Azaspirocyclic compounds as modulators of monoacylglycerol lipase

Abstract

The present invention provides azaspiro compounds of formula (I), and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof, pharmaceutical compositions containing them, methods for preparing them and methods of using them, including methods for treating disease states, disorders and conditions associated with MGL regulation, such as those associated with pain, mental disorders, neurological disorders (including but not limited to major depressive disorder, refractory depression, anxious depression, autism spectrum disorder, Asperger's syndrome, bipolar disorder), cancer and eye disorders: wherein X, R 1 , R 2a , R 2b , R 3 , m, n, o and p are defined herein.

Description

Technical Field

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

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

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

[0004] Therefore, MGL modulation provides an interesting strategy for enhancing the endocannabinoid system. A major advantage of this approach is that only brain regions that efficiently produce endocannabinoids will be modulated, thereby potentially minimizing the side effects associated with exogenous CB1 agonists. Pharmacological inactivation of MGL by covalent inhibitors in animals increases 2-AG levels in the brain and peripheral tissues and has been found to produce analgesic, anxiolytic, and anti-inflammatory effects that are dependent on CB1 and / or CB2 receptors (Long et al., Nat Chem Biol., 2009 Jan, 5(1):37-44; Ghosh et al., Life Sci., 2013 Mar 19, 92(8-9):498-505; Bedse et al., Biol Psychiatry., 2017 Oct 1, 82(7):488-499; Bernal-Chico et al., Glia., 2015 Jan, 63(1):163-76; Patel et al., Neurosci Biobehav Rev., 2017 May, 76(Pt A):56-66; Betse et al., Transl Psychiatry., 2018 Apr 26, 8(1):92). In addition to the role of MGL in terminating 2-AG signaling, MGL modulation (including MGL inhibition) also promotes CB1 / 2-independent effects on neuroinflammation (Nomura et al., Science., 2011 Nov 11, 334(6057):809-13).MGL modulation (including MGL inhibition) results in reduced pro-inflammatory prostaglandin signaling in animal models of traumatic brain injury (Katz et al., J Neurotrauma., 2015 Mar 1, 32(5):297-306; Zhang et al., J Cereb Blood Flow Metab., 2015 Mar 31, 35(4):443–453), neurodegenerative diseases including Alzheimer's disease (Piro et al., Cell Rep., 2012 Jun 28, 1(6):617-23; Wenzel et al., Life Sci., 2018 Aug 15, 207:314-322; Chen et al., Cell Rep., Nov. 29, 2012, 2(5):1329-39), Parkinson's disease (Nomura et al., Science, Nov. 11, 2011, 334(6057), 809-13; Pasquarelli et al., Neurochem Int., Nov. 2017, 110:14-24), amyotrophic lateral sclerosis (Pasquarelli et al., Neuropharmacology, Sept. 15, 2017, 124:157-169), multiple sclerosis (Hernadez-Torres et al., Angew Chem Int Ed., Nov. 2014, 134:157-169), Engl., Dec 8, 2014, 53(50):13765-70; Bernal-Chico et al., Glia., Jan 2015, 63(1):163-76), Huntington's disease (Covey et al., Neuropsychopharmacology, 2018, 43, 2056-2063), Tourette syndrome and status epilepticus (Terrone et al., Epilepsia., Jan 2018, 59(1), 79-91; von Ruden et al., Neurobiol Dis., May 2015, 77:238-45).

[0005] Thus, by enhancing the cannabinoid system and attenuating the pro-inflammatory cascade, MGL modulation (including MGL inhibition) offers an attractive therapeutic approach for the treatment of a wide range of complex diseases. Importantly, MGL modulation (including MGL inhibition) in animals does not produce the same effects as Δ 9 - The full range of neurobehavioral effects observed with THC and other CB1 agonists (Tuo et al., J Med Chem., 2017 Jan 12, 60(1), 4-46; Mulvihill et al., Life Sci., 2013 Mar 19, 92(8-9), 492-7).

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

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

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

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

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

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

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

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

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

[0015]

[0016] in

[0017] X is CH2 or O;

[0018] R 1 is H;

[0019] R 2a and R 2b Each independently selected from H and C 1-4 alkyl;

[0020] R 3 Selected from:

[0021] (i) phenyl, benzyl or monocyclic heteroaryl, each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SC 1-6 Alkyl, SF5, Si(CH3)3, NR a R b , C 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, phenyl, O-phenyl and O-pyridyl, wherein each cycloalkyl, phenyl or pyridyl is optionally substituted by one or two C 1-4 Alkyl, C 1-4 or two adjacent ring substituents on a phenyl, benzyl or monocyclic heteroaryl group are taken together with the atoms to which they are attached to form a fused monocyclic C 5-6 Cycloalkyl or heterocycloalkyl rings, each optionally substituted by one or two C 1-4 Alkyl, C 1-4 Substitution with haloalkyl or halo groups;

[0022] Where R a and R b Each independently is H or C 1-4 alkyl;

[0023] (ii) optionally C 1-4 Alkyl or halo substituted bicyclic heteroaryl; and

[0024] (iii) optionally C 1-4 Alkyl, C 1-4 Haloalkyl or halogen substituted C 3-6 Alkyl or C3-6 cycloalkyl; and

[0025] n, m, o and p are each independently 1 or 2;

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

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

[0028]

[0029] in

[0030] X is CH2 or O;

[0031] R 1 is H;

[0032] R 2a and R 2b Each independently selected from H and C 1-4 alkyl;

[0033] R 3 Selected from: C 3-6 Cycloalkyl; C 1-4 Alkyl substituted C 3-6 Cycloalkyl; phenyl; phenyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 haloalkyl, and C optionally substituted by CH3 or CF3 3-6 Cycloalkyl; pyridyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl and C 1-6 Haloalkyl; C 1-6 Alkyl substituted pyrimidinyl; and

[0034] n, m, o and p are each independently 1 or 2;

[0035] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof. DETAILED DESCRIPTION

[0036] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.

[0037] Unless specifically stated in a specific use example, the term "alkyl" refers to a straight or branched chain alkyl group having 1 to 8 carbon atoms in the chain. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that would be considered equivalent to any of the foregoing examples according to the ordinary skill in the art and the teachings provided herein. "C1-C4 alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms in the chain.

[0038] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic, fused polycyclic or spiro polycyclic carbocyclic ring having 3 to 12 ring atoms per carbocyclic ring. Illustrative examples of cycloalkyl groups include the following entities in the form of appropriate bonding moieties:

[0039] or

[0040] The term "halogen" or "halo" refers to chlorine, fluorine, bromine or iodine.

[0041] The term "haloalkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms in the chain, optionally replacing hydrogen with a halogen. As used herein, the term "C1-C4 haloalkyl" refers to a straight or branched alkyl group having 1 to 4 carbon atoms in the chain, optionally replacing hydrogen with a halogen. Examples of "haloalkyl" groups include trifluoromethyl (CF3), difluoromethyl (CF2H), monofluoromethyl (CH2F), pentafluoroethyl (CF2CF3), tetrafluoroethyl (CHFCF3), monofluoroethyl (CH2CH2F), trifluoroethyl (CH2CF3), tetrafluorotrifluoromethylethyl (CF(CF3)2), and groups that are considered to be equivalent to any of the foregoing examples according to those of ordinary skill in the art and the teachings provided herein.

[0042] The term "aryl" refers to a monocyclic aromatic carbocyclic ring (a ring structure in which the ring atoms are all carbon) having 6 atoms per ring (the carbon atoms in the aryl group are sp2 hybridized).

[0043] The term "phenyl" represents the following moiety:

[0044] The term "pyridinyl" or "pyridyl" refers to the following moiety:

[0045] The pyridyl or pyridyl moiety may be attached via any of the 2-, 3-, 4-, 5- or 6-carbon atoms.

[0046] The term "pyrimidinyl" refers to the moiety:

[0047] The pyrimidinyl moiety can be attached via any of the 2-, 4-, 5-, or 6-carbon atoms.

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

[0049] As used herein, the term "heterocycloalkyl" refers to a non-aromatic ring system, from 1 to 4 of the ring atoms are independently O, N or S, and the remaining ring atoms are carbon atoms, which may be optionally fused to another ring (aromatic or heteroaromatic). Non-limiting examples of exemplary heterocycloalkyls include:

[0050]

[0051] One skilled in the art will recognize that the heteroaryl, heterocycloalkyl, cycloalkyl, aryl groups listed or exemplified above are not exhaustive and that other species within the scope of these defined terms may also be selected.

[0052] The term "substituted" means that the specified group or moiety carries one or more substituents. The term "unsubstituted" means that the specified group does not carry a substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. If the term "substituted" is used to describe a structural system, it means that the substitution occurs at any valence-allowed position on the system.

[0053] The term "variable point of attachment" means that a group is allowed to be attached at more than one alternative position in the structure. The attachment always replaces a hydrogen atom on one of the ring atoms. In other words, all arrangements of bonding are represented by a single schematic, as shown in the following illustration.

[0054] or

[0055] or

[0056] or

[0057] One skilled in the art will recognize that if more than one such substituent is present on a given ring; then each substituent is bonded independently of all the other substituents. The groups listed or exemplified above are not exhaustive.

[0058] One skilled in the art will recognize that the cycloalkyl and aryl groups listed or exemplified above are not exhaustive and that other species within the scope of these defined terms may also be selected.

[0059] The terms "para", "meta" and "ortho" have meanings as understood in the art. Thus, for example, a fully substituted phenyl group has substituents at two "ortho" (o) positions adjacent to the point of attachment to the phenyl ring, two "meta" (m) positions, and one "para" (p) position opposite the point of attachment. To further clarify the positions of the substituents located on the phenyl ring, the 2 different ortho positions will be designated "ortho and ortho'", and the 2 different meta positions will be designated "meta and meta'".

[0060]

[0061] When referring to substituents on a pyridyl group, the terms "para", "meta", and "ortho" refer to the position of the substituent relative to the point of attachment of the pyridyl ring. For example, the structure below is described as having X in the ortho position. 1 Substituent, X in meta position 2 Substituents, and X in the para position 3 Substituents of 3-pyridyl:

[0062]

[0063] The term "substituted" means that the specified group or moiety carries one or more substituents. The term "unsubstituted" means that the specified group does not carry a substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted with one or more substituents. If the term "substituted" is used to describe a structural system, it means that the substitution occurs at any valence-allowed position on the system.

[0064] Any formula given herein is intended to represent compounds having the structure shown in the structural formula and certain variations or forms. Specifically, the compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of compounds with general formula and their mixtures are considered to be within the scope of such formulas. The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be prepared as individual (R)- or (S)-stereoisomers or as mixtures thereof. Therefore, any formula given herein is intended to represent racemates, one or more forms of their enantiomeric forms, one or more forms of their diastereomeric forms, and mixtures thereof. In addition, any formula given herein is intended to also refer to any one of the hydrates, solvates, and polymorphs of such compounds, and mixtures thereof, even if such forms are not explicitly listed.

[0065] The term "R" at a stereocenter indicates that the stereocenter has only the R-configuration, as defined in the art; similarly, the term "S" means that the stereocenter has only the S-configuration. As used herein, the term "RS" refers to a stereocenter that exists in a mixture of the R-configuration and the S-configuration.

[0066] A compound containing one stereocenter without a stereobond label is a mixture of 2 enantiomers. A compound containing 2 stereocenters, neither of which has a stereobond label, is a mixture of 4 diastereomers. A compound having 2 stereocenters, both labeled "RS", with stereobond labels, is a 2-component mixture with relative stereochemistry as indicated. An unlabeled stereocenter without a stereobond label is a mixture of R- and S-configurations. For unlabeled stereocenters with stereobond labels, the absolute stereochemistry is as stated.

[0067] Reference to a compound herein represents a reference to any of: (a) the form of such compound actually mentioned, and (b) any form of such compound in the medium in which the compound is considered when referring to the compound. For example, reference to a compound such as R-COOH herein encompasses reference to any of: for example, R-COOH(s), R-COOH(sol), and R-COO-(sol). In this example, R-COOH(s) refers to a solid compound, which may be in the form of a tablet or some other solid pharmaceutical composition or formulation, for example; R-COOH(sol) refers to an undissociated form of the compound in a solvent; and R-COO-(sol) refers to a dissociated form of the compound in a solvent, such as a dissociated form of the compound in an aqueous environment, whether such dissociated form is derived from R-COOH, a salt thereof, or from any other entity that, upon dissociation in the medium in question, produces R-COO-. In another example, a statement such as "exposing an entity to a compound of formula R-COOH" refers to exposing the entity to one or more forms of the compound R-COOH present in the medium in which the exposure occurs. In yet another example, a statement such as "reacting an entity with a compound of formula R-COOH" refers to reacting (a) such entity (as one or more chemically related forms of such entity present in the medium in which the reaction occurs) with (b) one or more chemically related forms of the compound R-COOH present in the medium in which the reaction occurs. In this regard, if the entity is, for example, in an aqueous environment, it is understood that the compound R-COOH is in the same medium and that the entity is therefore being exposed to substances such as R-COOH(aq) and / or R-COO-(aq), wherein the subscript "(aq)" represents "aqueous" according to its conventional meaning in chemistry and biochemistry. The carboxylic acid functional group is selected in these naming examples; however, this selection is not intended to be limiting, but is merely illustrative. It should be understood that similar examples can be provided with other functional groups, including but not limited to hydroxyl groups, basic nitrogen members (such as those in amines), and any other groups that interact or transform in a known manner in a medium containing the compound. Such interactions and transformations include, but are not limited to, dissociation, association, tautomerism, solvolysis including hydrolysis, solvation including hydration, protonation and deprotonation. No further examples are provided herein in this regard, as these interactions and transformations in a given medium are known to any ordinary technician in the art.

[0068] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number in enriched form. Examples of isotopes that may be incorporated into the compounds of the invention in excess of natural abundance include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H (or chemical symbol D), 3 H (or chemical symbol T), 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F. 36 Cl and 125 I. Such isotope-labeled compounds can be used for metabolic studies (preferably with 14 C labeling), reaction kinetic studies (e.g. 2 H or 3 H labeling), detection or imaging techniques [such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)], including tissue distribution assays of drugs or substrates, or can be used for radiation therapy of patients. Specifically, 18 F or 11 C-labeled compounds may be particularly preferred for PET or SPECT studies. In addition, compounds labeled with heavier isotopes such as deuterium (i.e. 2 H or D) can provide certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents to carry out the procedures disclosed in the "Schemes" or in the "Examples and Preparations" described below.

[0069] When referring to any formula given herein, for a specified variable, the selection of a specific part from a list of possible species is not intended to limit the selection of the same species when such variable appears elsewhere. In other words, unless otherwise indicated, when a variable appears more than once, the selection of that species from a specified list is independent of the selection of that species for the same variable elsewhere in the formula.

[0070] Terminology C n-m Alkyl refers to an aliphatic chain, whether straight or branched, in which the total number of carbon members N in the chain satisfies n≤N≤m, and m>n.

[0071] When the same multiple substituents are assigned to multiple groups, the specific individual substituent assignments assigned to each of such groups are intended to be independently selected relative to the specific individual substituents assigned to the remaining groups. By way of example, but not limitation, if each of the groups Q and R can be H or F, the selection of H or F for Q is made independently of the selection of H or F for R, so that unless otherwise expressly stated, the selection of the assignment to Q does not determine or determine the selection of the assignment to R, or vice versa, the selection of the assignment to R does not determine or determine the selection of the assignment to Q. In this regard, the exemplary claim expressions will be understood to mean "each of Q and R is independently H or F", or "each of Q and R is independently selected from H and F".

[0072] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise.Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art.

[0073] In another example, the present invention covers zwitterionic compounds by referring to compounds known to form zwitterions, even if it is not explicitly mentioned in its zwitterionic form. Terms such as one or more zwitterions and their synonyms zwitterionic compounds are standard names recognized by IUPAC, which are well known and part of the standard set of defined scientific names. In this regard, the name zwitterion is assigned the name identifier CHEBI:27369 by the molecular entity dictionary of the Chemical Entities of Biological Inerest (ChEBI). It is well known that zwitterions or zwitterionic compounds are neutral compounds with formal unit charges of opposite signs. Sometimes, these compounds are referred to by the term "inner salts". Other materials call these compounds "dipole ions", but this term is considered to be a misnomer by other other materials. As a specific example, aminoacetic acid (amino acid glycine) has the formula H2NCH2COOH, and it is a zwitterion. + H3NCH2COO -The forms exist in some medium (in this case, in a neutral medium). The terms zwitterion, zwitterionic compound, inner salt, and dipole ion fall within the scope of the present invention in accordance with their known and recognized meanings, as understood in any case by one of ordinary skill in the art. Since it is not necessary to name every embodiment that one of ordinary skill in the art would recognize, the structures of zwitterionic compounds associated with the compounds of the present invention are not explicitly given herein. However, they are part of the embodiments of the present invention. In this regard, no further examples are provided herein, as the interactions and transformations that lead to the production of various forms of a given compound in a given medium are known to anyone of ordinary skill in the art.

[0074] When referring to any formula given herein, for a specified variable, the selection of a particular part from a list of possible species is not intended to limit the selection of the same species when the variable appears elsewhere. In other words, unless otherwise indicated, when a variable appears more than once, the selection of that species from a specified list is independent of the selection of that species for the same variable elsewhere in the formula.

[0075] Using the first example of substituent terminology, if the substituent S 1 实施例 is one of S1 and S2, and the substituent S 2 实施例 is one of S3 and S4, then these designations refer to the embodiments of the present invention given by the following selections: S 1 实施例 is S1 and S 2 实施例 It is S3; S 1 实施例 is S1 and S 2 实施例 It is S4; S 1 实施例 is S2 and S 2 实施例 It is S3; S 1 实施例 is S2 and S 2 实施例 is S4; and equivalents of each of such alternatives. The shorter term "S 1 实施例 is one of S1 and S2, and S 2 实施例 "is one of S3 and S4" is therefore used herein for brevity, but not in a limiting manner. The first example of substituent terminology stated above in general terms is intended to illustrate the different substituent assignments described herein.

[0076] Furthermore, when more than one designation is given for any member or substituent, embodiments of the invention include various groupings that can be made independently from the listed designations, and equivalents thereof. By way of a second example of substituent terminology, if a substituent S is described herein 实施例 is one of S1, S2 and S3, then the list refers to an embodiment of the present invention, in which S 实施例 It is S1; S 实施例 It is S2; S 实施例 It is S3; S 实施例 is one of S1 and S2; S 实施例 is one of S1 and S3; S 实施例 is one of S2 and S3; S 实施例 is one of S1, S2 and S3; and S 实施例 are any equivalents of each of these options. The shorter term "S 实施例 "is one of S1, S2 and S3" is therefore used herein for brevity, but not in a limiting manner. The second example of substituent terminology stated above in general terms is intended to illustrate the different substituent assignments described herein.

[0077] The name "C i -C j ", when applied herein to a class of substituents, is intended to refer to embodiments of the invention where each and every one of the numbers of carbon members from i to j (inclusive) is independently realized. By way of example, the term C1-C3 or C 1-3 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).

[0078] "Pharmaceutically acceptable salts" are intended to mean salts of acids or bases of compounds represented by formula (I) that are non-toxic, biologically tolerable, or otherwise biologically suitable for administration to a subject. See generally SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977, 66: 1-19, and Handbook of Pharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth, eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with patient tissues without undue toxicity, irritation, or allergic response.

[0079] The compounds of formula (I) may possess sufficiently acidic groups, sufficiently basic groups, or both types of functional groups, and therefore react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0080] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioate, hexyne-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

[0081] The compound of formula (I) may contain at least one nitrogen with basic properties, and thus the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, etc.; or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid , salicylic acid, oleic acid, palmitic acid, lauric acid, pyranosiduronic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as mandelic acid, citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid), sulfonic acid (such as lauryl sulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid), any compatible mixture of acids such as those given as examples herein, and any other acids and mixtures thereof deemed equivalent.

[0082] The compounds of formula (I) may contain a carboxylic acid moiety, and the desired pharmaceutically acceptable salts may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide, an alkaline earth metal hydroxide, any compatible mixture of bases such as those given as examples herein, and any other bases and mixtures thereof deemed by one of ordinary skill in the art to be equivalent or acceptable substitutes. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, carbonates, bicarbonates, primary, secondary, tertiary amines and cyclic amines such as benzylamine, pyrrolidine, piperidine, morpholine, piperazine, N-methylglucamine and tromethamine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0083] The compounds of the invention, including pharmaceutically acceptable salts thereof, either alone or in combination (collectively referred to as "active agents"), can be used as MGL modulators in the methods of the invention. Such methods for modulating MGL comprise administering a therapeutically effective amount of at least one chemical entity of the invention.

[0084] In some embodiments, MGL modulators are inhibitors and are used to diagnose a subject having or suffering from a disease, disorder or condition associated with MGL receptor activity, such as those described herein.Symptoms or disease states are intended to be included within the scope of "disease, disorder or condition".

[0085] Therefore, the present invention relates to methods for treating subjects diagnosed with or suffering from diseases, disorders or conditions associated with MGL receptor activity using the active agents described herein. The term "treatment" as used herein is intended to refer to the administration of an active agent or composition of the present invention to a subject for the purpose of achieving a therapeutic or preventive benefit by modulating MGL receptor activity. Treatment includes reversing, ameliorating, alleviating, inhibiting progression, reducing severity, or preventing a disease, disorder or condition associated with MGL modulation or one or more symptoms of such a disease, disorder or condition. The term "subject" refers to a mammalian patient, such as a human, in need of such treatment.

[0086] The term "composition" refers to a product comprising the specified ingredients in therapeutically effective amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0087] The term "MGL inhibitor" is intended to encompass compounds that interact with MGL to significantly reduce or eliminate its catalytic activity, thereby increasing the concentration of its substrate. The term "MGL-modulated" is used to refer to conditions affected by MGL enzyme modulation, including conditions affected by MGL enzyme inhibition. The present disclosure relates to methods for treating, ameliorating and / or preventing diseases, conditions or disorders associated with pain (including inflammatory pain), as well as psychiatric disorders, neurological disorders, cancers and ocular disorders by administering a therapeutically effective amount of an MGL modulator to a subject in need thereof.

[0088] The term "modulator" includes both inhibitors and activators, wherein "inhibitors" refer to compounds that reduce, prevent, inactivate, desensitize or downregulate MGL expression or activity, while "activators" refer to compounds that increase, activate, promote, sensitize or upregulate MGL expression or activity.

[0089] Unless otherwise indicated, as used herein, the term "affect" or "affected" (when referring to a disease, condition or disorder, that is affected by MGL inhibition) includes a reduction in the frequency and / or severity of one or more symptoms or clinical manifestations of the disease, condition or disorder; and / or includes preventing the development of the disease, condition or disorder or the development of one or more symptoms or clinical manifestations of the disease, condition or disorder.

[0090] In the method of treatment according to the present invention, at least one activating agent of the present invention of a therapeutically effective amount is administered to a subject suffering from or diagnosed as having such a disease, disorder or condition." Therapeutically effective amount" refers to the amount or dosage sufficient to produce the desired treatment or prevention beneficial effect in the subject who needs to carry out such treatment for a specified disease, disorder or condition as a whole. The effective amount or dosage of the activating agent of the present invention can be explored by conventional methods such as modeling, dose escalation studies or clinical trials, and explored by considering conventional factors, such as the mode or approach of administration or drug delivery, the pharmacokinetics of the reagent, the severity and course of the disease, disorder or condition, the therapy performed before or now performed by the subject, the health status of the subject and the response to the drug, and the judgment of the attending physician. For a 70kg person, the exemplary range of a suitable dosage is in single dose units or multiple dose units (e.g., BID, TID, QID or according to the needs of therapy), about 1 mg / day to 1000 mg / day.

