Arylpiperidines as monoacylglycerol lipase modulators

Abstract

The present invention provides an arylpiperidine compound of formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof, pharmaceutical compositions containing them, and methods of using them, including methods for treating disease states, disorders and conditions associated with MGL regulation, such as those associated with pain, mental disorders, neurological disorders (including but not limited to major depressive disorder, refractory depression, anxious depression, autism spectrum disorder, Asperger's syndrome, bipolar disorder), cancer and eye disorders: wherein X, R 2a , R 2b , R 3 , R 4 , R 5a and R 5b As defined herein.

Description

Technical Field

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

[0002] Cannabis and Δ have been used in folk medicine for therapeutic purposes since their 9 -An analogue of tetrahydrocannabinol. 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 (DiMarzo et al., Curr Opin Lipidol, 2007, 18, 129-140). CB2 is mainly 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) as well as in 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 found to be 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 is reported that the concentration of 2-AG is at least 100 times that of anandamide in rat brain (Buczynski and Parsons, Brit J Pharmacol, 2010, 160 (3), 423-42). Therefore, compared to anandamide, 2-AG may play a more important physiological role in the brain's endocannabinoid system (Sugiura et al., Prostaglandins Leukot Essent Fatty Acids., February-March 2002, 66 (2-3): 173-92). The endocannabinoid 2-AG is a full agonist of CB1 and CB2 receptors, while anandamide is a partial agonist of these two receptors (Suguira et al., Prog Lipid Res, 2006, 45 (5): 405-46). Unlike many classical neurotransmitters, endocannabinoids signal through a retrograde mechanism. They are synthesized in postsynaptic neurons as needed, 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 responsible for the hydrolysis of 2-AG 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 US A., Aug. 6, 2002, 99(16):10819-24). In the brain, MGL is localized in presynaptic neurons (Straiker et al., Mol Pharmacol., Dec. 2009, 76(6):1220-7) and astrocytes (Walter et al., J Neurosci., Sep. 15, 2004, 24(37):8068-74) in regions associated with high CB1 receptor density. Genetic ablation of MGL expression caused a 10-fold increase in brain 2-AG levels compared to wild-type controls without affecting anandamide concentrations (Schlosburg et al., Nat Neurosci., Sep. 2010, 13(9):1113-9).

[0004] Therefore, MGL modulation provides an interesting strategy for enhancing the endocannabinoid system. A major advantage of this approach is that only brain regions that efficiently produce endocannabinoids will be modulated, thereby potentially minimizing the side effects associated with exogenous CB1 agonists. Pharmacological inactivation of MGL by covalent inhibitors in animals increases 2-AG levels in the brain and peripheral tissues and has been found to produce analgesic, anxiolytic, and anti-inflammatory effects that are dependent 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; Betse et al., Transl Psychiatry., 2018 Apr 26, 8(1):92). In addition to the role of MGL 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 modulation (including MGL inhibition) results in reduced pro-inflammatory prostaglandin signaling in animal models of 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), neurodegenerative diseases 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., Nov. 29, 2012, 2(5):1329-39), Parkinson's disease (Nomura et al., Science, Nov. 11, 2011, 334(6057), 809-13; Pasquarelli et al., Neurochem Int., Nov. 2017, 110:14-24), amyotrophic lateral sclerosis (Pasquarelli et al., Neuropharmacology, Sept. 15, 2017, 124:157-169), multiple sclerosis (Hernadez-Torres et al., Angew Chem Int Ed., Nov. 2014, 134:157-169), Engl., Dec 8, 2014, 53(50):13765-70; Bernal-Chico et al., Glia., Jan 2015, 63(1):163-76), Huntington's disease (Covey et al., Neuropsychopharmacology, 2018, 43, 2056-2063), Tourette syndrome and status epilepticus (Terrone et al., Epilepsia., Jan 2018, 59(1), 79-91; von Ruden et al., Neurobiol Dis., May 2015, 77:238-45).

[0005] Thus, by enhancing the cannabinoid system and attenuating the pro-inflammatory cascade, MGL modulation (including MGL inhibition) offers an attractive therapeutic approach for the treatment of a wide range of complex diseases. Importantly, MGL modulation (including MGL inhibition) in animals does not produce the same effects as Δ 9 - The full range of neurobehavioral effects observed with THC 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] Low endocannabinoid activity is a risk factor for the treatment of depression, anxiety, and post-traumatic stress disorder. The thousands of years of human use of cannabis and the brief period of human treatment with the endocannabinoid antagonist rimonabant provide support for this hypothesis. 2-AG levels are reduced in individuals with major depressive disorder (Hill et al., Pharmacopsychiatry., March 2008, 41 (2): 48–53; Hill et al., Psychoneuroendocrinology., September 2009, 34 (8): 1257–1262.). Low circulating 2-AG levels predict the incidence of depression (Hauer et al., Rev Neurosci., 2012, 23 (5-6): 681-90). Circulating 2-AG has been found to be reduced 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 gradual decrease in circulating 2-AG levels, which was associated with the onset of a decrease in positive emotion measures (Yi et al., Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2016, 67 (3), 92-97). The CB1 receptor inverse agonist / antagonist rimonabant has been recalled from the market due to high incidences of severe depression and suicidal ideation (Christensen et al., The Lancet, 2007, 370, 1706-1713). Therefore, MGL modulators may be useful for treating 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, August 2018, 23 (8): 1798–1806).

[0007] Cannabinoid receptor agonists are clinically used to treat pain, spasticity, vomiting and anorexia (Di Marzo et al., Annu Rev Med., 2006, 57:553-74; Ligresti et al., Curr Opin Chem Biol., 2009 June, 13(3):321-31). Therefore, MGL modulators (including MGL inhibitors) may also potentially be used for these indications. MGL exerts CB1-dependent analgesic effects in animal models of toxic chemical pain, inflammatory pain, thermal pain and neuropathic pain (Guindon et al., Br J Pharmacol., 2011 August, 163(7):1464-78; Kinsey et al., J Pharmacol Exp Ther., 2009 September, 330(3):902-10; Long et al., Nat Chem Biol., 2009 January, 5(1):37-44). MGL blockade reduces mechanical and acetone-induced cold touch-induced allodynia in mice subjected to chronic compressive sciatic nerve injury (Kinsey et al., J Pharmacol Exp Ther., September 2009, 330(3):902-10). MGL inhibition produces tolerance, constipation, and opioid sparing events with reduced cannabinoid side effects (Wilkerson et al., J Pharmacol Exp Ther., April 2016, 357(1):145-56). MGL blockade is protective in an inflammatory bowel disease model (Alhouayek et al., FASEB J., August 2011, 25(8):2711-21). MGL inhibition also reverses nociceptive behaviors and proinflammatory markers induced by paclitaxel in a mouse model of chemotherapy-induced neuropathy (Curry et al., J Pharmacol Exp Ther., July 2018, 366(1):169-18). MGL inhibitors are also potentially useful in treating chronic inflammatory conditions of the bladder such as interstitial cystitis (Chinnadurai et al. 2019 Oct;131:109321).

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

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

[0010] MGL modulators (including MGL inhibitors) may have utility in modulating drug dependence on opioids. MGL blockade reduces the intensity of naloxone-prompted morphine withdrawal symptoms in mice. MGL blockade also attenuates natural withdrawal signs in morphine-dependent mice (Ramesh et al., J Pharmacol Exp Ther., October 2011, 339(1): 173-85).

[0011] MGL modulators are also potentially useful for treating ocular disorders, including but not limited to glaucoma and disease states due to elevated intraocular pressure (Miller et al., Pharmaceuticals, 2018, 11, 50). Summary of the invention

[0012] Embodiments of the invention relate to chemical entities, pharmaceutical compositions containing the chemical entities, methods of making and purifying the chemical entities, and methods of using the chemical entities to treat diseases, disorders, and conditions associated with MGL modulation. Additional embodiments of the invention are methods of using at least one chemical entity of the invention to treat a subject suffering from or diagnosed with a disease, disorder, or condition associated with MGL modulation.

[0013] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention.

[0014] Described herein are compounds of formula (I):

[0015]

[0016] in

[0017] X is CH2 or O;

[0018] R 2a and R 2b Each independently selected from H and C 1-4 alkyl;

[0019] R 3 Selected from:

[0020] (i) phenyl, benzyl or monocyclic heteroaryl, each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SC 1-6 Alkyl, SF5, Si(CH3)3, NR a R b , C 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, phenyl, O-phenyl and O-pyridyl, wherein each cycloalkyl, phenyl or pyridyl is optionally substituted by one or two C 1-4 Alkyl, C 1-4 or two adjacent ring substituents on the phenyl, benzyl or monocyclic heteroaryl group are taken together with the atoms to which they are attached to form a fused monocyclic C 5-6 Cycloalkyl or heterocycloalkyl rings, each optionally substituted by one or two C 1-4 Alkyl, C 1-4 Substitution with haloalkyl or halo groups;

[0021] Where R a and R b Each independently is H or C 1-4 alkyl;

[0022] (ii) optionally C 1-4 Alkyl or halo substituted bicyclic heteroaryl; and

[0023] (iii) optionally C 1-4 Alkyl, C 1-4 Haloalkyl or halogen substituted C 3-6 Alkyl or C 3-6 Cycloalkyl;

[0024] R4 Selected from: H, F and C 1-3 Alkyl; and

[0025] R 5a and R 5b Each independently selected from H and CH3;

[0026] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0027] In some embodiments, is a compound of formula (I):

[0028]

[0029] in

[0030] X is CH2 or O;

[0031] R 2a and R 2b Each independently selected from H and C 1-4 alkyl;

[0032] R 3 Selected from:

[0033] (a) phenyl; phenyl substituted by one, two or three members each independently selected from the following: halo, C 1-6 Alkyl, C 16 Halogenated alkyl, C(CH3)2OH, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SCH3, SF5, Si(CH3)3, N(CH3)2, C 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, phenyl, O-phenyl, O-pyridyl, and C substituted by CH3 3-6 Cycloalkyl; and

[0034] (b) C 1-6 Alkyl substituted pyridinyl; naphthyl;

[0035]

[0036] R 4 Selected from: H, F and C 1-3 Alkyl; and

[0037] R 5a and R 5b Each independently selected from H and CH3;

[0038] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof. DETAILED DESCRIPTION

[0039] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0040] Unless otherwise specified in a specific example of 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 would be considered equivalent to any of the foregoing examples based on common skills in the art and the teachings provided herein. "C 1-6 "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.

[0041] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic or spiro polycyclic carbocyclic ring having 3 to 12 ring atoms per carbocyclic ring. Illustrative examples of cycloalkyl groups include the following entities in the form of appropriate bonding moieties:

[0042]

[0043] The term "halogen" or "halo" refers to chlorine, fluorine, bromine or iodine.

[0044] The term "haloalkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the chain, which is optionally substituted with a halogen for hydrogen. 1-6 "Haloalkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms in the chain, which is optionally substituted with a halogen for hydrogen. As used herein, the term "C 1-4 "Haloalkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms in the chain, optionally replacing hydrogen with a halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that would be considered equivalent to any of the foregoing examples based on one of ordinary skill in the art and the teachings provided herein.

[0045] The term "aryl" refers to a monocyclic aromatic carbocyclic ring (a ring structure in which the ring atoms are all carbon) having 6 atoms per ring (the carbon atoms in the aryl group are sp2 hybridized).

[0046] The term "phenyl" represents the following moiety:

[0047] The term "pyridinyl" or "pyridyl" refers to the following moiety:

[0048] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system comprising 5 to 14 ring atoms, wherein 1 to 4 ring atoms in the ring atoms are independently O, N or S, and the remaining ring atoms are carbon atoms. In one embodiment, the heteroaryl group has 5 to 10 ring atoms. In another embodiment, the heteroaryl group is a monocyclic ring and has 5 or 6 ring atoms. In another embodiment, the heteroaryl group is a monocyclic ring and has 5 or 6 ring atoms and at least one nitrogen ring atom. The heteroaryl group is engaged via a ring carbon atom, and any nitrogen atom of the heteroaryl group may be optionally oxidized to a corresponding N-oxide. The term "heteroaryl" also encompasses heteroaryl groups fused to a benzene ring as defined above.

[0049]

[0050] As used herein, the term "heterocycloalkyl" refers to a non-aromatic ring system, from 1 to 4 of the ring atoms are independently O, N or S, and the remaining ring atoms are carbon atoms, which may be optionally fused to another ring (aromatic or heteroaromatic). Non-limiting examples of exemplary heterocycloalkyls include:

[0051]

[0052] One skilled in the art will recognize that the heteroaryl, heterocycloalkyl, cycloalkyl, aryl groups listed or exemplified above are not exhaustive and that other species within the scope of these defined terms may also be selected.

[0053] The term "substituted" means that the specified group or moiety carries one or more substituents. The term "unsubstituted" means that the specified group does not carry a substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. If the term "substituted" is used to describe a structural system, it means that the substitution occurs at any valence-allowed position on the system.

[0054] The term "variable point of attachment" means that a group is allowed to be attached at more than one alternative position in the structure. The attachment always replaces a hydrogen atom on one of the ring atoms. In other words, all arrangements of bonding are represented by a single schematic, as shown in the following illustration.

[0055]

[0056] One skilled in the art will recognize that if more than one such substituent is present on a given ring; then each substituent is bonded independently of all the other substituents. The groups listed or exemplified above are not exhaustive.

[0057] The term "substituted" means that the specified group or moiety carries one or more substituents. The term "unsubstituted" means that the specified group does not carry a substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. If the term "substituted" is used to describe a structural system, it means that the substitution occurs at any valence-allowed position on the system.

[0058] Any formula given herein is intended to represent compounds having the structure shown in the structural formula and certain variations or forms. Specifically, the compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds with general formula and their mixtures are considered to be within the scope of such formulas. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be prepared as individual (R)- or (S)-stereoisomers or as mixtures thereof. Therefore, any formula given herein is intended to represent racemates, one or more forms of their enantiomeric forms, one or more forms of their diastereomeric forms, and mixtures thereof. In addition, any formula given herein is intended to also refer to any one of the hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not explicitly listed.

[0059] The term "R" at a stereocenter indicates that the stereocenter has only the R-configuration, as defined in the art; similarly, the term "S" means that the stereocenter has only the S-configuration. As used herein, the term "RS" refers to a stereocenter that exists in a mixture of the R-configuration and the S-configuration.

[0060] A compound containing one stereocenter without a stereobond label is a mixture of 2 enantiomers. A compound containing 2 stereocenters, neither of which has a stereobond label, is a mixture of 4 diastereomers. A compound having 2 stereocenters, both labeled "RS", with stereobond labels, is a 2-component mixture with relative stereochemistry as indicated. An unlabeled stereocenter without a stereobond label is a mixture of R- and S-configurations. For unlabeled stereocenters with stereobond labels, the absolute stereochemistry is as stated.

[0061] Reference to a compound herein represents a reference to any of: (a) the form of such compound actually mentioned, and (b) any form of such compound in the medium in which the compound is considered when referring to the compound. For example, reference to a compound such as R-COOH herein encompasses reference to any of: for example, R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R-COOH(s) refers to a solid compound, which may be in the form of a tablet or some other solid pharmaceutical composition or formulation, for example; R-COOH(sol) refers to an undissociated form of the compound in a solvent; and R-COO-(sol) refers to a dissociated form of the compound in a solvent, such as a dissociated form of the compound in an aqueous environment, whether such dissociated form is derived from R-COOH, a salt thereof, or from any other entity that, upon dissociation in the medium in question, produces R-COO-. In another example, a statement such as "exposing an entity to a compound of formula R-COOH" refers to exposing the entity to one or more forms of the compound R-COOH present in the medium in which the exposure occurs. In yet another example, a statement such as "reacting an entity with a compound of formula R-COOH" refers to reacting (a) such entity (as one or more chemically related forms of such entity present in the medium in which the reaction occurs) with (b) one or more chemically related forms of the compound R-COOH present in the medium in which the reaction occurs. In this regard, if the entity is, for example, in an aqueous environment, it is understood that the compound R-COOH is in the same medium and that the entity is therefore being exposed to substances such as R-COOH(aq) and / or R-COO-(aq), wherein the subscript "(aq)" represents "aqueous" according to its conventional meaning in chemistry and biochemistry. The carboxylic acid functional group is selected in these naming examples; however, this selection is not intended to be limiting, but is merely illustrative. It should be understood that similar examples can be provided with other functional groups, including but not limited to hydroxyl groups, basic nitrogen members (such as those in amines), and any other groups that interact or transform in a known manner in a medium containing the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis including hydrolysis, solvation including hydration, protonation and deprotonation. No further examples are provided herein in this regard, as these interactions and transformations in a given medium are known to any ordinary technician in the art.

[0062] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number in enriched form. Examples of isotopes that may be incorporated into the compounds of the invention in excess of natural abundance include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 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 I. Such isotope-labeled compounds can be used for metabolic studies (preferably with 14 C labeling), reaction kinetic studies (e.g. 2 H or 3 H labeling), detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including tissue distribution assays of drugs or substrates, or can be used for radiation therapy of patients. Specifically, 18 F or 11 C-labeled compounds may be particularly preferred for PET or SPECT studies. In addition, compounds labeled with heavier isotopes such as deuterium (i.e. 2 H or D) can provide certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents to carry out the procedures disclosed in the "Schemes" or in the "Examples and Preparations" described below.

[0063] When referring to any formula given herein, for a specified variable, the selection of a specific part from a list of possible species is not intended to limit the selection of the same species when such variable appears elsewhere. In other words, unless otherwise indicated, when a variable appears more than once, the selection of that species from a specified list is independent of the selection of that species for the same variable elsewhere in the formula.

[0064] Terminology C n-m Alkyl refers to an aliphatic chain, whether straight or branched, in which the total number of carbon members N in the chain satisfies n≤N≤m, and m>n.

