Heterocyclic compounds useful as MAGL inhibitors

Abstract

The present invention relates to a compound of general formula (I): TIFF2023538757000059.tif35169 wherein X, Y, Z, A, L, B, and R 1 ~R 3 as described herein), compositions comprising the compounds, processes for making the compounds, and methods for using the compounds are provided.

Description

[Technical Field]

[0001] The present invention relates to organic compounds useful for the treatment or prevention in mammals, in particular to monoacylglycerol lipase (MAGL) inhibitors for the treatment or prevention in mammals of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, inflammatory bowel disease, abdominal pain, abdominal pain and / or visceral pain associated with irritable bowel syndrome. [Background technology]

[0002] Endocannabinoids (ECs) are signaling lipids that exert their biological effects by interacting with cannabinoid receptors (CBRs), CB1 and CB2. They regulate multiple physiological processes, including neuroinflammation, neurodegeneration, and tissue regeneration (Iannotti, FA et al., Prog. in Lipid Res. 2016, 62, 107). In the brain, the main endocannabinoid, 2-arachidonoylglycerol (2-AG), is produced by diacylglycerol lipase (DAGL) and hydrolyzed by monoacylglycerol lipase, MAGL. MAGL hydrolyzes 85% of 2-AG; the remaining 15% is hydrolyzed by ABHD6 and ABDH12 (Nomura, DK et al., Science 2011, 334, 809). MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes, and microglial cells (Chanda, PK et al., Mol. Pharmacol. 2010, 78, 996; Viader, A. et al., Cell. Rep. 2015, 12, 798). Hydrolysis of 2-AG leads to the formation of arachidonic acid (AA), a precursor of prostaglandins (PGs) and leukotrienes (LTs). AA oxidative metabolism is increased in inflamed tissues. Two major enzymatic pathways for arachidonic acid oxidation involved in the inflammatory process include cyclooxygenase, which produces PGs, and 5-lipoxygenase, which produces LTs. Among the various cyclooxygenase products formed during inflammation, PGE2 is one of the most important. These products have been detected at sites of inflammation, for example, in the cerebrospinal fluid of patients with neurodegenerative disorders, and are thought to contribute to the inflammatory response and disease progression. Mice lacking MAGL (Mgll- / -) have dramatically reduced 2-AG hydrolase activity and elevated 2-AG levels in the nervous system, whereas other arachidonoyl-containing phospholipids and neutral lipid species, including anandamide (AEA) and other free fatty acids, are unchanged. Conversely, levels of AA and AA-derived prostaglandins, as well as other eicosanoids, including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2), and thromboxane B2 (TXB2), are strongly reduced.Although phospholipase A2 (PLA2) enzyme has been considered the major source of AA, cPLA2-deficient mice have unaltered AA levels in their brains, reinforcing the important role of MAGL in the brain for regulating AA production and brain inflammatory processes.

[0003] Neuroinflammation is a common pathological feature of brain diseases, including, but not limited to, neurodegenerative diseases (e.g., multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, and psychiatric disorders such as anxiety and migraine). In the brain, the production of eicosanoids and prostaglandins regulates the neuroinflammatory process. The inflammatory progenitor lipopolysaccharide (LPS) produces a robust, time-dependent increase in brain eicosanoids that is significantly blunted in Mgll- / - mice. LPS treatment also induces a widespread increase in inflammatory cytokines, including interleukin-1-a (IL-1-a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a), which is prevented in Mgll- / - mice.

[0004] Neuroinflammation is characterized by the activation of innate immune cells in the central nervous system, microglia, and astrocytes. Anti-inflammatory drugs have been reported to suppress glial cell activation and the progression of diseases, including Alzheimer's disease and multiple sclerosis, in preclinical models (Lleo, A., Cell. Mol. Life Sci. 2007, 64, 1403). Importantly, genetic and / or pharmacological disruption of MAGL activity also inhibits LPS-induced activation of microglial cells in the brain (Nomura, DK et al., Science 2011, 334, 809).

[0005] Furthermore, genetic and / or pharmacological disruption of MAGL activity has been shown to be protective in several animal models of neurodegeneration, including, but not limited to, Alzheimer's disease, Parkinson's disease, and multiple sclerosis. For example, irreversible MAGL inhibitors have been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, JZ et al., Nat. Chem. Biol. 2009, 5, 37). Systemic injection of such inhibitors recapitulates the Mgll- / - mouse phenotype in the brain, including increased 2-AG levels, decreased AA levels and related eicosanoid production, and suppression of cytokine production and microglial activation after LPS-induced neuroinflammation (Nomura, DK et al., Science 2011, 334, 809), both of which identify MAGL as a druggable target.

[0006] Genetic and / or pharmacological disruption of MAGL activity increases the endogenous levels of 2-AG, a natural MAGL substrate, in the brain. 2-AG has been reported to have beneficial effects on pain, for example, antinociception in mice (Ignatowska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015, 353, 424) and psychiatric disorders such as depression in chronic stress models (Zhong P. et al., Neuropsychopharmacology 2014, 39, 1763).

[0007] Furthermore, oligodendrocytes (OLs) and their precursor cells (OPCs), which are myelinating cells in the central nervous system, express cannabinoid receptor 2 (CB2) on their membranes. 2-AG is an endogenous ligand for both CB1 and CB2 receptors. It has been reported that both cannabinoids and pharmacological inhibition of MAGL attenuate the vulnerability of OLs and OPCs to excitotoxic injury and may therefore be neuroprotective (Bernal-Chico, A. et al., Glia 2015, 63, 163). Additionally, pharmacological inhibition of MAGL increases the number of myelinating OLs in the mouse brain, suggesting that MAGL inhibition may promote OPC differentiation into myelinating OLs in vivo (Alpar, A. et al., Nat. Commun. 2014, 5, 4421). Inhibition of MAGL has also been shown to promote remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu, A. et al., J. Neurosci. 2017, 37, 8385).

[0008] Furthermore, in recent years, metabolism, especially lipid metabolism, has become increasingly important in cancer research. Researchers believe that de novo fatty acid synthesis plays an important role in tumor development. Many studies have shown that endocannabinoids have anti-tumorigenic effects, including antiproliferative, apoptosis-inducing, and anti-metastatic effects. MAGL, as a key degradative enzyme for both lipid metabolism and the endocannabinoid system, further contributes to various aspects of tumorigenesis, including glioblastoma, as part of gene expression profiles (Qin, H. et al., Cell Biochem. Biophys. 2014, 70, 33; Nomura, DK et al., Cell 2009, 140, 49; Nomura, DK et al., Chem. Biol. 2011, 18, 846; Jinlong, Y. et al., Nat. Commun. 2020, 11, 2978).