[0091] Once the subject's disease, disorder or condition improves, the dosage can be adjusted to preventive or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced to a level that maintains the desired therapeutic or preventive effect, depending on the symptoms. Of course, if the symptoms have been alleviated to an appropriate level, treatment can be stopped. However, the subject may require long-term intermittent treatment due to any recurrence of symptoms.

[0092] In addition, it is also envisioned that the compounds of the present invention are used alone, in combination with one or more other compounds of the present invention, or in combination with additional active ingredients for the treatment of the conditions described below. Additional active ingredients may be co-administered alone with at least one compound of the present invention, co-administered with an active agent of the present invention, or included in a pharmaceutical composition according to the present invention together with such agents. In an exemplary embodiment, the additional active ingredients are those active ingredients known or found to be effective in treating conditions, disorders or diseases associated with MGL regulation, such as another MGL inhibitor or a compound active against another target associated with the particular condition, disorder or disease. The combination may help to improve efficacy (e.g., by including in the combination a compound that enhances the potency or effectiveness of an active agent according to the present invention), reduce one or more side effects, or reduce the required dose of an active agent according to the present invention.

[0093] When referring to an inhibitory target, an "effective amount" means an amount sufficient to affect the regulation of MGL.

[0094] It is contemplated that the active agents of the invention are used alone or in combination with one or more additional active ingredients to formulate the pharmaceutical compositions of the invention.The pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one active agent according to the invention.

[0095] Pharmaceutically acceptable excipients commonly used in pharmaceutical compositions are non-toxic, biologically tolerable and otherwise biologically suitable substances for administration to a subject, such as inert substances, which are added to the pharmaceutical composition or otherwise used as vehicles, carriers or diluents to facilitate administration of the agent and are compatible therewith. Examples of such excipients include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.

[0096] The delivery form of the pharmaceutical composition containing one or more dosage units of the active agent can be prepared using pharmaceutically acceptable excipients and compounding techniques known or available to those skilled in the art. The composition can be administered in the method of the present invention by a suitable delivery route, such as oral, parenteral, rectal, topical or ocular administration, or by inhalation.

[0097] The preparation may be in the form of a tablet, capsule, sachet, dragee, powder, granule, lozenge, powder for reconstitution, liquid preparation or suppository. The composition may be formulated for any of a variety of routes of administration, such as intravenous infusion, topical administration or oral administration. Preferably, the composition may be formulated for oral administration.

[0098] For oral administration, the active agent of the present invention can be provided in the form of tablets or capsules, or as a solution, emulsion or suspension. In order to prepare an oral composition, the active agent can be formulated to produce, for example, a dosage of about 1 mg / day to 1000 mg / day in a single dose unit or multiple dose units as an exemplary range of suitable dosages for a 70 kg person.

[0099] Oral tablets may include one or more active ingredients mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, colorants and preservatives. Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Exemplary liquid oral excipients include ethanol, glycerol, water, etc. Starch, polyvinyl pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid are exemplary disintegrants. Binders may include starch and gelatin. Lubricants (when present) may be magnesium stearate, stearic acid or talcum powder. If desired, tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with enteric coatings.

[0100] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules or (hydroxypropyl) methylcellulose capsules. To prepare hard gelatin capsules, one or more active ingredients can be mixed with solid, semisolid or liquid diluents. The liquid for oral administration can be in the form of a suspension, solution, emulsion or syrup, or can be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid compositions may optionally include: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous vehicles, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and (if necessary) flavoring agents or coloring agents.

[0101] The activating agent of the present invention can also be administered by non-oral routes. For example, the composition can be formulated into suppositories, enemas or foams for rectal administration. For parenteral use, including intravenous, intramuscular, intraperitoneal or subcutaneous routes, the activating agent of the present invention can be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or provided in an oil acceptable to the parenteral. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms can be presented in unit dosage forms (such as ampoules or disposable injection devices), in multiple dose forms (such as vials) from which appropriate doses can be extracted, or in solid forms or pre-concentrates that can be used to prepare injectable preparations. Exemplary infusion doses range from about 1 to 1000 μg / kg / minute of the activating agent mixed with a pharmaceutically acceptable carrier, for a few minutes to a few days.

[0102] For topical administration, the active agent may be mixed with a pharmaceutical carrier at a concentration of about 0.01% to about 20%, preferably 0.1% to 10% drug to vehicle. Another way to administer the active agents of the present invention may utilize a patch formulation to achieve transdermal delivery.

[0103] Alternatively, in the methods of the present invention the active agent may be administered via the intranasal or oral route by inhalation, for example in the form of a spray formulation also containing a suitable carrier.

[0104] In another embodiment, the invention relates to a method of treating a subject suffering from or diagnosed with a disease, disorder or condition associated with MGL modulation, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of an active agent.

[0105] The compounds of formula (I) are useful in methods for treating, ameliorating and / or preventing diseases, conditions or disorders affected by MGL inhibition. Such methods include administering a therapeutically effective amount of a compound of formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof to a subject, including animals, mammals and humans in need of such treatment, improvement and / or prevention.

[0106] Specifically, the compound of formula (I) or its pharmaceutically acceptable salt, isotope, N-oxide, solvate and stereoisomer can be used to treat, improve and / or prevent diseases, disorders or disorders that cause pain, mental disorders, neurological disorders, cancer and eye disorders. More specifically, the compound of formula (I) or its pharmaceutically acceptable salt, isotope, N-oxide, solvate and stereoisomer can be used to treat, improve and / or prevent inflammatory pain, major depressive disorder, refractory depression, anxious depression or bipolar disorder, by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined herein or its pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer.

[0107] 1) Pain

[0108] Examples of inflammatory pain include, but are not limited to, pain due to a disease, condition, disorder, or pain state, including inflammatory bowel disease, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, fatigue, musculoskeletal disorders, skin disorders, toothache, febrile illnesses, burns, sunburn, snake bites, venomous snake bites, spider bites, insect bites, neurogenic bladder, interstitial cystitis, urinary tract infections, rhinitis, contact dermatitis / hypersensitivity, pruritus, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, post-mastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.

[0109] One type of inflammatory pain is inflammatory hyperalgesia / hypersensitivity. Examples of inflammatory hyperalgesia include diseases, conditions, disorders, or pain states, including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, postoperative pain, headache, toothache, burns, sunburn, insect bites, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact dermatitis / hypersensitivity and / or skin allergies, pruritus, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel disease (including Crohn's disease), ulcerative colitis, benign prostatic hypertrophy, and nasal hypersensitivity.

[0110] In one embodiment, the present invention relates to a method for treating, ameliorating and / or preventing inflammatory visceral hyperalgesia in which there is enhanced visceral irritability, the method comprising, consisting of and / or consisting essentially of the following steps: administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof. In another embodiment, the present invention relates to a method for treating inflammatory somatic hyperalgesia in which there is hypersensitivity to thermal, mechanical and / or chemical stimulation, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0111] Another embodiment of the present invention relates to a method for treating, ameliorating and / or preventing neuropathic pain. Examples of neuropathic pain include pain due to diseases, conditions, disorders or pain states, including cancer, neurological disorders, spinal and peripheral nerve surgery, brain tumors, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatica, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, prosthetic pain, fractures, oral neuropathic pain, Charcot pain, complex regional pain syndrome type I and II (CRPS I / II), radiculopathy, Guillain-Barre syndrome, meralgia paresthesia, burning mouth syndrome, optic neuritis, postfebrile neuritis, migratory neuritis, segmental neuritis, Gomberg's neuritis, neuronitis, cervicobrachial neuralgia, cranial neuralgia, geniculate ganglion neuralgia, glossopharyngeal neuralgia, neuralgic migraine, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, Morton's neuralgia, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, red neuralgia, Sluder's neuralgia, sphenopalatine ganglion neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvar pain, vidian neuralgia, or chemotherapy-induced neuropathy.

[0112] One type of neuropathic pain is neuropathic cold allodynia, which can be characterized by the presence of an abnormal pain state associated with a neuropathy in which there is a hypersensitivity to cold stimuli. Examples of neuropathic cold allodynia include allodynia due to a disease, condition, disorder, or pain state, including neuropathic pain (neuralgia), pain caused by spinal and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome type I and II (CRPS I / II), and radiculopathy.

[0113] In another embodiment, the present invention relates to a method for treating, ameliorating and / or preventing neuropathic cold touch-induced allodynia in which hypersensitivity to cold stimulation is present, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0114] 2) Mental disorders

[0115] Examples of psychiatric disorders include, but are not limited to, anxiety disorders such as social anxiety disorder, post-traumatic stress disorder, phobias, social phobia, specific phobias, panic disorders, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression disorders such as major depressive disorder, bipolar disorder, seasonal affective disorder, postpartum depression, manic depression, and bipolar depression. Mood disorders and mood disorders that can be treated according to the present invention include, but are not limited to, depression, hypomania, mania, and mixed forms of bipolar I disorder; bipolar II disorder; depressive disorders such as single depression or recurrent major depressive disorder, minor depressive disorder, refractory depression, anxious depression, bipolar disorder, postpartum onset depressive disorder, depressive disorder with psychotic symptoms; persistent mood disorders such as cyclothymia, dysthymia, euthymia; premenstrual dysphoric disorder; psychosis; and developmental disorders such as autism spectrum disorders and Asperger's syndrome.

[0116] 3) Neurological disorders

[0117] Examples of neurological disorders include, but are not limited to, tremor, dyskinesia, dystonia, spasticity, Tourette syndrome; neuromyelitis optica, Parkinson's disease; Alzheimer's disease; senile dementia; Huntington's chorea; epilepsy / epileptic disorders, and sleep disorders.

[0118] 4) Cancer

[0119] Examples of cancer include, but are not limited to, benign skin tumors, prostate tumors, ovarian tumors, and brain tumors (glioblastoma, medulloepithelioma, medulloblastoma, neuroblastoma, tumors of embryonal origin, astrocytoma, astroblastoma, ependymoma, oligodendroglioma, neuroepithelioma, epiphyseal tumors, ependymoblastoma, malignant meningioma, sarcoidosis, malignant melanoma, schwannoma).

[0120] 5) Eye diseases

[0121] Examples of eye disorders include, but are not limited to, intraocular hypertension, glaucoma, degeneration and apoptosis of retinal ganglion cells and neuroretinal cells.

[0122] Other embodiments of the present invention provide a method for modulating the activity of an MGL receptor, comprising modulating such receptor while present in a subject, the method comprising exposing the MGL receptor to a therapeutically effective amount of at least one compound selected from the compounds of the present invention.

[0123] In some embodiments of Formula (I), X is CH2. In some embodiments, X is O.

[0124] In some embodiments, R 2aand R 2b Each is H. In some embodiments, R 2a and R 2b Each is CH3. In some embodiments, R 2a is H, and R 2b For CH3.

[0125] In some embodiments, R 3 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 3 for In some embodiments, R 3 is phenyl, or phenyl substituted by one or two members each independently selected from the group consisting of Cl, F, CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3, cyclopropyl, cyclopropyl substituted by CF3, and cyclobutyl. 3 for

[0126]

[0127] In some embodiments, R 3 for or

[0128] In some embodiments, R 3 for or In some embodiments, R 3 is 4-trifluoromethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl or 3-cyclopropylphenyl.

[0129] In some embodiments, R 3 is phenyl; or phenyl substituted by one, two or three members independently selected from the following: Cl, F, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C(CH3)2OH, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SCH3, Si(CH3)3, SF5, N(CH3)2, C 3-6 Cycloalkyl, CH3, OC 3-6 Cycloalkyl, phenyl, O-phenyl and O-pyridyl substituted C 3-6 Cycloalkyl.

[0130] In some embodiments, R 3is phenyl substituted by one, two or three members independently selected from the group consisting of halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, SCH3, SF5 or Si(CH3)3.

[0131] In some embodiments, R 3 for or

[0132] In some embodiments, R 3 is 4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl or 3-(1-methylcyclopropyl)phenyl.

[0133] In some embodiments, R 3 is benzyl; tert-butyl; cyclohexyl; phenyl substituted with 1-methylcyclopropyl or 1-trifluoromethylcyclopropyl, or fused to a cyclobutenyl or cyclohexenyl ring; pyridinyl optionally substituted with trifluoromethyl, fluorine or methyl; pyrimidinyl optionally substituted with tert-butyl; or oxazolyl optionally substituted with tert-butyl. In some embodiments, R 3 is an optionally substituted bicyclic heteroaryl as described herein. 3 is phenyl optionally substituted as described herein.

[0134] In some embodiments, n and o are each 1. In some embodiments, n and o are each 2. In some embodiments, n is 1 and o is 2. In some embodiments, m and p are each 1. In some embodiments, m and p are each 2. In some embodiments, m is 1 and p is 2. In some embodiments, m, n, o and p are each 1. In some embodiments, m, n and p are each 1 and o is 2. In some embodiments, m, n, and o are each 1 and p is 2. In some embodiments, n and o are each 2 and m and p are each 1. In some embodiments, n and o are each 1 and m and p are each 2. In some embodiments, n, o and p are each 2 and m is 1.

[0135] Another embodiment of the present invention is a compound as shown in Table 1 below.

[0136] Table 1.

[0137]

[0138]

[0139]

[0140]

[0141]

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

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

[0144] (2r,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one;

[0145] (2s,4s)-2-((R*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

[0146] (2s,4R*)-2-((S*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and

[0147] (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one;

[0148] and pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof.

[0149] An additional embodiment of the present invention is a compound of formula (I) having formula (IA):

[0150]

[0151] in

[0152] X is CH2 or O;

[0153] R 2a and R 2b Each independently selected from H and CH3;

[0154] R 3 Selected from: C 3-6 Cycloalkyl; C 1--4 Alkyl substituted C 3-6 Cycloalkyl; phenyl; phenyl substituted by one or two members each independently selected from the following: C1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl; and and

[0155] m and p are each independently 1 or 2;

[0156] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0157] An additional embodiment of the present invention is a compound of formula (I) having formula (IB):

[0158]

[0159] in

[0160] X is O;

[0161] R 3 Selected from phenyl and C 1-6 an alkyl-substituted phenyl group; and

[0162] m and p are each 1;

[0163] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0164] An additional embodiment of the present invention is a compound of formula (I) having formula (IC):

[0165]

[0166] in

[0167] X is CH2 or O;

[0168] R 2a and R 2b Each independently selected from H and CH3;

[0169] R 3 Selected from: C 3-6 Cycloalkyl; phenyl; phenyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 haloalkyl, and C optionally substituted by CH3 or CF3 3-6 Cycloalkyl; pyridyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl and C 1-6 Haloalkyl; C 1-6 Alkyl substituted pyrimidinyl; and

[0170] m and p are each independently 1 or 2;

[0171] or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof.

[0172] An additional embodiment of the present invention is a pharmaceutical composition comprising:

[0173] (A) a therapeutically effective amount of at least one compound selected from the group consisting of a compound of formula (I), and a pharmaceutically acceptable salt, isotope, N-oxide, solvate, and stereoisomer of a compound of formula (I); and

[0174] (B) at least one pharmaceutically acceptable excipient.

[0175] An additional 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 in Table 1, pharmaceutically acceptable prodrugs of the compounds in Table 1, and pharmaceutically active metabolites of Table 1; and at least one pharmaceutically acceptable excipient.

[0176] An additional embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from a compound of Formula (IA), and a pharmaceutically acceptable salt, N-oxide or solvate of a compound of Formula (IA), a pharmaceutically acceptable prodrug of a compound of Formula (IA), and a pharmaceutically active metabolite of Formula (IA); and at least one pharmaceutically acceptable excipient.

[0177] An additional embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from a compound of formula (IB), and a pharmaceutically acceptable salt, N-oxide or solvate of a compound of formula (IB), a pharmaceutically acceptable prodrug of a compound of formula (IB), and a pharmaceutically active metabolite of formula (IB); and at least one pharmaceutically acceptable excipient.

[0178] An additional embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from a compound of formula (IC), and a pharmaceutically acceptable salt, N-oxide or solvate of a compound of formula (IC), a pharmaceutically acceptable prodrug of a compound of formula (IC), and a pharmaceutically active metabolite of formula (IC); and at least one pharmaceutically acceptable excipient.

[0179] The present invention also encompasses enantiomers and diastereomers of compounds of formula (I) (as well as formulas (IA), (IB) and (IC)). Also within the scope of the present invention are pharmaceutically acceptable salts, N-oxides or solvates of compounds of formula (I) (as well as formulas (IA), (IB) and (IC)). The present invention also encompasses pharmaceutically acceptable prodrugs of compounds of formula (I) (as well as formulas (IA), (IB) and (IC)) and pharmaceutically active metabolites of compounds of formula (I) (as well as formulas (IA), (IB) and (IC)).

[0180] The invention also encompasses isotopic variants of formula (I) (as well as formula (IA), (IB) and (IC)), such as deuterated compounds of formula (I). The invention also encompasses pharmaceutically acceptable salts, N-oxides or solvates of isotopic variants of compounds of formula (I) (as well as formula (IA), (IB) and (IC)). The invention also encompasses pharmaceutically acceptable prodrugs of isotopic variants of compounds of formula (I) (as well as formula (IA), (IB) and (IC)) and pharmaceutically active metabolites of isotopic variants of compounds of formula (I) (as well as formula (IA), (IB) and (IC)).

[0181] An additional embodiment of the invention is a method of treating a subject suffering from or diagnosed with a disease, disorder or condition mediated by MGL receptor activity, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound selected from compounds of formula (I) (as well as formulas (IA), (IB) and (IC)); pharmaceutically acceptable salts, isotopes, N-oxides, solvates and stereoisomers thereof, including enantiomers and diastereomers of compounds of formula (I) (as well as formulas (IA), (IB) and (IC)); isotopic variants of compounds of formula (I) (as well as formulas (IA), (IB) and (IC)); and pharmaceutically acceptable salts of all of the foregoing. Also described herein is the use of a compound of formula (I), (IA), (IB) or (IC) or a pharmaceutically acceptable salt, isotope, N-oxide, solvate or stereoisomer thereof in the preparation of a medicament. In some embodiments, the medicament is used to treat a disease, disorder or condition mediated by MGL receptor activity. Also described herein are compounds of Formula (I), (IA), (IB) or (IC) or pharmaceutically acceptable salts, isotopes, N-oxides, solvates or stereoisomers thereof for use in methods of treating a disease, disorder or condition mediated by MGL receptor activity.

[0182] Exemplary compounds that can be used in the methods of the present invention will now be described with reference to exemplary synthesis schemes for their general preparation and subsequent specific examples below. Those skilled in the art will recognize that, in order to obtain a variety of compounds herein, the starting materials can be appropriately selected so that, with or without protection as required, the final desired substituent will be carried throughout the reaction scheme to obtain the desired product. Alternatively, it may be necessary or desirable to replace the final desired substituent with a suitable group that can be subjected to the entire reaction scheme and replaced with the desired substituent where appropriate. Unless otherwise indicated, the variables are as defined above for formula (I). The reaction can be carried out between the melting point and reflux temperature of the solvent, and preferably between 0°C and the reflux temperature of the solvent. Conventional heating or microwave heating can be used to heat the reaction. The reaction can also be carried out in a closed pressure vessel at a normal reflux temperature higher than the solvent.

[0183] Abbreviations and acronyms used herein include the following:

[0184] Table 2.

[0185]

[0186]

[0187]

[0188] Preparation Example

[0189] Exemplary compounds useful in the methods of the present invention will now be described with reference to exemplary synthetic schemes for their general preparation below and for the specific examples that follow.

[0190] Solution 1

[0191]

[0192] According to Scheme 1, a compound of formula (V) (wherein R a C 1-4 Alkyl) is treated with hydroxylamine; using an additive such as sodium acetate (NaOAc) or the like; in a suitable solvent such as ethanol (EtOH) or the like; to obtain a compound of formula (VI).

[0193] The compound of formula (VII) is prepared from the compound of formula (VI) using an oxidizing agent (such as hydrogen peroxide, urea peroxide, etc.); in the presence of an activating agent (such as trifluoroacetic anhydride (TFAA)); in the presence of a base (such as disodium hydrogen phosphate); in a solvent (such as acetonitrile (ACN)).

[0194] Solution 2

[0195]

[0196] According to Scheme 2, compounds of formula (VIIIa) and (VIIIb) are prepared by reacting a compound of formula (VII) (R) in the presence of a base such as triethylamine (TEA). a C 1-4 The compound of formula (IX) is prepared by reacting a compound of formula (VIIIb) in a solvent (such as ethyl acetate (EtOAc), EtOH, etc.) with formaldehyde in a solvent (such as ACN, etc.). The compound of formula (IX) is prepared by hydrogenolysis of a compound of formula (VIIIb) in the presence of a catalyst (such as palladium on carbon (Pd / C), etc.) under an atmosphere of hydrogen (H2);

[0197] The compound of formula (X) is prepared by reacting the compound of formula (IX) with triphosgene in the presence of a base (such as TEA, etc.); in a solvent (such as tetrahydrofuran (THF), etc.). The compound of formula (XI) is prepared by acidic deprotection of the compound of formula (X) using an acid (such as trifluoroacetic acid (TFA), HCl in dioxane, etc.).

[0198] Solution 3

[0199]

[0200] According to Scheme 3, the compounds of formula (XIIa) and formula (XIIb) are prepared by the compound of formula (VII) (wherein R a is ethyl) and methyl acrylate; in the presence of a base (such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)); in a solvent (such as ACN). Using a reducing agent (such as sodium borohydride (NaBH4)); an additive (such as nickel(II) chloride hexahydrate); in a suitable solvent (such as methanol (MeOH)), the compound of formula (XIIa) is reduced and cyclized to obtain a compound of formula (XIII) (wherein X is CH2).

[0201] Solution 4

[0202]

[0203] According to Scheme 4, the compound of formula (XIV) is prepared by treating a compound of formula (VII) (wherein R a C 1-4alkyl); with acetaldehyde in the presence of a base (such as TEA, etc.); in a solvent (such as ACN, etc.) at a temperature ranging from 0°C to room temperature for a period of up to 18 hours. Compounds of formula (XIV) are subjected to hydrogenolysis using the conditions previously described; compounds of formula (XVa) and (XVb) are obtained.

[0204] Solution 5

[0205]

[0206] According to Scheme 5, a compound of formula (XVa) (wherein R a C 1-4 alkyl) with triphosgene to give a compound of formula (XVI). Subjecting the compound of formula (XVI) to the acidic deprotection conditions described previously gives a compound of formula (XVII) wherein X is O.

[0207] Solution 6

[0208]

[0209] According to Scheme 6, a compound of formula (XIX) (wherein p and m are each independently 1 or 2; and n and o are each independently 1 or 2; and R a tBu) is commercially available or can be synthesized from the compound of (XVIII). Under conditions known to those skilled in the art, the compound of formula (XVIII) is treated with a reducing agent (such as NaBH4, LiAlH4, LiBH4, diisobutylaluminum hydride (DIBAL-H), etc.); in a suitable solvent (such as tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), etc.), at a temperature in the range of -78°C to 0°C; reduction for a period of 30 minutes to 16 hours; to obtain a compound of formula (XIX). The compound of formula (XX) is synthesized from the compound of formula (XIX) using iodine (I2), an appropriate base such as imidazole; and triphenylphosphine (PPh3); in a suitable solvent (such as THF, etc.); in a temperature range of 0°C to room temperature within a period of 1 hour.

[0210] Solution 7

[0211]

[0212] According to Scheme 7, a compound of formula (XXI) (wherein m is 1, p is 1 or 2; n and o are each independently 1 or 2, and R 3 is cycloalkyl or aryl; and R atBu) is prepared from a compound of formula (XX) in a flow or batch manner, using an appropriate commercially available or synthetically obtained appropriately substituted aryl halide, boronic acid or organomagnesium halide, using a catalyst such as palladium (II) acetate, bis (dibenzylideneacetone) palladium, cobalt (II) bromide, cobalt (II) acetylacetonate, nickel (II) acetylacetonate, nickel (II) iodide, etc.; and a ligand such as dicyclohexyl (2', 6'-diisopropoxy-[1,1' -biphenyl]-2-yl)phosphine (RuPhos), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), N,N,N',N'-tetramethylethylenediamine, (1R,2R)-2-aminocyclohexanol, etc.; without base or with a suitable base such as sodium hexamethyldisilazide (NaHMDS), etc.; in a suitable solvent (such as THF) at a temperature range of 0°C-50°C over a period of 1-6 hours. Cleavage of the BOC protecting group on the compound of formula (XXI) is achieved according to procedures known to those skilled in the art, for example under acidic conditions, such as TFA / CH2Cl2, HCl / dioxane, etc., to provide a compound of formula (XXII).