[0065] When the same multiple substituents are assigned to multiple groups, the specific individual substituent assignments assigned to each of such groups are intended to be independently selected relative to the specific individual substituents assigned to the remaining groups. By way of example, but not limitation, if each of the groups Q and R can be H or F, the selection of H or F for Q is made independently of the selection of H or F for R, so that unless otherwise expressly stated, the selection of the assignment to Q does not determine or determine the selection of the assignment to R, or vice versa, the selection of the assignment to R does not determine or determine the selection of the assignment to Q. In this regard, the exemplary claim expressions will be understood to mean "each of Q and R is independently H or F", or "each of Q and R is independently selected from H and F".

[0066] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise.Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art.

[0067] In another example, the present invention covers zwitterionic compounds by referring to compounds known to form zwitterions, even if it is not explicitly mentioned in its zwitterionic form. Terms such as zwitterions and their synonyms zwitterionic compounds are standard names recognized by IUPAC, which are well known and part of the standard set of defined scientific names. In this regard, the name zwitterion is assigned the name identifier CHEBI:27369 by the molecular entity dictionary of the Chemical Entities of Biological Inerest (ChEBI). It is well known that zwitterions or zwitterionic compounds are neutral compounds with formal unit charges of opposite signs. Sometimes, these compounds are referred to by the term "inner salts". Other materials call these compounds "dipole ions", but this term is considered to be a misnomer by other other materials. As a specific example, aminoacetic acid (amino acid glycine) has the formula H2NCH2COOH, and it is a zwitterion. + H3NCH2COO -The forms exist in some medium (in this case, in a neutral medium). The terms zwitterion, zwitterionic compound, inner salt, and dipole ion fall within the scope of the present invention in accordance with their known and recognized meanings, as understood in any case by one of ordinary skill in the art. Since it is not necessary to name every embodiment that one of ordinary skill in the art would recognize, the structures of zwitterionic compounds associated with the compounds of the present invention are not explicitly given herein. However, they are part of the embodiments of the present invention. In this regard, no further examples are provided herein, as the interactions and transformations that lead to the production of various forms of a given compound in a given medium are known to anyone of ordinary skill in the art.

[0068] When referring to any formula given herein, for a specified variable, the selection of a particular part from a list of possible species is not intended to limit the selection of the same species when the variable appears elsewhere. In other words, unless otherwise indicated, when a variable appears more than once, the selection of that species from a specified list is independent of the selection of that species for the same variable elsewhere in the formula.

[0069] Using the first example of substituent terminology, if the substituent S 1 实施例 is one of S1 and S2, and the substituent S 2 实施例 is one of S3 and S4, then these designations refer to the embodiments of the present invention given by the following selections: S 1 实施例 is S1 and S 2 实施例 It is S3; S 1 实施例 is S1 and S 2 实施例 It is S4; S 1 实施例 is S2 and S 2 实施例 It is S3; S 1 实施例 is S2 and S 2 实施例 is S4; and equivalents of each of such alternatives. The shorter term "S 1 实施例 is one of S1 and S2, and S 2 实施例 "is one of S3 and S4" is therefore used herein for brevity, but not in a limiting manner. The first example of substituent terminology stated above in general terms is intended to illustrate the different substituent assignments described herein.

[0070] Furthermore, when more than one designation is given for any member or substituent, embodiments of the invention include various groupings that can be made independently from the listed designations, and equivalents thereof. By way of a second example of substituent terminology, if a substituent S is described herein 实施例 is one of S1, S2 and S3, then the list refers to an embodiment of the present invention, in which S 实施例 It is S1; S 实施例 It is S2; S 实施例 It is S3; S 实施例 is one of S1 and S2; S 实施例 is one of S1 and S3; S 实施例 is one of S2 and S3; S 实施例 is one of S1, S2 and S3; and S 实施例 are any equivalents of each of these options. The shorter term "S 实施例 "is one of S1, S2 and S3" is therefore used herein for brevity, but not in a limiting manner. The second example of substituent terminology stated above in general terms is intended to illustrate the different substituent assignments described herein.

[0071] The name "C i -C j "," when applied herein to a class of substituents, is intended to refer to embodiments of the invention in which each and every one of the numbers of carbon members from i to j (inclusive) is independently realized. By way of example, the terms C1-C3 independently refer to an embodiment having one carbon member (C1), an embodiment having two carbon members (C2), and an embodiment having three carbon members (C3).

[0072] "Pharmaceutically acceptable salts" are intended to mean salts of acids or bases of compounds represented by formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally SM 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 patient tissues without undue toxicity, irritation, or allergic response.

[0073] The compounds of formula (I) may possess sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and therefore react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0074] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0075] The compound of formula (I) may contain at least one nitrogen with basic properties, and thus the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, etc.; or an organic acid such as 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, pyranosiduronic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as mandelic acid, citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid), sulfonic acid (such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any compatible mixture of acids such as those given as examples herein, and any other acids and mixtures thereof deemed equivalent.

[0076] The compounds of formula (I) may contain a carboxylic acid moiety, and the desired pharmaceutically acceptable salts 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 given as examples herein, and any other bases and mixtures thereof deemed by one of ordinary skill in the art to be equivalent or acceptable substitutes. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, tertiary amines and cyclic amines such as benzylamine, pyrrolidine, piperidine, morpholine, piperazine, N-methylglucamine and tromethamine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0077] The compounds of the invention, including pharmaceutically acceptable salts thereof, either alone or in combination (collectively referred to as "active agents"), can be used as MGL modulators in the methods of the invention. Such methods for modulating MGL comprise administering a therapeutically effective amount of at least one chemical entity of the invention.

[0078] In some embodiments, MGL modulators are inhibitors and are used to diagnose a subject having 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".

[0079] Therefore, the present invention relates to methods for treating subjects diagnosed with or suffering from diseases, disorders or conditions associated with MGL receptor activity using the active agents described herein. The term "treatment" as used herein is intended to refer to the administration of an active agent or composition of the present invention to a subject for the purpose of achieving a therapeutic or preventive benefit by modulating MGL receptor activity. Treatment includes reversing, ameliorating, alleviating, inhibiting progression, reducing severity, or preventing a disease, disorder or condition associated with MGL modulation or one or more symptoms of such a disease, disorder or condition. The term "subject" refers to a mammalian patient, such as a human, in need of such treatment.

[0080] The term "composition" refers to a product comprising the specified ingredients in therapeutically effective amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0081] The term "MGL inhibitor" is intended to encompass compounds that interact with MGL to significantly reduce or eliminate its catalytic activity, thereby increasing the concentration of its substrate. The term "MGL-modulated" is used to refer to conditions affected by MGL enzyme modulation, including conditions affected by MGL enzyme inhibition. The present disclosure relates to methods for treating, ameliorating and / or preventing diseases, conditions or disorders associated with pain (including inflammatory pain), as well as psychiatric disorders, neurological disorders, cancers and ocular disorders by administering a therapeutically effective amount of an MGL modulator to a subject in need thereof.

[0082] The term "modulator" includes both inhibitors and activators, wherein "inhibitors" refer to compounds that reduce, prevent, inactivate, desensitize or downregulate MGL expression or activity, while "activators" refer to compounds that increase, activate, promote, sensitize or upregulate MGL expression or activity.

[0083] Unless otherwise indicated, as used herein, the term "affect" or "affected" (when referring to a disease, condition or disorder, that is affected by MGL inhibition) includes a reduction in the frequency and / or severity of one or more symptoms or clinical manifestations of the disease, condition or disorder; and / or includes preventing the development of the disease, condition or disorder or the development of one or more symptoms or clinical manifestations of the disease, condition or disorder.

[0084] In the method of treatment according to the present invention, at least one activating agent of the present invention of a therapeutically effective amount is administered to a subject suffering from or diagnosed as having such a disease, disorder or condition." Therapeutically effective amount" refers to the amount or dosage sufficient to produce the desired treatment or prevention beneficial effect in the subject who needs to carry out such treatment for a specified disease, disorder or condition as a whole. The effective amount or dosage of the activating agent of the present invention can be explored by conventional methods such as modeling, dose escalation studies or clinical trials, and explored by considering conventional factors, such as the mode or approach of administration or drug delivery, the pharmacokinetics of the reagent, the severity and course of the disease, disorder or condition, the therapy performed before or now performed by the subject, the health status of the subject and the response to the drug, and the judgment of the attending physician. For a 70kg person, the exemplary range of a suitable dosage is in single dose units or multiple dose units (e.g., BID, TID, QID or according to the needs of therapy), about 1 mg / day to 1000 mg / day.

[0085] Once the subject's disease, disorder or condition improves, the dosage can be adjusted to preventive or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced to a level that maintains the desired therapeutic or preventive effect, depending on the symptoms. Of course, if the symptoms have been alleviated to an appropriate level, treatment can be stopped. However, the subject may require long-term intermittent treatment due to any recurrence of symptoms.

[0086] In addition, it is also envisioned that the compounds of the present invention are used alone, in combination with one or more other compounds of the present invention, or in combination with additional active ingredients for the treatment of the conditions described below. Additional active ingredients may be co-administered alone with at least one compound of the present invention, co-administered with an active agent of the present invention, or included in a pharmaceutical composition according to the present invention together with such agents. In an exemplary embodiment, the additional active ingredients are those active ingredients known or found to be effective in treating conditions, disorders or diseases associated with MGL regulation, such as another MGL inhibitor or a compound active against another target associated with the particular condition, disorder or disease. The combination may help to improve efficacy (e.g., by including in the combination a compound that enhances the potency or effectiveness of an active agent according to the present invention), reduce one or more side effects, or reduce the required dose of an active agent according to the present invention.

[0087] When referring to an inhibitory target, an "effective amount" means an amount sufficient to affect the regulation of MGL.

[0088] It is contemplated that the active agents of the invention are used alone or in combination with one or more additional active ingredients to formulate the pharmaceutical compositions of the invention.The pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one active agent according to the invention.

[0089] Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are non-toxic, biologically tolerable and otherwise biologically suitable substances for administration to a subject, such as inert substances, which are added to the pharmaceutical composition or otherwise used as vehicles, carriers or diluents to facilitate administration of the agent and are compatible therewith. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0090] The delivery form of the pharmaceutical composition containing one or more dosage units of the active agent can be prepared using pharmaceutically acceptable excipients and compounding techniques known or available to those skilled in the art. The composition can be administered in the method of the present invention by a suitable delivery route, such as oral, parenteral, rectal, topical or ocular administration, or by inhalation.

[0091] The preparation may be in the form of a tablet, capsule, sachet, dragee, powder, granule, lozenge, powder for reconstitution, liquid preparation or suppository. The composition may be formulated for any of a variety of routes of administration, such as intravenous infusion, topical administration or oral administration. Preferably, the composition may be formulated for oral administration.

[0092] For oral administration, the active agent of the present invention can be provided in the form of tablets or capsules, or as a solution, emulsion or suspension. In order to prepare an oral composition, the active agent can be formulated to produce, for example, a dosage of about 1 mg / day to 1000 mg / day in a single dose unit or multiple dose units as an exemplary range of suitable dosages for a 70 kg person.

[0093] Oral tablets may include one or more active ingredients mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, colorants and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Exemplary liquid oral excipients include ethanol, glycerol, water, etc. Starch, polyvinyl pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid are exemplary disintegrants. Binders may include starch and gelatin. Lubricants (when present) may be magnesium stearate, stearic acid or talcum powder. If desired, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with enteric coatings.

[0094] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules or (hydroxypropyl) methylcellulose capsules. To prepare hard gelatin capsules, one or more active ingredients can be mixed with solid, semisolid or liquid diluents. The liquid for oral administration can be in the form of a suspension, solution, emulsion or syrup, or can be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid compositions may optionally include: 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, ethanol or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and (if necessary) flavoring agents or coloring agents.

[0095] The activating agent of the present invention can also be administered by non-oral routes. For example, the composition can be formulated into suppositories, enemas or foams for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal or subcutaneous routes, the activating agent of the present invention can be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or provided in an oil acceptable to the parenteral. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms can be presented in unit dosage forms (such as ampoules or disposable injection devices), in multiple dose forms (such as vials) from which appropriate doses can be extracted, or in solid forms or pre-concentrates that can be used to prepare injectable preparations. Exemplary infusion doses range from about 1 to 1000 μg / kg / minute of the activating agent mixed with a pharmaceutically acceptable carrier, for a few minutes to a few days.

[0096] For topical administration, the active agent may be mixed with a pharmaceutical carrier at a concentration of about 0.01% to about 20%, preferably 0.1% to 10% drug to vehicle. Another way to administer the active agents of the present invention may utilize a patch formulation to achieve transdermal delivery.

[0097] Alternatively, in the methods of the present invention the active agent may be administered via the intranasal or oral route by inhalation, for example in the form of a spray formulation also containing a suitable carrier.

[0098] In another embodiment, the invention relates to a method of treating a subject suffering from or diagnosed with a disease, disorder or condition associated with MGL modulation, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of an active agent.

[0099] The compounds of formula (I) are useful in methods for treating, ameliorating and / or preventing diseases, conditions or disorders affected by MGL inhibition. Such methods include administering a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof to a subject, including animals, mammals and humans in need of such treatment, improvement and / or prevention.

[0100] Specifically, the compound of formula (I) or its pharmaceutically acceptable salt, isotope, N-oxide, solvate and stereoisomer can be used to treat, improve and / or prevent diseases, disorders or disorders that cause pain, mental disorders, neurological disorders, cancer and eye disorders. More specifically, the compound of formula (I) or its pharmaceutically acceptable salt, isotope, N-oxide, solvate and stereoisomer can be used to treat, improve and / or prevent inflammatory pain, major depressive disorder, refractory depression, anxious depression or bipolar disorder, by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined herein or its pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer.

[0101] 1) Pain

[0102] Examples of inflammatory pain include, but are not limited to, pain due to a disease, condition, disorder, or pain state, including inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, fatigue, musculoskeletal disorders, skin disorders, toothache, febrile illnesses, burns, sunburn, snake bites, venomous snake bites, spider bites, insect bites, neurogenic 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.

[0103] One type of inflammatory pain is inflammatory hyperalgesia / hypersensitivity. Examples of inflammatory hyperalgesia include diseases, conditions, disorders, or pain states, including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, postoperative 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 disease (including Crohn's disease), ulcerative colitis, benign prostatic hypertrophy, and nasal hypersensitivity.

[0104] In one embodiment, the present invention relates to a method for treating, ameliorating and / or preventing inflammatory visceral hyperalgesia in which there is enhanced visceral irritability, the method comprising, consisting of and / or consisting essentially of the following steps: 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 another embodiment, the present invention relates to a method for treating inflammatory somatic hyperalgesia in which there is hypersensitivity to thermal, mechanical and / or chemical stimulation, 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.

[0105] Another embodiment of the present invention relates to a method for treating, ameliorating and / or preventing neuropathic pain. Examples of neuropathic pain include pain due to diseases, conditions, disorders or pain states, including cancer, neurological disorders, spinal and peripheral nerve surgery, brain tumors, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, 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, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, prosthetic pain, fractures, oral neuropathic pain, Charcot pain, complex regional pain syndrome type I and II (CRPS I / II), radiculopathy, Guillain-Barre syndrome, meralgia paresthesia, burning mouth syndrome, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gomberg's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate ganglion neuralgia, glossopharyngeal neuralgia, neuralgic migraine, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, Sluder's neuralgia, sphenopalatine ganglion neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvar pain, vidian neuralgia, or chemotherapy-induced neuropathy.

[0106] One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of an abnormal pain state associated with a neuropathy in which there is a hypersensitivity to cold stimuli. Examples of neuropathic cold allodynia include allodynia due to a disease, condition, disorder, or pain state, including neuropathic pain (neuralgia), pain caused by spinal and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome type I and II (CRPS I / II), and radiculopathy.

[0107] In another embodiment, the present invention relates to a method for treating, ameliorating and / or preventing neuropathic cold touch-induced allodynia in which hypersensitivity to cold stimulation 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.

[0108] 2) Mental disorders

[0109] Examples of psychiatric disorders include, but are not limited to, anxiety disorders such as social anxiety disorder, post-traumatic stress disorder, phobias, social phobia, specific phobias, panic disorders, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression disorders such as major depressive disorder, bipolar disorder, seasonal affective disorder, postpartum depression, manic depression, and bipolar depression. Mood disorders and mood disorders that can be treated according to the present invention include, but are not limited to, depression, hypomania, mania, and mixed forms of bipolar I disorder; bipolar II disorder; depressive disorders such as single depression or recurrent major depressive disorder, minor depressive disorder, refractory depression, anxious depression, bipolar disorder, postpartum onset depressive disorder, depressive disorder with psychotic symptoms; persistent mood disorders such as cyclothymia, dysthymia, euthymia; premenstrual dysphoric disorder; psychosis; and developmental disorders such as autism spectrum disorders and Asperger's syndrome.

[0110] 3) Neurological disorders

[0111] Examples of neurological disorders include, but are not limited to, tremor, dyskinesia, dystonia, spasticity, Tourette syndrome; neuromyelitis optica, Parkinson's disease; Alzheimer's disease; senile dementia; Huntington's chorea; epilepsy / epileptic disorders, and sleep disorders.

[0112] 4) Cancer

[0113] Examples of cancer include, but are not limited to, benign skin tumors, prostate tumors, ovarian tumors, and brain tumors (glioblastoma, medulloepithelioma, medulloblastoma, neuroblastoma, tumors of embryonal origin, astrocytoma, astroblastoma, ependymoma, oligodendroglioma, neuroepithelioma, epiphyseal tumors, ependymoblastoma, malignant meningioma, sarcoidosis, malignant melanoma, schwannoma).

[0114] 5) Eye diseases

[0115] Examples of eye disorders include, but are not limited to, intraocular hypertension, glaucoma, degeneration and apoptosis of retinal ganglion cells and neuroretinal cells.

[0116] Other embodiments of the present invention provide a method for modulating the activity of an MGL receptor, comprising modulating such receptor while present in a subject, the method comprising exposing the MGL receptor to a therapeutically effective amount of at least one compound selected from the compounds of the present invention.

[0117] In some embodiments of Formula (I), X is CH2. In some embodiments, X is O.

[0118] In some embodiments, R 2a and R 2bEach is H. In some embodiments, R 2a and R 2b Each is CH3. In some embodiments, R 2a is H, and R 2b For CH3.