[0009] The endocannabinoid system is also involved in many gastrointestinal physiological and physiopathological functions (Marquez, L. et al., PLoS One 2009, 4, e6893). All of these effects are primarily driven through cannabinoid receptors (CB1 and CB2). CB1 receptors are present throughout the gastrointestinal tract in animals and healthy humans, particularly in the enteric nervous system (ENS) and epithelial lining, as well as in smooth muscle cells of blood vessels in the colon wall (Wright, K. et al., Gastroenterology 2005, 129, 437; Duncan, M. et al., Aliment. Pharmacol. Ther. 2005, 22, 667). CB1 activation provides antiemetic, antimotility, and anti-inflammatory effects and helps regulate pain (Perisetti, A. et al., Ann. Gastroenterol. 2020, 33, 134). CB2 receptors are expressed in immune cells such as plasma cells and macrophages, the lamina propria of the GI tract (Wright, K. et al., Gastroenterology 2005, 129, 437), and the epithelium of human colonic tissue, primarily associated with inflammatory bowel disease (IBD). CB2 activation exerts an anti-inflammatory effect by reducing pro-inflammatory cytokines. MAGL expression is increased in colonic tissue from UC patients (Marquez, L. et al., PLoS One 2009, 4, e6893), and 2-AG levels are increased in the plasma of IBD patients (Grill, M. et al., Sci. Rep. 2019, 9, 2358). Several animal studies have demonstrated the potential of MAGL inhibitors for the symptomatic treatment of IBD. MAGL inhibition prevents TNBS-induced murine colitis and reduces local and circulating inflammatory markers via CB1 / CB2 MoA (Marquez, L. et al., PLoS One 2009, 4, e6893). Furthermore, MAGL inhibition improves intestinal wall integrity and intestinal permeability via CB1-driven MoA (Wang, J. et al., Biochem. Biophys. Res. Commun. 2020, 525, 962).

[0010] In conclusion, inhibiting the action and / or activation of MAGL is a promising new therapeutic strategy for treating or preventing neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, inflammatory bowel disease, abdominal pain, and abdominal pain associated with irritable bowel syndrome. Furthermore, inhibiting the action and / or activation of MAGL is a promising new therapeutic strategy for providing neuroprotection and myelin regeneration. 。 Summary of the Invention

[0011] In a first aspect, the present invention provides a compound of formula (I): [ka] (Wherein X, Y, Z, A, L, B and R 1 ~R 3 are as described herein) or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, the present invention provides a process for making a compound of formula (IA) or (IB) described herein, comprising: (a) an amine of formula 2: [ka] wherein X, Y, and Z are as described herein. to the carboxylic acid 3a: [ka] (Wherein L, A, B, and R 1 ~R 3 are as described herein) in the presence of a coupling reagent such as CDI, DCC, HATU, HBTU, HOBT, TBTU, T3P or Mukaiyama reagent, and optionally in the presence of a base such as TEA, DIPEA (Huenig base) or DMAP, to give a compound of formula (IB): [ka] (Wherein X, Y, Z, L, A, B and R 1 ~R 3 is as defined herein) or forming a compound of (b) an amine of formula 2: [ka] wherein X, Y, and Z are as described herein. to the carboxylic acid chloride 3b: [ka] (Wherein L, A, B, and R 1 ~R 3 are as described herein) in the presence of a base such as TEA, Huenig's base, pyridine, DMAP, or lithium bis(trimethylsilyl)amide to form a compound of formula (IB), 1 ~R 3 is as defined herein; or (c) a first amine of Formula 1: [ka] (Wherein A, B, L, and R 1 and R 3 are as described herein) to the second amine 2: [ka] wherein X, Y, and Z are as described herein. in the presence of a base such as sodium bicarbonate and a urea-forming reagent such as bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, or 1,1′-carbonyldiimidazole to produce a compound of formula (IA): [ka] (Wherein X, Y, Z, L, A, B and R 1 ~R 3 is as defined herein) To form a compound of The present invention provides a process including:

[0013] In a further aspect, the present invention provides a compound of formula (I) as described herein when prepared according to the process described herein.

[0014] In a further aspect, the present invention provides a compound of formula (I) as described herein for use as a therapeutically active substance.

[0015] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

[0016] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutical composition as described herein, for inhibiting monoacylglycerol lipase (MAGL) in a mammal.

[0017] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a mammal.

[0018] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, pain-associated spasticity, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain in a mammal. DETAILED DESCRIPTION OF THE INVENTION

[0019] definition It should be understood that any feature, integer, property, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where incompatible. All features disclosed in this specification (including any accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiment. The invention extends to any novel one or any novel combination of features disclosed in this specification (including any accompanying claims, abstract, and drawings), or any novel one or any novel combination of steps of any method or process so disclosed.

[0020] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched saturated hydrocarbon group having 1 to 12 carbon atoms. In some preferred embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6In other embodiments, alkyl groups include 1 to 3 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, alkyl groups include 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, but non-limiting example of alkyl is methyl.

[0021] The term "alkoxy" refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. An alkoxy group contains 1 to 12 carbon atoms, unless otherwise specified. In some preferred embodiments, an alkoxy group contains 1 to 6 carbon atoms ("C 1-6 In other embodiments, alkoxy groups contain 1 to 4 carbon atoms. In yet other embodiments, alkoxy groups contain 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred, but non-limiting example of alkoxy is methoxy.

[0022] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred, but non-limiting, examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0023] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms ("C3-C 10"Cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to cycloalkyl moieties (i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms) and spirocyclic moieties (i.e., the two rings are connected through one common ring atom) that consist of two saturated carbocyclic rings that share two carbon atoms. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. A particularly preferred example of cycloalkyl is cyclopropyl.

[0024] The terms "heterocyclyl" and "heterocycloalkyl" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic, ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of the ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to heterocyclic moieties consisting of two rings that share two ring atoms (i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms) and spirocyclic moieties (i.e., the two rings are connected through one common ring atom). Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6-oxo-3-piperidyl, morpholino, morpholin-2-yl, morpholin-3-yl, and 2-azaspiro[3.3]heptan-2-yl. Some preferred, but non-limiting examples of heterocyclyl groups include azetidinyl and 2-azaspiro[3.3]heptan-2-yl.

[0025] The term "aryl" refers to a group consisting of 6 to 14 ring members ("C6-C 14 -aryl"), preferably a monocyclic, bicyclic, or tricyclic carbocyclic ring system having 6 to 12 ring members, more preferably 6 to 10 ring members, wherein at least one ring of the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g., 9H-fluoren-9-yl). A particularly preferred, but non-limiting example of aryl is phenyl.

[0026] The term "heteroaryl" refers to a polyvalent monocyclic or bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring of the system is aromatic and at least one ring of the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O, S, and N. Some preferred, but non-limiting examples of heteroaryl include thiazolyl (e.g., thiazol-2-yl); oxazolyl (e.g., oxazol-2-yl); 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl; 1,2,4-oxadiazol-5-yl; pyridyl (e.g., 2-pyridyl); pyrazolyl (e.g., pyrazol-1-yl); imidazolyl (e.g., imidazol-1-yl); benzoxazolyl (e.g., benzoxazol-2-yl), and oxazolo[5,4-c]pyridin-2-yl.

[0027] A heterocyclic or heteroaromatic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted.

[0028] The term "cyano" refers to a -CN (nitrile) group.

[0029] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by halogen atoms, most preferably fluoro. Particularly preferred, but non-limiting, examples of haloalkyl are trifluoromethyl (CF) and trifluoroethyl (e.g., 2,2,2-trifluoroethyl).

[0030] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably fluoro. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two, or three hydrogen atoms of the alkoxy group are replaced by halogen atoms, most preferably fluoro. A particularly preferred, but non-limiting example of a haloalkoxy is trifluoromethoxy (-OCF).

[0031] The term "aryloxy" refers to an aryl group, as defined above, attached to the parent molecular moiety through an oxygen atom. A preferred, but non-limiting example of aryloxy is phenoxy.