[0213] Solution 8

[0214]

[0215] According to Scheme 8, a compound of formula (XVIII) (wherein n, m, o, p are each independently 1 or 2, and R a C 1-4 alkyl or benzyl) under conventional Grignard reaction conditions, in the presence of an organic magnesium halide (such as phenylmagnesium bromide, etc.); with or without additives (such as CeCl3, LaCl3, etc.); in a suitable solvent such as THF or diethyl ether (Et2O), etc.; react to provide a compound of formula (XXIII), wherein R 3 is aryl or C 3-6 Cycloalkyl.

[0216] Compounds of formula (XXIII) are reacted under acidic ion reducing conditions such as TFA using triethylsilane (TES) to reduce the alcohol and cleave the tert-butyloxycarbonyl group to form compounds of formula (XXII).

[0217] In a similar manner, a compound of formula (XVIII) wherein R a C 1-4 alkyl, m, n and o are 1, and p is 2) under Grignard conditions as previously described with an organic magnesium halide such as cyclobutylmagnesium chloride, cyclopentylmagnesium chloride, etc.; with an additive such as CeCl3, etc.; to provide a compound of formula (XXIII), wherein R 3 C3-6 The compound of formula (XVIII) (wherein R a C 1-4 alkyl, and m, n, o and p are 1) under elimination conditions with a dehydrating agent such as Burgess reagent, etc.; to eliminate the alcohol and provide a compound of formula (XXIV). The compound of formula (XXII) (wherein m, n, o and p are 1 and R 3 To be C 1-4 Alkyl substituted C 3-6 Cycloalkyl) is prepared in two steps from a compound of formula (XXIV) (wherein R 3 To be C 1-4 Alkyl substituted C 3-6 For example, hydrogenation of a compound of formula (XXIV) is achieved using the conditions described, followed by deprotection of the Boc protecting group using conditions known to those skilled in the art or as previously described, to provide a compound of formula (XXII), wherein R 3 For C 1-4 Alkyl substituted C 3-6 Cycloalkyl.

[0218] The compound of formula (XXIII) is reacted under elimination conditions (such as TFA) using triethylsilane (TES) to eliminate the alcohol and cleave the tert-butyloxycarbonyl group to form a compound of formula (XXIV). The compound of formula (XXIV) is reduced using hydrogenation conditions in the presence of a palladium catalyst (including but not limited to palladium on carbon, Pd(dppf)Cl2 or Pd(PPh3)4); in a suitable solvent or solvent system such as DMF, methanol, dioxane / water, etc.; to provide a compound of formula (XXII), wherein R 3 C 3-6 Cycloalkyl.

[0219] The compound of formula (XVIII) (wherein R a C 1-4 alkyl, m, n, o and p are 1) under Grignard conditions as previously described with an organic magnesium halide such as cyclohexylmagnesium bromide; to provide a compound of formula (XXV) wherein R 3 C 3-6 Alternatively, the compound of formula (XVIII) (m, n, o and p are 1, and R a C 1-4 The alkyl) is reacted under conventional Grignard reaction conditions (using the conditions described previously) in the presence of an organomagnesium halide (such as prop-1-en-2-ylmagnesium bromide). The subsequent cyclopropanation of the prop-1-en-2-yl group uses conditions such as diethylzinc; and diiodomethane; in a solvent such as DCM; to provide a compound of formula (XXIII) wherein R3 For C 1-4 Alkyl substituted C 3-6 Cycloalkyl.

[0220] The compound of formula (XXIII) (wherein R 3 C 3-6 cycloalkyl) with a halogenating agent such as thionyl chloride (SOCl2); using a catalyst such as 4-(dimethylamino)pyridine (DMAP); in a suitable solvent such as pyridine to provide a compound of formula (XXV). A compound of formula (XXII) (wherein m, n, o and p are 1 and R 3 C 3-6 Cycloalkyl) is prepared from compounds of formula (XXV) in two steps. In the first step, hydrogenation of the compound of formula (XXV) is achieved using the conditions previously described, followed by deprotection of the Boc protecting group using conditions known to those skilled in the art or as previously described.

[0221] The compound of formula (XVIII) (wherein R a is benzyl, n and o are 2, and m and p are 1) is reacted with an appropriately substituted aryl organomagnesium halide such as phenylmagnesium bromide under Grignard conditions as previously described to provide compounds of formula (XXIII) wherein R 3 After ion reduction, hydrogenation is carried out using the conditions described above to obtain a compound of formula (XXII), wherein R 3 It is phenyl.

[0222] Solution 9

[0223]

[0224] According to Scheme 9, tert-butyl 2-bromo-7-azaspiro[3.5]nonane-7-carboxylate is reacted under photochemical cross-coupling conditions in the presence of a commercially available or synthetically accessible appropriately substituted aryl or heteroaryl halide; with a photocatalyst such as (Ir[dF(CF3)ppy]2(dtbpy))PF6, etc.; a cross-coupling catalyst such as nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2(DME)), etc.; a base such as 2,6-lutidine or potassium carbonate, etc.; a suitable additive such as tris(trimethylsilyl)silane or tris(trimethylsilyl)silanol, etc.; a suitable solvent such as 1,2-dimethoxyethane (DME) or dimethyl sulfoxide (DMSO), etc. to provide a compound of formula (XXVI), wherein R 3is a suitably substituted aryl or heteroaryl group according to claim 1. Compounds of formula (XXVI) are subjected to Boc deprotection using the conditions previously described to provide compounds of formula (XXII) wherein n and o are 2, and m and p are 1.

[0225] Solution 10

[0226]

[0227] According to Scheme 10, the compound of formula (XXVII) (wherein R b C 3-6 Cycloalkyl) is commercially available or can be synthesized from 1,3-dibromobenzene in two steps. For example, 1,3-dibromobenzene is reacted with a suitable lithiation agent such as n-butyllithium (n-BuLi) in a suitable solvent such as THF at a temperature in the range of -78°C to -70°C, and then treated with a ketone such as cyclobutanone to provide 1-(3-bromophenyl)cyclobutan-1-ol. Subsequent ionic reduction of 1-(3-bromophenyl)cyclobutan-1-ol using the conditions previously described provides a compound of formula (XXVII) wherein R b C 3-6 Cycloalkyl.

[0228] Solution 11

[0229]

[0230] According to Scheme 11, the compound of formula (XXI) (wherein n, m and p are 1, o is 2, R 3 is phenyl, and R a C 1-4 Alkyl) is synthesized from a compound of formula (XVIII) using 4-methylbenzenesulfonyl hydrazide; in a suitable solvent (such as 1,4-dioxane, etc.); at a temperature of about 80°C; over a period of 2h-5h; and then adding a suitable base (potassium carbonate, etc.) and phenylboronic acid (which reacts at a temperature of about 110°C for a period of 5h-16h). Cleavage of the BOC protecting group on the compound of formula (XXI) is achieved according to the previously described method to obtain a compound of formula (XXII).

[0231] Solution 12

[0232]

[0233] According to Scheme 12, the compound of formula (I) (wherein R 1 is H and X is CH2 or O, and R 2a and R 2b Each independently is H or C1-4 The compound of formula (XXII) (wherein R 3 For example, a compound of formula (XXII) wherein m, n, o and p are each independently 1 or 2; reacted with a synthetically available appropriately substituted carboxylic acid of formula (XXVII) including compounds of formula (XI), (XIII) and (XVII), wherein the acid is activated with an appropriate activator (e.g., a carbodiimide such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI)) optionally in the presence of hydroxybenzotriazole (HOBt) and / or a catalyst such as 4-dimethylaminopyridine (DMAP); a halogenated triaminophosphonium salt such as (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) or a bromotripyrrolidinylphosphonium hexafluorophosphate a suitable pyridinium salt such as 2-chloro-1-methylpyridinium chloride; or another suitable coupling agent such as N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), 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-trioxatriphosphine-2,4,6-trioxide The coupling reaction is carried out in a suitable solvent (such as DCM, THF, DMF, etc.) at a temperature ranging from about 0°C to room temperature, optionally in the presence of a tertiary amine (such as N-methylmorpholine, N-ethyldiisopropylamine (DIPEA) or triethylamine (TEA)) to obtain a compound of formula (I).

[0234] The compound of formula (I) can be converted into their corresponding salt using methods known to those of ordinary skill in the art. For example, the amine of formula (I) is treated with trifluoroacetic acid, HCl or citric acid in a solvent (such as Et2O, CH2Cl2, THF, MeOH, chloroform or isopropanol) to provide the corresponding salt form. Alternatively, trifluoroacetic acid or formate is obtained by reversed-phase HPLC purification conditions. With a polar solvent (comprising a mixture of polar solvents and an aqueous mixture of polar solvents) or with a non-polar solvent (comprising a mixture of non-polar solvents), the crystalline form of a pharmaceutically acceptable salt of the compound of formula (I) can be obtained by recrystallization.

[0235] If the compounds according to the invention have at least one chiral center, they may exist in enantiomeric form accordingly. If the compounds have two or more chiral centers, they may exist in diastereomeric form in addition. It should be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0236] The compounds prepared according to the above scheme can be obtained as a single form, such as a single enantiomer, by form-specific synthesis or by resolution. Alternatively, the compounds prepared according to the above scheme can be obtained as a mixture of various forms, such as a racemic mixture (1: 1) or a non-racemic mixture (non-1: 1). In the case of obtaining a racemic mixture and a non-racemic mixture of enantiomers, conventional separation methods known to those of ordinary skill in the art such as chiral chromatography, recrystallization, diastereomeric salt formation, derivatization into diastereomeric adducts, biotransformation or enzymatic conversion can be used to separate the single enantiomer. In the case of obtaining a regional isomer mixture or a diastereomeric mixture, conventional methods such as chromatography or crystallization can be used to separate the single isomer, if applicable.

[0237] The following specific examples are provided to further illustrate the present invention and various preferred embodiments.

[0238] Example

[0239] In obtaining the compounds and corresponding analytical data described in the Examples below, the following experimental and analytical protocols were followed unless otherwise indicated.

[0240] Unless otherwise specified, the reaction mixtures are magnetically stirred at room temperature (rt) and under a nitrogen atmosphere. Where solutions are "dried", they are typically dried over a desiccant (such as Na2SO4 or MgSO4). Where mixtures, solutions and extracts are "concentrated", they are typically concentrated under reduced pressure on a rotary evaporator. Reactions under microwave irradiation conditions are carried out in a Biotage Initiator or CEM (microwave reactor) Discover instrument.

[0241] For reactions performed under continuous flow conditions, unless otherwise stated, "flow through the LTF-VS mixer" refers to the use of a Chemyx Fusion 100Touch syringe pump (LittleThings Factory GmbH (http: / / www.ltf-gmbh.com) connected to the LTF-VS mixer via 1 / 16" PTFE tubing.

[0242] Normal phase silica gel chromatography (FCC) was performed on silica gel (SiO2) using prepacked columns.

[0243] Preparative reverse phase high performance liquid chromatography (RP HPLC) was performed on either of the following equipment:

[0244] Method A Agilent HPLC with an Xterra Prep RP18 column (5 μM, 30 mm×100 mm or 50 mm×150 mm) or an XBridge C18 OBD column (5 μM, 30 mm×100 mm or 50 mm×150 mm), and a mobile phase of 5% ACN in 20 mM NH4OH for 2 minutes, followed by a gradient of 5%-99% ACN for 15 minutes, and then 99% ACN for 5 minutes, with a flow rate of 40 mL / min or 80 mL / min.

[0245] or

[0246] Method B Shimadzu LC-8A series HPLC with an Inertsil ODS-3 column (3 μm, 30 mm×100 mm, T=45° C.) maintained a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) for 1 minute, followed by a gradient of 5%-99% ACN for 6 minutes, and then 99% ACN for 3 minutes, with a flow rate of 80 mL / min.

[0247] or

[0248] Method C A Shimadzu LC-8A series HPLC with an XBridge C18 OBD column (5 μm, 50 mm×100 mm) was used with a mobile phase of 5% ACN in H2O (both containing 0.05% TFA) for 1 minute, followed by a gradient of 5%-99% ACN for 14 minutes, and then 99% ACN for 10 minutes, with a flow rate of 80 mL / min.

[0249] or

[0250] Method D Gilson HPLC with XBridge C18 column (5 μm, 100 mm×50 mm) maintained at a mobile phase of 5%-99% ACN in 20 mM NH 4 OH for 10 min, then at 99 ACN for 2 min, with a flow rate of 80 mL / min.

[0251] or

[0252] Method E ACCQ Prep HPLC with an XBridge C18 OBD column (5 μm, 50 mm×100 mm) was run with a mobile phase of 5% ACN in H2O (both with 0.05% TFA) for 1 min, followed by a gradient of 5%-95% ACN over 12 min, and then 95% ACN for 2 min, at a flow rate of 80 mL / min.

[0253] Preparative supercritical fluid high performance liquid chromatography (SFC) was performed on a Jasco preparative SFC system, an APS 1010 system from Bergerinstruments or a SFC-PICLAB-PREP 200 (PIC SOLUTION, Avignon, France). Separations were performed at 100 to 150 bar with a flow rate in the range of 40 to 60 mL / min. The column was heated to 35 to 40°C.

[0254] Unless otherwise indicated, mass spectra (MS) were obtained on an Agilent series 1100MSD using electrospray ionization (ESI) in positive ion mode. The calculated masses (calcd.) correspond to the exact masses.

[0255] Nuclear magnetic resonance (NMR) spectra were obtained on a Bruker DRX spectrometer. The multiplicity is defined as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, hept = septet, dd = doublet of doublet, dt = doublet of triplet, pd = quintet of doublet, ddd = doublet of doublet of doublet, tp = triplet of quintet, td = triplet of doublet, qd = quartet of doublet, dq = doublet of quartet, tt = triplet of triplet, td = triplet of doublet, m = multiplet, br = broad. It should be understood that for compounds containing exchangeable protons, the protons may or may not be visible in the NMR spectrum, depending on the choice of solvent used to perform the NMR spectrum and the concentration of the compound in solution.

[0256] Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoft Corp., Cambridge, MA) or OEMetaChem V1.4.0.4 (Open Eye).

[0257] Compounds designated as R* or S* are enantiomerically pure compounds of undetermined absolute configuration.

[0258] Intermediate 1: tert-butyl 3-nitrocyclobutanecarboxylate.

[0259]

[0260] 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 The mixture was filtered through a pad of 4% paraformaldehyde and the pad was washed with EtOH. The combined filtrates were evaporated and the residue was taken up 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): C9H 15 The calculated mass value of NO3 is 185.1; the measured m / z value is 186.2 [M+H] + .

[0261] Step B: tert-Butyl 3-nitrocyclobutanecarboxylate . To a suspension of urea 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 hour. The reaction mixture was stirred at room temperature for 1 hour. At 80 °C, the solution was added dropwise to a solution of tert-butyl 3-hydroxyiminocyclobutanecarboxylate (108 g, 0.58 mol) and disodium hydrogen phosphate (911 g, 6.42 mol) in MeCN (1 L) over 30 minutes. The reaction mixture was stirred at 80 °C for 30 minutes and then filtered through The filtrate was filtered through a pad 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 gel (0%-20% EtOAc in heptane) to give the title compound (89.6 g, 445 mmol, 76% yield) as a yellow oil, which was a mixture of cis-isomers / trans-isomers in a ratio of 1.3:1. The compound will not be detected in ESI + Ionization in the case of LCMS.

[0262] Intermediate 2: ethyl 3-nitrocyclobutanecarboxylate.

[0263]

[0264] The title compound was prepared in a manner similar to Intermediate 1 using ethyl 3-oxocyclobutane-1-carboxylate instead of tert-butyl 3-oxocyclobutane-1-carboxylate. + Ionization in the case of LCMS. 1 H NMR (300MHz, Chloroform-d) δ5.02–4.70 (m, 1H), 4.20 (q, J = 7.2Hz, 2H), 3.04–2.71 (m, 5H), 1.29 (t, J = 7.0Hz, 3H).

[0265] Intermediate 3: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0266]

[0267] Step A: (1s,3s)-tert-butyl 3-(hydroxymethyl)-3-nitrocyclobutane-1-carboxylate . To a solution of tert-butyl 3-nitrocyclobutanecarboxylate (intermediate 2, 89.6 g, 445 mmol) in MeCN (1 L) was added formaldehyde (37 wt % aqueous solution, 73 mL, 971 mmol). Triethylamine (TEA) (62 mL, 444 mmol) was added dropwise to the reaction mixture at 0 ° C, and the reactants were stirred at room temperature for 2 hours. The reaction mixture was evaporated, and the residue was purified by FCC on silica gel (0%-25% EtOAc in heptane) to give the title compound as a white powder (38.2 g, 165 mmol, 37% yield). MS (ESI): C 10 H 17 The calculated mass value of NO5 is 231.2; the measured m / z value is 254.1 [M+Na] + 3-(Hydroxymethyl)-3-nitrocyclobutanecarboxylic acid trans-tert-butyl ester was formed but not isolated.

[0268] Step B: (1s,3s)-tert-butyl 3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylate. To a solution of tert-butyl (1s,3s)-3-(hydroxymethyl)-3-nitrocyclobutanecarboxylate (38.2 g, 165 mmol) in EtOAc (600 mL) was added 10% palladium on carbon (Pd / C) (1.9 g). The reaction mixture was stirred at 50 °C under hydrogen (H2) (10 bar) for 1 hour. The reaction mixture was stirred by Filter through a pad of Celite. To the filtrate was added 10% Pd / C (1.9 g). The reaction mixture was stirred under H2 (10 bar) at 50°C for 2 hours. Filter through a pad of Celite and wash with EtOAc The combined filtrates were evaporated and the residue was triturated with diethyl ether (Et2O) to give the title compound as a white powder (18.6 g, 92.4 mmol, 55% yield). MS (ESI): C 10 H 19 The calculated mass value of NO3 is 201.1; the measured m / z value is 202.2 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ5.26–3.98(m,1H),3.74–2.94(m,4H),2.70–2.57(m,1H),2.20–2.07(m,2H),1.97–1.82(m,2H),1.39(s,9H).

[0269] Step C: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester . TEA (26 mL, 186 mmol) was added to a solution of (1s, 3s)-3-amino-3-(hydroxymethyl)cyclobutane-1-carboxylic acid tert-butyl ester (18.6 g, 92.4 mmol) in tetrahydrofuran (THF) (300 mL). A solution of triphosgene (9.6 g, 32.4 mmol) in THF (200 mL) was added dropwise to the mixture at -10 °C and stirred at room temperature for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate (600 mL) and the mixture was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was ground with Et2O to give the title compound (17.7 g, 77.9 mmol, 84% yield) as a white powder. MS (ESI): C 11 H 17 The calculated mass value of NO4 is 227.1; the measured m / z value is 228.2 [M+H] + .

[0270] Step D: (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid. To trifluoroacetic acid (TFA) (180 mL, 235 mmol) was added (2s, 4s)-6-oxo-7-oxa-5-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (17.7 g, 77.9 mmol) in batches at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated and the residue was triturated with Et2O to give the title compound as a white powder (12.9 g, 75.4 mmol, 96% yield). MS (ESI): The mass calculated value of C7H9NO3 is 171.0; the m / z found value is 172.1 [M+H] + . 1 H NMR (500MHz, DMSO-d6) δ12.26(br s,1H),8.08(s,1H),4.34(s,2H),2.79–2.66(m,1H),2.43–2.29(m,4H).

[0271] Intermediate 4: (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid

[0272]

[0273] Step A: (1r,3s)-ethyl 3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylate.

[0274] Methyl acrylate (10.3 mL, 114 mmol) was added to a solution of ethyl 3-nitrocyclobutanecarboxylate (intermediate 2, 16.6 g, 95.6 mmol) in MeCN (145 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (7.1 mL, 47.6 mmol) was added dropwise to the reaction mixture at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with saturated ammonium chloride and EtOAc, and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by FCC on silica gel (0%-15% EtOAc in heptane) to give the title compound (13.6 g, 52.6 mmol, 55% yield) as a colorless liquid. MS (ESI): C 11 H 17 The calculated mass value of NO6 is 259.1; the measured m / z value is 282.1 [M+Na] + . 1 H NMR (300MHz, Chloroform-d) δ4.17(q,J=7.1Hz,2H),3.70(s,3H),3.12–2.79(m,3H),2.69–2.49(m,2H),2.48–2.21(m,4H),1.27(t,J=7.1Hz,3H).

[0275] Step B: (2r,4s)-6-Oxo-5-azaspiro[3.4]octane-2-carboxylic acid.To a solution of (1r, 3s)-3-(3-methoxy-3-oxopropyl)-3-nitrocyclobutane-1-carboxylic acid ethyl ester (13.6 g, 52.6 mmol) in methanol (MeOH) (133 mL) was added nickel (II) chloride hexahydrate (12.5 g, 52.6 mmol). Sodium borohydride (NaBH4) (10 g, 264 mmol) was added to the reaction mixture in small portions at -10 °C, and the reaction mixture was stirred at 0 °C for 1 hour. Aqueous potassium carbonate solution (47 mL, 141 mmol, 3 M) (pH 10) was added dropwise to the reaction mixture at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was stirred by The mixture was filtered through a pad of 4% paraffin wax and the pad was washed with EtOH. The combined filtrates were evaporated. The residue was purified by FCC on silica gel eluting with chloroform:methanol:acetic acid (100:0:0→9:1:1) to give the title compound (4.8 g, 28.2 mmol, 53% yield) as an off-white powder. MS (ESI): C8H 11 The calculated mass value of NO3 is 169.1; the measured m / z value is 170.1 [M+H] + . 1 H NMR (300MHz, DMSO-d6) δ7.97(br s,1H),4.01–2.94(m,1H),2.82–2.65(m,1H),2.36–2.01(m,8H).

[0276] Intermediate 5: (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid.

[0277]

[0278] Step A: 3-(1-Hydroxyethyl)-3-nitro-cyclobutanecarboxylic acid tert-butyl ester. To a solution of tert-butyl 3-nitrocyclobutanecarboxylate (Intermediate 1, 11.7 g, 58.1 mmol) in MeCN (120 mL) was added acetaldehyde (19.6 mL, 349 mmol). TEA (8.1 mL, 58 mmol) was added dropwise to the reaction mixture at 0 °C, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the residue was purified by FCC on silica gel (0%-20% EtOAc in heptane) to give the title compound (10.5 g, 42.8 mmol) as a colorless oil. MS (ESI): C 11 H 19 The calculated mass value of NO5 is 245.1; the measured m / z value is 263.2 [M+H+NH3] + .

[0279] Step B: (1s,3s)-tert-butyl 3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylate.To a solution of tert-butyl 3-(1-hydroxyethyl)-3-nitro-cyclobutanecarboxylate (10.5 g, 42.8 mmol) in EtOAc (110 mL) was added 10% Pd / C (1 g). The reaction mixture was stirred at 50° C. under H2 (10 bar) for 1 hour. The reaction mixture was washed with water by 10% Pd / C (500 mg) was added to the filtrate, and the reaction mixture was stirred at 50° C. under H 2 (10 bar) for 2 h. The reaction mixture was filtered through The combined filtrates were evaporated and the residue was purified by FCC on silica gel eluting with chloroform:methanol:ammonium hydroxide (1:0:0→9:1:0.05) to give the title compound (3.6 g, 16.7 mmol, 39% yield) as a yellow oil. MS (ESI): C 11 H 21 The calculated mass value of NO3 is 215.2; the measured m / z value is 216.3 [M+H] + . 1 H NMR (300 MHz, Chloroform-d) δ 3.83–3.64 (m, 1H), 2.80–2.61 (m, 1H), 2.54 (br s, 2H), 2.52–2.27 (m, 3H), 2.14–1.93 (m, 2H), 1.45 (s, 9H), 1.22–1.13 (m, 3H). Additional fractions from the same purification were collected to give (1r, 3r)-tert-butyl 3-amino-3-(1-hydroxyethyl)cyclobutanecarboxylate (550 mg, crude product) as a yellow oil.

