Azaspirocyclic compounds as monoacylglycerol lipase modulators

Abstract

The present invention relates to azaspirocyclic compounds of formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing them, methods for their preparation, and methods of using them, including methods for treating pathologies, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological diseases (including, but not limited to, major depressive disorder, treatment-resistant depression, anxiety-related depression, autism spectrum disorder, Asperger's syndrome, bipolar disorder), cancer, and ophthalmic conditions: 1 , R 2a , R 2b , R 3 , m, n, o, and p are defined herein. [Formula 1] TIFF2023519367000187.tif37128

Description

[Technical Field]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0017] [ka] [In the formula, X is CH or O; R 1 is H, R 2a and R 2b are each independently H and C 1~4alkyl, R 3 is C 3~6 Cycloalkyl; C 1~4 Alkyl-substituted C 3~6 Cycloalkyl; Phenyl; Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 Alkyl, OC 1~6 Haloalkyl and C optionally substituted with CH3 or CF3 3~6 phenyl substituted with one or two members independently selected from cycloalkyl; halo, C 1~6 Alkyl, and C 1~6 pyridyl substituted with one or two members independently selected from haloalkyl; C 1~6 Alkyl-substituted pyrimidyl;

[0018] [ka] is selected from n, m, o, and p are each independently 1 or 2. and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof are described. DETAILED DESCRIPTION OF THE INVENTION

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

[0020] Unless specifically limited in a particular use, the term "alkyl" refers to a straight- or branched-chain alkyl group having 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that are deemed equivalent to any one of the above examples in light of ordinary skill in the art and the teachings provided herein. "C1-C4 alkyl" refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain.

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

[0022] [ka]

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

[0024] The term "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally replacing a hydrogen with a halogen. The term "C1-C4 haloalkyl," as used herein, refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain, optionally replacing a 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 deemed equivalent to any one of the foregoing examples given the ordinary skill in the art and the teachings provided herein.

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

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

[0027] [ka]

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

[0029] [ka]

[0030] The pyridinyl or pyridyl moiety can be attached via any one of the 2-, 3-, 4-, 5-, or 6-carbon atoms.

[0031] The term "pyrimidinyl" refers to the moiety:

[0032] [ka]

[0033] The pyrimidinyl moiety can be attached via any one of the 2-, 4-, 5-, or 6-carbon atoms.

[0034] As used herein, the term "heteroaryl" refers to an aromatic monocyclic or polycyclic ring system containing 5 to 14 ring atoms, wherein 1 to 4 ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms. In one embodiment, a heteroaryl group has 5 to 10 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, a heteroaryl group is monocyclic and has 5 or 6 ring atoms and at least one nitrogen ring atom. A heteroaryl group is bonded via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term "heteroaryl" also encompasses a heteroaryl group, as defined above, fused to a benzene ring.

[0035] The term "heterocycloalkyl," as used herein, refers to a ring system that is non-aromatic, in which 1 to 4 ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms, and which can optionally be fused to another ring (aromatic or heteroaromatic). Non-limiting examples of exemplary heterocycloalkyls include:

[0036] [ka]

[0037] Those of ordinary skill in the art will understand that the species of heteroaryl, heterocycloalkyl, cycloalkyl, and aryl groups listed or illustrated above are not exhaustive and that additional species may be selected within the scope of these defined terms.

[0038] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any position in the system where valency is allowed.

[0039] The term "variable point of attachment" means that a group may be attached at two or more alternative positions within a structure. The bond always replaces a hydrogen atom on one of the ring atoms. In other words, all permutations of the bond, as shown in the diagram below, are represented by a single diagram.

[0040] [ka]

[0041] Those skilled in the art will recognize that when more than one such substituent is present for a given ring, the binding of each substituent is independent of all others. The groups listed or exemplified above are not exhaustive.

[0042] Those of ordinary skill in the art will understand that the species of cycloalkyl or aryl groups listed or exemplified above are not exhaustive and that additional species may be selected within the scope of these defined terms.

[0043] The terms "para," "meta," and "ortho" have their art-recognized meanings. Thus, for example, a fully substituted phenyl group has substituents at both "ortho" (o) positions adjacent to the bonding site of the phenyl ring, both "meta" (m) positions, and one "para" (p) position opposite the bonding site. To further clarify the location of substituents on the phenyl ring, the two different ortho positions are designated ortho and ortho', and the two different meta positions are designated meta and meta', as illustrated below.

[0044] [ka]

[0045] When referring to substituents on a pyridyl group, the terms "para," "meta," and "ortho" refer to the position of the substituent relative to the point of attachment to the pyridyl ring. For example, the following structure shows an X in the ortho position: 1 Substituent, X in meta position 2 Substituents and X in the para position 3 Described as substituted 3-pyridyl:

[0046] [ka]

[0047] The term "substituted" means that the specified group or moiety has one or more substituents. The term "unsubstituted" means that the specified group has no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. When the term "substituted" is used to describe a structural system, it means that the substitution occurs at any position in the system where valency is allowed.

[0048] Any formula given herein is intended to represent the compound having the structure depicted by that structural formula, as well as specific variations or forms. Specifically, compounds of any formula given herein may have asymmetric centers and therefore may exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds of the general formula, as well as mixtures thereof, are considered to be within the scope of such formulas. Because compounds of the present invention may have one or more asymmetric centers, such compounds may be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Thus, any formula given herein is intended to represent a racemate, one or more of its enantiomeric forms, one or more of its diastereomeric forms, and mixtures thereof. Furthermore, any formula given herein is intended to refer to any one of hydrates, solvates, and polymorphs of such compounds, as well as mixtures thereof, even if such forms are not explicitly enumerated.

[0049] The term "R" at a stereocenter indicates that the stereocenter is in the R-configuration only, as defined in the art. Similarly, the term "S" means that the stereocenter is in the S-configuration only. As used herein, the term "RS" refers to a stereocenter that exists as a mixture of R- and S-configurations.

[0050] A compound containing one stereocenter depicted without a stereochemical bond designation is a mixture of two enantiomers. A compound containing two stereocenters depicted without a stereochemical bond designation is a mixture of four diastereomers. A compound containing two stereocenters labeled "RS" and depicted with a stereochemical bond designation is a binary mixture with the relative stereochemistry as depicted. An unlabeled stereocenter depicted without a stereochemical bond designation is a mixture of R- and S-configurations. For an unlabeled stereocenter depicted with a stereochemical bond designation, the absolute stereochemistry is as depicted.

[0051] Reference to a compound described herein refers to either (a) the actual stated form of the compound, or (b) any one of the forms of the compound in the medium in which the compound is believed to exist when named. For example, a reference to a compound such as R-COOH herein includes a reference to any one of R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R-COOH(s) refers to the solid compound, for example, as it may exist in a tablet or some other solid pharmaceutical composition or preparation, R-COOH(sol) refers to the undissociated form of the compound in the solvent, and R-COO-(sol) refers to the dissociated form of the compound in the solvent, for example, the dissociated form of the compound in an aqueous environment, regardless of whether such dissociated form is derived from R-COOH, its salt, or any other entity that generates R-COO- when believed to have dissociated in the medium. In another example, a phrase such as "exposing an entity to a compound of formula R-COOH" refers to exposing such entity to the form of the compound R-COOH present in the medium in which such exposure occurs. In yet another example, a phrase such as "reacting an entity with a compound of formula R-COOH" refers to (a) a chemically related form of such entity present in the medium in which such reaction occurs reacting with (b) a chemically related form of the compound R-COOH present in the medium in which such reaction occurs. In this context, when such an entity is present, for example, in an aqueous environment, it is understood that the entity is exposed to species such as R-COOH(aq) and / or R-COO-(aq) (the subscript "(aq)" denotes "aqueous solution" in accordance with its conventional meaning in chemistry and biochemistry), since the compound R-COOH is present in such same medium. In these nomenclature examples, a carboxylic acid functional group has been selected, but this selection is not intended to be limiting and is merely illustrative. It is understood that similar examples can be provided for other functional groups, including, but not limited to, hydroxyl, basic nitrogen members, such as nitrogen members in amines, and any other group that interacts or transforms in a known manner in a medium containing the compound.Such interactions and transformations include, but are not limited to, dissociation, association, tautomerization, solvolysis (including hydrolysis), solvation (including hydration), protonation, and deprotonation. Further examples in this regard are not provided herein, as these interactions and transformations that occur in a given medium are known to those skilled in the art.

[0052] Any formula given herein is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted in the formula given herein except that one or more atoms are replaced in enriched form with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention in excess of natural abundance include, respectively: 2 H (or chemical symbol D), 3 H (or chemical symbol T), 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Such isotopically labeled compounds are useful in metabolic studies, preferably 14 C), reaction kinetic studies (e.g., 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F or 11 C labeled compounds may be particularly preferred for PET or SPECT studies. Additionally, heavier isotopes, such as deuterium (i.e.,2 Substitution with, for example, H, or D, may confer certain therapeutic advantages as a result of greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by practicing the schemes described below or the procedures disclosed in the Examples and Preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0053] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a named variable is not intended to define the same selection of that species for that variable appearing elsewhere. In other words, when a variable appears more than once, the selection of the species from a named list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise indicated.

[0054] Term C n-m Alkyl refers to an aliphatic chain, whether straight or branched, where the total number of carbon members in the chain, N, satisfies n≦N≦m (m>n).

[0055] When the same substituents are assigned to various groups, the assignment of each specific individual substituent to each such group is meant to be made independently of the assignment of each specific individual substituent to the remaining groups. By way of example, and not by way of limitation, when each of the Q and R groups can be H or F, the selection of H or F for the Q group is made independently of the selection of H or F for the R group, and therefore the selection of the assignment for the Q group does not determine or condition the selection of the assignment for the R group, unless expressly indicated otherwise, and vice versa. In this regard, the exemplary claim language should be interpreted as "each of the Q and R groups is independently H or F" or "each of the Q and R groups is independently selected from H and F."

[0056] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both its individual enantiomers and mixtures, racemic or otherwise. Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0057] In another example, zwitterionic compounds are encompassed herein by reference to compounds known to form zwitterions, even if not explicitly named in their zwitterionic form. Terms such as zwitterion and its synonyms, zwitterionic compound, are well-known and standard names recognized by IUPAC that are part of the standard set of defined scientific names. In this context, the name zwitterion has been assigned the identifier CHEBI:27369 by the Chemical Entities of Biological Interest (ChEBI) dictionary of molecular entities. As is generally known, zwitterions or zwitterionic compounds are neutral compounds with formal unit charges of opposite signs. These compounds are sometimes referred to by the term "inner salt." While other sources refer to these compounds as "zwitterions," this latter term is a misnomer in still other sources. As a specific example, aminoethanoic acid (the amino acid glycine) has the formula HNCHCOOH and, in some media (in this case, neutral media), forms a zwitterionic form. + H3NCH2COO - Zwitterions, zwitterionic compounds, inner salts, and dipolar ions, in the known and well-established meanings of these terms, are within the scope of the present invention in all cases, as recognized by those skilled in the art. Since it is not necessary to name every embodiment that will be recognized by those skilled in the art, structures of zwitterionic compounds related to the compounds of the present invention are not explicitly shown herein. However, these are also part of the embodiments of the present invention. Because interactions and transformations in a given medium that lead to various forms of a given compound are known to those skilled in the art, further examples related thereto are not provided herein.

[0058] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a named variable is not intended to define the same selection of that species for that variable appearing elsewhere. In other words, when a variable appears more than once, the selection of the species from a named list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise indicated.

[0059] As a first example in the terminology of substituents, the substituent S 1 例 is one of S1 and S2, and the substituent S 2 例 If is one of S3 and S4, then these assignments are 1 例 is S1 and S 2 例 is S3;S 1 例 is S1 and S 2 例 is S4;S 1 例 is S2 and S 2 例 is S3;S 1 例 is S2 and S 2 例 is S4; and refers to embodiments of the invention provided according to the equivalents of each of such alternatives. Therefore, the shorter term "S 1 例 is one of S1 and S2, and S 2 例 is one of S3 and S4" is used for purposes of brevity and not as a limitation. The first example above of substituent terminology written in generic terms is meant to illustrate the various substituent assignments described herein.

[0060] Furthermore, when more than one assignment is given for any member or substituent, embodiments of the invention include the various groupings that can be made from the listed assignments and their equivalents when taken independently. As a second example in substituent terminology, the substituent S 例 When is described herein as being one of S1, S2, and S3, this list is 例 is S1;S 例 is S2;S 例 is S3;S 例 is one of S1 and S2; S 例 is one of S1 and S3; S 例 is one of S2 and S3; S 例 is one of S1, S2, and S3; and any equivalents of each of these alternatives. Therefore, the shorter term "S" is used herein. 例 is one of S1, S2, and S3" is used for purposes of brevity and not as a limitation. The second example above of substituent terminology stated in generic terms is intended to illustrate the various substituent assignments described herein.

[0061] Nomenclature “C i ~C j " (j>i)" when applied to a class of substituents herein is meant to refer to embodiments of the invention in which each and every carbon member number from i to j (inclusive) is independently realized. For example, the terms C1 to C3 or C 1~3 refers independently to embodiments having one carbon member (C1), embodiments having two carbon members (C2), and embodiments having three carbon members (C3).

[0062] "Pharmaceutically acceptable salt" is intended to mean an acid or base salt of a compound represented by Formula (I) that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with a patient's tissues without undue toxicity, irritation, or allergic response.

[0063] The compounds of formula (I) may have sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and thus may react with many inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts.

[0064] Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexyl phosphate ... Examples of suitable benzoates include benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, and mandelate.

[0065] Since the compounds of formula (I) may contain at least one nitrogen with basic character, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by cleavage with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, etc.), or an organic acid (e.g., acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyranolic acid, etc.). They can be prepared by treating the free base with any compatible mixture of acids such as sidylic acids (e.g., glucuronic acid or galacturonic acid), alpha-hydroxy acids (e.g., mandelic acid, citric acid, or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid), sulfonic acids (e.g., laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any other acid and mixture thereof that is considered equivalent.

[0066] The compound of formula (I) may contain a carboxylic acid moiety, and the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), alkali metal hydroxide, alkaline earth metal hydroxide, any compatible mixture of bases such as those provided herein as examples, and any other base and mixture thereof that is considered equivalent or acceptable substitute in light of the ordinary level of skill in the art. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, and tertiary amines, and cyclic amines such as benzylamine, pyrrolidine, piperidine, morpholine, piperazine, N-methyl-glucamine, and tromethamine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0067] The compounds of the present invention (collectively "active agents"), including the pharmaceutically acceptable salts thereof, whether alone or in combination, are useful as MGL modulators in the methods of the present invention. Such methods of modulating MGL include the use of a therapeutically effective amount of at least one chemical entity of the present invention.

[0068] In some embodiments, the MGL modulator is an inhibitor and is used in subjects diagnosed with or suffering from a disease, disorder, or condition associated with MGL receptor activity, such as those described herein. Symptoms or disease states are intended to be included within the scope of "disease, disorder, or condition."

[0069] Thus, the present invention relates to a method for treating a subject diagnosed with or suffering from a disease, disorder, or condition associated with MGL receptor activity using the active agents described herein. As used herein, the term "treat" or "treatment" is intended to refer to the administration of an active agent or composition of the present invention to a subject for the purpose of providing a therapeutic or prophylactic benefit through modulation of MGL receptor activity. Treatment includes reversing, ameliorating, alleviating, arresting the progression of, reducing the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such a disease, disorder, or condition associated with MGL modulation. The term "subject" refers to a mammalian patient, such as a human, in need of such treatment.

[0070] The term "composition" refers to a product containing therapeutically effective amounts of specified ingredients, as well as any product that results directly or indirectly from the combination of specified ingredients in specified amounts.

[0071] The term "MGL inhibitor" is intended to encompass compounds that interact with MGL and substantially reduce or eliminate the catalytic activity of MGL, thereby increasing the concentration of MGL substrates. The term "modulated by MGL" is used to refer to conditions affected by modulation of the MGL enzyme, including conditions affected by inhibition of the MGL enzyme. The present disclosure relates to methods for treating, ameliorating, and / or preventing pain-related diseases, conditions, or disorders (including inflammatory pain), as well as psychiatric disorders, neurological disorders, cancer, and ophthalmic conditions, by administering a therapeutically effective amount of an MGL modulator to a subject in need thereof.

[0072] The term "modulator" includes both inhibitors and activators, where an "inhibitor" refers to a compound that decreases, blocks, inactivates, desensitizes or downregulates the expression or activity of MGL, and an "activator" is a compound that increases, activates, promotes, sensitizes or upregulates the expression or activity of MGL.

[0073] As used herein, unless otherwise noted, the terms "affect" or "affected" (when referring to a disease, condition, or disorder affected by inhibition of MGL) include reducing the frequency and / or severity of one or more symptoms or manifestations of the disease, condition, or disorder, and / or preventing the progression of one or more symptoms or manifestations of the disease, condition, or disorder, or the progression of the disease, condition, or disorder.

[0074] In the treatment methods of the present invention, a therapeutically effective amount of at least one active agent of the present invention is administered to a subject suffering from or diagnosed with such a disease, disorder, or condition. A "therapeutically effective amount" refers to an amount or dose sufficient to generally provide the desired therapeutic or prophylactic benefit in a subject in need of such treatment for a specified disease, disorder, or condition. Effective amounts or doses of the active agents of the present invention can be determined by routine methods, such as modeling, dose escalation, or clinical trials, and taking into account routine factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease, disorder, or condition, previous or current treatments the subject has received, the subject's health status and response to the agent, and the judgment of the physician administering the treatment. For a 70 kg human, an exemplary range of suitable doses is about 1 to 1000 mg / day, in single or multiple dose units (e.g., BID, TID, QID, or as required by the modality).

[0075] Once the improvement of the target disease, disorder or condition occurs, the dosage can be adjusted for prevention or maintenance treatment.For example, dosage or administration frequency, or both, can be reduced according to the function of symptoms to the level that maintains the desired treatment or prevention effect.Of course, when the symptom is alleviated to an appropriate level, treatment can be stopped.However, if the symptom recurs, the target may need long-term intermittent treatment.

[0076] In addition, it is contemplated that the compounds of the present invention may be used alone, in combination with one or more other compounds of the present invention, or in combination with additional active ingredients in the treatment of the conditions described below. The additional active ingredients may be co-administered separately with at least one compound of the present invention and an active agent of the present invention, or such agents may be included in a pharmaceutical composition according to the present invention. In exemplary embodiments, the additional active ingredient is one known or discovered to be effective in treating a condition, disorder, or disease associated with MGL modulation, such as another MGL inhibitor or a compound active against another target associated with a particular condition, disorder, or disease. Such combinations may result in improved efficacy (e.g., by including a compound in the combination that enhances the efficacy or effectiveness of an agent according to the present invention), reduced one or more side effects, or a reduced required amount of an active agent according to the present invention.

[0077] When referring to inhibiting a target, "effective amount" means an amount sufficient to affect MGL regulation.

[0078] It is contemplated that pharmaceutical compositions of the invention may be formulated using the active agents of the invention, alone or in combination with one or more additional active ingredients, and the pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one active agent according to the invention.

[0079] Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are substances, e.g., inert substances, added to pharmacological compositions or otherwise used as vehicles, carriers, or diluents, that facilitate administration of a drug and are compatible with the drug, non-toxic, biologically acceptable, and otherwise biologically suitable for administration to a subject. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0080] A pharmaceutical composition delivery form containing one or more dosage units of an active agent can be prepared using pharmaceutically acceptable excipients and compounding techniques known or available to those skilled in the art, and the composition may be administered in the methods of the invention by a suitable delivery route, for example, oral, parenteral, rectal, topical, or ocular, or by inhalation.

[0081] The preparations may be in the form of tablets, capsules, sachets, dragees, powders, granules, lozenges, powders for reconstitution, liquid preparations, or suppositories. The compositions may be formulated for any one of several routes of administration, such as intravenous infusion, topical administration, or oral administration. Preferably, the compositions may be formulated for oral administration.

[0082] For oral administration, the active agent of the present invention may be provided in the form of a tablet or capsule, or as a solution, emulsion, or suspension. To prepare an oral composition, the active agent may be formulated to obtain a dosage for, for example, a 70 kg human, with an exemplary range of suitable dosages being about 1 to 1000 mg / day, in single or multiple dose units.

[0083] Oral tablets may contain one or more active ingredients, optionally mixed with compatible pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary oral liquid excipients include ethanol, glycerol, water, and the like. Exemplary disintegrants include starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid. Binders may include starch and gelatin. The lubricant, if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0084] Oral capsules include hard and soft gelatin or (hydroxypropyl) methylcellulose capsules. For hard gelatin capsules, one or more active ingredients may be mixed with a solid, semi-solid, or liquid diluent. Oral liquids may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and the like); non-aqueous vehicles such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid); wetting agents such as lecithin; and, if desired, flavorings or coloring agents.

[0085] The active agents of the present invention may also be administered parenterally. For example, compositions may be formulated as suppositories, enemas, or foams for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal, or subcutaneous routes, the agents of the present invention may be provided in a sterile aqueous solution or suspension, buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose forms, such as ampoules or disposable injection devices; in multi-dose forms, such as vials from which the appropriate dose can be dispensed; or in solid or pre-concentrated forms that can be used to prepare injectable formulations. Exemplary infusion dosages are those in which the agent, mixed with a pharmaceutical carrier, is infused at a rate of about 1 to 1,000 μg / kg / min over a period ranging from several minutes to several days.

[0086] For topical administration, the drug may be mixed with a pharmaceutical carrier at a concentration of about 0.01% to about 20%, preferably 0.1% to 10%, of drug relative to vehicle. Another mode of administering the drugs of the present invention may utilize a patch formulation for transdermal delivery.

[0087] In the methods of the present invention, the active agent may alternatively be administered by inhalation, nasal or oral routes, such as in a spray formulation (also containing a suitable carrier).

[0088] In a further embodiment, the present invention relates to a method for treating a subject suffering from or diagnosed with a disease, disorder, or condition associated with MGL modulation, comprising administering to a subject in need of such treatment a therapeutically effective amount of an active agent.