[0032] The term "cycloalkyloxy" refers to a cycloalkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. A preferred, but non-limiting example of cycloalkyloxy is cyclopropoxy.

[0033] The term "heteroaryloxy" refers to a heteroaryl group, as defined above, attached to the parent molecular moiety through an oxygen atom. A preferred, but non-limiting example of heteroaryloxy is pyridyloxy (e.g., 2-pyridyloxy, 3-pyridyloxy, or 4-pyridyloxy).

[0034] The term "heterocyclyloxy" refers to a heterocyclyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. A preferred, but non-limiting example of heterocyclyloxy is azetidinyloxy.

[0035] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base or free acid, without being biologically or otherwise undesirable. Salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid (especially hydrochloric acid), and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. Additionally, these salts can be prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc. A particular pharmaceutically acceptable salt of the compound of formula (I) is the hydrochloride salt.

[0036] The term "protecting group" (PG) refers to a group that selectively blocks a reactive site in a polyfunctional compound so that a chemical reaction, in the sense conventionally associated with synthetic chemistry, can be selectively carried out at an otherwise unprotected reactive site. The protecting group can be removed at an appropriate time. Exemplary protecting groups are amino-protecting, carboxy-protecting, or hydroxy-protecting groups. Specific protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), and benzyl (Bn). Further specific protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). An even more specific protecting group is tert-butoxycarbonyl (Boc). Exemplary protecting groups and their uses in organic synthesis are described, for example, in T.W. Greene and P.G.M. Butts, 5th This is described in "Protective Groups in Organic Chemistry" by John Wiley & Sons, Ed., 2014, New York.

[0037] The term "urea-forming reagent" refers to a compound that can react a first amine with a second amine to form a urea derivative. Non-limiting examples of urea-forming reagents include bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, and 1,1'-carbonyldiimidazole. The urea-forming reagents described in Sartori, G. et al., Green Chem. 2000, 2, 140 are incorporated herein by reference.

[0038] The compounds of formula (I) may contain several asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers, e.g. racemates, optically pure diastereoisomers, mixtures of diastereoisomers, racemates of diastereoisomers or racemic mixtures of diastereoisomers. In a preferred embodiment, the compounds of formula (I) according to the invention are cis-enantiomers of formula (Ia) or (Ib), respectively, as described herein.

[0039] According to the Cahn-Ingold-Prelog rules, the asymmetric carbon atom can be of the "R" or "S" configuration.

[0040] The abbreviation "MAGL" refers to the enzyme monoacylglycerol lipase. The terms "MAGL" and "monoacylglycerol lipase" are used interchangeably herein.

[0041] The term "treatment" as used herein includes (1) inhibiting a condition, disorder, or symptom (e.g., arresting, reducing, or delaying the onset of a disease or, in the case of maintenance treatment, the recurrence of a disease, the onset of at least one clinical or subclinical symptom of a disease); and / or (2) alleviating symptoms (i.e., causing regression of a condition, disorder, or symptom, or at least one of its clinical or subclinical symptoms). The benefit to the patient to be treated is either statistically significant or at least perceptible to the patient or the physician. However, it will be understood that when a pharmaceutical agent is administered to a patient to treat a disease, the result may not necessarily be effective treatment.

[0042] The term "prophylaxis" as used herein includes preventing or delaying the appearance of clinical symptoms of a condition, disorder or condition in a mammal, particularly a human, who may be affected by or predisposed to the condition, disorder or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder or condition.

[0043] The term "neuroinflammation," as used herein, refers to acute and chronic inflammation of nervous tissue, which are the major tissue components of two parts of the nervous system: the brain and spinal cord of the central nervous system (CNS), and the branching peripheral nerves of the peripheral nervous system (PNS). Chronic neuroinflammation is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Acute neuroinflammation usually occurs immediately after injury to the central nervous system, for example, as a result of traumatic brain injury (TBI).

[0044] The term "traumatic brain injury" (also known as "TBI" or "intracranial injury") relates to damage to the brain resulting from an external mechanical force such as rapid acceleration or deceleration, impact, blast wave, or penetration by a projectile.

[0045] The term "neurodegenerative disease" refers to diseases associated with the progressive loss of neuronal structure or function, including neuronal death. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

[0046] The term "mental disorder" (also called mental illness or mental disorder) relates to a behavioral or mental pattern that can cause distress or impaired functioning in life. Such characteristics may occur as persistent, relapsing, and remitting or single episodes. Examples of mental disorders include, but are not limited to, anxiety and depression.

[0047] The term "pain" refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Examples of pain include, but are not limited to, nociceptive pain, chronic pain (including idiopathic pain), neuropathic pain including chemotherapy-induced neuropathy, phantom limb pain, and syphilitic pain. A particular example of pain is neuropathic pain, which is caused by injury or disease affecting any part of the nervous system involved in bodily sensations (i.e., the somatosensory system). In one embodiment, the "pain" is neuropathic pain resulting from amputation or thoracotomy. In one embodiment, the "pain" is chemotherapy-induced neuropathy.

[0048] The term "neurotoxicity" relates to toxicity in the nervous system. It occurs when exposure to natural or man-made toxic substances (neurotoxins) alters the normal activity of the nervous system, causing damage to nervous tissue. Examples of neurotoxicity include, but are not limited to, exposure to substances used in chemotherapy, radiation treatment, drug therapy, drug abuse, and organ transplants, as well as neurotoxicity resulting from exposure to heavy metals, certain foods and food additives, pesticides, industrial and / or cleaning solvents, cosmetics, and some naturally occurring substances.

[0049] The term "cancer" refers to diseases characterized by the presence of a neoplasm or tumor, resulting from the abnormal and uncontrolled growth of cells (such cells are "cancer cells"). As used herein, the term cancer expressly includes, but is not limited to, hepatocellular carcinoma, colon carcinoma, and ovarian cancer.

[0050] As used herein, the term "mammal" includes both humans and non-humans, including, but not limited to, humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In particularly preferred embodiments, the term "mammal" refers to humans.

[0051] Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I): [ka] (In the formula, X is CH or N; Y and Z are CH or O, and at most one of Y and Z is O; L is a covalent bond, -CHR 4 selected from -, -O-, -OCH2-, -CH2O-, -CH2OCH2-, -CH2CH2-, -CF2CH2-, and -CH2CF2-; A is C6-C 14 - selected from aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl; B is a 4- to 10-membered heterocycle containing 1 to 2 nitrogen atoms; R 1 and R 2 are independently hydrogen, halogen, SF5, cyano, C 1-6 -Alkyl, C 1-6 -Alkoxy, Halo-C 1-6 -Alkyl, Halo-C 1-6 -Alkoxy, C6-C 14 -Aryl, C3-C 10 -cycloalkyl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, C6-C 14-aryloxy, C3-C 10 -cycloalkyloxy, 3- to 14-membered heterocyclyloxy, and 5- to 14-membered heteroaryloxy, wherein the 3- to 14-membered heterocyclyl, C-C 14 -Aryl, C3-C 10 -cycloalkyl, 5-14 membered heteroaryl, C6-C 14 -aryloxy, C3-C 10 Each of -cycloalkyloxy and 5- to 14-membered heteroaryloxy is optionally selected from halogen, C 1-6 -Alkyl, C 1-6 -Alkoxy, Halo-C 1-6 -Alkyl and halo-C 1-6 -substituted with 1 to 2 substituents selected from -alkoxy; or R 1 and R 2 together with the atom(s) to which they are attached, optionally one or more C 1-6 -Forms a 3- to 14-membered heterocycle substituted with alkyl; R 3 is hydrogen and C 1-6 - selected from alkyl; R 4 is hydrogen, C6-C 14 -aryl and halo-C6-C 14 -aryl) or a pharmaceutically acceptable salt thereof.