[0280] Step C: (2s,4s)-tert-butyl 8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylate. To a solution of (1s, 3s)-3-amino-3-(1-hydroxyethyl)cyclobutane-1-carboxylic acid tert-butyl ester (15.2 g, 70.4 mmol) in THF (240 mL) was added TEA (20 mL, 143 mmol). A solution of triphosgene (7.3 g, 24.6 mmol) in THF (170 mL) was added dropwise to the mixture at -10 °C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated sodium bicarbonate and extracted with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered and evaporated. The residue was purified by FCC (0%-35% EtOAc in heptane) on silica gel to give the title compound (6.1 g, 25.3 mmol, 35% yield) as a white powder. MS (ESI): C 12 H 19 The calculated mass value of NO4 is 241.1; the measured m / z value is 242.2 [M+H] + .

[0281] Step D: (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid . (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (6.1 g, 25.3 mmol) was added to TFA (60 mL, 784 mmol) at 0°C in batches, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated and the residue was triturated with Et2O to give the title compound as a white powder (4.3 g, 23.2 mmol, 91% yield). MS (ESI): C8H 11 The calculated mass value of NO4 is 185.1; the measured m / z value is 186.1 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ12.23(br s,1H),7.94(s,1H),4.50(q,J=6.4Hz,1H),2.68–2.59(m,1H),2.53–2.46(m,1H),2.41 –2.35(m,1H),2.32–2.24(m,1H),2.17(dd,J=12.0,10.1Hz,1H),1.30(d,J=6.5Hz,3H).

[0282] Intermediate 6: Benzyl 2-hydroxy-2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate.

[0283]

[0284] 2-Oxo-7-azaspiro [3.5] nonane-7-carboxylic acid benzyl ester (200mg, 0.73mmol) is dissolved in ether and cooled to -78°C. Phenylmagnesium bromide (1M in Et2O, 0.95mL, 0.95mmol) is added dropwise under stirring. The reaction mixture is stirred at -78°C for 4 hours, quenched with saturated NH4Cl aqueous solution, and distributed between water and DCM. The water layer is extracted twice with DCM, and the combined organic matter is concentrated and purified on silica gel (0%-100% EA / hexane) to obtain 131mg (51% yield) of the desired product. MS (ESI): C 22 H 25 The calculated mass value of NO3 is 351.2; the measured m / z value is 352.0 [M+H] + .

[0285] Intermediate 7: Benzyl 2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate.

[0286]

[0287] Benzyl 2-hydroxy-2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 6, 131 mg, 0.37 mmol) and triethylsilane (0.60 mL, 3.7 mmol) were dissolved in dry DCM, and TFA (0.29 mL, 3.7 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours, concentrated and purified on silica gel to obtain 101 mg (81% yield) of the desired product. MS (ESI): C 22 H 25 The calculated mass value of NO2 is 335.2; the measured m / z value is 336 [M+H] + .

[0288] Intermediate 8: 2-phenyl-7-azaspiro[3.5]nonane.

[0289]

[0290] Benzyl 2-phenyl-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 7, 101 mg, 0.30 mmol) was dissolved in 10 mL of ethyl acetate and 10% palladium on carbon (100 mg) was added. The reaction vessel was evacuated and backfilled with hydrogen, and the reaction mixture was stirred at room temperature for 2 hours and then heated by Filter and concentrate to obtain 39 mg (0.19 mmol, 64% yield) of the title compound, which was used directly in subsequent transformation. MS (ESI): C 14 H 19 The calculated mass value of N is 201.2; the measured m / z value is 202.1 [M+H] + .

[0291] Intermediate 9: tert-Butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0292]

[0293] Nickel(II) chloride ethylene glycol dimethyl ether complex (7.2 mg, 0.033 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (10.6 mg, 0.039 mmol) were dissolved in DME and stirred for 10 minutes. In a separate container, tert-butyl 2-bromo-7-azaspiro[3.5]nonane-7-carboxylate (100 mg, 0.30 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (3.7 mg, 0.0033 mmol), 2,6-lutidine (0.19 mL, 1.64 mmol), 1-bromo-3-tert-butylbenzene (105 mg, 0.49 mmol) and tris(trimethylsilyl)silane (0.20 mL, 0.66 mmol) were added. The solution of the nickel (II) complex was added to a second reaction vessel, and the mixture was bubbled with N2 for 10 minutes, sealed with parafilm, and stirred overnight in a Pennoc 450nm photoreactor (LED: 100% power, fan: maximum, stirring: 700RPM). The reaction mixture was concentrated, dissolved in dichloromethane, and purified on silica gel (0%-30% EA / hexane) to obtain a mixture of the desired product and silane byproduct (238 mg total mass). The mixture was carried to the next step without further purification. MS (ESI): C 23 H 35 The calculated mass value of NO2 is 357.3; the measured m / z value is 302.1 [M+2H-tBu] + .

[0294] Intermediate 10: tert-Butyl 2-(4-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0295]

[0296] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-4-methylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 The calculated mass value of NO2 is 315.2; the measured m / z value is 260.1 [M+2H-tBu] + .

[0297] Intermediate 11: tert-Butyl 2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0298]

[0299] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-2-methylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 The calculated mass value of NO2 is 315.2; the measured m / z value is 260.1 [M+2H-tBu] + .

[0300] Intermediate 12: tert-Butyl 2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0301]

[0302] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-3-cyclopropylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 The calculated mass value of NO2 is 341.2; the measured m / z value is 286.1 [M+2H-tBu] + .

[0303] Intermediate 13: tert-Butyl 2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0304]

[0305] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-3-isopropylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 The calculated mass value of NO2 is 343.3; the measured m / z value is 288.0 [M+2H-tBu] + .

[0306] Intermediate 14: tert-Butyl 2-(3-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0307]

[0308] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-3-methylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 29 The calculated mass value of NO2 is 315.2; the measured m / z value is 260.1 [M+2H-tBu] + .

[0309] Intermediate 15: tert-Butyl 2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0310]

[0311] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 3-bromoanisole instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 29 The calculated mass value of NO3 is 331.2; the measured m / z value is 276.0 [M+2H-tBu] + .

[0312] Intermediate 16: tert-Butyl 2-(3-trifluoromethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0313]

[0314] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-3-trifluoromethylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 26 The calculated mass value of F3NO3 is 385.2; the measured m / z value is 330.0 [M+2H-tBu] + .

[0315] Intermediate 17: tert-Butyl 2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0316]

[0317] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-2,3-dimethylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 The calculated mass value of NO2 is 329.2; the measured m / z value is 274.0 [M+2H-tBu] + .

[0318] Intermediate 18: 2-(2 , tert-butyl 4-(4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0319]

[0320] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-2,4-dimethylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 The calculated mass value of NO2 is 329.2; the measured m / z value is 274.2 [M+2H-tBu] + .

[0321] Intermediate 19: tert-Butyl 2-(2-(tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0322]

[0323] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 4-bromo-2-(tert-butyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 22 H 34 The calculated mass value of N2O2 is 358.3; the measured m / z value is 359.3 [M+H] + .

[0324] Intermediate 20: tert-Butyl 2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0325]

[0326] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-4-(tert-butyl)-1-toluene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 24 H 37 The calculated mass value of NO2 is 371.3; the measured m / z value is 316.2 [M+2H-tBu] + .

[0327] Intermediate 21: tert-Butyl 2-(3-trifluoromethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0328]

[0329] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 3-trifluoromethylbromobenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 26 The calculated mass value of F3NO2 is 369.2; the measured m / z value is 314.1 [M+2H-tBu] + .

[0330] Intermediate 22: tert-Butyl 2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0331]

[0332] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-2,5-dimethylbenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 The calculated mass value of NO2 is 329.2; the measured m / z value is 274.2 [M+2H-tBu] + .

[0333] Intermediate 23: tert-Butyl 2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0334]

[0335] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-6-(tert-butyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 22 H 34 The calculated mass value of N2O2 is 358.3; the measured m / z value is 359.3 [M+H] + .

[0336] Intermediate 24: tert-Butyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate ester.

[0337]

[0338] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 23 H 30 The calculated mass value of F3NO2 is 409.2; the measured m / z value is 354.2 [M+2H-tBu] + .

[0339] Intermediate 25: tert-Butyl 2-(3-chloro-4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0340]

[0341] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 4-bromo-2-chloro-1-(trifluoromethyl)benzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 25 The calculated mass value of ClF3NO2 is 403.2; the measured m / z value is 348.1 [M+2H-tBu] + .

[0342] Intermediate 26: tert-butyl 2-(4-methoxy-3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate ester.

[0343]

[0344] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 4-bromo-1-methoxy-2-(trifluoromethyl)benzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 31 The calculated mass value of ClF3NO3 is 399.2; the measured m / z value is 344.2 [M+2H-tBu] + .

[0345] Intermediate 27: tert-Butyl 2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0346]

[0347] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-4-(tert-butyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 22 H 34 The calculated mass value of N2O2 is 358.3; the measured m / z value is 359.2 [M+H] + .

[0348] Intermediate 28: tert-Butyl 2-(5-(tert-butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0349]

[0350] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-4-(tert-butyl)-1-fluorobenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 23 H 34The calculated mass value of FNO2 is 375.2; the measured m / z value is 320.2 [M+2H-tBu] + .

[0351] Intermediate 29: tert-Butyl 2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0352]

[0353] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-4-(tert-butyl)-2-ethoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 25 H 39 The calculated mass value of NO3 is 401.3; the measured m / z value is 346.2 [M+2H-tBu] + .

[0354] Intermediate 30: tert-Butyl 2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0355]

[0356] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-4-(tert-butyl)-2-methoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 24 H 37 The calculated mass value of NO3 is 387.3; the measured m / z value is 332.2 [M+2H-tBu] + .

[0357] Intermediate 31: 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane- tert-Butyl 7-carboxylate.

[0358]

[0359] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 5-bromo-2,2-difluorobenzo[d][1,3]dioxole instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 25 The calculated mass value of F2NO4 is 381.2; the measured m / z value is 326.0 [M+2H-tBu] + .

[0360] Intermediate 32: tert-Butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0361]

[0362] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-2-methoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 29 The calculated mass value of NO3 is 331.2; the measured m / z value is 276.1 [M+2H-tBu] + .

[0363] Intermediate 33: tert-Butyl 2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0364]

[0365] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 1-bromo-4-methoxybenzene instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 29 The calculated mass value of NO3 is 331.2; the measured m / z value is 276.1 [M+2H-tBu] + .

[0366] Intermediate 34: tert-Butyl 2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate ester.

[0367]

[0368] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-3-fluoro-6-(trifluoromethyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 19 H 24 The calculated mass value of F4N2O2 is 388.2; the measured m / z value is 333.1 [M+2H-tBu] + .

[0369] Intermediate 35: tert-Butyl 2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0370]

[0371] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-6-(trifluoromethyl)pyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 19 H 25The calculated mass value of F3N2O2 is 370.2; the measured m / z value is 315.1 [M+2H-tBu] + .

[0372] Intermediate 36: tert-Butyl 2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0373]

[0374] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 6-bromo-3-fluoro-2-methylpyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 19 H 27 The calculated mass value of FN2O2 is 334.2; the measured m / z value is 335.3 [M+H] + .

[0375] Intermediate 37: tert-Butyl 2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0376]

[0377] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 4-bromo-2-(tert-butyl)pyrimidine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 21 H 33 The calculated mass value of N3O2 is 359.3; the measured m / z value is 360.3 [M+H] + .

[0378] Intermediate 38: tert-Butyl 2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0379]

[0380] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-4-(tert-butyl)oxazole instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 32 The calculated mass value of N2O3 is 348.2; the measured m / z value is 293.2 [M+2H-tBu] + .

[0381] Intermediate 39: tert-Butyl 2-(2-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0382]

[0383] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 5-bromo-2-(tert-butyl)oxazole instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 20 H 32 The calculated mass value of N2O3 is 348.2; the measured m / z value is 349.3 [M+H] + .

[0384] Intermediate 40: tert-Butyl 2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate.

[0385]

[0386] The title compound was prepared in a similar manner to tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) using 2-bromo-3,5-difluoropyridine instead of 1-bromo-3-tert-butylbenzene. MS (ESI): C 18 H 24 The calculated mass value of F2N2O2 is 338.2; the measured m / z value is 283.1 [M+2H-tBu] + .

[0387] Intermediate 41: tert-butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate.

[0388]

[0389] Step A: tert-Butyl 2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate . Sodium borohydride (NaBH4) (239 mg, 6.32 mmol) was added portionwise to a solution of tert-butyl 2-oxo-8-azaspiro [4.5] decane-8-carboxylate (800 mg, 3.16 mmol) in methanol (MeOH) (60 mL) at 0°C. The mixture was stirred at room temperature for 6 hours. The solvent was evaporated under reduced pressure, and the residue was redissolved in ethyl acetate (EtOAc) and washed with hydrochloric acid (HCl) (0.1 N) and brine. The organic phase was separated, dried, filtered and evaporated under reduced pressure to give the title compound, which did not need to be further purified in the next step (841 mg, 100% yield). MS (ESI): C 14 H 25 The calculated mass value of NO3 is 255.2; the measured m / z value is 256.2 [M+H] + .

[0390] Step B: tert-Butyl 2-iodo-8-azaspiro[4.5]decane-8-carboxylate. Iodine (I2) (962 mg, 3.79 mmol) was added in batches to tert-butyl 2-hydroxy-8-azaspiro [4.5] decane-8-carboxylate (807 mg, 3.16 mmol), imidazole (323 mg, 4.74 mmol) and triphenylphosphine (PPh3) (995 mg, 3.79 mmol) in tetrahydrofuran (THF) (5.9 mL) at 0°C. The mixture was stirred for 1 h at RT. Excess I2 was quenched with 10% Na2S2O3. The aqueous phase was extracted with EtOAc and the combined organics were dried over MgSO4. The solids were removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (FCC) on silica gel (0%-15% EtOAc in heptane) to give the title compound (719 mg, 62% yield) as a colorless oil. MS (ESI): C 14 H 25 The calculated mass value of INO2 is 365.2; the measured m / z value is 366.1 [M+H] + .

[0391] Intermediate 42: tert-butyl 6-iodo-2-azaspiro[3.4]octane-2-carboxylate.

[0392]

[0393] The title compound was prepared in a similar manner to Intermediate 41 using 6-hydroxy-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester instead of 2-hydroxy-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester in step B. MS (ESI): C 12 H 20 The calculated mass value of INO2 is 337.2; the measured m / z value is 338.1 [M+H] + .

[0394] Intermediate 43: tert-Butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate.

[0395]

[0396] At 40 DEG C, a solution of 6-iodo-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl esters (intermediate 42, 435mg, 1.29mmol) in THF (2.6mL) was flowed through a post containing activated zinc at 0.25mL / min. The effluent solution was collected in a sealed vial containing bromobenzene (68 μL, 0.645mmol), palladium acetate (II) (7.2mg, 0.032mmol) and dicyclohexyl (2', 6'-diisopropoxy-[1,1'-biphenyl]-2-yl) phosphine (RuPhos) (30mg, 0.064mmol). The mixture was stirred at 50 DEG C for 90 minutes. Then, saturated NH4Cl and NH3 1: 1 solution (37% aqueous solution) was added, and the mixture was extracted with EtOAc. The organic phase was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified by FCC on silica gel (0%-100% EtOAc in heptane) to give the title compound (174 mg, 70% purity, 66% yield). MS (ESI): C 18 H 25 The calculated mass value of NO2 is 287.4; the measured m / z value is 288.3 [M+H] + .

[0397] Intermediate 44: (S*)-tert-Butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate.

[0398]

[0399] The title compound was prepared by chiral supercritical fluid chromatography of tert-butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) (stationary phase: Chiralpak IG 5μm 250*30mm, mobile phase: 90% CO2, 10% MeOH). MS (ESI): C 18 H 25 The calculated mass value of NO2 is 287.2; the measured m / z value is 288.0 [M+H] + .

[0400] Intermediate 45: (R*)-tert-Butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate.

[0401]

[0402] The title compound was prepared by chiral supercritical fluid chromatography of tert-butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) (stationary phase: Chiralpak IG 5μm 250*30mm, mobile phase: 90% CO2, 10% MeOH). MS (ESI): C 18 H 25The calculated mass value of NO2 is 287.2; the measured m / z value is 288.1 [M+H] + .

[0403] Intermediate 46: tert-Butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate.

[0404]

[0405] The title compound was prepared in a similar manner to tert-butyl 6-phenyl-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 43) using 4-bromotrifluorotoluene instead of bromobenzene. MS (ESI): C 19 H 24 The calculated mass value of F3NO2 is 355.1; the measured m / z value is 356.3 [M+H] + .

[0406] Intermediate 47: (S*)-tert-Butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate.

[0407]

[0408] The title compound was prepared by chiral supercritical fluid chromatography of tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 46) (stationary phase: Chiralpak IG 5μm 250*30mm, mobile phase: 95% CO2, 5% MeOH). MS (ESI): C 19 H 24 The calculated mass value of F3NO2 is 355.1; the measured m / z value is 341.1 [M-tBu+2H+MeCN] + .

[0409] Intermediate 48: (R*)-tert-Butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate.

[0410]

[0411] The title compound was prepared by chiral supercritical fluid chromatography of tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 46) (stationary phase: Chiralpak IG 5μm 250*30mm, mobile phase: 95% CO2, 5% MeOH). MS (ESI): C 19 H 24 The calculated mass value of F3NO2 is 355.1; the measured m / z value is 341.1 [M-tBu+2H+MeCN] + .

[0412] Intermediate 49: 6-Phenyl-2-azaspiro[3.3]heptane trifluoroacetate.

[0413]

[0414] Step A: tert-Butyl 6-hydroxy-6-phenyl-2-azaspiro[3.3]heptane-2-carboxylate. Phenylmagnesium bromide (2M in THF, 376 μL, 753 μmol) was added dropwise to a stirred solution of 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (70.0 mg, 331 μmol) in THF (1.7 mL) at -78 ° C. After the addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature. After 30 minutes, the reaction mixture was quenched by adding saturated NH4Cl (10 mL) aqueous solution, 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 crude product was purified by flash column chromatography (0%-100% EtOAc / hexane) on silica gel to give the title product (90.7 mg, 313 μmol, 95% yield) as a white solid, which can be used in step B without further purification. MS (ESI): C 17 H 23 The calculated mass value of NO3 is 289.2; the measured m / z value is 234.2 [M-tBu+2H] + .

[0415] Step B: 6-Phenyl-2-azaspiro[3.3]heptane trifluoroacetate. 6-Hydroxy-6-phenyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (90.0 mg, 311 μmol) was dissolved in trifluoroacetic acid (TFA) (1.07 mL), and the resulting solution was stirred at room temperature for 5 minutes. Triethylsilane (149 μL, 933 μmol) was added dropwise. After the addition was completed, the reaction mixture was vigorously stirred at room temperature for 2 hours. The solvent was then removed in vacuo to give the crude title product, which was used without further purification. MS (ESI): C 12 H 15 The calculated mass value of N is 173.2; the measured m / z value is 174.1 [M+H] + .

[0416] Intermediate 50: tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate

[0417]

[0418] Step A: tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate. Sodium borohydride (NaBH4) (1.80 g, 47.3 mmol) was added in batches to a 0°C methanol (MeOH) (50 mL) solution of 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (5.00 g, 23.7 mmol). The resulting mixture was stirred at 0°C for 30 minutes, then quenched with saturated NaHCO3, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried with anhydrous Na2SO4, and concentrated to give the title compound (4.86 g, 96% yield) as a white solid, which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3) δ4.24-4.11(m,1H),3.88(d,J=7.2Hz,4H),2.54(ddd,J=2.8,6.8,10.0Hz,2H),2.11-2.02(m,2H),1.93(br s,1H),1.43(s,9H).

[0419] Step B: tert-Butyl 6-iodo-2-azaspiro[3.3]heptane-2-carboxylate . 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (4.86 g, 22.8 mmol), toluene (50 mL), PPh3 (112 g, 45.6 mmol), 1H-imidazole (4.65 g, 68.4 mmol) and I2 (8.68 g, 34.2 mmol) were combined. The resulting reaction mixture was stirred at 100 ° C for 1 hour, then cooled to room temperature, quenched with saturated Na2SO3 aqueous solution, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and purified by FCC (eluent: petroleum ether: ethyl acetate = 1: 0 to 5: 1) to give the title compound as a white solid (6.24 g, 85% yield). MS (ESI): C 11 H 18 The calculated mass of INO2 is 323.0, and the measured m / z is 267.9 [M-tBu+2H] + .

[0420] Intermediate 51: 1-bromo-3-cyclobutylbenzene.

[0421]

[0422] Step A: 1-(3-bromophenyl)cyclobutan-1-ol. Under N2, n-BuLi (1.88mL, 2.5M in hexane, 4.71mmol) was added dropwise to a solution of 1,3-dibromobenzene (1.11g, 4.71mmol) in anhydrous THF (12mL) at -70°C. The resulting mixture was stirred at -78°C for 30 minutes and then treated with cyclobutanone (300mg, 4.28mmol). The reaction mixture was stirred at -78°C for 2 hours, then poured into a saturated NH4Cl aqueous solution and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 9:1) to give the title compound (811mg, 83% yield) as a yellow oil. 1 H NMR(400MHz, CDCl3)δ7.70(t,J=2.0Hz,1H),7.50-7.44(m,2H),7.31-7.28(m,1 H),2.63-2.54(m,2H),2.45-2.36(m,2H),2.14-2.03(m,2H),1.84-1.70(m,1H).

[0423] Step B: 1-Bromo-3-cyclobutylbenzene. Under N2, boron trifluoride etherate (312mg, 2.20mmol) is added dropwise to -70 ℃ 1-(3-bromophenyl) cyclobutanol (200mg, 0.88mmol) and triethylsilane (256mg, 2.20mmol) in dichloromethane (2mL) solution. The gained mixture is stirred at -70 ℃ for 2 hours, then poured into saturated NaHCO3, and extracted twice with dichloromethane. The combined organic extracts are washed with salt water, passed through anhydrous Na2SO4, dried, concentrated, and purified by FCC (eluent: petroleum ether: ethyl acetate=1:0 to 30:1) to obtain the title compound (160mg, 86% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ7.36 (s, 1H), 7.30 (td, J = 2.0, 7.2Hz, 1H), 7.19-7.10 (m, 2 H),3.56-3.48(m,1H),2.41-2.29(m,2H),2.18-1.97(m,3H),1.92-1.81(m,1H).

[0424] Intermediate 52: 7-Phenyl-2-azaspiro[3.5]nonane trifluoroacetate.

[0425]

[0426] The title compound was prepared in a manner analogous to 6-phenyl-2-azaspiro[3.3]heptane trifluoroacetate (Intermediate 49), except that tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate was used instead of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate in step A. MS (ESI): C 14 H 19 The calculated mass value of N is 201.2; the measured m / z value is 202.2 [M+H] + .

