,4s)-2-(4-(6-(tert-butyl)pyridin-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0446] [ka]

[0447] The title compound was prepared analogously to Example 4, using 5-bromo-2-tert-butylpyridine instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 29 Calculated mass for N3O3, 371.2; observed m / z, 372.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.36~8.31(m, 1H), 7.63(dd, J=8.3, 2.4Hz, 1H), 7.41(dd, J=8.2, 0.8Hz, 1H ), 4.69~4.61(m, 1H), 4.49(s, 2H), 4.04~3.96(m, 1H), 3.23~3.09(m, 2H), 2 .88(tt, J=12.2, 3.7Hz, 1H), 2.76(td, J=12.9, 2.8Hz, 1H), 2.65~2.52(m, 2 H), 2.52~2.42(m, 2H), 1.95~1.83(m, 2H), 1.66~1.51(m, 2H), 1.34(s, 9H).

[0448] Example 46: (2s,4s)-2-(4-(2-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0449] [ka]

[0450] The title compound was prepared analogously to Example 4, using 1-bromo-2-chlorobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 18 H 21 Calculated mass for ClN2O3, 348.1; observed m / z, 349.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.36(dd, J=7.8, 1.4Hz, 1H), 7.25~7.20(m, 1H), 7.20~7.12(m, 2H), 6.10(s, 1H), 4. 82~4.75(m, 1H), 4.39(s, 2H), 3.87~3.80(m, 1H), 3.27(tt, J=12.1, 3.5Hz, 1H), 3.1 7(td, J=13.1, 2.6Hz, 1H), 3.04(p, J=8.1Hz, 1H), 2.78~2.63(m, 3H), 2.54~2.45(m, 2H), 2.00~1.87(m, 2H), 1.59(qd, J=12.6, 4.2Hz, 1H), 1.48(qd, J=12.6, 4.2Hz, 1H).

[0451] Example 47: (2s,4s)-2-(4-(2,4-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0452] [ka]

[0453] The title compound was prepared analogously to Example 4, using 4-bromo-m-xylene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 26 Calculated mass for N2O3, 342.2; observed m / z, 343.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.03~6.96(m, 3H), 5.83(s, 1H), 4.81~4.72(m, 1H), 4.38(s, 2H), 3.87~3.77(m, 1H), 3.17~2.99(m, 2H), 2.92(tt, J=12 .1, 3.5Hz, 1H), 2.76~2.60(m, 3H), 2.55~2.44(m, 2H), 2.32(s, 3H), 2.29(s, 3H), 1.86~1.77(m, 2H), 1.65~1.46(m, 2H).

[0454] Example 48: (2s,4s)-2-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0455] [ka]

[0456] The title compound was prepared analogously to Example 4, using 4-bromodiphenyl ether instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 24 H 26 Calculated mass for N2O4, 406.2; observed m / z, 407.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.36~7.29(m, 2H), 7.16~7.05(m, 3H), 7.02~6.92(m, 4H), 5.78(s, 1H), 4.81~4.70(m, 1H), 4.38(s, 2H), 3.87~ 3.76(m, 1H), 3.18~2.97(m, 2H), 2.81~2.59(m, 4H), 2.56~2.42(m, 2H), 1.98~1.85(m, 2H), 1.65~1.43(m, 2H).

[0457] Example 49: (2s,4s)-2-(4-(3-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0458] [ka]

[0459] The title compound was prepared analogously to Example 4, using 4-bromo-2-methoxy-1-(trifluoromethyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.49(d, J=7.9Hz, 1H), 6.85~6.76(m, 2H), 6.00(s, 1H), 4.84~4.71(m, 1H), 4.38(s, 2H), 3.90(s, 3H), 3.89~3.79(m, 1H), 3.13 (td, J=13.1, 2.5Hz, 1H), 3.04(p, J=8.0Hz, 1H), 2.85~2.59(m, 4H), 2.56~2.42(m, 2H), 1.98~1.88(m, 2H), 1.64~1.45(m, 2H).

[0460] Example 50: (2s,4s)-2-(4-(2-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0461] [ka]

[0462] The title compound was prepared analogously to Example 4, using 1-bromo-2-cyclopropylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 26 Calculated mass for N2O3, 354.2; observed m / z, 355.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.21~7.10(m, 3H), 7.05(dd, J=7.8, 1.9Hz, 1H), 6.12(s, 1H), 4.84~4.76(m, 1 H), 4.39(s, 2H), 3.91~3.80(m, 1H), 3.43(tt, J=12.1, 3.5Hz, 1H), 3.16(td, J= 13.1, 2.5Hz, 1H), 3.05(p, J=8.1Hz, 1H), 2.80~2.63(m, 3H), 2.54~2.44(m, 2H) , 2.01~1.84(m, 3H), 1.69~1.51(m, 2H), 0.99~0.89(m, 2H), 0.71~0.60(m, 2H).

[0463] Example 51: (2r,4s)-2-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0464] [ka]

[0465] The title compound was prepared in analogy to Example 4, using 4-bromodiphenyl ether instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 25 H 28 Calculated mass for N2O3, 404.2; observed m / z, 405.1 [M+H] + . 1H NMR (400 MHz, CDCl) δ 7.36~7.29(m, 2H), 7.16~7.12(m, 2H), 7.12~7.07(m, 1H), 7.02~6.98( m, 2H), 6.98~6.91(m, 2H), 5.91(s, 1H), 4.81~4.71(m, 1H), 3.91~3.79( m, 1H), 3.16~2.98(m, 2H), 2.79~2.62(m, 2H), 2.62~2.48(m, 2H), 2.45~ 2.32(m, 4H), 2.27~2.19(m, 2H), 1.96~1.86(m, 2H), 1.61~1.45(m, 2H).

[0466] Example 52: (2s,4s)-2-(4-(2-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0467] [ka]

[0468] The title compound was prepared analogously to Example 4, using 3-bromo-2-methylbenzotrifluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.51(dd, J=7.8, 1.4Hz, 1H), 7.32(dd, J=8.0, 1.4Hz, 1H), 7.26(d, J=15.6Hz, 1H), 6.22(s, 1H), 4.84~4.76(m, 1H), 4.39(s, 2H), 3.91 ~3.82(m, 1H), 3.21~2.98(m, 3H), 2.77~2.64(m, 3H), 2.54~2.46(m, 2H), 2.44(d, J=1.6Hz, 3H), 1.89~1.79(m, 2H), 1.67~1.48(m, 2H).

[0469] Example 53: (2s,4s)-2-(4-(3-phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0470] [ka]

[0471] The title compound was prepared analogously to Example 4, using 1-bromo-3-phenoxybenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 24 H 26 Calculated mass for N2O4, 406.2; observed m / z, 407.2 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 7.37~7.29(m, 2H), 7.29~7.23(m, 1H), 7.13~7.07(m, 1H), 7.02~6.96(m , 2H), 6.92(dt, J=7.8, 1.3Hz, 1H), 6.88~6.82(m, 2H), 5.86(s, 1H), 4.79 ~4.68(m, 1H), 4.37(s, 2H), 3.86~3.75(m, 1H), 3.15~2.97(m, 2H), 2.79 ~2.59(m, 4H), 2.54~2.42(m, 2H), 1.97~1.87(m, 2H), 1.62~1.46(m, 2H).

[0472] Example 54: (2s,4s)-2-(4-(4-chloro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0473] [ka]

[0474] The title compound was prepared analogously to Example 4, using 5-bromo-2-chlorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19H 23 Calculated mass for ClN2O3, 362.1; observed m / z, 363.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.26(d, J=8.2Hz, 1H), 7.03(d, J=2.2Hz, 1H), 6.93(dd, J=8.2, 2.3Hz, 1H), 6.05(s, 1H), 4.79~4.71(m, 1H), 4.38(s, 2H), 3.86~3.7 5(m, 1H), 3.16~2.94(m, 2H), 2.75~2.60(m, 4H), 2.54~2.43(m, 2H), 2.35(s, 3H), 1.88(dq, J=12.9, 2.2Hz, 2H), 1.63~1.44(m, 2H).

[0475] Example 55: (2s,4s)-2-(4-(2-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0476] [ka]

[0477] The title compound was prepared analogously to Example 4, using 4-bromo-3-methoxybenzotrifluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.19(d, J=1.1Hz, 2H), 7.06(s, 1H), 6.01(s, 1H), 4.80~4.73(m, 1H), 4.38(s, 2H), 3.88(s, 3H), 3.85~3.76(m, 1H), 3. 27~3.10(m, 2H), 3.04(p, J=8.1Hz, 1H), 2.75~2.62(m, 3H), 2.55~2.44(m, 2H), 1.95~1.83(m, 2H), 1.63~1.44(m, 2H).

[0478] Example 56: (2s,4s)-2-(4-(2-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0479] [ka]

[0480] The title compound was prepared analogously to Example 4, using 1-bromo-2-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 21 Calculated mass for F3N2O4, 398.1; observed m / z, 399.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.30~7.20(m, 4H), 5.92(s, 1H), 4.82~4.74(m, 1H), 4.38(s, 2H), 3.87~3.78(m, 1H), 3.22~3.10(m, 2 H), 3.11~2.99(m, 1H), 2.76~2.62(m, 3H), 2.56~2.44(m, 2H), 1.92~1.81(m, 2H), 1.62~1.44(m, 2H).

[0481] Example 57: (2s,4s)-2-(4-([1,1'-biphenyl]-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0482] [ka]

[0483] The title compound was prepared analogously to Example 4, using 3-bromobiphenyl instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 24 H 26Calculated mass for N2O3, 390.2; observed m / z, 391.2 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 7.60~7.54(m, 2H), 7.48~7.32(m, 6H), 7.17(dt, J=7.5, 1.5Hz, 1H), 5.82( s, 1H), 4.83~4.74(m, 1H), 4.38(s, 2H), 3.84(d, J=13.4Hz, 1H), 3.20~3.1 0(m, 1H), 3.10~2.99(m, 1H), 2.83(tt, J=12.2, 3.6Hz, 1H), 2.76~2.60(m, 3H), 2.58~2.44(m, 2H), 1.98(dd, J=14.3, 3.8Hz, 2H), 1.76~1.54(m, 2H).

[0484] Example 58: (2s,4s)-2-(4-(4-methoxy-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0485] [ka]

[0486] The title compound was prepared analogously to Example 4, using 4-bromo-2-(trifluoromethoxy)anisole instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O5, 428.2; observed m / z, 429.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.09~7.01(m, 2H), 6.93(d, J=8.4Hz, 1H), 6.11(s, 1H), 4.79~4.70(m, 1H), 4.38(s, 2H), 3.87~3.79(m, 4H), 3.17~2.96(m, 2H), 2.75~2.61(m, 4H), 2.54~2.41(m, 2H), 1.90(dq, J=12.8, 2.1Hz, 2H), 1.61~1.39(m, 2H).

[0487] Example 59: (2s,4s)-2-(4-(4-(pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0488] [ka]

[0489] The title compound was prepared analogously to Example 4, using 2-(4-bromophenoxy)pyridine instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 23 H 25 Calculated mass for N3O4, 407.2; observed m / z, 408.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.21~8.17(m, 1H), 7.71~7.65(m, 1H), 7.23~7.15(m, 2H), 7.12~7.05(m, 2H) ), 7.01~6.96(m, 1H), 6.91(dt, J=8.3, 0.9Hz, 1H), 5.78(s, 1H), 4.77(d, J=1 3.6Hz, 1H), 4.38(s, 2H), 3.83(d, J=13.3Hz, 1H), 3.18~2.99(m, 2H), 2.83~ 2.59(m, 4H), 2.56~2.43(m, 2H), 1.94(d, J=13.2Hz, 2H), 1.70~1.46(m, 2H).

[0490] Example 60: (2s,4s)-2-(4-(4-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0491] [ka]

[0492] The title compound was prepared analogously to Example 4, using 5-bromo-2-chloro-1-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 20 Calculated mass for ClF3N2O4, 432.1; observed m / z, 433.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.41 (d. H), 3.17~3.07(m, 1H), 3.03(p, J=8.1Hz, 1H), 2.82~2.60(m, 4H), 2.53~2.43(m, 2H), 1.92(dq, J=12.8, 2.2Hz, 2H), 1.63~1.43(m, 2H).

[0493] Example 61: (2s,4s)-2-(4-(4-fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0494] [ka]

[0495] The title compound was prepared analogously to Example 4, using 4-bromo-1-fluoro-2-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 20 Calculated mass for F4N2O4, 416.1; observed m / z, 417.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.18~7.06(m, 3H), 5.94(s, 1H), 4.81~4.72(m, 1H), 4.38(s, 2H), 3.88~3.78(m, 1H), 3.12(td, J=13.1, 2. 5Hz, 1H), 3.08~2.97(m, 1H), 2.80~2.57(m, 4H), 2.55~2.42(m, 2H), 1.96~1.88(m, 2H), 1.62~1.43(m, 2H).

[0496] Example 62: (2s,4s)-2-(4-(2-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0497] [ka]

[0498] The title compound was prepared analogously to Example 4, using 1-bromo-2-chloro-3-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 20 Calculated mass for ClF3N2O4, 432.1; observed m / z, 433.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.27(d, J=7.9Hz, 1H), 7.22(dp, J=8.0, 1.4Hz, 1H), 7.14(dd, J=7.6, 1.7Hz, 1H), 6.05( s, 1H), 4.84~4.77(m, 1H), 4.38(s, 2H), 3.90~3.79(m, 1H), 3.33(tt, J=12.1, 3.4Hz, 1H ), 3.18(td, J=13.0, 2.5Hz, 1H), 3.04(p, J=8.1Hz, 1H), 2.77~2.62(m, 3H), 2.55~2.43( m, 2H), 2.00~1.89(m, 2H), 1.59(qd, J=12.7, 4.3Hz, 1H), 1.47(qd, J=12.6, 4.1Hz, 1H).

[0499] Example 63: (2s,4s)-2-(4-(2-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0500] [ka]

[0501] The title compound was prepared analogously to Example 4, using 2-bromo-6-(trifluoromethoxy)toluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.19(t, J=7.9Hz, 1H), 7.13~7.04(m, 2H), 5.98(s, 1H), 4.80(dt, J=14.2, 2.7Hz, 1H), 4.39(s, 2H), 3.90~3.79(m, 1H), 3.15(td, J =13.1, 2.4Hz, 1H), 3.10~2.94(m, 2H), 2.75~2.62(m, 3H), 2.55~2.44(m, 2H), 2.29(s, 3H), 1.90~1.80(m, 2H), 1.63~1.47(m, 2H).