[0052] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following formula (IA): [ka] (Wherein X, Y, Z, A, L, B and R 1 ~R 3 are as described herein) is a compound of

[0053] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the following formula (IB): [ka] (Wherein X, Y, Z, A, L, B and R 1 ~R 3 are as described herein) is a compound of

[0054] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, X is CH or N; Y is CH or O; Z is CH2, or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, L is a covalent bond, -CHR 4 -, and -CH2O-; A is C6-C 14 -aryl; R 1 is a halogen, halo-C 1-6 -Alkyl and halo-C 1-6 -Alkyl-substituted C3-C 10 - selected from cycloalkyl; R 2 is selected from hydrogen and halogen; R 4 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0056] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, L is selected from a covalent bond and —CH2O—; A is C6-C 14 -aryl; R 1 is Halo-C 1-6 -Alkyl and halo-C 1-6 -Alkyl-substituted C3-C 10 - selected from cycloalkyl; R 2 is selected from hydrogen and halogen, or a pharmaceutically acceptable salt thereof.

[0057] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, L is selected from a covalent bond and —CH2O—; A is phenyl; R 1 is selected from CF3 and (trifluoromethyl)cyclopropyl; R 2 is selected from hydrogen and fluoro, or a pharmaceutically acceptable salt thereof.

[0058] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, B is a 4- to 7-membered heterocycle containing one nitrogen atom; R 3 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0059] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, B is azetidinyl; R 3 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0060] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, X is CH or N; Y and Z are CH or O, and at most one of Y and Z is O; L is a covalent bond, -CHR 4 -, and -CH2O-; A is C6-C 14 -aryl; B is a 4- to 7-membered heterocycle containing one nitrogen atom; R 1 is a halogen, halo-C 1-6 -Alkyl and halo-C 1-6 -Alkyl-substituted C3-C 10 - selected from cycloalkyl; R 2 is selected from hydrogen and halogen; R 3 and R 4 and R are each hydrogen, or a pharmaceutically acceptable salt thereof.

[0061] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, X is CH or N; Y is CH or O; Z is CH2; L is selected from a covalent bond and —CH2O—; A is C6-C 14 -aryl; B is a 4- to 7-membered heterocycle containing one nitrogen atom; R 1 is Halo-C 1-6 -Alkyl and halo-C 1-6 -Alkyl-substituted C3-C 10 - selected from cycloalkyl; R 2 is selected from hydrogen and halogen; R 3 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0062] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, X is CH or N; Y is CH or O; Z is CH2; L is selected from a covalent bond and —CH2O—; A is phenyl; B is azetidinyl; R 1 is selected from CF3 and (trifluoromethyl)cyclopropyl; R 2 is selected from hydrogen and fluoro; R 3 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0063] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein Z is CH2.

[0064] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is selected from a covalent bond, —CH 2 —, and —CH 2 O—.

[0065] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is selected from a covalent bond and —CHO—.

[0066] In one embodiment, the present invention provides a method for treating a cancer cell comprising administering to a patient a cancer treatment ... 14 -aryl, or a pharmaceutically acceptable salt thereof.

[0067] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl.

[0068] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is a 4- to 7-membered heterocycle containing one nitrogen atom.

[0069] In a preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from azetidinyl and 2-azaspiro[3.3]heptan-2-yl.

[0070] In a particularly preferred embodiment, the present invention provides compounds of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is azetidinyl.

[0071] In one embodiment, the present invention provides a compound comprising R 1 is halogen, halo-C 1-6 -Alkyl and halo-C 1-6 -Alkyl-substituted C3-C 10 -cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0072] In a preferred embodiment, the present invention provides R 1 Halo-C 1-6 -Alkyl and halo-C 1-6 -Alkyl-substituted C3-C 10 -cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0073] In a particularly preferred embodiment, the present invention provides 1 is selected from CF3 and (trifluoromethyl)cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0074] In one embodiment, the present invention provides a compound comprising R 2 is selected from hydrogen and halogen, or a pharmaceutically acceptable salt thereof.

[0075] In a preferred embodiment, the present invention provides R 2 is selected from hydrogen and fluoro; or a pharmaceutically acceptable salt thereof.

[0076] In a preferred embodiment, the present invention provides R 3 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0077] In a preferred embodiment, the present invention provides R 4 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the following: [3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[rac-(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-g]indazol-7-yl]methanone; [3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; (-) or (+)-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone; (+) or (-)-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone; (-) or (+)-[6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; (+) or (-)-[6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; (-) or (+)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone; (+) or (-)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aS,8aR)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone; (-) or (+)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1S,9R)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; and (+) or (-)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1R,9S)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone.

[0079] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the following: (-) or (+)-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone; and (-) or (+)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone.

[0080] In certain embodiments, the present invention provides pharmaceutically acceptable salts, particularly hydrochloride salts, of compounds according to formula (I) described herein. In more particular embodiments, the present invention provides compounds according to formula (I) described herein as the free base.

[0081] In some embodiments, compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with an atom having a different atomic mass or mass number. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Exemplary isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Certain isotopically labeled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H and carbon-14, i.e., 14C are particularly useful for this purpose given their ease of incorporation and ready means of detection. For example, compounds of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0082] Heavier isotopes, such as deuterium, i.e. 2 Substitutions such as H may result in greater metabolic stability, for example, a longer in vivo half-life or lower dosage requirements, which may result in certain therapeutic advantages.

[0083] 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the Examples set forth below, by substituting an appropriate isotopically labeled reagent for a previously employed non-isotopically labeled reagent.

[0084] Manufacturing Process In one aspect, the present invention also provides a process for making a compound of formula (I) described herein.

[0085] The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following general scheme. The techniques required to carry out the reactions and purification of the resulting products are known to those skilled in the art. The substituents and indices used in the description of the following processes have the meanings given herein unless indicated to the contrary.

[0086] If one of the starting materials, intermediates or compounds of formula (I) contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more reaction steps, suitable protecting groups (as described in "Protective Groups in Organic Chemistry", T.W. Greene and P.G.M. Hutts, 5th Edition, 2014, John Wiley & Sons, New York) may be introduced prior to a critical step by applying methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature.

[0087] When the starting material or intermediate contains a stereocenter, the compound of formula (I) may be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as chiral HPLC, chiral SFC, or chiral crystallization. Racemates can be separated into their antipodes via diastereomeric salts, for example, by crystallization with an optically pure acid, or by separating the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. Starting materials and intermediates containing a stereocenter can also be separated to obtain diastereomerically / enantiomerically enriched starting materials and intermediates. The use of such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of the compound of formula (I) typically results in the respective diastereomerically / enantiomerically enriched compound of formula (I).

[0088] Those skilled in the art will recognize that in the synthesis of compounds of formula (I) (unless otherwise desired), an "orthogonal protecting group strategy" can be applied to cleave several protecting groups one at a time without affecting other protecting groups in the molecule. The principle of orthogonal protection is well known in the art and has been described in the literature (e.g., Barany, G., Merrifield, R.B., J. Am. Chem. Soc. 1977, 99, 7363; Waldmann, H. et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056).