[0427] Example 1: (2s, 4s)-2-(2-phenyl-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0428]

[0429] (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 20 mg, 0.117 mmol) and DIPEA (60 μL, 0.350 mmol) were dissolved in DMF (1 mL). HATU (69 mg, 0.175 mmol) and 2-phenyl-7-azaspiro[3.5]nonane (Intermediate 8, 28 mg, 0.140 mmol) were added, and the reaction mixture was stirred at room temperature for 1 hour and then purified by reverse phase basic HPLC (Gilson, 0%-100% MeCN / water, NH4OH regulator) to obtain 24.8 mg (0.070 mmol, 60% yield) of the title compound. MS (ESI): C 21 H 26 The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.0 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ7.31(dd,J=8.3,6.9Hz,2H),7.23–7.16(m,3H),5.69(s,1H),4.39–4.34(m,2H),3.67–3.43(m,3H),3.38–3.20( m,2H),3.08–2.95(m,1H),2.67–2.59(m,2H),2.52–2.42(m,2H),2.38– 2.28(m,2H),2.00–1.88(m,2H),1.79–1.67(m,2H),1.54–1.49(m,2H).

[0430] Example 2: (2s, 4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0431]

[0432] A solution of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9) in 4N HCl / dioxane (1 mL) was stirred for 30 minutes and concentrated. The residue was dissolved in DMF (1 mL), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 20 mg, 0.117 mmol), DIPEA (0.10 mL, 0.580 mmol) and HATU (69 mg, 0.180 mmol) were added, and the reaction mixture was stirred for 1 hour and then purified by reverse phase basic HPLC (Gilson, 0%-100% MeCN / water, NH4OH modifier) ​​to obtain 17.1 mg (0.042 mmol, 36% yield) of the title compound. MS (ESI): C 25 H 34 The calculated mass value of N2O3 is 410.3; the measured m / z value is 411.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.26(s,3H),7.09–7.01(m,1H),5.64(s,1H),4.42–4.28(m,2H),3.67–3.46(m,3H),3.40–3.20(m,2H),3.09–2 .95(m,1H),2.69–2.57(m,2H),2.54–2.42(m,2H),2.40–2.28(m,2H), 2.02–1.88(m,2H),1.81–1.70(m,2H),1.57–1.50(m,2H),1.32(s,9H).

[0433] Example 3: (2s, 4s)-2-(2-(p-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0434]

[0435] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(4-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 10) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 28 The calculated mass value of N2O3 is 368.2; the measured m / z value is 369.0 [M+H]+ . 1 H NMR(400MHz,Chloroform-d)δ7.16–7.08(m,4H),5.65(s,1H),4.42–4.33(m,2H),3.69–3.58(m,1H),3.57–3.40(m,2H),3.38–3.30(m,1H),3.27–3 .19(m,1H),3.12–2.91(m,1H),2.72–2.58(m,2H),2.54–2.40(m,2H),2.3 6–2.24(m,4H),1.98–1.85(m,2H),1.77–1.61(m,2H),1.60–1.46(m,3H).

[0436] Example 4: (2s, 4s)-2-(2-(o-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.

[0437]

[0438] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 11) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 28 The calculated mass value of N2O3 is 368.2; the measured m / z value is 369.0 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.25–7.09(m,4H),5.66(s,1H),4.40–4.24(m,2 H),3.71–3.58(m,2H),3.55–3.46(m,1H),3.42–3.35(m,1H),3.30–3.22(m,1H ),3.12–2.90(m,1H),2.69–2.57(m,2H),2.54–2.44(m,2H),2.39–2.26(m,2H) ,2.27–2.19(m,3H),2.00–1.87(m,2H),1.83–1.73(m,2H),1.53–1.48(m,2H).

[0439] Example 5: (2s,4s)-2-[2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0440]

[0441] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-cyclopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 12) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 24 H 30 The calculated mass value of N2O3 is 394.2; the measured m / z value is 395.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.20(t,J=7.6Hz,1H),7.02–6.94(m,1H),6.94–6.81(m,2H),5 .80(s,1H),4.40–4.35(m,2H),3.66–3.58(m,1H),3.59–3.42(m,2H),3.39–3.32(m,1H),3.27 –3.20(m,1H),3.08–2.87(m,1H),2.69–2.58(m,2H),2.53–2.41(m,2H),2.37–2.19(m,2H),1. 99–1.84(m,3H),1.79–1.68(m,2H),1.58–1.48(m,2H),0.98–0.90(m,2H),0.74–0.64(m,2H).

[0442] Example 6: (2s, 4s)-2-[2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0443]

[0444] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 13) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 24 H 32 The calculated mass value of N2O3 is 396.2; the measured m / z value is 397.0 [M+H] + .1 H NMR(400MHz,Chloroform-d)δ7.26–7.20(m,1H),7.11–6.98(m,3H),5.70(s,1H),4.37(d ,J=6.4Hz,2H),3.66–3.61(m,1H),3.58–3.45(m,2H),3.40–3.33(m,1H),3.26–3.20(m,1H) ),3.11–2.96(m,1H),2.94–2.83(m,1H),2.70–2.60(m,2H),2.54–2.41(m,2H),2.38–2.2 5(m,2H),2.02–1.86(m,2H),1.79–1.68(m,2H),1.55–1.49(m,2H),1.25(d,J=6.9Hz,6H).

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

[0446]

[0447] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 14) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 28 The calculated mass value of N2O3 is 368.2; the measured m / z value is 369.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.12(t,J=7.9Hz,1H),6.92(d,J=5.7Hz,3H),5.69 (s,1H),4.34-4.25(m,2H),3.61-3.50(m,1H),3.48-3.37(m,2H),3.33-3.26(m,1 H),3.20-3.08(m,1H),3.02-2.84(m,1H),2.63-2.51(m,2H),2.45-2.34(m,2H), 2.29-2.14(m,5H),1.85(q,J=11.4Hz,2H),1.69-1.61(m,2H),1.49-1.39(m,2H).

[0448] Example 8: (2s,4s)-2-[2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0449]

[0450] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 15) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 28 The calculated mass value of N2O4 is 384.2; the measured m / z value is 385.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.15(dd,J=9.2,7.7Hz,1H),6.75-6.70(m,1H),6.68-6.62(m,2H),5.60(s,1H),4.29(s,2H),3.73(s,3H),3.63-3.05(m ,5H),3.01-2.81(m,1H),2.62-2.50(m,2H),2.44-2.33(m,2H),2.23(t,J= 10.2Hz, 2H), 1.85 (t, J = 10.2Hz, 2H), 1.69-1.59 (m, 2H), 1.47-1.41 (m, 2H).

[0451] Example 9: (2s, 4s)-2-[2-[3-(trifluoromethoxy)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)- 7-Oxa-5-azaspiro[3.4]octan-6-one.

[0452]

[0453] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(trifluoromethoxy)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 16) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 25 The calculated mass value of F3N2O4 is 438.2; the measured m / z value is 439.2 [M+H] + .1 H NMR(400MHz,Chloroform-d)δ7.41-7.31(m,1H),7.17-7.11(m,1H),7.10-6.9 9(m,2H),5.81(s,1H),4.42-4.36(m,2H),3.69-3.49(m,3H),3.42-3.36(m,1H ),3.30-3.23(m,1H),3.12-2.95(m,1H),2.74-2.62(m,2H),2.55-2.45(m,2H) ,2.42-2.26(m,2H),2.03-1.91(m,2H),1.81-1.68(m,2H),1.58-1.50(m,2H).

[0454] Example 10: (2s,4s)-2-[2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0455]

[0456] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 17) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 23 H 30 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.2 [M+H] + . 1 H NMR (400MHz, Chloroform-d) δ7.05-6.92(m,3H),5.62(s,1H),4.29(d,J=8.3Hz,2H),3.69-3.51(m,2H),3.50-3.23(m,2H),3.21-3.07(m,1H),3.03-2. 86(m,1H),2.64-2.51(m,2H),2.47-2.34(m,2H),2.30-2.22(m,2H),2.20(s ,3H),2.05(s,3H),1.93-1.81(m,2H),1.74-1.63(m,2H),1.46-1.38(m,2H).

[0457] Example 11: (2r, 4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-nitrogen Heterospiro[3.4]octan-6-one.

[0458]

[0459] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octane-6-one (Example 2), except that (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 26 H 36 The calculated mass value of N2O2 is 408.3; the measured m / z value is 409.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.18(s,2H),6.96(d,J=7.0Hz,1H),5.76(s,1H) ,3.56–3.51(m,1H),3.51–3.35(m,2H),3.35–3.26(m,1H),3.21–3.12(m,1H),3 .02–2.85(m,1H),2.53–2.40(m,2H),2.34–2.21(m,5H),2.15(q,J=7.6Hz,2H) ,1.86(q,J=11.3Hz,2H),1.65(q,J=6.7,5.9Hz,2H),1.47(s,4H),1.24(s,9H).

[0460] Example 12: (2s,4s)-2-[2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0461]

[0462] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2,4-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 18) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 23 H 30 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.10-6.79(m,3H),5.60(s,1H),4.38-4.20(m,2H),3.63-3.11(m,6H),3.02-2.86(m,1H),2.6 3-2.51(m,2H),2.47-2.33(m,2H),2.26-2.16(m,4H),2.12(s,3H),1.95-1.78(m,2H),1.73-1.54(m,2H),1.45-1.37(m,2H).

[0463] Example 13: (2s,4s)-2-[2-(2-(tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0464]

[0465] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2-(tert-butyl)pyridin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 19) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 24 H 33 The calculated mass value of N3O3 is 411.3; the measured m / z value is 412.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.71(s,1H),7.44-7.31(m,2H),5.74(s,1H),4.42-4.20(m,2H),3.75-3.12(m,5H),3 .05-2.83(m,1H),2.61-2.48(m,2H),2.46-2.26(m,4H),2.09-1.80(m,2H),1.75-1.64(m,2H),1.64-1.40(m,11H).

[0466] Example 14: (2r, 4s)-2-(2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-yl)-5-azaspiro[3.4]octan-6-one).

[0467]

[0468] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(5-(tert-butyl)-2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 20) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 27 H 38 The calculated mass value of N2O2 is 422.3; the measured m / z value is 423.3 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ7.27–7.22(m,1H),7.17(dd,J=7.9,2.1Hz,1H),7.08(d,J=7.9Hz,1H),6.15(s,1H),3.65(s,2H),3.51(s,1H),3.4 1(s,1H),3.28(s,1H),3.12–2.94(m,1H),2.62–2.49(m,2H),2.43–2.32 (m,8H),2.32–2.18(m,5H),1.98(s,2H),1.63–1.50(m,2H),1.35(s,9H).

[0469] Example 15: 2-[2-[3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0470]

[0471] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 21) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C23 H 27 The calculated mass value of F3N2O2 is 420.2; the measured m / z value is 421.2 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ7.41–7.26(m,4H),6.01(s,1H),3.56(d,J=19.6Hz,2H),3.42(d,J=5.9Hz,1H),3.31(s,1H),3.19(s,1H),2.97(d ,J=16.1Hz,1H),2.52–2.42(m,2H),2.31(dd,J=11.3,4.4Hz,6H),2.16(t,J=7.8Hz,2H),1.87(d,J=9.9Hz,2H),1.67(s,2H),1.51–1.46(m,2H).

[0472] Example 16: (2r,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-yl)-5-azaspiro[3.4]octan-6-one).

[0473]

[0474] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octane-6-one (Example 2), except that 2-(6-(tert-butyl)-pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (Intermediate 23) was used instead of 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS(ESI):C 25 H 35 The calculated mass value of N3O2 is 409.3; the measured m / z value is 410.3 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ7.55–7.45(m,1H),7.14(d,J=7.8Hz,1H),6.89(t, J=6.6Hz,1H),5.97(s,1H),3.67–3.50(m,3H),3.41–3.35(m,1H),3.31–3.25(m, 1H),3.04(dp,J=11.2,8.5Hz,1H),2.60–2.49(m,2H),2.43–2.34(m,4H),2.29–2 .19(m,6H),1.73(t,J=5.8Hz,2H),1.64(d,J=4.2Hz,2H),1.39(d,J=1.9Hz,9H).

[0475] Example 17: (2r, 4s)-2-[2-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]-7-azaspiro[3.5]nonane- 7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0476]

[0477] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octane-6-one (Example 2), except that tert-butyl 2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 24) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS(ESI):C 26 H 31 The calculated mass value of F3N2O2 is 460.2; the measured m / z value is 461.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.31(d,J=8.1Hz,2H),7.09(d,J=8.1Hz,2H),5.84(s,1H),3.66–2.84(m,7H),2.44(dd,J=11.8,9. 3Hz,2H),2.35–2.19(m,5H),2.15(t,J=7.8Hz,2H),1.85(s,2H),1.64(s,2H),1.44(s,2H),1.29–1.14(m,2H),0.98–0.87(m,2H).

[0478] Example 18: (2r,4s)-2-[2-[3-chloro-4-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-yl)-5-azaspiro[3.4]octan-6-one).

[0479]

[0480] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3-chloro-4-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 25) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 23 H 26 The calculated mass value of ClF3N2O2 is 454.2; the measured m / z value is 455.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.63(d,J=8.2Hz,1H),7.37–7.32(m,1H),7.18(d,J =8.1Hz,1H),5.90(s,1H),3.68–3.48(m,3H),3.40(d,J=6.1Hz,1H),3.28(t,J=5.7 Hz,1H),3.13–2.95(m,1H),2.55(t,J=8.6Hz,2H),2.39(t,J=8.4Hz,6H),2.25(q,J =7.0Hz, 2H), 1.95 (q, J = 11.2Hz, 2H), 1.76 (d, J = 5.7Hz, 2H), 1.55 (d, J = 4.9Hz, 2H).

[0481] Example 19: (2r,4s)-2-[2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-nitrogen Heterospiro[3.4]octan-6-one.

[0482]

[0483] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2,5-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 22) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 24 H 32 The calculated mass value of N2O2 is 380.2; the measured m / z value is 381.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.04(d,J=6.9Hz,2H),6.95(d,J=8.1Hz,1H),5.89(s,1H),3.64(d,J=8.8Hz,2H),3.52(s,1H) ,3.40(s,1H),3.27(s,1H),3.04(s,1H),2.55(t,J=10.3Hz,2H),2.48–2.17(m,14H),1.96(s,2H),1.78(s,2H),1.54(s,2H).

[0484] Example 20: (2r, 4s)-2-[2-[4-methoxy-3-(trifluoromethyl)phenyl]-7-azaspiro[3.5]nonane- 7-carbonyl)-5-azaspiro[3.4]octan-6-one.

[0485]

[0486] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octane-6-one (Example 2), except that tert-butyl 2-(4-methoxy-3-(trifluoromethyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 26) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS(ESI):C 24 H 29The calculated mass value of F3N2O3 is 450.2; the measured m / z value is 451.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.40(s,1H),7.33(t,J=7.8Hz,1H),6.97(d,J=8.5Hz,1H) ,5.88(s,1H),3.91(s,3H),3.63(t,J=5.7Hz,1H),3.56–3.49(m,2H),3.39(t,J=5.6Hz, 1H),3.27(t,J=5.7Hz,1H),3.04(dt,J=12.6,8.5Hz,1H),2.64–2.48(m,2H),2.46–2.30 (m,6H),2.30–2.23(m,2H),1.91(q,J=11.5Hz,2H),1.75(q,J=6.3Hz,2H),1.59(s,2H).

[0487] Example 21: (2s, 4s)-2-(2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0488]

[0489] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(4-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 27) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 24 H 33 The calculated mass value of N3O3 is 411.3; the measured m / z value is 412.3 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ8.47–8.35(m,1H),7.18(s,2H),5.57(s,1H), 4.34–4.26(m,2H),3.62–3.52(m,1H),3.48–3.39(m,1H),3.33–3.26(m,1H), 3.22–3.11(m,1H),3.03–2.88(m,1H),2.62–2.51(m,2H),2.47–2.34(m,2H), 2.32–2.07(m,3H),1.76–1.64(m,2H),1.62–1.36(m,4H),1.26–1.23(m,9H).

[0490] Example 22: (2r, 4s)-2-(2-(5-(tert-butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-yl)-5-azaspiro[3.4]octan-6-one).

[0491]

[0492] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(5-(tert-butyl)-2-fluorophenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 28) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 26 H 35 The calculated mass value of FN2O2 is 426.3; the measured m / z value is 427.3 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.10(dd,J=9.1,6.1Hz,2H),6.83(t,J=9.5Hz,1H),5.78( s,1H),3.64–3.50(m,2H),3.45–3.38(m,1H),3.29(t,J=5.6Hz,1H),3.17(t,J=5.7Hz,1H ),2.94(dt,J=15.8,8.2Hz,1H),2.45(td,J=11.2,9.7,4.4Hz,2H),2.35–2.19(m,6H),2. 15(q,J=7.7Hz,2H),2.01–1.87(m,2H),1.67(q,J=6.3Hz,2H),1.48(s,2H),1.23(s,9H).

[0493] Example 23: (2r, 4s)-2-(2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7- Carbonyl)-5-azaspiro[3.4]octan-6-one.

[0494]

[0495] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octane-6-one (Example 2), except that tert-butyl 2-(5-(tert-butyl)-2-ethoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 29) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS(ESI):C 28 H 40 The calculated mass value of N2O3 is 452.3; the measured m / z value is 453.3 [M+H] + . 1H NMR (400MHz, Chloroform-d) δ7.13–7.05 (m, 2H), 6.66 (d, J = 9.1Hz, 1H), 5.82 (s, 1H),3.92(q,J=6.9Hz,2H),3.72–3.08(m,6H),3.04–2.83(m,1H),2.45(dd,J=11. 8,9.5Hz,2H),2.29(t,J=7.7Hz,3H),2.25–2.10(m,4H),1.88(t,J=10.6Hz,2H), 1.67(t,J=5.7Hz,2H), 1.43(t,J=5.7Hz,2H), 1.31(t,J=7.0Hz,3H), 1.23(s,9H).

[0496] Example 24: (2r, 4s)-2-[2-(o-tolyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0497]

[0498] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2-methylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 11) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 23 H 30 The calculated mass value of N2O2 is 366.2; the measured m / z value is 367.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.16–7.08(m,2H),7.07–6.99(m,2H),5.87(s,1H),3.62–3.46(m,2H),3.45–3.37(m,1H),3.31–3.28(m,1H),3.2 1–3.12(m,1H),3.01–2.85(m,1H),2.50–2.39(m,2H),2.35–2.19(m,6H) ,2.15(s,5H),1.94–1.80(m,2H),1.73–1.63(m,2H),1.47–1.41(m,2H).

[0499] Example 25: (2r, 4s)-2-[2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-aza Spiro[3.4]octan-6-one.

[0500]

[0501] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octane-6-one (Example 2), except that tert-butyl 2-(3-isopropylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 13) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 25 H 34 The calculated mass value of N2O2 is 394.3; the measured m / z value is 395.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.18–7.11(m,1H),7.02–6.91(m,3H),5.82(s, 1H),3.58–3.35(m,3H),3.29(s,1H),3.17(s,1H),3.01–2.87(m,1H),2.81(p ,J=6.9Hz,1H),2.45(t,J=10.3Hz,2H),2.34–2.19(m,6H),2.15(d,J=6.7Hz, 2H), 1.86 (d, J = 10.4Hz, 2H), 1.65 (s, 2H), 1.46 (s, 2H), 1.17 (d, J = 6.9Hz, 6H).

[0502] Example 26: (2r,4s)-2-[2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-nitrogen Heterospiro[3.4]octan-6-one.

[0503]

[0504] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 17) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS (ESI): C 24 H 32 The calculated mass value of N2O2 is 380.2; the measured m / z value is 381.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.05–6.97(m,2H),6.94(dd,J=6.4,2.6Hz,1H),5.85(s,1H),3.69–3.47(m,2H),3.35(d,J=36.7Hz,2H),3.16(s,1H) ,2.93(s,1H),2.45(dd,J=11.8,9.1Hz,2H),2.36–2.10(m,11H),2.05(s, 3H), 1.87 (d, J = 10.7Hz, 2H), 1.68 (d, J = 6.4Hz, 2H), 1.41 (t, J = 5.7Hz, 2H).

[0505] Example 27: (2r, 4s)-2-(2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7- Carbonyl)-5-azaspiro[3.4]octan-6-one.

[0506]

[0507] The title compound was prepared in a manner analogous to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octane-6-one (Example 2), except that tert-butyl 2-(5-(tert-butyl)-2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 30) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9), and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) was used instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3). MS(ESI):C27 H 38 The calculated mass value of N2O3 is 438.3; the measured m / z value is 439.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.14–7.05(m,2H),6.68(d,J=8.9Hz,1H),5.86(s,1H),3.71(s,3H),3.58(q,J=9.1Hz,1H),3.41(s,6H),3.01–2.87( m,1H),2.52–2.40(m,2H),2.35–2.24(m,3H),2.24–2.05(m,3H),1.86(t, J=10.7Hz, 2H), 1.67 (t, J=5.7Hz, 2H), 1.43 (t, J=5.7Hz, 2H), 1.23 (s, 9H).

[0508] Example 28: (2s,4s)-2-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-aza Spiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0509]

[0510] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 31) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 24 The calculated mass value of F2N2O5 is 434.2; the measured m / z value is 435.1 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ6.89(d,J=8.2Hz,1H),6.82(d,J=1.7Hz,1H),6.81–6. 74(m,1H),5.76(s,1H),4.33–4.23(m,2H),3.57–3.51(m,1H),3.48–3.35(m,2H),3.3 3–3.22(m,1H),3.20–3.10(m,1H),3.01–2.83(m,1H),2.63–2.50(m,2H),2.46–2.33 (m,2H),2.30–2.13(m,2H),1.87–1.73(m,2H),1.70–1.60(m,2H),1.50–1.40(m,2H).

[0511] Example 29: (2s,4s)-2-[2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0512]

[0513] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 32) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 28 The calculated mass value of N2O4 is 384.2; the measured m / z value is 385.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.10(d,J=7.6Hz,2H),6.86(t,J=7.3Hz,1H),6.75(d ,J=7.9Hz,1H),5.58(s,1H),4.29(s,2H),3.73(s,3H),3.61(dd,J=17.8,8.6Hz,1H) ,3.35(q,J=58.6,56.0Hz,4H),2.93(s,1H),2.61–2.48(m,2H),2.44–2.33(m,2H), 2.20(t,J=10.2Hz,2H), 1.83(t,J=10.6Hz,2H), 1.67(s,2H), 1.43(t,J=5.8Hz,2H).

[0514] Example 30: (2s, 4s)-2-[2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0515]

[0516] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(4-methoxyphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 11) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 28 The calculated mass value of N2O4 is 384.2; the measured m / z value is 385.1 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.07–6.95(m,2H),6.81–6.69(m,2H),5.67(s,1H),4.29(s,2H),3.71(s,3H),3.53(s,1H),3.40(dd,J=11.0,7.1Hz,2H), 3.27(s,1H),3.16(s,1H),2.92(s,1H),2.60–2.50(m,2H),2.46–2.35(m,2H ), 2.21 (t, J = 10.1Hz, 2H), 1.82 (d, J = 10.5Hz, 2H), 1.64 (s, 2H), 1.45 (s, 2H).

[0517] Example 31: (2s,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0518]

[0519] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 23) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 24 H 33 The calculated mass value of N3O3 is 411.3; the measured m / z value is 412.3 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.44–7.33(m,1H),7.10–6.95(m,1H),6.85–6.69(m,1H),5.66(s,1H),4.38–4.07(m,2H),3.61–3.36(m,3H),3.3 2–3.22(m,1H),3.22–3.12(m,1H),3.02–2.87(m,1H),2.62–2.50(m,2H) ,2.47–2.34(m,2H),2.22–2.09(m,4H),1.69–1.53(m,4H),1.29(s,9H).

[0520] Example 32: (2s, 4s)-2-(2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane- 7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0521]

[0522] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2,3-dimethylphenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 34) was used instead of tert-butyl 2-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 21 H 23 The calculated mass value of F4N3O3 is 441.2; the measured m / z value is 442.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.52–7.44(m,1H),7.42–7.31(m,1H),5.66(s,1 H),4.35–4.24(m,2H),3.98–3.76(m,1H),3.59–3.48(m,1H),3.49–3.39(m,1H ),3.31–3.22(m,1H),3.24–3.13(m,1H),2.99–2.87(m,1H),2.63–2.53(m,2H) ,2.47–2.33(m,1H),2.28–2.10(m,5H),1.73–1.63(m,2H),1.57–1.52(m,2H).

