Aminocyclobutanes as monoacylglycerol lipase modulators

Abstract

The present invention relates to aminocyclobutane compounds of formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof, pharmaceutical compositions containing same, and methods of using same, including methods of treating disease states, disorders, and conditions associated with MGL modulation, such as those associated with pain, psychiatric disorders, neurological disorders (including, but not limited to, major depressive disorder, treatment-resistant depression, anxiety-related depression, autism spectrum disorder, Asperger's syndrome, bipolar disorder), cancer, and ophthalmic conditions: 1 , R 2a , R 2b , R 3 , and R 4 is defined herein. [Formula 1] TIFF2023518556000128.tif21128

Description

[Technical Field]

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

[0002] Cannabis 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 responsible for the breakdown of 2-AG into 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 susceptibility to depression (Hauer et al., Rev Neurosci., 2012, 23(5-6):681-90). Decreased circulating concentrations 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 2-AG concentrations, which correlated with the onset of a decrease 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 have been used clinically to treat pain, spasticity, emesis, and anorexia (Di Marzo, et al., Annu Rev Med., 2006, 57:553-74; Ligresti et al., Curr Opin Chem Biol., 2009, Jun;13(3):321-31). Therefore, MGL modulators, including MGL inhibitors, are also useful for these indications. MGL exerts CB1-dependent analgesic effects in animal models of noxious chemical, inflammatory, thermal, and neuropathic pain (Guindon et al., Br J Pharmacol., 2011, Aug;163(7):1464-78; Kinsey et al., J Pharmacol Exp Ther., 2009, Sep;330(3):902-10; Long et al., Nat Chem Biol., 2009, Jan;5(1):37-44). MGL blockade reduces mechanical and acetone-induced cold allodynia in mice subjected to chronic sciatic nerve constriction injury (Kinsey et al., J Pharmacol Exp Ther., 2009, Sep;330(3):902-10). MGL inhibition results in an opiate-sparing event accompanied by decreased tolerance, constipation, and cannabis-like side effects (Wilkerson et al., J Pharmacol Exp Ther., 2016, Apr;357(1):145-56). MGL blockade is protective in models of inflammatory bowel disease (Alhouayek et al., FASEB J., 2011, Aug;25(8):2711-21). MGL inhibition also reverses paclitaxel-induced nociceptive behavior and proinflammatory markers in a mouse model of chemotherapy-induced neuropathy (Curry et al., J Pharmacol Exp Ther., 2018, Jul;366(1):169-18). MGL inhibitors are also potentially useful for treating chronic bladder inflammatory conditions, such as interstitial cystitis (Chinnadurai et al., 2019, Oct;131:109-321).

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

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

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

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

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

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

[0014] Formula (I):

[0015] [ka] (In the formula, X is CH2 or O; R 1 is H, R 2a and R 2b are each independently H and C 1-4 alkyl; R 3 teeth, (i) each optionally containing halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, OC 1-6 Alkyl, OC 1-6 Haloalkyl, SC 1-6 Alkyl, SF5, Si(CH3)3, NR a R b , C 3-6 Cycloalkyl, OC 3-6 Phenyl, benzyl, or monocyclic heteroaryl substituted with one, two, or three substituents selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl optionally contains one or two C1-4 Alkyl, C 1-4 or substituted with haloalkyl or halo groups, or two adjacent ring substituents in the phenyl, benzyl, or monocyclic heteroaryl, taken together with the atoms to which they are attached, form a fused monocyclic C 5-6 Forming a cycloalkyl or heterocycloalkyl ring, each ring 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, phenyl, benzyl, or monocyclic heteroaryl; (ii) Optionally, C 1-4 alkyl- or halo-substituted bicyclic heteroaryl; and (iii) Optionally, C 1-4 Alkyl, C 1-4 Haloalkyl or halo-substituted C 3-6 Alkyl or C 3-6 cycloalkyl Selected from; R 4 is C 1-6 alkyl) Described herein are compounds of the formula: and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

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

[0017] [ka] (In the formula, X is CH2 or O; R 1 is H, R 2a and R 2b are H, R 3 is C 1-6 Alkyl (optionally C 3-6 alkyl);C3-6 cycloalkyl; benzyl; phenyl; each independently halo, C 1-6 Alkyl, OC 1-6 Alkyl, C 3-6 Cycloalkyl and C substituted with CH3 or CF3 3-6 Phenyl substituted with one or two members selected from cycloalkyl; 2,3-dihydro-1H-inden-5-yl; bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and 5,6,7,8-tetrahydronaphthalen-2-yl. is selected from R 4 is C 1-6 alkyl) and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof. DETAILED DESCRIPTION OF THE INVENTION

[0018] As used herein, the terms "comprise," "contain," and "include" are used in their open, non-limiting sense.

[0019] Unless specifically limited in a particular use, the term "alkyl" refers to a straight- or branched-chain alkyl group having 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that are deemed equivalent to any one of the above examples in light of ordinary skill in the art and the teachings provided herein. "C1-6 alkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain. "C1-4 alkyl" refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain.

[0020] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic, or spiropolycyclic carbocycle having 3 to 12 ring atoms per carbocycle. Illustrative cycloalkyl groups include the following entities in the form of appropriately bonded moieties:

[0021] [ka]

[0022] The term "halogen" or "halo" refers to chlorine, fluorine, bromine, or iodine.

[0023] The term "haloalkyl" refers to a straight- or branched-chain alkyl group having 1 to 6 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. 1-4 The term "haloalkyl," as used herein, refers to a straight- or branched-chain alkyl group having 1 to 4 carbon atoms in the chain, optionally with a hydrogen replaced by a halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF), difluoromethyl (CFH), monofluoromethyl (CHF), pentafluoroethyl (CFCF), tetrafluoroethyl (CHFCF), monofluoroethyl (CHCHF), trifluoroethyl (CHCF), tetrafluorotrifluoromethylethyl (CF(CF)), as well as groups deemed equivalent to any one of the foregoing examples given ordinary skill in the art and the teachings provided herein.

[0024] 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.

[0025] [ka]

[0026] The term "heterocycloalkyl," as used herein, refers to a ring system that is non-aromatic, in which 1 to 4 ring atoms are independently O, N, or S, and the remaining ring atoms are carbon atoms, and which may optionally be fused to another ring (aromatic or heteroaromatic). Non-limiting examples of illustrative heterocycloalkyls include:

[0027] [ka]

[0028] 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).

[0029] The term "phenyl" refers to the following moiety:

[0030] [ka] Represents.

[0031] The term "2,3-dihydro-1H-inden-5-yl" refers to the moiety:

[0032] [ka] Represents.

[0033] The term "bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl" refers to the moiety:

[0034] [ka] Represents.

[0035] The term "5,6,7,8-tetrahydronaphthalen-2-yl" refers to the moiety:

[0036] [ka] Represents.

[0037] Those of ordinary skill in the art will understand that the species of heteroaryl, heterocycloalkyl, cycloalkyl, or 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 on a given ring, the binding of each substituent is independent of all others. The groups listed or exemplified above are not exhaustive.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] Any formula given herein is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have the structure depicted in the formula given herein except that one or more atoms are replaced in enriched form with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention in excess of natural abundance include, respectively: 2 H (or chemical symbol D), 3 H (or chemical symbol T), 11 C. 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, and 125 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Such isotopically labeled compounds are useful in metabolic studies, preferably 14 C), reaction kinetic studies (e.g., 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F or 11 C labeled compounds may be particularly preferred for PET or SPECT studies. Additionally, heavier isotopes, such as deuterium (i.e., 2Substitution with, for example, H, or D, may confer certain therapeutic advantages as a result of greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by practicing the schemes described below or the procedures disclosed in the Examples and Preparations by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents.

[0048] When referring to any formula provided herein, the selection of a particular moiety from a list of possible species for a specified variable is not intended to define the same selection of that species for the variable elsewhere. In other words, when a variable appears more than once, the selection of a species from a specified list is independent of the selection of the species for the same variable elsewhere in the formula, unless otherwise indicated.

[0049] 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).

[0050] 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 the Q and R groups can each be H or F, the selection of H or F for the Q group is made independently of the selection of H or F for the R group, and therefore the selection of the assignment for the Q group does not determine or condition the selection of the assignment for the R group, unless expressly indicated otherwise, and vice versa. In this regard, the exemplary claim language will be interpreted as "each of Q and R is independently H or F" or "each of Q and R is independently selected H and F."

[0051] 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.

[0052] 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 any case, as would be recognized by one skilled in the art. Since it is not necessary to name every embodiment that would be recognized by a skilled artisan, the structures of zwitterionic compounds related to the compounds of the present invention are not explicitly shown herein. However, they are also part of the embodiments of the present invention. Because the interactions and transformations in a given medium that lead to various forms of a given compound are known to one skilled in the art, further examples related thereto are not provided herein.

[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] 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;S1 例 is S2 and S 2 例 is S3;S1 例 is S2 and S 2 例 is S3;S1 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. 例 is S2 and S 2 例 is S4; and the equivalents of each of such alternatives refer to embodiments of the invention provided herein. Therefore, the shorter term "S1 例 is one of S1 and S2, and S 2 例 is one of S3 and S4" is used for brevity purposes and not as a limitation. Therefore, the shorter term "S1 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.

[0055] 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; as a second example in terms of substituents, 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. 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 brevity purposes and not as a limitation. Therefore, the shorter term "S 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.

[0056] Nomenclature “C i -C j " (j>i) when applied herein to a class of substituents is meant to refer to embodiments of the invention in which each and every number of carbon members from i to j, inclusive, is independently realized. As an example, the term C1-C3 independently refers to an embodiment having one carbon member (C1), an embodiment having two carbon members (C2), and an embodiment having three carbon members (C3).

[0057] "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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] The compounds of the present invention (collectively "active agent(s)"), including the pharmaceutically acceptable salts thereof, whether alone or in combination, are useful as MGL modulators in the methods of the present invention. Such methods of modulating MGL include the use of a therapeutically effective amount of at least one chemical entity of the present invention.

[0063] 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."

[0064] Thus, the present invention relates to a method of treating a subject diagnosed with or suffering from a disease, disorder, or condition associated with MGL receptor activity using the active agents described herein. As used herein, the term "treat" or "treatment" is intended to refer to the administration of an active agent or composition of the present invention to a subject for the purpose of providing a therapeutic or prophylactic benefit through modulation of MGL receptor activity. Treatment includes reversing, ameliorating, alleviating, arresting the progression of, reducing the severity of, or preventing a disease, disorder, or condition, or one or more symptoms of such a disease, disorder, or condition associated with MGL modulation. The term "subject" refers to a mammalian patient, e.g., a human, in need of such treatment.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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, syndrome, 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.

[0069] 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).

[0070] 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.

[0071] 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, co-administered separately with 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 reduced required dosage of the active agent according to the present invention.

[0072] When referring to inhibiting a target, "effective amount" means an amount sufficient to affect MGL regulation.

[0073] It is contemplated that pharmaceutical compositions of the invention may be formulated using the active agents of the invention, alone or in combination with one or more additional active ingredients, and include a therapeutically effective amount of at least one active agent according to the invention.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] For oral administration, the active agents of the present invention may be provided in tablet or capsule form, or as a solution, emulsion, or suspension. To prepare an oral composition, the active agent may be formulated to obtain a dosage for, for example, a 70 kg human; an exemplary range for a suitable dosage is about 1 to 1000 mg / day in single or multiple dosage units.

[0078] 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.

[0079] Capsules for oral administration include hard and soft gelatin or (hydroxypropyl)methylcellulose capsules. For hard gelatin capsules, one or more active ingredients may be mixed with a solid, semisolid, or liquid diluent. Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or another suitable vehicle before use. Such liquid compositions may optionally contain pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid); wetting agents such as lecithin; and, optionally, flavorings or coloring agents.

[0080] 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.

[0081] 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.

[0082] 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).

[0083] 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.

[0084] 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.

[0085] 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 diseases, conditions, or disorders that cause 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.

[0086] 1) Pain; Examples of inflammatory pain include, but are not limited to, pain due to a disease, pathological condition, syndrome, disorder, or painful condition 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.

[0087] Inflammatory hyperalgesia / hypersensitivity is a type of inflammatory pain. Examples of inflammatory hyperalgesia include diseases, conditions, disorders, or painful conditions such as inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal disorders, skin disorders, post-operative pain, headache, toothache, burns, sunburn, insect bites, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis / hypersensitivity and / or skin allergies, pruritus, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases such as Crohn's disease, ulcerative colitis, benign prostatic hyperplasia cough, and nasal hypersensitivity.

[0088] 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 is directed to a method for treating inflammatory somatic hyperalgesia in which hypersensitivity to thermal, mechanical, and / or chemical stimuli is present, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

[0089] Further embodiments of the present invention are directed to methods for treating, ameliorating, and / or preventing neuropathic pain, including but not limited to, cancer, neuropathy, spinal and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndromes, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatica, mandibular joint neuralgia, peripheral neuritis, polyneuropathy, stump pain, phantom limb pain, fractures, oral neuropathic pain, Charcot pain, complex pain, and the like. The term "pain" includes pain caused by diseases, syndromes, 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, genicular neuralgia, glossopharyngeal neuralgia, cluster headache, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, post-herpetic neuralgia, burning mouth syndrome, red neuralgia, Sluder's neuralgia, splenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian neuralgia.

[0090] One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of a neuropathy-related allodynic state in which there is hypersensitivity to cold stimuli. Examples of neuropathic cold allodynia include allodynia due to diseases, syndromes, pathological conditions, disorders, or pain conditions, including neuropathic pain (neuralgia), pain caused by surgery or trauma to the spinal cord and peripheral nerves, 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.

[0091] In a further embodiment, the present invention relates to a method for treating, ameliorating, and / or preventing neuropathic cold allodynia in which hypersensitivity to cold stimuli is present, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0092] 2) Mental disorders Examples of mental disorders include anxiety disorders such as social anxiety disorder, post-traumatic stress disorder, phobias, social phobia, specific phobias, panic disorder, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder; 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, including but not limited to bipolar disorder type I depression, mania, 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, euthymia; premenstrual dysphoric disorder; psychosis; and developmental disorders such as autism spectrum disorder and Asperger's syndrome.

[0093] 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.

[0094] 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).

[0095] 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.

[0096] 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.

[0097] In some embodiments of Formula (I), X is CH. In some embodiments, X is O.

[0098] In some embodiments, R 3 is tert-butyl. In some embodiments, R 3 teeth,

[0099] [ka]

[0100] [ka] In some embodiments, R 3 teeth,

[0101] [ka] In some embodiments, R 3 is benzyl, phenyl, or phenyl substituted with one or two members each independently selected from F, CH, CHCH, CH(CH), C(CH), OCH, cyclopropyl, cyclopropyl substituted with CF, and cyclobutyl. In some embodiments, R 3 is.

[0102] [ka]

[0103] In some embodiments, R 3 is 3,5-dimethylphenyl, 3-ethyl-5-methylphenyl, 4-ethyl-3-methylphenyl, 3-isopropylphenyl, or 3-tert-butylphenyl.