[0502] Example 64: (2r,4s)-2-(4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0503] [ka]

[0504] The title compound was prepared in analogy to Example 4, using 4-bromo-2-methyl-1-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 21 H 25 Calculated mass for F3N2O3, 410.2; observed m / z, 411.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.13(dq, J=8.5, 1.6Hz, 1H), 7.05(d, J=2.2Hz, 1H), 7.00(dd, J=8.4, 2.4Hz, 1H), 5.94(s, 1H), 4.76(d, J=13.3Hz, 1H), 3.85(d, J=13.5Hz, 1H), 3.14~2.98(m, 2H), 2.78~2.47(m, 4H), 2.44~2.32(m, 4H), 2.29(s, 3H), 2.27~2.19(m, 2H), 1.88(d, J=13.3Hz, 2H), 1.69~1.43(m, 2H).

[0505] Example 65: (2s,4s)-2-(4-(4-cyclopropyl-2-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0506] [ka]

[0507] The title compound was prepared analogously to Example 4, using 1-bromo-4-cyclopropyl-2-methylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 28 Calculated mass for N2O3, 368.2; observed m / z, 369.2 [M+H] + . 1H NMR (500MHz, CDCl3)δ 7.03~6.97(m, 1H), 6.91~6.84(m, 2H), 5.79(s, 1H), 4.81~4.71(m, 1H), 4.38(s , 2H), 3.82(d, J=13.4Hz, 1H), 3.12(td, J=13.1, 2.5Hz, 1H), 3.08~3.00(m, 1H), 2.91(tt, J=12.1, 3.5Hz, 1H), 2.74~2.60(m, 3H), 2.54~2.45(m, 2H), 2.31(s, 3H) ), 1.86~1.78(m, 3H), 1.58~1.45(m, 2H), 0.95~0.89(m, 2H), 0.68~0.62(m, 2H).

[0508] Example 66: (2s,4s)-2-(4-(3-(tert-butyl)-4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0509] [ka]

[0510] The title compound was prepared analogously to Example 4, using 4-bromo-2-tert-butyl-1-chlorobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 29 Calculated mass for ClN2O3, 404.2; observed m / z, 405.2 [M+H] + . 1 H NMR (500 MHz, CDCl) δ 7.28(d, J=8.1Hz, 1H), 7.21(d, J=2.2Hz, 1H), 6.93(dd, J=8.2, 2.3Hz, 1H ), 5.84(s, 1H), 4.80~4.73(m, 1H), 4.38(s, 2H), 3.85~3.78(m, 1H), 3.12 (td, J=13.1, 2.5Hz, 1H), 3.04(tt, J=8.6, 7.5Hz, 1H), 2.76~2.61(m, 4H) , 2.55~2.46(m, 2H), 1.93~1.86(m, 2H), 1.59~1.48(m, 2H), 1.47(s, 9H).

[0511] Example 67: (2s,4s)-2-(4-(3-(difluoromethoxy)-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0512] [ka]

[0513] The title compound was prepared analogously to Example 4, using 4-bromo-2-difluoromethoxy-1-methylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 24 Calculated mass for F2N2O4, 394.2; observed m / z, 395.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.16(dd, J=7.8, 0.9Hz, 1H), 6.94(dd, J=7.8, 1.8Hz, 1H), 6.90~6.87(m, 1H), 6.47(t, J=74.2Hz, 1H), 6.09(s, 1H), 4.79~4.72(m, 1H), 4.38(s, 2H), 3.87~3 .78(m, 1H), 3.11(td, J=13.1, 2.5Hz, 1H), 3.03(p, J=8.1Hz, 1H), 2.76~2.61( m, 4H), 2.52~2.44(m, 2H), 2.25(s, 3H), 1.94~1.87(m, 2H), 1.63~1.46(m, 2H).

[0514] Example 68: (2s,4s)-2-(4-(3-(tert-butyl)-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0515] [ka]

[0516] The title compound was prepared analogously to Example 4, using 4-bromo-2-tert-butyl-1-fluorobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 29 Calculated mass for FN2O3, 388.2; observed m / z, 389.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.07(dd, J=8.0, 2.2Hz, 1H), 6.99~6.89(m, 2H), 5.86(s, 1H), 4.79~4.73(m, 1H), 4.38(s, 2H), 3.82(dt, J=13.5, 2.3Hz, 1H), 3.11(td, J=13.1, 2.5Hz, 1H), 3.08~2.99(m, 1H), 2.77~2.61(m, 4H), 2.54~2.46(m, 2H), 1.90(dq, J=13.0, 2.2Hz, 2H), 1.65~1.46(m, 2H), 1.37(d, J=1.0Hz, 9H).

[0517] Example 69: (2r,4s)-2-(4-(2-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0518] [ka]

[0519] The title compound was prepared in analogy to Example 4, using 2-bromo-6-(trifluoromethoxy)toluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 21 H 25 Calculated mass for F3N2O3, 410.2; observed m / z, 411.2 [M+H] + .1 H NMR (500MHz, CDCl3)δ 7.19(t, J=8.0Hz, 1H), 7.12~7.05(m, 2H), 6.02(s, 1H), 4.79(d, J=13.3Hz, 1H), 3 .88(d, J=13.5Hz, 1H), 3.17~3.09(m, 1H), 3.06(t, J=8.4Hz, 1H), 2.99(tt, J=12. 1, 3.4Hz, 1H), 2.68(t, J=13.0Hz, 1H), 2.57(q, J=10.1, 9.5Hz, 2H), 2.44~2.34(m , 4H), 2.29(s, 3H), 2.27~2.19(m, 2H), 1.84(d, J=13.3Hz, 2H), 1.66~1.47(m, 2H).

[0520] Example 70: (2s,4s)-2-(4-(3-methyl-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0521] [ka]

[0522] The title compound was prepared analogously to Example 4, using 1-bromo-3-methyl-5-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 6.92(s, 1H), 6.89(s, 1H), 6.82(s, 1H), 6.10(s, 1H), 4.76(d, J=13.3Hz, 1H), 4.38(s, 2H), 3.83(d, J=13.5Hz, 1H) ), 3.16~2.95(m, 2H), 2.78~2.60(m, 4H), 2.54~2.43(m, 2H), 2.35(s, 3H), 1.95~1.87(m, 2H), 1.64~1.44(m, 2H).

[0523] Example 71: (2s,4s)-2-(4-(4-(difluoromethoxy)-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0524] [ka]

[0525] The title compound was prepared analogously to Example 4, using 4-bromo-1-(difluoromethoxy)-2-methylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 24 Calculated mass for F2N2O4, 394.2; observed m / z, 395.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.05~6.94(m, 3H), 6.46(t, J=74.3Hz, 1H), 6.21(s, 1H), 4.75(d, J=13.1Hz, 1H), 4.38(s, 2H), 3.82(d, J=13.5Hz, 1H), 3.17~2.95(m, 2H), 2.76~2.60(m, 4H), 2.54~2.43(m, 2H), 2.27(s, 3H), 1.95~1.83(m, 2H), 1.65~1.43(m, 2H).

[0526] Example 72: (2s,4s)-2-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0527] [ka]

[0528] The title compound was prepared analogously to Example 4, using 2-bromo-1-methyl-4-(trifluoromethyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.40~7.35(m, 1H), 7.35(d, J=1.8Hz, 1H), 7.27(d, J=7.7Hz, 1H), 6.02(s, 1H), 4.85~4.75(m, 1H), 4.39(s, 2H), 3.91~3.79(m, 1H), 3.20 ~3.10(m, 1H), 3.10~2.95(m, 2H), 2.79~2.59(m, 3H), 2.55~2.46(m, 2H), 2.41(s, 3H), 1.86(dt, J=14.2, 2.4Hz, 2H), 1.64~1.50(m, 2H).

[0529] Example 73: (2r,4s)-2-(4-(3-(tert-butyl)-4-chlorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0530] [ka]

[0531] The title compound was prepared in analogy to Example 4, using 4-bromo-2-tert-butyl-1-chlorobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 23 H 31 Calculated mass for ClN2O2, 402.2; observed m / z, 403.2 [M+H] + . 1H NMR (500MHz, CDCl3)δ 7.27(d, J=8.1Hz, 1H), 7.21(d, J=2.2Hz, 1H), 6.93(dd, J=8.1, 2.2Hz, 1H), 6.04(s, 1H), 4.75(s, 1H), 3.85(d, J=13.0Hz, 1H), 3.15~2. 98(m, 2H), 2.76~2.61(m, 2H), 2.56(s, 2H), 2.43~2.31(m, 4H), 2.29~2.19(m, 2H), 1.93~1.83(m, 2H), 1.62~1.48(m, 2H), 1.47(s, 9H).

[0532] Example 74: (2r,4s)-2-(4-(2-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0533] [ka]

[0534] The title compound was prepared in analogy to Example 4, using 1-bromo-2-chloro-3-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 20 H 22 Calculated mass for ClF3N2O3, 430.1; observed m / z, 431.1 [M+H] + . 1H NMR (500 MHz, CDCl) δ 7.31~7.26(m, 1H), 7.22(dp, J=8.2, 1.5Hz, 1H), 7.14(dd, J=7.8, 1.6Hz, 1 H), 6.09(s, 1H), 4.80(s, 1H), 3.87(s, 1H), 3.32(tt, J=12.1, 3.4Hz, 1H), 3 .16(s, 1H), 3.05(p, J=8.4Hz, 1H), 2.71(s, 1H), 2.61~2.52(m, 2H), 2.43~ 2.35(m, 4H), 2.24(t, J=7.6Hz, 2H), 2.01~1.86(m, 2H), 1.65~1.39(m, 2H).

[0535] Example 75: (2s,4s)-2-(4-(4-cyclopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0536] [ka]

[0537] The title compound was prepared analogously to Example 4, using 1-bromo-4-cyclopropoxybenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 26 Calculated mass for N2O4, 370.2; observed m / z, 371.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.12~7.06(m, 2H), 7.01~6.96(m, 2H), 5.97(s, 1H), 4.78~4.71(m, 1H), 4.38(s, 2H), 3.81(dd, J=13.8, 3.4Hz, 1H), 3.73~3.66(m, 1H), 3.11( td.

[0538] Example 76: (2s,4s)-2-(4-(2-fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0539] [ka]

[0540] The title compound was prepared analogously to Example 4, using 1-bromo-2-fluoro-3-(trifluoromethoxy)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 20 Calculated mass for F4N2O4, 416.1; observed m / z, 417.5 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.23~7.16(m, 1H), 7.15~7.06(m, 2H), 5.76(s, 1H), 4.79(d, J=13.4Hz, 1H), 4.38(s, 2H), 3.83(d, J=13.6Hz, 1H), 3.22~3. 09(m, 2H), 3.09~2.98(m, 1H), 2.75~2.61(m, 3H), 2.51(td, J=8.6, 4.4Hz, 2H), 1.92(t, J=11.4Hz, 2H), 1.73~1.60(m, 2H).

[0541] Example 77: (2s,4s)-2-(4-(3-(pentafluoro-λ 6 -sulfanayl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0542] [ka]

[0543] The title compound was prepared analogously to Example 4, using 3-bromophenylsulfur pentafluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 18 H 21 Calculated mass for F5N2O3S, 440.1; observed m / z, 441.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.64~7.61(m, 1H), 7.56(t, J=2.0Hz, 1H), 7.42(t, J=7.9Hz, 1H), 7.33(d, J=7. 7Hz, 1H), 5.74(s, 1H), 4.84~4.75(m, 1H), 4.38(s, 2H), 3.85(d, J=13.3Hz, 1H) , 3.14(td, J=13.1, 2.4Hz, 1H), 3.09~3.01(m, 1H), 2.84(tt, J=12.5, 3.8Hz, 1H ), 2.74~2.60(m, 3H), 2.55~2.47(m, 2H), 1.99~1.91(m, 2H), 1.67~1.52(m, 2H).

[0544] Example 78: (2s,4s)-2-(4-(4-(pentafluoro-λ 6 -sulfanayl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0545] [ka]

[0546] The title compound was prepared analogously to Example 4, using 4-bromophenylsulfur pentafluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 18 H 21 Calculated mass for F5N2O3S, 440.1; observed m / z, 441.1 [M+H] + . 1H NMR (500MHz, CDCl3)δ 7.73~7.66(m, 2H), 7.27(d, J=8.0Hz, 2H), 6.09(s, 1H), 4.82~4.76(m, 1H), 4.38(s, 2H), 3.89~3.80(m, 1H), 3.14(td, J=13.1, 2.5Hz, 1 H), 3.03(p, J=8.1Hz, 1H), 2.82(tt, J=12.2, 3.6Hz, 1H), 2.75~2.62(m, 3H), 2.53~2.45(m, 2H), 1.96~1.89(m, 2H), 1.66~1.48(m, 2H).

[0547] Example 79: (2r,4s)-2-(4-(3-(tert-butyl)-4-fluorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0548] [ka]

[0549] The title compound was prepared in analogy to Example 4, using 4-bromo-2-tert-butyl-1-fluorobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 23 H 31 Calculated mass for FN2O2, 386.2; observed m / z, 387.3 [M+H] + . 1H NMR (500MHz, CDCl3)δ 7.07(dd, J=8.0, 2.2Hz, 1H), 6.99~6.89(m, 2H), 6.02(s, 1H), 4.79~4.73(m, 1H), 3.87~3.80(m, 1H), 3.13~2.99(m, 2H), 2.75~2.6 2(m, 2H), 2.61~2.51(m, 2H), 2.42~2.32(m, 4H), 2.27~2.20(m, 2H), 1.93~1.84(m, 2H), 1.62~1.44(m, 2H), 1.37(d, J=1.0Hz, 9H).

[0550] Example 80: (2s,4s)-2-(4-(4-isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0551] [ka]

[0552] The title compound was prepared analogously to Example 4, using 1-bromo-4-isobutylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 30 Calculated mass for N2O3, 370.2; observed m / z, 371.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.08(s, 4H), 6.21(s, 1H), 4.74(d, J=13.2Hz, 1H), 4.38(s, 2H), 3.82(d, J=13.5Hz, 1H), 3.15~3.06(m, 1H), 3.02(q, J=8.2Hz, 1H), 2.77~2.63(m, 4H), 2.53~2.41(m, 4H), 1.95~1.87(m, 2H), 1.84(dt, J=13.5, 6.8Hz, 1H), 1.66~1.46(m, 2H), 0.89(d, J=6.6Hz, 6H).

[0553] Example 81: (racemic)-(2s,4s)-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0554] [ka]

[0555] The title compound was prepared in analogy to Example 4, using 1-bromo-4-(1-methylcyclopropyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 6) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 23 H 30 Calculated mass for N2O3, 382.2; observed m / z, 383.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.22~7.17(m, 2H), 7.11~7.06(m, 2H), 6.04(s, 1H), 4.79~4.71(m, 1H), 4.52(q , J=6.5Hz, 1H), 3.83~3.73(m, 1H), 3.11(tt, J=13.0, 2.2Hz, 1H), 3.02~2.92(m , 1H), 2.77~2.59(m, 4H), 2.48~2.37(m, 2H), 1.94~1.85(m, 2H), 1.66~1.49(m, 2H), 1.44(d, J=6.5Hz, 3H), 1.39(s, 3H), 0.86~0.80(m, 2H), 0.74~0.68(m, 2H).