[0119] In some embodiments, R 3 is phenyl; or phenyl substituted by one, two or three members independently selected from the following: Cl, F, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C(CH3)2OH, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SCH3, Si(CH3)3, SF5, N(CH3)2, C 3-6 Cycloalkyl, C substituted by CH3 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, phenyl, O-phenyl and O-pyridyl.

[0120] In some embodiments, R 3 is phenyl substituted by one, two or three members independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, SCH3, SF5 or Si(CH3)3.

[0121] In some embodiments, R 3 for

[0122]

[0123] In some embodiments, R 3 is 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl or 3-(1-methylcyclopropyl)phenyl.

[0124] 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; pyridinyl optionally substituted with trifluoromethyl, fluorine 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. 3 is phenyl optionally substituted as described herein.

[0125] In some embodiments, R4 is H, F, CH3 or CH2CH3. In some embodiments, R 4 For hydrogen.

[0126] In some embodiments, R 5a and R 5b Each is H. In some embodiments, R 5a is CH3 and R 5b is H. In some embodiments, R 5a H and R 5b For CH3.

[0127] In some embodiments of Formula (I), for

[0128] In some embodiments of Formula (I),

[0129] In some embodiments of Formula (I), for

[0130] In some embodiments of Formula (I), for

[0131] In some embodiments of Formula (I), for

[0132] Another embodiment of the present invention is a compound as shown in Table 1 below.

[0133] Table 1.

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0143] Another embodiment of the present invention is a compound selected from the group consisting of:

[0144] (2s,4s)-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

[0145] (2s,4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

[0146] (2s,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

[0147] (2r,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; and

[0148] (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

[0149] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0150] An additional embodiment of the present invention is a compound of formula (I) having formula (IA):

[0151]

[0152] in

[0153] R 3 Selected from:

[0154] (a) phenyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Haloalkyl, Si(CH3)3, C 3-6 Cycloalkyl, phenyl, O-phenyl and CH3-substituted C 3-6 Cycloalkyl; and

[0155] (b) and

[0156] R 5b is H or CH3;

[0157] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0158] An additional embodiment of the present invention is a compound of formula (I) having formula (IB):

[0159]

[0160] in

[0161] R 2a and R 2b Each independently selected from H and CH3;

[0162] R 3 Selected from:

[0163] (a) phenyl; phenyl substituted by one, two or three members each independently selected from the following: Cl, F, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 and

[0164] (b)

[0165]

[0166] R 4 Selected from: H, F, CH3 and CH2CH3;

[0167] R 5a is H or CH3; and

[0168] R 5b is H or CH3;

[0169] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0170] An additional embodiment of the present invention is a compound of formula (I) having formula (IC):

[0171]

[0172] in

[0173] X is CH2 or O; and

[0174] Ring A is selected from:

[0175]

[0176] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0177] An additional embodiment of the present invention is a compound of formula (I) having formula (ID):

[0178]

[0179] in

[0180] X is CH2 or O;

[0181] R 2a and R 2b Each independently selected from H and CH3;

[0182] R b Selected from: Cl, F, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 and

[0183] n is 0, 1, 2 or 3;

[0184] R 4 Selected from: H, F, CH3 and CH2CH3;

[0185] R 5a is H or CH3; and

[0186] R 5b is H or CH3;

[0187] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0188] An additional embodiment of the present invention is a pharmaceutical composition comprising:

[0189] (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; and

[0190] (B) at least one pharmaceutically acceptable excipient.

[0191] An additional embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of compounds in Table 1, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutically acceptable prodrugs of compounds in Table 1, and pharmaceutically active metabolites of compounds in Table 1; and at least one pharmaceutically acceptable excipient.

[0192] An additional 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.

[0193] An additional 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), and 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.

[0194] An additional 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), and 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.

[0195] An additional 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 (ID), and a pharmaceutically acceptable salt, N-oxide or solvate of a compound of formula (ID), a pharmaceutically acceptable prodrug of a compound of formula (ID), and a pharmaceutically active metabolite of formula (ID); and at least one pharmaceutically acceptable excipient.

[0196] Also within the scope of the present invention are enantiomers and diastereomers of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides or solvates (including combinations thereof) of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)), and pharmaceutically active metabolites of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)).

[0197] Also within the scope of the invention are isotopic variants of formula (I) (as well as formulas (IA) and (IB), (IC) and (ID)), for example, deuterated compounds of formula (I). Also within the scope of the invention are pharmaceutically acceptable salts, N-oxides or solvates (or combinations thereof) of isotopic variants of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)). Also within the scope of the invention are pharmaceutically acceptable prodrugs of isotopic variants of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)), and pharmaceutically active metabolites of isotopic variants of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)).

[0198] An additional 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, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound selected from: a compound 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 used to treat 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 in a method for treating a disease, disorder or condition mediated by MGL receptor activity.

[0199] An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder or condition mediated by MGL receptor activity, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound selected from compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)), enantiomers and diastereomers of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)), isotopic variants of compounds of formula (I) (as well as formulas (IA), (IB), (IC) and (ID)), and pharmaceutically acceptable salts of all of the foregoing. 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 used to treat a disease, disorder or condition mediated by MGL receptor activity. Also described herein are compounds of Formula (IA), (IB), (IC) or (ID), or pharmaceutically acceptable salts, isotopes, N-oxides, solvates or stereoisomers thereof, for use in methods of treating a disease, disorder or condition mediated by MGL receptor activity.

[0200] Exemplary compounds that can be used in the methods of the present invention will now be described with reference to exemplary synthesis schemes for their general preparation and subsequent specific examples below. Those skilled in the art will recognize that, in order to obtain a variety of compounds herein, the starting materials can be appropriately selected so that, with or without protection as required, the final desired substituent will be carried throughout the reaction scheme to obtain the desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that can be subjected to the entire reaction scheme and replaced with the desired substituent where appropriate. Unless otherwise indicated, the variables are as defined above for formula (I). The reaction can be carried out between the melting point and reflux temperature of the solvent, and preferably between 0°C and the reflux temperature of the solvent. Conventional heating or microwave heating can be used to heat the reaction. The reaction can also be carried out in a closed pressure vessel at a normal reflux temperature higher than the solvent.

[0201] Abbreviations and acronyms used herein include the following:

[0202] Table 2.

[0203]

[0204]

[0205]

[0206] Preparation Example

[0207] Exemplary compounds useful in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparation below and for the specific examples that follow.

[0208] Solution 1

[0209]

[0210] According to Scheme 1, a compound of formula (V) (wherein R a C 1-4 Alkyl) is treated with hydroxylamine; using an additive such as sodium acetate (NaOAc) or the like; in a suitable solvent such as ethanol (EtOH) or the like; to obtain a compound of formula (VI).

[0211] The compound of formula (VII) is prepared from the compound of formula (VI) using an oxidizing agent (such as hydrogen peroxide, urea peroxide, etc.); in the presence of an activating agent (such as trifluoroacetic anhydride (TFAA)); in the presence of a base (such as disodium hydrogen phosphate); in a solvent (such as acetonitrile (ACN)).

[0212] Solution 2

[0213]

[0214] 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), etc.; in a solvent such as ACN, etc. The compound of formula (IX) is prepared by hydrogenolysis of a compound of formula (VIIIb) in the presence of a catalyst such as palladium on carbon (Pd / C), etc.; in a solvent such as ethyl acetate (EtOAc), EtOH, etc.

[0215] The compound of formula (X) is prepared by reacting the compound of formula (IX) with triphosgene in the presence of a base (such as TEA, etc.); in a solvent (such as tetrahydrofuran (THF), etc.). The compound of formula (XI) (wherein X is O) is prepared by acidic deprotection of the compound of formula (X) using an acid (such as trifluoroacetic acid (TFA), HCl in dioxane, etc.).

[0216] Solution 3

[0217]

[0218] According to Scheme 3, compounds of formula (XIa) and formula (XIb) are prepared by a Michael-type reaction of a compound of formula (VII) with methyl acrylate in the presence of a base (such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) etc.) in a solvent (such as ACN etc.). A reducing agent (such as sodium borohydride (NaBH4) etc.) and an additive (such as nickel(II) chloride hexahydrate) etc. are used to reduce and cyclize the compound of formula (XIa) in a suitable solvent (such as methanol (MeOH) etc.) to obtain a compound of formula (XI) (wherein X is CH2).

[0219] Solution 4

[0220]

[0221] According to Scheme 4, the compound of formula (XII) is prepared by making a compound of formula (VII) (wherein R a C 1-4 alkyl); with acetaldehyde in the presence of a base (such as TEA, etc.); in a solvent (such as ACN, etc.) at a temperature ranging from 0°C to room temperature for a period of up to 18 hours. The compound of formula (XII) is subjected to hydrogenolysis using the conditions described previously; to obtain compounds of formula (XIIIa) and (XIIIb).

[0222] Solution 5

[0223]

[0224] According to Scheme 5, the compound of formula (XIIIa) (wherein R a The compound of formula (XIV) is subjected to ring closure conditions with triphosgene to obtain a compound of formula (XIV). The compound of formula (XIV) is subjected to acidic deprotection conditions as previously described to obtain a compound of formula (XV), wherein R 2a H and R 2b For CH3.

[0225] Solution 6

[0226]

[0227] According to Scheme 6, the compound of formula (XVI) is prepared from the compound of formula (XIIIa) in two steps. In the first step, the compound of formula (XIIIa) (wherein R ais tert-butyl) in the presence of a base such as TEA, etc.; in a solvent such as dichloromethane (DCM), etc., by reaction with di-tert-butyl dicarbonate. In the second step, oxidation to a ketone compound of formula (XVI) is achieved at a temperature ranging from about -78°C to room temperature (about 23°C) in a solvent such as EtOAc, DMSO, DCM, etc. using conditions known to those skilled in the art (e.g., DMP (Dess-martin periodinane), SO3-pyridine, Swern conditions [(COCl)2, DMSO, Et3N], PCC, etc.), to obtain a compound of formula (XVI), wherein PG is BOC, and R a is tert-butyl. 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. Under conventional Grignard reaction conditions, in the presence of an organic magnesium halide (such as methylmagnesium bromide, etc.); in a suitable solvent (such as Et2O, THF or a mixture thereof), at a temperature ranging from -40°C to room temperature; the compound of formula (XVI) is reacted to obtain 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, HCl / dioxane, etc.) are used to obtain 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 a compound of formula (XVIII) in two steps. In the first step, ring closure is achieved using conditions using triphosgene as previously described. Subsequent deprotection of the tert-butyl ester was achieved using conditions described previously.

[0228] Solution 7

[0229]

[0230] 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 an appropriate commercially available or synthetically available bromobenzene (such as 5-bromo-2-methylphenol); a catalyst (such as nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2 DME) or the like); a ligand (such as 1,10-phenanthroline); additives sodium tetrafluoroborate (NaBF4), manganese powder (Mn) and 4-ethylpyridine; in a solvent (such as MeOH); at a temperature of about 60°C over a period of 16 hours to 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 (CBr2F2) in the presence of a suitable base such as sodium hydride (NaH) and potassium tert-butoxide (KOtBu), etc., in a suitable solvent such as N,N-dimethylacetamide (DMA), etc. 4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine is prepared from tert-butyl 4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate using silver tetrafluoroborate (AgBF4) in a solvent such as DCM, etc., over a temperature range of -78°C to room temperature over a period of 16 hours.

[0231] Solution 8

[0232]

[0233] According to Scheme 8, tert-butyl 4-((2-aminopyridin-3-yl)ethynyl)piperidine-1-carboxylate is prepared by a Sonogashira reaction of commercially available or synthetically obtained tert-butyl 4-ethynylpiperidine-1-carboxylate and 2-amino-3-bromopyridine; cuprous iodide; a catalyst (such as bis(triphenylphosphine)palladium(II) dichloride, etc.); a base (such as TEA, etc.); in a solvent (such as N,N-dimethylformamide (DMF), etc.); at a temperature of about 100° C. over a period of 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, etc.; in a suitable solvent such as N-methyl-2-pyrrolidone (NMP), etc.; at a temperature of about 70°C over a period of 16 hours.

[0234] Solution 9

[0235]

[0236] According to Scheme 9, cleavage of the BOC protecting group on tert-butyl 4-bromopiperidine-1-carboxylate is achieved according to the methods described previously to give 4-bromopiperidine. 2a and R 2b is H or CH3, and X is CH2 or O) is prepared by conventional amide bond forming techniques such as coupling reactions well known to those skilled in the art (such as 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 acid conversion to an acid chloride). For example, 4-bromopiperidine is reacted with a synthetically obtainable appropriately substituted compound of formula (XXII) (which includes compounds of formula (XI) and (XV) wherein R 2a and R 2b is H or CH3, and X is CH2 or O), wherein the acid is activated with a suitable activating agent (e.g., a carbodiimide (such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC))), optionally in the presence of: hydroxybenzotriazole (HOBt) and / or a catalyst (such as 4-dimethylaminopyridine (DMAP)); a halogenated triaminophosphonium salt (such as BOP) or tripyrrolidinylphosphonium bromide hexafluorophosphate a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or another suitable coupling agent 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-trioxatriphosphine-2,4,6-trioxide In a suitable solvent (such as DCM, THF, DMF, etc.); optionally in the presence of a tertiary amine such as N-methylmorpholine, diisopropylethylamine (DIPEA) or TEA, the coupling reaction is carried out at a temperature ranging from 0°C to room temperature to obtain (2s, 4s)-2-(4-bromopiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. Compounds of formula (XIX) (wherein R 2a , R 2b is H, and X is O) and the formula R 3 -Br bromobenzene compound (where R 3 is phenyl substituted by one, two or three members independently selected from the group consisting of halo, OC 1-6 Haloalkyl and C 1-6 haloalkyl) is subjected to the coupling conditions described previously to give a compound of formula (I) wherein R 5a and R 5b For H.

[0237] Solution 10

[0238]

[0239] According to Scheme 10, tert-butyl 4-bromopiperidine-1-carboxylate; and R 3 -Br compounds (where R 3 is phenyl or pyridyl substituted by one, two or three members selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cycloalkyl, OC 1-6 Halogenated alkyl, phenyl, O-phenyl, O-pyridyl, Si(CH3)3, SF5, OC 1-4 Cycloalkyl, C(CH3)2OH or OC 1-6 alkyl) is subjected to coupling conditions as previously described; a compound of formula (XX) is obtained. Cleavage of the BOC protecting group on the compound of formula (XX) is achieved according to the methods previously described to obtain a compound of formula (XXI). The compound of formula (XXI) is coupled to a commercially available or synthetically obtainable compound of formula (XXII) (which includes compounds of formula (XI) and (XV), wherein R 2a and R 2b is H or CH3, and X is CH2 or O) to obtain a compound of formula (I), wherein R 4 , R 5a and R 5b For H.

[0240] Solution 11

[0241]

[0242] According to Scheme 11, the compound of formula (XXIV) (wherein R 5a and R 5beach independently H or CH3) in a metal-mediated cross-coupling reaction; with appropriately substituted aryl or heteroaryl boronic acids, boronates, etc.; under Suzuki conditions known to those skilled in the art; in the presence of a palladium catalyst (such as methanesulfonic acid (2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) (RuPhos-Pd-G3), [1,1'-bis(diphenylphosphino)ferrocene] dichloro palladium (II) (PdCl2 (dppf)), tetrakis (triphenylphosphine) palladium (0) (Pd (PPh3) 4) and the like); a base (such as K3PO4, K2CO3, Na2CO3, Cs2CO3 and the like); in the presence of potassium fluoride; in a suitable solvent (such as 1,4-dioxane, DMF, ethanol, water or a mixture thereof); at a temperature in the range of 60°C to 150°C; using conventional or microwave heating to react; to obtain a compound of formula (XXV). The compound of formula (XXV) is treated with benzyl bromide in a solvent (such as ACN and the like); to obtain a compound of formula (XXVI). The compound of formula (XXVI) is treated with a reducing agent (such as NaBH4 and the like); in a solvent (such as MeOH and the like); to obtain a compound of formula (XXVII). The compound of formula (XXVII) is reacted under hydrogenation conditions known to those skilled in the art (e.g., using H2) in the presence of a catalyst (e.g., Pd / C) in a suitable solvent (e.g., MeOH) to obtain a compound of formula (XXVIII). The compound of formula (XXVIII) is reacted with a compound of formula (XXII) (which includes compounds of formula (XI) and (XV), wherein R 2a and R 2b is H or CH3, and X is CH2 or O) to obtain a compound of formula (I), wherein R 4 For H.

[0243] Solution 12

[0244]

[0245] According to Scheme 12, 4-bromo-3-methylpyridine is alkylated using conditions previously described with benzyl bromide to provide 1-benzyl-4-bromo-3-methylpyridin-1-ium bromide. 1-Benzyl-4-bromo-3-methylpyridin-1-ium bromide is reduced using conditions previously described to provide 1-benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine. 1-Benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine; reacted with an appropriately substituted aryl or heteroaryl boronic acid of formula (XXIII) using Suzuki coupling conditions previously described to provide a compound of formula (XXVII). The compound of formula (XXVII) is subjected to hydrogenation conditions as previously described to provide a compound of formula (XXVIII). The compound of formula (XXVIII) is reacted with a compound of formula (XXII) (which includes compounds of formula (XI) and (XV) wherein R 2a and R 2b is H or CH3, and X is CH2 or O) to obtain a compound of formula (I), wherein R 4 For H, R 5a is H, and R 5b For CH3.

[0246] Solution 13

[0247]

[0248] According to Scheme 13, an appropriately substituted aryl bromide (such as 2-bromo-6-tert-butylpyridine) is treated with n-BuLi in a suitable solvent (such as THF, etc.); 1-tert-butyloxycarbonyl-4-piperidone; at a temperature ranging from -78°C to room temperature; over a period of 1 hour to 3 hours; to give tert-butyl 4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate. tert-butyl 4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate is reacted with a halogenating agent (such as thionyl chloride (SOCl2) or the like); a catalyst (such as 4-(dimethylamino)pyridine (DMAP) or the like); in a suitable solvent (such as pyridine, etc.); to give tert-butyl 6-(tert-butyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate. 6-(tert-butyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylic acid tert-butyl ester is reacted under hydrogenation conditions as described previously to give a compound of formula (XX) wherein R 3 For C 1-6Cleavage 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 previously described to provide a compound of formula (XXI). The compound of formula (XXI) is coupled to a compound of formula (XXII) (which includes compounds of formula (XI) and (XV), wherein R 2a and R 2b is H or CH3, and X is CH2 or O) to obtain a compound of formula (I), wherein R 4 For H.