[0523] Example 33: (2s, 4s)-2-(2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0524]

[0525] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(6-(trifluoromethyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 35) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 21 H 24 The calculated mass value of F3N3O3 is 423.2; the measured m / z value is 424.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.76–7.62(m,1H),7.46–7.39(m,1H),7.31–7.19(m,1H ),5.73(s,1H),4.41–4.23(m,2H),3.69–3.57(m,1H),3.55–3.51(m,1H),3.47–3.37(m ,1H),3.33–3.23(m,1H),3.22–3.11(m,1H),3.01–2.87(m,1H),2.63–2.52(m,2H),2.4 7–2.30(m,2H),2.27–2.19(m,2H),2.16–2.02(m,2H),1.69–1.59(m,2H),1.52(s,2H).

[0526] Example 34: (2s, 4s)-2-(2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0527]

[0528] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(5-fluoro-6-methylpyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 36) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 21 H 26 The calculated mass value of FN3O3 is 387.2; the measured m / z value is 388.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.19–7.10(m,1H),6.97–6.82(m,1H),5.63(s,1 H),4.41–4.24(m,2H),3.61–3.49(m,2H),3.47–3.38(m,1H),3.33–3.24(m,1H ),3.20–3.13(m,1H),3.02–2.87(m,1H),2.61–2.50(m,2H),2.48–2.33(m,5H) ,2.28–2.17(m,2H),2.05–1.93(m,2H),1.69–1.61(m,2H),1.59–1.49(m,2H).

[0529] Example 35: (2s,4s)-2-(2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0530]

[0531] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(2-(tert-butyl)pyrimidin-4-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 37) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 23 H 32 The calculated mass value of N4O3 is 412.2; the measured m / z value is 413.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.53–8.32(m,1H),6.90–6.78(m,1H),5.63(s ,1H),4.35–4.24(m,2H),3.57–3.50(m,1H),3.50–3.37(m,2H),3.31–3.26(m ,1H),3.23–3.17(m,1H),3.00–2.85(m,1H),2.60–2.52(m,2H),2.47–2.32(m ,2H),2.23–2.05(m,4H),1.68–1.58(m,2H),1.58–1.50(m,2H),1.34(s,9H).

[0532] Example 36: (2s,4s)-2-(2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0533]

[0534] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(4-(tert-butyl)oxazol-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 38) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 31 The calculated mass value of N3O4 is 401.2; the measured m / z value is 402.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.17–7.12(m,1H),5.62(s,1H),4.34–4.21(m,2H),3.60–3.47(m,2H),3.46–3.39(m,1H),3.26–3.21(m ,1H),3.19–3.12(m,1H),3.00–2.83(m,1H),2.60–2.51(m,2H),2.46–2.33(m,2H),2.26–2.06(m,4H),1.63–1.51(m,4H),1.17(s,9H).

[0535] Example 37: (2s,4s)-2-[2-(2-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0536]

[0537] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(4-(tert-butyl)oxazol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 39) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 22 H 31 The calculated mass value of N3O4 is 401.2; the measured m / z value is 402.3 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ6.56–6.47(m,1H),5.58(s,1H),4.36–4.25(m ,2H),3.55–3.47(m,1H),3.46–3.40(m,2H),3.30–3.22(m,1H),3.22–3.14(m ,1H),3.00–2.84(m,1H),2.61–2.49(m,2H),2.46–2.35(m,2H),2.21–2.10(m ,2H),1.98–1.84(m,2H),1.66–1.56(m,2H),1.53–1.47(m,2H),1.28(s,9H).

[0538] Example 38: (2s,4s)-2-(2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)- 7-Oxa-5-azaspiro[3.4]octan-6-one.

[0539]

[0540] The title compound was prepared in a manner similar to (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 2), except that tert-butyl 2-(3,5-difluoropyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 40) was used instead of tert-butyl 2-(3-(tert-butyl)phenyl)-7-azaspiro[3.5]nonane-7-carboxylate (Intermediate 9). MS (ESI): C 20 H 23 The calculated mass value of F2N3O3 is 391.2; the measured m / z value is 392.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ8.30–8.18(m,1H),7.10–6.98(m,1H),5.63(s,1 H),4.34–4.21(m,2H),3.84–3.68(m,1H),3.58–3.52(m,1H),3.47–3.41(m,1H ),3.31–3.22(m,1H),3.22–3.15(m,1H),3.01–2.86(m,1H),2.61–2.50(m,2H) ,2.45–2.35(m,2H),2.27–2.07(m,4H),1.72–1.58(m,2H),1.55–1.48(m,2H).

[0541] Example 39: (rac)-(2s,4s)-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0542]

[0543] Step A: tert-Butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate. A solution of 2-iodo-8-azaspiro [4.5] decane-8-carboxylic acid tert-butyl ester (intermediate 41, 719 mg, 1.97 mmol) in THF (3.9 mL) was flowed through a column containing activated zinc at 40 ° C (flow rate 0.5 mL / min). The solution flowing out was collected in a vial containing 4-bromotrifluorotoluene (0.18 mL, 1.31 mmol), bis(dibenzylideneacetone) palladium (Pd(dba)2) (38 mg, 0.066 mmol) and 2-dicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl (XPhos) (47 mg, 0.098 mmol). The mixture was stirred at 50 ° C for 4 hours. Then, saturated NH4Cl and NH3 1: 1 solution (37% aqueous solution) was added, and the mixture was extracted with EtOAc. The organic phase was separated, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified by FCC on silica gel (0%-15% EtOAc in heptane) to give the title compound (156 mg, 31% yield) as a yellow viscous oil. MS (ESI): C 21 H 28 The calculated mass value of F3NO2 is 383.2; the measured m / z value is 369.2 [M-tBu+2H+MeCN] + .

[0544] Step B: 2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane hydrochloride . To a solution of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate (10 mg, 0.026 mmol) in MeOH (52 μL) was added a solution of HCl in 1,4-dioxane (4 M, 65 μL). It was heated to 45 °C for 1 hour and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 16 H 20 The calculated mass value of F3N is 283.2; the measured m / z value is 284.1 [M+H] + .

[0545] step Step C: (rac)-(2s,4s)-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).2-(4-(Trifluoromethyl)phenyl)-8-azaspiro[4.5]decane hydrochloride was taken up in dimethylformamide (DMF) (0.26 mL) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 4 mg, 0.026 mmol), diisopropylethylamine (DIPEA) (14 μL, 0.078 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (11 mg, 0.029 mmol) were added thereto. It was stirred at room temperature for 1 hour. The reactants were filtered through a PTFE filter with MeOH and purified via reverse phase HPLC (5%-95% MeCN in 20 mM NH4OH solution) to give the title compound (11 mg, 97% yield). MS(ESI):C 23 H 27 The calculated mass value of F3N2O3 is 436.2; the measured m / z value is 437.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.54(d,J=8.1Hz,2H),7.35–7.30(m,2H),5.89(s,1H),4.37(d,J=1.8Hz,2H),3.70–3.53(m,2H),3.34(dt,J=11.0,5.6H z,2H),3.28–3.13(m,1H),3.01(pd,J=8.0,3.1Hz,1H),2.69–2.60(m,2H),2 .52-2.42(m,2H),2.21–2.01(m,2H),1.82–1.69(m,2H),1.60–1.42(m,6H).

[0546] Example 40: (rac)-(2s,4s)-8-methyl-2-(2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane alkane-8-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one.

[0547]

[0548] The title compound was prepared in a manner similar to Example 39 using (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 5) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in step C. MS (ESI): C 24 H 29 The calculated mass value of F3N2O3 is 450.2; the measured m / z value is 451.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.54(d,J=8.1Hz,2H),7.33(d,J=8.0Hz,2H),5 .89(s,1H),4.54-4.46(m,1H),3.71-3.53(m,2H),3.33(dt,J=10.9,5.8Hz,2H ),3.28-3.12(m,1H),3.01-2.91(m,1H),2.71-2.56(m,2H),2.44-2.33(m,2H) ,2.21-2.01(m,2H),1.84-1.69(m,2H),1.59-1.47(m,6H),1.46–1.41(m,3H).

[0549] Example 41: (rac)-(2s,4s)-2-(6-phenyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0550]

[0551] The title compound was prepared in a manner analogous to Step B and Step C of Example 39, using 6-phenyl-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Intermediate 43) in Step B instead of 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester. MS (ESI): C 20 H 24 The calculated mass value of N2O3 is 340.2; the measured m / z value is 341.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.34–7.27(m,2H),7.20(td,J=6.4,1.6Hz,3H),6.49(d,J=9.2Hz,1H),4.33(d,J=0.8Hz,2H),4.09–3.85 (m,4H),3.19–3.02(m,1H),2.76–2.65(m,1H),2.65–2.56(m,2H),2.48–2.37(m,2H),2.32(td,J=13.5,7.4Hz,1H),2.22–1.84(m,5H).

[0552] Example 42: (2r, 4S*)-2-((R*)-6-phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0553]

[0554] The title compound was prepared in a manner analogous to step B and step C of Example 39, using (R*)-6-phenyl-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Intermediate 45) instead of 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester in step B, and using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in step C. MS (ESI): C 21 H 26 The calculated mass value of N2O2 is 338.2; the measured m / z value is 339.2 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ7.32–7.27(m,2H),7.23–7.16(m,3H),6.34(s,1H),4.05–3.83(m,4H),3.10(s,1H),2.75(p,J=8.1Hz,1H),2.53–2.4 6(m,2H),2.38–2.26(m,5H),2.19(dd,J=8.4,7.3Hz,2H),2.18–2.10(m,1 H),2.10–2.02(m,1H),2.04–1.94(m,1H),1.88(s,1H),1.79–1.67(m,1H).

[0555] Example 43: (2r, 4R*)-2-((S*)-6-phenyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0556]

[0557] The title compound was prepared in a manner analogous to step B and step C of Example 39, using (S*)-6-phenyl-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Intermediate 44) instead of 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester in step B, and using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in step C. MS (ESI): C 21 H 26 The calculated mass value of N2O2 is 338.2; the measured m / z value is 339.2 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ7.33–7.27(m,2H),7.23–7.16(m,3H),6.35(s,1H),4.04–3.84(m,4H),3.10(s,1H),2.74(p, J=8.1Hz,1H),2.54–2.45(m,2H),2.38–2.25(m,5H),2.22–2.10(m,3H),2.10–1.94(m,2H),1.89(s,1H),1.79–1.67(m,1H).

[0558] Example 44: (rac)-(2s,4s)-2-(6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0559]

[0560] The title compound was prepared in a manner analogous to steps B and C of Example 39, using tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 46) instead of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate in step B. MS (ESI): C 21 H 23 The calculated mass value of F3N2O3 is 408.2; the measured m / z value is 409.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.55(d,J=8.1Hz,2H),7.30(d,J=8.0Hz,2H),6.56(d,J=10.5Hz,1H),4.33(s,2H),4 .05–3.86(m,4H),3.24–3.07(m,1H),2.74–2.66(m,1H),2.66–2.57(m,2H),2.49–2.28(m,3H),2.25–1.66(m,5H).

[0561] b Example 45: (2s, 4s)-2-((R*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2- carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0562]

[0563] The title compound was prepared in a manner analogous to steps B and C of Example 39 using (R*)-tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 48) instead of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate in step B. MS (ESI): C 21 H 23 The calculated mass value of F3N2O3 is 408.2; the measured m / z value is 409.1 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ7.55(d,J=8.1Hz,2H),7.30(d,J=7.9Hz,2H),6.60(d,J=13.9Hz,1H),4.33(s,2H),4.05–3.87(m,4H),3.24–3.07(m,1H),2 .74–2.66(m,1H),2.66–2.56(m,2H),2.48–2.39(m,2H),2.39–2.30(m,1H), 2.24–2.13(m,1H),2.13–1.96(m,2H),1.96–1.84(m,1H),1.80–1.65(m,1H).

[0564] Example 46: (2s,4R*)-2-((S*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0565]

[0566] The title compound was prepared in a manner analogous to steps B and C of Example 39 using (S*)-tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 47) instead of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate in step B. MS (ESI): C 21 H 23 The calculated mass value of F3N2O3 is 408.2; the measured m / z value is 409.2 [M+H] + . 1H NMR(500MHz,Chloroform-d)δ7.55(d,J=8.1Hz,2H),7.30(d,J=7.9Hz,2H),6.62(d,J=14.6Hz,1H),4.33(s,2H),4.05–3.89(m,4H),3.24–3.07(m,1H),2 .74–2.66(m,1H),2.66–2.58(m,2H),2.48–2.39(m,2H),2.39–2.30(m,1H), 2.23–2.13(m,1H),2.13–1.96(m,2H),1.96–1.84(m,1H),1.80–1.66(m,1H).

[0567] Example 47: (2r,4S*)-2-((R*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl 1-(4-(2-(4-(2-yl)-5-azaspiro[3.4]octan-6-one).

[0568]

[0569] The title compound was prepared in a manner analogous to step B and step C of Example 39, using (R*)-tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 48) instead of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate in step B, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in step C. MS (ESI): C 22 H 25 The calculated mass value of F3N2O2 is 406.2; the measured m / z value is 407.2 [M+H] + . 1 HNMR(500MHz,Chloroform-d)δ7.57–7.51(m,2H),7.30(d,J=8.0Hz,2H),6.44(s,1H),4.08–3.84(m,4H),3.16(s,1H),2.74( p,J=8.1Hz,1H),2.54–2.46(m,2H),2.39–2.28(m,5H),2.23–2.13(m,3H),2.14–1.97(m,2H),1.89(s,1H),1.80–1.66(m,1H).

[0570] Example 48: (2r,4R*)-2-((S*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylic acid 1-(4-(2-(4-(2-yl)-5-azaspiro[3.4]octan-6-one).

[0571]

[0572] The title compound was prepared in a manner analogous to step B and step C of Example 39, using (S*)-tert-butyl 6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carboxylate (Intermediate 47) instead of tert-butyl 2-(4-(trifluoromethyl)phenyl)-8-azaspiro[4.5]decane-8-carboxylate in step B, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in step C. MS (ESI): C 22 H 25 The calculated mass value of F3N2O2 is 406.2; the measured m / z value is 407.2 [M+H] + . 1 HNMR(500MHz,Chloroform-d)δ7.56–7.51(m,2H),7.32–7.27(m,2H),6.40(s,1H),4.05–3.85(m,4H),3.16(s,1H),2.74(p, J=8.1Hz,1H),2.54–2.47(m,2H),2.40–2.29(m,5H),2.23–2.12(m,3H),2.12–1.97(m,2H),1.90(s,1H),1.80–1.66(m,1H).

[0573] Example 49: (rac)-(2s,4s)-2-(6-(4-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0574]

[0575] The title compound was prepared in a manner similar to Example 39 using 6-iodo-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Intermediate 42) instead of 2-iodo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 41) and 1-bromo-4-tert-butylbenzene instead of 4-bromotrifluorotoluene in step A. MS (ESI): C 24 H 32 The calculated mass value of N2O3 is 396.2; the measured m / z value is 397.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.35–7.29(m,2H),7.15–7.09(m,2H),6.37(d,J=7.7Hz,1H),4.33(s,2H),4.03–3.86(m,4H),3.16-3.00(m,1H) ),2.76–2.67(m,1H),2.64–2.55(m,2H),2.48–2.38(m,2H),2.30(td,J =13.9,7.4Hz,1H),2.19–1.82(m,4H),1.80–1.68(m,1H),1.31(s,9H).

[0576] Example 50: (rac)-(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0577]

[0578] The title compound was prepared in a manner similar to Example 39 using 6-iodo-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Intermediate 42) instead of 2-iodo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 41) and 1-bromo-3-tert-butylbenzene instead of 4-bromotrifluorotoluene in step A. MS (ESI): C 24 H 32 The calculated mass value of N2O3 is 396.2; the measured m / z value is 397.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.25–7.22(m,2H),7.20(s,1H),7.04–6.98(m,1H),6.36(d,J=9.7Hz,1H),4.33(s,2H),4.04–3.88(m,4H),3.19–3.01 (m,1H),2.77–2.67(m,1H),2.65–2.55(m,2H),2.49–2.39(m,2H),2.32(t d,J=13.5,7.3Hz,1H),2.21–1.85(m,4H),1.82–1.68(m,1H),1.32(s,9H).

[0579] Example 51: (rac)-(2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl 1-(4-(2-(4-(2-(4-nitro-1-yl)-8-methyl-7-oxa-5-azaspiro[3.4]octan-6-one).

[0580]

[0581] The title compound was prepared in a manner similar to Example 39, using 6-iodo-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (Intermediate 42) instead of 2-iodo-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 41) in step A, and 1-bromo-3-tert-butylbenzene instead of 4-bromotrifluorotoluene, and (2s,4s)-8-methyl-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 5) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in step C. MS (ESI): C 25 H 34 The calculated mass value of N2O3 is 410.3; the measured m / z value is 411.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.25-7.22(m,2H),7.21(dt,J=3.2,1.5Hz,1H), 7.04-6.98(m,1H),6.39(d,J=7.3Hz,1H),4.49-4.41(m,1H),4.04-3.87(m,4H) ,3.19–3.01(m,1H),2.73-2.58(m,2H),2.58-2.48(m,1H),2.42-2.25(m,3H),2 .22-1.83(m,4H),1.81-1.68(m,1H),1.41(dt,J=6.5,1.5Hz,3H),1.32(s,9H).

[0582] Example 52: (rac)-(2s,4s)-2-(6-cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0583]

[0584] Step A: tert-Butyl 6-cyclopropyl-2-azaspiro[3.4]octane-2-carboxylate . Cyclopropylmagnesium bromide (0.75mL, 0.75mmol) was added to 6-iodo-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (intermediate 42, 169mg, 0.50mmol), acetylacetonatocobalt (II) (4.5mg, 0.018mmol) and N, N, N', N'-tetramethylethylenediamine (58mg, 0.50mmol) in THF (0.6mL) at 0°C. The mixture was stirred for 1 hour at this temperature. The reactant was quenched with NH4Cl / NH3 and the organic phase was separated, dried, filtered and evaporated under reduced pressure. The crude product was purified by FCC (EtOAc: DCM: heptane 0 / 30 / 70 to 50 / 50 / 0) on silica gel to obtain the title compound (89mg, 50% purity, 35% yield) as a colorless oil.

[0585] Step B: 6-Cyclopropyl-2-azaspiro[3.4]octan-2-ium chloride . To a solution of tert-butyl 6-cyclopropyl-2-azaspiro[3.4]decane-2-carboxylate (45 mg, 50% purity, 0.179 mmol) in MeOH (100 μL) was added a solution of HCl in 1,4-dioxane (4M, 0.45 mL). It was heated to 45 °C for 1 hour and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 10 H 17 The calculated mass value of N is 151.1; the measured m / z value is 152.1 [M+H] + .

[0586] Step C: ( rac)-(2s,4s)-2-(6-cyclopropyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one . 6-Cyclopropyl-2-azaspiro[3.4]octane-2-ium chloride was taken up in DMF (0.9 mL) and to it was added (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 31 mg, 0.179 mmol), DIPEA (94 μL, 0.537 mmol) and HATU (77 mg, 0.197 mmol). It was stirred at room temperature for 1 hour. The reaction was filtered through a PTFE filter with MeOH and purified via reverse phase HPLC (5%-95% MeCN in 20 mM NH4OH solution) to give the title compound (10 mg, 18% yield). MS (ESI): C 17 H 24 The calculated mass value of N2O3 is 304.2; the measured m / z value is 305.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ6.53(d,J=7.5Hz,1H),4.32(d,J=2.5Hz,2H),3. 98–3.84(m,2H),3.84(s,1H),3.79(s,1H),2.74–2.64(m,1H),2.64–2.54(m,2H ),2.45–2.36(m,2H),2.04–1.92(m,1H),1.92–1.71(m,3H),1.64–1.51(m,1H) ,1.46–1.26(m,2H),0.65–0.52(m,1H),0.44–0.35(m,2H),0.08–-0.01(m,2H).

[0587] Example 53: (rac)-(2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0588]

[0589] Step A: tert-Butyl 6-cyclohexyl-2-azaspiro[3.4]octane-2-carboxylate . Cyclohexylmagnesium chloride (1mL, 1mmol) was added to a solution of 6-iodo-2-azaspiro [3.4] octane-2-carboxylic acid tert-butyl ester (intermediate 42, 169mg, 0.5mmol), nickel acetylacetonate (II) (13mg, 0.05mmol), 4-fluorostyrene (12μL, 0.1mmol) and tetrabutylammonium iodide (554mg, 1.5mmol) in THF (0.41mL) and N-methyl-2-pyrrolidone (NMP) (0.24mL) at 0°C. The mixture was stirred at room temperature for 4 hours at this temperature. The reactant was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, separated, dried, and evaporated under reduced pressure to give a crude residue which was purified by FCC on silica gel (20%-80% DCM in heptane) to afford the title compound as a colorless oil (87 mg, 45% purity, 27% yield). MS (ESI): C 18 H 31 The calculated mass value of NO2 is 293.2; the measured m / z value is 294.2 [M+H] + .

[0590] Step B: 6-Cyclohexyl-2-azaspiro[3.4]octan-2-ium chloride . To a solution of tert-butyl 6-cyclohexyl-2-azaspiro[3.4]decane-2-carboxylate (44 mg, 45% purity, 0.15 mmol) in MeOH (100 μL) was added a solution of HCl in 1,4-dioxane (4M, 0.38 mL). It was heated to 45 °C for 1 hour and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 13 H 23 The calculated mass value of N is 193.2; the measured m / z value is 194.2 [M+H] + .

[0591] Step C: ( rac)-(2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one. 6-Cyclohexyl-2-azaspiro[3.4]octane-2-ium chloride was taken up in DMF (0.75 mL) and to it was added (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 26 mg, 0.15 mmol), DIPEA (79 μL, 0.45 mmol) and HATU (65 mg, 0.16 mmol). It was stirred at room temperature for 1.5 hours. The reaction was filtered through a PTFE filter with MeOH and purified via reverse phase HPLC (5%-95% MeCN in 20 mM NH4OH) to give the title compound (20 mg, 39% yield). MS (ESI): C 20 H 30 The calculated mass value of N2O3 is 346.2; the measured m / z value is 347.2 [M+H] + . 1 H NMR(500MHz,Chloroform-d)δ6.58(d,J=5.0Hz,1H),4.32(d,J=1.7Hz,2H),3.84(dd,J=31.7,21.3Hz,4H),2.72-2.63(m,1H),2.63–2.56(m,2H),2.4 4–2.35(m,2H),2.01–1.89(m,1H),1.87–1.74(m,4H),1.74–1.51(m,5H),1 .47–1.35(m,1H),1.32–1.09(m,4H),1.06–0.96(m,1H),0.94-0.80(m,2H).

[0592] Example 54: (rac)-(2r,4s)-2-(6-cyclohexyl-2-azaspiro[3.4]octane-2-carbonyl)-5-azaspiro [3.4] Octane-6-one.

[0593]

[0594] The title compound was prepared in a manner similar to Example 53 using (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in step C. MS (ESI): C 21 H 32 The calculated mass value of N2O2 is 344.2; the measured m / z value is 345.3 [M+H] + . 1HNMR(400MHz,Chloroform-d)δ6.18(s,1H),3.91–3.74(m,4H),2.72(pd,J=8.1,3.8Hz,1H),2.52–2.43(m,2H),2.38–2.26(m,4H),2.21–2.14(m,2 H),2.01–1.88(m,1H),1.87–1.66(m,7H),1.57(q,J=9.1,8.4Hz,2H),1.4 7–1.34(m,1H),1.34–1.10(m,4H),1.10–0.96(m,1H),0.96–0.80(m,2H).