[0089] The compounds of formula (I) are useful for the treatment, amelioration, and / or prevention of diseases, conditions, or disorders affected by the inhibition of MGL. Such methods comprise administering to a subject, including animals, mammals, and humans, in need of such treatment, amelioration, and / or prevention, a therapeutically effective amount of a compound of formula (I), or an enantiomer, diastereomer, solvate, or pharmaceutically acceptable salt thereof.

[0090] In particular, the compounds of formula (I), or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, are useful for treating, ameliorating, and / or preventing pain, psychiatric disorders, neurological disorders, cancer, and ophthalmic conditions. More specifically, the compounds of formula (I), or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, are useful for treating, ameliorating, and / or preventing inflammatory pain, major depressive disorder, treatment-resistant depression, anxiety-related depression, or bipolar disorder by administering a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, to a subject in need thereof.

[0091] 1) Pain; Examples of inflammatory pain include, but are not limited to, pain due to a disease, condition, disorder, or painful state including inflammatory bowel disease, visceral pain, migraine, post-operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor pains, musculoskeletal disorders, skin disorders, toothache, fever, burns, sunburn, snake bites, venomous snake bites, spider bites, insect stings, irritable bladder, interstitial cystitis, urinary tract infections, rhinitis, contact dermatitis / hypersensitivity, pruritus, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, post-mastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.

[0092] Inflammatory hyperalgesia / hypersensitivity is a type of inflammatory pain. Examples of inflammatory hyperalgesia include diseases, conditions, disorders, or painful conditions such as inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal disorders, skin disorders, post-operative pain, headache, toothache, burns, sunburn, insect bites, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infections, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis / hypersensitivity and / or skin allergies, pruritus, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, benign prostatic hyperplasia, and nasal hypersensitivity.

[0093] In one embodiment, the present invention relates to a method for treating, ameliorating, and / or preventing inflammatory visceral hyperalgesia in which enhanced visceral irritability is present, comprising, consisting of, and / or consisting essentially of administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. In a further embodiment, the present invention relates to a method for treating inflammatory somatic hyperalgesia in which hypersensitivity to thermal, mechanical, and / or chemical stimuli is present, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0094] Further embodiments of the present invention relate to methods for treating, ameliorating and / or preventing neuropathic pain, examples of which include cancer, neuropathy, spinal and peripheral nerve surgery, brain tumors, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndromes, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatica, mandibular joint neuralgia, peripheral neuritis, polyneuropathy, stump pain, phantom limb pain, fractures, oral neuropathic pain, Charcot pain, complex pain, and the like. The pain may be caused by diseases, conditions, disorders, or painful states including chronic regional pain syndrome I and II (CRPSI / II), radiculopathy, Guillain-Barré syndrome, dysaesthetic femoral neuralgia, burning mouth syndrome, optic neuritis, post-febrile neuritis, migratory neuritis, segmental neuritis, Gombort neuritis, neuronal injury, cervicobachial neuralgia, cranial neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, cluster headache, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, post-herpetic neuralgia, burning mouth syndrome, erythropoietin neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, vidian neuralgia, or chemotherapy-induced neuropathy.

[0095] Neuropathic cold allodynia is a type of neuropathic pain, which can be characterized by the presence of a neuropathy-related allodynic state in which hypersensitivity to cold stimuli is present. Examples of neuropathic cold allodynia include allodynia due to diseases, conditions, disorders, or pain states, including neuropathic pain (neuralgia), pain caused by spinal cord and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, post-herpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuropathy, complex regional pain syndrome I and II (CRPSI / II), and radiculopathy.

[0096] In a further embodiment, the present invention relates to a method for treating, ameliorating, and / or preventing neuropathic cold allodynia in which hypersensitivity to cold stimuli is present, 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.

[0097] 2) Mental disorders 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 disorder, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder; depression such as major depression, bipolar disorder, seasonal affective disorder, postpartum depression, manic depression, and bipolar depression, which can be treated according to the present invention; mood disorders and mood-affective disorders such as bipolar disorder type I depression, hypomania, mania, and mixed forms; bipolar disorder type II; depressive disorders such as single depressive episode or recurrent major depressive disorder, minor depressive disorder, treatment-resistant depression, anxious depression, bipolar disorder, depressive disorder with postpartum onset, depressive disorder with psychotic symptoms; persistent mood disorders such as cyclothymia, dysthymia, manic-depressive remission; premenstrual dysphoric disorder; psychosis; and developmental disorders such as autism spectrum disorder and Aspergillus syndrome.

[0098] 3) Neurological disorders Examples of neurological disorders include, but are not limited to, tremors, dyskinesia, dystonia, spasticity, Tourette's syndrome; neurofasciitis, Parkinson's disease, Alzheimer's disease, senile dementia; Huntington's disease; epilepsy / seizure disorders, and sleep disorders.

[0099] 4) Cancer: Examples of cancer include, but are not limited to, benign skin tumors, prostate tumors, ovarian tumors, brain tumors (glioblastoma, medulloepithelioma, medulloblastoma, neuroblastoma, embryonal tumor, astrocytoma, astroblastoma, ependymoma, oligodendroglioma, neuroepithelioma, epiphyseal adenoma, ependymoblastoma, malignant meningioma, sarcoma, malignant melanoma, schwannoma).

[0100] 5) Eye condition Examples of ocular conditions include, but are not limited to, ocular hypertension, glaucoma, degeneration and apoptosis of retinal ganglion cells and neuroretinal cells.

[0101] Another embodiment of the present invention provides a method for modulating MGL receptor activity, including when such receptor is present in a subject, comprising exposing the MGL receptor to a therapeutically effective amount of at least one compound selected from the compounds of the present invention.

[0102] In some embodiments of Formula (I), X is CH. In some embodiments, X is O.

[0103] In some embodiments, R 2a and R 2b are each H. In some embodiments, R 2a and R 2b are each CH3. In some embodiments, R 2a is H and R 2b is CH3.

[0104] In some embodiments, R 3 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R 3 teeth,

[0105] [ka] In some embodiments, R 3 is phenyl or phenyl substituted with one or two members each independently selected from Cl, F, CH, CH(CH), C(CH), CF, OCH, OCHCH, OCF, cyclopropyl, cyclopropyl substituted with CF, and cyclobutyl. 3 teeth,

[0106] [ka] is.

[0107] In some embodiments, R 3 teeth,

[0108] [ka] is.

[0109] In some embodiments, R 3 teeth,

[0110] [ka] In some embodiments, R 3 is 4-trifluoromethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-cyclopropylphenyl.

[0111] In some embodiments, R 3 is phenyl; or Cl, F, C 1~6 Alkyl, C 1~6 Haloalkyl, C(CH3)2OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, SCH3, Si(CH3)3, SF5, N(CH3)2, C 3~6 Cycloalkyl, C substituted with CH 3~6 Cycloalkyl, OC 3~6 phenyl substituted with 1, 2, or 3 members each independently selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl.

[0112] In some embodiments, R 3 Ha, Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 Alkyl, OC 1~6haloalkyl, SCH3, SF5, or phenyl substituted with 1, 2, or 3 members each independently selected from Si(CH3)3.

[0113] In some embodiments, R 3 teeth,

[0114] [ka] is.

[0115] In some embodiments, R 3 is 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-(1-methylcyclopropyl)phenyl.

[0116] In some embodiments, R 3 is benzyl; tert-butyl; cyclohexyl; phenyl substituted with 1-methylcyclopropyl or 1-trifluoromethylcyclopropyl or fused to a cyclobutenyl or cyclohexenyl ring; pyridyl optionally substituted with trifluoromethyl, fluoro, or methyl; pyrimidinyl optionally substituted with tert-butyl; or oxazolyl optionally substituted with tert-butyl. In some embodiments, R 3 is a bicyclic heteroaryl optionally substituted as described herein. In some embodiments, R 3 is phenyl optionally substituted as described herein.

[0117] In some embodiments, n and o are each 1. In some embodiments, n and o are each 2. In some embodiments, n is 1 and o is 2. In some embodiments, m and p are each 1. In some embodiments, m and p are each 2. In some embodiments, m is 1 and p is 2. In some embodiments, m, n, o, and p are each 1. In some embodiments, m, n, and p are each 1 and o is 2. In some embodiments, m, n, and o are each 1 and p is 2. In some embodiments, n and o are each 2 and m and p are each 1. In some embodiments, n and o are each 1 and m and p are each 2. In some embodiments, n, o, and p are each 2 and m is 1.

[0118] Further embodiments of the present invention include compounds as shown in Table 1 below.

[0119] [Table 1-1]

[0120] [Table 1-2]

[0121] [Table 1-3] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0122] A further embodiment of the present invention comprises: (2r,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-((R *)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4R * )-2-((S * )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0123] A further embodiment of the present invention is a compound of formula (IA):

[0124] [ka] [In the formula, X is CH or O; R 2a and R 2b are each independently selected from H and CH; R 3 is C 3~6 Cycloalkyl; C 1~4 Alkyl-substituted C 3~6 Cycloalkyl;phenyl;C 1~6 Alkyl, C 1~6 Haloalkyl, and C 3~6 phenyl substituted with one or two members each independently selected from cycloalkyl; and

[0125] [ka] is selected from m and p are each independently 1 or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0126] A further embodiment of the present invention is a compound of formula (IB):

[0127] [ka] [In the formula, X is O, R 3 is phenyl, and C 1~6 phenyl substituted with alkyl; m and p are each 1; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0128] A further embodiment of the present invention is a compound of formula (IC):

[0129] [ka] [In the formula, X is CH or O; R 2a and R 2b are each independently selected from H and CH; R 3 is C 3~6 Cycloalkyl; Phenyl; Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, OC 1~6 Alkyl, OC 1~6 Haloalkyl and C optionally substituted with CH3 or CF3 3~6 phenyl substituted with one or two members independently selected from cycloalkyl; halo, C 1~6 Alkyl, and C 1~6 pyridyl substituted with one or two members independently selected from haloalkyl; C 1~6 Alkyl-substituted pyrimidyl;

[0130] [ka] is selected from m and p are each independently 1 or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0131] A further embodiment of the present invention comprises: (A) a therapeutically effective amount of at least one compound selected from the group consisting of a compound of formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of compounds of formula (I), and (B) A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

[0132] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the compounds of Table 1, including pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers of the compounds of Table 1, pharmaceutically acceptable prodrugs of the compounds of Table 1, and pharmaceutically active metabolites of Table 1, and at least one pharmaceutically acceptable excipient.

[0133] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the compounds of formula (IA), as well as pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (IA), pharmaceutically acceptable prodrugs of compounds of formula (IA), and pharmaceutically active metabolites of compounds of formula (IA), and at least one pharmaceutically acceptable excipient.

[0134] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from compounds of formula (IB), as well as pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (IB), pharmaceutically acceptable prodrugs of compounds of formula (IB), and pharmaceutically active metabolites of formula (IB), and at least one pharmaceutically acceptable excipient.

[0135] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the compounds of formula (IC), as well as pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (IC), pharmaceutically acceptable prodrugs of compounds of formula (IC), and pharmaceutically active metabolites of compounds of formula (IC), and at least one pharmaceutically acceptable excipient.

[0136] Also within the scope of the present invention are enantiomers and diastereomers of compounds of formula (I) (and formulas (IA), (IB), and (IC)). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (I) (and formulas (IA), (IB), and (IC)). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of compounds of formula (I) (and formulas (IA), (IB), and (IC)), and pharmaceutically active metabolites of compounds of formula (I) (and formulas (IA), (IB), and (IC)).

[0137] Also within the scope of the present invention are isotopic variations of the compounds of formula (I) (and formulas (IA), (IB), and (IC)), such as deuterated compounds of formula (I). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of isotopic variations of the compounds of formula (I) (and formulas (IA), (IB), and (IC)). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of isotopic variations of the compounds of formula (I) (and formulas (IA), (IB), and (IC)), and pharmaceutically active metabolites of isotopic variations of the compounds of formula (I) (and formulas (IA), (IB), and (IC)).

[0138] A further embodiment of the present invention is a method of treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound selected from the compounds of formula (I) (and formulas (IA), (IB), and (IC)), pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, including enantiomers and diastereomers of the compounds of formula (I) (and formulas (IA), (IB), and (IC)), isotopic variants of the compounds of formula (I) (and formulas (IA), (IB), and (IC)), and pharmaceutically acceptable salts of all of the above. Also described herein is the use of a compound of formula (I), (IA), (IB), or (IC), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, in the preparation of a medicament. In some embodiments, the medicament is for the treatment of a disease, disorder, or condition mediated by MGL receptor activity. Also described herein are compounds of formula (I), (IA), (IB), or (IC), or pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers thereof, for use in methods for treating a disease, disorder, or condition mediated by MGL receptor activity.

[0139] Exemplary compounds useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation, followed by specific examples. To obtain the various compounds herein, those skilled in the art will understand that starting materials can be suitably selected so that the ultimately desired substituents are retained throughout the reaction scheme, with or without appropriate protection, to yield the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that is retained throughout the reaction scheme and can be appropriately substituted with the desired substituent. Unless otherwise specified, variables are as defined above with reference to Formula (I). The reaction can be carried out between the melting point and the reflux temperature of the solvent, preferably between 0° C. and the reflux temperature of the solvent. The reaction can be carried out under heating using conventional or microwave heating. The reaction can also be carried out in a sealed pressure vessel at a temperature higher than the normal reflux temperature of the solvent.

[0140] Abbreviations and acronyms used herein are as follows:

[0141] [Table 2-1]

[0142] [Table 2-2]

[0143] Preparation example Exemplary compounds useful in the methods of the present invention will now be described by reference to the following exemplary synthetic schemes for their general preparation and the following specific examples.

[0144] [ka]

[0145] According to Scheme 1, R a C 1~4The compound of formula (V), which is alkyl, is treated with hydroxylamine in a suitable solvent such as ethanol (EtOH) using an additive such as sodium acetate (NaOAc) to give the compound of formula (VI).

[0146] Compounds of formula (VII) are prepared from compounds of formula (VI) using an oxidizing agent such as hydrogen peroxide, urea hydrogen peroxide, in the presence of a base, such as disodium hydrogen phosphate, in the presence of an activating agent such as trifluoroacetic anhydride (TFAA) in a solvent such as acetonitrile (ACN).

[0147] [ka]

[0148] According to Scheme 2, compounds of formula (VIIIa) and (VIIIb) can be prepared by reacting R a C 1~4 The compound of formula (VII) is prepared by reacting the alkyl group with formaldehyde. The compound of formula (IX) is prepared by hydrogenolysis of the compound of formula (VIIIb) in a solvent such as ethyl acetate (EtOAc), EtOH, or the like, in the presence of a catalyst such as palladium on carbon (Pd / C) under an atmosphere of hydrogen gas (H).

[0149] Compounds of formula (X) are prepared by reaction of compounds of formula (IX) with triphosgene in the presence of a base such as TEA in a solvent such as tetrahydrofuran (THF). Compounds of formula (XI) are prepared by acidic deprotection of compounds of formula (X) using an acid such as trifluoroacetic acid (TFA), HCl in dioxane.

[0150] [ka]

[0151] According to Scheme 3, compounds of formula (XIIa) and formula (XIIb) can be prepared by reacting R a The compound of formula (XIIa) is prepared by a Michael-type reaction between a compound of formula (VII), where X is ethyl, and methyl acrylate. The compound of formula (XIIa) is reductively ring-closed using a reducing agent, such as sodium borohydride (NaBH), and an additive, such as nickel(II) chloride hexahydrate, in a suitable solvent, such as methanol (MeOH), to give a compound of formula (XIII), where X is CH.

[0152] [ka]

[0153] According to Scheme 4, compounds of formula (XIV) can be prepared by reacting R with acetaldehyde in the presence of a base such as TEA in a solvent such as ACN at temperatures ranging from 0° C. to room temperature for 18 hours. a C 1~4 The compound of formula (XIV) is prepared by reacting a compound of formula (VII) with a compound of formula (VII) where the compound is an alkyl group. The compound of formula (XIV) is hydrogenolyzed using the conditions described above to give compounds of formula (XVa) and (XVb).

[0154] [ka]

[0155] According to Scheme 5, R a C 1~4 Compounds of formula (XVa) where X is alkyl are subjected to ring closure conditions with triphosgene using the conditions previously described to give compounds of formula (XVI). Compounds of formula (XVI) are subjected to acidic deprotection conditions previously described to give compounds of formula (XVII) where X is O.

[0156] [ka]

[0157] According to Scheme 6, a compound of formula (XIX) is provided, wherein p and m are each independently 1 or 2, n and o are each independently 1 or 2, and R a Compounds in which tBu is tBu are commercially available or can be obtained synthetically from compounds of formula (XVIII). Compounds of formula (XVIII) can be reduced with a reducing agent such as NaBH4, LiAlH4, LiBH4, or diisobutylaluminum hydride (DIBAL-H) ​​in a suitable solvent such as tetrahydrofuran (THF), methanol (MeOH), or ethanol (EtOH) at temperatures ranging from -78°C to 0°C for 30 minutes to 16 hours to obtain compounds of formula (XIX). Compounds of formula (XX) can be synthesized from compounds of formula (XIX) using iodine (I2) and a suitable base such as imidazole and triphenylphosphine (PPh3) in a suitable solvent such as THF at temperatures ranging from 0°C to room temperature for 1 hour.

[0158] [ka]

[0159] According to Scheme 7, a compound of formula (XXI) is provided, wherein m is 1, p is 1 or 2, n and o are each independently 1 or 2, and R 3 is cycloalkyl or aryl, and R aCompounds in which is tBu can be prepared by the reaction of compounds of formula (XX) in flow or batch with a suitable commercially available or synthetically available substituted aryl halide, boronic acid, or organomagnesium halide using catalysts such as, for example, palladium(II) acetate, bis(dibenzylideneacetone)palladium, cobalt(II) bromide, cobalt(II) acetylacetonate, nickel(II) acetylacetonate, nickel(II) iodide, and dicyclohexyl(2',6'-diisopropoxy). The compound of formula (XXI) can be prepared using a ligand such as si-[1,1'-biphenyl]-2-ylphosphine (RuPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), N,N,N',N'-tetramethylethylenediamine, or (1R,2R)-2-aminocyclohexanol in the absence of a base or in the presence of a suitable base such as sodium hexamethyldisilazide (NaHMDS) in a suitable solvent such as THF at a temperature ranging from 0 to 50°C for 1 to 6 hours. Cleavage of the BOC protecting group of the compound of formula (XXI) can be carried out according to procedures well known to those skilled in the art, for example, under acidic conditions such as TFA / CHCl, HCl / dioxane, to give the compound of formula (XXII).

[0160] [ka]

[0161] According to Scheme 8, a compound of formula (XVIII) is provided, wherein n, m, o, and p are each independently 1 or 2; and R a But C 1~4 R is obtained by reacting a compound such as an alkyl or benzyl compound under conventional Grignard reaction conditions in the presence of an organomagnesium halide such as phenylmagnesium bromide, in the presence or absence of an additive such as CeCl, LaCl, or the like, in a suitable solvent such as THF or diethyl ether (EtO). 3 is aryl or C 3~6 A compound of formula (XXIII) is obtained in which the cycloalkyl group is cycloalkyl.

[0162] Compounds of formula (XXIII) are reacted with triethylsilane (TES) under acidic ion reducing conditions, such as TFA, to reduce the alcohol and cleave the tert-butoxycarbonyl group to produce compounds of formula (XXII).

[0163] In the same manner, compounds of formula (XVIII) in which R a C 1~4 Compounds in which m, n, and o are 1 and p is 2 can be reacted with an organomagnesium halide such as cyclobutylmagnesium chloride or cyclopentylmagnesium chloride in the presence of an additive such as CeCl3 under Grignard conditions as previously described to give R 3 C 3~6 Compounds of formula (XXIII) are obtained in which R is a cycloalkyl. Compounds of formula (XVIII) are obtained in which R is a cycloalkyl. a C 1~4 A compound in which m, n, o, and p are 1 is reacted with a dehydrating agent such as Burgess's reagent under elimination conditions to eliminate the alcohol and give a compound of formula (XXIV). A compound of formula (XXII), in which m, n, o, and p are 1, and R 3 But C 1~4 Alkyl-substituted C 3~6 Compounds in which R is a cycloalkyl 3 But C 1~4 Alkyl-substituted C 3~6 For example, hydrogenation of a compound of formula (XXIV) can be carried out using the conditions described, followed by deprotection of the Boc protecting group using conditions well known to those skilled in the art or described above, to form R 3 But C 1~4 Alkyl-substituted C 3~6 A compound of formula (XXII) is obtained in which the cycloalkyl is

[0164] Compounds of formula (XXIII) are reacted with triethylsilane (TES) under elimination conditions, such as TFA, to eliminate the alcohol and cleave the tert-butoxycarbonyl group to produce compounds of formula (XXIV). Compounds of formula (XXIV) are reduced using hydrogenation conditions in the presence of a palladium catalyst, including but not limited to palladium on carbon, Pd(dppf)Cl2, or Pd(PPh3)4, in a suitable solvent or solvent system, such as DMF, methanol, dioxane / water, etc., to give R 3 C 3~6 A compound of formula (XXII) is obtained in which the cycloalkyl is

[0165] A compound of formula (XVIII), wherein R a C 1~4 Compounds where m, n, o, and p are 1 can be reacted with an organomagnesium halide such as cyclobutylmagnesium bromide under Grignard conditions as previously described to give R 3 C 3~6 Alternatively, a compound of formula (XVIII) is obtained, wherein m, n, o, and p are 1 and R a C 1~4 Such a compound, which is an alkyl, is reacted in the presence of an organomagnesium halide such as prop-1-en-2-ylmagnesium bromide under conventional Grignard reaction conditions using the conditions described above. The prop-1-en-2-yl is then cyclopropanated using conditions such as diethylzinc and diiodomethane in a solvent such as DCM to give R 3 But C 1~4 Alkyl-substituted C 3~6 A compound of formula (XXIII) is obtained in which the cycloalkyl group is cycloalkyl.