[0249] The compound of formula (I) can be converted into their corresponding salt using methods known to those of ordinary skill in the art. For example, the amine of formula (I) is treated with trifluoroacetic acid, HCl or citric acid in a solvent (such as Et2O, CH2Cl2, THF, MeOH, chloroform or isopropanol) to provide the corresponding salt form. Alternatively, trifluoroacetic acid or formate is obtained by reversed-phase HPLC purification conditions. With a polar solvent (comprising a mixture of polar solvents and an aqueous mixture of polar solvents) or with a non-polar solvent (comprising a mixture of non-polar solvents), the crystalline form of a pharmaceutically acceptable salt of the compound of formula (I) can be obtained by recrystallization.

[0250] If the compounds according to the invention have at least one chiral center, they may exist in enantiomeric form accordingly. If the compounds have two or more chiral centers, they may exist in diastereomeric form in addition. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0251] The compounds prepared according to the above scheme can be obtained as a single form, such as a single enantiomer, by form-specific synthesis or by resolution. Alternatively, the compounds prepared according to the above scheme can be obtained as a mixture of various forms, such as a racemic mixture (1: 1) or a non-racemic mixture (non-1: 1). In the case of obtaining a racemic mixture and a non-racemic mixture of enantiomers, conventional separation methods known to those of ordinary skill in the art such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation or enzymatic conversion can be used to separate the single enantiomer. In the case of obtaining a regional isomer mixture or a diastereomeric mixture, conventional methods such as chromatography or crystallization can be used to separate the single isomer, if applicable.

[0252] The following specific examples are provided to further illustrate the present invention and various preferred embodiments.

[0253] Example

[0254] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0255] Unless otherwise specified, the reaction mixtures are magnetically stirred at room temperature (rt) and under a nitrogen atmosphere. Where solutions are "dried", they are typically dried over a desiccant (such as Na2SO4 or MgSO4). Where mixtures, solutions and extracts are "concentrated", they are typically concentrated under reduced pressure on a rotary evaporator. Reactions under microwave irradiation conditions are carried out in a Biotage Initiator or CEM (microwave reactor) Discover instrument.

[0256] For reactions performed under continuous flow conditions, unless otherwise stated, "flow through the LTF-VS mixer" refers to the use of a Chemyx Fusion 100Touch syringe pump (LittleThings Factory GmbH (http: / / www.ltf-gmbh.com) connected to the LTF-VS mixer via 1 / 16" PTFE tubing.

[0257] Normal phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using prepacked columns.

[0258] Preparative reverse phase high performance liquid chromatography (RP HPLC) was performed on either of the following equipment:

[0259] Method A Agilent HPLC with an Xterra Prep RP18 column (5 μM, 30 mm×100 mm or 50 mm×150 mm) or an XBridge C18 OBD column (5 μM, 30 mm×100 mm or 50 mm×150 mm), and a mobile phase of 5% ACN in 20 mM NH4OH for 2 minutes, followed by a gradient of 5%-99% ACN for 15 minutes, and then 99% ACN for 5 minutes, with a flow rate of 40 mL / min or 80 mL / min.

[0260] or

[0261] Method B Shimadzu LC-8A series HPLC with an Inertsil ODS-3 column (3 μm, 30 mm×100 mm, T=45° C.) maintained a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) for 1 minute, followed by a gradient of 5%-99% ACN for 6 minutes, and then 99% ACN for 3 minutes, with a flow rate of 80 mL / min.

[0262] or

[0263] Method C A Shimadzu LC-8A series HPLC with an XBridge C18 OBD column (5 μm, 50 mm×100 mm) was used with a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) for 1 minute, followed by a gradient of 5%-99% ACN for 14 minutes, and then 99% ACN for 10 minutes, with a flow rate of 80 mL / min.

[0264] or

[0265] Method D Gilson HPLC with XBridge C18 column (5 μm, 100 mm×50 mm) maintained at a mobile phase of 5%-99% ACN in 20 mM NH 4 OH for 10 min, then at 99 ACN for 2 min, with a flow rate of 80 mL / min.

[0266] or

[0267] Method E ACCQ Prep HPLC with an XBridge C18 OBD column (5 μm, 50 mm×100 mm) was run with a mobile phase of 5% ACN in H2O (both with 0.05% TFA) for 1 min, followed by a gradient of 5%-95% ACN over 12 min, and then 95% ACN for 2 min, at a flow rate of 80 mL / min.

[0268] Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on a Jasco preparative SFC system, an APS 1010 system from Bergerinstruments or a SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Separations were performed at 100 to 150 bar with a flow rate in the range of 40 to 60 mL / min. The column was heated to 35 to 40°C.

[0269] Unless otherwise indicated, mass spectra (MS) were obtained on an Agilent series 1100MSD using electrospray ionization (ESI) in positive ion mode. The calculated masses (calcd.) correspond to the exact masses.

[0270] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker DRX spectrometer. The multiplicity is defined as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, hept = septet, dd = doublet of doublet, dt = doublet of triplet, pd = quintet of doublet, ddd = doublet of doublet of doublet, tp = triplet of quintet, td = triplet of doublet, qd = quartet of doublet, dq = doublet of quartet, tt = triplet of triplet, td = triplet of doublet, m = multiplet, br = broad. It should 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.

[0271] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0272] Compounds designated as R* or S* are enantiomerically pure compounds of undetermined absolute configuration.

[0273] Intermediate 1: tert-Butyl 3-nitrocyclobutanecarboxylate .

[0274]

[0275] 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 The mixture was filtered through a pad of 4% paraformaldehyde and the pad was washed with EtOH. The combined filtrates were evaporated under reduced pressure and the residue was taken up 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): C9H 15 The calculated mass value of NO3 is 185.1; the measured m / z value is 186.2 [M+H] + .

[0276] Step B: tert-Butyl 3-nitrocyclobutanecarboxylate.At -10 ° C, a solution of TFAA (245 mL, 1.75 mol) in ACN (500 mL) was added dropwise to a suspension of urea peroxide (164 g, 1.74 mol) in ACN (1 L) over 1 hour. The reaction mixture was stirred at room temperature for 1 hour. At 80 ° C, it 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 minutes. The reaction mixture was stirred at 80 ° C for 30 minutes and then filtered. The mixture was filtered through a pad of 4% paraformaldehyde and the pad 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 gel (0%-20% EtOAc in heptane) to give the title compound (89.6 g, 76% yield) as a yellow oil, which is a mixture of cis-isomers / trans-isomers in a ratio of 1.3:1. The compound will not be detected in ESI + Ionization in the case of LCMS.

[0277] Intermediate 2: Ethyl 3-nitrocyclobutanecarboxylate .

[0278]

[0279] The title compound was prepared in a manner analogous to Intermediate 1 using ethyl 3-oxocyclobutane-1-carboxylate instead of tert-butyl 3-oxocyclobutane-1-carboxylate in Step A. The compound did not react with ESI + Ionization in the case of LCMS. 1 H NMR (300MHz, CDCl3) δ5.02–4.70 (m, 1H), 4.20 (q, J = 7.2Hz, 2H), 3.04–2.71 (m, 5H), 1.29 (t, J = 7.0Hz, 3H).

[0280] Intermediate 3: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid .

[0281]

[0282] Step A: (1s,3s)-tert-butyl 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% aqueous solution, 73 mL, 971 mmol). Triethylamine (TEA) (62 mL, 444 mmol) was added dropwise to the reaction mixture at 0°C, and the reactants were stirred at room temperature for 2 hours. The reaction mixture was evaporated, and the residue was purified by FCC on silica gel (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 The calculated mass value of NO5 is 231.2; the measured m / z value is 254.1 [M+Na] + 3-(Hydroxymethyl)-3-nitrocyclobutanecarboxylic acid trans-tert-butyl ester was formed but not isolated.

[0283] Step B: (1s,3s)-tert-butyl 3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate . To a solution of tert-butyl (1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutanecarboxylate (38 g, 165 mmol) in EtOAc (600 mL) was added 10% palladium on carbon (Pd / C) (1.9 g). The reaction mixture was stirred at 50 °C under hydrogen (H2) (10 bar) for 1 hour. The reaction mixture was stirred by Filter through a pad of Celite. To the filtrate was added 10% Pd / C (1.9 g). The reaction mixture was stirred under H2 (10 bar) at 50°C for 2 hours. Filter through a pad of Celite and wash with EtOAc The combined filtrates were evaporated and the residue was triturated with diethyl ether (Et2O) to give the title compound as a white powder (18.6 g, 92.4 mmol, 55% yield). MS (ESI): C 10 H 19 The calculated mass value of NO3 is 201.1; the measured m / z value is 202.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ5.26–3.98(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).

[0284] Step C: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester. TEA (26 mL, 186 mmol) was added to a solution of (1s, 3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylic acid tert-butyl ester (18.6 g, 92.4 mmol) in tetrahydrofuran (THF) (300 mL). A solution of triphosgene (9.6 g, 32.4 mmol) in THF (200 mL) was added dropwise to the mixture 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 ground with Et2O to give the title compound (17.7 g, 77.9 mmol, 84% yield) as a white powder. MS (ESI): C 11 H 17 The calculated mass value of NO4 is 227.1; the measured m / z value is 228.2 [M+H] + .

[0285] 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 (2s, 4s)-6-oxo-7-oxa-5-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (17.7 g, 77.9 mmol) in batches at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated and the residue was triturated with Et2O to give the title compound as a white powder (12.9 g, 75.4 mmol, 96% yield). MS (ESI): The mass calculated value of C7H9NO3 is 171.0; the m / z found value is 172.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.26(br s,1H),8.08(s,1H),4.34(s,2H),2.79–2.66(m,1H),2.43–2.29(m,4H).

[0286] Intermediate 4: (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid .

[0287]

[0288] Step A: (1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylic acid ethyl ester. 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 hour. 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 gel (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 The calculated mass value of NO6 is 259.1; the measured m / z value is 282.1 [M+Na] + . 1 H NMR (300MHz, Chloroform-d) δ4.17(q,J=7.1Hz,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=7.1Hz,3H).

[0289] 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 (NaBH4) (10 g, 264 mmol) was added to the reaction mixture in small portions 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) (pH 10) was added dropwise to the reaction mixture at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was stirred by The mixture was filtered through a pad of 4% paraffin wax and the pad was washed with EtOH. The combined filtrates were evaporated. The residue was purified by FCC on silica gel eluting with chloroform:methanol:acetic acid (100:0:0→9:1:1) to give the title compound (4.8 g, 28.2 mmol, 53% yield) as an off-white powder. MS (ESI): C8H 11 The calculated mass value of NO3 is 169.1; the measured m / z value is 170.1 [M+H] + . 1H NMR (300MHz, DMSO-d6) δ7.97(br s,1H),4.01–2.94(m,1H),2.82–2.65(m,1H),2.36–2.01(m,8H).

[0290] Intermediate 5: cis-3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylic acid tert-butyl ester .

[0291]

[0292] Step A: tert-Butyl 3-(1-hydroxyethyl)-3-nitro-cyclobutanecarboxylate . 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 gel (0%-20% EtOAc in heptane) to give the title compound (10.5 g) as a colorless oil in a mixture of cis and trans isomers. MS (ESI): C 11 H 19 The calculated mass value of NO5 is 245.1; the measured m / z value is 263.2 [M+H+NH3] + .

[0293] Step B: (1s,3s)-tert-butyl 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 EtOAc (110 mL) was added 10% Pd / C (1 g). The reaction mixture was stirred at 50° C. under H2 (10 bar) for 1 hour. The reaction mixture was washed with water by 10% Pd / C (500 mg) was added to the filtrate, and the reaction mixture was stirred at 50° C. under H 2 (10 bar) for 2 h. The reaction mixture was filtered through The combined filtrates were evaporated and the residue was purified by FCC on silica gel eluting with chloroform:methanol:ammonium hydroxide (1:0:0→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 The calculated mass value of NO3 is 215.2; the measured m / z value is 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 (1r, 3r)-tert-butyl 3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate (550 mg) as a yellow oil.

[0294] Intermediate 6: (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0295]

[0296] Step A: cis-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester . TEA (20 mL, 143 mmol) was added to a solution of (1s, 3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylic acid tert-butyl ester (intermediate 5, 15.2 g, 70.4 mmol) in THF (240 mL). A solution of triphosgene (7.3 g, 24.6 mmol) in THF (170 mL) was added dropwise to the mixture 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 gel (0%-35% EtOAc in heptane) to give the title compound (9.0 g, 52% yield) as a white powder. MS (ESI): C 12 H 19 The calculated mass value of NO4 is 241.1; the measured m / z value is 242.2 [M+H] + .

[0297] Step B: (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid . Cis-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (6.1 g, 25.3 mmol) was added to TFA (60 mL, 784 mmol) in batches 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 Et2O to give the title compound as a white powder (4.3 g, 91% yield). MS (ESI): C8H 11 The calculated mass value of NO4 is 185.1; the measured m / z value is 186.1 [M+H] + . 1H NMR(500MHz,DMSO-d6)δ12.23(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).

[0298] Intermediate 7: (2s,4s)-8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0299]

[0300] Step A: cis-tert-butyl 3-(tert-butoxycarbonylamino)-3-(1-hydroxyethyl)cyclobutanecarboxylate . To a solution of cis-3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylic acid tert-butyl ester (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 gel (25% EtOAc in heptane) to give the title compound as a white powder (3.0 g, 66% yield). MS (ESI): C 16 H 29 The calculated mass value of NO5 is 315.2; the measured m / z value is 338.2 [M+Na] + . 1 HNMR(500MHz, CDCl3)δ4.89(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).

[0301] Step B: cis-tert-butyl 3-acetyl-3-(tert-butoxycarbonylamino)cyclobutanecarboxylate. To a solution of cis-3-(tert-butoxycarbonylamino)-3-(1-hydroxyethyl)cyclobutanecarboxylic acid tert-butyl ester (3.0 g, 9.51 mmol) in DCM (60 mL) was added DMP (4.8 g, 11.4 mmol) at 10°C, and the reaction mixture was stirred at room temperature for 3 hours. Saturated NaHCO3 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 gel (0%-25% EtOAc in heptane) to give the title compound as a white powder (2.6 g, 8.17 mmol, 85% yield). MS (ESI): C 16 H 27 The calculated mass value of NO5 is 313.19; the measured m / z value is 336.2 [M+Na] + . 1 H NMR (500MHz, CDCl3) δ5.29(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).

[0302] Step C: cis-3-(tert-butoxycarbonylamino)-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylic acid tert-butyl ester . To a solution of cis-3-acetyl-3-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid tert-butyl ester (2.5 g, 7.98 mmol) in THF (50 mL) was added methylmagnesium bromide (8 mL, 24 mmol, 3 M in Et2O) dropwise 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 gel (0%-20% EtOAc in heptane) to give the title compound as a white powder (650 mg, 24% yield). MS (ESI): C 17 H 31 The calculated mass value of NO5 is 329.2; the measured m / z value is 174.2 [M+H-tBu-Boc] + . 1 H NMR(500MHz,CDCl3)δ4.91(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).

[0303] Step D: cis-tert-butyl 3-amino-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylate. To a solution of cis-3-(tert-butoxycarbonylamino)-3-(1-hydroxy-1-methyl-ethyl)cyclobutanecarboxylic acid tert-butyl ester (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 as a yellow oil (430 mg, 95% yield). MS (ESI): C 12 H 23 The calculated mass value of NO3 is 229.2; the measured m / z value is 230.4 [M+H] + .

[0304] Step E: cis-8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid tert-butyl Ester. TEA (770 μL, 5.52 mmol) was added to a solution of cis-3-amino-3-(1-hydroxy-1-methyl-ethyl) cyclobutanecarboxylic acid tert-butyl ester (630 mg, 2.75 mmol) in THF (10 mL). A solution of triphosgene (285 g, 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 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 gel (0%-35% EtOAc in heptane) to give the title compound (520 mg, 74% yield) as a white powder. MS (ESI): C 13 H 21 The calculated mass value of NO4 is 255.2; the measured m / z value is 256.2 [M+H] + . 1 HNMR(500MHz, CDCl3)δ6.06(br s,1H),2.73–2.63(m,3H),2.28–2.17(m,2H),1.45(s,9H),1.39(s,6H).

[0305] Step F: (2s,4s)-8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid . Cis-8,8-dimethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (520 mg, 2.04 mmol) was added to TFA (5.2 mL, 67.9 mmol) in batches 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 ground with Et2O to give the title compound as a white powder (330 g, 81% yield). MS (ESI): C9H 13 The calculated mass value of NO4 is 199.1; the measured m / z value is 200.1 [M+H]+ . 1 H NMR (300MHz, DMSO-d6) δ12.25(s,1H),7.84(s,1H),2.76–2.41(m,3H),2.33–2.17(m,2H),1.38(s,6H).

[0306] Intermediate 8: 4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine .

[0307]

[0308] Step A: tert-Butyl 4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate. In a dried pressure vial, N-tert-butyloxycarbonyl-4-bromopiperidine (200 mg, 0.742 mmol) was combined with 5-bromo-2-methylphenol (146 mg, 0.742 mmol), NiCl2(DME) (33 mg, 0.148 mmol), 1,10-phenanthroline (55 mg, 0.297 mmol), NaBF4 (42 mg, 0.371 mmol) and Mn (81 mg, 1.48 mmol). This was taken up in anhydrous MeOH (3.7 mL) and 4-ethylpyridine (43 μL, 0.371 mmol) was added. The vial was capped, purged with nitrogen (N2), and heated at 60°C for 18 hours. The mixture was diluted with EtOAc and filtered through Filter and concentrate under reduced pressure. Purify by FCC on silica gel (0%-30% EtOAc in hexanes) to give the title compound (116 mg, 54% yield). MS (ESI): C 17 H 25 The calculated mass value of NO3 is 291.2; the measured m / z value is 236.1 [M+2H-tBu] + .