[0104] In some embodiments, R 3 are phenyl; or each independently 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 3, OC 3-6 In some embodiments, R is phenyl substituted with one, two, or three members selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl. 3 are each independently halo, C 1-6 Alkyl, C 1-6 Haloalkyl, OC 1-6 Alkyl, OC 1-6 In some embodiments, R is phenyl substituted with one, two, or three members selected from haloalkyl, SCH, SF, or Si(CH). 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.

[0105] In some embodiments, R 3 teeth,

[0106] [ka] is.

[0107] In some embodiments, R 3 is 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl, or 3-(1-methylcyclopropyl)phenyl.

[0108] In some embodiments, R 2a is H and R 2b is CH3. In other embodiments, R 2a and R 2b are each CH. In some embodiments, R 2a and R 2b are each H.

[0109] In some embodiments, X is O and R 2a and R 2b are each H. In some embodiments, X is CH and R 2a and R 2b are each H. In some embodiments, X is O and R 3 are each independently F, C 1-6 and phenyl substituted with one or two members selected from alkyl, OCH3, cyclopropyl, cyclopropyl substituted with CH3 or CF3, and cyclobutyl.

[0110] In some embodiments, R 4 is CH3 or CH2CH3.

[0111] A further embodiment of the present invention is as follows:

[0112] [Table 1-1]

[0113] [Table 1-2] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0114] A further embodiment of the present invention comprises: (2r,4S)-N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and (2s,4S)-N-((1s,3S)-3-(4-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[0115] 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) at least one pharmaceutically acceptable excipient.

[0116] A further embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the compounds in Table 1, 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 the compounds of Table 1, and at least one pharmaceutically acceptable excipient.

[0117] Also within the scope of the present invention are enantiomers and diastereomers of compounds of formula (I). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of compounds of formula (I). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of compounds of formula (I) and pharmaceutically active metabolites of compounds of formula (I).

[0118] Also within the scope of the present invention are isotopic variants of the compounds of formula (I), such as, for example, deuterated compounds of formula (I). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides, or solvates of isotopic variants of the compounds of formula (I). Also within the scope of the present invention are pharmaceutically acceptable prodrugs of isotopic variants of the compounds of formula (I), and pharmaceutically active metabolites of isotopic variants of the compounds of formula (I).

[0119] A further embodiment of the present invention is a method for treating a subject suffering from or diagnosed with a disease, disorder, or condition mediated by MGL receptor activity, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound selected from the group consisting of a compound of formula (I), its pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers, including enantiomers and diastereomers, of the compound of formula (I), isotopic variants of the compound of formula (I), and pharmaceutically acceptable salts of all of the above. Also described herein is the use of a compound of formula (I), or its pharmaceutically acceptable salts, isotopes, N-oxides, solvates, or stereoisomers, in the preparation of a medicament. In some embodiments, the medicament is for treating a disease, disorder, or condition mediated by MGL receptor activity. Also described herein are compounds of formula (I), or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, for use in a method for treating a disease, disorder, or condition mediated by MGL receptor activity.

[0120] 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.

[0121] The abbreviations and acronyms used herein are as follows:

[0122] [Table 2-1]

[0123] [Table 2-2]

[0124] 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.

[0125] [ka]

[0126] According to Scheme 1, R a C 1-4 The alkyl compound of formula (V) 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). The compound of formula (VII) is prepared from the compound 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).

[0127] [ka]

[0128] According to Scheme 2, R a C 1-4Compounds of formula (VII), which is an alkyl group, are reacted with formaldehyde to prepare compounds of formula (VIIIa) and (VIIIb). Compounds of formula (IX) are prepared by hydrogenolysis of compounds of formula (VIIIb) in a solvent such as ethyl acetate (EtOAc) or EtOH in the presence of a catalyst such as palladium on carbon (Pd / C) under an atmosphere of hydrogen gas (H). Compounds of formula (X) are prepared by reaction of compounds of formula (IX) with triphosgene in a solvent such as tetrahydrofuran (THF) in the presence of a base such as TEA. Compounds of formula (XI) are prepared by acidic deprotection of compounds of formula (X) using an acid such as trifluoroacetic acid (TFA) or HCl in dioxane.

[0129] [ka]

[0130] According to Scheme 3, in a solvent such as ACN, in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), R a Compounds of formula (XIIa) and (XIIb) are prepared by a Michael-type reaction between a compound of formula (VII) where X is ethyl and methyl acrylate. Compounds of formula (XIIa) are reductively ring-closed using a reducing agent such as sodium borohydride (NaBH), an additive such as nickel(II) chloride hexahydrate in a suitable solvent such as methanol (MeOH) to give compounds of formula (XIII) where X is CH.

[0131] [ka]

[0132] According to Scheme 4, commercially available or synthetically available aryl halides of formula (XIV), where X is Cl or Br, and R 3 is C 1-6 Alkyl, OC 1-6 Alkyl, C 3-6 Cycloalkyl and CF3-substituted C3-6 (XV) (where M is an aryl group suitably substituted with cycloalkyl, and 5,6,7,8-tetrahydronaphthalen-2-yl) is reacted with magnesium metal as an additive, LiCl in a suitable solvent such as THF, DIBAL-H, etc., at a temperature ranging from about 0° C. to room temperature using the conditions described in Angew. Chem. Int. Ed. 2008, 47, 6802-6806 to provide a compound of formula (XV) (where M is MgLiCl).

[0133] Compounds of formula (XV) where M is Mg can be prepared by the reaction of compounds of formula (XIV) where X is Cl or Br and R 3 is C 1-6 Alkyl, OC 1-6 Alkyl, C 3-6 Cycloalkyl and CF3-substituted C 3-6 It is prepared by magnesium-halogen exchange using iPrMgCl in a suitable solvent such as THF at a temperature of about 0° C. for 2 hours with 5,6,7,8-tetrahydronaphthalen-2-yl (aryl group suitably substituted with cycloalkyl).

[0134] Compounds of formula (XV) where M is Li can be converted to compounds of formula (XIV) where X is Cl or Br and R 3 is prepared by lithium-halogen exchange with a suitably substituted aryl group.

[0135] [ka]

[0136] According to Scheme 5, tert-butylmethyl(3-oxocyclobutyl)carbamate is reacted with an aryl metal halide compound of formula (XV), where X is I, Cl, or Br, and R 3 is C 1-6 Alkyl, OC 1-6 Alkyl, C 3-6Cycloalkyl and CF3-substituted C 3-6 and 5,6,7,8-tetrahydronaphthalen-2-yl) in a suitable solvent such as THF at a temperature ranging from −78° C. to room temperature to give a compound of formula (XVI). Compounds of formula (XVI) are then ionically reduced using conditions known to those skilled in the art, for example by treatment with triethylsilane in a suitable solvent such as trifluoroacetic acid or a mixture of trifluoroacetic acid and DCM at a temperature ranging from 0° C. to room temperature to give compounds of formula (XVII) (wherein R 4 If incomplete reduction to the cyclobutyl ring is observed, excess triethylsilane and TFA can be used to obtain compounds of formula (XVII), where R 4 is CH3).

[0137] [ka]

[0138] According to Scheme 6, a compound of formula (XVI) 3 is C 1-6 Alkyl, OC 1-6 Alkyl, C 3-6 Cycloalkyl and CF3-substituted C 3-6 Treatment of a compound of formula (XVIII) with triethylsilane in a suitable solvent such as trifluoroacetic acid or a mixture of trifluoroacetic acid and DCM (an aryl group suitably substituted with cycloalkyl, and 5,6,7,8-tetrahydronaphthalen-2-yl) provides a compound of formula (XVIII).

[0139] The compound of formula (XVIII) is hydrogenated under conditions known to those skilled in the art or as previously described to give the compound of formula (XVII). For example, the compound of formula (XVIII) can be treated with 10% Pd / C under an atmosphere of H (30 bar) in a solvent such as MeOH at a temperature of 50° C. for 16 hours to give the compound of formula (XVII) (wherein R 4is CH3). If necessary, the compound of formula (XVII) is further purified under conditions known to those skilled in the art by using a three-step sequence involving (1) N-Boc protection, (2) purification using flash column chromatography on silica, and (3) Boc deprotection using TFA in DCM.

[0140] [ka]

[0141] According to Scheme 7, tert-butyl methyl(3-oxocyclobutyl)carbamate is subjected to Wittig olefination using NaH as a base in a suitable solvent such as DMSO at a temperature of 80° C. for 16 hours to give tert-butyl(3-benzylidenecyclobutyl)(methyl)carbamate. Hydrogenation of tert-butyl(3-benzylidenecyclobutyl)(methyl)carbamate, followed by N-Boc cleavage, is carried out using conditions well known to those skilled in the art or as previously described to give 3-benzyl-N-methylcyclobutan-1-amine.

[0142] [ka]

[0143] According to Scheme 8, 1-bromo-3-methyl-5-vinylbenzene is reacted in the presence of TfO, DMA, and 2,4,6-collidine in a formalketene [2 + 2] reaction to give an intermediate iminium salt, which is hydrolyzed in situ to give 3-(3-bromo-5-methylphenyl)cyclobutan-1-one. 3-(3-Bromo-5-methylphenyl)cyclobutan-1-one was then used in Suzuki cross-coupling reactions with 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane; [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dtbpf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)), palladium(II) bis(triphenylphosphine) dichloride (Pd( PPh3)2Cl2), a palladium catalyst such as XPhos-Pd-G2 precatalyst (chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)); a base such as K3PO4, aqueous Na2CO3, Na2CO3, or Cs2CO3 in a suitable solvent such as 1,2-dimethoxyethane, 1,4-dioxane, DMF, water, or a mixture thereof, at a temperature ranging from 60 to 180 °C using microwave or conventional heating for about 30 minutes to 16 hours to give a compound of formula (XX), where R 3 is a phenyl suitably substituted as defined in claim 1).

[0144] [ka]

[0145] According to Scheme 9, a compound of formula (XX) (wherein R 3 is C 1-6 Alkyl, C 3-6

[0033] The compound of formula (XVII) can be prepared by reacting N-benzhydrylethanamine, where R is a cycloalkyl, or a phenyl suitably substituted as described in claim 1, under reductive amination conditions with a suitable amine such as methylamine, N-benzhydrylethanamine, or a reducing agent such as sodium cyanoborohydride (NaBHCN), NaBH(OAc), or NaBH, in the presence of an acidic additive such as titanium(IV) isopropoxide, acetic acid, or the like, in a suitable solvent such as methanol, DCM, 1,2-dichloroethane, THF, or a mixture thereof, at room temperature for 14-24 hours to provide a compound of formula (XVII). If N-benzhydrylethanamine is used in the reductive amination, it can then be hydrogenolyzed under 15 psi of hydrogen gas using a suitable solvent such as Pd / C, a mixture of MeOH and aqueous HCl, or the like, to provide a compound of formula (XVII) where R is a cycloalkyl, or a phenyl suitably substituted as described in claim 1. 4 is CH2CH3).

[0146] [ka]

[0147] According to Scheme 10, a compound of formula (I), wherein R 1 is hydrogen and X is CH or O) are prepared by conventional amide bond forming techniques such as coupling reactions well known to those skilled in the art (such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide-hexafluorophosphate), BOP (benzotriazol-1-yloxy-tris(dimethylamino)phosphonium-hexafluorophosphate), or conversion of an acid to an acid chloride). For example, commercially available or synthetically available compounds of formula (XVII) (wherein R 3 is C 1-6 alkyl; benzyl; phenyl; each independently halo, C 1-6 Alkyl, OC 1-6 Alkyl, C 3-6 Cycloalkyl and CF3-substituted C 3-6The compound (XIX) is preferably a synthetically available, suitably substituted carboxylic acid (including compounds of formulae (XI) and (XIII)), and the acid is reacted 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 (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, optionally in the presence of a catalyst such as hydroxybenzotriazole (HOBt) and / or 4-dimethylaminopyridine (DMAP). The coupling agent may be activated with a halotrisaminophosphonium salt such as hexafluorophosphate (BOP) or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®), a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride, or another suitable coupling agent such as N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 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, and the like, 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).

[0148] 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.

[0149] The compounds prepared according to the above-described 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-described 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 separation methods known to those skilled in the art, such as chiral chromatography, supercritical fluid chromatography (SFC), 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.

[0150] The following specific examples are provided to further illustrate the invention and various preferred embodiments. [Example]

[0151] 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.

[0152] 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.

[0153] 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.

[0154] Normal-phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using prepacked cartridges.

[0155] Preparative reverse-phase high performance liquid chromatography (RP HPLC) was performed by one of the following methods. Method A. Agilent HPLC using an Xterra Prep RP18 column (5 μM, 30x100 or 50x150 mm) or an XBridge C18 OBD column (5 μM, 30x100 or 50x150 mm) at a flow rate of 40 or 80 mL / min, with a mobile phase of 5% ACN in 20 mM NH4OH, held for 2 minutes, followed by a gradient of 5-99% ACN over 15 minutes, then a 5-minute hold at 99% ACN, or or Method B. On an Agilent HPLC equipped with 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), a flow rate of 40 or 80 mL / min was used with a mobile phase of 5% ACN HO (both containing 0.05% TFA) held for 2 min, followed by a gradient of 5 to 99% ACN over 15 min, followed by a 5 min hold at 99% ACN, or or Method C. An ACCQ Prep HPLC equipped with an XBridge C18OBD column (5 μM, 50 × 100) was run at a flow rate of 80 mL / min using a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) with a 1-minute hold, followed by a gradient of 5 to 95% ACN over 12 minutes, followed by a 2-minute hold at 95% ACN. or Method D. Preparative reversed-phase high performance liquid chromatography using a Phenomenex Lux Cellulose-1 150 x 4.6 mm, 5 μm column, a mobile phase of 40% methanol + 0.1% diethylamine, and 60% CO2, isocratic.

[0156] Preparative supercritical fluid chromatography (SFC) was performed using: Method E. SFC instrument equipped with a Phenomenex Lux Cellulose-1 150 x 4.6 mm, 5 μm column, mobile phase of 40% methanol + 0.1% diethylamine, and 60% CO2, isocratic.

[0157] Mass spectra (MS) were obtained on an Agilent series 1100 MSD using electrospray ionization (ESI) in positive mode unless otherwise indicated. Calculated masses correspond to exact masses.

[0158] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker spectrometer. For 1H spectra, all chemical shifts are reported in parts per million (δ) and are relative to residual signals at 7.26, 3.31, and 2.50 ppm for CDCl3, CD3OD, and DMSO-d6, respectively. Multiplicity definitions are as follows: s = singlet, d = doublet, t = triplet, q = quartet, 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.

[0159] Compound names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0160] R * or S * Compounds designated as are enantiomerically pure compounds for which the absolute configuration has not been determined.

[0161] Intermediate 1: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0162] [ka]

[0163] 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; observed m / z: 186.2 [M+H] + .

[0164] 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, 0.584 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.

[0165] Step C: cis-tert-butyl 3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate. To a solution of tert-butyl 3-nitrocyclobutanecarboxylate (89.6 g, 445 mmol) in ACN (1 L) was added formaldehyde (37 wt% in water, 73 mL, 971 mmol). To the reaction mixture was added TEA (62 mL, 444 mmol) dropwise at 0° C., and the reaction was stirred at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by FCC on silica (0→30% EtOAc in heptane) to give the title compound (38.2 g, 37% yield) as a white powder. MS (ESI): C 10 H 17 Calculated mass of NO5: 231.2; observed m / z: 254.1 [M+Na] + trans-tert-butyl 3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate was formed but not isolated.