[0166] R 3 C 3~6Compounds of formula (XXIII), such as cycloalkyl, can be reacted with a halogenating reagent, such as thionyl chloride (SOCl2), using a catalyst, such as 4-(dimethylamino)pyridine (DMAP), in a suitable solvent, such as pyridine, to provide compounds of formula (XXV). Compounds of formula (XXV), wherein m, n, o, and p are 1, and R 3 C 3~6 Such compounds that are cycloalkyl are prepared in two steps from compounds of formula (XXV): In the first step, hydrogenation of compounds of formula (XXV) is carried out using conditions as described above, followed by deprotection of the Boc protecting group using conditions well known to those skilled in the art or as described above.

[0167] A compound of formula (XVIII), wherein R a is benzyl, n and o are 2, and m and p are 1, can be reacted with an appropriately substituted arylorganomagnesium halide such as phenylmagnesium bromide under Grignard conditions as described above to give R 3 Compounds of formula (XXIII) are obtained in which R is phenyl. Ionic reduction followed by hydrogenation using the conditions described above gives compounds of formula (XXIII) in which R is phenyl. 3 is phenyl.

[0168] [ka]

[0169] According to Scheme 9, tert-butyl 2-bromo-7-azaspiro[3.5]nonane-7-carboxylate can be reacted under photochemical cross-coupling conditions in the presence of a commercially available or synthetically available appropriately substituted aryl or heteroaryl halide with a photocatalyst such as (Ir[dF(CF3)ppy]2(dtbpy))PF6, a cross-coupling catalyst such as nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2(DME)), a base such as 2,6-dimethylpyridine or potassium carbonate, a suitable additive such as tris(trimethylsilyl)silane or tris(trimethylsilyl)silanol, and a suitable solvent such as 1,2-dimethoxyethane (DME) or dimethyl sulfoxide (DMSO) to afford R 3 is an appropriately substituted aryl or heteroaryl as defined in claim 1. Compounds of formula (XXVI) are subjected to Boc deprotection using conditions as described above to provide compounds of formula (XXII) where n and o are 2 and m and p are 1.

[0170] [ka]

[0171] According to Scheme 10, R b C 3~6 Compounds of formula (XXVII) that are cycloalkyl are either commercially available or can be obtained by a two-step synthesis from 1,3-dibromobenzene. For example, reaction of 1,3-dibromobenzene with a suitable lithiation reagent, such as n-butyllithium (n-BuLi), in a suitable solvent, such as THF, at temperatures ranging from −78° C. to −70° C., followed by treatment with a ketone, such as cyclobutanone, provides 1-(3-bromophenyl)cyclobutan-1-ol. Ionic reduction of 1-(3-bromophenyl)cyclobutan-1-ol using the conditions described above then provides R b C 3~6 A compound of formula (XXVII) is obtained in which the cycloalkyl is

[0172] [ka]

[0173] According to Scheme 11, a compound of formula (XXI) is provided, wherein m, n, and p are 1, o is 2, and R 3 is phenyl and R a C 1~4 Compounds with alkyl groups can be synthesized from compounds of formula (XVIII) using 4-methylbenzenesulfonhydrazide in a suitable solvent such as 1,4-dioxane at about 80°C for 2-5 hours, followed by reaction with phenylboronic acid in the presence of a suitable base such as potassium carbonate at about 110°C for 5-16 hours. Cleavage of the BOC protecting group of compounds of formula (XXI) using the methods described above provides compounds of formula (XXII).

[0174] [ka]

[0175] According to Scheme 12, a compound of formula (I) wherein R 1 is H, X is CH2 or O, and R 2a and R 2b are each independently H or C 1~4 The compound where R is alkyl 3is cycloalkyl, aryl, heteroaryl from a compound of formula (XXII) by conventional amide bond formation techniques such as coupling reactions well known to those skilled in the art (e.g., HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide-hexafluorophosphate), BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate), or conversion of an acid to an acid chloride). For example, a compound of formula (XXII), in which m, n, o, and p are each independently 1 or 2, may be reacted with a synthetically available appropriately substituted carboxylic acid of formula (XXVII), including compounds of formulas (XI), (XIII), and (XVIII), where the acid is optionally activated with a suitable activating reagent, for example, a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC, or EDCI); (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; The coupling agent may be activated with a halotrisaminophosphonium salt such as bromotripyrrolidinophosphonium hexafluorophosphate (BOP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®); a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride, or other suitable coupling agent such as N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®).The coupling reaction is carried out in a suitable solvent such as DCM, THF, DMF, optionally in the presence of a tertiary amine such as N-methylmorpholine, N-ethyldiisopropylamine (DIPEA), or triethylamine (TEA) at a temperature ranging from about 0° C. to room temperature to provide a compound of formula (I).

[0176] The compound of formula (I) may be converted into its corresponding salt using methods known to those skilled in the art. For example, the amine of formula (I) may be treated with trifluoroacetic acid, HCl, or citric acid in a solvent such as EtO, CHCl, THF, MeOH, chloroform, or isopropanol to obtain the corresponding salt form. Alternatively, reverse-phase HPLC purification conditions may result in the trifluoroacetate salt or formate salt. The crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) may be obtained in crystalline form by recrystallization from a polar solvent (including a mixture of polar solvents and an aqueous mixture of polar solvents) or a nonpolar solvent (including a mixture of nonpolar solvents).

[0177] When the compounds according to the present invention have at least one chiral center, they may consequently exist as enantiomers. When the compounds have two or more chiral centers, they may additionally exist as diastereomers. It is understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0178] The compounds prepared according to the above schemes can be obtained in a single form, such as a single enantiomer, by form-specific synthesis or by resolution. Alternatively, the compounds prepared according to the above schemes can be obtained as a mixture of various forms, such as a racemic (1:1) mixture or a non-racemic (non-1:1) mixture. When racemic and non-racemic mixtures of enantiomers are obtained, single enantiomers can be isolated using conventional isolation methods known to those skilled in the art, such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization to diastereomeric adducts, biotransformation, or enzymatic conversion. When regioisomeric or diastereomeric mixtures are obtained, single isomers can be separated, as appropriate, using conventional methods, such as chromatography or crystallization.

[0179] The following specific examples are provided to further illustrate the invention and various preferred embodiments. [Example]

[0180] In obtaining the compounds described in the Examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0181] Unless otherwise noted, reaction mixtures were magnetically stirred under a nitrogen atmosphere at room temperature (rt). Solutions were generally dried over a drying agent such as NaSO or MgSO. Mixtures, solutions, and extracts were typically concentrated under reduced pressure on a rotary evaporator. Reactions under microwave irradiation conditions were performed in a Biotage Initiator or CEM (Microwave Reactor) Discover instrument.

[0182] For reactions conducted under continuous flow conditions, "flowing through an LTF-VS mixer" refers to the use of a Chemyx Fusion 100 touch syringe pump in series with an LTF-VS mixer (Little Things Factory GmbH (http: / / www.ltf-gmbh.com) via 1 / 16 inch PTFE tubing, unless otherwise specified.

[0183] Normal-phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using prepacked cartridges.

[0184] Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed by one of the following methods. Method A. Agilent HPLC was run on an Xterra Prep RP18 column (5 μM, 30 × 100 or 50 × 150 mm) or an XBridge C18 OBD column (5 μM, 30 × 100 or 50 × 150 mm) at a flow rate of 40 or 80 mL / min using a mobile phase of 5% ACN in 20 mM NH4OH with a 2-minute hold, followed by a 5-99% ACN gradient over 15 minutes, followed by a 5-minute hold at 99% ACN. or Method B. Performed on a Shimadzu LC-8A series HPLC using an Inertsil ODS-3 column (3 μm, 30 × 100 mm, T = 45 °C) at a flow rate of 80 mL / min with a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) held for 1 min, followed by a 5-99% ACN gradient over 6 min, followed by a 3 min hold at 99% ACN. or Method C. Shimadzu LC-8A series HPLC was used with an XBridge C18 OBD column (5 μm, 50 × 100 mm) at a flow rate of 80 mL / min. The mobile phase was 5% ACN in H2O (both containing 0.05% TFA) with a 1-min hold, followed by a 5-99% ACN gradient over 14 min, followed by a 10-min hold at 99% ACN. or Method D. The analysis was performed on a Gilson HPLC using an XBridge C18 column (5 μm, 100 × 50 mm) at a flow rate of 80 mL / min, with a mobile phase change from 5 to 99% ACN in 20 mM NH4OH over 10 min, followed by a 2 min hold at 99% ACN. or Method E. An ACCQ Prep HPLC equipped with an XBridge C18OBD column (5 μM, 50 × 100) was used at a flow rate of 80 mL / min with a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) held for 1 min, followed by a gradient of 5–95% ACN over 12 min, followed by a 2 min hold at 95% ACN.

[0185] Preparative supercritical fluid high-performance liquid chromatography (SFC) was performed on either a Jasco preparative SFC system, a Berger Instruments APS 1010 system, or an SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Separations were performed at 100–150 bar with flow rates ranging from 40–60 mL / min. The column was heated to 35–40 °C.

[0186] Mass spectra (MS) were obtained on an Agilent Series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated (calcd.) masses correspond to exact masses.

[0187] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker DRX spectrometer. Multiplicity definitions are as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, hept = heptet, dd = double doublet, dt = double triplet, pd = quintuple doublet, ddd = double doublet. tp = triple pentet (triplet of a doublet of a doublet), td = triple doublet (triplet of a doublet), qd = quadruple doublet (quartet of a doublet), dq = double quartet (doublet of a quartet), tt = triple triplet (triplet of triplets), td = triple doublet (triplet of doublets), m = multiplet, br = broad. It will be understood that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectrum and the concentration of the compound in solution.

[0188] Compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0189] R * or S * Compounds designated as are enantiomerically pure compounds for which the absolute configuration has not been determined.

[0190] Intermediate 1: tert-butyl 3-nitrocyclobutanecarboxylate.

[0191] [ka]

[0192] Step A: tert-Butyl 3-hydroxyiminocyclobutanecarboxylate. To a solution of tert-butyl 3-oxocyclobutane-1-carboxylate (100 g, 588 mmol) in ethanol (EtOH) (1.8 L) was added sodium acetate (NaOAc) (192 g, 2340 mmol) and hydroxylamine hydrochloride (81 g, 1166 mmol). The reaction mixture was stirred at reflux for 4 hours and then filtered through a pad of Celite®, which was washed with EtOH. The combined filtrate was evaporated, and the residue was dissolved in ethyl acetate (EtOAc) and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give the title compound (108 g, 584 mmol, 99% yield) as a white solid. MS (ESI): CH 15 Calculated mass of NO3: 185.1; measured m / z: 186.2 [M+H] + .

[0193] Step B: tert-Butyl 3-nitrocyclobutanecarboxylate. To a suspension of urea hydrogen peroxide (164 g, 1.74 mol) in acetonitrile (MeCN) (1 L) was added a solution of trifluoroacetic anhydride (TFAA) (245 mL, 1.75 mol) in MeCN (500 mL) dropwise at −10° C. over 1 h. The reaction mixture was stirred at room temperature for 1 h. This solution was added dropwise to a solution of tert-butyl 3-hydroxyiminocyclobutanecarboxylate (108 g, 0.58 mol) and disodium hydrogen phosphate (911 g, 6.42 mol) in MeCN (1 L) over 30 min at 80° C. The reaction mixture was stirred at 80° C. for 30 min, then filtered through a pad of Celite®, and the pad was washed with MeCN. The combined filtrate was diluted with EtOAc. The mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by flash column chromatography (FCC) on silica (0-20% EtOAc in heptane) to give the title compound (89.6 g, 445 mmol, 76% yield) as a yellow oil as a 1.3:1 mixture of cis / trans isomers. + Does not ionize by LCMS.

[0194] Intermediate 2: Ethyl 3-nitrocyclobutanecarboxylate.

[0195] [ka]

[0196] The title compound was prepared in a similar manner to Intermediate 1, using ethyl 3-oxocyclobutane-1-carboxylate instead of tert-butyl 3-oxocyclobutane-1-carboxylate. + Does not ionize by LCMS. 1 H NMR (300 MHz, chloroform-d) δ 5.02-4.70 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.04-2.71 (m, 5H), 1.29 (t, J = 7.0 Hz, 3H).

[0197] Intermediate 3: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0198] [ka]

[0199] Step A: tert-Butyl (1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate. To a solution of tert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 2, 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 reaction was stirred at room temperature for 2 h. The reaction mixture was evaporated, and the residue was purified by FCC on silica (0-25% EtOAc in heptane) to give the title compound (38.2 g, 165 mmol, 37% yield) as a white powder. MS (ESI): C 10 H 17Calculated mass of NO5: 231.2; measured m / z: 254.1 [M+Na] + trans-tert-butyl 3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate was formed but not isolated.

[0200] Step B: tert-Butyl (1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate. To a solution of tert-butyl (1s,3s)-3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate (38.2 g, 165 mmol) in 600 mL of EtOAc was added 1.9 g of 10% palladium on carbon (Pd / C). The reaction mixture was stirred under 10 bar of hydrogen (H) at 50° C. for 1 hour. The reaction mixture was filtered through a pad of Celite®. To the filtrate was added 1.9 g of 10% Pd / C. The reaction mixture was stirred under 10 bar of H at 50° C. for 2 hours. The reaction mixture was filtered through a pad of Celite®, and the Celite® was washed with EtOAc. The combined filtrates were evaporated and the residue was triturated with diethyl ether (EtO) to give the title compound (18.6 g, 92.4 mmol, 55% yield) as a white powder. MS (ESI): C 10 H 19 Calculated mass of NO3: 201.1; measured m / z: 202.2 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 5.26-3.98(m,1H),3.74-2.94(m,4H),2.70-2.57(m,1H),2.20-2.07(m,2H),1.97-1.82(m,2H),1.39(s,9H).

[0201] Step C: tert-Butyl (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solution of tert-butyl (1s,3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate (18.6 g, 92.4 mmol) in tetrahydrofuran (THF) (300 mL) was added TEA (26 mL, 186 mmol). To the mixture was added a solution of triphosgene (9.6 g, 32.4 mmol) in THF (200 mL) dropwise at −10° C. and stirred at room temperature for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate (600 mL), and the mixture was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was triturated with EtO to give the title compound (17.7 g, 77.9 mmol, 84% yield) as a white powder. MS(ESI):C 11 H 17 Calculated mass of NO4: 227.1; measured m / z: 228.2 [M+H] + .

[0202] Step D: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. To trifluoroacetic acid (TFA) (180 mL, 235 mmol) was added tert-butyl (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (17.7 g, 77.9 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated, and the residue was triturated with EtO to give the title compound (12.9 g, 75.4 mmol, 96% yield) as a white powder. MS (ESI): calculated mass for C7H9NO3 171.0; m / z found 172.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ 12.26 (br s, 1H), 8.08 (s, 1H), 4.34 (s, 2H), 2.79-2.66 (m, 1H), 2.43-2.29 (m, 4H).

[0203] Intermediate 4: (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid

[0204] [ka]

[0205] Step A: Ethyl (1r,3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate. To a solution of ethyl 3-nitrocyclobutanecarboxylate (Intermediate 2, 16.6 g, 95.6 mmol) in MeCN (145 mL) was added methyl acrylate (10.3 mL, 114 mmol). 1,8-Diazabicyclo[5.4.0]undec-7-ene (7.1 mL, 47.6 mmol) was added dropwise to the reaction mixture at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with saturated ammonium chloride and EtOAc, and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by FCC on silica (0-15% EtOAc in heptane) to give the title compound (13.6 g, 52.6 mmol, 55% yield) as a colorless liquid. MS (ESI): C 11 H 17 Calculated mass of NO6: 259.1; measured m / z: 282.1 [M+Na] + . 1 H NMR (300 MHz, chloroform-d) δ 4.17 (q, J = 7.1 Hz, 2H), 3.70 (s, 3H), 3.12-2.79 (m, 3H), 2.69-2.49 (m, 2H), 2.48-2.21 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H).

[0206] 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, 52.6 mmol) in methanol (MeOH) (133 mL) was added nickel(II) chloride hexahydrate (12.5 g, 52.6 mmol). Sodium borohydride (NaBH) (10 g, 264 mmol) was added portionwise to the reaction mixture at -10 °C, and the reaction mixture was stirred at 0 °C for 1 hour. Aqueous potassium carbonate solution (47 mL, 141 mmol, 3 M) was added dropwise to the reaction mixture at 0 °C (pH 10), and the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was filtered through a pad of Celite®, and the pad was washed with EtOH. The combined filtrates were evaporated. The residue was purified by silica FCC eluting with chloroform:methanol:acetic acid (100:0:0 to 9:1:1) to give the title compound (4.8 g, 28.2 mmol, 53% yield) as an off-white powder. MS (ESI): CH 11 Calculated mass of NO3: 169.1; measured m / z: 170.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ 7.97 (br s, 1H), 4.01-2.94 (m, 1H), 2.82-2.65 (m, 1H), 2.36-2.01 (m, 8H).

[0207] Intermediate 5: (2s,4s)-8-Methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0208] [ka]

[0209] 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 MeCN (120 mL) was added acetaldehyde (19.6 mL, 349 mmol). To the reaction mixture was added TEA (8.1 mL, 58 mmol) dropwise at 0° C., and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the residue was purified by FCC on silica (0-20% EtOAc in heptane) to give the title compound (10.5 g, 42.8 mmol) as a colorless oil. MS (ESI): C 11 H 19 Calculated mass of NO5: 245.1; observed M / z: 263.2 [M+H+NH3] + .

[0210] Step B: tert-Butyl (1s,3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate. To a solution of tert-butyl 3-(1-hydroxyethyl)-3-nitro-cyclobutanecarboxylate (10.5 g, 42.8 mmol) in 110 mL of EtOAc was added 1 g of 10% Pd / C. The reaction mixture was stirred at 50° C. under 10 bar of H 2 for 1 h. The reaction mixture was filtered through a pad of Celite®. To the filtrate was added 500 mg of 10% Pd / C, and the reaction mixture was stirred at 50° C. under 10 bar of H 2 for 2 h. The reaction mixture was filtered through a pad of Celite®, and the pad was washed with EtOAc. The combined filtrates were evaporated and the residue was purified by FCC on silica eluting with chloroform:methanol:ammonium hydroxide (1:0:0 to 9:1:0.05) to give the title compound (3.6 g, 16.7 mmol, 39% yield) as a yellow oil. MS (ESI): C 11 H 21 Calculated mass of NO3: 215.2; measured m / z: 216.3 [M+H] + . 1H NMR (300 MHz, chloroform-d) δ 3.83-3.64 (m, 1H), 2.80-2.61 (m, 1H), 2.54 (br s, 2H), 2.52-2.27 (m, 3H), 2.14-1.93 (m, 2H), 1.45 (s, 9H), 1.22-1.13 (m, 3H). Additional fractions from the same purification were collected to give tert-butyl (1r,3r)-3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate (550 mg, crude) as a yellow oil.

[0211] Step C: tert-Butyl (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solution of tert-butyl (1s,3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate (15.2 g, 70.4 mmol) in THF (240 mL) was added TEA (20 mL, 143 mmol). To the mixture was added a solution of triphosgene (7.3 g, 24.6 mmol) in THF (170 mL) dropwise at -10 °C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate and extracted with EtOAc. The combined organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by FCC on silica (0-35% EtOAc in heptane) to give the title compound (6.1 g, 25.3 mmol, 35% yield) as a white powder. MS (ESI): 12 H 19 Calculated mass of NO4: 241.1; measured m / z: 242.2 [M+H] + .

[0212] Step D: (2s,4s)-8-Methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. tert-Butyl (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (6.1 g, 25.3 mmol) was added portionwise to TFA (60 mL, 784 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated, and the residue was triturated with EtO to give the title compound (4.3 g, 23.2 mmol, 91% yield) as a white powder. MS (ESI): CH 11 Calculated mass of NO4: 185.1; measured m / z: 186.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ 12.23(br s,1H),7.94(s,1H),4.50(q,J=6.4Hz,1H),2.68-2.59(m,1H),2.53-2.46(m,1H),2.41 -2.35(m,1H),2.32-2.24(m,1H),2.17(dd,J=12.0,10.1Hz,1H),1.30(d,J=6.5Hz,3H).

[0213] Intermediate 6: Benzyl 2-hydroxy-2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate.

[0214] [ka]

[0215] Benzyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (200 mg, 0.73 mmol) was dissolved in diethyl ether and cooled to -78 °C. Phenylmagnesium bromide (1 M in EtO, 0.95 mL, 0.95 mmol) was added dropwise with stirring. The reaction mixture was stirred at -78 °C for 4 h, quenched with saturated aqueous NH4Cl, and partitioned between water and dichloromethane. The aqueous layer was extracted twice with DCM, and the combined organic layers were concentrated and purified on silica gel (0-100% ethyl acetate / hexanes) to give 131 mg (51% yield) of the desired product. MS (ESI): C 22 H25 Calculated mass of NO3: 351.2; measured m / z: 352.0 [M+H] + .

[0216] Intermediate 7: Benzyl 2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate.

[0217] [ka]

[0218] Benzyl 2-hydroxy-2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 6, 131 mg, 0.37 mmol) and triethylsilane (0.60 mL, 3.7 mmol) were dissolved in dry DCM, and TFA (0.29 mL, 3.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h, concentrated, and purified on silica gel to give 101 mg (81% yield) of the desired product. MS (ESI): C 22 H 25 Calculated mass of NO2: 335.2; measured m / z: 336 [M+H] + .

[0219] Intermediate 8: 2-phenyl-7-azaspiro[3.5]nonane.

[0220] [ka]

[0221] Benzyl 2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 7, 101 mg, 0.30 mmol) was dissolved in 10 mL of ethyl acetate, and 10% palladium on carbon (100 mg) was added. The reaction vessel was degassed and filled with hydrogen gas, and the reaction mixture was stirred at room temperature for 2 hours, then filtered through Celite® and concentrated. 39 mg (0.19 mmol, 64% yield) of the title compound was obtained, which was used directly in the subsequent transformation. MS (ESI): C 14 H 19Calculated mass of N: 201.2; measured m / z: 202.1 [M+H] + .