[0556] Example 82: (2s,4s)-2-(4-(3-(2-hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0557] [ka]

[0558] The title compound was prepared analogously to Example 4, using 2-(3-bromophenyl)propan-2-ol instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 28 Calculated mass for N2O4, 372.2; observed m / z, 355.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.31~7.22(m, 3H), 7.06(dt, J=7.2, 1.7Hz, 1H), 6.17(s, 1H), 4.80~4.72(m, 1H), 4.39(s, 2H), 3.88~3.79(m, 1H), 3.12(td, J=13. 1, 2.5Hz, 1H), 3.05(d, J=11.0Hz, 2H), 2.81~2.62(m, 4H), 2.54~2.43(m, 2H), 1.96~1.87(m, 2H), 1.68~1.53(m, 2H), 1.51(s, 6H).

[0559] Example 83: (2s,4s)-2-(4-(3-isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0560] [ka]

[0561] The title compound was prepared analogously to Example 4, using 1-bromo-3-isobutylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 30 Calculated mass for N2O3, 370.2; observed m / z, 371.2 [M+H] + . 1H NMR (400 MHz, CDCl) δ 7.21(t, J=7.6Hz, 1H), 7.00(tt, J=7.3, 1.3Hz, 2H), 6.95(t, J=1.8Hz, 1H) , 5.90(s, 1H), 4.80~4.71(m, 1H), 4.38(s, 2H), 3.82(d, J=13.4Hz, 1H), 3. 17~2.98(m, 2H), 2.76~2.62(m, 4H), 2.54~2.41(m, 4H), 1.97~1.88(m, 2H) , 1.83(dq, J=13.5, 6.8Hz, 1H), 1.67~1.48(m, 2H), 0.90(d, J=6.6Hz, 6H).

[0562] Example 84: (2s,4s)-2-(4-(4-(2-hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0563] [ka]

[0564] The title compound was prepared analogously to Example 4, using 2-(4-bromophenyl)propan-2-ol instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 28 Calculated mass for N2O4, 372.2; observed m / z, 355.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.38~7.32(m, 2H), 7.17~7.12(m, 2H), 5.87(s, 1H), 4.76(d, J=13.3Hz, 1H), 4.38(s, 2H), 3.82(d, J=13.4H) z, 1H), 3.06(s, 5H), 2.79~2.61(m, 4H), 2.50(dd, J=12.7, 8.8Hz, 2H), 1.93(d, J=12.9Hz, 2H), 1.51(s, 6H).

[0565] Example 85: (2s,4s)-2-(4-(3,5-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0566] [ka]

[0567] The title compound was prepared analogously to Example 4, using 5-bromo-m-xylene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 26 Calculated mass for N2O3, 342.2; observed m / z, 343.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 6.86(s, 1H), 6.79(s, 2H), 6.32(d, J=38.7Hz, 1H), 4.80~4.70(m, 1H), 4.39(s, 2H), 3.85~3.77(m, 1H), 3.14~3.06(m, 1H) , 3.02(pd, J=8.2, 1.5Hz, 1H), 2.76~2.61(m, 4H), 2.52~2.43(m, 2H), 2.29(s, 6H), 1.93~1.86(m, 2H), 1.65~1.48(m, 2H).

[0568] Example 86: (2s,4s)-2-(4-(2,4-difluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0569] [ka]

[0570] The title compound was prepared analogously to Example 4, using 1-bromo-2,4-difluoro-3-methylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 22Calculated mass for F2N2O3, 364.2; observed m / z, 365.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 6.92(td, J=8.5, 6.2Hz, 1H), 6.79(td, J=8.6, 1.5Hz, 1H), 5.86(s, 1H), 4.82~4.75(m, 1H), 4.38(s, 2H), 3.87~3.80(m, 1H), 3.14(td, J=1 3.1, 2.6Hz, 1H), 3.09~3.01(m, 2H), 2.74~2.62(m, 3H), 2.54~2.45(m, 2H), 2.18(t, J=1.9Hz, 3H), 1.92~1.82(m, 2H), 1.68~1.47(m, 2H).

[0571] Example 87: (2s,4s)-2-(4-(4-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0572] [ka]

[0573] The title compound was prepared analogously to Example 4, using (4-bromophenyl)trimethylsilane instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 30 Calculated mass for N2O3Si, 386.2; observed m / z, 387.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.51~7.45(m, 2H), 7.20~7.14(m, 2H), 6.01(s, 1H), 4.76(s, 1H), 4.38(s, 2H), 3.83(s, 1H), 3.19~ 3.00(m, 2H), 2.78~2.62(m, 4H), 2.53~2.45(m, 2H), 1.96~1.89(m, 2H), 1.59(s, 2H), 0.25(s, 9H).

[0574] Example 88: (2s,4s)-2-(4-(4-fluoro-2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0575] [ka]

[0576] The title compound was prepared analogously to Example 4, using 1-bromo-4-fluoro-2,3-dimethylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 25 Calculated mass for FN2O3, 360.2; observed m / z, 361.2 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 6.92(dd, J=8.7, 5.7Hz, 1H), 6.84(t, J=8.9Hz, 1H), 6.20(s, 1H), 4.81~4 .73(m, 1H), 4.38(s, 2H), 3.88~3.80(m, 1H), 3.13(td, J=13.1, 2.4Hz, 1H ), 3.08~2.91(m, 2H), 2.77~2.63(m, 3H), 2.48(tt, J=9.9, 2.0Hz, 2H), 2. 25(s, 3H), 2.20(d, J=2.2Hz, 3H), 1.86~1.78(m, 2H), 1.62~1.44(m, 2H).

[0577] Example 89: (2s,4s)-2-(4-(2,5-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0578] [ka]

[0579] The title compound was prepared analogously to Example 4, using 2,5-dimethylbromobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 26 Calculated mass for N2O3, 342.2; observed m / z, 343.2 [M+H] + . 1 H NMR (500 MHz, CDCl) δ 7.05(dd, J=7.6, 1.0Hz, 1H), 6.93(d, J=6.9Hz, 2H), 6.15(s, 1H), 4.82~4.74 (m, 1H), 4.39(s, 2H), 3.88~3.81(m, 1H), 3.13(td, J=13.1, 2.5Hz, 1H), 3.04 (p, J=8.1Hz, 1H), 2.93(tt, J=12.1, 3.5Hz, 1H), 2.78~2.64(m, 3H), 2.54~2. 43(m, 2H), 2.30(s, 3H), 2.29(s, 3H), 1.88~1.79(m, 2H), 1.67~1.48(m, 2H).

[0580] Example 90: (2s,4s)-2-(4-(3-ethyl-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0581] [ka]

[0582] The title compound was prepared analogously to Example 4, using 4-bromo-2-ethyl-1-fluorobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 25 Calculated mass for FN2O3, 360.2; observed m / z, 361.2 [M+H] + . 1H NMR (500MHz, CDCl3)δ 6.99(dd, J=7.3, 2.0Hz, 1H), 6.97~6.90(m, 2H), 6.14(s, 1H), 4.79~4.71(m, 1H), 4.38(s, 2H), 3.86~3.78(m, 1H), 3.11(td, J=13.1, 2 .5Hz, 1H), 3.03(p, J=8.1Hz, 1H), 2.75~2.60(m, 6H), 2.53~2.44(m, 2H), 1.93~1.86(m, 2H), 1.63~1.46(m, 2H), 1.21(t, J=7.6Hz, 3H).

[0583] Example 91: (2s,4s)-2-(4-(3,5-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0584] [ka]

[0585] The title compound was prepared analogously to Example 4, using 5-bromo-1,3-difluoro-2-methylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 19 H 22 Calculated mass for F2N2O3, 364.2; observed m / z, 365.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 6.69~6.63(m, 2H), 5.99(s, 1H), 4.78~4.72(m, 1H), 4.38(s, 2H), 3.85~3.79(m, 1H), 3.10(td, J=13.1, 2.5Hz, 1H), 3. 07~2.98(m, 1H), 2.75~2.59(m, 4H), 2.53~2.46(m, 2H), 2.15(t, J=1.7Hz, 3H), 1.94~1.85(m, 2H), 1.59~1.43(m, 2H).

[0586] Example 92: (2S * ,4s,8R *)-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0587] [ka]

[0588] The title compound was prepared via isolation of (racemic)-(2s,4s)-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 81) by supercritical fluid chromatography (stationary phase: Whelk O1 SS, 5 μm, 250 × 21 mm; mobile phase: 30% MeOH, 70% CO with 0.2% TEA). MS (ESI): C 23 H 30 Calculated mass for N2O3, 382.2; observed m / z, 383.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.22~7.16(m, 2H), 7.11~7.06(m, 2H), 5.86(s, 1H), 4.79~4.72(m, 1H), 4.51(q, J =6.5Hz, 1H), 3.79(d, J=13.5Hz, 1H), 3.11(t, J=13.0Hz, 1H), 2.99(tt, J=8.8, 6. 6Hz, 1H), 2.76~2.55(m, 4H), 2.48~2.37(m, 2H), 1.94~1.85(m, 2H), 1.67~1.48(m , 2H), 1.44(d, J=6.5Hz, 3H), 1.39(s, 3H), 0.86~0.80(m, 2H), 0.75~0.68(m, 2H).

[0589] Example 93: (2R * ,4s,8s * )-8-Methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0590] [ka]

[0591] The title compound was prepared via isolation of (racemic)-(2s,4s)-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 81) by supercritical fluid chromatography (stationary phase: Whelk O1 SS, 5 μm, 250 × 21 mm; mobile phase: 30% MeOH, 70% CO with 0.2% TEA). MS (ESI): C 23 H 30 Calculated mass for N2O3, 382.2; observed m / z, 383.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.22~7.16(m, 2H), 7.12~7.06(m, 2H), 6.02(s, 1H), 4.79~4.72(m, 1H), 4.52(q, J=6 .5Hz, 1H), 3.79(dd, J=13.3, 3.6Hz, 1H), 3.11(tt, J=13.0, 2.1Hz, 1H), 2.98(tt, J=8 .6, 6.9Hz, 1H), 2.76~2.55(m, 4H), 2.48~2.37(m, 2H), 1.94~1.85(m, 2H), 1.67~1.4 8(m, 2H), 1.45(d, J=6.5Hz, 3H), 1.39(s, 3H), 0.87~0.81(m, 2H), 0.74~0.69(m, 2H).

[0592] Example 94: (2s,4s)-2-(4-(3-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0593] [ka]

[0594] The title compound was prepared analogously to Example 4, using 1-bromo-3-(trimethylsilyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 21 H 30 Calculated mass for N2O3Si, 386.2; observed m / z, 387.2 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 7.39(dt, J=7.2, 1.3Hz, 1H), 7.33~7.28(m, 2H), 7.16(dt, J=7.6, 1.7Hz , 1H), 6.01(s, 1H), 4.82~4.72(m, 1H), 4.39(s, 2H), 3.87~3.79(m, 1H), 3.13(td, J=13.1, 2.5Hz, 1H), 3.04(q, J=8.1Hz, 1H), 2.81~2.60(m, 4H) , 2.54~2.44(m, 2H), 1.96~1.88(m, 2H), 1.70~1.49(m, 2H), 0.26(s, 9H).

[0595] Example 95: (2r,4s)-2-(4-(4-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0596] [ka]

[0597] The title compound was prepared in analogy to Example 4, using (4-bromophenyl)trimethylsilane instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 22 H 32 Calculated mass for N2O2Si, 384.2; observed m / z, 385.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.50~7.44(m, 2H), 7.20~7.14(m, 2H), 5.92(s, 1H), 4.80~4.70(m, 1H), 3.85(d, J=13.3Hz, 1H), 3.16~2.98(m, 2H), 2.78~2.47(m, 4H), 2.44~2.31(m, 4H), 2.27~2.20(m, 2H), 1.91(d, J=13.4Hz, 2H), 1.69~1.50(m, 2H), 0.26(s, 9H).

[0598] Example 96: (2r,4s)-2-(4-(3-isobutylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0599] [ka]

[0600] The title compound was prepared in analogy to Example 4, using 1-bromo-3-isobutylbenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 23 H 32 Calculated mass for N2O2, 368.2; observed m / z, 369.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.21(t, J=7.6Hz, 1H), 7.02~6.97(m, 2H), 6.95(d, J=1.8Hz, 1H), 6.08(s, 1H), 4.79~4.71(m, 1H), 3.88~3.79(m, 1H), 3.14~2.98(m, 2H), 2. 76~2.51(m, 4H), 2.45(d, J=7.1Hz, 2H), 2.43~2.33(m, 4H), 2.27~2.19(m, 2H), 1.94~1.76(m, 3H), 1.67~1.48(m, 2H), 0.89(d, J=6.6Hz, 6H).

[0601] Example 97: (2s,4s)-2-(4-(4-(tert-butyl)-3-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0602] [ka]

[0603] The title compound was prepared analogously to Example 4, using 4-bromo-1-tert-butyl-2-methoxybenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 23 H 32 Calculated mass for N2O4, 400.2; observed m / z, 401.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.20(dd, J=7.8, 2.5Hz, 1H), 6.74~6.64(m, 2H), 6.62~3.07(m, 1H), 4.80~4.72(m, 1H), 4.39(s, 2H), 3.88~3.77(m, 4H), 3.17~2.96(m, 2H), 2.78~2.61(m, 4H), 2.52~2.42(m, 2H), 1.97~1.88(m, 2H), 1.67~1.46(m, 2H), 1.35(s, 9H).

[0604] Example 98: (2s,4s)-2-(4-(4-methoxy-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0605] [ka]

[0606] The title compound was prepared analogously to Example 4, using 4-methoxy-3-(trifluoromethyl)bromobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.36(d, J=2.3Hz, 1H), 7.30(dd, J=8.5, 2.4Hz, 1H), 6.95(d, J=8.6Hz, 1H), 6.02(s, 1H), 4.82~4.71(m, 1H), 4.38(s, 2H), 3.8 8(s, 3H), 3.86~3.79(m, 1H), 3.17~2.98(m, 2H), 2.79~2.61(m, 4H), 2.54~2.44(m, 2H), 1.94~1.86(m, 2H), 1.63~1.44(m, 2H).

[0607] Example 99: (racemic)-(2s,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0608] [ka]

[0609] The title compound was prepared analogously to Example 4, using 1-bromo-4-(sec-butyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A. MS (ESI): C 22 H 30 Calculated mass for N2O3, 370.2; observed m / z, 371.2 [M+H] + . 1H NMR (500 MHz, CDCl) δ 7.10(q, J=8.4Hz, 4H), 6.05(s, 1H), 4.78~4.71(m, 1H), 4.38(s, 2H), 3.8 5~3.78(m, 1H), 3.11(td, J=13.1, 2.5Hz, 1H), 3.03(p, J=8.1Hz, 1H), 2.7 6~2.63(m, 4H), 2.57(hept, J=7.0Hz, 1H), 2.52~2.43(m, 2H), 1.96~1.88 (m, 2H), 1.65~1.47 (m, 4H), 1.22 (d, J=7.0Hz, 3H), 0.82 (t, J=7.4Hz, 3H).