[0166] Step D: cis-tert-butyl 3-amino-3-(hydroxymethyl)cyclobutanecarboxylate. To a solution of cis-tert-butyl 3-(hydroxymethyl)-3-nitro-cyclobutanecarboxylate (38.2 g, 165 mmol) in EtOAc (600 mL) was added 10% Pd / C (1.9 g). The reaction mixture was stirred under H2 (10 bar) at 50 °C for 1 h. The mixture was filtered through a pad of Celite®. To the filtrate was added 10% Pd / C (1.9 g). The reaction mixture was stirred under H2 (10 bar) at 50 °C for 2 h. The reaction mixture was filtered through a pad of Celite®, and the Celite® was washed with EtOAc. The combined filtrate was evaporated under reduced pressure, and the residue was triturated with diethyl ether (Et2O) to give the title compound (18.6 g, 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] + . 1H 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).

[0167] Step E: cis-tert-butyl 6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solution of cis-tert-butyl 3-amino-3-(hydroxymethyl)cyclobutanecarboxylate (18.6 g, 92.4 mmol) in 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 (NaHCO) (600 mL), and the mixture was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was triturated with EtO to give the title compound (17.7 g, 84% yield) as a white powder. MS (ESI): C 11 H 17 Calculated mass of NO4: 227.1; observed m / z: 228.2 [M+H] + .

[0168] Step F: (2s,4s)-6-Oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. To TFA (180 mL, 235 mmol) was added cis-tert-butyl 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 under reduced pressure, and the residue was triturated with EtO to give the title compound (12.9 g, 96% yield) as a white powder. MS (ESI): mass calculated for C7H9NO3 171.0; m / z found 172.1 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ 12.3 (br s, 1H), 8.08 (s, 1H), 4.34 (s, 2H), 2.79-2.66 (m, 1H), 2.43-2.29 (m, 4H).

[0169] Intermediate 2: (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid.

[0170] [ka]

[0171] Step A: Ethyl 3-nitrocyclobutanecarboxylate. The title compound was prepared analogously to Intermediate 1, Steps A-B, using ethyl 3-oxocyclobutane-1-carboxylate instead of tert-butyl 3-oxocyclobutane-1-carboxylate in Step A. The compound is shown in ESI + Does not ionize by LCMS. 1 H NMR(300MHz, CDCl3)δ 5.02-4.70(m,1H),4.20(q,J=7.2Hz,2H),3.04-2.71(m,5H),1.29(t,J=7.0Hz,3H).

[0172] Step B: cis-Ethyl 3-(3-methoxy-3-oxo-propyl)-3-nitro-cyclobutanecarboxylate. To a solution of ethyl 3-nitrocyclobutanecarboxylate (16.6 g, 95.6 mmol) in ACN (145 mL) was added methyl acrylate (10.3 mL, 114 mmol). DBU (7.1 mL, 47.6 mmol) was added dropwise to the reaction mixture at 0° C., and the reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was diluted with saturated ammonium chloride and EtOAc, and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by FCC on silica (0→15% EtOAc in heptane) to give the title compound (13.6 g, 55% yield) as a colorless liquid. MS (ESI): C 11 H 17Calculated mass of NO6: 259.1; observed m / z: 282.1 [M+Na] + . 1 H NMR (300MHz, Chloroform-d) δ 4.17(q,J=7.1Hz,2H),3.70(s,3H),3.12-2.79(m,3H),2.69-2.49(m,2H),2.48-2.21(m,4H),1.27(t,J=7.1Hz,3H).

[0173] Step C: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic acid. To a solution of cis-ethyl 3-(3-methoxy-3-oxopropyl)-3-nitro-cyclobutanecarboxylate (13.6 g, 52.5 mmol) in MeOH (133 mL) was added nickel(II) chloride hexahydrate (12.5 g, 52.6 mmol). To the reaction mixture, NaBH (10 g, 264 mmol) was added portionwise at -10 °C, and the reaction mixture was stirred at 0 °C for 1 hour. To the reaction mixture, aqueous KCO (47 mL, 141 mmol, 3 M) was added dropwise 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 concentrated under reduced pressure. At this stage, saponification of the crude ester to the carboxylic acid was observed. The residue was purified by FCC on silica eluting with chloroform:methanol:acetic acid (100:0:0 to 9:1:1) to give the title compound (4.8 g, 53% yield) as an off-white powder. MS (ESI): Calculated mass C8H 11 NO3 169.1; m / z measured, 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).

[0174] Intermediate 3: 3-(4-(tert-butyl)phenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0175] [ka]

[0176] Step A: tert-Butyl (3-(4-(tert-butyl)phenyl)-3-hydroxycyclobutyl)(methyl)carbamate. (4-(tert-butyl)phenyl)magnesium bromide (2 M in THF, 376 μL, 753 μmol) was added dropwise to a stirred solution of tert-butyl methyl (3-oxocyclobutyl)carbamate (100 mg, 502 μmol) in tetrahydrofuran (THF) (1.7 mL) at 0 °C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature. After 30 min, the reaction mixture was quenched by adding 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 product (107 mg, 321 μmol, 64% yield) as a yellow oil and as a ca. 4:1 mixture of cis and trans isomers, which was used in Step B without further purification. MS (ESI): C 20 H 31 Calculated mass of NO3, 333.2; observed m / z, 260.1 [M-CH4H8-OH] + .

[0177] Step B: 3-(4-(tert-butyl)phenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt. tert-Butyl (3-(4-(tert-butyl)phenyl)-3-hydroxycyclobutyl)(methyl)carbamate (107 mg, 321 μmol) was dissolved in trifluoroacetic acid (TFA) (1.07 mL), and the resulting solution was stirred at room temperature for 5 minutes. Triethylsilane (369 μL, 2.25 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred vigorously at room temperature for 1 hour. The solvent was then removed in vacuo to give the crude title product, which was used without further purification. MS (ESI): C 15 H 23Calculated mass of N, 217.2; observed m / z, 218.1 [M+H] + .

[0178] Intermediate 4: 3-(3-(tert-butyl)phenyl)-N-methylcyclobutan-1-amine, TFA salt.

[0179] [ka]

[0180] Step A: (3-(tert-butyl)phenyl)magnesium bromide, lithium chloride complex. A vial was charged with a stir bar and lithium chloride (112 mg, 2.64 mmol), sealed with a septum, and dried under vacuum using a heat gun. The vial was cooled to room temperature and backfilled with N. Magnesium turnings (128 mg, 5.28 mmol) were then rapidly added, and the vial was again evacuated and backfilled with N. THF (5.3 mL) was added, and the resulting mixture was stirred vigorously at room temperature until all LiCl was dissolved (approximately 5 min). Diisobutylaluminum hydride (1 M in THF, 21.1 μL) was added dropwise, and the resulting pale yellow solution was stirred vigorously at room temperature for 5 min. The reaction vial was cooled to 0 °C, and 1-bromo-3-(tert-butyl)benzene (363 μL, 2.11 mmol) was added dropwise. The ice bath was removed and the resulting pale yellow mixture was stirred at room temperature for 2 hours. The resulting brown solution containing the title product was used as is, assuming a concentration of 0.37 M.

[0181] Step B: 3-(3-(tert-butyl)phenyl)-N-methylcyclobutan-1-amine, trifluoroacetate. The title compound was prepared analogously to Intermediate 3, using (3-(tert-butyl)phenyl)magnesium bromide, lithium chloride complex in place of 4-(tert-butyl)phenyl)magnesium bromide in Step A. MS (ESI): C 15 H 23 Calculated mass of N, 217.2; observed m / z, 218.1 [M+H] + .

[0182] Intermediate 5: 3-(3,5-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0183] [ka]

[0184] Step A: tert-Butyl (3-(3,5-dimethylphenyl)-3-hydroxycyclobutyl)(methyl)carbamate. (3,5-Dimethylphenyl)magnesium bromide (0.5 M in THF, 8.73 mL, 4.37 mmol) was added dropwise to a stirred solution of tert-butyl methyl (3-oxocyclobutyl)carbamate (670 mg, 3.36 μmol) in tetrahydrofuran (THF) (1.7 mL) at 0 °C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature. After 1 h, the reaction mixture was quenched by adding 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 product (646 mg, 2.12 mmol, 63% yield) as a yellow oil, which was used in Step B without further purification. MS (ESI): C 18 H 27 Calculated mass of NO3, 305.2; observed m / z, 232.2 [M-CH4H8-OH] + .

[0185] Step B: 3-(3,5-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate. tert-Butyl (3-(3,5-dimethylphenyl)-3-hydroxycyclobutyl)(methyl)carbamate (670 mg, 2.19 mmol) was dissolved in trifluoroacetic acid (TFA) (7.3 mL), and the resulting solution was stirred at room temperature for 5 minutes. Triethylsilane (3.5 mL, 21.9 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred vigorously at room temperature for 20 hours. The solvent was then removed in vacuo to give the crude title product, which was used without further purification. MS (ESI): C 13 H 19 Calculated mass of N, 189.2; observed m / z, 190.2 [M+H] + .

[0186] Intermediate 6: 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0187] [ka]

[0188] Step A. tert-Butyl (3-hydroxy-3-(3-isopropylphenyl)cyclobutyl)(methyl)carbamate. In a round-bottom flask, n-BuLi (1.6 M in hexane, 1.2 mL, 1.8 mmol, 1.2 equiv.) was added dropwise to a solution of 1-bromo-3-isopropylbenzene (300 mg, 1.5 mmol, 1 equiv.) in dry THF (10 mL, 7.7 mL / mmol) at −78° C. The reaction mixture was stirred at −78° C. for 40 min. Then, a solution of tert-butyl-N-methyl-N-(3-oxocyclobutyl)carbamate (300 mg, 1.5 mmol, 1 equiv.) in dry THF (2 mL) was added dropwise, and the reaction mixture was stirred at the same temperature for an additional 1.5 h. The reaction mixture was warmed to room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, and the organic phase was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo to give the title product (480 mg, crude) as a brown oil, which was used in Step B without further purification. MS (ESI): C 19 H 29 Calculated mass of NO3, 319.2; observed m / z, 246.1 [M-C4H8-OH] + .

[0189] Step B. 3-(3-Isopropylphenyl)-N-methylcyclobut-2-en-1-amine, TFA salt. In a round-bottom flask, trifluoroacetic acid (0.11 mL, 1 eq.) was added to a mixture of tert-butyl(3-hydroxy-3-(3-isopropylphenyl)cyclobutyl)(methyl)carbamate (480 mg, 1.5 mmol, 1 eq.), triethylsilane (1.68 mL, 7 eq.), and dichloromethane (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and then additional trifluoroacetic acid (0.78 mL) was added to the reaction mixture and stirred at room temperature for 16 hours. The solvent was then removed in vacuo, and excess trifluoroacetic acid was co-distilled with toluene. The crude title product (302 mg, crude) thus obtained as a brown oil was used in Step C without further purification. MS (ESI): C 14 H 19 Calculated mass of N, 201.2; observed m / z, 202.1 [M+H]+ .

[0190] Step C. 3-(3-Isopropylphenyl)-N-methylcyclobutan-1-amine, TFA salt. In a high pressure vessel, palladium on carbon (10%, 15% m / m) was added to a solution of 3-(3-isopropylphenyl)-N-methylcyclobut-2-en-1-amine, trifluoroacetate (300 mg, 1.5 mmol) in methanol (50 mL, 33 mL / mmol). The vessel was sealed, charged with hydrogen (30 bar), and heated at 50° C. for 16 hours. The system was cooled, and the reaction mixture was filtered through Celite®. The solvent was removed under vacuum to give the crude title product (300 mg, crude) as a light brown oil, which was used without further purification. MS (ESI): C 14 H 21 Calculated mass of N, 203.2; observed m / z, 204.2 [M+H] + .

[0191] Intermediate 7: 3-(3-Methoxyphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0192] [ka]

[0193] The title compound was prepared analogously to Intermediate 6, using 1-bromo-3-methoxybenzene instead of 1-bromo-3-isopropylbenzene and isopropylmagnesium chloride instead of n-BuLi in Step A. MS(ESI): C 12 H 17 Calculated mass of N, 191.1; observed m / z, 192.1 [M+H] + .

[0194] Intermediate 8: 3-(4-isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0195] [ka]

[0196] Step A. tert-Butyl (3-hydroxy-3-(4-isopropylphenyl)cyclobutyl)(methyl)carbamate. In a round-bottom flask, n-BuLi (1.6 M in hexane, 784 μL, 1.26 mmol, 1.25 equiv.) was added dropwise to a solution of 1-bromo-4-isopropylbenzene (200 mg, 1.00 mmol, 1 equiv.) in dry THF (4 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h. Then, a solution of tert-butyl-N-methyl-N-(3-oxocyclobutyl)carbamate (200 mg, 1.00 mmol, 1 equiv.) in dry THF (4 mL) was added dropwise, and the reaction mixture was stirred at the same temperature for an additional 2 h. The reaction mixture was warmed to room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, and the organic phase was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo to give the title product (321 mg, crude) as a brown oil, which was used without further purification. MS (ESI): C 19 H 29 Calculated mass of NO3, 319.2; observed m / z, 246.1 [M-C4H8-OH] + .

[0197] Step B. 3-(4-Isopropylphenyl)-N-methylcyclobut-2-en-1-amine, trifluoroacetate salt. In a round-bottom flask, trifluoroacetic acid (150 μL, 1 equiv.) was added to a mixture of tert-butyl(3-hydroxy-3-(4-isopropylphenyl)cyclobutyl)(methyl)carbamate (641 mg, 2.01 mmol, 1 equiv.), triethylsilane (2.24 mL, 7 equiv.), and dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and then additional trifluoroacetic acid (1 mL) was added to the reaction mixture and stirred at room temperature for 16 hours. Thereafter, the solvent was removed in vacuo, and excess trifluoroacetic acid was co-distilled with toluene. The crude title product (404 mg, crude) thus obtained as a brown oil was used without further purification. MS (ESI): C 14 H 19Calculated mass of N, 201.2; observed m / z, 202.1 [M+H] + .

[0198] Step C. 3-(4-Isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate. In a pressure vessel, palladium on carbon (10%, 15% m / m) was added to a solution of 3-(4-isopropylphenyl)-N-methylcyclobut-2-en-1-amine, trifluoroacetate (404 mg) in methanol (50 mL) at 0° C. under a N atmosphere. The vessel was sealed, charged with hydrogen (30 bar), and heated at 50° C. for 16 h. The system was cooled, and the reaction mixture was filtered through Celite®. The solvent was removed under vacuum to give the crude title product (408 mg, crude) as a light brown oil, which was carried on to Step D without further purification. MS (ESI): C 14 H 21 Calculated mass of N, 203.2; observed m / z, 204.2 [M+H] + .