[0222] Intermediate 9: tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0223] [ka]

[0224] Nickel(II) chloride (ethylene glycol dimethyl ether complex) (7.2 mg, 0.033 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (10.6 mg, 0.039 mmol) were dissolved in DME and stirred for 10 min. In a separate vessel, tert-butyl 2-bromo-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, 0.30 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (3.7 mg, 0.0033 mmol), 2,6-dimethylpyridine (0.19 mL, 1.64 mmol), 1-bromo-3-tert-butylbenzene (105 mg, 0.49 mmol), and tris(trimethylsilane)silane (0.20 mL, 0.66 mmol) were added. The solution of nickel(II) complex was added to a second reaction vessel, and the mixture was sparged with N2 for 10 minutes, sealed with parafilm, and stirred overnight in a Pennoc 450 nm photoreactor (LED: 100% power, fan: max, stirring: 700 RPM). The reaction mixture was concentrated, dissolved in dichloromethane, and purified on silica gel (0-30% EA / hexanes) to give a mixture of the desired product and a silane by-product (total mass 238 mg). This mixture was used in the next step without further purification. MS (ESI): C 23 H 35 Calculated mass of NO2: 357.3; measured m / z: 302.1 [M+2H-tBu] + .

[0225] Intermediate 10: tert-butyl 2-(4-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0226] [ka]

[0227] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-4-methylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 Calculated mass of NO2: 315.2; measured m / z: 260.1 [M+2H-tBu] + .

[0228] Intermediate 11: tert-butyl 2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0229] [ka]

[0230] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-2-methylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 Calculated mass of NO2: 315.2; measured m / z: 260.1 [M+2H-tBu] + .

[0231] Intermediate 12: tert-butyl 2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0232] [ka]

[0233] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-3-cyclopropylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 Calculated mass of NO2: 341.2; measured m / z: 286.1 [M+2H-tBu] + .

[0234] Intermediate 13: tert-butyl 2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0235] [ka]

[0236] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-3-isopropylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 Calculated mass of NO2: 343.3; measured m / z: 288.0 [M+2H-tBu] + .

[0237] Intermediate 14: tert-butyl 2-(3-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0238] [ka]

[0239] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-3-methylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 29 Calculated mass of NO2: 315.2; measured m / z: 260.1 [M+2H-tBu] + .

[0240] Intermediate 15: tert-butyl 2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0241] [ka]

[0242] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 3-bromoanisole instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 29 Calculated mass of NO3: 331.2; measured m / z: 276.0 [M+2H-tBu] + .

[0243] Intermediate 16: tert-butyl 2-(3-trifluoromethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0244] [ka]

[0245] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-3-trifluoromethoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 26 Calculated mass of F3NO3: 385.2; measured m / z: 330.0 [M+2H-tBu] + .

[0246] Intermediate 17: tert-Butyl 2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0247] [ka]

[0248] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-2,3-dimethylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 Calculated mass of NO2: 329.2; measured m / z: 274.0 [M+2H-tBu] + .

[0249] Intermediate 18: tert-Butyl 2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0250] [ka]

[0251] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-2,4-dimethylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 Calculated mass of NO2: 329.2; measured m / z: 274.2 [M+2H-tBu] + .

[0252] Intermediate 19: tert-butyl 2-(2-(tert-butyl)-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0253] [ka]

[0254] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 4-bromo-2-(tert-butyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 22 H 34 Calculated mass of N2O2: 358.3; measured m / z: 359.3 [M+H] + .

[0255] Intermediate 20: tert-butyl 2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0256] [ka]

[0257] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-4-(tert-butyl)-1-methylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 24 H 37 Calculated mass of NO2: 371.3; measured m / z: 316.2 [M+2H-tBu] + .

[0258] Intermediate 21: tert-butyl 2-(3-trifluoromethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0259] [ka]

[0260] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 3-trifluoromethylbromobenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 26 Calculated mass of F3NO2: 369.2; measured m / z: 314.1 [M+2H-tBu] + .

[0261] Intermediate 22: tert-butyl 2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0262] [ka]

[0263] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-2,5-dimethylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 Calculated mass of NO2: 329.2; measured m / z: 274.2 [M+2H-tBu] + .

[0264] Intermediate 23: tert-butyl 2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0265] [ka]

[0266] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-6-(tert-butyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 22 H 34 Calculated mass of N2O2: 358.3; measured m / z: 359.3 [M+H] + .

[0267] Intermediate 24: tert-butyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0268] [ka]

[0269] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 23 H 30 Calculated mass of F3NO2: 409.2; measured m / z: 354.2 [M+2H-tBu] + .

[0270] Intermediate 25: tert-butyl 2-(3-chloro-4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0271] [ka]

[0272] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 4-bromo-2-chloro-1-(trifluoromethyl)benzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 25 Calculated mass of ClF3NO2: 403.2; measured m / z: 348.1 [M+2H-tBu] + .

[0273] Intermediate 26: tert-butyl 2-(4-methoxy-3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0274] [ka]

[0275] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 4-bromo-1-methoxy-2-(trifluoromethyl)benzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 Calculated mass of ClF3NO3: 399.2; measured m / z: 344.2 [M+2H-tBu] + .

[0276] Intermediate 27: tert-butyl 2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0277] [ka]

[0278] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-4-(tert-butyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 22 H 34 Calculated mass of N2O2: 358.3; measured m / z: 359.2 [M+H] + .

[0279] Intermediate 28: tert-butyl 2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0280] [ka]

[0281] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-4-(tert-butyl)-1-fluorobenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 23 H 34 Calculated mass of FNO2: 375.2; measured m / z: 320.2 [M+2H-tBu] + .

[0282] Intermediate 29: tert-butyl 2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0283] [ka]

[0284] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-4-(tert-butyl)-2-ethoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 25 H 39 Calculated mass of NO3: 401.3; measured m / z: 346.2 [M+2H-tBu] + .

[0285] Intermediate 30: tert-butyl 2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0286] [ka]

[0287] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-4-(tert-butyl)-2-methoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 24 H 37 Calculated mass of NO3: 387.3; measured m / z: 332.2 [M+2H-tBu] + .

[0288] Intermediate 31: tert-butyl 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0289] [ka]

[0290] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 5-bromo-2,2-difluorobenzo[d][1,3]dioxole instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 25 Calculated mass of F2NO4: 381.2; measured m / z: 326.0 [M+2H-tBu] + .

[0291] Intermediate 32: tert-butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0292] [ka]

[0293] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-2-methoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 29 Calculated mass of NO3: 331.2; measured m / z: 276.1 [M+2H-tBu] + .

[0294] Intermediate 33: tert-butyl 2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0295] [ka]

[0296] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 1-bromo-4-methoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 29 Calculated mass of NO3: 331.2; measured m / z: 276.1 [M+2H-tBu] + .

[0297] Intermediate 34: tert-butyl 2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0298] [ka]

[0299] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 19 H 24 Calculated mass of F4N2O2: 388.2; measured m / z: 333.1 [M+2H-tBu] + .

[0300] Intermediate 35: tert-butyl 2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0301] [ka]

[0302] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-6-(trifluoromethyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 19 H 25 Calculated mass of F3N2O2: 370.2; measured m / z: 315.1 [M+2H-tBu] + .

[0303] Intermediate 36: tert-butyl 2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0304] [ka]

[0305] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 6-bromo-3-fluoro-2-methylpyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 19 H 27 Calculated mass of FN2O2: 334.2; measured m / z: 335.3 [M+H] + .

[0306] Intermediate 37: tert-butyl 2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0307] [ka]

[0308] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 4-bromo-2-(tert-butyl)pyrimidine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 33 Calculated mass of N3O2: 359.3; measured m / z: 360.3 [M+H] + .

[0309] Intermediate 38: tert-butyl 2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0310] [ka]

[0311] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-4-(tert-butyl)oxazole instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 32 Calculated mass of N2O3: 348.2; measured m / z: 293.2 [M+2H-tBu] + .

[0312] Intermediate 39: tert-butyl 2-(2-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0313] [ka]

[0314] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 5-bromo-2-(tert-butyl)oxazole instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 32 Calculated mass of N2O3: 348.2; measured m / z: 349.3 [M+H] + .

[0315] Intermediate 40: tert-butyl 2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0316] [ka]

[0317] The title compound was prepared in a manner similar to that of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), using 2-bromo-3,5-difluoropyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 18 H 24 Calculated mass of F2N2O2: 338.2; measured m / z: 283.1 [M+2H-tBu] + .

[0318] Intermediate 41: tert-Butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate.

[0319] [ka]

[0320] Step A: tert-Butyl 2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate. Sodium borohydride (NaBH) (239 mg, 6.32 mmol) was added portionwise to a solution of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (800 mg, 3.16 mmol) in methanol (MeOH) (60 mL) at 0 °C. The mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was redissolved in ethyl acetate (EtOAc) and washed with hydrochloric acid (HCl) (0.1 N) and brine. The organic phase was separated, dried, filtered, and evaporated under reduced pressure to give the title compound (841 mg, 100% yield), which was used in the next step without further purification. MS (ESI): C 14 H 25 Calculated mass of NO3: 255.2; measured m / z: 256.2 [M+H] + .

[0321] Step B: tert-Butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate. Iodine (I2) (962 mg, 3.79 mmol) was added portionwise to a solution of tert-butyl 2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (807 mg, 3.16 mmol), imidazole (323 mg, 4.74 mmol), and triphenylphosphine (PPh3) (995 mg, 3.79 mmol) in tetrahydrofuran (THF) (5.9 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. Excess I2 was quenched with 10% Na2S2O3. The aqueous phase was extracted with EtOAc, and the combined organic phases were dried over MgSO4. The solids were removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (FCC) on silica (0→15% heptane in heptane) to give the title compound as a colorless oil (719 mg, 62% yield). MS (ESI): C 14 H 25 Calculated mass of INO2: 365.2; measured m / z: 366.1 [M+H] + .

[0322] Intermediate 42: tert-Butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate.

[0323] [ka]

[0324] The title compound was prepared analogously to Step B of Intermediate 41, using tert-butyl 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate instead of tert-butyl 2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate. MS (ESI): C 12 H 20 Calculated mass of INO2: 337.2; measured m / z: 338.1 [M+H] + .

[0325] Intermediate 43: tert-Butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate.

[0326] [ka]

[0327] A solution of tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 42, 435 mg, 1.29 mmol) in THF (2.6 mL) was loaded onto a column containing activated zinc at 0.25 mL / min at 40 °C. The effluent was collected in a sealed vessel containing bromobenzene (68 μL, 0.645 mmol), palladium(II) acetate (7.2 mg, 0.032 mmol), and dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (RuPhos) (30 mg, 0.064 mmol). The mixture was stirred at 50 °C for 90 min. A 1:1 solution of saturated NH4Cl and NH3 (37% aqueous solution) was then added, and the mixture was extracted with EtOAc. The organic phase was separated, dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by FCC on silica (0-100% EtOAc in heptane) to give the title compound (174 mg, 70% purity, 66% yield). MS (ESI): C 18 H 25 Calculated mass of NO2: 287.4; measured m / z: 288.3 [M+H] + .

[0328] Intermediate 44: tert-Butyl (S * )-6-phenyl-2-azaspiro[3.4]octane-2-carboxylate.

[0329] [ka]

[0330] The title compound was prepared by chiral supercritical fluid chromatography of tert-butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) (stationary phase: Chiralpak IG 5 μm 250 × 30 mm, mobile phase: 90% CO 2 , 10% MeOH). MS (ESI): C 18 H 25 Calculated mass of NO2: 287.2; measured m / z: 288.0 [M+H] + .

[0331] Intermediate 45: tert-Butyl (R * )-6-phenyl-2-azaspiro[3.4]octane-2-carboxylate.

[0332] [ka]

[0333] The title compound was prepared by chiral supercritical fluid chromatography of tert-butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) (stationary phase: Chiralpak IG 5 μm 250 × 30 mm, mobile phase: 90% CO 2 , 10% MeOH). MS (ESI): C 18 H 25 Calculated mass of NO2: 287.2; measured m / z: 288.1 [M+H] + .

[0334] Intermediate 46: tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate.

[0335] [ka]

[0336] The title compound was prepared in a similar manner to tert-butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) using 4-bromobenzotrifluoride instead of bromobenzene. MS (ESI): C 19 H 24 Calculated mass of F3NO2: 355.1; measured m / z: 356.3 [M+H] + .

[0337] Intermediate 47: tert-Butyl (S * )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate.

[0338] [ka]

[0339] The title compound was prepared by chiral supercritical fluid chromatography of tert-butyl 6-(4-trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 46) (stationary phase: Chiralpak IG 5 μm 250 × 30 mm, mobile phase: 95% CO 2 , 5% MeOH). MS (ESI): C 19 H 24 Calculated mass of F3NO2: 355.1; measured m / z: 341.1 [M-tBu + 2H + MeCN] + .

[0340] Intermediate 48: tert-Butyl (R * )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate.

[0341] [ka]

[0342] The title compound was prepared by chiral supercritical fluid chromatography of tert-butyl 6-(4-trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 46) (stationary phase: Chiralpak IG 5 μm 250 × 30 mm, mobile phase: 95% CO 2 , 5% MeOH). MS (ESI): C 19 H 24 Calculated mass of F3NO2: 355.1; measured m / z: 341.1 [M-tBu + 2H + MeCN] + .

[0343] Intermediate 49: 6-Phenyl-2-azaspiro[3.3]heptane, trifluoroacetate salt.

[0344] [ka]

[0345] Step A: tert-Butyl 6-hydroxy-6-phenyl-2-azaspiro[3.3]heptane-2-carboxylate. Phenylmagnesium bromide (2 M in THF, 376 μL, 753 μmol) was added dropwise to a stirred solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (70.0 mg, 331 μmol) in THF (1.7 mL) at −78 °C. After the addition was complete, the ice bath was removed, and the resulting mixture was stirred at room temperature. After 30 min, the reaction mixture was quenched by the addition of saturated aqueous NH₄Cl (10 mL), and the resulting aqueous mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica (0-100% EtOAc / Hex) to afford the title compound (90.7 mg, 313 μmol, 95% yield) as a white solid, which was used in Step B without further purification. MS (ESI): C 17 H 23 Calculated mass of NO3: 289.2; measured m / z: 234.2 [M-tBu+2H] + .

[0346] Step B: 6-Phenyl-2-azaspiro[3.3]heptane, trifluoroacetate. tert-Butyl 6-hydroxy-6-phenyl-2-azaspiro[3.3]heptane-2-carboxylate (90.0 mg, 311 μmol) was dissolved in trifluoroacetic acid (TFA) (1.07 mL), and the resulting solution was stirred at room temperature for 5 minutes. Triethylsilane (149 μL, 933 μmol) was added dropwise. After the addition was complete, the reaction mixture was stirred vigorously at room temperature for 2 hours. The solvent was then removed in vacuo to give the crude title compound, which was used without further purification. MS (ESI): C 12 H 15 Calculated mass of N: 173.2; measured m / z: 174.1 [M+H] + .

[0347] Intermediate 50: tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

[0348] [ka]

[0349] Step A: tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate. Sodium borohydride (NaBH) (1.80 g, 47.3 mmol) was added portionwise to a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (5.00 g, 23.7 mmol) in methanol (50 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min, then quenched with saturated NaHCO and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous NaSO, and concentrated to give the title compound (4.86 g, 96% yield) as a white solid, which was used in the next step without further purification. 1 H NMR(400MHz, CDCl3)δ 4.24-4.11(m,1H),3.88(d,J=7.2Hz,4H),2.54(ddd,J=2.8,6.8,10.0Hz,2H),2.11-2.02(m,2H),1.93(br s,1H),1.43(s,9H).

[0350] Step B: tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate. tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (4.86 g, 22.8 mmol), toluene (50 mL), PPh3 (112 g, 45.6 mmol), 1H-imidazole (4.65 g, 68.4 mmol), and I2 (8.68 g, 34.2 mmol) were added. The resulting mixture was stirred at 100 °C for 1 h, cooled to room temperature, quenched with saturated aqueous Na2SO3, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 5:1) to give the title compound (6.24 g, 85% yield) as a white solid. MS(ESI):C 11 H 18 Calculated mass of INO2: 323.0, measured m / z: 267.9 [M-tBu+2H] + .

[0351] Intermediate 51: 1-Bromo-3-cyclobutylbenzene.

[0352] [ka]

[0353] Step A: 1-(3-Bromophenyl)cyclobutan-1-ol. n-BuLi (1.88 mL, 2.5 M in hexanes, 4.71 mmol) was added dropwise to a solution of 1,3-dibromobenzene (1.11 g, 4.71 mmol) in dry THF (12 mL) at −70 °C under N 2 . The resulting mixture was stirred at −78 °C for 30 min and then treated with cyclobutanone (300 mg, 4.28 mmol). The reaction mixture was stirred at −78 °C for 2 h, poured into saturated aqueous NH 4 Cl, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na 2 SO 4 , concentrated, and purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 9:1) to give the title compound (811 mg, 83% yield) as a yellow oil.1 H NMR(400MHz,CDCl3)δ 7.70(t,J=2.0Hz,1H),7.50-7.44(m,2H),7.31-7.28(m,1H),2.63-2.54(m,2H),2.45-2.36(m,2H),2.14-2.03(m,2H),1.84-1.70(m,1H).

[0354] Step B: 1-Bromo-3-cyclobutylbenzene. Boron trifluoride diethyl etherate (312 mg, 2.20 mmol) was added dropwise under N to a solution of 1-(3-bromophenyl)cyclobutanol (200 mg, 0.88 mmol) and triethylsilane (256 mg, 2.20 mmol) in dichloromethane (2 mL) at −70 °C. The reaction mixture was stirred at −70 °C for 2 h, then poured into saturated NaHCO and extracted twice with dichloromethane. The combined organic extracts were washed with brine, dried over anhydrous NaSO, concentrated, and purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 30:1) to give the title compound (160 mg, 86% yield) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 7.36(s,1H),7.30(td,J=2.0,7.2Hz,1H),7.19-7.10(m,2H),3.56-3.48(m,1H),2.41-2.29(m,2H),2.18-1.97(m,3H),1.92-1.81(m,1H).

[0355] Intermediate 52: 7-Phenyl-2-azaspiro[3.5]nonane, trifluoroacetate salt.

[0356] [ka]

[0357] The title compound was prepared in a manner similar to that of 6-phenyl-2-azaspiro[3.3]heptane, trifluoroacetate (Intermediate 49), except that tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate in Step A. MS (ESI): C 14 H 19 Calculated mass of N: 201.2; measured m / z: 202.2 [M+H] + .

[0358] Example 1: (2s,4s)-2-(2-phenyl-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0359] [ka]

[0360] (2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 20 mg, 0.117 mmol) and DIPEA (60 μL, 0.350 mmol) were dissolved in DMF (1 mL). HATU (69 mg, 0.175 mmol) and 2-phenyl-7-azaspiro[3.5]nonane (Intermediate 8, 28 mg, 0.140 mmol) were added, and the reaction mixture was stirred at room temperature for 1 h. It was then purified by reverse-phase basic HPLC (Gilson, 0-100% MeCN / water, NH4OH modifier) ​​to give 24.8 mg (0.070 mmol, 60% yield) of the title compound. MS (ESI): C 21 H 26 Calculated mass of N2O3: 354.2; measured m / z: 355.0 [M+H] + . 1H NMR(500MHz,chloroform-d)δ 7.31(dd,J=8.3,6.9Hz,2H),7.23-7.16(m,3H),5.69(s,1H),4.39-4.34(m,2H),3.67-3.43(m,3H),3.38-3.20(m,2H),3.08-2 .95(m,1H),2.67-2.59(m,2H),2.52-2.42(m,2H),2.38-2.28(m,2H),2.00-1.88(m,2H),1.79-1.67(m,2H),1.54-1.49(m,2H).

[0361] Example 2: (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0362] [ka] .

[0363] A solution of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) in 4N HCl / dioxane (1 mL) was stirred for 30 minutes and concentrated. The residue was dissolved in DMF (1 mL), and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 20 mg, 0.117 mmol), DIPEA (0.10 mL, 0.580 mmol), and HATU (69 mg, 0.180 mmol) were added. The reaction mixture was stirred for 1 hour and then purified by reverse-phase basic HPLC (Gilson, 0-100% MeCN / water, NH4OH modifier) ​​to give 17.1 mg (0.042 mmol, 36% yield) of the title compound. MS (ESI): C 25 H 34 Calculated mass of N2O3: 410.3; measured m / z: 411.1 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.26(s,3H),7.09-7.01(m,1H),5.64(s,1H),4.42-4.28(m,2H),3.67-3.46(m,3H),3.40-3.20(m,2H),3.09-2.95(m,1H),2. 69-2.57(m,2H),2.54-2.42(m,2H),2.40-2.28(m,2H),2.02-1.88(m,2H),1.81-1.70(m,2H),1.57-1.50(m,2H),1.32(s,9H).

[0364] Example 3: (2s,4s)-2-(2-(p-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0365] [ka]

[0366] The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(4-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 10). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; measured m / z: 369.0 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.16-7.08(m,4H),5.65(s,1H),4.42-4.33(m,2H),3.69-3.58(m,1H),3.57-3.40(m,2H),3.38-3.30(m,1H),3.27-3.19(m,1H),3. 12-2.91(m,1H),2.72-2.58(m,2H),2.54-2.40(m,2H),2.36-2.24(m,4H),1.98-1.85(m,2H),1.77-1.61(m,2H),1.60-1.46(m,3H).

[0367] Example 4: (2s,4s)-2-(2-(o-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0368] [ka]

[0369] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 11). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; measured m / z: 369.0 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.25-7.09(m,4H),5.66(s,1H),4.40-4.24(m,2H),3.71-3.58(m,2H) ,3.55-3.46(m,1H),3.42-3.35(m,1H),3.30-3.22(m,1H),3.12-2.90( m,1H),2.69-2.57(m,2H),2.54-2.44(m,2H),2.39-2.26(m,2H),2.27- 2.19(m,3H),2.00-1.87(m,2H),1.83-1.73(m,2H),1.53-1.48(m,2H).