[0610] Example 100: (racemic)-(2r,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0611] [ka]

[0612] The title compound was prepared in analogy to Example 4, using 1-bromo-4-(sec-butyl)benzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in Step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 23 H 32 Calculated mass for N2O2, 368.2; observed m / z, 369.2 [M+H] + . 1H NMR (500MHz, CDCl3)δ 7.14~7.06(m, 4H), 6.09(s, 1H), 4.78~4.71(m, 1H), 3.88~3.80(m, 1H), 3.14~2.99(m, 2H), 2.75~2.61(m, 2H), 2.61~2.51(m, 3H), 2. 42~2.31(m, 4H), 2.27~2.19(m, 2H), 1.90(dt, J=13.5, 3.2Hz, 2H), 1.65~1.48(m, 4H), 1.22(d, J=7.0Hz, 3H), 0.82(t, J=7.4Hz, 3H).

[0613] Example 101: (2s,4s)-2-(4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0614] [ka]

[0615] The title compound was prepared analogously to Steps B and C of Example 4, except that in Step B, tert-butyl 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate (Intermediate 9) was used instead of tert-butyl 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate. MS (ESI): C 19 H 22 Calculated mass for N4O3, 354.2; observed m / z, 355.2 [M+H] + . 1H NMR (500MHz, CDCl3)δ 11.32(s, 1H), 8.24~8.19(m, 1H), 7.85(dd, J=7.8, 1.5Hz, 1H), 7.07~7.02(m, 1H), 6.21~6.18(m, 1H), 4.73(d, J=12.9Hz, 1H), 4.39(s, 2H), 3.85 (d.

[0616] Example 102: (2s,4s)-2-[4-(6-fluorobenzofuran-3-yl)piperidine-1-carbonyl]-6-oxa-8-azaspiro[3.4]octan-7-one.

[0617] [ka]

[0618] The title compound was prepared analogously to Example 4, Step C, using 4-(6-fluorobenzofuran-3-yl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 21 Calculated mass for FN2O4, 372.1; observed m / z, 373.1 [M+H] + . 1H NMR (400MHz, chloroform-d)δ 7.45(dd, J=8.6, 5.3Hz, 1H), 7.37(d, J=1.0Hz, 1H), 7.19(dd, J=9.0, 2.3Hz, 1H), 7.01(d dd, J=9.4, 8.6, 2.3Hz, 1H), 5.70(s, 1H), 4.73(d, J=13.4Hz, 1H), 4.38(s, 2H), 3.83(d, J= 13.9Hz, 1H), 3.19(t, J=13.0Hz, 1H), 3.10~2.92(m, 2H), 2.79(t, J=12.8Hz, 1H), 2.66(d, J=7.3Hz, 2H), 2.55~2.45(m, 2H), 2.12(d, J=13.5Hz, 2H), 1.65(dd, J=25.4, 12.0Hz, 2H).

[0619] Example 103: (2s,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0620] [ka]

[0621] The title compound was prepared analogously to Example 4, Step C, using 4-(4-trifluoromethylphenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 21 Calculated mass for F3N2O3, 382.1; observed m / z, 383.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.56(d, J=7.8Hz, 2H), 7.29(d, J=7.9Hz, 2H), 6.53(s, 1H), 4.77(d, J=11.7Hz, 1H), 4.38(s, 2H), 3.86(d, J=12.6Hz, 1H), 3.21~3.07(m, 1H), 3.07~2.93(m, 1H), 2.90~2.60(m, 4H), 2.55~2.38(m, 2H), 1.92(d, J=12.2Hz, 2H), 1.69~1.47(m, 2H).

[0622] Example 104: (2s,4s)-2-(4-(benzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0623] [ka]

[0624] The title compound was prepared analogously to Step C of Example 4, using 4-(benzofuran-2-yl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 22 Calculated mass for N2O4, 354.2; observed m / z, 355.2 [M+H] + . 1 H NMR (500 MHz, CDCl) δ 7.53~7.47(m, 1H), 7.43~7.38(m, 1H), 7.25~7.16(m, 2H), 6.39(t, J=1.0Hz, 1H), 5.98(s, 1H), 4.67~4.58(m, 1H), 4.38(s, 2H), 3.84~3.74(m , 1H), 3.24~3.13(m, 1H), 3.08~2.97(m, 2H), 2.90~2.81(m, 1H), 2.73~ 2.62(m, 2H), 2.52~2.44(m, 2H), 2.20~2.08(m, 2H), 1.77~1.59(m, 2H).

[0625] Example 105: (2s,4s)-2-(4-(naphthalen-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0626] [ka]

[0627] The title compound was prepared analogously to Example 4, Step C, using 4-(2-naphthyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 22 H 24 Calculated mass for N2O3, 364.2; observed m / z, 365.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.84~7.75(m, 3H), 7.63~7.59(m, 1H), 7.50~7.41(m, 2H), 7.35~7.30(m, 1H), 5.93(s, 1H), 4.86~4.74(m, 1H), 4.39(s, 2H), 3.92~3.80(m, 1) H), 3.25~3.12(m, 1H), 3.12~3.01(m, 1H), 2.98~2.85(m, 1H), 2.80~2.62(m, 3H), 2.58~2.45(m, 2H), 2.08~1.94(m, 2H), 1.82~1.54(m, 2H).

[0628] Example 106: (2s,4s)-2-(4-(1H-indol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0629] [ka]

[0630] The title compound was prepared analogously to Step C of Example 4, using 2-(piperidin-4-yl)-1H-indole instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 23 Calculated mass for N3O3, 353.2; observed m / z, 354.2 [M+H] + . 1H NMR (500MHz, CDCl3)δ 8.51(s, 1H), 7.56~7.50(m, 1H), 7.35~7.31(m, 1H), 7.15~7.10(m, 1H), 7.1 0~7.03(m, 1H), 6.48(s, 1H), 6.26~6.21(m, 1H), 4.68(d, J=13.3Hz, 1H), 4. 41(s, 2H), 3.82(d, J=13.6Hz, 1H), 3.22~3.12(m, 1H), 3.08~2.94(m, 2H), 2 .84~2.66(m, 3H), 2.56~2.42(m, 2H), 2.11~2.01(m, 2H), 1.79~1.66(m, 2H).

[0631] Example 107: (2s,4s)-2-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0632] [ka]

[0633] The title compound was prepared analogously to Step C of Example 4, using 4-(4-(trifluoromethoxy)phenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 21 Calculated mass for F3N2O4, 398.1; observed m / z, 399.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.22~7.17(m, 2H), 7.17~7.13(m, 2H), 6.03(s, 1H), 4.80~4.74(m, 1H), 4.38(s, 2H), 3.87~3.80(m, 1H), 3.12(td, J=13.1, 2.5Hz, 1H ), 3.03(p, J=8.1Hz, 1H), 2.77(tt, J=12.1, 3.6Hz, 1H), 2.73~2.63(m, 3H), 2.54~2.45(m, 2H), 1.94~1.88(m, 2H), 1.64~1.47(m, 2H).

[0634] Example 108: (2s,4s)-2-(4-(4-(methylthio)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0635] [ka]

[0636] The title compound was prepared analogously to Step C of Example 4, using 4-(4-methylsulfanyl-phenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 Calculated mass for N2O3S, 360.2; observed m / z, 361.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.26~7.21(m, 2H), 7.15~7.09(m, 2H), 5.91(s, 1H), 4.87~4.65(m, 1H), 4.40(s, 2H), 3.96~3.72(m, 1H), 3. 22~2.99(m, 2H), 2.80~2.60(m, 4H), 2.55~2.48(m, 3H), 2.49(s, 3H), 1.96~1.86(m, 2H), 1.70~1.64(m, 1H).

[0637] Example 109: (2s,4s)-2-(4-(4-(dimethylamino)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0638] [ka]

[0639] The title compound was prepared analogously to Step C of Example 4, using N,N-dimethyl-4-(piperidin-4-yl)aniline instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C20 H 27 Calculated mass for N3O3, 357.2; observed m / z, 358.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.13~7.00(m, 2H), 6.84~6.61(m, 2H), 5.90(s, 1H), 4.78~4.69(m, 1H), 4.38(s, 2H), 3.85~3.76(m, 1H), 3.15~3.06( m, 1H), 3.06~2.98(m, 1H), 2.94(s, 6H), 2.74~2.61(m, 4H), 2.55~2.44(m, 2H), 1.93~1.84(m, 2H), 1.74~1.43(m, 2H).

[0640] Example 110: (2s,4s)-2-(4-(5-chlorobenzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0641] [ka]

[0642] The title compound was prepared analogously to Step C of Example 4, using 4-(5-chloro-1-benzofuran-2-yl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 21 Calculated mass for ClN2O4, 388.1; observed m / z, 389.0 [M+H] + . 1H NMR (400 MHz, CDCl) δ 7.45(d, J=2.1Hz, 1H), 7.31(d, J=8.7Hz, 1H), 7.21~7.14(m, 1H), 6.36~ 6.31(m, 1H), 6.28(s, 1H), 4.73~4.51(m, 1H), 4.38(s, 2H), 3.89~3.72( m, 1H), 3.26~3.07(m, 1H), 3.07~2.94(m, 2H), 2.93~2.75(m, 1H), 2.75~ 2.61(m, 2H), 2.55~2.41(m, 2H), 2.20~2.05(m, 2H), 1.76~1.57(m, 2H).

[0643] Example 111: (2s,4s)-2-(4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0644] [ka]

[0645] The title compound was prepared analogously to Example 4, Step C, using 4-phenylpiperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 22 Calculated mass for N2O3, 314.2; observed m / z, 315.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.35~7.28(m, 2H), 7.25~7.13(m, 3H), 6.29(s, 1H), 4.81~4.69(m, 1H), 4.39(s, 2H), 3.90~3.76(m, 1H), 3.19~ 3.07(m, 1H), 3.07~2.96(m, 1H), 2.81~2.60(m, 4H), 2.53~2.41(m, 2H), 1.98~1.87(m, 2H), 1.69~1.47(m, 2H).

[0646] Example 112: (2s,4s)-2-(4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0647] [ka]

[0648] The title compound was prepared analogously to Example 4, Step C, using 4-(4-methylphenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 Calculated mass for N2O3, 328.2; observed m / z, 329.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.16~7.09(m, 2H), 7.09~7.03(m, 2H), 6.41(s, 1H), 4.81~4.67(m, 1H), 4.39(s, 2H), 3.87~3.77(m, 1H), 3.18~3.06( m, 1H), 3.06~2.96(m, 1H), 2.79~2.59(m, 4H), 2.53~2.40(m, 2H), 2.32(s, 3H), 1.97~1.84(m, 2H), 1.66~1.46(m, 2H).

[0649] Example 113: (2s,4s)-2-(4-(naphthalen-1-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0650] [ka]

[0651] The title compound was prepared analogously to Step C of Example 4, using 4-(naphthalen-1-yl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 22 H 24 Calculated mass for N2O3, 364.2; observed m / z, 365.1 [M+H] + . 1H NMR (400MHz, CDCl3)δ 8.08(d, J=8.3Hz, 1H), 7.90~7.84(m, 1H), 7.74(d, J=8.2Hz, 1H), 7.57~7.46(m, 2H), 7 .46~7.39(m, 1H), 7.35~7.28(m, 1H), 6.45(s, 1H), 4.92~4.77(m, 1H), 4.39(s, 2H), 3. 98~3.84(m, 1H), 3.64~3.51(m, 1H), 3.34~3.20(m, 1H), 3.12~3.00(m, 1H), 2.92~2.79 (m, 1H), 2.79~2.67(m, 2H), 2.54~2.42(m, 2H), 2.14~2.02(m, 2H), 1.84~1.60(m, 2H).

[0652] Example 114: (2s,4s)-2-(4-(4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0653] [ka]

[0654] The title compound was prepared analogously to Example 4, Step C, using 4-(4-fluorophenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 Calculated mass for FN2O3, 332.2; observed m / z, 333.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.17~7.09(m, 2H), 7.03~6.95(m, 2H), 6.08(s, 1H), 4.83~4.68(m, 1H), 4.38(s, 2H), 3.88~3.76(m, 1H), 3.19~ 3.06(m, 1H), 3.06~2.97(m, 1H), 2.80~2.59(m, 4H), 2.56~2.43(m, 2H), 1.97~1.83(m, 2H), 1.65~1.42(m, 2H).

[0655] Example 115: (2s,4s)-2-(4-(3-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0656] [ka]

[0657] The title compound was prepared analogously to Example 4, Step C, using 4-(3-chlorophenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 Calculated mass for ClN2O3, 348.1; observed m / z, 349.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.26~7.12(m, 3H), 7.08~7.02(m, 1H), 6.45(s, 1H), 4.84~4.63(m, 1H), 4.38(s, 2H), 3.91~3.72(m, 1 H), 3.22~2.93(m, 2H), 2.80~2.56(m, 4H), 2.55~2.39(m, 2H), 1.99~1.80(m, 2H), 1.68~1.42(m, 2H).

[0658] Example 116: (2s,4s)-2-(4-(o-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0659] [ka]

[0660] The title compound was prepared analogously to Example 4, Step C, using 4-(2-methylphenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24Calculated mass for N2O3, 328.2; observed m / z, 329.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.21~7.07(m, 4H), 6.37(s, 1H), 4.84~4.72(m, 1H), 4.39(s, 2H), 3.90~3.79(m, 1H), 3.19~3.09(m, 1H), 3. 09~2.90(m, 2H), 2.79~2.61(m, 3H), 2.53~2.42(m, 2H), 2.35(s, 3H), 1.90~1.79(m, 2H), 1.66~1.48(m, 2H).

[0661] Example 117: (2s,4s)-2-(4-(4-ethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0662] [ka]

[0663] The title compound was prepared analogously to Example 4, Step C, using 4-(4-ethylphenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 26 Calculated mass for N2O3, 342.2; observed m / z, 343.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.18~7.12(m, 2H), 7.12~7.06(m, 2H), 6.23(s, 1H), 4.80~4.68(m, 1H), 4.39(s, 2H), 3.88~3.74(m, 1H), 3.18~ 2.97(m, 2H), 2.79~2.55(m, 6H), 2.53~2.40(m, 2H), 1.96~1.85(m, 2H), 1.67~1.47(m, 2H), 1.29~1.18(m, 3H).