[0595] Example 55: (rac)-(2s,4s)-2-(6-cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0596]

[0597] Step A: tert-Butyl 6-cyclopentyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate. 2-tert-Butyloxycarbonyl-6-oxo-2-azaspiro[3.4]octane (100 mg, 0.439 mmol) was absorbed in anhydrous THF (0.3 M) in a dried flask under N2. Cerium (III) chloride (CeCl3) (162 mg, 0.659 mmol) was added and stirred at room temperature for 1 hour. The reactant was cooled to 0 ° C and cyclopentylmagnesium bromide (2M in THF, 0.33 mL) was added dropwise. The reactant was allowed to warm to room temperature and stirred for 16 hours. The reactant was quenched with saturated NH4Cl aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (33 mg, 25% yield) was obtained by purification via FCC (0%-60% EtOAc in hexane) on silica gel. MS (ESI): C 17 H 29 The calculated mass value of NO3 is 295.2; the measured m / z value is 222.2 [M+H-tBu-OH] + .

[0598] Step B: 6-Cyclopentyl-2-azaspiro[3.4]octan-2-ium 2,2,2-trifluoroacetate . 6-Cyclopentyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylic acid tert-butyl ester (33 mg, 0.112 mmol) was taken up in trifluoroacetic acid (TFA) (0.75 mL) and stirred at room temperature for 5 minutes. Triethylsilane (TES) (54 μL, 0.335 mmol) was added and stirred at room temperature for 2 hours, then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 12 H 21 The calculated mass value of N is 179.2; the measured m / z value is 180.2 [M+H] +.

[0599] Step C: (rac)-(2s,4s)-2-(6-cyclopentyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one. 6-Cyclopentyl-2-azaspiro[3.4]octane-2-ium 2,2,2-trifluoroacetate (16 mg, 0.054 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 9 mg, 0.054 mmol) were taken up in DMF (0.15 M). DIPEA (38 μL, 0.218 mmol) and HATU (26 mg, 0.066 mmol) were added and the reaction was stirred at room temperature for 72 hours. The crude mixture was filtered through a PTFE filter with MeOH and purified via reverse phase HPLC (5%-95% MeCN in 20 mM NH4OH in water) to give the title compound (12 mg, 66% yield). MS (ESI): C 19 H 28 The calculated mass value of N2O3 is 332.2; the measured m / z value is 333.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ6.58(d,J=4.7Hz,1H),4.32(d,J=1.1Hz,2H),3.92–3.77(m,4H),2.73-2.63(m,1H),2.64–2.56(m,2 H),2.46–2.36(m,2H),1.97(td,J=13.4,7.2Hz,1H),1.88–1.65(m,6H),1.65–1.38(m,6H),1.34-1.21(m,1H),1.16–0.99(m,2H).

[0600] Example 56: (rac)-(2s,4s)-2-(6-cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.

[0601]

[0602] Step A: tert-Butyl 6-cyclobutyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate.2-tert-Butyloxycarbonyl-6-oxo-2-azaspiro [3.4] octane (50 mg, 0.22 mmol) was absorbed in anhydrous THF (0.6 M) in a dried flask under N2. CeCl3 (81 mg, 0.33 mmol) was added and stirred at room temperature for 45 minutes. The reactant was cooled to 0 ° C and cyclobutylmagnesium chloride (0.5 M in THF, 0.66 mL) was added dropwise. The reactant was warmed to room temperature and stirred for 6 hours. The reactant was quenched with saturated NH4Cl aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The title compound (33 mg, 53% yield) was obtained by purification via FCC (0%-100% EtOAc in hexane) on silica gel. MS (ESI): C 16 H 27 The calculated mass value of NO3 is 281.2; the measured m / z value is 208.2 [M+H-tBu-OH] + .

[0603] Step B: 6-Cyclobutyl-2-azaspiro[3.4]oct-6-en-2-ium 2,2,2-trifluoroacetate . tert-Butyl 6-cyclobutyl-6-hydroxy-2-azaspiro[3.4]octane-2-carboxylate (26 mg, 0.092 mmol) was taken up in TFA (0.62 mL) and stirred at room temperature for 5 minutes. TES (45 μL, 0.277 mmol) was added and stirred at room temperature for 1 hour before being concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 11 H 17 The calculated mass value of N is 163.1; the measured m / z value is 164.2 [M+H] + .

[0604] Step C: 6-Cyclobutyl-2-azaspiro[3.4]octan-2-ium 2,2,2-trifluoroacetate . 6-Cyclobutyl-2-azaspiro[3.4]oct-6-ene-2-ium 2,2,2-trifluoroacetate (26 mg, 0.094 mmol) was taken up in ethanol (EtOH) (0.9 mL). Palladium on carbon (Pd / C) (10 mg, 0.009 mmol) was added, and the reaction vessel was evacuated and placed under a balloon of hydrogen (H2) to stir at room temperature for 16 hours. The reaction mixture was stirred by Filter with MeOH and concentrate under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 11 H 19 The calculated mass value of N is 165.2; the measured m / z value is 166.2 [M+H] + .

[0605] Step D: (rac)-(2s,4s)-2-(6-cyclobutyl-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-nitrogen Heterospiro[3.4]octan-6-one.6-Cyclobutyl-2-azaspiro[3.4]octane-2-ium 2,2,2-trifluoroacetate (26 mg, 0.093 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 17 mg, 0.098 mmol) were taken up in DMF (0.6 mL). DIPEA (48 μL, 0.279 mmol) and HATU (40 mg, 0.102 mmol) were added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was filtered through a PTFE filter with MeOH and purified via reverse phase HPLC (5%-95% MeCN in 20 mM NH4OH in water) to give the title compound (5 mg, 17% yield). MS (ESI): C 18 H 26 The calculated mass value of N2O3 is 318.2; the measured m / z value is 319.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ6.34(s,1H),4.32(s,2H),3.76–3.59(m,4H),2.75–2.63(m,1H),2. 63–2.51(m,2H),2.47–2.35(m,2H),1.89(d,J=15.9Hz,2H),1.80–1.48(m,9H),1.48–1.27(m,3H).

[0606] Example 57: (rac)-(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0607]

[0608] Step A: tert-Butyl 2-(3-(tert-butyl)phenyl)-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate . 2-Oxo-8-azaspiro [4.5] octane-8-carboxylic acid tert-butyl alcohol (100 mg, 0.375 mmol) was absorbed in anhydrous THF (1.9 mL) solution in a dried flask under N2 and cooled to -78 °C. 3-tert-Butylphenylmagnesium bromide (0.5 M in THF, 1.12 mL) was added dropwise. It was warmed to room temperature and stirred for 1.5 hours, then quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (68 mg, 47% yield) was obtained by purification via FCC on silica gel (0%-100% EtOAc in hexane). MS (ESI): C 24 H 37 The calculated mass value of NO3 is 387.3; the measured m / z value is 332.2 [M-tBu+2H] + .

[0609] Step B: 2-(3-(tert-Butyl)phenyl)-8-azaspiro[4.5]decan-8-ium 2,2,2-trifluoroacetate . tert-Butyl 2-(3-(tert-butyl)phenyl)-2-hydroxy-8-azaspiro[4.5]decane-8-carboxylate (68 mg, 0.175 mmol) was taken up in TFA (0.58 mL) and stirred at room temperature for 5 minutes. TES (85 μL) was added and stirred at room temperature for 1 hour before being concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 19 H 29 The calculated mass value of N is 271.2; the measured m / z value is 272.2 [M+H] + .

[0610] Step C: (rac)-(2s,4s)-2-(2-(3-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl)- 7-Oxa-5-azaspiro[3.4]octan-6-one. 2-(3-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-ium 2,2,2-trifluoroacetate (20 mg, 0.052 mmol) and (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 10 mg, 0.057 mmol) were taken up in DMF (0.5 mL). DIPEA (27 μL, 0.156 mmol) and HATU (24 mg, 0.062 mmol) were added and the reaction was stirred at room temperature for 3 hours. The reaction mixture was filtered through a PTFE filter with MeOH and purified via reverse phase HPLC (5%-95% MeCN in 20 mM NH4OH in water) to give the title compound (16 mg, 73% yield). MS (ESI): C 26 H 36 The calculated mass value of N2O3 is 424.3; the measured m / z value is 425.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.25–7.20(m,3H),7.08–7.02(m,1H),6.19(d,J=5.6Hz,1H),4.38(d,J=2.1Hz,2H),3.67–3.52(m,2H),3.40–3.27(m,2H ),3.23–3.07(m,1H),3.07–2.93(m,1H),2.72–2.61(m,2H),2.52–2.40(m, 2H),2.19–2.00(m,2H),1.84–1.67(m,3H),1.66–1.44(m,5H),1.32(s,9H).

[0611] Example 58: (rac)-(2s,4s)-2-(2-(4-(tert-butyl)phenyl)-8-azaspiro[4.5]decane-8-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0612]

[0613] The title compound was prepared in a manner similar to Example 57 using 4-tert-butylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide in step A. MS (ESI): C 26 H 36 The calculated mass value of N2O3 is 424.3; the measured m / z value is 425.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.35–7.28(m,2H),7.19–7.13(m,2H),6.10(d, J=4.7Hz,1H),4.37(d,J=1.9Hz,2H),3.66–3.49(m,2H),3.40–3.25(m,2H),3. 21–3.06(m,1H),2.99(pd,J=8.1,3.7Hz,1H),2.71–2.61(m,2H),2.51–2.39( m,2H),2.17–1.96(m,2H),1.82–1.65(m,3H),1.65–1.41(m,5H),1.31(s,9H).

[0614] Example 59: (2s,4s)-2-(2-(3-isopropylphenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0615]

[0616] The title compound was prepared in a manner similar to Example 57 using tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate and 3-isopropylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide in step A. MS (ESI): C 23 H 30 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.25–7.19(m,1H),7.12–7.05(m,1H),7.05–6.97(m,2H),6.41–6.23(m,1H),4.41–4.30(m,2H),3.67–3.25(m,5H) ,2.88(qd,J=18.0,15.3,10.0Hz,2H),2.72–2.58(m,2H),2.57–2.29(m, 4H), 2.28–2.09 (m, 2H), 2.09–1.82 (m, 2H), 1.25 (dd, J = 6.9, 1.3Hz, 6H).

[0617] Example 60: (2s,4s)-2-(2-(3-(tert-butyl)phenyl)-6-azaspiro[3.4]octane-6-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0618]

[0619] The title compound was prepared in a manner similar to Example 57 using tert-butyl 2-oxo-6-azaspiro[3.4]octane-6-carboxylate instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate in step A. MS (ESI): C 24 H 32 The calculated mass value of N2O3 is 396.2; the measured m / z value is 397.3 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.26–7.21(m,2H),7.21-7.16(m,1H),7.05–6.99(m,1H),6.21(d,J=25.8Hz,1H),4.40–4.30(m,2H),3.6 8–3.26(m,5H),2.98–2.78(m,1H),2.70–2.58(m,2H),2.55–2.30(m,4H),2.26–2.10(m,2H),2.10–1.83(m,2H),1.32(d,J=1.3Hz,9H).

[0620] Example 61: (rac)-(2s,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)- 7-Oxa-5-azaspiro[3.4]octan-6-one.

[0621]

[0622] The title compound was prepared in a manner similar to Example 57 using 2-tert-butyloxycarbonyl-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate and 3-isopropylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide in step A. MS (ESI): C 23 H 30 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.2 [M+H] + . 1H NMR(400MHz,Chloroform-d)δ7.23(t,J=7.6Hz,1H),7.10–6.98(m,3H),6.61–6 .51(m,1H),4.33(s,2H),4.03–3.87(m,4H),3.17-3.00(m,1H),2.88(hept,J=6 .9Hz,1H),2.75–2.66(m,1H),2.66–2.58(m,2H),2.48–2.37(m,2H),2.31(td,J =13.5,7.3Hz,1H),2.20–1.83(m,4H),1.80–1.67(m,1H),1.24(d,J=6.9Hz,6H).

[0623] Example 62: (rac)-(2r,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)- 5-Azaspiro[3.4]octan-6-one.

[0624]

[0625] The title compound was prepared in a manner similar to Example 57 using 2-tert-butyloxycarbonyl-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate and 3-isopropylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide in step A, and (2r,4s)-6-oxo-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 4) instead of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3) in step C. MS (ESI): C 24 H 32 The calculated mass value of N2O2 is 380.2; the measured m / z value is 381.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.23(t,J=7.6Hz,1H),7.09–6.98(m,3H),6.38(s,1H),4.04–3.84(m,4H),3.09(dp,J=18.1,8.8Hz,1H),2.87(hept,J=6. 9Hz,1H),2.75(p,J=8.1Hz,1H),2.55–2.45(m,2H),2.38–2.25(m,5H),2.22 –2.16(m,2H),2.16–1.82(m,4H),1.81–1.66(m,1H),1.24(d,J=6.9Hz,6H).

[0626] Example 63: (rac)-(2s,4s)-2-(6-(4-isopropylphenyl)-2-azaspiro[3.4]octane-2-carbonyl)- 7-Oxa-5-azaspiro[3.4]octan-6-one.

[0627]

[0628] The title compound was prepared in a manner similar to Example 57 using 2-tert-butyloxycarbonyl-6-oxo-2-azaspiro[3.4]octane instead of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate and 4-isopropylphenylmagnesium bromide instead of 3-tert-butylphenylmagnesium bromide in step A. MS (ESI): C 23 H 30 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.16(d,J=8.2Hz,2H),7.11(d,J=8.3Hz,2H),6.55 (d,J=7.9Hz,1H),4.33(s,2H),4.02–3.86(m,4H),3.16–2.97(m,1H),2.88(hept, J=6.9Hz,1H),2.75–2.66(m,1H),2.66–2.57(m,2H),2.48–2.36(m,2H),2.30(td, J=13.6,7.3Hz,1H),2.19–1.83(m,4H),1.76–1.64(m,1H),1.24(d,J=6.9Hz,6H).

[0629] Example 64: (2s, 4s)-2-(2-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0630]

[0631] Step A: tert-Butyl 2-phenyl-6-azaspiro[3.4]octane-6-carboxylate. 2-Oxo-6-azaspiro [3.4] octane-6-carboxylic acid tert-butyl ester (100mg, 0.444mmol) and 4-methylbenzenesulfonyl hydrazide (85mg, 0.444mmol) were absorbed in 1,4-dioxane (0.9mL) and heated at 80°C for 2.5 hours. Potassium carbonate (K2CO3) (92mg, 0.666mmol) and phenylboronic acid (85mg, 0.666mmol) were added and heated at 110°C for 10 hours. The reactant was quenched with saturated NaHCO3 aqueous solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound (13mg, 10% yield) was obtained by purification via FCC (0%-20% EtOAc in hexane) on silica gel. MS (ESI): C 18 H 25 The calculated mass value of NO2 is 287.2; the measured m / z value is 232.2 [M-tBu+2H]+ .

[0632] Step B: 2-phenyl-6-azaspiro[3.4]octan-6-ium chloride . To a solution of tert-butyl 2-phenyl-6-azaspiro[3.4]decane-6-carboxylate (13 mg, 0.045 mmol) in MeOH (91 μL) was added a solution of HCl in 1,4-dioxane (4 M, 0.11 mL). It was heated to 45 °C for 1 hour and then concentrated under reduced pressure. The title compound was used in the next step without further purification. MS (ESI): C 13 H 17 The calculated mass value of N is 187.1; the measured m / z value is 188.1 [M+H] + .

[0633] Step C: (2s,4s)-2-(2-phenyl-6-azaspiro[3.4]octane-6-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one. 2-Phenyl-6-azaspiro[3.4]octane-6-ium chloride was taken up in DMF (0.45 mL) and to it was added (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 8 mg, 0.047 mmol), DIPEA (24 μL, 0.136 mmol) and HATU (19.5 mg, 0.050 mmol). It was stirred at room temperature for 16 hours. The reaction was filtered through a PTFE filter with MeOH and purified via reverse phase HPLC (5%-95% MeCN in 20 mM NH4OH) to give the title compound (11 mg, 75% yield). MS (ESI): C 20 H 24 The calculated mass value of N2O3 is 340.2; the measured m / z value is 341.2 [M+H] + . 1 H NMR(400MHz,Chloroform-d)δ7.31(td,J=7.6,3.7Hz,2H),7.19(dd,J=7.6,4.4Hz,3H),6.49–6.34(m,1H),4.41–4.29(m,2H), 3.70–3.26(m,5H),2.87(dp,J=31.6,8.2Hz,1H),2.76–2.57(m,2H),2.57–2.29(m,4H),2.28–2.10(m,2H),2.10–1.82(m,2H).

[0634] Example 65: (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0635]

[0636] Step A: tert-Butyl 6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylate. (3-tert-butyl)phenyl)boric acid (881 mg, 4.95 mmol), (1R, 2R)-2-aminocyclohexanol (57 mg, 0.495 mmol) and nickel (II) iodide (155 mg, 0.495 mmol) were dissolved in isopropanol (10 mL). The resulting mixture was stirred at 25 ° C for 30 minutes under N2 atmosphere, and then treated with NaHMDS (4.95 mL, 1M in THF, 4.95 mmol). The resulting mixture was stirred for 10 minutes under nitrogen atmosphere, followed by the addition of a solution of 6-iodo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (intermediate 50, 800 mg, 2.47 mmol) in isopropanol (5 mL). The resulting mixture was stirred at 70°C for 14 hours under a nitrogen atmosphere, then concentrated and purified by FCC (eluent: petroleum ether:ethyl acetate = 1:0 to 5:1) to give the title compound (800 mg, 67% yield) as a pale yellow oil. MS (ESI): C 21 H 31 The calculated mass value of NO2 is 329.2, and the measured m / z value is 274.2 [M-tBu+2H] + . 1 H NMR (400MHz, CDCl3) δ7.26-7.20(m,2H),7.19-7.12(m,1H),7.03-6.97(m,1H),4.06(s,2H),3. 85(s,2H),3.45-3.31(m,1H),2.61-2.54(m,2H),2.33-2.24(m,2H),1.44(s,9H),1.31(s,9H).

[0637] Step B: 6-(3-tert-Butyl)phenyl)-2-azaspiro[3.3]heptane. 6-(3-tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (300 mg, 0.628 mmol) was dissolved in a mixture of TFA (1 mL) and DCM (1 mL). The resulting mixture was stirred at room temperature for 2 hours and then concentrated to give the title compound (150 mg, crude product) as a yellow oil, which was used in the next step without further purification. MS (ESI): C 16 H 23 The calculated mass value of N is 229.2, and the measured m / z value is 230.2 [M+H] + .

[0638] Step C: (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa- 5-Azaspiro[3.4]octan-6-one.HATU (333 mg, 0.876 mmol) was added to a solution of (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (75 mg, 0.438 mmol), 6-(3-tert-butyl)phenyl)-2-azaspiro[3.3]heptane (150 mg, crude product) and DIPEA (283 mg, 2.19 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 12 h, then poured into H2O and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and purified by FCC (eluent: dichloromethane: methanol = 1: 0 to 10: 1), and then repurified by reverse phase HPLC using a Boston Prime C18, 150 mm × 30 mm × 5 μm column (eluent: 55%-85% (v / v) CH3CN and H2O, containing 0.04% NH3 and 10 mM NH4HCO3) to give the title compound as a white solid (89.3 mg, 53% yield). MS (ESI): C 23 H 30 The calculated mass value of N2O3 is 382.2; the measured m / z value is 383.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.40-7.30(m,3H),7.12-7.08(m,1H),6.65(br s,1H),4.44(d,J=6.0Hz,2H),4.32(s,1H),4.26(s,1H),4.10(s,1H),4.05(s ,1H),3.61-3.43(m,1H),2.86-2.67(m,5H),2.57-2.39(m,4H),1.42(s,9H).

[0639] Example 66: (2s, 4s)-2-(6-(m-tolyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one.

[0640]

[0641] The title compound was prepared in a manner similar to (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that m-tolylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 20 H 24 The calculated mass value of N2O3 is 340.2; the measured m / z value is 341.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.24-7.17(m,1H),7.05-6.94(m,3H),6.63(br d,J=7.6Hz,1H),4.35(d,J=5.6Hz,2H),4.24-4.13(m,2H),3.98(d,J=17.2Hz,2H),3.47-3.32(m,1H),2.77-2.53(m,5H),2.48-2.27(m,7H).

[0642] Example 67: (2s,4s)-2-(6-(3-isopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0643]

[0644] The title compound was prepared in a manner similar to (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that 3-isopropylphenylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 22 H 28 The calculated mass value of N2O3 is 368.2; the measured m / z value is 369.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.26-7.22(m,1H),7.09(d,J=7.6Hz,1H),7.02-6.98(m,2H),6.27(br s,1H),4.34(d,J=5.6Hz,2H),4.23-4.15(m,2H),3.98(d,J=18.8Hz,2H),3.50-3.34(m,1H) ,2.89(td,J=6.8,14.0Hz,1H),2.75-2.56(m,5H),2.50-2.29(m,4H),1.25(d,J=6.8Hz,6H).

[0645] Example 68: (2s,4s)-2-(6-(3,4-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0646]

[0647] The title compound was prepared in a manner similar to (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that 3,4-dimethylphenylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 21 H26 The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.07 (d, J = 7.6Hz, 1H), 6.95-6.88 (m, 2H), 6.35 (br s,1H),4.33(d,J=5.6Hz,2H),4.22-4.12(m,2H),4.00-3.91(m,2H),3.45-3.28(m,1H),2.76- 2.65(m,1H),2.62-2.52(m,4H),2.48-2.39(m,2H),2.35-2.27(m,2H),2.24(d,J=6.8Hz,6H).

[0648] Example 69: (2s, 4s)-2-(6-cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-aza Spiro[3.4]octan-6-one.

[0649]

[0650] Step A: tert-Butyl 6-cyclohexyl-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate . Cyclohexylmagnesium bromide (7.1mL, 1M in THF, 7.10mmol) is added dropwise to a cooling (-65°C, dry ice / acetone) solution of 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.0g, 4.73mmol) in THF (20mL). The resulting mixture is stirred for 4 hours, while gradually warming to room temperature, then quenched with a saturated NH4Cl aqueous solution, and extracted twice with ethyl acetate. The combined organic extracts are washed with brine, dried by anhydrous Na2SO4, and purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 3:1) to obtain the title compound (498mg, 36% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.96(s,2H),3.84(s,2H),2.31(br d,J=13.2Hz,2H),2.10(br d,J=12.8Hz,2H),1.80(br d,J=12.4Hz,2H),1.68(br d,J=12.4Hz,3H),1.43(s,9H),1.28-1.11(m,4H),1.06-0.93(m,2H).

[0651] Step B: tert-Butyl 6-cyclohexylidene-2-azaspiro[3.3]heptane-2-carboxylate. At 0 ° C, thionyl chloride (SOCl2) (245 μL, 3.37mmol) was added to a mixture of 6-cyclohexyl-6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (498mg, 1.69mmol) and DMAP (20.6mg, 0.169mmol) in pyridine (10mL). The resulting mixture was stirred for 2 hours, and gradually warmed to room temperature to obtain a yellow solution, followed by saturated NaHCO3 quenching, and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried by anhydrous Na2SO4, and purified by FCC (eluent: petroleum ether: ethyl acetate = 1: 0 to 10: 1) to obtain the title compound (341mg, 73% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ3.91(s,4H),2.76(s,4H),1.94-1.88(m,4H),1.52-1.44(m,6H),1.43(s,9H).