[0199] Step D. tert-Butyl (3-(4-isopropylphenyl)cyclobutyl)(methyl)carbamate. 3-(4-Isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (408 mg) from Step C above was redissolved in dichloromethane (9 mL, 4.5 mL / mmol). DMAP (123 mg, 1 mmol, 0.5 equiv), triethylamine (420 μL, 3 mmol, 1.5 equiv), and di-tert-butyl dicarbonate (922 μL, 4 mmol, 2 equiv) were added sequentially. The reaction mixture was stirred at room temperature for 72 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO and water. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure. The crude N-Boc product was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 90:10) as eluent to give tert-butyl (3-(4-isopropylphenyl)cyclobutyl)(methyl)carbamate (168 mg, 555 μmol, 28% yield) as a colorless oil. MS (ESI): C 19 H 21Calculated mass of NO2: 303.2; m / z: 248.2 [M-C4H8+H] + .

[0200] Step E. 3-(4-Isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt. tert-Butyl (3-(4-isopropylphenyl)cyclobutyl)(methyl)carbamate (168 mg, 555 μmol) obtained from Step D above was redissolved in DCM (3 mL). Trifluoroacetic acid (494 μL, 6 mmol, 12 equiv) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was then removed under vacuum and excess trifluoroacetic acid was co-distilled with toluene to give the title product as a brown oil. The product was used without further purification. MS (ESI): C 14 H 21 Calculated mass of N, 203.2; observed m / z, 204.1 [M+H] + .

[0201] Intermediate 9: 3-(3-(tert-butyl)-4-fluorophenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0202] [ka]

[0203] Step A. tert-Butyl (3-(3-(tert-butyl)-4-fluorophenyl)-3-hydroxycyclobutyl)(methyl)carbamate. In a round-bottom flask, n-BuLi (1.6 M in hexane, 588 μL, 941 μmol, 1.25 equiv.) was added dropwise to a solution of 4-bromo-2-(tert-butyl)-1-fluorobenzene (174 mg, 753 μmol, 1 equiv.) in dry THF (4 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h. Then, a solution of tert-butyl-N-methyl-N-(3-oxocyclobutyl)carbamate (150 mg, 753 μmol, 1 equiv.) in dry THF (4 mL) was added dropwise, and the reaction mixture was stirred at the same temperature for an additional 2 h. The reaction mixture was warmed to room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, and the organic phase was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo to give the title product (265 mg, crude) as a golden oil, which was used in Step B without further purification. MS (ESI): C 20 H 30 Calculated mass of FNO3: 351.2; observed m / z: 278.0 [M-C4H8-OH] + .

[0204] Step B. 3-(3-(tert-butyl)-4-fluorophenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt. In a round-bottom flask, trifluoroacetic acid (112 μL, 1 equiv.) was added to a mixture of tert-butyl (3-(3-(tert-butyl)-4-fluorophenyl)-3-hydroxycyclobutyl)(methyl)carbamate (529 mg, 1.51 mmol, 1 equiv.), triethylsilane (1.68 mL, 10.5 mmol, 7 equiv.), and dichloromethane (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and then an additional amount of trifluoroacetic acid (800 μL) was added to the reaction mixture, which was stirred at room temperature for 72 hours. The solvent was then removed in vacuo, and excess trifluoroacetic acid was codistilled with toluene. The crude title product thus obtained as a brown oil (354 mg, crude) was used in Step C without further purification. MS(ESI):C 15 H 22Calculated mass of FN, 235.2; observed m / z, 236.2 [M+H] + .

[0205] Step C. tert-Butyl (3-(3-(tert-butyl)-4-fluorophenyl)cyclobutyl)(methyl)carbamate. 3-(3-(tert-butyl)-4-fluorophenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (522 mg), prepared in Step B above, was redissolved in dichloromethane (13 mL). DMAP (135 mg, 1.00 mmol, 0.5 equiv), triethylamine (618 μL, 4.44 mmol, 2 equiv), and di-tert-butyl dicarbonate (1.02 mL, 4.44 mmol, 2 equiv) were added sequentially. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude N-Boc product was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 90:10) as eluent to give tert-butyl (3-(4-isopropylphenyl)cyclobutyl)(methyl)carbamate (744 mg, 775 μmol, 35% yield) as a colorless oil. MS (ESI): C 20 H 30 Calculated mass of FNO2: 335.2; m / z, observed: 278.1 [M-C4H8+H] + .

[0206] Step D. 3-(3-(tert-butyl)-4-fluorophenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt. tert-Butyl (3-(3-(tert-butyl)-4-fluorophenyl)cyclobutyl)(methyl)carbamate (260 mg, 775 μmol) obtained from Step C above was redissolved in DCM (4 mL). Trifluoroacetic acid (1.4 mL) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was then removed under vacuum and excess trifluoroacetic acid was co-distilled with toluene to give the title product as a brown oil. The product was used without further purification. MS (ESI): C 15 H22 Calculated mass of FN, 235.2; observed m / z, 236.2 [M+H] + .

[0207] Intermediate 10: N-methyl-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutan-1-amine, trifluoroacetate salt.

[0208] [ka]

[0209] Step A. tert-Butyl (3-hydroxy-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)(methyl)carbamate. In a round-bottom flask, n-BuLi (1.6 M in hexanes, 784 μL, 1.26 mmol, 1.2 equiv) was added dropwise to a solution of 1-bromo-3-(1-(trifluoromethyl)cyclopropyl)benzene (266 mg, 1.00 mmol, 1 equiv) in dry THF (4 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h. Then, a solution of tert-butyl-N-methyl-N-(3-oxocyclobutyl)carbamate (200 mg, 1.00 mmol, 1 equiv) in dry THF (4 mL) was added dropwise, and the reaction mixture was stirred at the same temperature for an additional 2 h. The reaction mixture was warmed to room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic phase was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo to give the title product (480 mg, crude) as a golden oil, which was used in Step B without further purification. MS (ESI): C 20 H 26 Calculated mass of F3NO3, 385.2; observed m / z, 312.1 [M-C4H8-OH] + .

[0210] Step B N-Methyl-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobut-2-en-1-amine, trifluoroacetate salt. In a round-bottom flask, trifluoroacetic acid (149 μL, 1 equiv.) was added to a mixture of tert-butyl(3-hydroxy-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)(methyl)carbamate (774 mg, 2.01 mmol, 1 equiv.), triethylsilane (2.24 mL, 7 equiv.), and dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and then additional trifluoroacetic acid (1 mL) was added to the reaction mixture and stirred at room temperature for 16 hours. Thereafter, the solvent was removed in vacuo, and the excess trifluoroacetic acid was co-distilled with toluene. The crude title product (536 mg, crude) thus obtained as a brown oil was used in Step C without further purification. MS (ESI): C 15 H 16 Calculated mass of F3N: 267.1; observed m / z: 268.2 [M+H] + .

[0211] Step CN - Methyl-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutan-1-amine, trifluoroacetate salt. In a high pressure vessel, palladium on carbon (10%, 15% m / m) was added to a solution of the intermediate N-methyl-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobut-2-en-1-amine (530 mg, 2 mmol) obtained from Step B in methanol (50 mL, 25 mL / mmol). The vessel was sealed, charged with hydrogen (30 bar), and heated at 50°C for 16 hours. The system was cooled, and the reaction mixture was filtered through Celite®. The solvent was removed under vacuum to give the crude title product, N-methyl-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutan-1-amine, trifluoroacetate, as a light brown oil (540 mg, 2 mmol, 99% yield), which was purified as follows: The crude title product was redissolved in dichloromethane (9 mL, 4.5 mL / mmol), and DMAP (122 mg, 1 mmol, 0.5 equiv), triethylamine (0.42 mL, 3 mmol, 1.5 equiv), and di-tert-butyl dicarbonate (0.9 mL, 4 mmol, 2 equiv) were added sequentially. The reaction mixture was stirred at room temperature for 48 h. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude N-Boc product was purified by flash column chromatography on silica gel using heptane / EtOAc (100:0 to 90:10) as the eluent to afford tert-butyl methyl (3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)carbamate as a colorless oil (186 mg, 0.5 mmol, 25% yield), which was redissolved in DCM (4 mL). Trifluoroacetic acid (0.45 mL, 6 mmol, 12 equiv.) was added, and the reaction mixture was stirred at room temperature for 16 h. The solvent was then removed under vacuum, and excess trifluoroacetic acid was co-distilled with toluene to afford the title product as a brown oil. The product was used in the next step without further purification. MS (ESI): C 15 H 18 Calculated mass of F3N: 269.1; observed m / z: 270.1 [M+H]+ .

[0212] Intermediate 11: N-methyl-3-(o-tolyl)cyclobutan-1-amine, trifluoroacetate salt.

[0213] [ka]

[0214] Step A. tert-Butyl (3-hydroxy-3-(o-tolyl)cyclobutyl)(methyl)carbamate. In a round-bottom flask, isopropylmagnesium chloride (1.1 mL, 2.2 mmol, 2 M, 1.5 equiv.) was added dropwise to a solution of 2-iodotoluene (287 μL, 2.2 mmol, 1.5 equiv.) in dry THF (15 mL, 7 mL / mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Then, a solution of tert-butyl-N-methyl-N-(3-oxocyclobutyl)carbamate (300 mg, 1 equiv.) in dry THF (3 mL) was added dropwise, and the reaction mixture was stirred at the same temperature for an additional 1.5 h. The reaction mixture was warmed to room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, and the organic phase was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo to give the crude title product (439 mg), which was used in Step B without further purification. MS (ESI): C 17 H 25 Calculated mass of NO3, 291.2; observed m / z, 218.1 [M-C4H8-OH] + .

[0215] Step B: N-methyl-3-(o-tolyl)cyclobut-2-en-1-amine, trifluoroacetate salt. In a round-bottom flask, trifluoroacetic acid (112 μL, 1 equivalent) was added to a mixture of tert-butyl (3-hydroxy-3-(o-tolyl)cyclobutyl)(methyl)carbamate (439 mg, 1.51 mmol, 1 equivalent), triethylsilane (1.68 mL, 7 equivalents), and dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours, and then additional trifluoroacetic acid (800 μL) was added to the reaction mixture, which was stirred at room temperature for 72 hours. The solvent was then removed in vacuo, and excess trifluoroacetic acid was co-distilled with toluene. The crude title product (261 mg, crude) thus obtained as a brown oil was used in Step C without further purification. MS (ESI): Calculated mass C 12 H 15 N, 173.1; m / z observed, 174.1 [M+H] + .

[0216] Step C-N - Methyl-3-(o-tolyl)cyclobutan-1-amine, trifluoroacetate. In a pressure vessel, 10% palladium on carbon (40 mg, 15% m / m) was added to a solution of N-methyl-3-(o-tolyl)cyclobut-2-en-1-amine, trifluoroacetate (261 mg, 1.51 mmol) in methanol (50 mL). The vessel was sealed, charged with hydrogen (30 bar), and heated at 50° C. for 16 hours. The system was cooled, and the reaction mixture was filtered through Celite®. The solvent was removed under vacuum to give the crude title product (264 mg, crude) as a brown oil, which was used without further purification. MS (ESI): C 12 H 17 Calculated mass of N, 175.1; observed m / z, 176.1 [M+H] + .

[0217] Intermediate 12: N-methyl-3-(m-tolyl)cyclobutan-1-amine, trifluoroacetate salt.

[0218] [ka]

[0219] The title compound was prepared analogously to Intermediate 6, using 1-iodo-3-methylbenzene instead of 1-bromo-3-isopropylbenzene and isopropylmagnesium chloride instead of n-BuLi in Step A. MS(ESI): C 12 H 17 Calculated mass of N, 175.1; observed m / z, 176.1 [M+H] + .

[0220] Intermediate 13: 3-(3-ethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0221] [ka]

[0222] The title compound was prepared analogously to Intermediate 8, using 1-bromo-3-ethylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 13 H 19 Calculated mass of N, 189.2; observed m / z, 190.2 [M+H] + .

[0223] Intermediate 14: 3-(2,3-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0224] [ka]

[0225] The title compound was prepared analogously to Intermediate 8, using 1-bromo-2,3-dimethylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 13 H 19 Calculated mass of N, 189.2; observed m / z, 190.2 [M+H] + .

[0226] Intermediate 15: 3-(4-cyclopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0227] [ka]

[0228] The title compound was prepared analogously to Intermediate 9, using 1-bromo-4-cyclopropylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 14 H 19 Calculated mass of N, 201.2; observed m / z, 202.2 [M+H] + .

[0229] Intermediate 16: 3-(3,4-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0230] [ka]

[0231] The title compound was prepared analogously to Intermediate 8, using 4-bromo-1,2-dimethylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 13 H 19 Calculated mass of N, 189.2; observed m / z, 190.1 [M+H] + .

[0232] Intermediate 17: 3-(3-fluoro-4-isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0233] [ka]

[0234] Step A. tert-Butyl (3-(3-fluoro-4-isopropylphenyl)-3-hydroxycyclobutyl)(methyl)carbamate. In a round-bottom flask, n-BuLi (1.6 M in hexane, 784 μL, 1.26 mmol, 1.25 equiv.) was added dropwise to a solution of 4-bromo-2-fluoro-1-isopropylbenzene (218 mg, 1.00 mmol, 1 equiv.) in dry THF (10 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h. Then, a solution of tert-butyl-N-methyl-N-(3-oxocyclobutyl)carbamate (300 mg, 1.50 mmol, 1 equiv.) in dry THF (4 mL) was added dropwise, and the reaction mixture was stirred at the same temperature for an additional 2 h. The reaction mixture was then warmed to room temperature and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc, and the organic phase was washed with brine. The organic layer was dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo to give the title product (480 mg, crude) as a brown oil, which was used in Step B without further purification. MS (ESI): C 19 H 28 Calculated mass of FNO3: 337.2; observed m / z: 264.1 [M-C4H8-OH] + .

[0235] Step B. 3-(3-Fluoro-4-isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt. In a round-bottom flask, trifluoroacetic acid (3.3 mL, 45 mmol, 45 equiv.) was added dropwise to a solution of tert-butyl (3-(3-fluoro-4-isopropylphenyl)-3-hydroxycyclobutyl)(methyl)carbamate (339 mg, 1 mmol, 1 equiv.), triethylsilane (1.1 mL, 7 mmol, 7 equiv.) in DCM (3.3 mL, 3.3 mL / mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2.5 h. The solvent was then removed under reduced pressure and co-distilled with toluene. Excess EtSiH and TFA were removed under high vacuum for 30 min to give the crude title product, which was used without further purification. MS (ESI): C 14 H 20 Calculated mass of FN, 221.2; observed m / z, 222.2 [M+H] + .

[0236] Intermediate 18: 3-(4-Fluoro-3-isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0237] [ka]

[0238] The title compound was prepared analogously to Intermediate 17, using 1-fluoro-4-iodo-2-isopropylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI):C 14 H 20 Calculated mass of FN, 221.2; observed m / z, 222.2 [M+H] + .

[0239] Intermediate 19: 3-(2,4-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0240] [ka]

[0241] The title compound was prepared analogously to Intermediate 17, using 1-bromo-2,4-dimethylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 13 H 19 Calculated mass of N, 189.2; observed m / z, 190.2 [M+H] + .