[0370] Example 5: (2s,4s)-2-[2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one.

[0371] [ka]

[0372] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 12). MS (ESI): C 24 H 30 Calculated mass of N2O3: 394.2; measured m / z: 395.1 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.20 (t, J = 7.6 Hz, 1H), 7.02-6.94 (m, 1H), 6.94-6.81 (m, 2H), 5.80 (s, 1H), 4.40-4.35 (m, 2H), 3.66-3.58 (m, 1H), 3.59-3.42 (m, 2H), 3.39-3.32 (m, 1H), 3.27-3.20 (m, 1H), 3 .08-2.87(m,1H),2.69-2.58(m,2H),2.53-2.41(m,2H),2.37-2.19(m,2H),1.99-1.8 4(m,3H),1.79-1.68(m,2H),1.58-1.48(m,2H),0.98-0.90(m,2H),0.74-0.64(m,2H).

[0373] Example 6: (2s,4s)-2-[2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one.

[0374] [ka]

[0375] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 13). MS (ESI): C 24 H 32 Calculated mass of N2O3: 396.2; measured m / z: 397.0 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.26-7.20 (m, 1H), 7.11-6.98 (m, 3H), 5.70 (s, 1H), 4.37 (d, J = 6.4 Hz, 2H), 3.66-3.61 (m, 1H), 3.58-3.45 (m, 2H), 3.40-3.33 (m, 1H), 3.26-3.20 (m, 1H), 3.11-2.96 ( m,1H),2.94-2.83(m,1H),2.70-2.60(m,2H),2.54-2.41(m,2H),2.38-2.25(m,2H) ),2.02-1.86(m,2H),1.79-1.68(m,2H),1.55-1.49(m,2H),1.25(d,J=6.9Hz,6H).

[0376] Example 7: (2s,4s)-2-[2-(m-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one.

[0377] [ka]

[0378] The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(3-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 14). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; measured m / z: 369.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.12(t,J=7.9Hz,1H),6.92(d,J=5.7Hz,3H),5.69(s,1H),4.34-4.25(m, 2H),3.61-3.50(m,1H),3.48-3.37(m,2H),3.33-3.26(m,1H),3.20-3.08 (m,1H),3.02-2.84(m,1H),2.63-2.51(m,2H),2.45-2.34(m,2H),2.29-2 .14(m,5H),1.85(q,J=11.4Hz,2H),1.69-1.61(m,2H),1.49-1.39(m,2H).

[0379] Example 8: (2s,4s)-2-[2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one.

[0380] [ka]

[0381] The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 15). MS (ESI): C 22 H 28 Calculated mass of N2O4: 384.2; measured m / z: 385.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.15(dd,J=9.2,7.7Hz,1H),6.75-6.70(m,1H),6.68-6.62(m,2H),5.60(s,1H),4.29(s,2H),3.73(s,3H),3.63-3.05(m,5H),3.01-2. 81(m,1H),2.62-2.50(m,2H),2.44-2.33(m,2H),2.23(t,J=10.2Hz,2H),1.85(t,J=10.2Hz,2H),1.69-1.59(m,2H),1.47-1.41(m,2H).

[0382] Example 9: (2s,4s)-2-[2-[3-(trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0383] [ka]

[0384] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(3-(trifluoromethoxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 16). MS (ESI): C 22 H 25 Calculated mass of F3N2O4: 438.2; measured m / z: 439.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.41-7.31(m,1H),7.17-7.11(m,1H),7.10-6.99(m,2H),5.81(s,1H) ,4.42-4.36(m,2H),3.69-3.49(m,3H),3.42-3.36(m,1H),3.30-3.23( m,1H),3.12-2.95(m,1H),2.74-2.62(m,2H),2.55-2.45(m,2H),2.42- 2.26(m,2H),2.03-1.91(m,2H),1.81-1.68(m,2H),1.58-1.50(m,2H).

[0385] Example 10: (2s,4s)-2-[2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one.

[0386] [ka]

[0387] The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 17). MS (ESI): C 23 H 30 Calculated mass of N2O3: 382.2; measured m / z: 383.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.05-6.92(m,3H),5.62(s,1H),4.29(d,J=8.3Hz,2H),3.69-3.51(m,2H),3.50-3.23(m,2H),3.21-3.07(m,1H),3.03-2.86(m,1H),2.64 -2.51(m,2H),2.47-2.34(m,2H),2.30-2.22(m,2H),2.20(s,3H),2.05(s,3H),1.93-1.81(m,2H),1.74-1.63(m,2H),1.46-1.38(m,2H).

[0388] Example 11: (2r,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0389] [ka]

[0390] The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 26 H 36 Calculated mass of N2O2: 408.3; measured m / z: 409.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.18(s,2H),6.96(d,J=7.0Hz,1H),5.76(s,1H),3.56-3.51(m,1H),3. 51-3.35(m,2H),3.35-3.26(m,1H),3.21-3.12(m,1H),3.02-2.85(m,1 H),2.53-2.40(m,2H),2.34-2.21(m,5H),2.15(q,J=7.6Hz,2H),1.86(q,J=11.3Hz,2H),1.65(q,J=6.7,5.9Hz,2H),1.47(s,4H),1.24(s,9H).

[0391] Example 12: (2s,4s)-2-[2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one.

[0392] [ka]

[0393] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 18). MS (ESI): C 23 H 30 Calculated mass of N2O3: 382.2; measured m / z: 383.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.10-6.79(m,3H),5.60(s,1H),4.38-4.20(m,2H),3.63-3.11(m,6H),3.02-2.86(m,1H),2.63-2.51(m,2H), 2.47-2.33(m,2H),2.26-2.16(m,4H),2.12(s,3H),1.95-1.78(m,2H),1.73-1.54(m,2H),1.45-1.37(m,2H).

[0394] Example 13: (2s,4s)-2-[2-(2-(tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0395] [ka]

[0396] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(2-(tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 19). MS (ESI): C 24 H 33 Calculated mass of N3O3: 411.3; measured m / z: 412.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 8.71(s,1H),7.44-7.31(m,2H),5.74(s,1H),4.42-4.20(m,2H),3.75-3.12(m,5H),3.05-2.83(m,1 H),2.61-2.48(m,2H),2.46-2.26(m,4H),2.09-1.80(m,2H),1.75-1.64(m,2H),1.64-1.40(m,11H).

[0397] Example 14: (2r,4s)-2-(2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0398] [ka]

[0399] tert-butyl 2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 20) was used in place of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) to prepare (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of carboxylic acid (Intermediate 3). MS (ESI): C 27 H 38 Calculated mass of N2O2: 422.3; measured m / z: 423.3 [M+H] + . 1H NMR(500MHz,chloroform-d)δ 7.27-7.22(m,1H),7.17(dd,J=7.9,2.1Hz,1H),7.08(d,J=7.9Hz,1H),6.15(s,1H),3.65(s,2H),3.51(s,1H),3.41(s,1H),3.28( s,1H),3.12-2.94(m,1H),2.62-2.49(m,2H),2.43-2.32(m,8H),2.32-2.18(m,5H),1.98(s,2H),1.63-1.50(m,2H),1.35(s,9H).

[0400] Example 15: 2-[2-[3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0401] [ka]

[0402] tert-butyl 2-(3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 21) was used in place of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carbohydrate was used. The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 23 H 27 Calculated mass of F3N2O2: 420.2; measured m / z: 421.2 [M+H] + . 1H NMR(500MHz,chloroform-d)δ 7.41-7.26(m,4H),6.01(s,1H),3.56(d,J=19.6Hz,2H),3.42(d,J=5.9Hz,1H),3.31(s,1H),3.19(s,1H),2.97(d,J=16.1Hz,1H) ,2.52-2.42(m,2H),2.31(dd,J=11.3,4.4Hz,6H),2.16(t,J=7.8Hz,2H),1.87(d,J=9.9Hz,2H),1.67(s,2H),1.51-1.46(m,2H).

[0403] Example 16: (2r,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0404] [ka]

[0405] tert-butyl 2-(6-(tert-butyl)-pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 23) instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was used in the reaction of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate (Intermediate 24). The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of carboxylic acid (Intermediate 3). MS (ESI): C 25 H 35 Calculated mass of N3O2: 409.3; measured m / z: 410.3 [M+H] + . 1H NMR(500MHz,chloroform-d)δ 7.55-7.45(m,1H),7.14(d,J=7.8Hz,1H),6.89(t,J=6.6Hz,1H),5.97(s ,1H),3.67-3.50(m,3H),3.41-3.35(m,1H),3.31-3.25(m,1H),3.04(dp, J=11.2,8.5Hz,1H),2.60-2.49(m,2H),2.43-2.34(m,4H),2.29-2.19(m, 6H), 1.73(t,J=5.8Hz,2H),1.64(d,J=4.2Hz,2H),1.39(d,J=1.9Hz,9H).

[0406] Example 17: (2r,4s)-2-[2-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0407] [ka]

[0408] Instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), tert-butyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 24) was used to prepare (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane- The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of 2-carboxylic acid (Intermediate 3). MS (ESI): C 26 H 31 Calculated mass of F3N2O2: 460.2; measured m / z: 461.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.31(d,J=8.1Hz,2H),7.09(d,J=8.1Hz,2H),5.84(s,1H),3.66-2.84(m,7H),2.44(dd,J=11.8,9.3Hz,2H),2.35- 2.19(m,5H),2.15(t,J=7.8Hz,2H),1.85(s,2H),1.64(s,2H),1.44(s,2H),1.29-1.14(m,2H),0.98-0.87(m,2H).

[0409] Example 18: (2r,4s)-2-[2-[3-chloro-4-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0410] [ka]

[0411] tert-butyl 2-(3-chloro-4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 25) instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of the carboxylic acid (Intermediate 3). MS (ESI): C 23 H 26 Calculated mass of ClF3N2O2: 454.2; measured m / z: 455.1 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.63(d,J=8.2Hz,1H),7.37-7.32(m,1H),7.18(d,J=8.1Hz,1H),5.90(s,1 H),3.68-3.48(m,3H),3.40(d,J=6.1Hz,1H),3.28(t,J=5.7Hz,1H),3.13-2 .95(m,1H),2.55(t,J=8.6Hz,2H),2.39(t,J=8.4Hz,6H),2.25(q,J=7.0Hz ,2H),1.95(q,J=11.2Hz,2H),1.76(d,J=5.7Hz,2H),1.55(d,J=4.9Hz,2H).

[0412] Example 19: (2r,4s)-2-[2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one.

[0413] [ka]

[0414] tert-butyl 2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 22) instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was used to prepare (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid ( The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of Intermediate 3). MS (ESI): C 24 H 32 Calculated mass of N2O2: 380.2; measured m / z: 381.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.04(d,J=6.9Hz,2H),6.95(d,J=8.1Hz,1H),5.89(s,1H),3.64(d,J=8.8Hz,2H),3.52(s,1H),3.40(s,1H),3 .27(s,1H),3.04(s,1H),2.55(t,J=10.3Hz,2H),2.48-2.17(m,14H),1.96(s,2H),1.78(s,2H),1.54(s,2H).

[0415] Example 20: (2r,4s)-2-[2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0416] [ka]

[0417] tert-butyl 2-(4-methoxy-3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 26) instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of the carboxylic acid (Intermediate 3). MS (ESI): C 24 H 29 Calculated mass of F3N2O3: 450.2; measured m / z: 451.1 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.40(s,1H),7.33(t,J=7.8Hz,1H),6.97(d,J=8.5Hz,1H),5.88(s,1H),3.91(s ,3H),3.63(t,J=5.7Hz,1H),3.56-3.49(m,2H),3.39(t,J=5.6Hz,1H),3.27(t,J =5.7Hz,1H),3.04(dt,J=12.6,8.5Hz,1H),2.64-2.48(m,2H),2.46-2.30(m,6H) ,2.30-2.23(m,2H),1.91(q,J=11.5Hz,2H),1.75(q,J=6.3Hz,2H),1.59(s,2H).

[0418] Example 21: (2s,4s)-2-(2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0419] [ka]

[0420] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 27). MS (ESI): C 24 H 33 Calculated mass of N3O3: 411.3; measured m / z: 412.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 8.47-8.35(m,1H),7.18(s,2H),5.57(s,1H),4.34-4.26(m,2H),3.62-3.52(m,1H),3.48-3.39(m,1H),3.33-3.26(m,1H),3.22-3.11(m,1) H),3.03-2.88(m,1H),2.62-2.51(m,2H),2.47-2.34(m,2H),2.32-2.07(m,3H),1.76-1.64(m,2H),1.62-1.36(m,4H),1.26-1.23(m,9H).

[0421] Example 22: (2r,4s)-2-(2-(5-(tert-butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0422] [ka]

[0423] tert-butyl 2-(5-(tert-butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 28) instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of the carboxylic acid (Intermediate 3). MS (ESI): C 26 H 35 Calculated mass of FN2O2: 426.3; measured m / z: 427.3 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.10 (dd, J = 9.1, 6.1 Hz, 2H), 6.83 (t, J = 9.5 Hz, 1H), 5.78 (s, 1H), 3.64-3.50 (m, 2H), 3.45-3.38 (m, 1H), 3.29 (t, J = 5.6 Hz, 1H), 3.17 (t, J = 5.7 Hz, 1H), 2.94 (dt, J = 1 5.8,8.2Hz,1H),2.45(td,J=11.2,9.7,4.4Hz,2H),2.35-2.19(m,6H),2.15(q,J =7.7Hz,2H),2.01-1.87(m,2H),1.67(q,J=6.3Hz,2H),1.48(s,2H),1.23(s,9H).

[0424] Example 23: (2r,4s)-2-(2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0425] [ka]

[0426] tert-butyl 2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 29) instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of the carboxylic acid (Intermediate 3). MS (ESI): C 28 H 40 Calculated mass of N2O3: 452.3; measured m / z: 453.3 [M+H] + .1 H NMR(400MHz,chloroform-d)δ 7.13-7.05(m,2H),6.66(d,J=9.1Hz,1H),5.82(s,1H),3.92(q,J=6.9Hz, 2H),3.72-3.08(m,6H),3.04-2.83(m,1H),2.45(dd,J=11.8,9.5Hz,2H), 2.29(t,J=7.7Hz,3H),2.25-2.10(m,4H),1.88(t,J=10.6Hz,2H),1.67(t ,J=5.7Hz,2H),1.43(t,J=5.7Hz,2H),1.31(t,J=7.0Hz,3H),1.23(s,9H).

[0427] Example 24: (2r,4s)-2-[2-(o-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one.

[0428] [ka]

[0429] tert-butyl 2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 11) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 12) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of Intermediate 3. MS(ESI): C 23 H 30 Calculated mass of N2O2: 366.2; measured m / z: 367.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.16-7.08(m,2H),7.07-6.99(m,2H),5.87(s,1H),3.62-3.46(m,2H),3.45-3.37(m,1H),3.31-3.28(m,1H),3.21-3.12(m,1H), 3.01-2.85(m,1H),2.50-2.39(m,2H),2.35-2.19(m,6H),2.15(s,5H),1.94-1.80(m,2H),1.73-1.63(m,2H),1.47-1.41(m,2H).

[0430] Example 25: (2r,4s)-2-[2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one.

[0431] [ka]

[0432] tert-butyl 2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 13) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) to produce (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid ( The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of Intermediate 3). MS (ESI): C 25 H 34 Calculated mass of N2O2: 394.3; measured m / z: 395.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.18-7.11(m,1H),7.02-6.91(m,3H),5.82(s,1H),3.58-3.35(m,3H),3.29(s,1H),3.17(s,1H),3.01-2.87(m,1H),2.81(p,J=6.9Hz,1H), 2.45(t,J=10.3Hz,2H),2.34-2.19(m,6H),2.15(d,J=6.7Hz,2H),1.86(d,J=10.4Hz,2H),1.65(s,2H),1.46(s,2H),1.17(d,J=6.9Hz,6H).

[0433] Example 26: (2r,4s)-2-[2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one.

[0434] [ka]

[0435] tert-butyl 2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 17) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), to produce (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid ( The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of Intermediate 3). MS (ESI): C 24 H 32 Calculated mass of N2O2: 380.2; measured m / z: 381.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.05-6.97(m,2H),6.94(dd,J=6.4,2.6Hz,1H),5.85(s,1H),3.69-3.47(m,2H),3.35(d,J=36.7Hz,2H),3.16(s,1H),2.93(s,1H),2 .45(dd,J=11.8,9.1Hz,2H),2.36-2.10(m,11H),2.05(s,3H),1.87(d,J=10.7Hz,2H),1.68(d,J=6.4Hz,2H),1.41(t,J=5.7Hz,2H).

[0436] Example 27: (2r,4s)-2-(2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0437] [ka]

[0438] tert-butyl 2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 30) instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of the carboxylic acid (Intermediate 3). MS (ESI): C 27 H 38 Calculated mass of N2O3: 438.3; measured m / z: 439.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.14-7.05(m,2H),6.68(d,J=8.9Hz,1H),5.86(s,1H),3.71(s,3H),3.58(q,J=9.1Hz,1H),3.41(s,6H),3.01-2.87(m,1H),2.52-2. 40(m,2H),2.35-2.24(m,3H),2.24-2.05(m,3H),1.86(t,J=10.7Hz,2H),1.67(t,J=5.7Hz,2H),1.43(t,J=5.7Hz,2H),1.23(s,9H).

[0439] Example 28: (2s,4s)-2-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0440] [ka]

[0441] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 31). MS (ESI): C 22 H 24 Calculated mass of F2N2O5: 434.2; measured m / z: 435.1 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 6.89(d,J=8.2Hz,1H),6.82(d,J=1.7Hz,1H),6.81-6.74(m,1H),5.76(s,1H) ,4.33-4.23(m,2H),3.57-3.51(m,1H),3.48-3.35(m,2H),3.33-3.22(m,1H) ,3.20-3.10(m,1H),3.01-2.83(m,1H),2.63-2.50(m,2H),2.46-2.33(m,2H) ,2.30-2.13(m,2H),1.87-1.73(m,2H),1.70-1.60(m,2H),1.50-1.40(m,2H).

[0442] Example 29: (2s,4s)-2-[2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0443] [ka]

[0444] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 32). MS (ESI): C 22 H 28 Calculated mass of N2O4: 384.2; measured m / z: 385.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.10(d,J=7.6Hz,2H),6.86(t,J=7.3Hz,1H),6.75(d,J=7.9Hz,1H),5.58(s ,1H),4.29(s,2H),3.73(s,3H),3.61(dd,J=17.8,8.6Hz,1H),3.35(q,J=58 .6,56.0Hz,4H),2.93(s,1H),2.61-2.48(m,2H),2.44-2.33(m,2H),2.20(t ,J=10.2Hz,2H),1.83(t,J=10.6Hz,2H),1.67(s,2H),1.43(t,J=5.8Hz,2H).

[0445] Example 30: (2s,4s)-2-[2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one.

[0446] [ka]

[0447] The title compound was prepared in a manner similar to that of (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 11). MS (ESI): C 22 H 28 Calculated mass of N2O4: 384.2; measured m / z: 385.1 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.07-6.95(m,2H),6.81-6.69(m,2H),5.67(s,1H),4.29(s,2H),3.71(s,3H),3.53(s,1H),3.40(dd,J=11.0,7.1Hz,2H),3.27(s,1H),3. 16(s,1H),2.92(s,1H),2.60-2.50(m,2H),2.46-2.35(m,2H),2.21(t,J=10.1Hz,2H),1.82(d,J=10.5Hz,2H),1.64(s,2H),1.45(s,2H).

[0448] Example 31: (2s,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0449] [ka]

[0450] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 23). MS (ESI): C 24 H 33 Calculated mass of N3O3: 411.3; measured m / z: 412.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.44-7.33(m,1H),7.10-6.95(m,1H),6.85-6.69(m,1H),5.66(s,1H),4.38-4.07(m,2H),3.61-3.36(m,3H),3.32-3.22(m,1H), 3.22-3.12(m,1H),3.02-2.87(m,1H),2.62-2.50(m,2H),2.47-2.34(m,2H),2.22-2.09(m,4H),1.69-1.53(m,4H),1.29(s,9H).

[0451] Example 32: (2s,4s)-2-(2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0452] [ka]

[0453] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 34). MS (ESI): C 21 H 23 Calculated mass of F4N3O3: 441.2; measured m / z: 442.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.52-7.44(m,1H),7.42-7.31(m,1H),5.66(s,1H),4.35-4.24(m,2H) ,3.98-3.76(m,1H),3.59-3.48(m,1H),3.49-3.39(m,1H),3.31-3.22( m,1H),3.24-3.13(m,1H),2.99-2.87(m,1H),2.63-2.53(m,2H),2.47- 2.33(m,1H),2.28-2.10(m,5H),1.73-1.63(m,2H),1.57-1.52(m,2H).

[0454] Example 33: (2s,4s)-2-(2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0455] [ka]

[0456] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 35). MS (ESI): C 21 H 24 Calculated mass of F3N3O3: 423.2; measured m / z: 424.2 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.76-7.62 (m, 1H), 7.46-7.39 (m, 1H), 7.31-7.19 (m, 1H), 5.73 (s, 1H), 4.41-4.23 (m, 2H), 3.69-3.57 (m, 1H), 3.55-3.51 (m, 1H), 3.47-3.37 (m, 1H), 3.33-3.2 3(m,1H),3.22-3.11(m,1H),3.01-2.87(m,1H),2.63-2.52(m,2H),2.47-2.30 (m,2H),2.27-2.19(m,2H),2.16-2.02(m,2H),1.69-1.59(m,2H),1.52(s,2H).

[0457] Example 34: (2s,4s)-2-(2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0458] [ka]

[0459] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 36). MS (ESI): C 21 H 26 Calculated mass of FN3O3: 387.2; measured m / z: 388.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.19-7.10(m,1H),6.97-6.82(m,1H),5.63(s,1H),4.41-4.24(m,2H) ,3.61-3.49(m,2H),3.47-3.38(m,1H),3.33-3.24(m,1H),3.20-3.13( m,1H),3.02-2.87(m,1H),2.61-2.50(m,2H),2.48-2.33(m,5H),2.28- 2.17(m,2H),2.05-1.93(m,2H),1.69-1.61(m,2H),1.59-1.49(m,2H).