[0309] Step B: tert-Butyl 4-(3-(bromodifluoromethoxy)-4-methylphenyl)piperidine-1-carboxylate. Under N2, in a dried flask, tert-butyl 4-(3-hydroxy-4-methylphenyl)piperidine-1-carboxylate (108 mg, 0.371 mmol) was absorbed in DMA (0.75 mL) and cooled to 0 ° C. NaH (71 mg, 1.85 mmol) was added thereto and the mixture was heated to room temperature and stirred for 1.5 hours. After cooling to 0 ° C, a solution of CBr2F2 (0.29 mL, 2.96 mmol) in DMA (0.75 mL) was added dropwise and stirred at room temperature for 3 hours. Cooled back to 0 ° C to add KOtBu (127 mg, 1.11 mmol), then heated to 80 ° C for 24 hours. The reactant was cooled, water was added, extracted with EtOAc, dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by FCC on silica gel (0% - 50% EtOAc in hexanes) to afford the title compound (36 mg, 23% yield).

[0310] 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) was added AgBF4 (52 mg, 0.262 mmol) at -78°C. The reaction was heated 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 The calculated mass value of F3NO is 259.1; the measured m / z value is 260.1 [M+H] + .

[0311] Intermediate 9: tert-Butyl 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate .

[0312]

[0313] 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 N2) was heated in a sealed pressure vial at 100°C under N2. After 15 h, the reaction was cooled to room temperature and the mixture was passed through Filter using EtOAc as eluent. Wash the filtrate with brine, dry over (Na2SO4), filter and concentrate under reduced pressure. Purify via FCC on silica gel (0%-100% EtOAc in hexane) to give the title compound as a brown oil (209 mg, 60% yield). MS (ESI): C 17 H 23 The calculated mass value of N3O2 is 301.2; the measured m / z value is 302.2 [M+H] + .

[0314] 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 KOtBu (1.8 mL, 1 M in THF) dropwise by a syringe at room temperature under N2. The resulting solution was heated to 70 ° C for 16 hours. It was then diluted with water and extracted with EtOAc. The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by FCC on silica gel (0%-100% EtOAc in hexane) gave the title compound (93 mg, 51% yield) as an off-white solid. MS (ESI): C 17 H 23 The calculated mass value of N3O2 is 301.2; the measured m / z value is 302.2 [M+H] + .

[0315] Intermediate 10: (racemic)-(cis)-3-methyl-4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine .

[0316]

[0317] The title compound was prepared in an analogous manner to cis-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine (Intermediate 28) using 4-methyl-3-(trifluoromethyl)phenylboronic acid in place of 3-(trifluoromethoxy)phenylboronic acid.

[0318] Intermediate 11: (2s,4s)-2-(4-bromopiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one .

[0319]

[0320] To a solution of N-tert-butyloxycarbonyl-4-bromopiperidine (210 mg, 0.795 mmol) in MeOH (1 mL) was added a solution of hydrochloric acid (HCl) in 1,4-dioxane (4 M, 1.5 mL) It was heated to 45 °C for 1 hour before being concentrated under reduced pressure. The residue was redissolved in DMF (2 mL) and (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) were added. It 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) to give the title compound (117 mg, 46% yield). MS (ESI): C 12 H 17 The calculated mass of BrN2O3 is 316.0; the measured m / z is 317.0 [M+H] + .

[0321] Intermediate 12: 1-Benzyl-4-bromo-5-methyl-1,2,3,6-tetrahydropyridine .

[0322]

[0323] 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 at 70°C overnight. 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 The calculated mass of BrN is 262.0; the measured m / z is 262.0 [M] + .

[0324] 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. NaBH4 (330 mg, 8.7 mmol) was slowly added under stirring. The reaction mixture was stirred at 0°C for 30 minutes, concentrated under reduced pressure, and partitioned between DCM and water. The organic layer was concentrated under reduced pressure and purified by FCC on silica gel (0%-50% EtOAc in hexanes) to give the title compound (381 mg, 49% yield). MS (ESI): C 13H 16 The calculated mass of BrN is 265.0; the measured m / z is 266.0 [M+H] + .

[0325] Intermediate 13: 4-(3-(tert-butyl)phenyl)-3-methylpyridine .

[0326]

[0327] 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 methanesulfonic acid-2-dicyclohexylphosphine-2', 6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) (RuPhos Pd G3) (243 mg, 0.29 mmol) were absorbed in 1,4-dioxane (40 mL), and under N2, the reaction mixture was stirred at 100 ° C overnight. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was distributed between DCM and water. The aqueous layer was extracted with DCM, and the combined organic matter was concentrated under reduced pressure and purified by FCC (0%-100% EtOAc in hexane) on silica gel to obtain the title compound (805 mg, 61% yield). MS(ESI):C 16 H 19 The calculated mass value of N is 225.2; the measured m / z value is 226.2 [M+H] + .

[0328] Intermediate 14: 4-(4-(tert-butyl)phenyl)-2-methylpyridine .

[0329]

[0330] The title compound was prepared in a similar manner 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 The calculated mass value of N is 225.2; the measured m / z value is 226.2 [M+H] + .

[0331] Intermediate 15: 4-(4-(trifluoromethyl)phenyl)-2-methylpyridine.

[0332]

[0333] The title compound was prepared in a similar manner 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 The calculated mass value of F3N is 237.1; the measured m / z value is 238.1 [M+H] + .

[0334] Intermediate 16: 4-(3-(tert-butyl)phenyl)-2-methylpyridine .

[0335]

[0336] The title compound was prepared in a similar manner 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 The calculated mass value of N is 225.2; the measured m / z value is 226.2 [M+H] + .

[0337] Intermediate 17: 4-([1,1'-biphenyl]-3-yl)-3-methylpyridine .

[0338]

[0339] The title compound was prepared in a similar manner 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 The calculated mass value of N is 245.1; the measured m / z value is 246.0 [M+H] + .

[0340] Intermediate 18: 1-Benzyl-4-(3-(tert-butyl)phenyl)-5-methyl-1,2,3,6-tetrahydropyridine .

[0341]

[0342] The title compound was prepared in a similar manner 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 The calculated mass value of N is 319.2; the measured m / z value is 320.3 [M+H] + .

[0343] Intermediate 19: 1-Benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine.

[0344]

[0345] The title compound was prepared in a similar manner 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 The calculated mass value of N is 319.2; the measured m / z value is 320.3 [M+H] + . The olefin isomers were not clearly identified.

[0346] Intermediate 20: 1-Benzyl-6-methyl-4-(4-(trifluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine .

[0347]

[0348] The title compound was prepared in a similar manner 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 The calculated mass value of F3N is 331.2; the measured m / z value is 332.1 [M+H] + . The olefin isomers were not clearly identified.

[0349] Intermediate 21: 1-Benzyl-4-(4-(tert-butyl)phenyl)-6-methyl-1,2,3,6-tetrahydropyridine .

[0350]

[0351] The title compound was prepared in a similar manner 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 The calculated mass value of N is 319.2; the measured m / z value is 320.1 [M+H] + . The olefin isomers were not clearly identified.

[0352] Intermediate 22: 4-([1,1'-biphenyl]-3-yl)-1-benzyl-5-methyl-1,2,3,6-tetrahydropyridine .

[0353]

[0354] The title compound was prepared in a similar manner 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 The calculated mass value of N is 339.2; the measured m / z value is 340.3 [M+H] + .

[0355] Intermediate 23: (racemic)-(cis)-3-methyl-4-(4-(tert-butyl)phenyl)piperidine .

[0356]

[0357] 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 taken up in EtOAc (20 mL). The reaction vessel was evacuated and backfilled with H2. The reaction mixture was stirred at room temperature for 3 hours and then filtered through a column of HPLC. Filtered, concentrated under reduced pressure, and used directly in subsequent transformations without further purification (183 mg, 0.791 mmol, 94% yield). MS (ESI): C 16 H 25 The calculated mass value of N is 231.2; the measured m / z value is 232.2 [M+H] + .

[0358] Intermediate 24: (racemic)-(cis)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine .

[0359]

[0360] The title compound was prepared in a manner analogous 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 The calculated mass value of N is 251.2; the measured m / z value is 252.1 [M+H] + .

[0361] Intermediate 25: 4-(4-(tert-butyl)phenyl)-2-methylpiperidine .

[0362]

[0363] The title compound (mixture of four diastereomers) was prepared in a manner analogous 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 The calculated mass value of N is 251.2; the measured m / z value is 252.1 [M+H] + .

[0364] Intermediate 26: 4-(4-(trifluoromethyl)phenyl)-2-methylpiperidine .

[0365]

[0366] The title compound (mixture of four diastereomers) was prepared in a manner analogous 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 The calculated mass value of F3N is 243.1; the measured m / z value is 244.1 [M+H] + .

[0367] Intermediate 27: 4-(3-(tert-butyl)phenyl)-2-methylpiperidine .

[0368]

[0369] The title compound (mixture of four diastereomers) was prepared in a manner analogous 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 The calculated mass value of N is 251.2; the measured m / z value is 252.1 [M+H] + .

[0370] Intermediate 28: (racemic)-(cis)-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine .

[0371]

[0372] 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) were taken up in dioxane and the reaction mixture was stirred overnight at 100 ° C under N2. 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 organics were concentrated under reduced pressure and purified by FCC on silica gel (0%-100% EtOAc in hexanes) to give the title compound (70 mg, 0.20 mmol, 54% yield). MS (ESI): C 20 H 20 The calculated mass value of F3NO is 347.2; the measured m / z value is 348.1 [M+H] + .

[0373] Step B: (rac)-(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 taken up in EtOAc. The reaction vessel was evacuated and backfilled with H2, and the reaction mixture was stirred at room temperature overnight. The mixture was filtered and concentrated under reduced pressure to give the title compound (56 mg, 0.22 mmol, 107% yield). MS (ESI): C 13 H 16 The calculated mass value of F3NO is 259.1; the measured m / z value is 260.1 [M+H] + .

[0374] Intermediate 29: (racemic)-(cis)-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidine .

[0375]

[0376] The title compound was prepared in a similar manner 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 The calculated mass value of F3N is 243.1; the measured m / z value is 244.1 [M+H] + .

[0377] Intermediate 30: (racemic)-(cis)-3-methyl-4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine .

[0378]

[0379] The title compound was prepared in a similar manner 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 The calculated mass value of F3NO is 273.1; the measured m / z value is 274.2 [M+H] + .

[0380] Intermediate 31: (racemic)-(cis)-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidine .

[0381]

[0382] The title compound was prepared in a manner analogous 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 The calculated mass value of F3NO is 259.1; the measured m / z value is 260.0 [M+H] + .

[0383] Intermediate 32: (racemic)-(cis)-3-methyl-4-(3-fluoro-4-(trifluoromethoxy)phenyl)piperidine .

[0384]

[0385] The title compound was prepared in a manner similar 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 The calculated mass value of F4NO is 277.1; the measured m / z value is 278.2 [M+H] + .

[0386] Intermediate 33: (racemic)-(cis)-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine .

[0387]

[0388] The title compound was prepared in a manner analogous 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 The calculated mass value of F3N is 243.1; the measured m / z value is 244.1 [M+H] + .

[0389] Intermediate 34: (racemic)-(cis)-3-methyl-4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine .

[0390]

[0391] The title compound was prepared in an analogous manner 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.

[0392] Example 1: (2s,4s)-2-(4-(3-(2,2,2-trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0393]

[0394] In an oven-dried pressure 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), NiCl2(DME) (4.5 mg, 0.020 mmol), 1,10-phenanthroline (7.3 mg, 0.040 mmol), NaBF4 (5.6 mg, 0.050 mmol) and Mn (11 mg, 0.200 mmol). This was taken up in anhydrous MeOH (0.5 mL) and 4-ethylpyridine (5.7 μL, 0.050 mmol) was added. The vial was capped, purged with N2, and heated at 60 °C for 18 h. The mixture was diluted with EtOAc and filtered through Filter and concentrate under reduced pressure. Purify via reverse phase HPLC (5%-95% ACN in 20 mM NH4OH solution) to give the title compound (23 mg, 58% yield). MS (ESI): C 20 H 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.30 (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=10.9Hz,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).

[0395] Example 2: (2s, 4s)-2-(4-(3-fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0396]

[0397] The title compound was prepared in a manner similar 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 The calculated mass value of F4N2O4 is 416.1; the measured m / z value is 417.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.88–6.79(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).

[0398] Example 3: (2s, 4s)-2-(4-(2-fluoro-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0399]

[0400] The title compound was prepared in a manner similar 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 The calculated mass value of F4N2O4 is 416.1; the measured m / z value is 417.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.11–7.03(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).

[0401] Example 4: (2s, 4s)-2-(4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0402]

[0403] Step A: tert-Butyl 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate. In a dried pressure vial, N-tert-butyloxycarbonyl-4-bromopiperidine (30 mg, 0.111 mmol) was combined with 1-bromo-2-methyl-4-(trifluoromethyl)benzene (27 mg, 0.111 mmol), NiCl2(DME) (2.5 mg, 0.011 mmol), 1,10-phenanthroline (4 mg, 0.022 mmol), NaBF4 (6 mg, 0.056 mmol) and Mn (12 mg, 0.223 mmol). This was taken up in anhydrous MeOH (0.6 mL) and 4-ethylpyridine (6.4 μL, 0.056 mmol) was added. The vial was capped, purged with N2, and heated at 60°C for 18 hours. The mixture was diluted with EtOAc and filtered through Filter and concentrate under reduced pressure. Purify by FCC on silica gel (0%-15% EtOAc in hexanes) to give the title compound (31 mg, 81% yield). MS (ESI): C 18 H 24 The calculated mass value of F3NO2 is 343.2; the measured m / z value is 288.0 [M+2H-tBu] + .

[0404] Step B: 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride . To a solution of tert-butyl 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (31 mg, 0.090 mmol) in MeOH (0.2 mL) was added a solution of HCl in 1,4-dioxane (4 M, 0.23 mL). It was heated to 45 °C for 1 hour and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 13 H 17 The calculated mass of ClF3N is 279.1; the measured m / z is 244.1 [M-Cl] +.

[0405] Step C: (2s,4s)-2-(4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one . 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride was taken up in DMF (0.6 mL) and to it 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). It 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 solution) to give the title compound (30 mg, 85% yield). MS (ESI): C 20 H 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.45–7.38(m,2H),7.22(d,J=7.9Hz,1H),6.22(s,1H),4.91–4.68(m,1H),4.39(s,2H),3.96–3.7 8(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).

[0406] Example 5: (2s, 4s)-2-(4-(4-(difluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0407]

[0408] The title compound was prepared in a manner similar 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 The calculated mass value of F2N2O3 is 364.2; the measured m / z value is 365.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.49–7.42(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).

[0409] Example 6: (2s, 4s)-2-(4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0410]

[0411] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O4 is 398.1; the measured m / z value is 399.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.33(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).

[0412] Example 7: (2s, 4s)-2-(4-(2-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0413]

[0414] The title compound was prepared in a manner similar 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 23The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.14–7.08(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).

[0415] Example 8: (2s, 4s)-2-(4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0416]

[0417] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.15–7.09(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).

[0418] Example 9: (2s, 4s)-2-(4-(4-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0419]

[0420] The title compound was prepared in a manner similar 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 26The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.09–6.99(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).

[0421] Example 10: (2s, 4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0422]

[0423] The title compound was prepared in a manner similar 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 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.53(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).

[0424] Example 11: (2s, 4s)-2-(4-(4-isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0425]

[0426] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 356.2; the measured m / z value is 357.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.20–7.13(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,1 H),3.06–2.96(m,1H),2.93–2.81(m,1H),2.79–2.61(m,4H),2.53–2.4 0(m,2H),1.98–1.83(m,2H),1.66–1.46(m,2H),1.23(d,J=6.9Hz,6H).

[0427] Example 12: (2s, 4s)-2-(4-(4-(difluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0428]

[0429] The title compound was prepared in a manner similar 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 The calculated mass value of F2N2O4 is 380.2; the measured m / z value is 381.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.20–7.13(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),3.87–3.77(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).

[0430] Example 13: (2s, 4s)-2-(4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0431]

[0432] The title compound was prepared in a manner similar 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 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.1 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.40(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,1 H),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).

[0433] Example 14: (2s, 4s)-2-(4-(3-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0434]

[0435] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 370.2; the measured m / z value is 371.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.28–7.23(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).

[0436] Example 15: (2s, 4s)-2-(4-(3-isopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0437]

[0438] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 356.2; the measured m / z value is 357.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.26–7.21(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).

[0439] Example 16: (2r, 4s)-2-(4-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0440]

[0441] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O2 is 394.2; the measured m / z value is 395.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.40(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,1H),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).

[0442] Example 17: (2r, 4s)-2-(4-(4-cyclopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octane-6- ketone.

[0443]

[0444] The title compound was prepared in a manner similar 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 28 The calculated mass value of N2O2 is 352.2; the measured m / z value is 353.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.09–7.04(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).

[0445] Example 18: (2r, 4s)-2-(4-(3-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0446]

[0447] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O2 is 394.2; the measured m / z value is 395.1 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.53(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).

[0448] Example 19: (2s, 4s)-2-(4-(2-fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0449]

[0450] The title compound was prepared in a manner similar 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 The calculated mass value of FN2O3 is 346.2; the measured m / z value is 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.05–6.98(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).

[0451] Example 20: (2s, 4s)-2-(4-(4-(2,2,2-trifluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0452]

[0453] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.1 [M+H] + .1 H NMR (400MHz, CDCl3) δ7.26–7.21(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).

[0454] Example 21: (2s, 4s)-2-(4-(3-fluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0455]

[0456] The title compound was prepared in a manner similar 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 23 The calculated mass value of FN2O3 is 346.2; the measured m / z value is 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.14–7.07(m,1H),6.87–6.79(m,2H),4.79–4.70(m,1H),4.38(s,2H),3.86–3.76(m,1H),3.1 7–2.97(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).

[0457] Example 22: (2r, 4s)-2-(4-(3-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octane- 6-Keto.