[0664] Example 118: (2s,4s)-2-(4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0665] [ka]

[0666] The title compound was prepared analogously to Example 4, Step C, using 4-(3-trifluoromethylphenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 21 Calculated mass for F3N2O3, 382.1; observed m / z, 383.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.52~7.34(m, 4H), 5.96(s, 1H), 4.85~4.73(m, 1H), 4.39(s, 2H), 3.90~3.79(m, 1H), 3.20~3.09(m, 1H), 3.09~ 2.97(m, 1H), 2.88~2.77(m, 1H), 2.77~2.61(m, 3H), 2.56~2.45(m, 2H), 1.99~1.89(m, 2H), 1.62~1.50(m, 2H).

[0667] Example 119: (2s,4s)-2-(4-(2-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0668] [ka]

[0669] The title compound was prepared analogously to Example 4, Step C, using 4-(2-fluorophenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H21 Calculated mass for FN2O3, 332.2; observed m / z, 333.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.24~7.06(m, 3H), 7.06~6.98(m, 1H), 6.11(s, 1H), 4.81~4.72(m, 1H), 4.38(s, 2H), 3.88~3.78(m, 1 H), 3.20~2.96(m, 3H), 2.77~2.63(m, 3H), 2.54~2.42(m, 2H), 1.96~1.83(m, 2H), 1.69~1.50(m, 2H).

[0670] Example 120: (2s,4s)-2-(4-(3-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0671] [ka]

[0672] The title compound was prepared analogously to Example 4, Step C, using 4-(3-fluorophenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 Calculated mass for FN2O3, 332.2; observed m / z, 333.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.31~7.23(m, 1H), 6.99~6.84(m, 3H), 5.96(s, 1H), 4.81~4.70(m, 1H), 4.38(s, 2H), 3.89~3.77(m, 1 H), 3.19~2.96(m, 2H), 2.82~2.60(m, 4H), 2.55~2.44(m, 2H), 1.98~1.87(m, 2H), 1.61~1.45(m, 2H).

[0673] Example 121: (2s,4s)-2-(4-(4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0674] [ka]

[0675] The title compound was prepared analogously to Example 4, Step C, using 4-(4-chlorophenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 Calculated mass for ClN2O3, 348.1; observed m / z, 349.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.31~7.27(m, 2H), 7.14~7.08(m, 2H), 5.84(s, 1H), 4.80~4.71(m, 1H), 4.38(s, 2H), 3.86~3.76(m, 1 H), 3.17~2.98(m, 2H), 2.79~2.60(m, 4H), 2.55~2.45(m, 2H), 1.95~1.85(m, 2H), 1.59~1.44(m, 2H).

[0676] Example 122: (2s,4s)-2-(4-(m-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0677] [ka]

[0678] The title compound was prepared analogously to Example 4, Step C, using 4-(3-methylphenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 Calculated mass for N2O3, 328.2; observed m / z, 329.1 [M+H]+ . 1 H NMR (400MHz, CDCl3)δ 7.23~7.16(m, 1H), 7.06~7.01(m, 1H), 7.01~6.94(m, 2H), 6.01(s, 1H), 4.80~4.69(m, 1H), 4.38(s, 2H), 3.87~3.76( m, 1H), 3.17~2.98(m, 2H), 2.77~2.61(m, 4H), 2.54~2.43(m, 2H), 2.34(s, 3H), 1.96~1.85(m, 2H), 1.65~1.47(m, 2H).

[0679] Example 123: (2s,4s)-2-(4-(4-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0680] [ka]

[0681] The title compound was prepared analogously to Step C of Example 4, using 4-(4-methoxyphenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 Calculated mass for N2O4, 344.2; observed m / z, 345.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.13~7.06(m, 2H), 6.88~6.81(m, 2H), 6.08(s, 1H), 4.80~4.69(m, 1H), 4.38(s, 2H), 3.85~3.78(m, 1H), 3. 79(s, 3H), 3.16~2.97(m, 2H), 2.76~2.59(m, 4H), 2.53~2.42(m, 2H), 1.96~1.84(m, 2H), 1.64~1.43(m, 2H).

[0682] Example 124: (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0683] [ka]

[0684] The title compound was prepared analogously to Step C of Example 4, using 4-[4-(tert-butyl)phenyl]piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 22 H 30 Calculated mass for N2O3, 370.2; observed m / z, 371.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.36~7.29(m, 2H), 7.16~7.07(m, 2H), 6.00(s, 1H), 4.81~4.70(m, 1H), 4.38(s, 2H), 3.87~3.76(m, 1H), 3. 16~2.98(m, 2H), 2.78~2.60(m, 4H), 2.54~2.42(m, 2H), 1.98~1.85(m, 2H), 1.65~1.44(m, 2H), 1.31(s, 9H).

[0685] Example 125: (2r,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0686] [ka]

[0687] The title compound was prepared analogously to Step C of Example 4, using 4-(4-trifluoromethylphenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C20 H 23 Calculated mass for F3N2O2, 380.2; observed m / z, 381.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.57(d, J=8.0Hz, 2H), 7.29(d, J=8.0Hz, 2H), 6.10(s, 1H), 4.83~4.73(m, 1H), 3.92~3.82(m, 1H), 3.18~2.99(m, 2H), 2.87~2. 75(m, 1H), 2.72~2.62(m, 1H), 2.62~2.50(m, 2H), 2.43~2.33(m, 4H), 2.27~2.19(m, 2H), 1.95~1.86(m, 2H), 1.68~1.49(m, 2H).

[0688] Example 126: (2r,4s)-2-(4-(5-chlorobenzofuran-2-yl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0689] [ka]

[0690] The title compound was prepared in analogy to Step C of Example 4, using 4-(5-chloro-1-benzofuran-2-yl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 21 H 23 Calculated mass for ClN2O3, 386.1; observed m / z, 387.0 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.47~7.42(m, 1H), 7.34~7.27(m, 1H), 7.21~7.12(m, 1H), 6.41~5.99(m, 2H), 4.70~4.55(m, 1H), 3.88~3.76(m, 1H), 3.22~3.09(m, 1H), 3.09~2.92(m, 2H), 2.87~2.74(m, 1H), 2.61~2.48(m, 2H), 2.43~2.31(m, 4H), 2.27~2.18(m, 2H), 2.18~2.04(m, 2H), 1.76~1.55(m, 2H).

[0691] Example 127: (2r,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0692] [ka]

[0693] The title compound was prepared in analogy to Step C of Example 4, using 4-[4-(tert-butyl)phenyl]piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 23 H 32 Calculated mass for N2O2, 368.2; observed m / z, 369.1 [M+H] + . 1H NMR (500MHz, CDCl3)δ 7.36~7.30(m, 2H), 7.15~7.09(m, 2H), 6.02(s, 1H), 4.79~4.71(m, 1H), 3.88~3.79(m, 1H), 3.14~2.99(m, 2H), 2.76~2.6 2(m, 2H), 2.62~2.50(m, 2H), 2.44~2.32(m, 4H), 2.26~2.20(m, 2H), 1.95~1.85(m, 2H), 1.65~1.48(m, 2H), 1.31(s, 9H).

[0694] Example 128: (2s,4s)-2-(4-methyl-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0695] [ka]

[0696] The title compound was prepared analogously to Example 4, Step C, using 4-methyl-4-phenylpiperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 Calculated mass for N2O3, 328.2; observed m / z, 329.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.38~7.28(m, 4H), 7.25~7.19(m, 1H), 6.09(s, 1H), 4.36(s, 2H), 3.81~3.73(m, 1H), 3.54~3.39(m, 2H), 3.32~3.23(m, 1H), 2.98(p, J=8.1Hz, 1H), 2.72~2.55(m, 2H), 2.51~2.37(m, 2H), 2.20~2.05(m, 2H), 1.77~1.61(m, 2H), 1.27(s, 3H).

[0697] Example 129: (2s,4s)-2-(4-(6-chlorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0698] [ka]

[0699] The title compound was prepared analogously to Step C of Example 4, using 6-chloro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 20 Calculated mass for ClN3O4, 389.1; observed m / z, 390.1 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 7.60(d, J=1.6Hz, 1H), 7.58(d, J=8.4Hz, 1H), 7.31(dd, J=8.4, 1.7Hz, 1H) , 5.75(s, 1H), 4.60(d, J=13.5Hz, 1H), 4.39(s, 2H), 3.88(d, J=13.5Hz, 1H ), 3.34 (tt, J=11.0, 3.9Hz, 1H), 3.30~3.18 (m, 1H), 3.11~2.91 (m, 2H), 2. 76~2.60(m, 2H), 2.56~2.46(m, 2H), 2.21~2.09(m, 2H), 2.01~1.80(m, 2H).

[0700] Example 130: (2s,4s)-2-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0701] [ka]

[0702] The title compound was prepared analogously to Step C of Example 4, using 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 21 Calculated mass for ClN4O4, 416.1; observed m / z, 417.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.04~7.95(m, 2H), 7.49~7.43(m, 2H), 5.63(s, 1H), 4.48(d, J=13.4Hz, 1H), 4.38(s, 2H), 3.80(d, J=14.0Hz, 1H), 3 .33~3.19(m, 2H), 3.09~2.98(m, 2H), 2.71~2.60(m, 2H), 2.56~2.47(m, 2H), 2.23~2.14(m, 2H), 1.97~1.82(m, 2H).

[0703] Example 131: (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one.

[0704] [ka]

[0705] The title compound was prepared in analogy to Step C of Example 4, using 4-[4-(tert-butyl)phenyl]piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride, and (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 6) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.3 [M+H]+ . 1 H NMR (400 MHz, CDCl) δ 7.36~7.30(m, 2H), 7.14~7.08(m, 2H), 6.07(s, 1H), 4.80~4.70(m, 1H), 4.52(q, J=6.5Hz, 1H), 3.84~3.73(m, 1H), 3.18~3.05(m, 1H), 2.98(tt, J=8.7, 7.0Hz, 1H), 2.79~2.57(m, 4H), 2.50~2.36(m, 2H), 1.92(dt, J=13.7, 2.2Hz, 2H), 1.67~1.48(m, 2H), 1.45(d, J=6.5Hz, 3H), 1.31(s, 9H).

[0706] Example 132: (2S * ,4s,8R * )-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one.

[0707] [ka]

[0708] The title compound was prepared via isolation of (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one (Example 131) by supercritical fluid chromatography (stationary phase: Lux Cellulose 4, 5 μm, 250 × 21 mm; mobile phase: 50% MeOH, 50% CO). MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.3 [M+H] + . 1H NMR (500 MHz, CDCl) δ 7.35~7.31(m, 2H), 7.13~7.09(m, 2H), 5.91(s, 1H), 4.80~4.72(m, 1H), 4. 51(q, J=6.5Hz, 1H), 3.79(d, J=13.5Hz, 1H), 3.11(t, J=13.2Hz, 1H), 2.99 (tt, J=8.7, 6.7Hz, 1H), 2.77~2.58(m, 4H), 2.47~2.37(m, 2H), 1.92(dd, J =13.9, 3.5Hz, 2H), 1.62~1.48(m, 2H), 1.45(d, J=6.5Hz, 3H), 1.31(s, 9H).

[0709] Example 133: (2R * ,4s,8s * )-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one.

[0710] [ka]

[0711] The title compound was prepared via isolation of (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one (Example 131) by chiral supercritical fluid chromatography (stationary phase: Lux Cellulose 4, 5 μm, 250 × 21 mm; mobile phase: 50% MeOH, 50% CO). MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.3 [M+H] + . 1H NMR (500MHz, CDCl3)δ 7.37~7.30(m, 2H), 7.14~7.08(m, 2H), 5.99(s, 1H), 4.80~4.71(m, 1H), 4.52 (q, J=6.5Hz, 1H), 3.80(dd, J=13.8, 3.4Hz, 1H), 3.11(tt, J=13.0, 2.4Hz, 1H) , 2.99(tt, J=8.7, 6.7Hz, 1H), 2.77~2.59(m, 4H), 2.47~2.37(m, 2H), 1.92(dt , J=13.7, 2.4Hz, 2H), 1.67~1.49(m, 2H), 1.45(d, J=6.4Hz, 3H), 1.31(s, 9H).

[0712] Example 134: (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8,8-dimethyl-7-oxa-5-azaspiro[3.4]octan-6-one.

[0713] [ka]

[0714] The title compound was prepared in analogy to Step C of Example 4, using 4-[4-(tert-butyl)phenyl]piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride, and (2s,4s)-8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 7) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 24 H 34 Calculated mass for N2O3, 398.3; observed m / z, 399.3 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.36~7.31(m, 2H), 7.15~7.08(m, 2H), 6.19(s, 1H), 4.82~4.72(m, 1H), 3.83~3.73(m, 1H), 3.18~2.99(m, 2H), 2. 80~2.61(m, 4H), 2.43~2.32(m, 2H), 1.92(dt, J=13.5, 3.2Hz, 2H), 1.70~1.47(m, 2H), 1.41(s, 6H), 1.31(s, 9H).

[0715] Example 135: (2s,4s)-2-(4-(4-chlorophenyl)-4-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0716] [ka]

[0717] The title compound was prepared analogously to Step C of Example 4, using 4-(4-chlorophenyl)-4-methyl-piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 23 Calculated mass for ClN2O3, 362.1; observed m / z, 363.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.34~7.28(m, 2H), 7.26~7.21(m, 2H), 6.22(s, 1H), 4.36(s, 2H), 3.78~3.69(m, 1H), 3.55~3.38(m, 2H), 3.31~3.22(m, 1H), 2.97(p, J=8.2Hz, 1H), 2.71~2.56(m, 2H), 2.51~2.35(m, 2H), 2.10~1.99(m, 2H), 1.71~1.62(m, 2H), 1.25(s, 3H).

[0718] Example 136: (2s,4s)-2-(4-(benzo[d]thiazol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0719] [ka]

[0720] The title compound was prepared analogously to Step C of Example 4, using 2-(4-piperidyl)-1,3-benzothiazole instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 21 Calculated mass for N3O3S, 371.1; observed m / z, 372.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.97(dt, J=8.2, 0.9Hz, 1H), 7.86(dt, J=8.0, 0.9Hz, 1H), 7.49~7.44(m, 1H), 7.39 ~7.34(m, 1H), 6.19(s, 1H), 4.69~4.60(m, 1H), 4.38(s, 2H), 3.89~3.80(m, 1H), 3.3 5(tt, J=11.2, 3.9Hz, 1H), 3.26~3.16(m, 1H), 3.02(p, J=8.2Hz, 1H), 2.94~2.85(m , 1H), 2.75~2.64(m, 2H), 2.54~2.44(m, 2H), 2.29~2.18(m, 2H), 1.92~1.78(m, 2H).

[0721] Example 137: (2s,4s)-2-(4-methyl-4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0722] [ka]

[0723] The title compound was prepared analogously to Example 4, Step C, using 4-methyl-4-(p-tolyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 26 Calculated mass for N2O3, 342.2; observed m / z, 343.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.18(q, J=8.3Hz, 4H), 5.96~5.85(m, 1H), 4.36(s, 2H), 3.82~3.73(m, 1H), 3.50~3.38(m, 2H), 3.30~3.22(m, 1H), 3.04 ~2.93(m, 1H), 2.70~2.54(m, 2H), 2.51~2.38(m, 2H), 2.33(s, 3H), 2.16~2.05(m, 2H), 1.72~1.64(m, 2H), 1.25(s, 3H).