[0089] Those skilled in the art will recognize that the reaction sequence may vary depending on the reactivity and nature of the intermediates.

[0090] More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the Examples, or similar methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. For reaction conditions described in the literature that affect the reactions described, see, for example, Richard C. Larock, 2001. nd"Comprehensive Organic Transformations: A Guide to Functional Group Preparations," Ed., 1999, John Wiley & Sons, New York. The reactions could be easily carried out with or without solvent. There are no particular limitations on the nature of the solvent used, so long as it does not adversely affect the reaction or the reagents involved and is capable of dissolving the reagents to at least some extent. The reactions described can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the invention. It is convenient to carry out the reactions described at temperatures ranging from -78°C to reflux. The reaction time can also vary widely, depending on many factors, particularly the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days is usually sufficient to produce the intermediates and compounds described. The reaction order is not limited to the order shown in the scheme, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities.

[0091] If starting materials or intermediates are not commercially available or their synthesis is not described in the literature, they can be prepared by analogy with existing procedures for analogous materials or as outlined in the experimental section.

[0092] The following abbreviations are used herein: AcOH = acetic acid, ACN = acetonitrile, Bn = benzyl, Boc = tert-butyloxycarbonyl, CAS RN = Chemical Abstracts Registry Number, Cbz = benzyloxycarbonyl, DAST = (diethylamino)sulfur trifluoride, DBU = 1,8-diazabicyclo[5,4,0]undec-7-ene, DEAD = diethyl azodicarboxylate, DIAD = diisopropyl azodicarboxylate, DMAP = 4-dimethylaminopyridine, DME = dimethoxyethane, DMEDA = N,N'-dimethylethylenediamine, DMF = N,N-dimethylformamide, DIPEA = N,N-diisopropylethylamine, dppf = 1,1 bis(diphenylphosphino)ferrocene, EDC HCl = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, EI = electron impact, ESI = electrospray ionization, EtOAc = ethyl acetate, EtOH = ethanol, h = hour, FA = formic acid, HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, HBTU = O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluorophosphate, HOBt = 1-hydroxy-1H-benzotriazole, HPLC = high-performance liquid chromatography ply, iPrMgCl = isopropylmagnesium chloride, LG = leaving group, LiHMDS = lithium bis(trimethylsilyl)amide, min = minute, mL = milliliter, MPLC = medium pressure liquid chromatography, MS = mass spectrum, nBuLi = n-butyllithium, T3P = propylphosphonic anhydride, PG = protecting group, Pd / C = palladium on activated carbon, R = any group, RT = room temperature, SFC = supercritical fluid chromatography, TBME = tert-butyl methyl ether, TEA = triethylamine, TFA = trifluoroacetic acid, THF = tetrahydrofuran, Hal = halogen.

[0093] X, Y, Z, B, R 3 , L, A, R 1 and R 2Compounds of formula IA, wherein: is as described herein, can be synthesized analogously to literature procedures and / or as shown, for example, in Scheme 1. [ka]

[0094] Thus, compound 1 is reacted with intermediate 2 in the presence of a urea-forming reagent, such as bis(trichloromethyl)carbonate, using a suitable base and a solvent, such as sodium bicarbonate in DCM, to obtain a compound of formula I (step a). Additional urea-forming reagents include, but are not limited to, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, or 1,1'-carbonyldiimidazole. This type of reaction and the use of these reagents have been widely described in the literature (e.g., Sartori, G. et al., Green Chem. 2000, 2, 140; Ghosh, A. K. et al., J. Med. Chem. 2015, 58, 2895). Those skilled in the art will recognize that the order of addition of reagents can be important in this type of reaction due to the reactivity and stability of the carbamoyl chloride formed as an intermediate and to avoid the formation of undesired symmetrical urea by-products.

[0095] X, Y, Z, B, R 3 , L, A, R 1 and R 2 Compounds of formula IB, wherein: is as described herein, can be synthesized analogously to literature procedures and / or as shown, for example, in Scheme 2. [ka]

[0096] Thus, intermediate 2 can be coupled with an activated form of carboxylic acid 3a (G = OH) or carboxylic acid chloride 3b (G = Cl) to give compound IB (step a). This type of amide coupling has been widely described in the literature and can be achieved by using coupling reagents such as CDI, DCC, HATU, HBTU, HOBT, TBTU, T3P or Mukaiyama's reagent (Mukaiyama, T., Angew. Chem., Int. Ed. Engl. 1979, 18, 707) in a suitable solvent such as DMF, DMA, DCM or dioxane, optionally in the presence of a base (e.g., TEA, DIPEA (Huenig's base) or DMAP).

[0097] Alternatively, carboxylic acids 3a can be converted to their acid chlorides 3b by treatment with, for example, thionyl chloride or oxalyl chloride, neat or optionally in a solvent such as DCM. Subsequent reaction of the acid chloride with intermediate 2 in a suitable solvent such as DCM or DMF and a base (e.g., TEA, Hunig's base, pyridine, DMAP, or lithium bis(trimethylsilyl)amide) at a temperature ranging from 0° C. to the reflux temperature of the solvent or solvent mixture provides compounds IB (step a).

[0098] In some embodiments, tricyclic pyrrolidine intermediate 2 is of type 2a and 2b, respectively. Intermediates of type 2a where Q is CH and intermediates of type 2b where Q is O can be prepared by methods well known to those skilled in the art, as exemplified by the general synthetic procedure outlined in Scheme 3. [ka]

[0099] If intermediates 6 (Q = CH) or 10 (Q = O) are not commercially available, they can be prepared by reacting 2-cyclohexen-1-one (4) and 2H-pyran-3(6H)-one (9), respectively, with N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzenemethanamine in the presence of a suitable acid, such as TFA, in a solvent, such as DCM (step a), similar to literature procedures, e.g., Kubas, H. et al., Bioorg. Med. Chem. Lett. 2013, 23, 6370.

[0100] Intermediates 6 and 10, respectively, can then be reacted with 1,1-dimethoxy-N,N-dimethylmethanamine, for example in toluene, preferably at elevated temperature, to give intermediates 7 and 11, respectively (step b).

[0101] Intermediate 7 can be cyclized with hydrazine dihydrochloride in a suitable solvent such as MeOH in the presence of a suitable base such as NaOH at a temperature ranging from 0° C. to the boiling point of the solvent to give intermediate 8 (step c).

[0102] The benzyl group in intermediate 8 can be converted by methods known to those skilled in the art, for example, by methods described by TW Greene and PG M Hutts, 5 th The cleavage can be carried out as described in "Protective Groups in Organic Chemistry" by John Wiley & Sons, Ed., 2014, New York, and hydrogenation using a suitable catalyst in a suitable solvent, such as palladium on charcoal in MeOH, gives intermediate 2a (step d).

[0103] Intermediate 11 can be cyclized with hydrazine monohydrate in a suitable solvent such as EtOH, optionally in the presence of a suitable base such as NaOH, at a temperature ranging from 0° C. to the boiling point of the solvent to give intermediate 12 (step c).

[0104] The benzyl group in intermediate 12 can be removed as described above for step d to give intermediate 2b.

[0105] In some embodiments, tricyclic pyrrolidine intermediate 2 is an intermediate of type 2c. Intermediates of type 2c can be prepared by methods well known to those skilled in the art and exemplified by the general synthetic procedure outlined in Scheme 4. [ka]

[0106] Intermediate 6 can be reacted with 1-azido-4-nitrobenzene in the presence of ammonium acetate in a suitable solvent such as DMF at a temperature ranging from room temperature to the boiling point of the solvent to give intermediate 13 (step a).