[0652] Step C: tert-Butyl 6-cyclohexyl-2-azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-cyclohexylidene-2-azaspiro[3.3]heptane-2-carboxylate (341 mg, 1.23 mmol) and wet Pd / C (200 mg, 10 wt%, 0.189 mmol) were combined in MeOH (10 mL). The suspension was stirred at room temperature under H2 (15 psi) for 2 h and then heated to room temperature by Filtered through a pad of Celite® and concentrated to give the title compound (320 mg, 93% yield) as a colorless oil. 1 H NMR(400MHz, CDCl3)δ3.90(s,2H),3.75(s,2H),2.22-2.08(m,2H),1.79-1.72 (m,3H),1.69-1.58(m,5H),1.42(s,9H),1.20-1.01(m,4H),0.77-0.64(m,2H).

[0653] Step D: 6-cyclohexyl-2-azaspiro[3.3]heptane 6-cyclohexyl-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (150 mg, 0.537 mmol) was dissolved in a mixture of TFA (2 mL) and dichloromethane (4 mL). The mixture was stirred at room temperature for 2 hours and then concentrated to give the title compound as a yellow oil (160 mg, as a crude TFA salt), which was used in the next step without further purification. 1H NMR(400MHz, CDCl3)δ8.28(br s,1H),4.16-4.10(m,2H),3.97(br s,2H),2.34-2.26(m,2H),1.90-1.77(m,3H),1.70-1.58(m,5H),1.19-0.99(m,4H),0.78-0.65(m,2H).

[0654] Step E: (2s,4s)-2-(6-cyclohexyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one HATU (222 mg, 0.584 mmol) was added to a solution of (2s, 4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (50 mg, 0.292 mmol), 6-cyclohexyl-2-azaspiro[3.3]heptane (160 mg, crude product) and DIPEA (189 mg, 1.46 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 3 hours, then poured into H2O and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by FCC (eluent: dichloromethane: methanol = 1:0 to 10:1) and then purified by preparative HPLC using a Welch Xtimate C18, 100 mm × 40 mm × 3 μm column (eluent: 50%-60% (v / v) CH3CN and H2O, containing 0.225% HCOOH) to give the title compound as a white solid (58.4 mg, 60% yield). MS (ESI): C 19 H 28 The calculated mass value of N2O3 is 332.2; the measured m / z value is 333.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ6.26(br s,1H),4.32(d,J=1.2Hz,2H),4.07-3.97(m,2H),3.91-3.82(m,2H),2.71-2.61(m,1H),2.59-2.52(m,2H),2.4 6-2.38(m,2H),2.24-2.14(m,2H),1.87-1.75(m,3H),1.73-1.63(m,5H),1.20-1.00(m,4H),0.79-0.64(m,2H).

[0655] Example 70: (2s,4s)-2-(6-(3,5-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0656]

[0657] The title compound was prepared in a manner similar to (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that 3,5-dimethylphenylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 21 H 26 The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ6.85(s,1H),6.77(s,2H),6.30(br s,1H),4.33(d,J=5.2Hz,2H),4.23-4.12(m,2H),4.00-3.91(m,2H),3.44-3.26(m ,1H),2.78-2.63(m,1H),2.62-2.51(m,4H),2.49-2.39(m,2H),2.37-2.24(m,8H).

[0658] Example 71: (2s,4s)-2-(6-(2,4-dimethylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0659]

[0660] The title compound was prepared in a manner similar to (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that 2,4-dimethylphenylboronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 21 H 26 The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ7.06-6.94(m,3H),6.26(br s,1H),4.33(d,J=5.6Hz,2H),4.26-4.14(m,2H),3.99-3.89(m,2H),3.55-3.40(m,1 H),2.77-2.55(m,5H),2.49-2.40(m,2H),2.34-2.25(m,5H),2.19(d,J=3.6Hz,3H).

[0661] Example 72: (2s, 4s)-2-(6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0662]

[0663] Step A: tert-Butyl 6-(3-cyclopropylphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate . n-BuLi (0.49mL, 2.5M in hexane, 1.23mmol) was added dropwise to a solution of 1-bromo-3-cyclopropylbenzene (224mg, 1.14mmol) in THF (5mL) at -78°C. The resulting mixture was stirred at -78°C for 0.5 hours and then treated with a solution of 6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (200mg, 0.947mmol) in THF (5mL). The mixture was stirred for another 2 hours, after which it was poured into a saturated NH4Cl aqueous solution and extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated, and purified by FCC (eluent: petroleum ether: ethyl acetate = 1:0 to 3:1) to give the title compound (230mg, 71% yield) as a yellow solid. MS (ESI): C 20 H 27 The calculated mass value of NO3 is 329.2, and the measured m / z value is 659.4 [2M+H] + . 1 H NMR (400MHz, CDCl3) δ7.26-7.24(m,1H),7.20-7.12(m,2H),6.98(d,J=8.0Hz,1H),4.08(s,2H),3.82(s,2H),2.80-2. 73(m,2H),2.58-2.52(m,2H),2.05(s,1H),1.44(s,9H),1.27(t,J=7.2Hz,1H),1.03-0.95(m,2H),0.74-0.68(m,2H).

[0664] Step B: 6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane . 6-(3-cyclopropylphenyl)-6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (230 mg, 0.674 mmol) was dissolved in TFA (1 mL). The resulting mixture was stirred for 20 minutes and then treated with triethylsilane (235 mg, 2.02 mmol). The mixture was stirred for another 2 hours and then concentrated to give the title compound (220 mg, crude product) as a colorless oil, which was used in the next step without further purification. MS (ESI): C 15 H 19 The calculated mass value of N is 213.2, and the measured m / z value is 214.1 [M+H] + .

[0665] Step C: (2s,4s)-2-(6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-oneHATU (222 mg, 0.584 mmol) was added to a solution of (2s, 4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 50 mg, 0.292 mmol), 6-(3-cyclopropylphenyl)-2-azaspiro[3.3]heptane (220 mg, 0.672 mmol) and DIPEA (0.24 mL, 1.46 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 16 hours, after which it was poured into a saturated NH4Cl aqueous solution and extracted three times with ethyl acetate. The combined organic extracts were washed three times with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by FCC (eluent: dichloromethane: methanol = 1: 0 to 97: 3), followed by preparative HPLC using a Phenomenex Gemini-NX, 80 mm × 30 mm × 3 μm column (eluent: 41%-51% (v / v) CH3CN and H2O, containing 10 mM NH4HCO3) to give the title compound as a white solid (37.9 mg, 35% yield). MS (ESI): C 22 H 26 The calculated mass value of N2O3 is 366.2; the measured m / z value is 367.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.23-7.18(m,1H),6.96(d,J=7.6Hz,1H),6.92-6.87(m,2H),6.19(br s,1H),4.34(d,J=5.2Hz,2H),4.23-4.13(m,2H),3.97(d,J=19.2Hz,2H),3.48-3.32(m,1H),2.78-2.66(m,1H),2 .65-2.54(m,4H),2.51-2.41(m,2H),2.39-2.26(m,2H),1.92-1.84(m,1H),0.99-0.93(m,2H),0.72-0.66(m,2H).

[0666] Example 73: (2s, 4s)-2-(6-(3-cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxo Hetero-5-azaspiro[3.4]octan-6-one.

[0667]

[0668] The title compound was prepared in a manner similar to (2s,4s)-2-(6-(3-(cyclobutylphenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 72), except that 1-bromo-3-cyclobutylbenzene (Intermediate 51) was used instead of 1-bromo-3-cyclopropylbenzene. MS (ESI): C 23 H 28 The calculated mass value of N2O3 is 380.2; the measured m / z value is 381.1 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.26-7.22(m,1H),7.07(d,J=8.0Hz,1H),7.00-6.96(m,2H),6.34(br s,1H),4.34(s,1H),4.32(s,1H),4.21(s,1H),4.15(s,1H),3.99(s,1H),3.94(s,1H),3.52(quin,J=8.8Hz,1H),3.47-3.32(m,1H),2 .77-2.65(m,1H),2.64-2.55(m,4H),2.48-2.40(m,2H),2.39-2.28(m,4H),2.19-2.08(m,2H),2.08-1.97(m,1H),1.89-1.79(m,1H).

[0669] Example 74: (2s,4s)-2-(6-(2,3-dihydro-1H-inden-5-yl)-2-azaspiro[3.3]heptane-2-carbonyl 1-(4-(2-(4-(2-(4-nitrophenyl)-7-oxa-5-azaspiro[3.4]octan-6-one).

[0670]

[0671] The title compound was prepared in a manner similar to (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 65), except that (2,3-dihydro-1H-inden-5-yl)boronic acid was used instead of 3-(tert-butyl)phenylboronic acid. MS (ESI): C 22 H 26 The calculated mass value of N2O3 is 366.2; the measured m / z value is 367.1 [M+H] + . 1H NMR (400MHz, CDCl3) δ7.16(d,J=7.6Hz,1H),7.04(brs,1H),6.93(d,J=7.6Hz,1H),6.22(br s,1H),4.33(d,J=4.8Hz,2H),4.24-4.11(m,2H),4.01-3.91(m,2H),3.47-3.31(m,1H),2.92-2.83(m ,4H),2.77-2.65(m,1H),2.63-2.53(m,4H),2.49-2.40(m,2H),2.37-2.25(m,2H),2.11-2.02(m,2H).

[0672] Example 75: (2s, 4s)-2-(6-phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0673]

[0674] Triethylamine (110 μL, 794 μmol) was added dropwise to a stirred mixture of 6-phenyl-2-azaspiro[3.3]heptane (Intermediate 49, 25.0 mg, 87.0 μmol), (2s,4s)-6-oxo-7-oxa-5-azaspiro[3.4]octane-2-carboxylic acid (Intermediate 3, 14.9 mg, 87.0 μmol) and HATU (41.0 mg, 95.7 μmol) in N,N-dimethylacetamide (870 μL) solution at 0°C. The reaction mixture was stirred at room temperature for 14 hours and then diluted with water (1 mL). The title product (23.4 mg, 71.7 μmol, 82% yield) was obtained by purification by reverse phase HPLC (MeCN / H2O, 0.05% TFA). MS (ESI): C 19 H 22 The calculated mass value of N2O3 is 326.2; the measured m / z value is 327.2 [M+H] + . 1 H NMR (500MHz, Methanol-d4) δ7.34-7.25(m,2H),7.24-7.13(m,3H),4.48(d,J=10.6Hz,2H),4.32(s,1 H),4.13(s,1H),4.09(s,1H),3.90(s,1H),3.50-3.39(m,1H),2.91-2.78(m,1H),2.66-2.29(m,8H).

[0675] Example 76: (2s, 4s)-2-(7-phenyl-2-azaspiro[3.5]nonane-2-carbonyl)-7-oxa-5-azaspiro [3.4] Octane-6-one.

[0676]

[0677] The title compound was prepared in a manner similar to (2s,4s)-2-(6-phenyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one (Example 75), except that 7-phenyl-2-azaspiro[3.5]heptane (Intermediate 52) was used instead of 6-phenyl-2-azaspiro[3.3]heptane (Intermediate 49). MS (ESI): C 21 H 26 The calculated mass value of N2O3 is 354.2; the measured m / z value is 355.2 [M+H] + . 1 H NMR(500MHz,Methanol-d4)δ7.32-7.12(m,5H),4.49(d,J=5.38Hz,2H),3.96(s,1H),3.83(s,1H),3.77(s,1H),3.64 (s,1H),2.95-2.82(m,1H),2.59-2.39(m,5H),2.07-1.98(m,2H),1.88-1.79(m,2H),1.68(m,2H),1.58-1.44(m,2H).

[0678] Example 77: (2s, 4s)-2-(6-cyclopentyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-aza Spiro[3.4]octan-6-one .

[0679]

[0680] The title compound was prepared in a manner similar to Example 69 using cyclopentylmagnesium bromide instead of cyclohexylmagnesium bromide in step A. MS (ESI): C 18 H 26 The calculated mass value of N2O3 is 318.2; the measured m / z value is 319.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ6.21(br s,1H),4.32(d,J=1.2Hz,2H),4.06(s,1H),4.00(s,1H),3.94(s,1H),3.88(s,1H),2.74-2.64(m,1H),2.59-2.52(m,2 H),2.47-2.39(m,2H),2.28-2.18(m,2H),2.05-1.91(m,1H),1.89-1.63(m,5H),1.58-1.48(m,4H),1.10-0.99(m,2H).

[0681] Example 78: (2s, 4s)-2-(6-cyclobutyl-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-aza Spiro[3.4]octan-6-one .

[0682]

[0683] The title compound was prepared in a manner similar to Example 69 using cyclobutylmagnesium bromide instead of cyclohexylmagnesium bromide in step A. MS (ESI): C 17 H 24 The calculated mass value of N2O3 is 304.2; the measured m / z value is 305.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ6.21(br s,1H),4.32(d,J=1.2Hz,2H),4.08-3.84(m,4H),2.74-2.63(m,1H),2.59-2.52(m,2H),2.4 8-2.39(m,2H),2.32-2.12(m,4H),2.01-1.90(m,2H),1.88-1.74(m,4H),1.59-1.49(m,2H).

[0684] Example 79: (2s,4s)-2-(6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxo 5-azaspiro[3.4]octan-6-one .

[0685]

[0686] Step A: tert-Butyl 6-hydroxy-6-(prop-1-en-2-yl)-2-azaspiro[3.3]heptane-2-carboxylate . Prop-1-en-2-ylmagnesium bromide (0.5M in THF, 7.1mL, 3.55mmol) was added dropwise to a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (500mg, 2.37mmol) in THF (20mL) at -78°C. The resulting mixture was stirred for 2 hours, then quenched with saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by FCC (0%-30% EtOAc in ether) to give the title compound (270mg, 45% yield) as a white solid. MS (ESI): C 14 H 23 The calculated mass value of NO3 is 253.2; the measured m / z value is 197.9 [M+2H-tBu] + .

[0687] Step B: tert-Butyl 6-hydroxy-6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate. A solution of TFA (0.41mL, 5.33mmol) in DCM (2.0mL) was added dropwise to a solution of diethylzinc (1M in hexane, 5.3mL, 5.33mmol) in DCM (2.0mL) at 0°C. The resulting mixture was stirred for 20 minutes, then treated with a solution of diiodomethane (0.43mL, 5.33mmol) in DCM (2.0mL) and stirred for another 20 minutes. Finally, a solution of 6-hydroxy-6-(prop-1-ene-2-yl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (270mg, 1.07mmol) in DCM (4.0mL) was added to the reaction mixture, and the reaction mixture was stirred for 30 minutes. The reaction mixture was quenched with saturated NH4Cl aqueous solution, and extracted with EtOAc. The combined organic extracts were washed with saturated NaHCO3 aqueous solution and brine, and dried by Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by FCC (0%-40% EtOAc in ether) to afford the title compound (220 mg, 34% yield) as a white solid. MS (ESI): C 15 H 25 The calculated mass value of NO3 is 267.2; the measured m / z value is 212.0 [M+2H-tBu] + .

[0688] Step C: tert-Butyl 6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-5-ene-2-carboxylate . To a solution of 6-hydroxy-6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (220 mg, 0.823 mmol) in toluene (3.0 mL) was added Burgess reagent (methyl N-(triethylsulfonyl)carbamate) (294 mg, 1.23 mmol), and the reaction mixture was heated to 120 ° C and stirred for 16 hours. The reaction mixture was cooled to room temperature, then poured into a saturated NaHCO3 aqueous solution, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue (FCC, SiO2, 0%-10% EtOAc in ether) was purified to give the title compound (70 mg, 34% yield) as a colorless oil.

[0689] Step D: tert-Butyl 6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylate A solution of tert-butyl 6-(1-methylcyclopropyl)-2-azaspiro[3.3]hept-5-ene-2-carboxylate (850 mg, 3.41 mmol) and wet Pd / C (80 mg, 10 wt%) in EtOAc (20 mL) was stirred at room temperature under H2 (15 psi) for 2 h. The reaction mixture was stirred for 2 h at room temperature. The pad was filtered through Celite® and the pad was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by RP-HPLC (30%-90% ACN in H2O with 0.05% NH3) to give the title product as a colorless oil (102 mg, 12% yield).

[0690] Step E: 6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane . TFA (1.5mL, 19.7mmol) was added dropwise to a solution of 6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (102mg, 0.406mmol) in DCM (5.0mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (100mg) as a brown oil, which was used in the next step without further purification.

[0691] Step F: (2s,4s)-2-(6-(1-methylcyclopropyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5- Azaspiro[3.4]octan-6-one . HATU (215 mg, 0.566 mmol) was added to a solution of (2s, 4s)-6-oxo-7-oxa-5-azaspiro [3.4] octane-2-carboxylic acid (Intermediate 3, 64.5 mg, 0.377 mmol), 6-(1-methylcyclopropyl)-2-azaspiro [3.3] heptane (100 mg, 0.377 mmol) and DIPEA (0.31 mL, 1.89 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into a saturated NH4Cl aqueous solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by RP-HPLC (31%-61% ACN in H2O solution, containing 10 mM NH4HCO3) to give the title compound (110 mg, 96% yield). MS(ESI):C 17 H 24 The calculated mass value of N2O3 is 304.2; the measured m / z value is 305.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ6.12(br s,1H),4.32(s,2H),4.08-3.99(m,2H),3.93-3.83(m,2H),2.73-2.65(m,1H),2.58-2.51(m,2H),2.49-2.40(m,2H) ,2.27-2.15(m,1H),2.08(q,J=10.0Hz,2H),1.81-1.68(m,2H),0.98(s,3H),0.29-0.23(m,2H),0.21-0.15(m,2H).

[0692] Biological data

[0693] The assay used to measure the in vitro activity of MGL was adapted from an assay for another serine hydrolase (FAAH) described in Wilson et al., 2003 ("A high-throughput-compatible assay for determining the activity of fatty acid amide hydrolase". Wilson SJ, Lovenberg TW, Barbier AJ., Anal Biochem., 2003 Jul 15; 318(2): 270-5.). The assay involves combining endogenously expressed MGL from HeLa cells with the test compound, adding [glycerol-1,3- 3 H]-oleoylglycerol, incubated for one hour, and then the cleavage of [1,3- 3 The amount of cleaved tritiated glycerol that passes through the carbon filter is proportional to the activity of the MGL enzyme in the specific well / assay conditions.

[0694] The standard conditions for this assay are 300 nM [glycerol-1,3- 3 H]-oleoylglycerol was combined with human MGL from HeLa cells and the test compound for one hour, and then the reaction was filtered through activated charcoal and tritium in the flow-through was measured. The test compound concentration in the screening mode was 10 μM, and the IC 50 The highest compound concentration in the assay was determined empirically. MGL is the major hydrolase in HeLa cells / cell homogenates.

[0695] Table 3.

[0696]

[0697]

[0698]

[0699]

[0700]

[0701] NT means not tested.

Claims

1. A compound of formula (I): in X is CH2 or O; R 1 is H; R 2a and R 2b Each independently selected from H and C 1-4 alkyl; R 3 Selected from: (i) phenyl or a monocyclic heteroaryl group having 5 or 6 ring atoms, each of which is optionally substituted by one, two or three substituents selected from the group consisting of halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, SC 1-6 Alkyl, SF5, Si(CH3)3, NR a R b , C 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, phenyl, O-phenyl and O-pyridyl, wherein each cycloalkyl, phenyl or pyridyl is optionally substituted by one or two C 1-4 Alkyl, C 1-4 or two adjacent ring substituents on the phenyl or monocyclic heteroaryl having 5 or 6 ring atoms are taken together with the atoms to which they are attached to form a fused monocyclic C 5-6 Cycloalkyl or heterocycloalkyl rings, each optionally substituted by one or two C 1-4 Alkyl, C 1-4 Substitution with haloalkyl or halo groups; Where R a and R b Each independently is H or C 1-4 Alkyl; and (ii) optionally C 1-4 Alkyl, C 1-4 Haloalkyl or halogen substituted C 3-6 cycloalkyl; and n, m, o and p are each independently 1 or 2; or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound according to claim 1, wherein R 3 Selected from: C 3-6 Cycloalkyl; C 1-4 Alkyl substituted C 3-6 Cycloalkyl; phenyl; phenyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 haloalkyl, and C optionally substituted by CH3 or CF3 3-6 Cycloalkyl; pyridyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl and C 1-6 Haloalkyl; C 1-6 Alkyl substituted pyrimidinyl; 3. The compound according to claim 1, wherein X is CH2. The compound according to claim 1 , wherein X is O.

5. The compound according to claim 1, wherein (a) R 2a and R 2b each is H; or (b) R 2a and R 2b each is CH3; or (c) R 2a H and R 2b For CH3.

6. The compound according to claim 1, wherein R 3 for (a) cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (b) (c)R 3 is phenyl, or phenyl substituted by one or two members each independently selected from the group consisting of Cl, F, CH3, CH(CH3)2, C(CH3)3, CF3, OCH3, OCH2CH3, OCF3, cyclopropyl, cyclopropyl substituted by CF3, and cyclobutyl; (d) (e) (f) or (g) 4-trifluoromethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2,4-dimethylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl or 3-cyclopropylphenyl.

7. The compound according to claim 1, wherein: (a) n and o are each 1; (b) n and o are each 2; (c) n is 1 and o is 2; (d) m and p are each 1; (e) m and p are each 2; (f) m is 1 and p is 2; (g) m, n, o and p are each 1; (h) m, n and p are each 1 and o is 2; (i) m, n and o are each 1 and p is 2; (j) n and o are each 2 and m and p are each 1; (k) n and o are each 1 and m and p are each 2; or (l) n, o and p are each 2 and m is 1.

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

9. The compound according to claim 8, wherein the compound is selected from: (2r,4s)-2-(2-(6-(tert-butyl)pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carbonyl)-5-azaspiro[3.4]octan-6-one; (2s,4s)-2-((R*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; (2s,4R*)-2-((S*)-6-(4-(trifluoromethyl)phenyl)-2-azaspiro[3.4]octane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and (2s,4s)-2-(6-(3-(tert-butyl)phenyl)-2-azaspiro[3.3]heptane-2-carbonyl)-7-oxa-5-azaspiro[3.4]octan-6-one; and pharmaceutically acceptable salts and stereoisomers.

10. The compound according to claim 1, which has the structure of formula (IA): in X is CH2 or O; R 2a and R 2b Each independently selected from H and CH3; R 3 Selected from: C 3-6 Cycloalkyl; C 1-4 Alkyl substituted C 3-6 Cycloalkyl; phenyl; phenyl substituted by one or two members each independently selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl; and and m and p are each independently 1 or 2; or a pharmaceutically acceptable salt or stereoisomer thereof.

11. The compound according to claim 1, which has the structure of formula (IB): in X is O; R 3 Selected from: phenyl and C 1-6 an alkyl-substituted phenyl group; and m and p are each 1; or a pharmaceutically acceptable salt or stereoisomer thereof.

12. The compound according to claim 1, which has the structure of formula (IC): in X is CH2 or O; R 2a and R 2b Each independently selected from H and CH3; R 3 Selected from: C 3-6 Cycloalkyl; phenyl; phenyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl and C 3-6 Cycloalkyl; pyridyl substituted by one or two members independently selected from the following: halo, C 1-6 Alkyl and C 1-6 Haloalkyl; C 1-6 Alkyl substituted pyrimidinyl; and m and p are each independently 1 or 2; or a pharmaceutically acceptable salt or stereoisomer thereof.

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

14. A pharmaceutical composition, comprising: (A) a therapeutically effective amount of at least one compound according to claim 8 or a pharmaceutically acceptable salt or stereoisomer thereof; and (B) at least one pharmaceutically acceptable excipient.

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

16. The use according to claim 15, wherein the MGL receptor mediated disease, disorder or condition is selected from the group consisting of pain, psychiatric disorders, neurological disorders, cancer and eye disorders.

17. The use according to claim 15, wherein the MGL receptor-mediated disease, disorder or condition is selected from the group consisting of major depressive disorder, refractory depression, anxious depression, autism spectrum disorder, Asperger's syndrome and bipolar disorder.

18. The use according to claim 15, wherein the MGL receptor-mediated disease, disorder or condition is inflammatory pain.

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