[0724] Example 138: (2s,4s)-2-(4-fluoro-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0725] [ka]

[0726] The title compound was prepared analogously to Example 4, Step C, using 4-fluoro-4-phenylpiperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 Calculated mass for FN2O3, 332.2; observed m / z, 333.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.42~7.29(m, 5H), 6.03(s, 1H), 4.70~4.62(m, 1H), 4.39(s, 2H), 3.74~3.66(m, 1H), 3.50(td, J =13.2, 2.7Hz, 1H), 3.12~3.01(m, 2H), 2.76~2.64(m, 2H), 2.56~2.46(m, 2H), 2.13~1.78(m, 4H).

[0727] Example 139: (2s,4s)-2-(4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0728] [ka]

[0729] The title compound was prepared analogously to Step C of Example 4, using 4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine (Intermediate 8) instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.20~7.15(m, 1H), 7.03~6.98(m, 2H), 6.18(s, 1H), 4.80~4.71(m, 1H), 4.38(s, 2H), 3.87~3.78(m, 1H), 3.11(td, J=13.1, 2 .5Hz, 1H), 3.03(p, J=8.2Hz, 1H), 2.78~2.60(m, 4H), 2.51~2.44(m, 2H), 2.27(s, 3H), 1.95~1.87(m, 2H), 1.63~1.46(m, 2H).

[0730] Example 140: (2s,4s)-2-(4-(4-chlorophenyl)-4-ethylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0731] [ka]

[0732] TEA (40 μL, 0.280 mmol) was added dropwise to a stirring mixture of 4-(4-chlorophenyl)-4-ethylpiperidine hydrochloride (25.1 mg, 96.4 μmol), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 15.0 mg, 87.6 μmol), and HATU (41.3 mg, 96.4 μmol) in DMA (876 μL) at 0° C. The reaction mixture was stirred at room temperature for 14 hours and then diluted with water. Purification by reverse-phase HPLC (ACN / HO, 0.05% TFA) gave the title compound (25.3 mg, 67.1 μmol, 77% yield). MS (ESI): C 20 H 25 Calculated mass for ClN2O3, 376.2; observed m / z, 377.1 [M+H] + . 1 H NMR (500MHz, methanol-d4)δ 7.39~7.29(m, 4H), 4.47(m, 2H), 3.95(tm, 1H), 3.61(m, 1H), 3.21~3.02(m, 3H), 2.60~2.34(m, 4H), 2.24~2.13(m, 2H), 1.73~1.56(m, 4H), 0.58(t, J=7.5Hz, 3H).

[0733] Example 141: (racemic)-(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0734] [ka]

[0735] A solution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 20 mg, 0.12 mmol), HATU (50 mg, 0.13 mmol), and DIPEA (60 μL, 0.35 mmol) in DMF (1 mL) was stirred for 10 min. Racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 12, 30 mg, 0.13 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was purified by reverse-phase HPLC (Gilson, 0-100% ACN / water, NH4OH modifier) ​​to give the title compound (9.2 mg, 0.24 mmol, 20% yield). MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.37~7.29(m, 2H), 7.10~7.02(m, 2H), 5.83(d, J=13.3Hz, 1H), 4.90~4.56(m, 1H), 4.38(d, J=12.7Hz, 2H), 3.91~3.58(m, 1H), 3.4 6~2.86(m, 3H), 2.77~2.37(m, 5H), 2.22~2.08(m, 1H), 2.07~1.93(m, 1H), 1.71(d, J=13.5Hz, 1H), 1.31(s, 9H), 0.70~0.61(m, 3H).

[0736] Example 142: (2s, 4s * )-2-((3R * ,4R * )-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0737] [ka]

[0738] A sample of racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141, 54.4 mg) was resolved using chiral supercritical fluid chromatography (Chiralcel OZ column, eluent of 70% CO, 15% MeOH, 15% iPrOH, 0.2% isopropylamine) to give the title compound (20.4 mg, 0.053 mmol, 75% yield, 100% ee). MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.36~7.29(m, 2H), 7.09~7.04(m, 2H), 6.43(s, 1H), 4.86~4.54(m, 1H), 4.42~4.33(m, 2H), 3.94~3.83(m, 1H), 3.42~2.85(m, 4H), 2.83~2.37(m, 4H), 2.22~1.93(m, 2H), 1.78~1.64(m, 1H), 1.31(s, 9H), 0.72~0.58(m, 3H).

[0739] Example 143: (2s, 4R * )-2-((3S * ,4S * )-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0740] [ka]

[0741] A sample of racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141, 54.4 mg) was resolved using chiral supercritical fluid chromatography (Chiralcel OZ column, eluent of 70% CO, 15% MeOH, 15% iPrOH, 0.2% isopropylamine) to give the title compound (21.7 mg, 0.056, 80% yield, ee 89%). MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.2 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.36~7.28(m, 2H), 7.09~7.01(m, 2H), 6.66(s, 1H), 4.86~4.50(m, 1H), 4.39(d, J=13.3Hz, 2H), 3.93~3.85(m, 1H), 3.45~2. 86(m, 3H), 2.83~2.63(m, 3H), 2.59~2.33(m, 2H), 2.35~1.90(m, 2H), 1.87~1.60(m, 1H), 1.31(s, 9H), 0.65(d, J=7.0Hz, 3H).

[0742] Example 144: (racemic)-(2r,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0743] [ka]

[0744] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 24 H 34 Calculated mass for N2O2, 382.3; observed m / z, 383.3 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.36~7.31(m, 2H), 7.09~7.05(m, 2H), 5.86(d, J=12.2Hz, 1H), 4.88~4.51(m, 1H), 4.01~3.58(m, 1H), 3.43~2.83 (m, 4H), 2.70~2.43(m, 3H), 2.44~2.31(m, 3H), 2.29~2.19(m, 2H), 2.19~1.94(m, 2H), 1.70(s, 1H), 1.31(s, 9H), 0.66(d, J=7.0Hz, 3H).

[0745] Example 145: (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0746] [ka]

[0747] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using 4-(4-(tert-butyl)phenyl)-2-methylpiperidine (Intermediate 25) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.2 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 7.36–7.30 (m, 2H), 7.15–7.08 (m, 2H), 6.08–5.70 (m, 1H), 5.14–3.56 (m, 2H), 3.38–2.43 (m, 6H), 2.26–1.86 (m, 2H), 1.82–1.43 (m, 5H), 1.31 (s, 9H), 1.28–1.16 (m, 3H). The product is a mixture of diastereomers.

[0748] Example 146: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0749] [ka]

[0750] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.3 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.38~7.29(m, 1H), 7.10~7.06(m, 2H), 6.98(s, 1H), 6.22~6.12(m, 1H), 4.93~4.55(m, 1H), 4.46~4.28(m, 2H), 3.95~3.61(m, 1H), 3. 53~3.31(m, 1H), 3.19~2.87(m, 3H), 2.78~2.62(m, 3H), 2.60~2.40(m, 2H), 2.24~2.08(m, 1H), 2.06~1.90(m, 1H), 0.68~0.63(m, 3H).

[0751] Example 147: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0752] [ka]

[0753] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-3-methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine (Intermediate 30) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 24). MS (ESI): C 21 H 25 Calculated mass for F3N2O4, 426.2; observed m / z, 427.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.16~7.11(m, 1H), 7.01~6.98(m, 1H), 6.98~6.94(m, 1H), 6.22(s, 1H), 4.89~4.58(m, 1H), 4.42~4.34(m, 2H), 3.92~3.61(m, 1H), 3.52~3.3 4(m, 1H), 3.19~2.83(m, 3H), 2.78~2.61(m, 3H), 2.60~2.40(m, 2H), 2.30(s, 3H), 2.20~2.05(m, 1H), 2.04~1.88(m, 1H), 0.71~0.59(m, 3H).

[0754] Example 148: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0755] [ka]

[0756] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidine (Intermediate 29) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.2 [M+H] + . 1H NMR (400MHz, CDCl3)δ 7.50~7.41(m, 2H), 7.40~7.36(m, 1H), 7.35~7.32(m, 1H), 6.54~6.49(m, 1H), 4.96~4.59(m, 1H), 4.45~4.35(m, 2H), 4.02~3.5 9(m, 1H), 3.53~3.33(m, 2H), 3.23~2.88(m, 2H), 2.82~2.38(m, 4H), 2.29~1.95(m, 2H), 1.95~1.73(m, 1H), 0.68~0.62(m, 3H).

[0757] Example 149: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0758] [ka]

[0759] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidine (Intermediate 31) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C 20 H 23 Calculated mass for F3N2O4, 412.2; observed m / z, 413.1 [M+H] + . 1H NMR (500MHz, CDCl3)δ 7.22~7.09(m, 4H), 5.85~5.62(m, 1H), 4.93~4.56(m, 1H), 4.42~4.33(m, 2H), 3.96~3.55(m, 1H), 3.42~2.81(m, 4H), 2.77~2.41(m, 4H), 2.22~1.88(m, 2H), 1.79~1.68(m, 1H), 0.68~0.61(m, 3H).

[0760] Example 150: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0761] [ka]

[0762] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-3-methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine (Intermediate 32) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C 20 H 22 Calculated mass for F4N2O4, 430.2; observed m / z, 431.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.26~7.23(m, 1H), 7.01~6.90(m, 2H), 5.76~5.63(m, 1H), 4.89~4.59(m, 1H), 4.41~4.34(m, 2H), 3.93~3.6 2(m, 1H), 3.41~2.86(m, 4H), 2.73~2.42(m, 4H), 2.22~1.85(m, 2H), 1.77~1.66(m, 1H), 0.73~0.60(m, 3H).

[0763] Example 151: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0764] [ka]

[0765] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine (Intermediate 33) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.61~7.57(m, 2H), 7.30~7.24(m, 2H), 5.81~5.72(m, 1H), 4.93~4.55(m, 1H), 4.42~4.27(m, 2H), 3.94~3.6 3(m, 1H), 3.46~2.90(m, 4H), 2.79~2.40(m, 4H), 2.24~1.94(m, 2H), 1.80~1.67(m, 1H), 0.72~0.59(m, 3H).

[0766] Example 152: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0767] [ka]

[0768] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-3-methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine (Intermediate 10) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C 21 H 25 Calculated mass for F3N2O3, 410.2; observed m / z, 411.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.39~7.34(m, 1H), 7.25~7.22(m, 1H), 7.21~7.14(m, 1H), 5.84~5.73(m, 1H), 4.89~4.58(m, 1H), 4.42~4.30(m, 2H), 3.95~3.58(m, 1H), 3.43~2.86(m, 4H), 2.76~2.41(m, 7H), 2.24~1.95(m, 2H), 1.76~1.69(m, 1H), 0.68~0.55(m, 3H).

[0769] Example 153: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0770] [ka]

[0771] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-3-methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine (Intermediate 34) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C 21 H 25 Calculated mass for F3N2O3, 410.2; observed m / z, 411.2 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.58~7.43(m, 1H), 7.07~7.01(m, 2H), 5.86~5.77(m, 1H), 4.90~4.59(m, 1H), 4.43~4.32(m, 2H), 3.94~3.62(m, 1H), 3.43~2.89(m, 4H), 2.74~2.42(m, 7H), 2.22~2.09(m, 1H), 2.07~1.93(m, 1H), 1.78~1.68(m, 1H), 0.67~0.61(m, 3H).

[0772] Example 154: (racemic)-(2s,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0773] [ka]

[0774] The title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine (Intermediate 24) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). MS (ESI): C 25 H 28 Calculated mass for N2O3, 404.2; observed m / z, 405.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.59~7.56(m, 2H), 7.48~7.42(m, 3H), 7.41~7.32(m, 3H), 7.14~7.10(m, 1H), 5.81~5.64(m, 1H), 4.90~4.59(m, 1H), 4.45~4.2 8(m, 2H), 3.94~3.59(m, 1H), 3.45~2.91(m, 4H), 2.74~2.43(m, 5H), 2.27~2.01(m, 1H), 1.83~1.73(m, 1H), 0.78~0.64(m, 3H).

[0775] Example 155: (racemic)-(2r,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0776] [ka]

[0777] The title compound was prepared in analogy to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141) using racemic cis-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine (Intermediate 24) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23) and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS(ESI):C 26 H 30 Calculated mass for N2O2, 402.2; observed m / z, 403.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.60~7.55(m, 2H), 7.49~7.33(m, 6H), 7.15~7.11(m, 1H), 5.93~5.81(m, 1H), 4.92~4.58(m, 1H), 3. 95~3.65(m, 1H), 3.42~2.90(m, 3H), 2.76~2.00(m, 11H), 1.83~1.74(m, 1H), 0.70(d, J=7.0Hz, 3H).

[0778] Example 156: (2s, 4R * )-2-((2S * ,4R * )-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0779] [ka]

[0780] A diastereomeric mixture of the title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141), using 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine (Intermediate 26) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). This mixture was separated twice via chiral supercritical fluid chromatography (CHIRALPAK AD-H column, 70% CO, 30% MeOH eluent, followed by CHIRACEL OJ-H column, 93% CO, 7% MeOH eluent) to give the title compounds. MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.56(d, J=8.1Hz, 2H), 7.30(d, J=8.1Hz, 2H), 6.64(s, 1H), 4.39(s, 3H), 3.39(d, J=98.3Hz, 1H), 3.01(q, J=8.1Hz, 1H), 2.84~2.72(m, 2H) , 2.72~2.63(m, 1H), 2.48(tdd, J=12.2, 10.3, 3.8Hz, 2H), 2.25~2.10(m, 1H), 2.08~1.98(m, 1H), 1.78~1.63(m, 3H), 1.21(d, J=6.4Hz, 3H).

[0781] Example 157: (2s, 4s * )-2-((2R * ,4S * )-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0782] [ka]

[0783] A diastereomeric mixture of the title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141), using 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine (Intermediate 26) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). This mixture was separated twice via chiral supercritical fluid chromatography (CHIRALPAK AD-H column, 70% CO, 30% MeOH eluent, followed by CHIRACEL OJ-H column, 93% CO, 7% MeOH eluent) to give the title compounds. MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.59~7.53(m, 2H), 7.30(d, J=8.1Hz, 2H), 6.38(s, 1H), 4.39(s, 3H), 3.28(s, 1H), 3.02(p, J=8.0Hz, 1H), 2.77(ddt, J=12.1, 7.5, 1 .5Hz, 2H), 2.68~2.63(m, 1H), 2.56~2.45(m, 2H), 2.24~2.12(m, 1H), 2.07~1.99(m, 1H), 1.86~1.64(m, 3H), 1.21(d, J=6.4Hz, 3H).