[0460] Example 35: (2s,4s)-2-(2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0461] [ka]

[0462] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 37). MS (ESI): C 23 H 32 Calculated mass of N4O3: 412.2; measured m / z: 413.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 8.53-8.32(m,1H),6.90-6.78(m,1H),5.63(s,1H),4.35-4.24(m,2H),3.57-3.50(m,1H),3.50-3.37(m,2H),3.31-3.26(m,1H),3.23-3.1 7(m,1H),3.00-2.85(m,1H),2.60-2.52(m,2H),2.47-2.32(m,2H),2.23-2.05(m,4H),1.68-1.58(m,2H),1.58-1.50(m,2H),1.34(s,9H).

[0463] Example 36: (2s,4s)-2-(2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0464] [ka]

[0465] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 38). MS (ESI): C 22 H 31 Calculated mass of N3O4: 401.2; measured m / z: 402.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.17-7.12(m,1H),5.62(s,1H),4.34-4.21(m,2H),3.60-3.47(m,2H),3.46-3.39(m,1H),3.26-3.21(m,1H),3.19-3.1 2(m,1H),3.00-2.83(m,1H),2.60-2.51(m,2H),2.46-2.33(m,2H),2.26-2.06(m,4H),1.63-1.51(m,4H),1.17(s,9H).

[0466] Example 37: (2s,4s)-2-[2-(2-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0467] [ka]

[0468] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(4-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 39). MS (ESI): C 22 H 31 Calculated mass of N3O4: 401.2; measured m / z: 402.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 6.56-6.47(m,1H),5.58(s,1H),4.36-4.25(m,2H),3.55-3.47(m,1H),3.46-3.40(m,2H),3.30-3.22(m,1H),3.22-3.14(m,1H),3.00-2.8 4(m,1H),2.61-2.49(m,2H),2.46-2.35(m,2H),2.21-2.10(m,2H),1.98-1.84(m,2H),1.66-1.56(m,2H),1.53-1.47(m,2H),1.28(s,9H).

[0469] Example 38: (2s,4s)-2-(2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0470] [ka]

[0471] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) was replaced with tert-butyl 2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 40). MS (ESI): C 20 H 23 Calculated mass of F2N3O3: 391.2; measured m / z: 392.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 8.30-8.18(m,1H),7.10-6.98(m,1H),5.63(s,1H),4.34-4.21(m,2H) ,3.84-3.68(m,1H),3.58-3.52(m,1H),3.47-3.41(m,1H),3.31-3.22( m,1H),3.22-3.15(m,1H),3.01-2.86(m,1H),2.61-2.50(m,2H),2.45- 2.35(m,2H),2.27-2.07(m,4H),1.72-1.58(m,2H),1.55-1.48(m,2H).

[0472] Example 39: (rac)-(2s,4s)-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0473] [ka]

[0474] Step A: tert-Butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate. A solution of tert-butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 41, 719 mg, 1.97 mmol) in THF (3.9 mL) was loaded onto a column containing activated zinc at 40 °C (flow rate 0.5 mL / min). The effluent was collected in a vessel containing 4-bromobenzotrifluoride (0.18 mL, 1.31 mmol), bis(dibenzylideneacetone)palladium (Pd(dba)2) (38 mg, 0.066 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) (47 mg, 0.098 mmol). The mixture was stirred at 50 °C for 4 h. A 1:1 solution of saturated NH4Cl and NH3 (37% aqueous solution) was then added, and the mixture was extracted with EtOAc. The organic phase was separated, dried over Na2SO4, filtered, and the solvent was removed in vacuo. The residue was purified by FCC on silica (0-15% EtOAc in heptane) to give the title compound (156 mg, 31% yield) as a yellow viscous oil. MS (ESI): C 21 H 28 Calculated mass of F3NO2: 383.2; measured m / z: 369.2 [M-tBu + 2H + MeCN] + .

[0475] Step B: 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane hydrochloride. To a solution of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate (10 mg, 0.026 mmol) in MeOH (52 μL) was added HCl in 1,4-dioxane (4 M, 65 μL). This was heated to 45° C. for 1 h and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 16 H 20 Calculated mass of F3N: 283.2; measured m / z: 284.1 [M+H] + .

[0476] Step C: (rac)-(2s,4s)-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. 2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane hydrochloride was dissolved in dimethylformamide (DMF) (0.26 mL), and to this was added (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 4 mg, 0.026 mmol), diisopropylethylamine (DIPEA) (14 μL, 0.078 mmol), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (11 mg, 0.029 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered through a PTFE filter with MeOH and purified by reverse phase HPLC (5-95% MeCN in 20 mM NH4OH in water) to give the title compound (11 mg, 97% yield). MS (ESI): C 23 H 27 Calculated mass of F3N2O3: 436.2; measured m / z: 437.2 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.54(d,J=8.1Hz,2H),7.35-7.30(m,2H),5.89(s,1H),4.37(d,J=1.8Hz,2H),3.70-3.53(m,2H),3.34(dt,J=11.0,5.6Hz,2H),3.28-3. 13(m,1H),3.01(pd,J=8.0,3.1Hz,1H),2.69-2.60(m,2H),2.52-2.42(m,2H),2.21-2.01(m,2H),1.82-1.69(m,2H),1.60-1.42(m,6H).

[0477] Example 40: (rac)-(2s,4s)-8-methyl-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0478] [ka]

[0479] The title compound was prepared in a manner similar to Example 39, using (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 5) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 24 H 29 Calculated mass of F3N2O3: 450.2; measured m / z: 451.2 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.54(d,J=8.1Hz,2H),7.33(d,J=8.0Hz,2H),5.89(s,1H),4.54-4.46(m,1H),3.71-3.53(m,2H),3.33(dt,J=10.9,5.8Hz,2H),3.28-3.12(m ,1H),3.01-2.91(m,1H),2.71-2.56(m,2H),2.44-2.33(m,2H),2.21- 2.01(m,2H),1.84-1.69(m,2H),1.59-1.47(m,6H),1.46-1.41(m,3H).

[0480] Example 41: (rac)-(2s,4s)-2-(6-phenyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0481] [ka]

[0482] The title compound was prepared in a manner similar to Steps B and C of Example 39, using tert-butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) instead of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate in Step B. MS (ESI): C 20 H 24 Calculated mass of N2O3: 340.2; measured m / z: 341.2 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.34-7.27(m,2H),7.20(td,J=6.4,1.6Hz,3H),6.49(d,J=9.2Hz,1H),4.33(d,J=0.8Hz,2H),4.09-3.85(m,4H),3.19- 3.02(m,1H),2.76-2.65(m,1H),2.65-2.56(m,2H),2.48-2.37(m,2H),2.32(td,J=13.5,7.4Hz,1H),2.22-1.84(m,5H).

[0483] Example 42: (2r, 4S * )-2-((R * )-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0484] [ka]

[0485] In Step B, tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate was replaced with tert-butyl (R *The title compound was prepared in a manner similar to Steps B and C of Example 39, using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 21 H 26 Calculated mass of N2O2: 338.2; measured m / z: 339.2 [M+H] + . 1 H NMR(500MHz,chloroform-d)δ 7.32-7.27(m,2H),7.23-7.16(m,3H),6.34(s,1H),4.05-3.83(m,4H),3.10(s,1H),2.75(p,J=8.1Hz,1H),2.53-2.46(m,2H),2.38- 2.26(m,5H),2.19(dd,J=8.4,7.3Hz,2H),2.18-2.10(m,1H),2.10-2.02(m,1H),2.04-1.94(m,1H),1.88(s,1H),1.79-1.67(m,1H).

[0486] Example 43: (2r, 4R * )-2-((S * )-6-Phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0487] [ka]

[0488] In Step B, tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate was replaced with tert-butyl (S *The title compound was prepared in a manner similar to Steps B and C of Example 39, using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 21 H 26 Calculated mass of N2O2: 338.2; measured m / z: 339.2 [M+H] + . 1 H NMR(500MHz,chloroform-d)δ 7.33-7.27(m,2H),7.23-7.16(m,3H),6.35(s,1H),4.04-3.84(m,4H),3.10(s,1H),2.74(p,J=8.1Hz,1H),2 .54-2.45(m,2H),2.38-2.25(m,5H),2.22-2.10(m,3H),2.10-1.94(m,2H),1.89(s,1H),1.79-1.67(m,1H).

[0489] Example 44: (rac)-(2s,4s)-2-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0490] [ka]

[0491] The title compound was prepared in a manner similar to Steps B and C of Example 39, using tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 46) instead of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate in Step B. MS (ESI): C 21 H 23 Calculated mass of F3N2O3: 408.2; measured m / z: 409.2 [M+H] + .1 H NMR(400MHz,chloroform-d)δ 7.55(d,J=8.1Hz,2H),7.30(d,J=8.0Hz,2H),6.56(d,J=10.5Hz,1H),4.33(s,2H),4.05-3.86(m,4 H),3.24-3.07(m,1H),2.74-2.66(m,1H),2.66-2.57(m,2H),2.49-2.28(m,3H),2.25-1.66(m,5H).

[0492] Example 45: (2s,4s)-2-((R * )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0493] [ka]

[0494] In Step B, tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate was replaced with tert-butyl (R * The title compound was prepared in a manner similar to Steps B and C of Example 39 using 4-(trifluoromethyl)phenyl)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 48). MS (ESI): C 21 H 23 Calculated mass of F3N2O3: 408.2; measured m / z: 409.1 [M+H] + . 1H NMR(500MHz,chloroform-d)δ 7.55(d,J=8.1Hz,2H),7.30(d,J=7.9Hz,2H),6.60(d,J=13.9Hz,1H),4.33(s,2H),4.05-3.87(m,4H),3.24-3.07(m,1H),2.74-2.66(m,1 H),2.66-2.56(m,2H),2.48-2.39(m,2H),2.39-2.30(m,1H),2.24-2.13(m,1H),2.13-1.96(m,2H),1.96-1.84(m,1H),1.80-1.65(m,1H).

[0495] Example 46: (2s, 4R * )-2-((S * )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0496] [ka]

[0497] In Step B, tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate was replaced with tert-butyl (S * The title compound was prepared in a manner similar to Steps B and C of Example 39 using 4-(trifluoromethyl)phenyl)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 47). MS (ESI): C 21 H 23 Calculated mass of F3N2O3: 408.2; measured m / z: 409.2 [M+H] + . 1H NMR(500MHz,chloroform-d)δ 7.55(d,J=8.1Hz,2H),7.30(d,J=7.9Hz,2H),6.62(d,J=14.6Hz,1H),4.33(s,2H),4.05-3.89(m,4H),3.24-3.07(m,1H),2.74-2.66(m,1 H),2.66-2.58(m,2H),2.48-2.39(m,2H),2.39-2.30(m,1H),2.23-2.13(m,1H),2.13-1.96(m,2H),1.96-1.84(m,1H),1.80-1.66(m,1H).

[0498] Example 47: (2r, 4S * )-2-((R * )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0499] [ka]

[0500] In Step B, tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate was replaced with tert-butyl (R * The title compound was prepared in a manner similar to Steps B and C of Example 39, using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 22 H 25 Calculated mass of F3N2O2: 406.2; measured m / z: 407.2 [M+H] + . 1H NMR(500MHz,chloroform-d)δ 7.57-7.51(m,2H),7.30(d,J=8.0Hz,2H),6.44(s,1H),4.08-3.84(m,4H),3.16(s,1H),2.74(p,J=8.1Hz,1H) ,2.54-2.46(m,2H),2.39-2.28(m,5H),2.23-2.13(m,3H),2.14-1.97(m,2H),1.89(s,1H),1.80-1.66(m,1H).

[0501] Example 48: (2r, 4R * )-2-((S * )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0502] [ka]

[0503] In Step B, tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate was replaced with tert-butyl (S * The title compound was prepared in a manner similar to Steps B and C of Example 39, using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 22 H 25 Calculated mass of F3N2O2: 406.2; measured m / z: 407.2 [M+H] + . 1H NMR(500MHz,chloroform-d)δ 7.56-7.51(m,2H),7.32-7.27(m,2H),6.40(s,1H),4.05-3.85(m,4H),3.16(s,1H),2.74(p,J=8.1Hz,1H),2 .54-2.47(m,2H),2.40-2.29(m,5H),2.23-2.12(m,3H),2.12-1.97(m,2H),1.90(s,1H),1.80-1.66(m,1H).

[0504] Example 49: (rac)-(2s,4s)-2-(6-(4-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0505] [ka]

[0506] The title compound was prepared in a manner similar to Example 39, using tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 42) instead of tert-butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 41) in Step A, and 1-bromo-4-tert-butylbenzene instead of 4-bromobenzotrifluoride. MS (ESI): C 24 H 32 Calculated mass of N2O3: 396.2; measured m / z: 397.2 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.35-7.29(m,2H),7.15-7.09(m,2H),6.37(d,J=7.7Hz,1H),4.33(s,2H),4.03-3.86(m,4H),3.16-3.00(m,1H),2.76-2.67(m ,1H),2.64-2.55(m,2H),2.48-2.38(m,2H),2.30(td,J=13.9,7.4Hz,1H),2.19-1.82(m,4H),1.80-1.68(m,1H),1.31(s,9H).

[0507] Example 50: (rac)-(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0508] [ka]

[0509] The title compound was prepared in a manner similar to Example 39, using tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 42) instead of tert-butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 41) in Step A, and 1-bromo-3-tert-butylbenzene instead of 4-bromobenzotrifluoride. MS (ESI): C 24 H 32 Calculated mass of N2O3: 396.2; measured m / z: 397.2 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.25-7.22(m,2H),7.20(s,1H),7.04-6.98(m,1H),6.36(d,J=9.7Hz,1H),4.33(s,2H),4.04-3.88(m,4H),3.19-3.01(m,1H),2.77- 2.67(m,1H),2.65-2.55(m,2H),2.49-2.39(m,2H),2.32(td,J=13.5,7.3Hz,1H),2.21-1.85(m,4H),1.82-1.68(m,1H),1.32(s,9H).

[0510] Example 51: (rac)-(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one.

[0511] [ka]

[0512] The title compound was prepared in a manner similar to Example 39, using tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 42) instead of tert-butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 41) in Step A, 1-bromo-3-tert-butylbenzene instead of 4-bromobenzotrifluoride, and (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 5) 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 34 Calculated mass of N2O3: 410.3; measured m / z: 411.3 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.25-7.22(m,2H),7.21(dt,J=3.2,1.5Hz,1H),7.04-6.98(m,1H),6.3 9(d,J=7.3Hz,1H),4.49-4.41(m,1H),4.04-3.87(m,4H),3.19-3.01(m, 1H),2.73-2.58(m,2H),2.58-2.48(m,1H),2.42-2.25(m,3H),2.22-1. 83(m,4H),1.81-1.68(m,1H),1.41(dt,J=6.5,1.5Hz,3H),1.32(s,9H).

[0513] Example 52: (rac)-(2s,4s)-2-(6-cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0514] [ka]

[0515] Step A: tert-Butyl 6-cyclopropyl-2-azaspiro[3.4]octane-2-carboxylate. Cyclopropylmagnesium bromide (0.75 mL, 0.75 mmol) was added to a solution of tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 42, 169 mg, 0.50 mmol), cobalt(II) acetylacetonate (4.5 mg, 0.018 mmol), and N,N,N',N'-tetramethylethylenediamine (58 mg, 0.50 mmol) in THF (0.6 mL) at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with NH4Cl / NH3, and the organic phase was separated, dried, filtered, and evaporated under reduced pressure. The crude product was purified by FCC on silica (EtOAc:DCM:heptane 0 / 30 / 70 to 50 / 50 / 0) to give the title compound as a colorless oil (89 mg, 50% purity, 35% yield).

[0516] Step B: 6-Cyclopropyl-2-azaspiro[3.4]octan-2-nium chloride. To a solution of tert-butyl 6-cyclopropyl-2-azaspiro[3.4]octane-2-carboxylate (45 mg, 50% purity, 0.179 mmol) in MeOH (100 μL) was added HCl in 1,4-dioxane (4 M, 0.45 mL). This was heated to 45° C. for 1 h and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 10 H 17 Calculated mass of N: 151.1; measured m / z: 152.1 [M+H] + .

[0517] Step C: (rac)-(2s,4s)-2-(6-cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. 6-Cyclopropyl-2-azaspiro[3.4]octan-2-nium chloride was dissolved in DMF (0.9 mL). To this was added (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 31 mg, 0.179 mmol), DIPEA (94 μL, 0.537 mmol), and HATU (77 mg, 0.197 mmol). The mixture was stirred at room temperature for 1 hour. The reaction was filtered through a PTFE filter with MeOH and purified by reverse phase HPLC (5-95% MeCN in 20 mM NH4OH in water) to give the title compound (10 mg, 18% yield). MS (ESI): C 17 H 24 Calculated mass of N2O3: 304.2; measured m / z: 305.2 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 6.53(d,J=7.5Hz,1H),4.32(d,J=2.5Hz,2H),3.98-3.84(m,2H),3.84( s,1H),3.79(s,1H),2.74-2.64(m,1H),2.64-2.54(m,2H),2.45-2.36( m,2H),2.04-1.92(m,1H),1.92-1.71(m,3H),1.64-1.51(m,1H),1.46- 1.26(m,2H),0.65-0.52(m,1H),0.44-0.35(m,2H),0.08--0.01(m,2H).

[0518] Example 53: (rac)-(2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0519] [ka]

[0520] Step A: tert-Butyl 6-cyclohexyl-2-azaspiro[3.4]octane-2-carboxylate. Cyclohexylmagnesium chloride (1 mL, 1 mmol) was added to a solution of tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 42, 169 mg, 0.5 mmol), nickel(II) acetylacetonate (13 mg, 0.05 mmol), 4-fluorostyrene (12 μL, 0.1 mmol), and tetrabutylammonium iodide (554 mg, 1.5 mmol) in THF (0.41 mL) and N-methyl-2-pyrrolidone (NMP) (0.24 mL) at 0 °C. The mixture was stirred at this temperature for 4 h at room temperature. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, separated, dried, and evaporated under reduced pressure to give a crude residue which was purified by FCC on silica (20-80% DCM in heptane) to give the title compound as a colorless oil (87 mg, 45% purity, 27% yield). MS (ESI): C 18 H 31 Calculated mass of NO2: 293.2; measured m / z: 294.2 [M+H] + .

[0521] Step B: 6-Cyclohexyl-2-azaspiro[3.4]octan-2-nium chloride. To a solution of tert-butyl 6-cyclohexyl-2-azaspiro[3.4]octane-2-carboxylate (44 mg, 45% purity, 0.15 mmol) in MeOH (100 μL) was added HCl in 1,4-dioxane (4 M, 0.38 mL). This was heated to 45° C. for 1 h and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 13 H 23 Calculated mass of N: 193.2; measured m / z: 194.2 [M+H] + .

[0522] Step C: (rac)-(2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. 6-Cyclohexyl-2-azaspiro[3.4]octan-2-nium chloride was dissolved in DMF (0.75 mL) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 26 mg, 0.15 mmol), DIPEA (79 μL, 0.45 mmol), and HATU (65 mg, 0.16 mmol) were added. The mixture was stirred at room temperature for 1.5 hours. The reaction was filtered through a PTFE filter with MeOH and purified by reverse phase HPLC (5-95% MeCN in 20 mM NH4OH in water) to give the title compound (20 mg, 39% yield). MS (ESI): C 20 H 30 Calculated mass of N2O3: 346.2; measured m / z: 347.2 [M+H] + . 1 H NMR(500MHz,chloroform-d)δ 6.58(d,J=5.0Hz,1H),4.32(d,J=1.7Hz,2H),3.84(dd,J=31.7,21.3Hz,4H),2.72-2.63(m,1H),2.63-2.56(m,2H),2.44-2.35(m,2H), 2.01-1.89(m,1H),1.87-1.74(m,4H),1.74-1.51(m,5H),1.47-1.35(m,1H),1.32-1.09(m,4H),1.06-0.96(m,1H),0.94-0.80(m,2H).

[0523] Example 54: (rac)-(2r,4s)-2-(6-cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0524] [ka]

[0525] The title compound was prepared in a manner similar to Example 53, using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in Step C. MS (ESI): C 21 H 32 Calculated mass of N2O2: 344.2; measured m / z: 345.3 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 6.18(s,1H),3.91-3.74(m,4H),2.72(pd,J=8.1,3.8Hz,1H),2.52-2.43(m,2H),2.38-2.26(m,4H),2.21-2.14(m,2H),2.01-1.88( m,1H),1.87-1.66(m,7H),1.57(q,J=9.1,8.4Hz,2H),1.47-1.34(m,1H),1.34-1.10(m,4H),1.10-0.96(m,1H),0.96-0.80(m,2H).

[0526] Example 55: (rac)-(2s,4s)-2-(6-cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0527] [ka]

[0528] Step A: tert-Butyl 6-cyclopentyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate. In an oven-dried flask under N, 2-boc-6-oxo-2-azaspiro[3.4]octane (100 mg, 0.439 mmol) was dissolved in anhydrous THF (0.3 M). Cerium(III) chloride (CeCl) (162 mg, 0.659 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0 °C, and cyclopentylmagnesium bromide (2 M in THF, 0.33 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous NH4Cl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by FCC on silica (0-60% EtOAc in hexanes) gave the title compound (33 mg, 25% yield). MS (ESI): C 17 H 29 Calculated mass of NO3: 295.2; measured m / z: 222.2 [M+H-tBu-OH] + .

[0529] Step B: 6-Cyclopentyl-2-azaspiro[3.4]octan-2-nium 2,2,2-trifluoroacetate. tert-Butyl 6-cyclopentyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (33 mg, 0.112 mmol) was dissolved in trifluoroacetic acid (TFA) (0.75 mL) and stirred at room temperature for 5 minutes. Triethylsilane (TES) (54 μL, 0.335 mmol) was added, and the mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 12 H 21 Calculated mass of N: 179.2; measured m / z: 180.2 [M+H] + .