[0458]

[0459] The title compound was prepared in a manner similar 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 32The calculated mass value of N2O2 is 368.2; the measured m / z value is 369.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.26–7.22(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,1 H),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).

[0460] Example 23: (2s, 4s)-2-(4-(3-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0461]

[0462] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.22–7.15(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,1H),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).

[0463] Example 24: (2s,4s)-2-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)piperidin-1- Carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0464]

[0465] The title compound was prepared in a manner similar 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): C19 H 20 The calculated mass value of F2N2O5 is 394.1; the measured m / z value is 395.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.00–6.95(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).

[0466] Example 25: (2s, 4s)-2-(4-(4-cyclobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0467]

[0468] The title compound was prepared in a manner similar 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 28 The calculated mass value of N2O3 is 368.2; the measured m / z value is 369.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.21–7.14(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).

[0469] Example 26: (2s,4s)-2-(4-(3-(1,1-difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0470]

[0471] The title compound was prepared in a manner similar 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 24The calculated mass value of F2N2O3 is 378.2; the measured m / z value is 379.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.40–7.33(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).

[0472] Example 27: (2s, 4s)-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0473]

[0474] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 368.2; the measured m / z value is 369.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.22–7.16(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).

[0475] Example 28: (2s,4s)-2-(4-(4-(1,1-difluoroethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0476]

[0477] The title compound was prepared in a manner similar 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): C 20 H24 The calculated mass value of F2N2O3 is 378.2; the measured m / z value is 360.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.45(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).

[0478] Example 29: (2s, 4s)-2-(4-(3-fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0479]

[0480] The title compound was prepared in a manner similar 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 The calculated mass value of FN2O3 is 346.2; the measured m / z value is 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.79–6.73(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).

[0481] Example 30: (2s,4s)-2-(4-(2,3-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0482]

[0483] The title compound was prepared in a manner similar to Example 4 using 1-bromo-2,3-difluoro-4-toluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in step A. MS (ESI): C 19 H22 The calculated mass value of F2N2O3 is 364.2; the measured m / z value is 365.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.91–6.84(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).

[0484] Example 31: (2s,4s)-2-(4-(2,5-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0485]

[0486] The title compound was prepared in a manner similar to Example 4 using 1-bromo-2,5-difluoro-4-toluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in step A. MS (ESI): C 19 H 22 The calculated mass value of F2N2O3 is 364.2; the measured m / z value is 365.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.88–6.80(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).

[0487] Example 32: (2r, 4s)-2-(4-(4-isopropylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octane-6- ketone.

[0488]

[0489] The title compound was prepared in a manner similar 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 The calculated mass value of N2O2 is 354.2; the measured m / z value is 355.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.19–7.13(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).

[0490] Example 33: (2s, 4s)-2-(4-(2-fluoro-5-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0491]

[0492] The title compound was prepared in a manner similar 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 The calculated mass value of FN2O3 is 346.2; the measured m / z value is 347.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.01–6.85(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).

[0493] Example 34: (2s, 4s)-2-(4-(3,4-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0494]

[0495] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 342.2; the measured m / z value is 343.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.07(d,J=7.7Hz,1H),6.95(d,J=1.9Hz,1H),6.91(dd,J=7.7 ,2.0Hz,1H),6.42(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).

[0496] Example 35: (2s,4s)-2-(4-(2,3-dihydro-1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0497]

[0498] The title compound was prepared in a manner similar 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 26 The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.16(d,J=7.7Hz,1H),7.05(s,1H),6.95(dd,J=7.7,1.7Hz,1H),6.11(s,1H),4.79–4.71(m,1H),4.38(s,2H),3.86–3.78( m,1H),3.16–2.95(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).

[0499] Example 36: (2s, 4s)-2-(4-(3-chloro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0500]

[0501] The title compound was prepared in a manner similar 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 The calculated mass value of ClN2O3 is 362.1; the measured m / z value is 363.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.19–7.12(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).

[0502] Example 37: (2s, 4s)-2-(4-(2-fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0503]

[0504] The title compound was prepared in a manner similar 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 The calculated mass value of FN2O3 is 346.2; the measured m / z value is 347.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.10–7.00(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,1 H),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).

[0505] Example 38: (2s, 4s)-2-(4-(3-isopropoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0506]

[0507] The title compound was prepared in a manner similar 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 28 The calculated mass value of N2O4 is 372.2; the measured m / z value is 373.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.20(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),2.5 2–2.41(m,2H),1.96–1.89(m,2H),1.65–1.46(m,2H),1.32(d,J=6.1Hz,6H).

[0508] Example 39: (2r, 4s)-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0509]

[0510] The title compound was prepared in a manner similar 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 The calculated mass value of N2O2 is 366.2; the measured m / z value is 367.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.21–7.16(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).

[0511] Example 40: (2s, 4s)-2-(4-(3-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0512]

[0513] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 368.2; the measured m / z value is 369.2 [M+H] + . 1H NMR(400MHz, CDCl3)δ7.22(t,J=7.6Hz,1H),7.13–7.09(m,1H),7.07(t,J=1.9Hz,1H),6.9 7(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).

[0514] Example 41: (2r, 4s)-2-(4-(3-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0515]

[0516] The title compound was prepared in a manner similar 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 The calculated mass value of N2O2 is 366.2; the measured m / z value is 367.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.22(t,J=7.6Hz,1H),7.11(dt,J=7.7,1.5Hz,1H),7.07(t,J=1. 9Hz,1H),6.97(dt,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).

[0517] Example 42: (2s,4s)-2-(4-(1H-inden-5-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0518]

[0519] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 352.2; the measured m / z value is 353.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.37 (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).

[0520] Example 43: (2s, 4s)-2-(4-(2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0521]

[0522] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 342.2; the measured m / z value is 343.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.12–7.06(m,1H),7.06–7.02(m,1H),6.99(dd,J=7.5 ,1.7Hz,1H),5.89(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).

[0523] Example 44: (2s, 4s)-2-(4-(4-fluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0524]

[0525] The title compound was prepared in a manner similar 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 The calculated mass value of FN2O3 is 346.2; the measured m / z value is 347.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.00–6.95(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).

[0526] Example 45: (2s, 4s)-2-(4-(6-(tert-butyl)pyridin-3-yl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0527]

[0528] The title compound was prepared in a manner similar 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 The calculated mass value of N3O3 is 371.2; the measured m / z value is 372.2 [M+H] + .1 H NMR (400MHz, Methanol-d4) δ8.36–8.31 (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,2H),2.52-2.42(m,2H),1.95-1.83(m,2H),1.66-1.51(m,2H),1.34(s,9H).

[0529] Example 46: (2s,4s)-2-(4-(2-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0530]

[0531] The title compound was prepared in a manner similar 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 The calculated mass value of ClN2O3 is 348.1; the measured m / z value is 349.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.36 (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=12.1,3.5H z,1H),3.17(td,J=13.1,2.6Hz,1H),3.04(p,J=8.1Hz,1H),2.78–2.63(m,3H),2.54–2.4 5(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).

[0532] Example 47: (2s, 4s)-2-(4-(2,4-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0533]

[0534] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 342.2; the measured m / z value is 343.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.03–6.96(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),2.9 2(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).

[0535] Example 48: (2s,4s)-2-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0536]

[0537] The title compound was prepared in a manner similar 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 The calculated mass value of N2O4 is 406.2; the measured m / z value is 407.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.36–7.29(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).

[0538] Example 49: (2s, 4s)-2-(4-(3-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0539]

[0540] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.49 (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).

[0541] Example 50: (2s, 4s)-2-(4-(2-cyclopropylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0542]

[0543] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.21–7.10(m,3H),7.05(dd,J=7.8,1.9Hz,1H),6.12(s,1H), 4.84–4.76(m,1H),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).

[0544] Example 51: (2r, 4s)-2-(4-(4-phenoxyphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octane-6- ketone.

[0545]

[0546] The title compound was prepared in a manner similar to Example 4, using 4-bromodiphenyl ether 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 25 H 28 The calculated mass value of N2O3 is 404.2; the measured m / z value is 405.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.36–7.29(m,2H),7.16–7.12(m,2H),7.12–7.07(m,1 H),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).

[0547] Example 52: (2s, 4s)-2-(4-(2-methyl-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0548]

[0549] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.51(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).

[0550] Example 53: (2s,4s)-2-(4-(3-phenoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0551]

[0552] The title compound was prepared in a manner similar 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 The calculated mass value of N2O4 is 406.2; the measured m / z value is 407.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.37–7.29(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).

[0553] Example 54: (2s, 4s)-2-(4-(4-chloro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0554]

[0555] The title compound was prepared in a manner similar to Example 4 using 5-bromo-2-chlorotoluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in step A. MS (ESI): C 19 H 23The calculated mass value of ClN2O3 is 362.1; the measured m / z value is 363.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.26(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) ,3.86–3.75(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).

[0556] Example 55: (2s, 4s)-2-(4-(2-methoxy-4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0557]

[0558] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.19(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).

[0559] Example 56: (2s, 4s)-2-(4-(2-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0560]

[0561] The title compound was prepared in a manner similar 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 H21 The calculated mass value of F3N2O4 is 398.1; the measured m / z value is 399.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.30–7.20(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,2H),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).

[0562] Example 57: (2s,4s)-2-(4-([1,1'-biphenyl]-3-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0563]

[0564] The title compound was prepared in a manner similar to Example 4 using 3-bromobiphenyl instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in step A. MS (ESI): C 24 H 26 The calculated mass value of N2O3 is 390.2; the measured m / z value is 391.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.60–7.54(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) ,3.20–3.10(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).

[0565] Example 58: (2s, 4s)-2-(4-(4-methoxy-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0566]

[0567] The title compound was prepared in a manner similar 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 H23 The calculated mass value of F3N2O5 is 428.2; the measured m / z value is 429.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.09–7.01(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).

[0568] Example 59: (2s, 4s)-2-(4-(4-(pyridin-2-yloxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0569]

[0570] The title compound was prepared in a manner similar 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 The calculated mass value of N3O4 is 407.2; the measured m / z value is 408.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.21-8.17(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=13.6Hz,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).

[0571] Example 60: (2s, 4s)-2-(4-(4-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0572]

[0573] The title compound was prepared in a manner similar 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 The calculated mass value of ClF3N2O4 is 432.1; the measured m / z value is 433.1 [M+H] + . 1 HNMR(400MHz, CDCl3)δ7.41(d,J=8.3Hz,1H),7.16–7.09(m,1H),7.07(dd,J=8.4,2.0Hz,1H),6.06(s,1H),4.82-4.73(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),2.82–2.60(m,4 H),2.53–2.43(m,2H),1.92(dq,J=12.8,2.2Hz,2H),1.63–1.43(m,2H).

[0574] Example 61: (2s, 4s)-2-(4-(4-fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0575]

[0576] The title compound was prepared in a manner similar 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 The calculated mass value of F4N2O4 is 416.1; the measured m / z value is 417.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.18–7.06(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).

[0577] Example 62: (2s, 4s)-2-(4-(2-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0578]

[0579] The title compound was prepared in a manner similar 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 The calculated mass value of ClF3N2O4 is 432.1; the measured m / z value is 433.1 [M+H] + . 1 HNMR (400MHz, CDCl3) δ7.27 (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).

[0580] Example 63: (2s, 4s)-2-(4-(2-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0581]

[0582] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.19(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).

[0583] Example 64: (2r, 4s)-2-(4-(3-methyl-4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-aza Spiro[3.4]octan-6-one.

[0584]

[0585] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O3 is 410.2; the measured m / z value is 411.2 [M+H] + . 1 HNMR (400MHz, CDCl3) δ7.13(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).

[0586] Example 65: (2s, 4s)-2-(4-(4-cyclopropyl-2-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0587]

[0588] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 368.2; the measured m / z value is 369.2 [M+H] + . 1H NMR(500MHz, CDCl3)δ7.03–6.97(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).

[0589] Example 66: (2s, 4s)-2-(4-(3-(tert-butyl)-4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0590]

[0591] The title compound was prepared in a manner similar 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 The calculated mass value of ClN2O3 is 404.2; the measured m / z value is 405.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.28(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).

[0592] Example 67: (2s, 4s)-2-(4-(3-(difluoromethoxy)-4-methylphenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0593]

[0594] The title compound was prepared in a manner similar 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 The calculated mass value of F2N2O4 is 394.2; the measured m / z value is 395.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.16 (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,2 H),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).

[0595] Example 68: (2s, 4s)-2-(4-(3-(tert-butyl)-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0596]

[0597] The title compound was prepared in a manner similar 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 The calculated mass value of FN2O3 is 388.2; the measured m / z value is 389.2 [M+H] + . 1 H NMR(500MHz, CDCl3)δ7.07(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(t d,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).

[0598] Example 69: (2r, 4s)-2-(4-(2-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-aza Spiro[3.4]octan-6-one.

[0599]

[0600] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O3 is 410.2; the measured m / z value is 411.2 [M+H] + . 1 H NMR(500MHz, CDCl3)δ7.19(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).

[0601] Example 70: (2s, 4s)-2-(4-(3-methyl-5-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0602]

[0603] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ6.92(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).

[0604] Example 71: (2s, 4s)-2-(4-(4-(difluoromethoxy)-3-methylphenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0605]

[0606] The title compound was prepared in a manner similar 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 The calculated mass value of F2N2O4 is 394.2; the measured m / z value is 395.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.05–6.94(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).

[0607] Example 72: (2s, 4s)-2-(4-(2-methyl-5-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0608]

[0609] The title compound was prepared in a manner similar 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): C 20 H 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.2 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.40–7.35(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).

[0610] Example 73: (2r,4s)-2-(4-(3-(tert-butyl)-4-chlorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4] Octane-6-one.

[0611]

[0612] The title compound was prepared in a manner similar 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 The calculated mass value of ClN2O2 is 402.2; the measured m / z value is 403.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.27(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).

[0613] Example 74: (2r, 4s)-2-(4-(2-chloro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0614]

[0615] The title compound was prepared in a manner similar 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 The calculated mass value of ClF3N2O3 is 430.1; the measured m / z value is 431.1 [M+H] + . 1 HNMR(500MHz, CDCl3)δ7.31–7.26(m,1H),7.22(dp,J=8.2,1.5Hz,1H),7.14(dd ,J=7.8,1.6Hz,1H),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).

[0616] Example 75: (2s, 4s)-2-(4-(4-cyclopropyloxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0617]

[0618] The title compound was prepared in a manner similar 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 The calculated mass value of N2O4 is 370.2; the measured m / z value is 371.2 [M+H] + . 1H NMR(500MHz, CDCl3)δ7.12–7.06(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,J=13.2,2.5Hz,1H),3.07–2.99(m,1H),2.74–2.62(m,4H),2 .53-2.44(m,2H),1.94–1.85(m,2H),1.63–1.42(m,2H),0.79–0.72(m,4H).

[0619] Example 76: (2s, 4s)-2-(4-(2-fluoro-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0620]

[0621] The title compound was prepared in a manner similar 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 The calculated mass value of F4N2O4 is 416.1; the measured m / z value is 417.5 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.23–7.16(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).

[0622] Example 77: (2s, 4s)-2-(4-(3-(pentafluoro-λ 6 -sulfanyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0623]

[0624] The title compound was prepared in a manner similar to Example 4 using 3-bromophenylsulfur pentafluoride instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in step A. MS (ESI): C 18 H 21The calculated mass value of F5N2O3S is 440.1; the measured m / z value is 441.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.64–7.61(m,1H),7.56(t,J=2.0Hz,1H),7.42(t,J=7.9Hz,1 H),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=1 3.3Hz,1H),3.14(td,J=13.1,2.4Hz,1H),3.09–3.01(m,1H),2.84(tt,J=12.5,3.8H z,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).

[0625] Example 78: (2s, 4s)-2-(4-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0626]

[0627] The title compound was prepared in a manner similar 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 The calculated mass value of F5N2O3S is 440.1; the measured m / z value is 441.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.73–7.66(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,1H),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).

[0628] Example 79: (2r,4s)-2-(4-(3-(tert-butyl)-4-fluorophenyl)piperidine-1-carbonyl)-5-azaspiro[3.4] Octane-6-one.

[0629]

[0630] The title compound was prepared in a manner similar 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 The calculated mass value of FN2O2 is 386.2; the measured m / z value is 387.3 [M+H] + . 1 H NMR(500MHz, CDCl3)δ7.07(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) ,2.75–2.62(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).

[0631] Example 80: (2s, 4s)-2-(4-(4-isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0632]

[0633] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 370.2; the measured m / z value is 371.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.08(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).

[0634] Example 81: (racemic)-(2s,4s)-8-methyl-2-(4-(4-(1-methylcyclopropyl)phenyl)piperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0635]

[0636] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.22–7.17(m,2H),7.11–7.06(m,2H),6.04(s,1H),4.79–4.7 1(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),1.66–1.4 9(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).

[0637] Example 82: (2s, 4s)-2-(4-(3-(2-hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0638]

[0639] The title compound was prepared in a manner similar 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 The calculated mass value of N2O4 is 372.2; the measured m / z value is 355.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.31-7.22(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).

[0640] Example 83: (2s, 4s)-2-(4-(3-isobutylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0641]

[0642] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 370.2; the measured m / z value is 371.2 [M+H] + . 1 H NMR(400MHz, CDCl3) δ7.21(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=13.4 Hz,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).

[0643] Example 84: (2s, 4s)-2-(4-(4-(2-hydroxypropan-2-yl)phenyl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0644]

[0645] The title compound was prepared in a manner similar 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 28The calculated mass value of N2O4 is 372.2; the measured m / z value is 355.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.38-7.32(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=13.4Hz,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).

[0646] Example 85: (2s, 4s)-2-(4-(3,5-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0647]

[0648] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 342.2; the measured m / z value is 343.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ6.86 (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).

[0649] Example 86: (2s,4s)-2-(4-(2,4-difluoro-3-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0650]

[0651] The title compound was prepared in a manner similar to Example 4 using 1-bromo-2,4-difluoro-3-toluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in step A. MS (ESI): C 19 H 22 The calculated mass value of F2N2O3 is 364.2; the measured m / z value is 365.1 [M+H]+ . 1 H NMR (500MHz, CDCl3) δ6.92(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=13.1,2.6Hz,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).