[0107] The benzyl group in intermediate 13 can be removed as described in Scheme 3, step d to give intermediate 2c (step c).

[0108] In some embodiments, tricyclic pyrrolidine intermediate 2 is an intermediate of type 2d. Intermediates of type 2d can be prepared by methods well known to those skilled in the art and exemplified by the general synthetic procedure outlined in Scheme 5. [ka]

[0109] 4H-pyran-4-one 14 is reacted with N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzenemethanamine (5) in a suitable solvent such as ACN at a temperature ranging from room temperature to the boiling point of the solvent to give intermediate 15 (Step a).

[0110] Reduction of the double bond in intermediate 15 applying conditions well known in the art, for example hydrogenation in the presence of a suitable catalyst such as palladium on charcoal in a suitable solvent such as EtOAc or MeOH or mixtures thereof, gives intermediate 16 (step b).

[0111] Reaction of intermediate 16 with 1-azido-4-nitrobenzene in the presence of ammonium acetate as described in Scheme 4, step a, gives intermediate 17 (step c).

[0112] In some embodiments, intermediate 1 is an intermediate of type 1a. 1 , R 2 , R 3 Intermediate 1a, where A and B are as described herein, can be prepared by methods known in the art and as exemplified by the general synthetic procedure outlined in Scheme 6. [ka]

[0113] Intermediate 18, commercially available or prepared by methods known in the glycosyltransferase art, where PG represents a suitable protecting group and X is bromide or iodide, can be subjected to a cross-coupling reaction, such as a Negishi, Heck, Stille, Suzuki, Sonogashira, or Buchwald-Hartwig coupling reaction, with compound 19, commercially available or prepared by methods known in the art, where FG represents a suitable functional group, such as chloro, bromo, iodo, -OSO2 alkyl (e.g., mesylate (methanesulfonate)), -OSO2 fluoroalkyl (e.g., triflate (trifluoromethanesulfonate)), or -OSO2 aryl (e.g., tosylate (p-toluenesulfonate)). This type of reaction has been widely described in the literature and is well known to those skilled in the art (Step a).

[0114] For example, intermediate 18 can be obtained commercially or by reaction with a suitable catalyst (e.g., dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium(II) dichloromethane adduct with triphenylphosphine, tetrakis(triphenylphosphine)palladium(0) or palladium(II) acetate) in a suitable solvent (e.g., dioxane, dimethoxyethane, water, toluene, DMF or mixtures thereof) and a suitable base (e.g., NaCO, NaHCO, KF, KCO or TEA) at a temperature between room temperature and the boiling point of the solvent or solvent mixture. stReaction with aryl or heteroaryl boronic acids 19a (FG = B(OH)2) or boronic esters 19b (FG = e.g., 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (pinacol) ester), prepared using literature procedures described in "Boronic Acids - Preparation and Applications in Organic Synthesis and Medicine," Ed., 2005, John Wiley & Sons, New York, can give intermediates 20 (step a). This type of Suzuki reaction has been widely described in the literature (e.g., Suzuki, A., Pure Appl. Chem. 1991, 63, 419; Suzuki, A., Miyaura, N., Chem. Rev. 1995, 95, 2457; Suzuki, A., J. Organomet. Chem. 1999, 576, 147; Polshettiwar, V. et al., Chem. Sus. Chem. 2010, 3, 502) and is well known to those skilled in the art. Alternatively, aryl- or heteroaryl-trifluoroborate 19c (FG = BF3) can be used in a cross-coupling reaction applying a palladium catalyst such as, for example, tetrakis(triphenylphosphine)-palladium(0), palladium(II) acetate or dichloro[1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloromethane adduct in a solvent such as toluene, THF, dioxane, water or a mixture thereof, in the presence of a suitable base such as cesium carbonate or potassium phosphate at a temperature between room temperature and the boiling point of the solvent or solvent mixture (step a).

[0115] Alternatively, intermediate 18 can be reacted with aryl or heteroarylstannane 19d (FG is Sn(alkyl)3, where alkyl is optionally n-butyl or methyl) using a suitable catalyst and solvent, such as tetrakis(triphenylphosphine)-palladium(0), in DMF at a temperature between room temperature and the boiling point of the solvent or solvent mixture to give intermediate 20 (step a). Stille reactions of this type are well known in the art and have been described in literature such as Farina, V. et al., Org. React. 1997, 50, 1; Cordovilla, C. et al., ACS Catal. 2015, 5, 3040.

[0116] Further, intermediate 18 can be reacted with an aryl or heteroaryl zinc halide 19e (FG is ZnHal and Hal, preferably bromide or iodide), either commercially available or prepared by literature methods, using a suitable catalyst and solvent system, such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and copper(I) iodide in DMA, or tetrakis(triphenylphosphine)palladium(0) in THF or DMF, at a temperature between room temperature and the boiling point of the solvent, to give intermediate 20 (step a). Negishi reactions of this type are well known in the art and have been described in the literature, such as Gavryushin, A. et al., Org. Lett., 2005, 7, 4871; Haas, D. et al., ACS Catal. 2016, 6, 1540; Negishi, E.-I., Acc. Chem. Res. 1982, 15, 340. Alternatively, intermediate 20 can be prepared by first converting intermediate 18, where X is, for example, an iodide, to the corresponding zinc species by applying literature methods (e.g., reaction of 18 with Zn powder in the presence of chlorotrimethylsilane and 1,2-dibromoethane in a suitable solvent such as DMA), followed by coupling the zinc species with an aryl- or heteroaryl bromide or iodide under the conditions described above.

[0117] Alternatively, intermediate 18, where X is preferably bromide, can be subjected to cross-electrophilic coupling with aryl- or heteroaryl bromides 19f, where FG represents bromide, using a suitable photocatalyst such as nickel catalysts like [Ir{dF(CF)ppy}(dtbpy)]PF ([4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N,N']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate), NiClglyme (dichloro(dimethoxyethane)nickel), 4,4'-di-tert-butyl-2,2'-dipyridyl, and tris(trimethylsilyl)silane in the presence of a suitable base such as anhydrous sodium carbonate in a solvent such as DME under irradiation with a 420 nm blue light lamp. This type of reaction is described in the literature (step a), such as Zhang, P. et al., J. Am. Chem. Soc. 2016, 138, 8084; Prier, C. K. et al., Chem. Rev. 2013, 113, 5322.

[0118] Furthermore, intermediate 18, in which LG is preferably iodine, can be subjected to Suzuki-Miyaura cross-coupling with arylboronic acid 21 (FG = B(OH)2) in the presence of rac-(1R,2R)-2-aminocyclohexan-1-ol and a suitable base such as sodium bis(trimethylsilyl)amide in a suitable solvent such as iPrOH, dioxane, THF, or DME, preferably iPrOH, at a temperature between room temperature and the boiling point of the solvent, using a suitable nickel catalyst such as nickel(II) iodide, optionally with microwave heating, to give intermediate 22. This type of reaction has been described in the literature, e.g., Dequirez, G. et al., ChemistrySelect 2017, 2, 8841 (Step c).

[0119] Intermediate 22 can be converted to compound R by applying one of the cross-coupling methods previously described. 2 -FG23 to provide intermediate 20 (step d).