[0530] Step C: (rac)-(2s,4s)-2-(6-cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. 6-Cyclopentyl-2-azaspiro[3.4]octan-2-nium 2,2,2-trifluoroacetate (16 mg, 0.054 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 9 mg, 0.054 mmol) were dissolved in DMF (0.15 M). DIPEA (38 μL, 0.218 mmol) and HATU (26 mg, 0.066 mmol) were added, and the reaction was stirred at room temperature for 72 h. The crude mixture was filtered through a PTFE filter with MeOH and purified by reverse-phase HPLC (5-95% MeCN in 20 mM NH4OH in water) to give the title compound (12 mg, 66% yield). MS (ESI): C 19 H 28 Calculated mass of N2O3: 332.2; measured m / z: 333.3 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 6.58(d,J=4.7Hz,1H),4.32(d,J=1.1Hz,2H),3.92-3.77(m,4H),2.73-2.63(m,1H),2.64-2.56(m,2H),2.46-2.36 (m,2H),1.97(td,J=13.4,7.2Hz,1H),1.88-1.65(m,6H),1.65-1.38(m,6H),1.34-1.21(m,1H),1.16-0.99(m,2H).

[0531] Example 56: (rac)-(2s,4s)-2-(6-cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0532] [ka]

[0533] Step A: tert-Butyl 6-cyclobutyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate. In an oven-dried flask under N, 2-boc-6-oxo-2-azaspiro[3.4]octane (50 mg, 0.22 mmol) was dissolved in anhydrous THF (0.6 M). CeCl (81 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 45 min. The reaction was cooled to 0 °C, and cyclobutylmagnesium chloride (0.5 M in THF, 0.66 mL) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 6 h. The reaction was quenched with saturated aqueous NH Cl, extracted with EtOAc, dried over Na SO , filtered, and concentrated in vacuo. Purification by FCC on silica (0–100% EtOAc in hexanes) afforded the title compound (33 mg, 53% yield). MS(ESI):C 16 H 27 Calculated mass of NO3: 281.2; measured m / z: 208.2 [M+H-tBu-OH] + .

[0534] Step B: 6-Cyclobutyl-2-azaspiro[3.4]oct-6-en-2-nium 2,2,2-trifluoroacetate. tert-Butyl 6-cyclobutyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (26 mg, 0.092 mmol) was dissolved in TFA (0.62 mL) and stirred at room temperature for 5 minutes. TES (45 μL, 0.277 mmol) was added, and the mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 11 H 17 Calculated mass of N: 163.1; measured m / z: 164.2 [M+H] + .

[0535] Step C: 6-Cyclobutyl-2-azaspiro[3.4]octan-2-nium 2,2,2-trifluoroacetate. 6-Cyclobutyl-2-azaspiro[3.4]oct-6-ene-2-nium 2,2,2-trifluoroacetate (26 mg, 0.094 mmol) was dissolved in ethanol (EtOH) (0.9 mL). Palladium on carbon (Pd / C) (10 mg, 0.009 mmol) was added, and the reaction vessel was degassed and placed under a hydrogen (H) balloon and stirred at room temperature for 16 hours. The reaction mixture was filtered through Celite® with MeOH and concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 11 H 19 Calculated mass of N: 165.2; measured m / z: 166.2 [M+H] + .

[0536] Step D: (rac)-(2s,4s)-2-(6-cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. 6-Cyclobutyl-2-azaspiro[3.4]octan-2-nium 2,2,2-trifluoroacetate (26 mg, 0.093 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 17 mg, 0.098 mmol) were dissolved in DMF (0.6 mL). DIPEA (48 μL, 0.279 mmol) and HATU (40 mg, 0.102 mmol) were added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was filtered through a PTFE filter with MeOH and purified by reverse phase HPLC (5-95% MeCN in 20 mM NH4OH in water) to give the title compound (5 mg, 17% yield). MS (ESI): C 18 H 26 Calculated mass of N2O3: 318.2; measured m / z: 319.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 6.34(s,1H),4.32(s,2H),3.76-3.59(m,4H),2.75-2.63(m,1H),2.63-2.51(m,2H) ,2.47-2.35(m,2H),1.89(d,J=15.9Hz,2H),1.80-1.48(m,9H),1.48-1.27(m,3H).

[0537] Example 57: (rac)-(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0538] [ka]

[0539] Step A: tert-Butyl 2-(3-(tert-butyl)phenyl)-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate. In an oven-dried flask under N, tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (100 mg, 0.375 mmol) was dissolved in anhydrous THF (1.9 mL) and cooled to -78 °C. 3-tert-Butylphenylmagnesium bromide (0.5 M in THF, 1.12 mL) was added dropwise. This was allowed to warm to room temperature and stirred for 1.5 h before being quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-100% EtOAc in hexanes) afforded the title compound (68 mg, 47% yield). MS (ESI): C 24 H 37 Calculated mass of NO3: 387.3; measured m / z: 332.2 [M-tBu+2H] + .

[0540] Step B: 2-(3-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-nium 2,2,2-trifluoroacetate. tert-Butyl 2-(3-(tert-butyl)phenyl)-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (68 mg, 0.175 mmol) was dissolved in TFA (0.58 mL) and stirred at room temperature for 5 minutes. TES (85 μL) was added, and the mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 19 H 29 Calculated mass of N: 271.2; observed m / z: 272.2 [M+H] + .

[0541] Step C: (rac)-(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. 2-(3-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-nium 2,2,2-trifluoroacetate (20 mg, 0.052 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 10 mg, 0.057 mmol) were dissolved in DMF (0.5 mL). DIPEA (27 μL, 0.156 mmol) and HATU (24 mg, 0.062 mmol) were added, and the reaction was stirred at room temperature for 3 h. The reaction mixture was filtered through a PTFE filter with MeOH and purified by reverse phase HPLC (5-95% MeCN in 20 mM NH4OH in water) to give the title compound (16 mg, 73% yield). MS (ESI): C 26 H 36 Calculated mass of N2O3: 424.3; measured m / z: 425.3 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.25-7.20(m,3H),7.08-7.02(m,1H),6.19(d,J=5.6Hz,1H),4.38(d,J=2.1Hz,2H),3.67-3.52(m,2H),3.40-3.27(m,2H),3.23-3.07( m,1H),3.07-2.93(m,1H),2.72-2.61(m,2H),2.52-2.40(m,2H),2.19-2.00(m,2H),1.84-1.67(m,3H),1.66-1.44(m,5H),1.32(s,9H).

[0542] Example 58: (rac)-(2s,4s)-2-(2-(4-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0543] [ka]

[0544] The title compound was prepared in a manner similar to Example 57, using 4-tert-butylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide in Step A. MS (ESI): C 26 H 36 Calculated mass of N2O3: 424.3; measured m / z: 425.3 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.35-7.28(m,2H),7.19-7.13(m,2H),6.10(d,J=4.7Hz,1H),4.37(d,J=1.9Hz,2H),3.66-3.49(m,2H),3.40-3.25(m,2H),3.21-3.06(m,1H) ),2.99(pd,J=8.1,3.7Hz,1H),2.71-2.61(m,2H),2.51-2.39(m,2H),2.17-1.96(m,2H),1.82-1.65(m,3H),1.65-1.41(m,5H),1.31(s,9H).

[0545] Example 59: (2s,4s)-2-(2-(3-isopropylphenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0546] [ka]

[0547] The title compound was prepared in a manner similar to Example 57, using tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate in Step A, and 3-isopropylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide. MS (ESI): C 23 H 30 Calculated mass of N2O3: 382.2; measured m / z: 383.3 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.25-7.19(m,1H),7.12-7.05(m,1H),7.05-6.97(m,2H),6.41-6.23(m,1H),4.41-4.30(m,2H),3.67-3.25(m,5H),2.88(qd,J=1 8.0,15.3,10.0Hz,2H),2.72-2.58(m,2H),2.57-2.29(m,4H),2.28-2.09(m,2H),2.09-1.82(m,2H),1.25(dd,J=6.9,1.3Hz,6H).

[0548] Example 60: (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0549] [ka]

[0550] The title compound was prepared in a manner analogous to Example 57, using tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate in Step A. MS (ESI): C 24 H 32 Calculated mass of N2O3: 396.2; measured m / z: 397.3 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.26-7.21(m,2H),7.21-7.16(m,1H),7.05-6.99(m,1H),6.21(d,J=25.8Hz,1H),4.40-4.30(m,2H),3.68-3.26(m,5H) ,2.98-2.78(m,1H),2.70-2.58(m,2H),2.55-2.30(m,4H),2.26-2.10(m,2H),2.10-1.83(m,2H),1.32(d,J=1.3Hz,9H).

[0551] Example 61: (rac)-(2s,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0552] [ka]

[0553] The title compound was prepared in a manner similar to Example 57, using 2-boc-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate in Step A and 3-isopropylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide. MS (ESI): C 23 H 30 Calculated mass of N2O3: 382.2; measured m / z: 383.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.23(t,J=7.6Hz,1H),7.10-6.98(m,3H),6.61-6.51(m,1H),4.33(s,2H) ),4.03-3.87(m,4H),3.17-3.00(m,1H),2.88(hept,J=6.9Hz,1H),2.75 -2.66(m,1H),2.66-2.58(m,2H),2.48-2.37(m,2H),2.31(td,J=13.5,7 .3Hz,1H),2.20-1.83(m,4H),1.80-1.67(m,1H),1.24(d,J=6.9Hz,6H).

[0554] Example 62: (rac)-(2r,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0555] [ka]

[0556] The title compound was prepared in a manner similar to Example 57, using 2-boc-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate in Step A, 3-isopropylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide, 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 24 H 32 Calculated mass of N2O2: 380.2; measured m / z: 381.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.23(t,J=7.6Hz,1H),7.09-6.98(m,3H),6.38(s,1H),4.04-3.84(m,4H),3.09(dp,J=18.1,8.8Hz,1H),2.87(hept,J=6.9Hz,1H),2.75 (p,J=8.1Hz,1H),2.55-2.45(m,2H),2.38-2.25(m,5H),2.22-2.16(m,2H),2.16-1.82(m,4H),1.81-1.66(m,1H),1.24(d,J=6.9Hz,6H).

[0557] Example 63: (rac)-(2s,4s)-2-(6-(4-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0558] [ka]

[0559] The title compound was prepared in a manner similar to Example 57, using 2-boc-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate in Step A and 4-isopropylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide. MS (ESI): C 23 H 30 Calculated mass of N2O3: 382.2; measured m / z: 383.2 [M+H] + . 1H NMR(400MHz,chloroform-d)δ 7.16(d,J=8.2Hz,2H),7.11(d,J=8.3Hz,2H),6.55(d,J=7.9Hz,1H),4.33 (s,2H),4.02-3.86(m,4H),3.16-2.97(m,1H),2.88(hept,J=6.9Hz,1H),2 .75-2.66(m,1H),2.66-2.57(m,2H),2.48-2.36(m,2H),2.30(td,J=13.6 ,7.3Hz,1H),2.19-1.83(m,4H),1.76-1.64(m,1H),1.24(d,J=6.9Hz,6H).

[0560] Example 64: (2s,4s)-2-(2-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0561] [ka]

[0562] Step A: tert-Butyl 2-phenyl-6-azaspiro[3.4]octane-6-carboxylate. tert-Butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate (100 mg, 0.444 mmol) and 4-methylbenzenesulfonhydrazide (85 mg, 0.444 mmol) were dissolved in 1,4-dioxane (0.9 mL) and heated to 80 °C for 2.5 h. Potassium carbonate (KCO) (92 mg, 0.666 mmol) and phenylboronic acid (85 mg, 0.666 mmol) were added, and the mixture was heated to 110 °C for 10 h. The reaction was quenched with saturated aqueous NaHCO and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. Purification by FCC on silica (0-20% EtOAc in hexanes) gave the title compound (13 mg, 10% yield). MS (ESI): C 18 H 25 Calculated mass of NO2: 287.2; measured m / z: 232.2 [M-tBu+2H] + .

[0563] Step B: 2-Phenyl-6-azaspiro[3.4]octan-6-nium chloride. To a solution of tert-butyl 2-phenyl-6-azaspiro[3.4]octane-6-carboxylate (13 mg, 0.045 mmol) in MeOH (91 μL) was added HCl in 1,4-dioxane (4 M, 0.11 mL). This was heated to 45° C. for 1 h and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 13 H 17 Calculated mass of N: 187.1; measured m / z: 188.1 [M+H] + .

[0564] Step C: (2s,4s)-2-(2-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. 2-Phenyl-6-azaspiro[3.4]octan-6-nium chloride was dissolved in DMF (0.45 mL) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 8 mg, 0.047 mmol), DIPEA (24 μL, 0.136 mmol), and HATU (19.5 mg, 0.050 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction was filtered through a PTFE filter with MeOH and purified by reverse phase HPLC (5-95% MeCN in 20 mM NH4OH in water) to give the title compound (11 mg, 75% yield). MS (ESI): C 20 H 24 Calculated mass of N2O3: 340.2; measured m / z: 341.2 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.31(td,J=7.6,3.7Hz,2H),7.19(dd,J=7.6,4.4Hz,3H),6.49-6.34(m,1H),4.41-4.29(m,2H),3.70-3.26(m, 5H),2.87(dp,J=31.6,8.2Hz,1H),2.76-2.57(m,2H),2.57-2.29(m,4H),2.28-2.10(m,2H),2.10-1.82(m,2H).

[0565] Example 65: (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0566] [ka]

[0567] Step A: tert-Butyl 6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate. (3-(tert-butyl)phenyl)boronic acid (881 mg, 4.95 mmol), (1R,2R)-2-aminocyclohexanol (57 mg, 0.495 mmol), and nickel(II) iodide (155 mg, 0.495 mmol) were dissolved in isopropanol (10 mL). The resulting mixture was stirred under N atmosphere at 25 °C for 30 min and then treated with NaHMDS (4.95 mL, 1 M in THF, 4.95 mmol). The resulting mixture was stirred under a nitrogen atmosphere for 10 minutes, followed by the addition of a solution of tert-butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 50, 800 mg, 2.47 mmol) in isopropanol (5 mL). The resulting mixture was stirred under a nitrogen atmosphere at 70 °C for 14 hours, then concentrated and purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 5:1) to give the title compound (800 mg, 67% yield) as a pale yellow oil. MS (ESI): C 21 H 31 Calculated mass of NO2: 329.2, measured m / z: 274.2 [M-tBu+2H] + . 1 H NMR(400MHz,CDCl3)δ 7.26-7.20(m,2H),7.19-7.12(m,1H),7.03-6.97(m,1H),4.06(s,2H),3.85(s,2H), 3.45-3.31(m,1H),2.61-2.54(m,2H),2.33-2.24(m,2H),1.44(s,9H),1.31(s,9H).

[0568] Step B: 6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane. tert-Butyl 6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 0.628 mmol) was dissolved in a mixture of TFA (1 mL) and DCM (1 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated to give the title compound (150 mg, crude) as a yellow oil, which was used in the next step without further purification. MS (ESI): C 16 H 23 Calculated mass of N: 229.2 m / z: 230.2 [M+H] + .

[0569] Step C: (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. HATU (333 mg, 0.876 mmol) was added to a solution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (75 mg, 0.438 mmol), 6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane (150 mg, crude), and DIPEA (283 mg, 2.19 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 12 h, poured into HO, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and purified by FCC (eluent: dichloromethane:methanol = 1:0 to 10:1), followed by repurification by reverse-phase HPLC using a Boston Prime C18, 150 mm x 30 mm x 5 μm column (eluent: 55% to 85% (v / v) CH3CN and HO with 0.04% NH3 and 10 mM NH4HCO3) to give the title compound (89.3 mg, 53% yield) as a white solid. MS (ESI): C 23 H 30 Calculated mass of N2O3: 382.2; measured m / z: 383.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ 7.40-7.30(m,3H),7.12-7.08(m,1H),6.65(br s,1H),4.44(d,J=6.0Hz,2H),4.32(s,1H),4.26(s,1H),4.10(s,1H),4.05(s ,1H),3.61-3.43(m,1H),2.86-2.67(m,5H),2.57-2.39(m,4H),1.42(s,9H).

[0570] Example 66: (2s,4s)-2-(6-(m-tolyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0571] [ka]

[0572] The title compound was prepared in a manner similar to that of (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that m-tolylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 20 H 24 Calculated mass of N2O3: 340.2; measured m / z: 341.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.24-7.17(m,1H),7.05-6.94(m,3H),6.63(br d,J=7.6Hz,1H),4.35(d,J=5.6Hz,2H),4.24-4.13(m,2H),3.98(d,J=17.2Hz,2H),3.47-3.32(m,1H),2.77-2.53(m,5H),2.48-2.27(m,7H).

[0573] Example 67: (2s,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0574] [ka]

[0575] The title compound was prepared in a manner similar to that of (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that 3-isopropylphenylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; measured m / z: 369.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.26-7.22(m,1H),7.09(d,J=7.6Hz,1H),7.02-6.98(m,2H),6.27(br s,1H),4.34(d,J=5.6Hz,2H),4.23-4.15(m,2H),3.98(d,J=18.8Hz,2H),3.50-3.34(m,1H) ,2.89(td,J=6.8,14.0Hz,1H),2.75-2.56(m,5H),2.50-2.29(m,4H),1.25(d,J=6.8Hz,6H).

[0576] Example 68: (2s,4s)-2-(6-(3,4-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0577] [ka]

[0578] The title compound was prepared in a manner similar to that of (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that 3,4-dimethylphenylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 21 H 26 Calculated mass of N2O3: 354.2; measured m / z: 355.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.07(d,J=7.6Hz,1H),6.95-6.88(m,2H),6.35(br s,1H),4.33(d,J=5.6Hz,2H),4.22-4.12(m,2H),4.00-3.91(m,2H),3.45-3.28(m,1H),2.76- 2.65(m,1H),2.62-2.52(m,4H),2.48-2.39(m,2H),2.35-2.27(m,2H),2.24(d,J=6.8Hz,6H).

[0579] Example 69: (2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0580] [ka]

[0581] Step A: tert-Butyl 6-cyclohexyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate. Cyclohexylmagnesium bromide (7.1 mL, 1 M THF solution, 7.10 mmol) was added dropwise to a cooled (-65 °C, dry ice / acetone) solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 4.73 mmol) in THF (20 mL). The resulting mixture was stirred for 4 h while gradually warming to room temperature, then quenched with saturated aqueous NH4Cl and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 3:1) to give the title compound (498 mg, 36% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 3.96(s,2H),3.84(s,2H),2.31(br d,J=13.2Hz,2H),2.10(br d,J=12.8Hz,2H),1.80(br d,J=12.4Hz,2H),1.68(br d,J=12.4Hz,3H),1.43(s,9H),1.28-1.11(m,4H),1.06-0.93(m,2H).

[0582] Step B: tert-Butyl 6-cyclohexylidene-2-azaspiro[3.3]heptane-2-carboxylate. Thionyl chloride (SOCl) (245 μL, 3.37 mmol) was added to a mixture of tert-butyl 6-cyclohexyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (498 mg, 1.69 mmol) and DMAP (20.6 mg, 0.169 mmol) in pyridine (10 mL) at 0 °C. The resulting mixture was stirred for 2 h while gradually warming to room temperature to give a yellow solution, which was then quenched with saturated NaHCO and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous NaSO, and purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 10:1) to give the title compound (341 mg, 73% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ 3.91 (s, 4H), 2.76 (s, 4H), 1.94-1.88 (m, 4H), 1.52-1.44 (m, 6H), 1.43 (s, 9H).

[0583] Step C: tert-Butyl 6-cyclohexyl-2-azaspiro[3.3]heptane-2-carboxylate. tert-Butyl 6-cyclohexylidene-2-azaspiro[3.3]heptane-2-carboxylate (341 mg, 1.23 mmol) and wet Pd / C (200 mg, 10 wt%, 0.189 mmol) were combined in MeOH (10 mL). The suspension was stirred under H (15 psi) at room temperature for 2 h, filtered through a pad of Celite®, and concentrated to give the title compound (320 mg, 93% yield) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 3.90(s,2H),3.75(s,2H),2.22-2.08(m,2H),1.79-1.72(m,3H),1.69-1.58(m,5H),1.42(s,9H),1.20-1.01(m,4H),0.77-0.64(m,2H).

[0584] Step D: 6-Cyclohexyl-2-azaspiro[3.3]heptane. tert-Butyl 6-cyclohexyl-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, 0.537 mmol) was dissolved in a mixture of TFA (2 mL) and dichloromethane (4 mL). The mixture was stirred at room temperature for 2 hours and then concentrated to give the title compound (160 mg, as a crude TFA salt) as a yellow oil, which was used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ 8.28(br s,1H),4.16-4.10(m,2H),3.97(br s,2H),2.34-2.26(m,2H),1.90-1.77(m,3H),1.70-1.58(m,5H),1.19-0.99(m,4H),0.78-0.65(m,2H).

[0585] Step E: (2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. HATU (222 mg, 0.584 mmol) was added to a solution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (50 mg, 0.292 mmol), 6-cyclohexyl-2-azaspiro[3.3]heptane (160 mg, crude product), and DIPEA (189 mg, 1.46 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 3 hours, poured into H2O, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by FCC (eluent: dichloromethane:methanol = 1:0 to 10:1) followed by preparative HPLC using a Welch Xtimate C18, 100 mm x 40 mm x 3 μm column (eluent: 50% to 60% (v / v) CH3CN and HO containing 0.225% HCOOH) to give the title compound (58.4 mg, 60% yield) as a white solid. MS (ESI): C 19 H 28 Calculated mass of N2O3: 332.2; measured m / z: 333.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 6.26(br s,1H),4.32(d,J=1.2Hz,2H),4.07-3.97(m,2H),3.91-3.82(m,2H),2.71-2.61(m,1H),2.59-2.52(m,2H),2.4 6-2.38(m,2H),2.24-2.14(m,2H),1.87-1.75(m,3H),1.73-1.63(m,5H),1.20-1.00(m,4H),0.79-0.64(m,2H).