[0784] Example 158: (2s, 4s * )-2-((2R * ,4R * )-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0785] [ka]

[0786] A diastereomeric mixture of the title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141), using 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine (Intermediate 26) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). This mixture was separated twice via chiral supercritical fluid chromatography (CHIRALPAK AD-H column, 70% CO, 30% MeOH eluent, followed by CHIRACEL OJ-H column, 93% CO, 7% MeOH eluent) to give the title compounds. MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.57(d, J=8.1Hz, 2H), 7.32~7.28(m, 2H), 6.23~6.10(m, 1H), 5.12~4.62(m, 1H), 4.43~4.37(m, 2H), 4.23~3.59(m, 1H) ), 3.35~2.84(m, 3H), 2.80~2.58(m, 2H), 2.56~2.42(m, 2H), 1.98~1.72(m, 3H), 1.64~1.50(m, 1H), 1.41~1.19(m, 3H).

[0787] Example 159: (2s, 4R * )-2-((2S * ,4S * )-2-Methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0788] [ka]

[0789] A diastereomeric mixture of the title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141), using 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine (Intermediate 26) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). This mixture was separated twice via chiral supercritical fluid chromatography (CHIRALPAK AD-H column, 70% CO, 30% MeOH eluent, followed by CHIRACEL OJ-H column, 93% CO, 7% MeOH eluent) to give the title compounds. MS (ESI): C 20 H 23 Calculated mass for F3N2O3, 396.2; observed m / z, 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.57(d, J=8.0Hz, 2H), 7.30(d, J=7.9Hz, 2H), 6.32~6.14(m, 1H), 5.16~4.59(m, 1H), 4.45~4.37(m, 2H), 4.21~ 3.59(m, 1H), 3.35~2.84(m, 3H), 2.81~2.58(m, 2H), 2.57~2.41(m, 2H), 1.98~1.49(m, 4H), 1.43~1.18(m, 3H).

[0790] Example 160: (2s, 4s * )-2-((3R * ,4R * )-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0791] [ka]

[0792] A sample of racemic (2s,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 154, 76 mg) was resolved using chiral supercritical fluid chromatography (Lux-3 Cellulose column, 55% CO2, 45% MeOH eluent) to give the title compound (28 mg, 0.053 mmol, 74% yield, 100% ee). MS (ESI): C 25 H 28 Calculated mass for N2O3, 404.2; observed m / z, 405.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.59~7.55(m, 2H), 7.48~7.31(m, 7H), 7.14~7.09(m, 1H), 6.43~6.38(m, 1H), 4.92~4.58(m, 1H), 4.45~4.27(m, 2H), 3.95~3.62(m, 1H), 3.46~2.90(m, 3H), 2.80~2.63(m, 2H), 2.59~2.37(m, 2H), 2.28~2.15(m, 1H), 2.13~2.01(m, 1H), 1.81~1.74(m, 1H), 0.71~0.67(m, 3H).

[0793] Example 161: (2s, 4R * )-2-((3S * ,4S * )-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0794] [ka]

[0795] A sample of racemic (2s,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 154, 76 mg) was resolved using chiral supercritical fluid chromatography (Lux-3 Cellulose column, 55% CO2, 45% MeOH eluent) to give the title compound (28.9 mg, 0.053 mmol, 76% yield, 100% ee). MS (ESI): C 25 H 28 Calculated mass for N2O3, 404.2; observed m / z, 405.1 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.60~7.55(m, 2H), 7.47~7.32(m, 6H), 7.16~7.09(m, 1H), 6.51~6.43(m, 1H), 4.90~4.60(m, 1H), 4.45~4.32(m, 2H), 3.96~3.62(m, 1H), 3.44~2.91(m, 3H), 2.81~2.64(m, 3H), 2.60~2.36(m, 2H), 2.29~2.14(m, 1H), 2.13~2.00(m, 1H), 1.82~1.74(m, 1H), 0.75~0.65(m, 3H).

[0796] Example 162: (racemic)-(2s,4R)-2-((2s,4S)-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0797] [ka]

[0798] A diastereomeric mixture of the title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141), using 4-(3-(tert-butyl)phenyl)-2-methylpiperidine (Intermediate 27) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). This mixture was separated via chiral supercritical fluid chromatography (IG column, 40% MeOH, 60% CO, 0.1% diethylamine eluent) to give the title compound. MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.29~7.21(m, 3H), 7.21~7.18(m, 1H), 7.02~6.97(m, 1H), 5.88~5.75(m, 1H), 5.10~4.60(m, 1H), 4.41~4.28(m, 2H), 4.22~3.55(m, 1H), 3.37~2.83(m, 3H), 2.80~2.43(m, 3H), 1.98~1.76(m, 2H), 1.65~1.47(m, 2H), 1.35~1.24(m, 12H).

[0799] Example 163: (2s, 4R * )-2-((2S * ,4R * )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0800] [ka]

[0801] A sample of (2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 145) was separated by chiral supercritical fluid chromatography (OJ-H column, 15% EtOH, 85% CO eluent) to give the title compound. MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.33(d, J=8.4Hz, 2H), 7.11(d, J=8.3Hz, 2H), 6.18(s, 1H), 4.38(s, 2H), 3.08~2.98(m, 1H), 2.80~2.72(m, 1H), 2.71~2 .59(m, 2H), 2.56~2.44(m, 2H), 2.14(s, 1H), 2.06~1.92(m, 1H), 1.82~1.63(m, 5H), 1.31(s, 9H), 1.19(d, J=6.4Hz, 3H).

[0802] Example 164: (2s, 4s * )-2-((2R * ,4R * )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0803] [ka]

[0804] A sample of (2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 145) was separated by chiral supercritical fluid chromatography (OJ-H column, 15% EtOH, 85% CO eluent) to give the title compound. MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.0 [M+H]+ . 1 H NMR (500MHz, CDCl3)δ 7.36~7.30(m, 2H), 7.15~7.09(m, 2H), 5.88~5.74(m, 1H), 5.09~4.59(m, 1H), 4.43~4.34(m, 2H), 4.19~3.5 2(m, 1H), 3.32~2.83(m, 3H), 2.77~2.42(m, 4H), 1.98~1.69(m, 3H), 1.57~1.39(m, 1H), 1.37~1.22(m, 12H).

[0805] Example 165: (2s, 4s * )-2-((2R * ,4S * )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0806] [ka]

[0807] A sample of (2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 145) was separated by chiral supercritical fluid chromatography (OJ-H column, 15% EtOH, 85% CO eluent) to give the title compound. MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.36~7.29(m, 2H), 7.14~7.08(m, 2H), 6.14(s, 1H), 4.38(s, 2H), 3.08~2.95(m, 1H), 2.79~2.73(m, 1H), 2.72~2.58 (m, 2H), 2.56~2.39(m, 2H), 2.14(s, 1H), 2.04~1.96(m, 1H), 1.82~1.63(m, 5H), 1.31(s, 9H), 1.19(d, J=6.4Hz, 3H).

[0808] Example 166: (2s, 4R * )-2-((2S * ,4S * )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0809] [ka]

[0810] A sample of (2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 145) was separated by chiral supercritical fluid chromatography (OJ-H column, 15% EtOH, 85% CO eluent) to give the title compound. MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.35~7.32(m, 2H), 7.15~7.09(m, 2H), 5.91~5.65(m, 1H), 5.11~4.56(m, 1H), 4.41~4.35(m, 2H), 4.19~3.4 8(m, 1H), 3.34~2.82(m, 3H), 2.76~2.43(m, 4H), 1.97~1.72(m, 3H), 1.58~1.46(m, 1H), 1.35~1.23(m, 12H).

[0811] Example 167: (2s, 4R * )-2-((2S * ,4R * )-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0812] [ka]

[0813] A diastereomeric mixture of the title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141), using 4-(3-(tert-butyl)phenyl)-2-methylpiperidine (Intermediate 27) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). This mixture was separated via chiral supercritical fluid chromatography (IG column, 40% MeOH, 60% CO, 0.1% diethylamine eluent) to give the title compound. MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.29~7.15(m, 3H), 7.02~6.97(m, 1H), 6.22(s, 1H), 4.38(s, 2H), 3.49(d, J=4.2Hz, 2H), 3.07~2.97(m, 1H), 2.80~2.74(m, 1H), 2.73~2.60(m, 2H), 2.57~2.41(m, 2H), 2.16(s, 1H), 2.04~1.95(m, 1H), 1.75~1.64(m, 3H), 1.32(s, 9H), 1.20(d, J=6.4Hz, 3H).

[0814] Example 168: (2s, 4s * )-2-((2R * ,4S * )-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0815] [ka]

[0816] A diastereomeric mixture of the title compound was prepared analogously to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 141), using 4-(3-(tert-butyl)phenyl)-2-methylpiperidine (Intermediate 27) instead of racemic cis-3-methyl-4-(4-(tert-butyl)phenyl)piperidine (Intermediate 23). This mixture was separated via chiral supercritical fluid chromatography (IG column, 40% MeOH, 60% CO, 0.1% diethylamine eluent) to give the title compound. MS (ESI): C 23 H 32 Calculated mass for N2O3, 384.2; observed m / z, 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3)δ 7.31~7.22(m, 3H), 7.20~7.17(m, 1H), 7.03~6.90(m, 1H), 6.11(s, 1H), 4.39(d, J=6.0Hz, 2H), 3.54~3.43(m, 2H), 3.03(p, J=8.0Hz, 1H), 2.80~ 2.59(m, 3H), 2.50(tdd, J=12.0, 10.0, 3.4Hz, 1H), 2.16(s, 1H), 2.06~1.94(m, 1H), 1.68(s, 3H), 1.32(d, J=1.5Hz, 9H), 1.20(d, J=6.4Hz, 3H).

[0817] Example 169: (2s,4s)-2-(4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0818] [ka]

[0819] Step A: tert-Butyl 4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate. In an oven-dried flask under N, 2-bromo-6-tert-butylpyridine (144 mg, 0.639 mmol) was added to anhydrous THF (2.5 mL) and cooled to −78° C. To this reaction mixture was added n-BuLi (0.37 mL, 0.590 mmol), and the reaction was stirred at −78° C. for 30 minutes. 1-Boc-4-piperidone (100 mg, 0.492 mmol) was added, and the reaction mixture was stirred at −78° C. for 1 hour. After warming to room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC (0-50% EtOAc in hexanes) gave the title compound (115 mg, 70% yield). MS (ESI): C 19 H 30 Calculated mass for N2O3, 334.2; observed m / z, 335.3 [M+H] + .

[0820] Step B: tert-Butyl 6-(tert-butyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate. To a solution of tert-butyl 4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate (50 mg, 0.149 mmol) in pyridine (0.75 mL) cooled to 0 °C, DMAP (1.9 mg, 0.0150 mmol) and thionyl chloride (21 μL, 0.299 mmol) were added. The reaction mixture was then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS (ESI): C 19 H 28 Calculated mass for N2O2, 316.2; observed m / z, 317.3 [M+H] + .

[0821] Step C: tert-Butyl 4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carboxylate. To a solution of tert-butyl 6-(tert-butyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (47 mg, 0.149 mmol) in EtOH (1.5 mL) was added Pd / C (16 mg, 0.0149 mmol, 10 wt%). The reaction mixture was purged with H and stirred at room temperature for 16 hours. The reaction was filtered through Celite® and washed with MeOH. The resulting filtrate was concentrated under reduced pressure to give the title compound, which was used in the next step without further purification. MS (ESI): C 19 H 30 Calculated mass for N2O2, 318.2; observed m / z, 319.3 [M+H] + .

[0822] Step D: 2-(tert-butyl)-6-(piperidin-4-yl)pyridine. A solution of tert-butyl 4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carboxylate (47 mg, 0.148 mmol) in HCl (1.25 M in EtOH, 1.2 mL) was stirred at 45° C. for 1 hour. The reaction was concentrated under reduced pressure, and the resulting title compound was used in the next step without further purification. MS (ESI): C 14 H 22 Calculated mass for N2, 218.2; observed m / z, 219.2 [M+H] + .

[0823] Step E: (2s,4s)-2-(4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. To a solution of 2-(tert-butyl)-6-(piperidin-4-yl)pyridine (37 mg, 0.170 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 26 mg, 0.155 mmol) in DMF (0.70 mL) was added DIPEA (0.10 mL, 0.590 mmol) and HATU (63 mg, 0.162 mmol). The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a PTFE filter and purified via RP-HPLC (5-95% ACN in 20 mM NH4OH in water) to give the title compound (36 mg, 66% yield). MS (ESI): C 21 H 29 Calculated mass for N3O3, 371.2; observed m / z, 372.3 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.51 (t, J = 7.8 Hz, 1H), 7.14 (dd, J = 8.0, 0.8 Hz, 1H), 6.89 (dd, J = 7.6, 0.8 Hz, 1H), 6.28 (s, 1H), 4.69–4.60 (m, 1H), 4.38 (s, 2H), 3.87–3.78 (m, 1H), 3.22–3.10 (m, 1H). , 3.04(p, J=8.2Hz, 1H), 2.90(tt, J=11.3, 3.8Hz, 1H), 2.87~2.75(m, 1H), 2.76~2. 64(m, 2H), 2.52~2.41(m, 2H), 2.02~1.93(m, 2H), 1.82~1.67(m, 2H), 1.32(s, 9H).

[0824] Biological data The assay used to measure the in vitro activity of MGL is adapted from that used for another serine hydrolase (FAAH) described by Wilson et al., 2003 (A high-throughput assay compatible with determining the activity of fatty acid amide hydrolase. Wilson SJ, Lovenberg TW, Barbier AJ. Anal Biochem. 2003 Jul 15;318(2):270-5.). This assay combines endogenously expressed MGL from HeLa cells with a test compound and induces the production of [glycerol-1,3- 3 After incubation for 1 hour, the cleaved [1,3-H]-oleoylglycerol was passed through a charcoal filter. 3 The amount of cleaved tritiated glycerol that passes through the carbon filter is proportional to the activity of the MGL enzyme in that particular well / test condition.

[0825] The standard conditions for this assay were: 300 nM [glycerol-1,3- 3 [H]-oleoylglycerol was mixed with human MGL derived from HeLa cells and test compounds for 1 hour, after which the reaction mixture was filtered through activated charcoal and tritium was measured in the flow-through fraction. The test compound concentration in the screening mode was 10 μM, and the IC 50 The highest concentration of compound in the assay is determined empirically. MGL is the major hydrolase in HeLa cells / cell homogenates.

[0826] [Table 3-1]

[0827] [Table 3-2]

[0828] [Table 3-3]

[0829]

Table 3-4

[0830]

Table 3-5

[0831]

Table 3-6

[0832]

Table 3-7

change

change

change

[10] R 3 teeth,

change

[11] R 3 is 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-(1-methylcyclopropyl)phenyl.