[0242] Intermediate 20: 3-(4-ethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0243] [ka]

[0244] The title compound was prepared analogously to Intermediate 17, using 1-bromo-4-ethylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 13 H 19 Calculated mass of N, 189.2; observed m / z, 190.1 [M+H] + .

[0245] Intermediate 21: 3-(4-ethyl-3-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0246] [ka]

[0247] The title compound was prepared analogously to Intermediate 17, using 4-bromo-1-ethyl-2-methylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 14 H 21 Calculated mass of N, 203.2; observed m / z, 204.2 [M+H] + .

[0248] Intermediate 22: 3-(3-cyclobutylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0249] [ka]

[0250] The title compound was prepared analogously to Intermediate 17, using 1-bromo-3-cyclobutylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI):C 15 H 21 Calculated mass of N, 215.2; observed m / z, 216.2 [M+H] + .

[0251] Intermediate 23: 3-(4-cyclopropyl-3-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0252] [ka]

[0253] The title compound was prepared analogously to Intermediate 17, using 4-bromo-1-cyclopropyl-2-methylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI):C 15 H 21 Calculated mass of N, 215.2; observed m / z, 216.2 [M+H] + .

[0254] Intermediate 24: 3-(3-cyclopropyl-4-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0255] [ka]

[0256] The title compound was prepared analogously to Intermediate 17, using 4-bromo-2-cyclopropyl-1-methylbenzene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 15 H 21 Calculated mass of N, 215.2; observed m / z, 216.2 [M+H] + .

[0257] Intermediate 25: N-methyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)cyclobutan-1-amine, trifluoroacetate salt.

[0258] [ka]

[0259] The title compound was prepared analogously to Intermediate 17, using 6-bromo-1,2,3,4-tetrahydronaphthalene instead of 1-bromo-3-isopropylbenzene in Step A. MS(ESI): C 15 H 21 Calculated mass of N, 215.2; observed m / z, 216.2 [M+H] + .

[0260] Intermediate 26: 3-Benzyl-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0261] [ka]

[0262] Step A. tert-Butyl (3-benzylidenecyclobutyl)(methyl)carbamate. In a round-bottom flask, a solution of sodium hydride (80 mg, 2.0 mmol) in dry DMSO (16 mL) was stirred at 80° C. for 20 minutes. The mixture was cooled to 0° C., and a solution of benzyltriphenylphosphonium chloride (1.25 g, 3.2 mmol) in dry DMSO (7 mL) was added. The resulting mixture was stirred at room temperature for 30 minutes. Then, tert-butyl methyl (3-oxocyclobutyl)carbamate (400 mg, 2.0 mmol) in dry DMSO (7 mL) was added, and the resulting reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO, filtered, and concentrated under reduced pressure to give a dark orange oil. Purification by flash column chromatography using heptane / EtOAc (100:0 to 90:10) gave the title product as a beige oil, which was used in Step B without further purification. MS (ESI): C 17 H 23 Calculated mass of NO2, 273.2; m / z, observed, 218.1 [M-C4H8+H] + .

[0263] Step B. (3-Benzylcyclobutyl)(methyl)carbamic acid. In a pressure vessel, palladium on carbon (10%, 15% m / m) was added to a solution of tert-butyl (3-benzylidenecyclobutyl)(methyl)carbamate (296 mg, 1.08 mmol) in methanol (50 mL). The vessel was sealed, charged with hydrogen (30 bar), and heated at 50° C. for 16 h. The system was cooled, and the reaction mixture was filtered through Celite®. The solvent was removed under vacuum to give the crude title product (299 mg, crude) as a light brown oil, which was used in Step C without further purification. MS (ESI): C 17 H 25 Calculated mass of NO2, 219.1; observed m / z, 220.2 [M+H] + .

[0264] Step C. 3-Benzyl-N-methylcyclobutan-1-amine, trifluoroacetate salt. In a round-bottom flask, trifluoroacetic acid (1.9 mL, 24 mmol, 24 equiv.) was added to a solution of (3-benzyl-cyclobutyl)-methyl-carbamic acid tert-butyl ester (298 mg, 1 mmol, 1 equiv.) in DCM (5.5 mL, 5.5 mL / mmol), and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under vacuum, and excess trifluoroacetic acid was co-distilled with toluene to give (3-benzyl-cyclobutyl)-methyl-amine as a brown oil. The product was used without further purification. MS (ESI): C 12 H 17 Calculated mass of N, 175.1; observed m / z, 176.2 [M+H] + .

[0265] Intermediate 27: 3-(tert-butyl)-N-methylcyclobutan-1-amine.

[0266] [ka]

[0267] In a round-bottom flask, a mixture of 3-(tert-butyl)cyclobutan-1-one (200 mg, 1.5 mmol, 1 equiv.), methylamine (7.53 mL, 2 M in THF, 15.1 mmol, 10 equiv.), titanium(IV) isopropoxide (0.92 mL, 3.0 mmol, 2 equiv.), and 1,2-dichloroethane (32 mL, 21 mL / mmol) was stirred at room temperature for 16 hours under nitrogen. Sodium triacetoxyborohydride (3.2 g, 15.0 mmol, 10 equiv.) was then added, and the reaction mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was quenched with saturated aqueous NH4Cl, and the product was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO, filtered, and concentrated under reduced pressure to give a beige solid, which was purified by silica flash column chromatography using DCM:MeOH:NH (100:0:0 to 98:2:0.1) as eluent to give (3-tert-butyl-cyclobutyl)-methyl-amine as a mixture of cis / trans isomers. MS (ESI): CH 19 Calculated mass of N, 141.2; observed m / z, 142.2 [M+H] + .

[0268] Intermediate 28: 3-(3-chloro-5-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0269] [ka]

[0270] The title compound was prepared analogously to Intermediate 17, using 1-bromo-3-chloro-5-methylbenzene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS(ESI): C 12 H 16 Calculated mass of ClN, 209.1; observed m / z, 210.1 [M+H] + .

[0271] Intermediate 29: (1s,3s)-3-(3,5-dimethylphenyl)-N-ethylcyclobutan-1-amine, HCl salt.

[0272] [ka]

[0273] Step A: 3-(3-Bromo-5-methylphenyl)cyclobutan-1-one. TfO (3.73 mL, 22.1 mmol) was added to a solution of N,N-dimethylacetamide (2.06 mL, 22.2 mmol) and 1,2-dichloroethane (8 mL). The resulting mixture was stirred at room temperature for 30 minutes and then treated with a solution of 1-bromo-3-methyl-5-vinylbenzene (3.35 g, 17.0 mmol), 2,4,6-collidine (2.92 mL, 22.1 mmol), and 1,2-dichloroethane (8 mL). The reaction mixture was stirred at 90 °C for 16 hours, cooled to room temperature, and diluted with water (32 mL). The resulting mixture was stirred at 90 °C for an additional 18 hours, cooled to room temperature, poured into HO (100 mL), and extracted with dichloromethane (50 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure, and the resulting residue was purified by FCC (eluent: petroleum ether:ethyl acetate=0:1→5:1) to afford the title compound (2.5 g, 62%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 7.26-7.23(m,2H),7.03(s,1H),3.67-3.57(m,1H),3.53-3.43(m,2H),3.28-3.18(m,2H),2.35(s,3H).

[0274] Step B: 3-(3,5-Dimethylphenyl)cyclobutan-1-one. A mixture of 3-(3-bromo-5-methylphenyl)cyclobutanone (1.00 g, 4.18 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (788 mg, 6.28 mmol), K2CO3 (1.73 g, 12.5 mmol), 1,4-dioxane (10 mL), and HO (2.5 mL) was added to a 20 mL tube. The reaction mixture was sparged with Ar for 5 min and then treated with Pd(dppf)Cl2·CHCl2 (342 mg, 0.419 mmol). The reaction mixture was sparged with Ar for an additional 5 min. The resulting mixture was heated and stirred at 90 °C for 2 h, then cooled to room temperature. It was poured into HO (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure, and the resulting residue was purified by FCC (eluent: petroleum ether:ethyl acetate=0:1→5:1) to afford the title compound (180 mg, 25%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 6.95-6.91(m,3H),3.67-3.58(m,1H),3.53-3.42(m,2H),3.30-3.20(m,2H),2.34(s,6H).

[0275] Step C: (1s,3s)-N-Benzhydryl-3-(3,5-dimethylphenyl)-N-ethylcyclobutan-1-amine. NaBH(OAc)3 (2.43 g, 11.5 mmol) was added to a solution of 3-(3,5-dimethylphenyl)cyclobutanone (1.0 g, 5.7 mmol), N-benzhydrylethanamine (1.21 g, 5.73 mmol), and dichloromethane (10 mL). AcOH (0.25 mL) was then added to the reaction mixture. After stirring the reaction mixture at room temperature for 12 hours, it was poured into saturated NaHCO3 (20 mL) and extracted with dichloromethane (30 mL × 3). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 → 5:1) to give the still impure product (1.2 g, crude) as a clear oil. The product after chromatography was combined with another crude batch of product (prepared separately from 180 mg of 3-(3,5-dimethylphenyl)cyclobutanone according to the same procedure as above) and further purified by preparative HPLC using a Phenomenex Gemini NX-C18 150 mm × 40 mm × 5 μm column (eluent: 85% → 90% (v / v) CH3CN and HO containing 0.04% NH3 + 10 mM NH4HCO3). The product thus purified was suspended in water (10 mL), and the mixture was frozen using dry ice / acetone, then lyophilized to dryness to give the title product (200 mg). MS (ESI): C 27 H 31 Calculated mass of N, 369.3; observed m / z, 370.3 [M+H] + .

[0276] Step D: (1s,3s)-3-(3,5-dimethylphenyl)-N-ethylcyclobutan-1-amine, HCl salt. (1s,3s)-N-benzhydryl-3-(3,5-dimethylphenyl)-N-ethylcyclobutan-1-amine (200 mg, 0.541 mmol), methanol (30 mL), dry Pd / C (100 mg, 10% dry Pd / C), and concentrated HCl (0.1 mL) were added to a 100 mL hydrogenation bottle. The resulting mixture was stirred under H2 (15 psi) at room temperature for 16 hours. The suspension was filtered through a pad of Celite®, and the pad was washed with methanol (100 mL). The mixture was concentrated to dryness under reduced pressure to give the product (200 mg), which was used in the next step without further purification. LC-MS (ESI):R T =0.77 min,C 14 H 21 Calculated mass of N: 203.17 m / z: 204.3 [M+H] + .MS(ESI):C 14 H 21 Calculated mass of N, 203.2; observed m / z, 204.3 [M+H] + .

[0277] Intermediate 30: 3-Cyclohexyl-N-methylcyclobutan-1-amine.

[0278] [ka]

[0279] The title compound was prepared analogously to Intermediate 27, using 3-cyclohexylcyclobutan-1-one instead of 3-(tert-butyl)cyclobutan-1-one. MS(ESI): C 11 H 21 Calculated mass of N, 167.2; observed m / z, 168.2 [M+H] + .

[0280] Intermediate 31: N-methyl-3-(4-(1-methylcyclopropyl)phenyl)cyclobutan-1-amine, trifluoroacetate salt.

[0281] [ka]

[0282] The title compound was prepared analogously to Intermediate 17, using 1-bromo-4-(1-methylcyclopropyl)benzene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS (ESI): C 15 H 21 Calculated mass of N, 215.2; observed m / z, 216.2 [M+H] + .

[0283] Intermediate 32: N-methyl-3-(3-(1-methylcyclopropyl)phenyl)cyclobutan-1-amine, trifluoroacetate salt.

[0284] [ka]

[0285] The title compound was prepared analogously to Intermediate 17, using 1-bromo-3-(1-methylcyclopropyl)benzene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS (ESI): C 15 H 21 Calculated mass of N, 215.2; observed m / z, 216.2 [M+H] + .

[0286] Intermediate 33: 3-(3-ethyl-5-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0287] [ka]

[0288] The title compound was prepared analogously to Intermediate 17, using 1-bromo-3-ethyl-5-methylbenzene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS(ESI): C14 H 21 Calculated mass of N, 203.2; observed m / z, 204.1 [M+H] + .

[0289] Intermediate 34: 3-(3-cyclopropyl-5-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0290] [ka]

[0291] The title compound was prepared analogously to Intermediate 17, using 1-bromo-3-cyclopropyl-5-methylbenzene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS(ESI): C 15 H 21 Calculated mass of N, 215.2; observed m / z, 216.2 [M+H] + .

[0292] Intermediate 35: 3-(3-isopropyl-5-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0293] [ka]

[0294] Step A: 1-Bromo-3-methyl-5-(prop-1-en-2-yl)benzene. Nitrogen gas (N) was bubbled through a solution of 1-bromo-3-iodo-5-methylbenzene (1.0 g, 3.37 mmol) in 1,4-dioxane (7.5 mL) and water (2.5 mL) in a pressure flask for 5 minutes. While maintaining the N bubble, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.62 mL, 3.37 mmol), cesium carbonate (2.37 g, 7.26 mmol), and dppfPdCl (404 mg, 495 μmol) were added sequentially. N bubble was continued for an additional 5 minutes, after which the pressure cap was sealed with a screw cap, and the reaction mixture was stirred at 90 °C. After 16 hours, the reaction mixture was filtered through a pad of Celite®. The filtrate was collected, diluted with EtOAc, and washed with water and brine. The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography using heptane / EtOAc (100:0 to 90:10) as the eluent to give the title compound (382 mg, 1.81 mmol) as a brownish oil. 1 H NMR (300MHz, Chloroform-d): 7.39 (s, 1H), 7.23 (s, 1H), 7.18 (s, 1H), 5.22 (d, J = 73.9Hz, 2H), 2.33 (s, 3H), 2.11 (s, 3H).

[0295] Step B: 3-(3-Isopropyl-5-methylphenyl)-N-methylcyclobutan-1-amine. The title compound was prepared analogously to Intermediate 17, using 1-bromo-3-methyl-5-(prop-1-en-2-yl)benzene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS (ESI): C 15 H 23 Calculated mass of N, 217.1; observed m / z, 218.2 [M+H] + .

[0296] Intermediate 36: 3-(3-cyclopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0297] [ka]

[0298] The title compound was prepared analogously to Intermediate 17, using 1-bromo-3-cyclopropylbenzene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS(ESI):C 14 H 19 Calculated mass of N, 201.2; observed m / z, 202.1 [M+H] + .

[0299] Intermediate 37: 3-(2,3-Dihydro-1H-inden-5-yl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0300] [ka]

[0301] The title compound was prepared analogously to Intermediate 17, using 5-bromo-2,3-dihydro-1H-indene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS(ESI): C 14 H 19 Calculated mass of N, 201.2; observed m / z, 202.2 [M+H] + .

[0302] Intermediate 38: 3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-N-methylcyclobutan-1-amine, trifluoroacetate salt.

[0303] [ka]

[0304] The title compound was prepared analogously to Intermediate 17, using 3-bromobicyclo[4.2.0]octa-1(6),2,4-triene instead of 4-bromo-2-fluoro-1-isopropylbenzene in Step A. MS(ESI): C 13 H 17 Calculated mass of N, 187.1; observed m / z, 188.1 [M+H] + .