[0586] Example 70: (2s,4s)-2-(6-(3,5-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0587] [ka]

[0588] The title compound was prepared in a manner similar to that of (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that 3,5-dimethylphenylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 21 H 26 Calculated mass of N2O3: 354.2; measured m / z: 355.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 6.85(s,1H),6.77(s,2H),6.30(br s,1H),4.33(d,J=5.2Hz,2H),4.23-4.12(m,2H),4.00-3.91(m,2H),3.44-3.26(m ,1H),2.78-2.63(m,1H),2.62-2.51(m,4H),2.49-2.39(m,2H),2.37-2.24(m,8H).

[0589] Example 71: (2s,4s)-2-(6-(2,4-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0590] [ka]

[0591] The title compound was prepared in a manner similar to that of (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that 2,4-dimethylphenylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 21 H 26 Calculated mass of N2O3: 354.2; measured m / z: 355.1 [M+H]+ . 1 H NMR(400MHz,CDCl3)δ 7.06-6.94(m,3H),6.26(br s,1H),4.33(d,J=5.6Hz,2H),4.26-4.14(m,2H),3.99-3.89(m,2H),3.55-3.40(m,1 H),2.77-2.55(m,5H),2.49-2.40(m,2H),2.34-2.25(m,5H),2.19(d,J=3.6Hz,3H).

[0592] Example 72: (2s,4s)-2-(6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0593] [ka]

[0594] Step A: tert-Butyl 6-(3-cyclopropylphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate. n-BuLi (0.49 mL, 2.5 M hexane solution, 1.23 mmol) was added dropwise to a solution of 1-bromo-3-cyclopropylbenzene (224 mg, 1.14 mmol) in THF (5 mL) at −78 °C. The resulting mixture was stirred at −78 °C for 0.5 h and then treated with a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 0.947 mmol) in THF (5 mL). The mixture was stirred for an additional 2 h, then poured into saturated aqueous NH4Cl and extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 3:1) to give the title compound (230 mg, 71% yield) as a yellow solid. MS (ESI): C 20 H 27 Calculated mass of NO3: 329.2, measured m / z: 659.4 [2M+H] + . 1H NMR(400MHz,CDCl3)δ 7.26-7.24(m,1H),7.20-7.12(m,2H),6.98(d,J=8.0Hz,1H),4.08(s,2H),3.82(s,2H),2.80-2.73(m,2H), 2.58-2.52(m,2H),2.05(s,1H),1.44(s,9H),1.27(t,J=7.2Hz,1H),1.03-0.95(m,2H),0.74-0.68(m,2H).

[0595] Step B: 6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane. tert-Butyl 6-(3-cyclopropylphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (230 mg, 0.674 mmol) was dissolved in TFA (1 mL). The resulting mixture was stirred for 20 minutes and then treated with triethylsilane (235 mg, 2.02 mmol). The mixture was stirred for an additional 2 hours and then concentrated to give the title compound (220 mg, crude) as a colorless oil, which was used in the next step without further purification. MS (ESI): C 15 H 19 Calculated mass of N: 213.2, measured m / z: 214.1 [M+H] + .

[0596] Step C: (2s,4s)-2-(6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. HATU (222 mg, 0.584 mmol) was added to a solution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 50 mg, 0.292 mmol), 6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane (220 mg, 0.672 mmol), and DIPEA (0.24 mL, 1.46 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 16 h, poured into saturated aqueous NH4Cl, and extracted three times with ethyl acetate. The combined organic extracts were washed three times with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by FCC (eluent: dichloromethane:methyl alcohol = 1:0 to 97:3) followed by preparative HPLC using a Phenomenex Gemini-NX, 80 mm x 30 mm x 3 μm column (eluent: 41% to 51% (v / v) CH3CN and HO containing 10 mM NH4HCO3) to give the title compound (37.9 mg, 35% yield) as a white solid. MS (ESI): C 22 H 26 Calculated mass of N2O3: 366.2; measured m / z: 367.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.23-7.18(m,1H),6.96(d,J=7.6Hz,1H),6.92-6.87(m,2H),6.19(br s,1H),4.34(d,J=5.2Hz,2H),4.23-4.13(m,2H),3.97(d,J=19.2Hz,2H),3.48-3.32(m,1H),2.78-2.66(m,1H),2 .65-2.54(m,4H),2.51-2.41(m,2H),2.39-2.26(m,2H),1.92-1.84(m,1H),0.99-0.93(m,2H),0.72-0.66(m,2H).

[0597] Example 73: (2s,4s)-2-(6-(3-cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0598] [ka]

[0599] The title compound was prepared in a manner similar to that of (2s,4s)-2-(6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 72), except that 1-bromo-3-cyclobutylbenzene (Intermediate 51) was used instead of 1-bromo-3-cyclopropylbenzene. MS (ESI): C 23 H 28 Calculated mass of N2O3: 380.2; measured m / z: 381.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.26-7.22(m,1H),7.07(d,J=8.0Hz,1H),7.00-6.96(m,2H),6.34(br s,1H),4.34(s,1H),4.32(s,1H),4.21(s,1H),4.15(s,1H),3.99(s,1H),3.94(s,1H),3.52(quin,J=8.8Hz,1H),3.47-3.32(m,1H),2 .77-2.65(m,1H),2.64-2.55(m,4H),2.48-2.40(m,2H),2.39-2.28(m,4H),2.19-2.08(m,2H),2.08-1.97(m,1H),1.89-1.79(m,1H).

[0600] Example 74: (2s,4s)-2-(6-(2,3-dihydro-1H-inden-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0601] [ka]

[0602] The title compound was prepared in a manner similar to that of (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that (2,3-dihydro-1H-inden-5-yl)boronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 22 H 26 Calculated mass of N2O3: 366.2; measured m / z: 367.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.16(d,J=7.6Hz,1H),7.04(br s,1H),6.93(d,J=7.6Hz,1H),6.22(br s,1H),4.33(d,J=4.8Hz,2H),4.24-4.11(m,2H),4.01-3.91(m,2H),3.47-3.31(m,1H),2.92-2.83(m ,4H),2.77-2.65(m,1H),2.63-2.53(m,4H),2.49-2.40(m,2H),2.37-2.25(m,2H),2.11-2.02(m,2H).

[0603] Example 75: (2s,4s)-2-(6-phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0604] [ka]

[0605] Triethylamine (110 μL, 794 μmol) was added dropwise to a stirred mixture of 6-phenyl-2-azaspiro[3.3]heptane (Intermediate 49, 25.0 mg, 87.0 μmol), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 14.9 mg, 87.0 μmol), and HATU (41.0 mg, 95.7 μmol) in N,N-dimethylacetamide (870 μL) at 0°C. The reaction mixture was stirred at room temperature for 14 h and then diluted with water (1 mL). Purification by reverse-phase HPLC (MeCN / HO, 0.05% TFA) afforded the title product (23.4 mg, 71.7 μmol, 82% yield). MS (ESI): C 19 H 22 Calculated mass of N2O3: 326.2; measured m / z: 327.2 [M+H] + . 1 H NMR (500 MHz, methanol-d₄) δ 7.34-7.25 (m, 2H), 7.24-7.13 (m, 3H), 4.48 (d, J = 10.6 Hz, 2H), 4.32 (s, 1H), 4.13 (s, 1H), 4.09 (s, 1H), 3.90 (s, 1H), 3.50-3.39 (m, 1H), 2.91-2.78 (m, 1H), 2.66-2.29 (m, 8H).

[0606] Example 76: (2s,4s)-2-(7-phenyl-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0607] [ka]

[0608] The title compound was prepared in a manner similar to that of (2s,4s)-2-(6-phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 75), except that 7-phenyl-2-azaspiro[3.5]heptane (Intermediate 52) was used instead of 6-phenyl-2-azaspiro[3.3]heptane (Intermediate 49). MS (ESI): C 21H 26 Calculated mass of N2O3: 354.2; measured m / z: 355.2 [M+H] + . 1 H NMR(500MHz, methanol-d4)δ 7.32-7.12(m,5H),4.49(d,J=5.38Hz,2H),3.96(s,1H),3.83(s,1H),3.77(s,1H),3.64(s,1H),2.95- 2.82(m,1H),2.59-2.39(m,5H),2.07-1.98(m,2H),1.88-1.79(m,2H),1.68(m,2H),1.58-1.44(m,2H).

[0609] Example 77: (2s,4s)-2-(6-cyclopentyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0610] [ka]

[0611] The title compound was prepared in a manner similar to Example 69, using cyclopentylmagnesium bromide instead of cyclohexylmagnesium bromide in Step A. MS (ESI): C 18 H 26 Calculated mass of N2O3: 318.2; measured m / z: 319.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 6.21(br s,1H),4.32(d,J=1.2Hz,2H),4.06(s,1H),4.00(s,1H),3.94(s,1H),3.88(s,1H),2.74-2.64(m,1H),2.59-2.52(m,2 H),2.47-2.39(m,2H),2.28-2.18(m,2H),2.05-1.91(m,1H),1.89-1.63(m,5H),1.58-1.48(m,4H),1.10-0.99(m,2H).

[0612] Example 78: (2s,4s)-2-(6-cyclobutyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0613] [ka]

[0614] The title compound was prepared in a manner similar to Example 69, using cyclobutylmagnesium bromide instead of cyclohexylmagnesium bromide in Step A. MS (ESI): C 17 H 24 Calculated mass of N2O3: 304.2; measured m / z: 305.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 6.21(br s,1H),4.32(d,J=1.2Hz,2H),4.08-3.84(m,4H),2.74-2.63(m,1H),2.59-2.52(m,2H),2.4 8-2.39(m,2H),2.32-2.12(m,4H),2.01-1.90(m,2H),1.88-1.74(m,4H),1.59-1.49(m,2H).

[0615] Example 79: (2s,4s)-2-(6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0616] [ka]

[0617] Step A: tert-Butyl 6-hydroxy-6-(prop-1-en-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate. Prop-1-en-2-ylmagnesium bromide (0.5 M in THF, 7.1 mL, 3.55 mmol) was added dropwise to a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.37 mmol) in THF (20 mL) at −78 °C. The reaction mixture was stirred for 2 h, then quenched with saturated aqueous NH₄Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0–30% EtOAc in ether) to give the title compound as a white solid (270 mg, 45% yield). MS (ESI): C 14 H 23 Calculated mass of NO3: 253.2; measured m / z: 197.9 [M+2H-tBu] + .

[0618] Step B: tert-Butyl 6-hydroxy-6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate. A solution of TFA (0.41 mL, 5.33 mmol) in DCM (2.0 mL) was added dropwise to a solution of diethylzinc (1 M in hexane, 5.3 mL, 5.33 mmol) in DCM (2.0 mL) at 0 °C. The resulting mixture was stirred for 20 min, then treated with a solution of diiodomethane (0.43 mL, 5.33 mmol) in DCM (2.0 mL) and stirred for an additional 20 min. Finally, a solution of tert-butyl 6-hydroxy-6-(prop-1-en-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate (270 mg, 1.07 mmol) in DCM (4.0 mL) was added to the reaction mixture, and the reaction mixture was stirred for 30 min. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by FCC (0-40% EtOAc in ether) to give the title compound as a white solid (220 mg, 34% yield). MS (ESI): C15 H 25 Calculated mass of NO3: 267.2; measured m / z: 212.0 [M+2H-tBu] + .

[0619] Step C: tert-Butyl 6-(1-methylcyclopropyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate. To a solution of tert-butyl 6-hydroxy-6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate (220 mg, 0.823 mmol) in toluene (3.0 mL), Burgess reagent (methyl N-(triethylammoniumsulfonyl)carbamate) (294 mg, 1.23 mmol) was added, and the reaction mixture was heated to 120 °C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified (FCC, SiO.sub.2, 0-10% EtOAc in ether) to give the title compound as a colorless oil (70 mg, 34% yield).

[0620] Step D: tert-Butyl 6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate. A solution of tert-butyl 6-(1-methylcyclopropyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (850 mg, 3.41 mmol) and wet Pd / C (80 mg, 10 wt.%) in 20 mL of EtOAc was stirred under H (15 psi) at room temperature for 2 h. The reaction mixture was filtered through a pad of Celite®, and the pad was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by RP-HPLC (30–90% ACN in H O containing 0.05% NH) to give the title product as a colorless oil (102 mg, 12% yield).

[0621] Step E: 6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane. TFA (1.5 mL, 19.7 mmol) was added dropwise to a solution of tert-butyl 6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate (102 mg, 0.406 mmol) in DCM (5.0 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (100 mg) as a brown oil, which was used in the next step without further purification.

[0622] Step F: (2s,4s)-2-(6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one. HATU (215 mg, 0.566 mmol) was added to a solution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 64.5 mg, 0.377 mmol), 6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane (100 mg, 0.377 mmol), and DIPEA (0.31 mL, 1.89 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (31-61% ACN in H0 containing 10 mM NHHCO) to give the title compound (110 mg, 96% yield). MS (ESI): C 17 H 24 Calculated mass of N2O3: 304.2; measured m / z: 305.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ 6.12(br s,1H),4.32(s,2H),4.08-3.99(m,2H),3.93-3.83(m,2H),2.73-2.65(m,1H),2.58-2.51(m,2H),2.49-2.40(m,2H) ,2.27-2.15(m,1H),2.08(q,J=10.0Hz,2H),1.81-1.68(m,2H),0.98(s,3H),0.29-0.23(m,2H),0.21-0.15(m,2H).

[0623] Biological data The assay used to measure the in vitro activity of MGL is adapted from that used 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.). This assay combines endogenously expressed MGL from HeLa cells with a test compound and induces [glycerol-1,3- 3 After adding [H]-oleoylglycerol and incubating for 1 hour, the cleaved [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 that particular well / test condition.

[0624] The standard conditions for this assay were: 300 nM [glycerol-1,3- 3 [H]-oleoylglycerol was mixed with human MGL derived from HeLa cells and test compounds for 1 hour, after which the reaction mixture was filtered through activated charcoal and tritium was measured in the flow-through fraction. The test compound concentration in the screening mode was 10 μM, and the IC 50The highest concentration of compound in the assay is determined empirically. MGL is the major hydrolase in HeLa cells / cell homogenates.

[0625] [Table 3-1]

[0626] [Table 3-2]

[0627] [Table 3-3]

[0628] [Table 3-4] NT means not tested. The present invention includes the following embodiments. [Claim 1] Compounds of formula (I): [ka] [In the formula, X is CH 2 or O, R 1 is H, R 2a and R 2b are each independently H and C 1~4 alkyl, R 3 teeth, (i) Halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-OH, OC 1~6 Alkyl, OC 1~6 Haloalkyl, SC 1~6 Alkyl, SF 5 , Si(CH 3 ) 3 , N.R. a R b 、C 3~6 Cycloalkyl, OC 3~6 phenyl, benzyl, or monocyclic heteroaryl, each optionally substituted with one, two, or three substituents selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl, provided that each cycloalkyl, phenyl, or pyridyl is selected from one or two C 1~4 Alkyl, C 1~4 or two adjacent ring substituents on a phenyl, benzyl, or monocyclic heteroaryl are fused together with the atoms to which they are attached to form a monocyclic C 5~6 cycloalkyl or heterocycloalkyl rings, each ring optionally containing one or two C 1~4 Alkyl, C 1~4 substituted with haloalkyl or halo groups; R a and R b are each independently H or C 1~4 alkyl), (ii) C 1~4 bicyclic heteroaryl optionally substituted with alkyl or halo, and (iii)C 1~4 Alkyl, C 1~4 C optionally substituted with haloalkyl or halo 3~6 Alkyl or C 3~6 cycloalkyl; n, m, o, and p are each independently 1 or 2. or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. [Claim 2] Compounds of formula (I):

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Claims

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

2. Compounds of formula (I): 【Chemistry 2】 [In the formula, X is CH ２ or O, R １ is H, R ２ａ and R ２ｂ are each independently H and C １～４ alkyl, R ３ is C ３～６ Cycloalkyl; C １～４ Alkyl-substituted C ３～６ Cycloalkyl; Phenyl; Halo, C １～６ Alkyl, C １～６ Haloalkyl, OC １～６ Alkyl, OC １～６ Haloalkyl, and CH ３ or CF ３ C optionally substituted with ３～６ phenyl substituted with 1 or 2 members each independently selected from cycloalkyl; halo, C １～６ Alkyl, and C １～６ pyridyl substituted with 1 or 2 members each independently selected from haloalkyl; １～６ Alkyl-substituted pyrimidyl; 【Transformation 3】 is selected from n, m, o, and p are each independently 1 or 2. or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

3. X is CH ２ 3. The compound according to claim 1 or 2, wherein

4. 3. The compound of claim 1 or 2, wherein X is O.

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

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

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

8. R ３ The compound according to any one of claims 1 to 4, wherein is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

9. R ３ but, 【Chemistry 4】 The compound according to any one of claims 1 to 4,

10. R ３ is phenyl, or Cl, F, CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ , C.F. ３ , OCH ３ , OCH ２ CH ３ , OCF ３ , cyclopropyl, CF ３ 5. The compound of claim 1, wherein the phenyl is substituted with one or two members independently selected from cyclopropyl substituted with cyclopropyl, and cyclobutyl.

11. R ３ but, 【Transformation 5】 The compound according to any one of claims 1 to 4,

12. R ３ but, 【Transformation 6】 The compound according to any one of claims 1 to 4,

13. R ３ but, 【Transformation 7】 The compound according to any one of claims 1 to 4,

14. R ３ The compound of any one of claims 1 to 4, wherein is 4-trifluoromethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-cyclopropylphenyl.

15. The compound according to any one of claims 1 to 4, wherein n and o are each 1.

16. The compound according to any one of claims 1 to 4, wherein n and o are each 2.

17. The compound according to any one of claims 1 to 4, wherein n is 1 and o is 2.

18. The compound according to any one of claims 1 to 4, wherein m and p are each 1.

19. The compound according to any one of claims 1 to 4, wherein m and p are each 2.

20. The compound according to any one of claims 1 to 4, wherein m is 1 and p is 2.

21. The compound according to any one of claims 1 to 4, wherein m, n, o, and p are each 1.

22. The compound according to any one of claims 1 to 4, wherein m, n, and p are each 1 and o is 2.

23. The compound according to any one of claims 1 to 4, wherein m, n, and o are each 1 and p is 2.

24. The compound according to any one of claims 1 to 4, wherein n and o are each 2, and m and p are each 1.

25. The compound according to any one of claims 1 to 4, wherein n and o are each 1, and m and p are each 2.

26. The compound according to any one of claims 1 to 4, wherein n, o, and p are each 2 and m is 1.

27. (2s,4s)-2-(2-phenyl-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(p-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(o-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(m-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-[3-(trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(2-(tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-(2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; 2-[2-[3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-[2-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-[2-[3-chloro-4-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-[2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-[2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-(2-(5-(tert-butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-(2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-[2-(o-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-[2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-[2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl]-5-azaspiro[3.4]octan-6-one; (2r,4s)-2-(2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-[2-(2-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-8-methyl-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-phenyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2r, 4S ＊ )-2-((R ＊ )-6-phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; (2nd, 4th round ＊ )-2-((S ＊ )-6-phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-((R ＊ )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s, 4R ＊ )-2-((S ＊ )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2r, 4S ＊ )-2-((R ＊ )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; (2nd, 4th round ＊ )-2-((S ＊ )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-(4-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2r,4s)-2-(6-cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(2-(4-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(3-isopropylphenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (rac)-(2r,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro[3.4]octan-6-one; (rac)-(2s,4s)-2-(6-(4-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(2-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(m-tolyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(3,4-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(3,5-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(2,4-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(3-cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-(2,3-dihydro-1H-inden-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(7-phenyl-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-(6-cyclopentyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2S,4s)-2-(6-cyclobutyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and (2s,4s)-2-(6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

28. (2r,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-((R ＊ )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s, 4R ＊ )-2-((S ＊ )-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one, and compounds selected from pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers.

29. Structure of Formula (IA): 【Transformation 8】 [In the formula, X is CH ２ or O, R ２ａ and R ２ｂ are each independently H and CH ３ is selected from R ３ is C ３～６ Cycloalkyl; C １～４ Alkyl-substituted C ３～６ Cycloalkyl; phenyl; C １～６ Alkyl, C １～６ Haloalkyl, and C ３～６ phenyl substituted with one or two members each independently selected from cycloalkyl; and 【Chemistry 9】 is selected from m and p are each independently 1 or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

30. Structure of formula (IB): 【Chemistry 10】 [In the formula, X is O, R ３ is phenyl, and C １～６ phenyl substituted with alkyl; m and p are each 1; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

31. Structure of formula (IC): 【Chemistry 11】 [In the formula, X is CH ２ or O, R ２ａ and R ２ｂ are each independently H and CH ３ is selected from R ３ is C ３～６ Cycloalkyl; Phenyl; Halo, C １～６ Alkyl, C １～６ Haloalkyl, OC １～６ Alkyl, OC １～６ Haloalkyl, and C ３～６ phenyl substituted with 1 or 2 members each independently selected from cycloalkyl; halo, C １～６ Alkyl, and C １～６ pyridyl substituted with 1 or 2 members each independently selected from haloalkyl; １～６ Alkyl-substituted pyrimidyl; 【Chemistry 12】 is selected from m and p are each independently 1 or 2; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

32. (A) a therapeutically effective amount of at least one compound according to any one of claims 1 to 31; (B) at least one pharmaceutically acceptable excipient.

33. 33. The pharmaceutical composition of claim 32, wherein the compound is a compound of claim 27.

34. 32. A pharmaceutical composition for treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by MGL receptor activity, comprising at least one compound according to any one of claims 1 to 31.

35. 35. The pharmaceutical composition of claim 34, wherein the MGL receptor-mediated disease, disorder, or condition is selected from pain, a psychiatric disorder, a neurological condition, cancer, and an ophthalmic condition.

36. 35. The pharmaceutical composition of claim 34, wherein the MGL receptor-mediated disease, disorder or condition is selected from major depressive disorder, treatment-resistant depression, anxious depression, autism spectrum disorder, Asperger's syndrome, and bipolar disorder.

37. 35. The pharmaceutical composition of claim 34, wherein the MGL receptor-mediated disease, disorder or condition is inflammatory pain.

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