[0652] Example 87: (2s, 4s)-2-(4-(4-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0653]

[0654] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3Si is 386.2; the measured m / z value is 387.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.51-7.45(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).

[0655] Example 88: (2s,4s)-2-(4-(4-fluoro-2,3-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0656]

[0657] The title compound was prepared in a manner similar 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 The calculated mass value of FN2O3 is 360.2; the measured m / z value is 361.2 [M+H] + .1 H NMR (400MHz, CDCl3) δ6.92 (dd, J=8.7, 5.7Hz, 1H), 6.84 (t, J=8.9Hz, 1H), 6.2 0(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,2 H), 2.25 (s, 3H), 2.20 (d, J = 2.2Hz, 3H), 1.86-1.78 (m, 2H), 1.62-1.44 (m, 2H).

[0658] Example 89: (2s,4s)-2-(4-(2,5-dimethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0659]

[0660] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 342.2; the measured m / z value is 343.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.05 (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).

[0661] Example 90: (2s, 4s)-2-(4-(3-ethyl-4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0662]

[0663] The title compound was prepared in a manner similar to Example 4 using 4-bromo-2-ethyl-1-fluorobenzene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in step A. MS (ESI): C20 H 25 The calculated mass value of FN2O3 is 360.2; the measured m / z value is 361.2 [M+H] + . 1 H NMR(500MHz, CDCl3)δ6.99(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).

[0664] Example 91: (2s,4s)-2-(4-(3,5-difluoro-4-methylphenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0665]

[0666] The title compound was prepared in a manner similar to Example 4 using 5-bromo-1,3-difluoro-2-toluene instead of 1-bromo-2-methyl-4-(trifluoromethyl)benzene in step A. MS (ESI): C 19 H 22 The calculated mass value of F2N2O3 is 364.2; the measured m / z value is 365.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ6.69-6.63(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=13.1,2.5 Hz,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).

[0667] 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.

[0668]

[0669] The title compound was prepared by separation of (rac)-(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 containing 0.2% TEA, 70% CO2). MS (ESI): C 23 H 30 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.22-7.16(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).

[0670] 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.

[0671]

[0672] The title compound was prepared by separation of (rac)-(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 containing 0.2% TEA, 70% CO2). MS (ESI): C 23 H 30 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.22-7.16(m,2H),7.12-7.06(m,2H),6.02(s,1H),4.79-4.72(m,1 H),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 -1.48(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).

[0673] Example 94: (2s, 4s)-2-(4-(3-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0674]

[0675] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3Si is 386.2; the measured m / z value is 387.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.39 (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).

[0676] Example 95: (2r, 4s)-2-(4-(4-(trimethylsilyl)phenyl)piperidine-1-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0677]

[0678] The title compound was prepared in a manner similar to Example 4 using (4-bromophenyl)trimethylsilane 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 32 The calculated mass value of N2O2Si is 384.2; the measured m / z value is 385.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.50-7.44(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).

[0679] Example 96: (2r, 4s)-2-(4-(3-isobutylphenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octane-6- ketone.

[0680]

[0681] The title compound was prepared in a manner similar 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 The calculated mass value of N2O2 is 368.2; the measured m / z value is 369.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.21 (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).

[0682] Example 97: (2s, 4s)-2-(4-(4-(tert-butyl)-3-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0683]

[0684] The title compound was prepared in a manner similar 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 The calculated mass value of N2O4 is 400.2; the measured m / z value is 401.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.20(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),3.8 8–3.77(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).

[0685] Example 98: (2s, 4s)-2-(4-(4-methoxy-3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0686]

[0687] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.2 [M+H]+ . 1 H NMR (400MHz, CDCl3) δ7.36(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),3.88(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).

[0688] Example 99: (racemic)-(2s,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0689]

[0690] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 370.2; the measured m / z value is 371.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.10 (q, J=8.4Hz, 4H), 6.05 (s, 1H), 4.78–4.71 (m, 1H), 4.38(s,2H),3.85–3.78(m,1H),3.11(td,J=13.1,2.5Hz,1H),3.03(p,J=8.1H z,1H),2.76-2.63(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).

[0691] Example 100: (racemic)-(2r,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0692]

[0693] The title compound was prepared in a manner similar 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 The calculated mass value of N2O2 is 368.2; the measured m / z value is 369.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.14–7.06(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).

[0694] Example 101: (2s, 4s)-2-(4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0695]

[0696] The title compound was prepared in a manner similar to Step B and Step C of Example 4, using tert-butyl 4-(1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate (Intermediate 9) instead of tert-butyl 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate in Step B. MS (ESI): C 19 H 22 The calculated mass value of N4O3 is 354.2; the measured m / z value is 355.2 [M+H] + . 1H NMR (500MHz, CDCl3) δ11.32(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,J=13.6Hz,1H),3.26–3.15(m,1H),3.14–2.97(m,2H),2 .90–2.68(m,3H),2.53–2.42(m,2H),2.22–2.12(m,2H),1.86–1.64(m,3H).

[0697] Example 102: (2s, 4s)-2-[4-(6-fluorobenzofuran-3-yl)piperidine-1-carbonyl)-6-oxa-8-azepine Spiro[3.4]octan-7-one.

[0698]

[0699] The title compound was prepared in a manner similar to step C of Example 4 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 The calculated mass value of FN2O4 is 372.1; the measured m / z value is 373.1 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.45 (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(ddd,J=9.4,8.6,2.3Hz,1H),5.70(s,1H),4.73(d,J=13.4Hz,1H),4.38(s,2 H),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).

[0700] Example 103: (2s, 4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0701]

[0702] The title compound was prepared in a manner similar to step C of Example 4 using 4-(4-trifluoromethylphenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 21 The calculated mass value of F3N2O3 is 382.1; the measured m / z value is 383.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.56(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).

[0703] Example 104: (2s, 4s)-2-(4-(Benzofuran-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0704]

[0705] The title compound was prepared in a manner similar 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 The calculated mass value of N2O4 is 354.2; the measured m / z value is 355.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.53–7.47(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).

[0706] Example 105: (2s,4s)-2-(4-(naphthalen-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0707]

[0708] The title compound was prepared in a manner similar to step C of Example 4 using 4-(2-naphthyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 22 H 24 The calculated mass value of N2O3 is 364.2; the measured m / z value is 365.2 [M+H] + . 1 HNMR(400MHz, CDCl3)δ7.84–7.75(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),3.9 2–3.80(m,1H),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).

[0709] Example 106: (2s, 4s)-2-(4-(1H-indol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0710]

[0711] The title compound was prepared in a manner similar 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 The calculated mass value of N3O3 is 353.2; the measured m / z value is 354.2 [M+H] + . 1HNMR(500MHz, CDCl3)δ8.51(s,1H),7.56–7.50(m,1H),7.35–7.31(m,1H),7.15– 7.10(m,1H),7.10–7.03(m,1H),6.48(s,1H),6.26–6.21(m,1H),4.68(d,J=13.3 Hz,1H),4.41(s,2H),3.82(d,J=13.6Hz,1H),3.22–3.12(m,1H),3.08–2.94(m,2 H),2.84–2.66(m,3H),2.56–2.42(m,2H),2.11–2.01(m,2H),1.79–1.66(m,2H).

[0712] Example 107: (2s, 4s)-2-(4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azepine Spiro[3.4]octan-6-one.

[0713]

[0714] The title compound was prepared in a manner similar 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 The calculated mass value of F3N2O4 is 398.1; the measured m / z value is 399.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.22–7.17(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).

[0715] Example 108: (2s, 4s)-2-(4-(4-(methylthio)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0716]

[0717] The title compound was prepared in a manner similar to step C of Example 4 using 4-(4-methylthio-phenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C19 H 24 The calculated mass value of N2O3S is 360.2; the measured m / z value is 361.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.26–7.21(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).

[0718] Example 109: (2s, 4s)-2-(4-(4-(dimethylamino)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0719]

[0720] The title compound was prepared in a manner similar 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): C 20 H 27 The calculated mass value of N3O3 is 357.2; the measured m / z value is 358.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.13–7.00(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).

[0721] Example 110: (2s, 4s)-2-(4-(5-chlorobenzofuran-2-yl)piperidin-1-carbonyl)-7-oxa-5-aza Spiro[3.4]octan-6-one.

[0722]

[0723] The title compound was prepared in a manner similar 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): C20 H 21 The calculated mass value of ClN2O4 is 388.1; the measured m / z value is 389.0 [M+H] + . 1 H NMR(400MHz, CDCl3) δ7.45(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).

[0724] Example 111: (2s, 4s)-2-(4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane-6- ketone.

[0725]

[0726] The title compound was prepared in a manner similar to step C of Example 4 using 4-phenylpiperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 22 The calculated mass value of N2O3 is 314.2; the measured m / z value is 315.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.35–7.28(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).

[0727] Example 112: (2s, 4s)-2-(4-(p-Tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0728]

[0729] The title compound was prepared in a manner similar to step C of Example 4 using 4-(4-methylphenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 The calculated mass value of N2O3 is 328.2; the measured m / z value is 329.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.16–7.09(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).

[0730] Example 113: (2s, 4s)-2-(4-(naphthalen-1-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0731]

[0732] The title compound was prepared in a manner similar to step C of Example 4 using 4-(decalin-1-yl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 22 H 24 The calculated mass value of N2O3 is 364.2; the measured m / z value is 365.1 [M+H] + . 1 HNMR(400MHz, CDCl3)δ8.08(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),4.3 9(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).

[0733] Example 114: (2s,4s)-2-(4-(4-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0734]

[0735] The title compound was prepared in a manner similar to step C of Example 4 using 4-(4-fluorophenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 The calculated mass value of FN2O3 is 332.2; the measured m / z value is 333.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.17–7.09(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).

[0736] Example 115: (2s,4s)-2-(4-(3-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0737]

[0738] The title compound was prepared in a manner similar to step C of Example 4 using 4-(3-chlorophenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 The calculated mass value of ClN2O3 is 348.1; the measured m / z value is 349.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.26–7.12(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,1H),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).

[0739] Example 116: (2s,4s)-2-(4-(o-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0740]

[0741] The title compound was prepared in a manner similar to step C of Example 4 using 4-(2-methylphenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 The calculated mass value of N2O3 is 328.2; the measured m / z value is 329.1 [M+H] + . 1 HNMR(400MHz, CDCl3)δ7.21–7.07(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).

[0742] Example 117: (2s, 4s)-2-(4-(4-ethylphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4] Octane-6-one.

[0743]

[0744] The title compound was prepared in a manner similar to step C of Example 4 using 4-(4-ethylphenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 20 H 26 The calculated mass value of N2O3 is 342.2; the measured m / z value is 343.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.18–7.12(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).

[0745] Example 118: (2s, 4s)-2-(4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0746]

[0747] The title compound was prepared in a manner similar to step C of Example 4 using 4-(3-trifluoromethylphenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 21 The calculated mass value of F3N2O3 is 382.1; the measured m / z value is 383.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.52–7.34(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).

[0748] Example 119: (2s,4s)-2-(4-(2-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0749]

[0750] The title compound was prepared in a manner similar to step C of Example 4 using 4-(2-fluorophenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 The calculated mass value of FN2O3 is 332.2; the measured m / z value is 333.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.24–7.06(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,1H),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).

[0751] Example 120: (2s,4s)-2-(4-(3-fluorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0752]

[0753] The title compound was prepared in a manner similar to step C of Example 4 using 4-(3-fluorophenyl)piperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 The calculated mass value of FN2O3 is 332.2; the measured m / z value is 333.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.31–7.23(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,1H),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).

[0754] Example 121: (2s,4s)-2-(4-(4-chlorophenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0755]

[0756] The title compound was prepared in a manner similar to step C of Example 4 using 4-(4-chlorophenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 The calculated mass value of ClN2O3 is 348.1; the measured m / z value is 349.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.31–7.27(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,1H),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).

[0757] Example 122: (2s,4s)-2-(4-(m-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0758]

[0759] The title compound was prepared in a manner similar to step C of Example 4 using 4-(3-methylphenyl)piperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 The calculated mass value of N2O3 is 328.2; the measured m / z value is 329.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.23–7.16(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).

[0760] Example 123: (2s, 4s)-2-(4-(4-methoxyphenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0761]

[0762] The title compound was prepared in a manner similar 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 The calculated mass value of N2O4 is 344.2; the measured m / z value is 345.1 [M+H] + . 1 HNMR(400MHz, CDCl3)δ7.13–7.06(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).

[0763] Example 124: (2s, 4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0764]

[0765] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 370.2; the measured m / z value is 371.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.36–7.29(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).

[0766] Example 125: (2r,4s)-2-(4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octane Alkane-6-one.

[0767]

[0768] The title compound was prepared in a manner similar 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): C 20 H 23 The calculated mass value of F3N2O2 is 380.2; the measured m / z value is 381.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.57(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).

[0769] Example 126: (2r,4s)-2-(4-(5-chlorobenzofuran-2-yl)piperidine-1-carbonyl)-5-azaspiro[3.4] Octane-6-one.

[0770]

[0771] The title compound was prepared in a manner similar 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 The calculated mass value of ClN2O3 is 386.1; the measured m / z value is 387.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.47–7.42(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),2.4 3–2.31(m,4H),2.27–2.18(m,2H),2.18–2.04(m,2H),1.76–1.55(m,2H).

[0772] Example 127: (2r,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-5-azaspiro[3.4]octane Alkane-6-one.

[0773]

[0774] The title compound was prepared in a manner similar 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 The calculated mass value of N2O2 is 368.2; the measured m / z value is 369.1 [M+H] + . 1HNMR(500MHz, CDCl3)δ7.36–7.30(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 ),2.76–2.62(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).

[0775] Example 128: (2s,4s)-2-(4-methyl-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0776]

[0777] The title compound was prepared in a manner similar to step C of Example 4 using 4-methyl-4-phenylpiperidine instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 24 The calculated mass value of N2O3 is 328.2; the measured m / z value is 329.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.38–7.28(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),3.3 2-3.23(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).

[0778] Example 129: (2s, 4s)-2-(4-(6-chlorobenzo[d]isoxazol-3-yl)piperidine-1-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0779]

[0780] The title compound was prepared in a manner similar 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 The calculated mass value of ClN3O4 is 389.1; the measured m / z value is 390.1 [M+H] + .1 H NMR (400MHz, CDCl3) δ7.60(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).

[0781] 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.

[0782]

[0783] The title compound was prepared in a manner similar 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 The calculated mass value of ClN4O4 is 416.1; the measured m / z value is 417.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.04–7.95(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).

[0784] 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.

[0785]

[0786] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.3 [M+H] + . 1 HNMR(400MHz, CDCl3)δ7.36–7.30(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).

[0787] Example 132: (2S*, 4s, 8R*)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0788]

[0789] The title compound was prepared by separation of (rac)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidin-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% CO2). MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.3 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.35–7.31(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).

[0790] Example 133: (2R*, 4s, 8S*)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8-methyl-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0791]

[0792] The title compound was prepared by separation of (rac)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidin-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% CO2). MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.3 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.37–7.30(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).

[0793] Example 134: (2s,4s)-2-(4-(4-(tert-butyl)phenyl)piperidine-1-carbonyl)-8,8-dimethyl-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0794]

[0795] The title compound was prepared in a manner similar 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 The calculated mass value of N2O3 is 398.3; the measured m / z value is 399.3 [M+H] + . 1 HNMR (400MHz, CDCl3) δ7.36–7.31(m,2H),7.15–7.08(m,2H),6.19(s,1H),4.82–4.72(m,1H),3.83–3.73(m,1H),3.18–2.9 9(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).

[0796] Example 135: (2s, 4s)-2-(4-(4-chlorophenyl)-4-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0797]

[0798] The title compound was prepared in a manner similar to step C of Example 4 using 4-(4-chlorophenyl)-4-methylpiperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 23 The calculated mass value of ClN2O3 is 362.1; the measured m / z value is 363.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.34-7.28(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),3.3 1-3.22(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).

[0799] Example 136: (2s, 4s)-2-(4-(Benzo[d]thiazol-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0800]

[0801] The title compound was prepared in a manner similar to step C of Example 4 using 2-(4-piperidinyl)-1,3-benzothiazole instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 19 H 21 The calculated mass value of N3O3S is 371.1; the measured m / z value is 372.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.97 (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),3.35(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).

[0802] Example 137: (2s, 4s)-2-(4-methyl-4-(p-tolyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0803]

[0804] The title compound was prepared in a manner similar to step C of Example 4 using 4-methyl-4-(p-tolyl)piperidinium hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C20 H 26 The calculated mass value of N2O3 is 342.2; the measured m / z value is 343.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.18(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).

[0805] Example 138: (2s,4s)-2-(4-fluoro-4-phenylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octane Alkane-6-one.

[0806]

[0807] The title compound was prepared in a manner similar to step C of Example 4 using 4-fluoro-4-phenylpiperidine hydrochloride instead of 4-(2-methyl-4-(trifluoromethyl)phenyl)piperidin-1-ium chloride. MS (ESI): C 18 H 21 The calculated mass value of FN2O3 is 332.2; the measured m / z value is 333.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.42-7.29(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).

[0808] Example 139: (2s, 4s)-2-(4-(4-methyl-3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0809]

[0810] The title compound was prepared in a manner similar 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 H23 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.20–7.15(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 .

[0811] Example 140: (2s, 4s)-2-(4-(4-chlorophenyl)-4-ethylpiperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0812]

[0813] TEA (40 μL, 0.280 mmol) was added dropwise to a stirred 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) solution at 0°C. The reaction mixture was stirred at room temperature for 14 hours and then diluted with water. The title compound (25.3 mg, 67.1 μmol, 77% yield) was obtained by purification by reverse phase HPLC (ACN / H2O, 0.05% TFA). MS (ESI): C 20 H 25 The calculated mass value of ClN2O3 is 376.2; the measured m / z value is 377.1 [M+H] + . 1 H NMR(500MHz,Methanol-d4)δ7.39-7.29(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).