[0305] Example 1: (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0306] [ka]

[0307] Triethylamine (110 μL, 794 μmol) was added dropwise to a stirred mixture of N-methyl-3-phenylcyclobutan-1-amine (approximately 4:1 cis:trans mixture, 40.0 mg, 248 μmol), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 1, 42.4 mg, 248 μmol), and HATU (117 mg, 273 μmol) in N,N-dimethylacetamide (2.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 14 hours and then diluted with water (1 mL). Purification by RP-HPLC (Method B, ACN / HO, 0.05% TFA) gave the title product in 49% isolated yield and (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 2) in 9% yield. MS (ESI): C 18 H 22 Calculated mass of N2O3: 314.2; observed m / z: 315.1 [M+H] + . 1H NMR(500MHz,METHANOL-d4)δ 7.36-7.11(m,5H),4.79-4.70(m,0.5H),4.52(s,1H),4.48(s,1H),4.45-4.34(m,0.5H),3.24-3.04(m,2H),2.95(m,3H),2.63-2.18(m,8H).

[0308] Example 2: (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0309] [ka]

[0310] The title compound was isolated from Example 1. MS(ESI):C 18 H 22 Calculated mass of N2O3: 314.2; observed m / z: 315.1 [M+H] + . 1 H NMR(500MHz,METHANOL-d4)δ 7.38-7.13(m,5H),5.16-5.03(m,0.5H),4.69-4.54(m,0.5H),4.48(s,1H),4.45(s ,1H),3.58-3.43(m,1H),3.14-2.99(m,4H),2.86-2.62(m,2H),2.58-2.31(m,5H).

[0311] Example 3: (2s,4S)—N-((1s,3S)-3-(3-cyclobutylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0312] [ka]

[0313] The title compound was prepared analogously to Example 10, using 3-(3-cyclobutylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 22) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; observed m / z: 369.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.29-7.13(m,1H),7.10-7.00(m,3H),4.82-4.68(m,0.5H),4.50(m,2H),4.45-4.32(m,0.5H ),3.61-3.46(m,1H),3.25-3.03(m,2H),2.95(m,3H),2.63-1.97(m,13H),1.92-1.81(m,1H).

[0314] Example 4: (2s,4S)—N-((1s,3S)-3-(4-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0315] [ka]

[0316] The title compound was prepared similarly to Example 1, using 3-(4-(tert-butyl)phenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 3, cis / trans mixture) instead of N-methyl-3-phenylcyclobutan-1-amine. Purification by RP-HPLC (Method B, ACN / HO, 0.05% TFA) gave the title product in 72% isolated yield and (2s,4S)-N-((1r,3R)-3-(4-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 5) in 5% isolated yield. MS (ESI): C 22 H 30Calculated mass of N2O3: 370.2; observed m / z: 371.3 [M+H] + . 1 H NMR(500MHz,METHANOL-d4)δ 7.42-7.31(m,2H),7.19(m,2H),4.80-4.71(m,0.4H),4.54(s,1.1H),4.50(s,0.9H),4.44-4.35(m,0.6H) ),3.25-3.07(m,2H),2.97(m,3H),2.65-2.44(m,6H),2.42-2.33(m,1H),2.29-2.19(m,1H),1.32(m,9H).

[0317] Example 5: (2s,4S)—N-((1r,3R)-3-(4-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0318] [ka]

[0319] The title compound was isolated from Example 4. MS(ESI):C 22 H 30 Calculated mass of N2O3: 370.2; observed m / z: 371.1 [M+H] + . 1 H NMR(500MHz,METHANOL-d4)δ 7.45-7.36(m,2H),7.30-7.25(m,2H),5.17-5.04(m,0.5H),4.66-4.57(m,0.5H),4.52-4.45(m ,2H),3.57-3.39(m,1H),3.06(m,3H),2.66-2.86(m,2H),2.59-2.32(m,7H),1.36-1.30(m,9H).

[0320] Example 6: (2s,4S)—N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0321] [ka]

[0322] The title compound was prepared similarly to Example 1, using 3-(3-(tert-butyl)phenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt (Intermediate 4, cis / trans mixture) instead of N-methyl-3-phenylcyclobutan-1-amine. Purification by RP-HPLC (Method B, ACN / HO, 0.05% TFA) gave the title product in 89% isolated yield. MS (ESI): C 22 H 30 Calculated mass of N2O3: 370.2; observed m / z: 371.3 [M+H] + . 1 H NMR(500MHz,METHANOL-d4)δ 7.30-7.19(m,3H),7.12-7.00(m,1H),4.78-4.69(m,0.5H),4.54-4.46(m,2H),4.44-4.35(m,0.5H),3 .25-3.03(m,2H),2.95(m,3H),2.65-2.43(m,6H),2.40-2.31(m,1H),2.28-2.17(m,1H),1.31(m,9H).

[0323] Example 7: (2r,4S)—N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide.

[0324] [ka]

[0325] The title compound was prepared similarly to Example 6, using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 2) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 1). Purification by RP-HPLC (Method B, ACN / HO, 0.05% TFA) gave the title product. MS (ESI): C 23 H 32 Calculated mass of N2O2, 368.2; observed m / z, 369.2 [M+H] + . 1 H NMR(500MHz,METHANOL-d4)δ 7.29-7.18(m,3H),7.13-7.00(m,1H),4.76(m,0.5H),4.48-4.35(m,0.5H),3.28 -3.09(m,2H),2.96(m,3H),2.65-2.54(m,2H),2.52-2.18(m,10H),1.31(m,9H).

[0326] Example 8: (2s,4S)—N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0327] [ka]

[0328] The title compound was prepared similarly to Example 1, using 3-(3,5-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 5, cis / trans mixture) instead of N-methyl-3-phenylcyclobutan-1-amine. Purification by RP-HPLC (Method B, ACN / HO, 0.05% TFA) afforded the title product and (2s,4S)-N-((1r,3R)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 9). MS (ESI): C 20 H 26Calculated mass of N2O3: 342.2; observed m / z: 343.2 [M+H] + . 1 H NMR(500MHz,METHANOL-d4)δ 6.90-6.77(m,3H),4.77-4.67(m,0.5H),4.50(m,2H),4.43-4.30(m,0.5H), 3.23-3.04 (m, 2H), 2.99-2.90 (m, 3H), 2.61-2.40 (m, 6H), 2.38-2.11 (m, 8H).

[0329] Example 9: (2s,4S)—N-((1r,3R)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0330] [ka]

[0331] The title compound was isolated from Example 8. MS(ESI):C 20 H 26 Calculated mass of N2O3: 342.2; observed m / z: 343.1 [M+H] + . 1 H NMR(500MHz,METHANOL-d4)δ 6.93(s,2H),6.83(m,1H),5.08(m,0.5H),4.61-4.40(m,2.5H),3.51-3 .35(m,1H),3.15-3.01(m,4H),2.80-2.61(m,2H),2.59-2.21(m,12H).

[0332] Example 10: (2s,4S)—N-((1s,3S)-3-(3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0333] [ka]

[0334] In a round-bottom flask, a solution of propylphosphonic anhydride in EtOAc (T3P® (1 mL, 1.7 mmol, 50%, 1.25 equiv.) and DIPEA (655 μL, 3.7 mmol, 2.5 equiv.) were added to a solution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 1, 282 mg, 1.65 mmol, 1.2 equiv.) in dry DMF (7.5 mL, 5 mL / mmol). The mixture was stirred at room temperature for 10 min, then a solution of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6, 300 mg, 1.5 mmol, 1 equiv.) in DMF (1 mL) was added and the reaction mixture was cooled to 77° C. The mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to give a dark brown oil. The crude material was purified by flash column chromatography (silica, DCM / MeOH (9:1) in DCM, 0% to 10%) to give the product as a mixture of cis / trans isomers. This mixture was further purified by supercritical fluid chromatography (SFC) (Method D, isocratic mode: 40% methanol + 0.1% diethylamine and 60% CO2) to give the cis isomer, the title product (52.3 mg, 0.15 mmol, 10% yield). MS (ESI): C 21 H 28 Calculated mass of N2O3: 356.2; observed m / z: 357.2 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 7.31-7.15(m,1H),7.14-6.99(m,3H),4.80-4.66(m,0.5H),4.50(m,2H),4.45-4.32(m,0.5H),3.26-3.01(m ,2H),2.96(m,3H),2.93-2.81(m,1H),2.67-2.40(m,6H),2.43-2.28(m,1H),2.29-2.16(m,1H),1.24(m,6H).

[0335] Example 11: (2s,4S)—N-((1s,3S)-3-(3-methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0336] [ka]

[0337] The title compound was prepared similarly to Example 10, using 3-(3-methoxyphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate salt (Intermediate 7) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6) and HBTU instead of T3P® as the coupling agent. Purification by SFC (Method E) gave the title product and (2s,4S)-N-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 12). MS (ESI): C 19 H 24 Calculated mass of N2O4: 344.2; observed m / z: 345.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.25-7.17(m,1H),6.87-6.81(m,1H),6.81-6.72(m,2H),4.79-4.69(m,0.5H),4.50(m,2H),4.45-4.31(m,0 .5H),3.78(m,3H),3.22-3.00(m,2H),2.95(m,3H),2.63-2.42(m,6H),2.40-2.32(m,1H),2.27-2.16(m,1H).

[0338] Example 12: (2s,4S)—N-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0339] [ka]

[0340] The title compound was isolated from Example 11. MS(ESI):C 19 H 24 Calculated mass of N2O4: 344.2; observed m / z: 345.1 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 7.29-7.20(m,1H),6.95-6.87(m,2H),6.80-6.72(m,1H),5.13-5.04(m,0.5H),4.58-4.47(m,2 .5H),3.80(m,3H),3.56-3.41(m,1H),3.17-3.04(m,4H),2.84-2.64(m,2H),2.57-2.32(m,6H).

[0341] Example 13: (2s,4S)—N-((1s,3S)-3-(4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0342] [ka]

[0343] The title compound was prepared analogously to Example 10, using 3-(4-isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 8) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 21 H 28 Calculated mass of N2O3: 356.2; observed m / z: 357.2 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ 7.17(m,4H),4.81-4.68(m,0.5H),4.50(m,2H),4.46-4.31(m,0.5H),3.25-2.8 1(m,6H),2.62-2.43(m,6H),2.41-2.28(m,1H),2.28-2.13(m,1H),1.23(m,6H).

[0344] Example 14: (2s,4S)—N-((1s,3S)-3-(3-(tert-butyl)-4-fluorophenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0345] [ka]

[0346] The title compound was prepared analogously to Example 10, using 3-(3-(tert-butyl)-4-fluorophenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 9) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 22 H 29 Calculated mass of FN2O3: 388.2; observed m / z: 389.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.21-7.05(m,2H),7.04-6.89(m,1H),4.80-4.64(m,0.5H),4.50(m,2H),4.46-4.32(m,0.5H),3.2 6-3.00(m,2H),2.95(m,3H),2.68-2.39(m,6H),2.41-2.25(m,1H),2.27-2.09(m,1H),1.37(s,9H).

[0347] Example 15: (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0348] [ka]

[0349] The title compound was prepared analogously to Example 10, using N-methyl-3-(3-(1-trifluoromethyl)cyclopropyl)phenyl)cyclobutan-1-amine, trifluoroacetate (Intermediate 10) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). Purification by SFC (Method E) gave the title product and (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 16). MS (ESI): C 22 H 25 Calculated mass of F3N2O3: 422.2; observed m / z: 423.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.38-7.18(m,4H),4.77-4.67(m,0.5H),4.50(m,2H),4.47-4.32(m,0.5H),3.27 -3.0.3(m,2H),2.95(m,3H),2.71-2.12(m,8H),1.38-1.27(m,2H),1.06(m,2H).

[0350] Example 16: (2s,4S)—N-methyl-6-oxo-N-((1r,3R)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0351] [ka]

[0352] The title compound was isolated from Example 15. MS (ESI): C 22 H 25 Calculated mass of F3N2O3: 422.1; observed m / z: 423.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.43(s,1H),7.39-7.26(m,3H),5.17-5.00(m,0.5H),4.67-4.51(m,1.5H),4.46(m,2H),3.66-3.43(m ,1H),3.18-3.05(m,4H),2.92-2.65(m,2H),2.60-2.32(m,6H),1.42-1.29(m,2H),1.16-0.98(m,2H).

[0353] Example 17: (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0354] [ka]

[0355] The title compound was prepared analogously to Example 10, using N-methyl-3-(o-tolyl)cyclobutan-1-amine, trifluoroacetate (Intermediate 11) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). Purification by SFC (Method E) gave the title product and (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 18). MS (ESI): C 19 H 24 Calculated mass of N2O3: 328.2; observed m / z: 329.1 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ 7.33-6.93(m,4H),4.84-4.71(m,0.5H),4.51(m,2H),4.46-4.35(m,0.5H),3.27-3.0.1(m,2H),2.94(m,3H),2.71-2.12(m,11H).

[0356] Example 18: (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0357] [ka]

[0358] The title product was isolated from Example 17. MS (ESI): C 19 H 24 Calculated mass of N2O3: 328.2; observed m / z: 329.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.47(d,J=7.6Hz,1H),7.29-7.01(m,3H),5.15-4.95(m,0.5H),4.66-4.51(m,1H),4.46(m,2) H),3.72-3.53(m,1H),3.17-3.04(m,4H),2.89-2.62(m,2H),2.60-2.25(m,6H),2.21(m,3H).

[0359] Example 19: (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0360] [ka]

[0361] The title compound was prepared analogously to Example 10, using N-methyl-3-(m-tolyl)cyclobutan-1-amine, trifluoroacetate (Intermediate 12) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). Purification by SFC (Method E) gave the title product and (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 20). MS (ESI): C 19 H 24 Calculated mass of N2O3: 328.2; observed m / z: 329.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.23-7.08(m,1H),7.07-6.95(m,3H),4.78-4.67(m,0.5H),4.50(m,2H), 4.45-4.32(m,0.5H),3.23-3.02(m,3H),2.95(m,3H),2.62-2.30(m,10H).

[0362] Example 20: (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0363] [ka]

[0364] The title compound was isolated from Example 19. MS (ESI): C 19 H 24 Calculated mass of N2O3: 328.2; observed m / z: 329.1 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ 7.15-6.99(m,3H),6.96-6.88(m,1H),5.06-4.94(m,0.5H),4.54-4.43(m,0.5H),4.3 7(m,2H),3.45-3.28(m,1H),3.05-2.91(m,4H,2.75-2.53(m,2H),2.48-2.20(m,9H).

[0365] Example 21: (2s,4S)—N-((1s,3S)-3-(3-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0366] [ka]

[0367] The title compound was prepared analogously to Example 10, using N-methyl-3-(m-tolyl)cyclobutan-1-amine, trifluoroacetate (Intermediate 13) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 20 H 26 Calculated mass of N2O3: 342.2; observed m / z: 343.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.30-7.09(m,1H),7.10-6.96(m,3H),4.79-4.67(m,0.5H),4.50(m,2H),4.47-4 .30(m,0.5H),3.25-3.03(m,2H),2.95(m,3H),2.70-2.16(m,10H),1.22(m,3H).