[0120] The bromo or iodo substituent in intermediate 22 can be converted to a boronic acid or boronic ester (e.g., pinacol ester) according to literature methods or as outlined in step a to give intermediate 24 (step e).

[0121] Intermediate 24 can be prepared, for example, from compounds R 1 where FG is, for example, bromine or iodine. 2 -FG23 can be converted to intermediate 20 using Suzuki coupling reaction applying the conditions described in step a (step f).

[0122] Removal of the protecting group from intermediate 20 by applying methods known or described in the art gives, for example, intermediate 1a (step b).

[0123] In some embodiments, intermediate 1 is an intermediate of type 1b. 1 , R 2 , R 3 , R 4 Intermediate 1b, where A and B are as described herein, can be prepared by a variety of conditions, which can be exemplified by the general synthetic procedure outlined in Scheme 7. [ka]

[0124] Addition of organometallic compounds of type 25, where MX is, for example, Li or MgCl, MgBr or MgI, to intermediate 26, where PG is a suitable protecting group, for example, a Boc group, gives intermediate 27 (step a). This type of reaction is well known in the art and has been described in the literature (Walsh, D.A. et al., J. Med. Chem. 1989, 32, 105; He, S. et al., J. Med. Chem. 2014, 57, 1543; Senter, T. et al., Bioorg. Med. Chem. Lett. 2015, 25, 2720). If compound 25 (Grignard reagent) where MX = MgHal, where Hal is Cl, Br, or I, is not commercially available, it can be prepared, for example, by the reaction of the corresponding aryl or heteroaryl halide 19g with magnesium in a suitable solvent such as THF at a temperature ranging from 0°C to the boiling point of the solvent, optionally in the presence of a catalytic amount of iodine (step d). Alternatively, a lithium halogen exchange reaction can be carried out with aryl or heteroaryl halide 19g using a solution of LiHMDS or nBuLi, preferably nBuLi, in a solvent such as THF, diethyl ether, n-pentane, n-hexane, or a mixture thereof, preferably THF, at a temperature ranging from -20°C to -78°C, preferably at -78°C, to generate the corresponding lithiated aryl or heteroaryl intermediate (M = Li). The nucleophilic addition of the in situ prepared lithiated aryl or heteroaryl intermediate to a ketone of type 26, where PG is a suitable protecting group such as a Boc group, in a solvent such as THF at a temperature preferably at −78° C., gives the corresponding tertiary alcohol 27 (step a).

[0125] Subsequent elimination of the tertiary hydroxy group in intermediate 27, optionally with simultaneous removal of an acid-labile protecting group (e.g., a Boc protecting group), using acidic conditions such as 4 M HCl in dioxane in a solvent such as MeOH, or preferably TFA in DCM, gives the corresponding olefin intermediate 28 (step b).

[0126] Heterogeneous catalytic hydrogenation of olefin 28 using a catalyst such as Pd(OH) or Pd / C in a solvent such as THF, MeOH, EtOH, EtOAc or mixtures thereof, preferably THF, under atmospheric pressure of hydrogen, for example, gives intermediates of type 1b (step c).

[0127] Intermediate 26 is commercially available and / or can be prepared similarly to methods described in the literature, such as Ashton, K. et al., Bioorg.Med.Chem.Lett. 2011, 21, 5191; WO2012 / 155199; WO2016 / 180536; Hutchings, K. et al., Bioorg.Med.Chem.Lett. 2008, 18, 5087; WO2007 / 117557; Zhang, X., MacMillan, D. W. C., J. Am. Chem. Soc. 2017, 139, 11353; Liu, F. et al., J. Med. Chem. 2017, 60, 5507.

[0128] In some embodiments, intermediate 1 is an intermediate of type 1c. 1 , R 2 , R 3 Intermediate 1c, where A and B are as described herein, can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 8. [ka]

[0129] Ketone 29, where PG is a suitable protecting group, is either commercially available or can be prepared by methods known in the art and can be subjected to a Wittig reaction with alkylidenetriphenylphosphorane of type 30a in a suitable solvent such as THF, methyl-THF, or DMSO to give intermediate 31 (Step a). Phosphorane 30a, the corresponding phosphonium salt, can be formed by treatment with a suitable base such as nBuLi, NaH, or KOtBu in a suitable solvent such as THF, dioxane, or methyl-THF, and can be isolated or used in situ. Similarly, phosphonium salts are readily available from aryl / heteroaryl / heterocycle-substituted alkyl halides (halides are Cl, Br, and I) and triphenylphosphine in a suitable solvent such as toluene. Heat can be applied to accelerate or complete the reaction (e.g., "Preparation, Properties and Reactions of Phosphonium Salts" by H.J. Cristau, F. Plenat in The Chemistry of Organophosphorus Compounds: Phosphonium Salts, Ylides And Phosphoranes (Patai's Chemistry of Functional Groups), Vol. 3, Frank R. Hartley (Ed.), Series Editor: Prof. Saul Patai, John Wiley & Sons, New York).

[0130] Alternatively, intermediate 31 can be obtained using a Horner-Wadsworth-Emmons (HWE) reaction with ketone 29 and phosphonate 30b, R ais alkyl, e.g., methyl or ethyl. Phosphonate 30b is α-metallated in situ using a suitable base and solvent, such as NaH, nBuLi, or KOtBu in THF (step a). Phosphonate 30b is readily prepared, for example, using the Arbuzov reaction by alkylating aryl / heteroaryl / heterocyclic halides (halides are Cl, Br, and I) with commercially available trialkyl phosphites (e.g., Brill, T.B., Landon, S.J., Chem. Rev. 1984, 84, 577).

[0131] Both types of olefination reactions have been widely described in the literature (e.g., Bisceglia, JA, Orelli, LR, Curr. Org. Chem. 2015, 19, 744; Maryanoff, BE, Reitz, AB, Chem. Rev. 1989, 89, 863; Wadsworth Jr., WS, Org. React. 1977, 25, 73; Nicolaou, KC, Hartner, MW, Gunzner, JL, Nadin, A., Liebigs Ann. / Recueil 1997, 1283; Stec, WJ, Acc. Chem. Res. 1983, 16, 411).

[0132] Reduction of the double bond in intermediate 31 with, for example, hydrogen in the presence of a suitable catalyst, such as palladium on charcoal, in a suitable solvent or solvent mixture, such as EtOAc, MeOH, or AcOH, gives compound 32 (step b).

[0133] The Boc group can be prepared by methods known in the art (e.g., the Boc group using TFA in DCM or 4 M HCl in dioxane at temperatures between 0° C. and room temperature, the Cbz group using hydrogen in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH) in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and the Cbz ... using hydrogen in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH) in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and the Cbz group using hydrogen in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH) in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and the Cbz group using hydrogen in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH) thRemoval of the protecting group from intermediate 32 by application of a protective group (such as those described in "Protective Groups in Organic Chemistry" by John Wiley & Sons, Ed., 2014, John Wiley & Sons, New York) gives intermediate 1c (step c).