[0814] Example 141: (racemic)-(2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin- 1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0815]

[0816] 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 minutes. 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 at room temperature overnight. The reaction mixture was purified by reverse phase HPLC (Gilson, 0%-100% ACN / water, NH4OH regulator) to give the title compound (9.2 mg, 0.24 mmol, 20% yield). MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.37–7.29(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),3.46–2.86(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).

[0817] Example 142: (2s, 4S*)-2-((3R*, 4R*)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0818]

[0819] 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 separated using chiral supercritical fluid chromatography (Chiralcel OZ column, 70% CO2, 15% MeOH, 15% iPrOH, 0.2% isopropylamine eluent) to give the title compound (20.4 mg, 0.053 mmol, 75% yield, 100% ee). MS (ESI): C 23 H 32The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.36–7.29(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).

[0820] Example 143: (2s, 4R*)-2-((3S*, 4S*)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0821]

[0822] 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 separated using chiral supercritical fluid chromatography (Chiralcel OZ column, 70% CO2, 15% MeOH, 15% iPrOH, 0.2% isopropylamine eluent) to give the title compound (21.7 mg, 0.056, 80% yield, 89% ee). MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.36–7.28(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).

[0823] Example 144: (racemic)-(2r,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin- 1-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0824]

[0825] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-7-oxa-5-azaspiro[3.4]octane-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 The calculated mass value of N2O2 is 382.3; the measured m / z value is 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).

[0826] Example 145: (racemic)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)- 7-Oxa-5-azaspiro[3.4]octan-6-one.

[0827]

[0828] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.2 [M+H] + . 1H NMR (400MHz,CDCl3)δ7.36–7.30(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.

[0829] Example 146: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidin

[0063]

[0064] 1-[(2-((2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one])-1-[(2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one]

[0830]

[0831] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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): C 20 H 23 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.38–7.29(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).

[0832] Example 147: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-methyl-4-(trifluoromethoxy)

[0063]

[0064] 1-(4-(phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0833]

[0834] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 The calculated mass value of F3N2O4 is 426.2; the measured m / z value is 427.2 [M+H] + . 1 H NMR(400MHz, CDCl3)δδ7.16–7.11(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 ),3.52–3.34(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).

[0835] Example 148: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidin

[0063]

[0064] 1-[(2-((2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one])-1-[(2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one]

[0836]

[0837] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-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 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.2 [M+H] + . 1H NMR(400MHz, CDCl3)δδ7.50–7.41(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 ),4.02–3.59(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).

[0838] Example 149: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidin

[0063]

[0064] 1-[(2-((2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one])-1-[(2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one]

[0839]

[0840] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 The calculated mass value of F3N2O4 is 412.2; the measured m / z value is 413.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.22–7.09(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).

[0841] Example 150: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-fluoro-4-(trifluoromethoxy)benzene

[0063] The invention relates to 7-oxa-5-azaspiro[3.4]octan-6-one.

[0842]

[0843] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-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 The calculated mass value of F4N2O4 is 430.2; the measured m / z value is 431.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.26–7.23(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) ,3.93–3.62(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).

[0844] Example 151: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidin

[0063]

[0064] 1-[(2-((2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one])-1-[(2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one]

[0845]

[0846] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-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 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.0 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.61–7.57(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) ,3.94–3.63(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).

[0847] Example 152: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-methyl-3-(trifluoromethyl)benzene

[0063] The invention relates to 7-oxa-5-azaspiro[3.4]octan-6-one.

[0848]

[0849] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 The calculated mass value of F3N2O3 is 410.2; the measured m / z value is 411.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.39–7.34(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).

[0850] Example 153: (racemic)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-methyl-4-(trifluoromethyl)benzene

[0063] The invention relates to 7-oxa-5-azaspiro[3.4]octan-6-one.

[0851]

[0852] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-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 The calculated mass value of F3N2O3 is 410.2; the measured m / z value is 411.2 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.58–7.43(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).

[0853] Example 154: (racemic)-(2s,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidin

[0063]

[0064] 1-[(2-((2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one])-1-[(2-pyridine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one]

[0854]

[0855] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 The calculated mass value of N2O3 is 404.2; the measured m / z value is 405.1 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.59–7.56(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) ,4.45–4.28(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).

[0856] Example 155: (racemic)-(2r,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidin

[0063]

[0064]

[0065] 1-[(2-((2-pyridine-1-carbonyl)-5-azaspiro[3.4]octan-6-one].

[0857]

[0858] The title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 The calculated mass value of N2O2 is 402.2; the measured m / z value is 403.1 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.60–7.55(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).

[0859] Example 156: (2s, 4R*)-2-((2S*, 4R*)-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0860]

[0861] The diastereomeric mixture of the title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 by chiral supercritical fluid chromatography (CHIRALPAK AD-H column, 70% CO2, 30% MeOH eluent, then CHIRACEL OJ-H column, 93% CO2, 7% MeOH eluent) to give the title compound. MS (ESI): C 20 H 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.56(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).

[0862] Example 157: (2s, 4S*)-2-((2R*, 4S*)-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0863]

[0864] The diastereomeric mixture of the title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 by chiral supercritical fluid chromatography (CHIRALPAK AD-H column, 70% CO2, 30% MeOH eluent, then CHIRACEL OJ-H column, 93% CO2, 7% MeOH eluent) to give the title compound. MS (ESI): C 20 H 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.59-7.53(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=1 2.1,7.5,1.5Hz,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).

[0865] Example 158: (2s, 4S*)-2-((2R*, 4R*)-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0866]

[0867] The diastereomeric mixture of the title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 by chiral supercritical fluid chromatography (CHIRALPAK AD-H column, 70% CO2, 30% MeOH eluent, then CHIRACEL OJ-H column, 93% CO2, 7% MeOH eluent) to give the title compound. MS (ESI): C20 H 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.57 (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).

[0868] Example 159: (2s,4R*)-2-((2S*,4S*)-2-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0869]

[0870] The diastereomeric mixture of the title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 by chiral supercritical fluid chromatography (CHIRALPAK AD-H column, 70% CO2, 30% MeOH eluent, then CHIRACEL OJ-H column, 93% CO2, 7% MeOH eluent) to give the title compound. MS (ESI): C 20 H 23 The calculated mass value of F3N2O3 is 396.2; the measured m / z value is 397.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.57(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).

[0871] Example 160: (2s, 4S*)-2-((3R*, 4R*)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0872]

[0873] 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 separated 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 The calculated mass value of N2O3 is 404.2; the measured m / z value is 405.1 [M+H] + . 1 HNMR(500MHz, CDCl3)δ7.59-7.55(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),2.2 8-2.15(m,1H),2.13-2.01(m,1H),1.81-1.74(m,1H),0.71-0.67(m,3H).

[0874] Example 161: (2s, 4R*)-2-((3S*, 4S*)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0875]

[0876] 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 separated 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 The calculated mass value of N2O3 is 404.2; the measured m / z value is 405.1 [M+H] +. 1 H NMR (500MHz, CDCl3) δ7.60-7.55(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),2.2 9-2.14(m,1H),2.13-2.00(m,1H),1.82-1.74(m,1H),0.75-0.65(m,3H).

[0877] Example 162: (racemic)-(2s,4R)-2-((2S,4S)-4-(3-(tert-butyl)phenyl)-2-methylpiperidin- 1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0878]

[0879] The diastereomeric mixture of the title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 by chiral supercritical fluid chromatography (IG column, 40% MeOH, 60% CO2, 0.1% diethylamine eluent) to give the title compound. MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.29–7.21(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).

[0880] Example 163: (2s, 4R*)-2-((2S*, 4R*)-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0881]

[0882] A sample of (2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidin-1-yl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 145) was separated by chiral supercritical fluid chromatography (OJ-H column, 15% EtOH, 85% CO2 eluent) to give the title compound. MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.33(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,1 H),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).

[0883] Example 164: (2s, 4S*)-2-((2R*, 4R*)-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0884]

[0885] A sample of (2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidin-1-yl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 145) was separated by chiral supercritical fluid chromatography (OJ-H column, 15% EtOH, 85% CO2 eluent) to give the title compound. MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.36–7.30(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) ,4.19–3.52(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).

[0886] Example 165: (2s, 4S*)-2-((2R*, 4S*)-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0887]

[0888] A sample of (2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidin-1-yl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 145) was separated by chiral supercritical fluid chromatography (OJ-H column, 15% EtOH, 85% CO2 eluent) to give the title compound. MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.36–7.29(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).

[0889] Example 166: (2s, 4R*)-2-((2S*, 4S*)-4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0890]

[0891] A sample of (2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidin-1-yl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 145) was separated by chiral supercritical fluid chromatography (OJ-H column, 15% EtOH, 85% CO2 eluent) to give the title compound. MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.0 [M+H] + . 1H NMR (500MHz, CDCl3) δ7.35–7.32(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) ,4.19–3.48(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).

[0892] Example 167: (2s, 4R*)-2-((2S*, 4R*)-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0893]

[0894] The diastereomeric mixture of the title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 by chiral supercritical fluid chromatography (IG column, 40% MeOH, 60% CO2, 0.1% diethylamine eluent) to give the title compound. MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.29–7.15(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).

[0895] Example 168: (2s, 4S*)-2-((2R*, 4S*)-4-(3-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0896]

[0897] The diastereomeric mixture of the title compound was prepared in a manner analogous to racemic (2s,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidin-1-yl)-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 by chiral supercritical fluid chromatography (IG column, 40% MeOH, 60% CO2, 0.1% diethylamine eluent) to give the title compound. MS (ESI): C 23 H 32 The calculated mass value of N2O3 is 384.2; the measured m / z value is 385.0 [M+H] + . 1 H NMR (500MHz, CDCl3) δ7.31–7.22(m,3H),7.20–7.17(m,1H),7.03–6.90(m,1 H),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).

[0898] Example 169: (2s, 4s)-2-(4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one .

[0899]

[0900] Step A: tert-Butyl 4-(6-(tert-butyl)pyridin-2-yl)-4-hydroxypiperidine-1-carboxylate. Under N2, in a dried flask, 2-bromo-6-tert-butylpyridine (144 mg, 0.639 mmol) was absorbed in anhydrous THF (2.5 mL) solution and cooled to -78°C. To this reaction mixture was added n-BuLi (0.37 mL, 0.590 mmol), and the reactants were stirred at -78°C for 30 minutes. 1-tert-Butyloxycarbonyl-4-piperidone (100 mg, 0.492 mmol) was added, and the reaction mixture was stirred at -78°C for 1 hour. After heating to room temperature, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (115 mg, 70% yield) was obtained by purification by FCC (0%-50% EtOAc in hexane). MS (ESI): C 19 H 30 The calculated mass value of N2O3 is 334.2; the measured m / z value is 335.3 [M+H] + .

[0901] 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 heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution 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 The calculated mass value of N2O2 is 316.2; the measured m / z value is 317.3 [M+H] + .

[0902] 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 H2 and stirred at room temperature for 16 h. The reaction was filtered and washed with MeOH. The 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 The calculated mass value of N2O2 is 318.2; the measured m / z value is 319.3 [M+H]+ .

[0903] 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 title compound was used in the next step without further purification. MS (ESI): C 14 H 22 The calculated mass value of N2 is 218.2; the measured m / z value is 219.2 [M+H] + .

[0904] Step E: (2s,4s)-2-(4-(6-(tert-butyl)pyridin-2-yl)piperidine-1-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-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 reactant was stirred at room temperature for 1 hour. The reaction mixture was filtered through a PTFE filter and purified by RP-HPLC (5%-95% ACN in 20 mM NH4OH aqueous solution) to give the title compound (36 mg, 66% yield). MS (ESI): C 21 H 29 The calculated mass value of N3O3 is 371.2; the measured m / z value is 372.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.51(t,J=7.8Hz,1H),7.14(dd,J=8.0,0.8Hz,1H),6.89(d d,J=7.6,0.8Hz,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).

[0905] Biological data

[0906] The assay used to measure the in vitro activity of MGL was adapted from an assay for another serine hydrolase (FAAH) described in Wilson et al., 2003 ("A high-throughput-compatible assay for determining the activity of fatty acid amide hydrolase". Wilson SJ, Lovenberg TW, Barbier AJ., Anal Biochem., 2003 Jul 15; 318(2): 270-5.). The assay involves combining endogenously expressed MGL from HeLa cells with the test compound, adding [glycerol-1,3- 3 H]-oleoylglycerol, incubated for one hour, and then the cleavage of [1,3- 3 The amount of cleaved tritiated glycerol that passes through the carbon filter is proportional to the activity of the MGL enzyme in the specific well / assay conditions.

[0907] The standard conditions for this assay are 300 nM [glycerol-1,3- 3 H]-oleoylglycerol was combined with human MGL from HeLa cells and the test compound for one hour, and then the reaction was filtered through activated charcoal and tritium in the flow-through was measured. The test compound concentration in the screening mode was 10 μM, and the IC 50 The highest compound concentration in the assay was determined empirically. MGL is the major hydrolase in HeLa cells / cell homogenates.

[0908] Table 3.

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

Claims

1. A compound of formula (I): in X is CH2 or O; R 2a and R 2b Each independently selected from H and C 1-4 alkyl; R 3 Selected from: (a) phenyl; phenyl substituted by one, two or three members each independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C(CH3)2OH、OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SCH3, SF5, Si(CH3)3, N(CH3)2, C 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, phenyl, O-phenyl, O-pyridyl, and C substituted by CH3 3-6 Cycloalkyl; and (b) C 1-6 Alkyl substituted pyridyl; R 4 Selected from: H, F and C 1-3 Alkyl; and R 5a and R 5b Each independently selected from H and CH3; or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound according to claim 1, wherein X is CH2.

3. The compound according to claim 1, wherein X is O.

4. The compound according to claim 1, wherein R 2a and R 2b Each is H.

5. The compound according to claim 1, wherein R 2a and R 2b Each is CH3.

6. The compound according to claim 1, wherein R 2a H and R 2b For CH3.

7. The compound according to claim 1, wherein R 3 is phenyl; or phenyl substituted by one, two or three members independently selected from the following: Cl, F, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C(CH3)2OH, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SCH3, Si(CH3)3, SF5, N(CH3)2, C 3-6 Cycloalkyl, C substituted by CH3 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, phenyl, O-phenyl and O-pyridyl.

8. The compound according to claim 7, wherein R 3 is phenyl substituted by one, two or three members independently selected from the following: Cl, F, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, SCH3, SF5 and Si(CH3)3.

9. The compound according to claim 1, wherein R 3 for 10. The compound according to claim 7, wherein R 3 is 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl or 3-(1-methylcyclopropyl)phenyl.

11. The compound according to claim 1, wherein R 4 It is H, F, CH3 or CH2CH3.

12. The compound according to claim 1, wherein R 5a and R 5b Each is H.

13. The compound according to claim 1, wherein R 5a is CH3 and R 5b H, or R 5a H and R 5b For CH3.

14. The compound according to claim 1, wherein for 15. A compound selected from: (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-(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-cyclopropyloxyphenyl)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-sulfanyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(4-(4-(pentafluoro-λ6-sulfanyl)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; (rac)-(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; (rac)-(2s,4s)-2-(4-(4-(sec-butyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(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; (rac)-(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; (rac)-(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; (rac)-(2r,4S)-2-((3R,4R)-4-(4-(tert-butyl)phenyl)-3-methylpiperidine-1-carbonyl)-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(4-(4-(tert-butyl)phenyl)-2-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(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; (rac)-(2s,4S)-2-((3R,4R)-3-methyl-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(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; (rac)-(2s,4S)-2-((3R,4R)-3-methyl-4-(4-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(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; (rac)-(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; (rac)-(2s,4S)-2-((3R,4R)-4-([1,1'-biphenyl]-3-yl)-3-methylpiperidine-1-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(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; (rac)-(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-methylpiperidin-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 and stereoisomers thereof.

16. The compound according to claim 1, which has the structure of formula (IA): in R 3 Selected from: (a) phenyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Haloalkyl, Si(CH3)3, C 3-6 Cycloalkyl, phenyl, O-phenyl and CH3-substituted C 3-6 Cycloalkyl; and (b) and R 5b is H or CH3; or a pharmaceutically acceptable salt or stereoisomer thereof.

17. The compound according to claim 1, which has the structure of formula (IB): in R 2a and R 2b Each independently selected from H and CH3; R 3 Selected from: (a) phenyl; phenyl substituted by one, two or three members each independently selected from the following: Cl, F, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 and (b) R 4 Selected from: H, F, CH3 and CH2CH3; R 5a is H or CH3; and R 5b is H or CH3; or a pharmaceutically acceptable salt or stereoisomer thereof.

18. The compound according to claim 1, which has the structure of formula (IC): in X is CH2 or O; and Ring A is selected from: or a pharmaceutically acceptable salt or stereoisomer thereof.

19. The compound according to claim 1, which has the structure of formula (ID): in X is CH2 or O; R 2a and R 2b Each independently selected from H and CH3; R b Selected from: Cl, F, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 and n is 0, 1, 2 or 3; R 4 Selected from: H, F, CH3 and CH2CH3; R 5a is H or CH3; and R 5b is H or CH3; or a pharmaceutically acceptable salt or stereoisomer thereof.

20. A pharmaceutical composition, comprising: (A) a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof; and (B) at least one pharmaceutically acceptable excipient.

21. Use of a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for treating a subject suffering from or diagnosed with a disease, disorder or condition mediated by MGL receptor activity, optionally wherein the MGL receptor-mediated disease, disorder or condition is selected from: pain, psychiatric disorder and neurological disorder.

22. Use of a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for treating a subject suffering from or diagnosed with a disease, disorder or condition mediated by MGL receptor activity, optionally wherein the MGL receptor-mediated disease, disorder or condition is selected from: major depressive disorder, refractory depression, anxious depression, autism spectrum disorder and bipolar disorder.

23. Use of a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for treating a subject suffering from or diagnosed with a disease, disorder or condition mediated by MGL receptor activity, optionally wherein the MGL receptor-mediated disease, disorder or condition is Asperger's syndrome.

24. Use of a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof in the preparation of a medicament for treating a subject suffering from or diagnosed with a disease, disorder or condition mediated by MGL receptor activity, optionally wherein the MGL receptor mediated disease, disorder or condition is inflammatory pain.

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