[0368] Example 22: (2s,4S)—N-((1s,3S)-3-(2,3-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0369] [ka]

[0370] The title compound was prepared analogously to Example 10, using 3-(2,3-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 14) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). Purification by SFC (Method E) gave the title product and (2s,4S)-N-((1r,3R)-3-(2,3-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 23). MS (ESI): C 20 H 26 Calculated mass of N2O3: 342.2; observed m / z: 343.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.14-7.02(m,2H),7.02-6.95(m,1H),4.81-4.71(m,0.5H),4.50(m,2H),4.46-4.34(m,0.5H),3.42-3.33(m,1H),3.2 8-3.14(m,0.5H),3.14-3.00(m,0.5H),2.91(m,3H),2.69-2.39(m,6H),2.39-2.28(m,1H),2.26(m,3H),2.17(m,4H).

[0371] Example 23: (2s,4S)—N-((1r,3R)-3-(2,3-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0372] [ka]

[0373] The title product was isolated from Example 22. MS (ESI): C 20 H 26 Calculated mass of N2O3: 342.2; observed m / z: 343.2 [M+H]+ . 1 H NMR(400MHz,Methanol-d4)δ 7.30(d,J=7.6Hz,1H),7.15-6.98(m,2H),5.04-4.92(m,0.5H),4.56-4.45(m,3H),3.73-3.57(m ,1H),3.15-3.04(m,4H),2.87-2.74(m,1H),2.74-2.62(m,1H),2.59-2.27(m,9H),2.11(m,3H).

[0374] Example 24: (2s,4S)—N-((1s,3S)-3-(4-cyclopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0375] [ka]

[0376] The title compound was prepared analogously to Example 10, using 3-(4-cyclopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 15) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 21 H 26 Calculated mass of N2O3: 354.2; observed m / z: 355.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.17-7.05(m,2H),7.07-6.88(m,2H),4.81-4.67(m,0.5H),4.48(m,2H),4.42-4.30(m,0.5H),3.25-2 .99(m,2H),2.95(m,3H),2.68-2.13(m,8H),1.96-1.77(m,1H),1.00-0.84(m,2H),0.71-0.52(m,2H).

[0377] Example 25: (2s,4S)—N-((1s,3S)-3-(3,4-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0378] [ka]

[0379] The title compound was prepared analogously to Example 10, using 3-(3,4-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 16) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 20 H 26 Calculated mass of N2O3: 342.2; observed m / z: 343.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.09-6.91(m,3H),4.81-4.63(m,0.5H),4.50(m,2H),4.44-4.30(m,0.5H ),3.25-3.02(m,2H),2.95(m,3H),2.61-2.41(m,6H),2.40-2.09(m,10H).

[0380] Example 26: (2s,4S)—N-((1s,3S)-3-(3-fluoro-4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0381] [ka]

[0382] The title compound was prepared analogously to Example 10, using 3-(3-fluoro-4-isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate, Intermediate 17 instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 21 H 27 Calculated mass of FN2O3: 374.2; observed m / z: 375.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.28-7.04(m,1H),7.09-7.04(m,1H),6.98(d,J=11.8Hz,1H),4.85-4.39(m,0.5H),4.56(m,2H),4.50-4.39(m,0. 5H),3.30-3.12(m,3H),3.03-2.97(m,3H),2.68-2.49(m,6H),2.45-2.35(m,1H),2.32-2.22(m,1H),1.30(m,6H).

[0383] Example 27: (2s,4S)—N-((1s,3S)-3-(4-fluoro-3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0384] [ka]

[0385] The title compound was prepared analogously to Example 10, using 3-(4-fluoro-3-isopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 18) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 21 H 27 Calculated mass of FN2O3: 374.2; observed m / z: 375.2 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ 7.17-7.02(m,2H),7.01-6.88(m,1H),4.79-4.65(m,0.5H),4.50(m,2H),4.46- 4.32(m,0.5H),3.26-3.02(m,3H),2.95(m,3H),2.65-2.13(m,8H),1.25(m,6H).

[0386] Example 28: (2s,4S)—N-((1s,3S)-3-(2,4-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0387] [ka]

[0388] The title compound was prepared analogously to Example 10, using 3-(2,4-dimethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 19) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 20 H 26 Calculated mass of N2O3: 342.2; observed m / z: 343.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.16-7.05(m,1H),7.02-6.90(m,2H),4.81-4.69(m,0.5H),4.50(m,2H),4.46-4.3 3(m,0.5H),3.28-3.02(m,2H),2.92(m,3H),2.67-2.41(m,6H),2.36-2.09(m,8H).

[0389] Example 29: (2s,4S)—N-((1s,3S)-3-(4-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0390] [ka]

[0391] The title compound was prepared analogously to Example 10, using 3-(4-ethylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 20) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 20 H 26 Calculated mass of N2O3: 342.2; observed m / z: 343.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.19-7.11(m,4H),4.82-4.66(m,0.5H),4.50(m,2H),4.47-4.31(m,0.5H), 3.24-3.01(m,2H),2.95(m,3H),2.69-2.13(m,10H),1.20(t,J=7.6Hz,3H).

[0392] Example 30: (2s,4S)—N-((1s,3S)-3-(4-ethyl-3-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0393] [ka]

[0394] The title compound was prepared analogously to Example 10, using 3-(4-ethyl-3-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 21) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 21 H 28 Calculated mass of N2O3: 356.2; observed m / z: 357.2 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ 7.09-6.97(m,3H),4.78-4.65(m,0.5H),4.54-4.46(m,2H),4.42-4.30(m ,0.5H),3.24-3.02(m,2H),2.95(m,3H),2.65-2.14(m,14H),1.17(m,3H).

[0395] Example 31: (2s,4S)—N-((1s,3S)-3-(4-cyclopropyl-3-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0396] [ka]

[0397] The title compound was prepared in a similar manner to Example 10, using 3-(4-cyclopropyl-3-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 23) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). The crude material was purified by flash column chromatography using DCM / MeOH (100:0 to 98:2) and then further purified by reverse-phase chromatography using Method D (25 mM NH4HCO3 pH8 / ACN:MeOH (1:1) (59:41 to 17:83) as eluent) to give the title product. MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; observed m / z: 369.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.04-6.85(m,3H),4.80-4.65(m,0.5H),4.54-4.45(m,2H),4.42-4.26(m,0.5H),3.25-2.99(m, 2H), 2.95(m, 3H), 2.63-2.10(m, 11H), 1.97-1.74(m, 1H), 0.98-0.79(m, 2H), 0.63-0.45(m, 2H).

[0398] Example 32: (2s,4S)—N-((1s,3S)-3-(3-cyclopropyl-4-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0399] [ka]

[0400] The title compound was prepared analogously to Example 10, using 3-(3-cyclopropyl-4-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 24) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; observed m / z: 369.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.12-7.00(m,1H),7.02-6.93(m,1H),6.82(br s,1H),4.77-4.64(m,0.5H),4.50(m,2H),4.44-4.29(m,0.5H),3.25-2.99(m,2H),2.9 4(m,3H),2.60-2.10(m,11H),1.99-1.78(m,1H),1.00-0.81(m,2H),0.67-0.47(m,2H).

[0401] Example 33: (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0402] [ka]

[0403] The title compound was prepared analogously to Example 10, using N-methyl-3-(5,6,7,8-tetrahydronaphthalen-2-yl)cyclobutan-1-amine, trifluoroacetate (Intermediate 25) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; observed m / z: 369.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 6.99-6.86(m,4H),4.78-4.66(m,0.5H),4.50(m,2H),4.42-4.30(m,0.5H),3.26-3 .00(m,2H),2.95(m,3H),2.79-2.67(m,4H),2.63-2.12(m,8H),1.85-1.71(m,4H).

[0404] Example 34: (2s,4S)—N-((1r,3S)-3-benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0405] [ka]

[0406] The title compound was prepared analogously to Example 10, using 3-benzyl-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 26) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). Purification by SFC (Method E) gave the title product and (2s,4S)-N-((1s,3R)3-benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 35). MS (ESI): C 19 H 24 Calculated mass of N2O3: 328.2; observed m / z: 329.1 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ 7.32-7.20(m,2H),7.20-7.06(m,3H),4.69-4.53(m,0.5H),4.48(m,2H),4.28-4.14(m,0.5H),3.19-2.99(m,1H),2. 92-2.79(m,3H),2.72(t,J=7.0Hz,2H),2.59-2.34(m,4H),2.34-2.10(m,3H),2.08-1.90(m,1H),1.90-1.75(m,1H).

[0407] Example 35: (2s,4S)—N-((1s,3R)-3-benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0408] [ka]

[0409] The title product was isolated from Example 34. MS (ESI): C 19 H 24 Calculated mass of N2O3: 328.2; observed m / z: 329.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 7.37-7.08(m,5H),5.15-4.93(m,0.5H),4.48(m,2H),4.43-4.26(m,0.5H),3.17-2.76(m,6H),2.62-2.21(m,7H),2.11-1.81(m,2H).

[0410] Example 36: (2s,4S)—N-((1s,3S)-3-(tert-butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0411] [ka]

[0412] The title compound was prepared analogously to Example 10, using 3-(tert-butyl)-N-methylcyclobutan-1-amine (Intermediate 27) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). Purification by SFC (Method E) gave the title product and (2s,4S)-N-((1r,3R)-3-(tert-butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 37). MS (ESI): C 16 H 26 Calculated mass of N2O3: 294.2; observed m / z: 295.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 4.60-4.43(m,2.5H),4.26-4.05(m,0.5H),3.24-2.96(m,1H),2.89(m,3H) ),2.61-2.35(m,4H),2.11-1.93(m,3H),1.92-1.78(m,2H),0.87(m,9H).

[0413] Example 37: (2s,4S)—N-((1r,3R)-3-(tert-butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0414] [ka]

[0415] The title product was isolated from Example 36. MS (ESI): C 16 H 26 Calculated mass of N2O3: 294.2; observed m / z: 295.1 [M+H] + . 1H NMR(400MHz,Methanol-d4)δ 4.93-4.78(m,0.5H),4.51-4.42(m,2H),4.40-4.23(m,0.5H),3.14-3.01(m,1H),2 .99(m,3H),2.58-2.37(m,4H),2.37-2.26(m,1H),2.26-1.96(m,4H),0.90(m,9H).

[0416] Example 38: (2s,4S)—N-((1s,3S)-3-cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0417] [ka]

[0418] The title compound was prepared similarly to Example 11, using 3-cyclohexyl-N-methylcyclobutan-1-amine (Intermediate 30) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). Purification by SFC (method: SFC-Lux Amylose-2, column Phenomenex Lux Amylose-2 150 x 4.6 mm, 5 μm, isocratic mode: 13% ethanol + 0.1% diethylamine and 87% CO2) gave the title product and (2s,4S)-N-((1r,3R)-3-cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 39). MS (ESI): C 18 H 28 Calculated mass of N2O3: 320.2; observed m / z: 321.2 [M+H] + . 1H NMR(400MHz,Methanol-d4):4.65-4.53(m,0.5H),4.48(d,J=6.4Hz,2H),4.24-4.13(m,0.5H),3.18-2.99(m,1H),2.88(d,J=9.9Hz, 3H),2.58-2.39(m,4H),2.28-2.16(m,2H),1.91-1.81(m,1H),1.78-1.57(m,7H),1.27-1.09(m,4H),0.82(dd,J=23.3,11.5Hz,2H).

[0419] Example 39: (2s,4S)—N-((1r,3R)-3-cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0420] [ka]

[0421] The title product was isolated from Example 38. MS (ESI): C 18 H 28 Calculated mass of N2O3: 320.2; observed m / z: 321.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):4.95-4.85(m,0.5H),4.48(d,J=5.5Hz,2H),4.46-4.35(m,0.5H),3.14-3.00(m,1H),2.96(d,J=7.6Hz,3H) ,2.59-2.39(m,4H),2.39-2.28(m,1H),2.28-2.18(m,1H),2.13-1.95(m,2H),1.95-1.59(m,6H),1.43-1.08(m,4H),0.87-0.65(m,2H).

[0422] Example 40: (2s,4S)-N-methyl-N-((1s,3S)-3-(4-(1-methylcyclopropyl)phenyl)cyclobutyl)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0423] [ka]

[0424] The title compound was prepared analogously to Example 11, using N-methyl-3-(4-(1-methylcyclopropyl)phenyl)cyclobutan-1-amine, trifluoroacetate (Intermediate 31) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). Purification by preparative HPLC (Method: MAP4AC (25 mM NH4HCO3) / (MeCN:MeOH 1:1); 39 / 61→11 / 89) afforded the title product and (2s,4S)-N-((1s,3S)-3-(4-(sec-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide (Example 41). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; observed m / z: 369.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):7.26-7.10(m,4H),4.80-4.68(m,0.5H),4.50(d,J=14.4Hz,2H),4.43-4.32(m,0.5H),3.24-3.02(m ,2H),2.95(m,3H),2.62-2.43(m,6H),2.39-2.28(m,1H),2.26-2.15(m,1H),1.37(s,3H),0.84-0.78(m,2H),0.72-0.65(m,2H).

[0425] Example 41: (2s,4S)—N-((1s,3S)-3-(4-(Sec-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0426] [ka]

[0427] The title product was isolated from Example 40. MS (ESI): C 22 H 30 Calculated mass of N2O3: 370.2; observed m / z: 372.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):7.20-7.08(m,4H),4.79-4.68(m,0.5H),4.50(d,J=14.9Hz,2H),4.45-4.33(m,0.5H),3.24-3.03(m, 2H), 2.96(d,J=7.0Hz,3H),2.64-2.42(m,7H),2.35(m,1H),2.22(m,1H),1.68-1.51(m,2H),1.24-1.18(m,3H),0.84-0.75(m,3H).

[0428] Example 42: (2s,4S)-N-methyl-N-((1s,3S)-3-(3-(1-methylcyclopropyl)phenyl)cyclobutyl)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0429] [ka]

[0430] The title compound was prepared in a similar manner to Example 11, using N-methyl-3-(3-(1-methylcyclopropyl)phenyl)cyclobutan-1-amine, trifluoroacetate (Intermediate 32) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; observed m / z: 369.2 [M+H] + . 1H NMR(400MHz,Methanol-d4):7.24-7.17(m,1H),7.14-7.02(m,3H),4.80-4.68(m,0.5H),4.50(d,J=15.5Hz,2H),4.43-4.32(m,0.5H),3.23-3. 02(m,2H),2.95(d,J=7.2Hz,3H),2.63-2.43(m,6H),2.41-2.30(m,1H) ,2.27-2.15(m,1H),1.38(s,3H),0.84-0.80(m,2H),0.73-0.68(m,2H).

[0431] Example 43: (2s,4S)—N-((1s,3S)-3-(3-ethyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0432] [ka]

[0433] The title compound was prepared in a similar manner to Example 11, using 3-(3-ethyl-5-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 33) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 21 H 28 Calculated mass of N2O3: 356.2; observed m / z: 357.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):6.89-6.81(m,3H),4.80-4.67(m,0.5H),4.50(d,J=15.0Hz,2H),4.45-4.32(m,0.5H),3.25 -3.02(m,2H),2.95(m,3H),2.65-2.39(m,8H),2.39-2.30(m,1H),2.29(d,J=2.5Hz,3H),2.26-2.14(m,1H),1.20(m,3H).