[12] R 4 are H, F, and CH 3 , or CH 2 CH 3 The compound according to any one of the above [1] to

[11] ,

[13] R 4 is H.

[14] R 5a and R 5b and each represent H.

[15] R 5a is CH 3 and R 5b is H. The compound according to any one of the above [1] to [4].

[16] R 5a is H and R 5b is CH 3 The compound according to any one of the above [1] to [4],

[17]

change

[18]

change

[19]

change

[20]

change

[21]

change

[22] (2s,4s)-2-(4-(3-(2,2,2-trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(difluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(difluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-cyclopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(2,2,2-trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-cyclobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(1,1-difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(1,1-difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,3-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,5-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-isopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3,4-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,3-dihydro-1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-chloro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-isopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(6-(tert-butyl)pyridin-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,4-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chloro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-([1,1'-biphenyl]-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methoxy-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-cyclopropyl-2-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(tert-butyl)-4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(difluoromethoxy)-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(tert-butyl)-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(2-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(difluoromethoxy)-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-(tert-butyl)-4-chlorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(2-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-cyclopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(pentafluoro-λ6-sulfanayl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(pentafluoro-λ6-sulfanayl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-(tert-butyl)-4-fluorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4s)-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(2-hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(2-hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3,5-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,4-difluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-fluoro-2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,5-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-ethyl-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3,5-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2S * ,4s,8R * )-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2R * ,4s,8s * )-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-isobutylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(tert-butyl)-3-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methoxy-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2r,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-[4-(6-fluorobenzofuran-3-yl)piperidine-1-carbonyl]-6-oxa-8-azaspiro[3.4]octan-7-one, (2s,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(benzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(naphthalen-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(1H-indol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(methylthio)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(dimethylamino)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(5-chlorobenzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(naphthalen-1-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(o-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-ethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(m-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(5-chlorobenzofuran-2-yl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-methyl-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(6-chlorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one, (2S * ,4s,8R * )-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one, (2R * ,4s,8s * )-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8,8-dimethyl-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chlorophenyl)-4-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(benzo[d]thiazol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-methyl-4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-fluoro-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chlorophenyl)-4-ethylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s * )-2-((3R * ,4R * )-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4R * )-2-((3S * ,4S * )-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2r,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2r,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4R * )-2-((2S * ,4R * )-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s * )-2-((2R * ,4S * )-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s * )-2-((2R * ,4R * )-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4R * )-2-((2S * ,4S * )-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s * )-2-((3R * ,4R * )-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4R * )-2-((3S * ,4S * )-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4R)-2-((2S,4S)-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4R * )-2-((2S * ,4R * )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s * )-2-((2R * ,4R * )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s * )-2-((2R * ,4S * )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4R * )-2-((2S * ,4S * )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4R * )-2-((2S * ,4R * )-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s * )-2-((2R * ,4S * )-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, and (2s,4s)-2-(4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[23] (2s,4s)-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, and (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[24] Formula (IA):

change

change

[25] Formula (IB):

change

change

change

[26] Formula (IC):

change

change

[27] Expression (ID):

change

change

[28] (A) a therapeutically effective amount of at least one compound according to any one of [1], [2], or

[22] to

[27] ; (B) at least one pharmaceutically acceptable excipient.

[29] The pharmaceutical composition of claim 28, wherein the compound is the compound of claim 22.

[30] A method for treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound according to any one of [1], [2], or

[22] to

[27] .

[31] The method according to

[30] , wherein the disease, disorder, or condition mediated by the MGL receptor is selected from pain, psychiatric disorders, neurological conditions, cancer, and eye conditions.

[32] The method according to

[30] , wherein the disease, disorder, or condition mediated by the MGL receptor is selected from major depressive disorder, treatment-resistant depression, anxious depression, autism spectrum disorder, Asperger's syndrome, and bipolar disorder.

[33] The method according to

[30] , wherein the disease, disorder, or condition mediated by the MGL receptor is inflammatory pain.

Claims

1. Formula (I): 【Chemical 1】 (In the formula, X is CH ２ or O, R ２ａ and R ２ｂ are each independently H and C １～４ alkyl, R ３ teeth, (i) phenyl, benzyl, or monocyclic heteroaryl, each of which is selected from halo, C １～６ Alkyl, C １～６ Haloalkyl, C １～６ Alkyl-OH, OC １～６ Alkyl, OC １～６ Haloalkyl, SC １～６ Alkyl, SF ５ , Si(CH ３ ) ３ , N.R. ａ R ｂ , C ３～６ Cycloalkyl, OC ３～６ Phenyl, benzyl, or monocyclic heteroaryl optionally substituted with one, two, or three substituents selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl of said substituents is selected from one or two C １～４ Alkyl, C １～４ or two adjacent ring substituents on said phenyl, benzyl, or monocyclic heteroaryl, together with the atoms to which they are attached, form a fused monocyclic C ５～６ Form a cycloalkyl or heterocycloalkyl ring, and each fused ring is one or two C １～４ Alkyl, C １～４ optionally substituted with haloalkyl or halo groups; R ａ and R ｂ are each independently H or C １～４ alkyl), (ii) C １～４ bicyclic heteroaryl optionally substituted with alkyl or halo; 【Chemistry 1-2】 a bicyclic heteroaryl selected from , and (iii) C １～４ Alkyl, C １～４ C optionally substituted with haloalkyl or halo ３～６ Alkyl or C ３～６ cycloalkyl; R ４ are H, F, and C １～３ alkyl, R ５ａ and R ５ｂ are each independently H and CH ３ (selected from or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

2. Formula (I): 【Chemistry 2】 (In the formula, X is CH ２ or O, R ２ａ and R ２ｂ are each independently H and C １～４ alkyl, R ３ teeth, (a) phenyl; halo, C １～６ Alkyl, C １～６ Haloalkyl, C(CH ３ ) ２ OH, O.C. １～６ Alkyl, OC １～６ Haloalkyl, SCH ３ , SF ５ , Si(CH ３ ) ３ , N(CH ３ ) ２ , C ３～６ Cycloalkyl, OC ３～６ Cycloalkyl, phenyl, O-phenyl, O-pyridyl, and CH ３ C substituted with ３～６ phenyl substituted with 1, 2, or 3 members each independently selected from cycloalkyl; and (b) C １～６ Alkyl-substituted pyridyl; naphthyl; 【Chemistry 3】 is selected from R ４ are H, F, and C １～３ alkyl, R ５ａ and R ５ｂ are each independently H and CH ３ (selected from or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

3. X is CH ２ 3. The compound of claim 1 or 2, wherein:

4. 3. The compound of claim 1 or 2, wherein X is O, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

5. R ２ａ and R ２ｂ The compound of any one of claims 1 to 4, wherein each is H, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

6. R ２ａ and R ２ｂ are CH ３ 5. The compound of any one of claims 1 to 4, wherein:

7. R ２ａ is H and R ２ｂ is CH ３ 5. The compound of any one of claims 1 to 4, wherein:

8. R ３ is phenyl; or Cl, F, C １～６ Alkyl, C １～６ Haloalkyl, C(CH ３ ) ２ OH, O.C. １～６ Alkyl, OC １～６ Haloalkyl, SCH ３ , Si(CH ３ ) ３ , SF ５ , N(CH ３ ) ２ , C ３～６ Cycloalkyl, CH ３ C substituted with ３～６ Cycloalkyl, OC ３～６ 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, wherein the phenyl is substituted with one, two, or three members each independently selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl.

9. R ３ Ha, Halo, C １～６ Alkyl, C １～６ Haloalkyl, OC １～６ Alkyl, OC １～６ Haloalkyl, SCH ３ , SF ５ , or Si(CH ３ ) ３ or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

10. R ３ teeth, 【Chemistry 4】 8. The compound of any one of claims 1 to 7, wherein:

11. R ３ is 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-(1-methylcyclopropyl)phenyl, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

12. R ４ are H, F, and CH ３ , or CH ２ CH ３ 12. The compound of any one of claims 1 to 11, wherein:

13. R ４ is H, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

14. R ５ａ and R ５ｂ The compound of any one of claims 1 to 4, wherein each is H, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

15. R ５ａ is CH ３ and R ５ｂ is H, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

16. R ５ａ is H and R ５ｂ is CH ３ 5. The compound of any one of claims 1 to 4, wherein:

17. 【Chemical 5】 3. The compound of claim 1 or 2, wherein:

18. 【Chemical 6】 3. The compound of claim 1 or 2, wherein:

19. 【Chemical 7】 3. The compound of claim 1 or 2, wherein:

20. [Chemical 8] 3. The compound of claim 1 or 2, wherein:

21. [Chemical 9] 3. The compound of claim 1 or 2, wherein:

22. (2s,4s)-2-(4-(3-(2,2,2-trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(difluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(difluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-cyclopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(2,2,2-trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-cyclobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(1,1-difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(1,1-difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,3-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,5-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-isopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3,4-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,3-dihydro-1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-chloro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-isopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(6-(tert-butyl)pyridin-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,4-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chloro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-([1,1′-biphenyl]-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methoxy-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-cyclopropyl-2-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(tert-butyl)-4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(difluoromethoxy)-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(tert-butyl)-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(2-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(difluoromethoxy)-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-(tert-butyl)-4-chlorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(2-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-cyclopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(pentafluoro-λ6-sulfanayl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(pentafluoro-λ6-sulfanayl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-(tert-butyl)-4-fluorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4s)-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(2-hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(2-hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3,5-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,4-difluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-fluoro-2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2,5-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-ethyl-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3,5-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2S ＊ , 4s, 8R ＊ )-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2R ＊ , 4s, 8s ＊ )-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(3-isobutylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(tert-butyl)-3-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methoxy-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2r,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-[4-(6-fluorobenzofuran-3-yl)piperidine-1-carbonyl]-6-oxa-8-azaspiro[3.4]octan-7-one, (2s,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(benzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(naphthalen-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(1H-indol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(methylthio)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(dimethylamino)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(5-chlorobenzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(naphthalen-1-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(o-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-ethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(2-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(m-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(5-chlorobenzofuran-2-yl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-methyl-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(6-chlorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one, (2S ＊ , 4s, 8R ＊ )-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one, (2R ＊ , 4s, 8s ＊ )-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8,8-dimethyl-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chlorophenyl)-4-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(benzo[d]thiazol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-methyl-4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-fluoro-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-chlorophenyl)-4-ethylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4s ＊ )-2-((3R ＊ , 4R ＊ )-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4R ＊ )-2-((3S ＊ , 4S ＊ )-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2r,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4S)-2-((3R,4R)-4-([1,1′-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2r,4S)-2-((3R,4R)-4-([1,1′-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, (2s, 4R ＊ )-2-((2S ＊ , 4R ＊ )-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4s ＊ )-2-((2R ＊ , 4S ＊ )-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4s ＊ )-2-((2R ＊ , 4R ＊ )-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4R ＊ )-2-((2S ＊ , 4S ＊ )-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4s ＊ )-2-((3R ＊ , 4R ＊ )-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4R ＊ )-2-((3S ＊ , 4S ＊ )-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (racemic)-(2s,4R)-2-((2S,4S)-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4R ＊ )-2-((2S ＊ , 4R ＊ )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4s ＊ )-2-((2R ＊ , 4R ＊ )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4s ＊ )-2-((2R ＊ , 4S ＊ )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4R ＊ )-2-((2S ＊ , 4S ＊ )-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4R ＊ )-2-((2S ＊ , 4R ＊ )-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s, 4s ＊ )-2-((2R ＊ , 4S ＊ )-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, and (2s,4s)-2-(4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

23. (2s,4s)-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2s,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, (2r,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one, and (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

24. Formula (IA): 【Chemistry 10】 (In the formula, R ３ teeth, (a) Halo, C １～６ Alkyl, C １～６ Haloalkyl, OC １～６ Haloalkyl, Si(CH ３ ) ３ , C ３～６ Cycloalkyl, phenyl, O-phenyl, and CH ３ C substituted with ３～６ phenyl substituted with one or two members each independently selected from cycloalkyl; and (b) 【Chemistry 11】 is selected from R ５ｂ is H or CH ３ is) 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

25. Formula (IB): 【Chemistry 12】 (In the formula, R ２ａ and R ２ｂ are each independently H and CH ３ is selected from R ３ teeth, (a) Phenyl; Cl, ​​F, C １～６ Alkyl, C １～６ Haloalkyl, C(CH ３ ) ２ OH, O.C. １～６ Alkyl, OC １～６ Haloalkyl, SCH ３ , SF ５ , Si(CH ３ ) ３ , N(CH ３ ) ２ , cyclopropyl, cyclobutyl, O-cyclopropyl, phenyl, O-phenyl, O-pyridyl, and 【Chemistry 13】 phenyl substituted with 1, 2, or 3 members each independently selected from (b) 【Chemistry 14】 is selected from R ４ are H, F, and CH ３ , and C.H. ２ CH ３ is selected from R ５ａ is H or CH ３ and R ５ｂ is H or CH ３ is) 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

26. Formula (IC): 【Chemistry 15】 (In the formula, X is CH ２ or O, Ring A is 【Chemistry 16】 (selected from 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

27. Formula (ID): 【Chemistry 17】 (In the formula, X is CH ２ or O, R ２ａ and R ２ｂ are each independently H and CH ３ is selected from R ｂ are Cl, F, C １～６ Alkyl, C １～６ Haloalkyl, C(CH ３ ) ２ OH, O.C. １～６ Alkyl, OC １～６ Haloalkyl, SCH ３ , SF ５ , Si(CH ３ ) ３ , N(CH ３ ) ２ , cyclopropyl, cyclobutyl, O-cyclopropyl, phenyl, O-phenyl, O-pyridyl, and 【Chemistry 18】 is selected from n is 0, 1, 2, or 3; R ４ are H, F, and CH ３ , and C.H. ２ CH ３ is selected from R ５ａ is H or CH ３ and R ５ｂ is H or CH ３ is) 2. The compound of claim 1 having the structure: or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

28. (A) a therapeutically effective amount of at least one compound of any one of claims 1, 2, or 22-27, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; (B) at least one pharmaceutically acceptable excipient.

29. 29. The pharmaceutical composition of claim 28, wherein the compound is a compound of claim 22.

30. 30. The pharmaceutical composition of claim 28 or 29 for treating a subject suffering from or diagnosed with a disease or disorder mediated by the MGL receptor.

31. 31. The pharmaceutical composition of claim 30, wherein the disease or disorder mediated by the MGL receptor is selected from pain, a psychiatric disease or disorder, a neurological disease or disorder, cancer, and an eye disease or disorder.

32. 31. The pharmaceutical composition of claim 30, wherein the disease or disorder mediated by the MGL receptor is selected from major depressive disorder, treatment-resistant depression, anxious depression, autism spectrum disorder, Asperger's syndrome, and bipolar disorder.

33. 31. The pharmaceutical composition of claim 30, wherein the disease or disorder mediated by the MGL receptor is inflammatory pain.

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