[0434] Example 44: (2s,4S)—N-((1s,3S)-3-(3-cyclopropyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0435] [ka]

[0436] The title compound was prepared in a similar manner to Example 11, using 3-(3-cyclopropyl-5-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 34) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 22 H 28 Calculated mass of N2O3: 368.2; observed m / z: 369.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):6.83(m,1H),6.74(d,J=4.0Hz,1H),6.70(m,1H),4.79-4.67(m,0.5H),4.50(d,J=14.6Hz,2H),4.42-4.31(m,0.5H),3.24-3 .02(m,2H),2.95(m,3H),2.60-2.42(m,6H),2.38-2.28(m,1H),2.27(m,3H), 2.24-2.14(m,1H), 1.90-1.78(m,1H), 0.97-0.85(m,2H), 0.67-0.58(m,2H).

[0437] Example 45: (2s,4S)—N-((1s,3S)-3-(3-isopropyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0438] [ka]

[0439] The title compound was prepared in a manner similar to Example 11, using 3-(3-isopropyl-5-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 35) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 22 H 30 Calculated mass of N2O3: 370.2; observed m / z: 371.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):6.87(m,3H),4.77-4.65(m,0.5H),4.50(d,J=15.1Hz,2H),4.45-4.29(m,0 .5H),3.25-3.02(m,2H),2.95(m,3H),2.89-2.77(m,1H),2.62-2.42(m,6H),2.42-2.30(m,1H),2.30(m 3H), 2.26-2.14(m, 1H), 1.22(m, 6H).

[0440] Example 46: (2s,4S)—N-((1s,3S)-3-(3-chloro-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0441] [ka]

[0442] The title compound was prepared in a manner similar to Example 11, using 3-(3-chloro-5-methylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 28) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 19 H 23 Calculated mass of ClN2O3: 362.1; observed m / z: 363.1 [M+H] + . 1H NMR(400MHz,Methanol-d4):7.06-7.01(m,2H),7.00(m,1H),4.78-4.66(m,0.8H),4.50(d,J=14.4Hz,2H),4.46-4.33(m ,0.5H),3.24-3.02(m,2H),2.94(d,J=8.1Hz,3H),2.64-2.41(m,6H),2.40-2.33(m,1H),2.32(m,3H),2.26-2.16(m,1H).

[0443] Example 47: (2s,4S)—N-((1s,3S)-3-(3-cyclopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0444] [ka]

[0445] The title compound was prepared analogously to Example 11, using 3-(3-cyclopropylphenyl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 36) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 21 H 26 Calculated mass of N2O3: 354.2; observed m / z: 355.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):7.22-7.10(m,1H),7.07-6.98(m,1H),6.98-6.92( m,1H),6.92-6.83(m,1H),4.80-4.67(m,0.5H),4.50(d,J=15.1Hz,2H),4.46-4. 30(m,0.5H),3.25-3.02(m,2H),2.95(m,3H),2.62-2.42(m,6H),2.40-2.29(m,1 H),2.25-2.16(m,1H),1.95-1.83(m,1H),0.98-0.89(m,2H),0.72-0.59(m,2H).

[0446] Example 48: (2s,4S)—N-((1s,3S)-3-(2,3-dihydro-1H-inden-5-yl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0447] [ka]

[0448] The title compound was prepared in a manner similar to Example 11, using 3-(2,3-dihydro-1H-inden-5-yl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 37) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 21 H 26 Calculated mass of N2O3: 354.2; observed m / z: 355.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):7.18-7.03(m,2H),7.05-6.85(m,1H),4.81-4.67(m,0.5H),4.50(d,J=14.5Hz,2H),4.42-4.31(m,0.5H),3 .27-3.02(m,2H),2.95(d,J=7.5Hz,3H),2.91-2.80(m,4H),2.63-2.41(m,6H),2.41-2.26(m,1H),2.26-2.12(m,1H),2.11-1.95(m,2H).

[0449] Example 49: (2s,4S)—N-((1s,3S)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0450] [ka]

[0451] The title compound was prepared in a similar manner to Example 11, using 3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)-N-methylcyclobutan-1-amine, trifluoroacetate (Intermediate 38) instead of 3-(3-isopropylphenyl)-N-methylcyclobutan-1-amine (Intermediate 6). MS (ESI): C 20 H 24 Calculated mass of N2O3: 340.2; observed m / z: 341.2 [M+H] + . 1 H NMR(400MHz,Methanol-d4):7.08-7.01(m,1H),6.98-6.91(m,2H),4.79-4.67(m,0.5H),4.50(d,J=14.4Hz,2H),4.43-4.3 2(m,0.5H),3.22-3.03(m,6H),2.95(d,J=7.6Hz,3H),2.61-2.41(m,6H),2.33(td,J=10.0,2.8Hz,1H),2.24-2.13(m,1H).

[0452] Example 50: (2s,4S)—N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-ethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide.

[0453] [ka]

[0454] T3P (0.440 mL, 50% purity in ethyl acetate, 0.739 mmol) was added to a solution of (1s,3s)-3-(3,5-dimethylphenyl)-N-ethylcyclobutan-1-amine, HCl salt (Intermediate 29, 200 mg), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 1, 84.0 mg, 0.491 mmol), triethylamine (0.81 mL, 5.94 mmol), and dichloromethane (5 mL) at 0 °C (ice / water). The resulting mixture was stirred for 2 h while gradually warming to room temperature, then poured into water (50 mL) and extracted with dichloromethane (30 mL × 3). The combined organic extracts were dried over anhydrous NaSO, filtered, and concentrated to dryness under reduced pressure to give the crude product, which was purified by preparative HPLC using a Boston Prime C18 150 x 30 mm x 5 μm column (eluent: 50% → 80% (v / v) CHCN and HO with 0.05% NH + 10 mM NHHCO) to give the pure product. The product was suspended in water (10 mL) and the mixture was frozen using dry ice / acetone, then lyophilized to dryness to give the title compound (55.3 mg, 32%). MS (ESI): C 21 H 28 Calculated mass of N2O3: 356.2; observed m / z: 357.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d):6.87(m,1H),6.82(m,2H),5.98(m,1H),4.70-4.59(m,0.5H),4.38(d,J=9.8Hz,2H),4.15-4.02(m,0.5H),3.54-3.42 (m,1H),3.36-3.27(m,1H),3.21-2.96(m,2H),2.75-2.58(m,4H),2.56-2 .46(m,2H),2.36-2.22(m,7H),2.17-2.06(m,1H),1.13(t,J=6.9Hz,3H).

[0455] 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 incubation for 1 hour, the cleaved [1,3-H]-oleoylglycerol was passed through a charcoal filter. 3 The amount of cleaved tritiated glycerol that passes through the carbon filter is proportional to the activity of the MGL enzyme in that particular well / test condition.

[0456] The standard conditions for this assay were: 300 nM [glycerol-1,3- 3 [H]-oleoylglycerol was mixed with human MGL derived from HeLa cells and test compounds for 1 hour, after which the reaction mixture was filtered through activated charcoal and tritium was measured in the flow-through fraction. The test compound concentration in the screening mode was 10 μM, and the IC 50 The highest concentration of compound in the assay is determined empirically. MGL is the major hydrolase in HeLa cells / cell homogenates.

[0457] [Table 3-1]

[0458] [Table 3-2]

[0459] [Table 3-3] NT means not tested. The present invention includes the following embodiments. [1] 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) each optionally containing 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 substituted with one, two, or three substituents selected from cycloalkyl, phenyl, O-phenyl, and O-pyridyl, wherein each cycloalkyl, phenyl, or pyridyl optionally contains one or two C 1~4 Alkyl, C 1~4 or substituted with haloalkyl or halo groups, or two adjacent ring substituents in said phenyl, benzyl, or monocyclic heteroaryl together with the atoms to which they are attached form a fused 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, phenyl, benzyl, or monocyclic heteroaryl; (ii) Optionally, C 1~4 alkyl- or halo-substituted bicyclic heteroaryl; and (iii) Optionally, C 1~4 Alkyl, C 1~4 Haloalkyl or halo-substituted C 3~6 Alkyl or C 3~6 cycloalkyl Selected from; R 4 is C 1~6 alkyl) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof. [2] Formula (I):

change

change

change

change

change

[10] R 3 is 3,5-dimethylphenyl, 3-ethyl-5-methylphenyl, 4-ethyl-3-methylphenyl, 3-isopropylphenyl, or 3-tert-butylphenyl.

[11] X is O and R 2a and R 2b and each represents H.

[12] X is CH 2 and R 2a and R 2b and each represents H.

[13] X is O and R3 However, each independently F, C 1-6 Alkyl, OCH 3 , cyclopropyl, CH 3 or CF 3 The compound according to [1] or [2] above, wherein the phenyl is phenyl substituted with one or two members selected from cyclopropyl substituted with cyclobutyl.

[14] R 4 But CH 3 or CH 2 CH 3 The compound according to any one of the above [1] to

[13] ,

[15] (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-cyclobutylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(4-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2r,4S)-N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-(tert-butyl)-4-fluorophenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(2,3-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(2,3-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-cyclopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3,4-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-fluoro-4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-fluoro-3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(2,4-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-ethyl-3-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-cyclopropyl-3-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-cyclopropyl-4-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3S)-3-benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3R)-3-benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(tert-butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(tert-butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-N-((1s,3S)-3-(4-(1-methylcyclopropyl)phenyl)cyclobutyl)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-(Sec-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-N-((1s,3S)-3-(3-(1-methylcyclopropyl)phenyl)cyclobutyl)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-ethyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-cyclopropyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-isopropyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-chloro-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-cyclopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(2,3-dihydro-1H-inden-5-yl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and (2s,4S)-N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-ethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[16] (2r,4S)-N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and (2s,4S)-N-((1s,3S)-3-(4-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and pharmaceutically acceptable salts, isotopes, N-oxides, solvates, and stereoisomers thereof.

[17] A pharmaceutical composition comprising: (A) a therapeutically effective amount of at least one compound according to any one of [1], [2],

[15] , or

[16] ; (B) at least one pharmaceutically acceptable excipient; The pharmaceutical composition comprising:

[18] The pharmaceutical composition according to

[17] , wherein the compound is the compound according to

[15] .

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

[15] , or

[16] .

[20] The method according to

[19] , wherein the disease, disorder, or condition mediated by the MGL receptor is selected from pain, a psychiatric condition, a neurological condition, cancer, and an eye condition.

[21] The method according to

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

[22] The method according to

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

Claims

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

2. Formula (I): 【Chemistry 2】 (In the formula, X is CH ２ or O, R １ is H, R ２ａ and R ２ｂ are each H, R ３ is C １～６ Alkyl (optionally C ３～６ alkyl); C ３～６ cycloalkyl; benzyl; phenyl; each independently halo, C １～６ Alkyl, OC １～６ Alkyl, C ３～６ Cycloalkyl, and CH ３ or CF ３ C substituted with ３～６ Phenyl substituted with one or two members selected from cycloalkyl; 2,3-dihydro-1H-inden-5-yl; bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl; and 5,6,7,8-tetrahydronaphthalen-2-yl. is selected from R ４ is C １～６ alkyl) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

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

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

5. R ３ The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, wherein is tert-butyl.

6. R ３ but, 【Chemistry 3】 【Chemistry 4】 5. The compound of any one of claims 1 to 4, wherein:

7. R ３ but, 【Chemistry 5】 5. The compound of any one of claims 1 to 4, wherein:

8. R ３ benzyl, phenyl, or each independently F, CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ３ , OCH ３ , cyclopropyl, CH ３ Or CF ３ 5. The compound of any one of claims 1 to 4, wherein phenyl is substituted with one or two members selected from cyclopropyl substituted with cyclopropyl, and cyclobutyl, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

9. R ３ but, 【Chemistry 6】 5. The compound of any one of claims 1 to 4, wherein:

10. R ３ is 3,5-dimethylphenyl, 3-ethyl-5-methylphenyl, 4-ethyl-3-methylphenyl, 3-isopropylphenyl, or 3-tert-butylphenyl, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

11. X is O and R ２ａ and R ２ｂ 3. The compound of claim 1 or 2, wherein each is H, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

12. X is CH ２ and R ２ａ and R ２ｂ 3. The compound of claim 1 or 2, wherein each is H, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

13. X is O and R ３ However, each independently F, C １－６ Alkyl, OCH ３ , cyclopropyl, CH ３ or CF ３ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof, wherein R is phenyl substituted with one or two members selected from cyclopropyl substituted with cyclopropyl, and cyclobutyl.

14. R ４ But CH ３ or CH ２ CH ３ 14. The compound of any one of claims 1 to 13, wherein:

15. (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-phenylcyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-cyclobutylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(4-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2r,4S)-N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(3-methoxyphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-(tert-butyl)-4-fluorophenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(o-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1r,3R)-3-(m-tolyl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(2,3-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(2,3-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-cyclopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3,4-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-fluoro-4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-fluoro-3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(2,4-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-ethyl-3-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-cyclopropyl-3-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-cyclopropyl-4-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-6-oxo-N-((1s,3S)-3-(5,6,7,8-tetrahydronaphthalen-2-yl)cyclobutyl)-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3S)-3-benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3R)-3-benzylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(tert-butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-(tert-butyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1r,3R)-3-cyclohexylcyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-N-((1s,3S)-3-(4-(1-methylcyclopropyl)phenyl)cyclobutyl)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-(Sec-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-methyl-N-((1s,3S)-3-(3-(1-methylcyclopropyl)phenyl)cyclobutyl)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-ethyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-cyclopropyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-isopropyl-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-chloro-5-methylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-cyclopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(2,3-dihydro-1H-inden-5-yl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and (2s,4S)-N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-ethyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

16. (2r,4S)-N-((1s,3S)-3-(3-(tert-butyl)phenyl)cyclobutyl)-N-methyl-6-oxo-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3,5-dimethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(3-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; (2s,4S)-N-((1s,3S)-3-(4-isopropylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; and (2s,4S)-N-((1s,3S)-3-(4-ethylphenyl)cyclobutyl)-N-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxamide; or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof.

17. 1. A pharmaceutical composition comprising: (A) a therapeutically effective amount of at least one compound of any one of claims 1, 2, 15, or 16, or a pharmaceutically acceptable salt, isotope, N-oxide, solvate, or stereoisomer thereof; (B) at least one pharmaceutically acceptable excipient; and The pharmaceutical composition comprising:

18. 18. The pharmaceutical composition of claim 17, wherein the compound is a compound of claim 15.

19. 19. The pharmaceutical composition according to claim 17 or 18, for treating a subject suffering from or diagnosed with a disease or disorder mediated by the MGL receptor.

20. 20. The pharmaceutical composition of claim 19, wherein the disease or disorder mediated by the MGL receptor is selected from pain, a psychiatric disease or disorder, a neurological disease or disorder, cancer, and an eye disease or disorder.

21. 20. The pharmaceutical composition of claim 19, wherein the disease or disorder mediated by the MGL receptor is selected from major depressive disorder, treatment-resistant depression, anxious depression, autism spectrum disorder, Asperger's syndrome, and bipolar disorder.

22. 20. The pharmaceutical composition of claim 19, wherein the disease or disorder mediated by the MGL receptor is inflammatory pain.

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