[0134] In some embodiments, intermediate 1 is an intermediate of type 1d. 1 , R 2 , R 3 Intermediate 1d, where A and B are as described herein, can be prepared by methods well known in the art and as exemplified by the general synthetic procedure outlined in Scheme 9. [ka]

[0135] Alcohols of type 33 can be subjected to the Mitsunobu reaction of intermediate 34, where PG is a suitable protecting group such as Cbz, Boc, or Bn, with an appropriate phosphine such as triphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIAD in a suitable solvent such as THF to give intermediate 19 (step a). Mitsunobu reactions of this type have been widely described in the literature (e.g., Fletcher, S., Org. Chem. Front. 2015, 2, 739; Kumara Swamy, KC, et al., Chem. Rev. 2009, 109, 2551).

[0136] Removal of the protecting group from intermediate 35 by applying literature methods and methods described, for example, in Scheme 8, step c below, gives intermediate 1D (step b).

[0137] Alternatively, intermediate 35 may be prepared from alcohol 33, which can be alkylated with compound 36, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base in a suitable solvent (e.g., sodium hydride in DMF) at a temperature between 0°C and the boiling point of the solvent (step c).

[0138] Furthermore, intermediate 35 can be synthesized via alkylation of alcohols of type 34 with compound 37 under the conditions described in step c.

[0139] In some embodiments, intermediate 1 is an intermediate of type 1e. 1 , R 2 , R 3 Intermediate 1e, where A and B are as described herein, can be prepared by a variety of conditions, which can be exemplified by the general synthetic procedure outlined in Scheme 10. [ka]

[0140] Alcohols of type 33 can be reacted with intermediate 38, where PG is a suitable protecting group such as Cbz, Boc, or Bn, in a suitable solvent such as THF using a suitable phosphine such as triphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIAD (step a) to give intermediate 39. Mitsunobu reactions of this type have been widely described in the literature (e.g., Fletcher, S., Org. Chem. Front. 2015, 2, 739; Kumara Swamy, KC, et al., Chem. Rev. 2009, 109, 2551).

[0141] Removal of the protecting group from intermediate 39 by applying literature methods and methods described, for example, in Scheme 8, step c below, gives intermediate 1e (step b).

[0142] Alternatively, intermediate 39 may be prepared from alcohol 33, which can be alkylated with compound 40, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base such as Cs2CO3, Huenig's base, or NaH in a suitable solvent, such as DMF, at a temperature between 0°C and the boiling point of the solvent (step c).

[0143] For example, intermediate 1e can be reacted with intermediate 2 using conditions described in Scheme 1, step a to give R 1 , R 2 , R 3 , A, B, X, Y and Z are as defined herein to give compounds of type IC. [ka]

[0144] Alternatively, compounds of type IC can be prepared according to Scheme 11. [ka]

[0145] Alcohols of type 33 can be subjected to the Mitsunobu reaction of intermediate 41 with an appropriate phosphine, such as triphenylphosphine, and a dialkyl azodicarboxylate, such as DEAD or DIAD, in a suitable solvent, such as THF, to give compounds ID (step a). Mitsunobu reactions of this type have been widely described in the literature (e.g., Fletcher, S., Org. Chem. Front. 2015, 2, 739; Kumara Swamy, KC, et al., Chem. Rev. 2009, 109, 2551).

[0146] Alternatively, compound IC may be prepared directly from alcohol 33, which can be alkylated with compound 42, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base such as Cs2CO3, Huenig's base, or NaH in a suitable solvent, such as DMF, at a temperature between 0°C and the boiling point of the solvent (step b).

[0147] In some embodiments, intermediate 1 is an intermediate of type 1f. 1 , R 2 , R 3 Intermediate 1f, where A and B are as described herein, can be prepared by methods known in the art and as exemplified by the general synthetic procedure outlined in Scheme 12. [ka]

[0148] Intermediate 44 can be prepared from alcohol 34, which is commercially available or prepared by methods known to those skilled in the art, and where LG is a suitable leaving group such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), by alkylation with compound 43, where LG is a suitable leaving group such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base, such as sodium hydride, Huenig's base, or potassium tert-butoxide, in a suitable solvent (e.g., DMF or THF) at a temperature between 0°C and the boiling point of the solvent (step a).

[0149] The Boc group can be synthesized by methods known in the art (e.g., the Boc group using TFA in DCM at temperatures between 0° C. and room temperature, the Cbz group using hydrogen in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH) in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and the Cbz ... using hydrogen in the presence of a suitable catalyst such as Pd on charcoal or Pd(OH) in a suitable solvent such as MeOH, EtOH, EtOAc, or mixtures thereof, and the Cbz group can be synthesized by methods known in the art (e.g. th Removal of the protecting group from intermediate 44 by application of a protective group (such as those described in "Protective Groups in Organic Chemistry" by John Wiley & Sons, New York, 2014) gives intermediate 1f (step b).

[0150] In some embodiments, intermediate 1 is an intermediate of type 1g. 1 , R 2 , R 3 Intermediate 1g, where A and B are as described herein, can be prepared by a variety of conditions, which can be exemplified by the general synthetic procedure outlined in Scheme 13. [ka]

[0151] Alcohols of type 45 can be subjected to the Mitsunobu reaction of intermediate 38, where PG is a suitable protecting group such as Cbz, Boc, or Bn, with an appropriate phosphine such as triphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIAD in a suitable solvent such as THF to give intermediate 46 (step a). Mitsunobu reactions of this type have been widely described in the literature (e.g., Fletcher, S., Org. Chem. Front. 2015, 2, 739; Kumara Swamy, KC, et al., Chem. Rev. 2009, 109, 2551).

[0152] Removal of the protecting group from intermediate 46 by applying literature methods and methods described, for example, in Scheme 4, step c below, gives intermediate 1f (step b).

[0153] Alternatively, intermediate 46 may be prepared from alcohol 45, which can be alkylated with compound 40, where LG is a suitable leaving group, such as chlorine, bromine, iodine, OSO2 alkyl (e.g., methanesulfonate), OSO2 fluoroalkyl (e.g., trifluoromethanesulfonate), or OSO2 aryl (e.g., p-toluenesulfonate), using a suitable base such as Cs2CO3, Huenig's base, or NaH in a suitable solvent, such as DMF, at a temperature between 0°C and the boiling point of the solvent (step c).

[0154] In some embodiments, intermediate 1 is an intermediate of type 1g and 1h, respectively. 1 , R 2 , R 3 Intermediates of type 1g and 1h, where A and B are as described herein, can be prepared by methods well known to those skilled in the art, as exemplified by the general synthetic procedure outlined in Scheme 14. [ka]

[0155] Aldehydes 47, either commercially available or prepared by methods known in the art, can be subjected to a Wittig or Horner-Wadsworth-Emmons (HWE) reaction using alkylidene triphenylphosphoranes of type 30a and phosphonates 30b, respectively, using conditions described, for example, in Scheme 8, step a, to give intermediates 48 (step a).

[0156] Reduction of the double bond in intermediate 48 applying literature conditions or conditions described in Scheme 5, step b or Scheme 7, step c gives compound 49 (step b).

[0157] Removal of the protecting group from intermediate 49, applying methods known in the art, as outlined in Scheme 8, step c, gives intermediate 1e (step c).

[0158] Removal of the protecting group from intermediate 48, as outlined in Scheme 8, step c, applying methods known in the art, gives intermediate 1f (step d).

[0159] In another embodiment, intermediate 1 is an intermediate of type 1g. 1 , R 2 , R 3 Intermediates of type 1g, where A and B are as described herein, can be prepared by methods well known in the art, as exemplified by the general synthetic procedure outlined in Scheme 15. [ka]

[0160] The carboxylic acid functionality in derivatives 50, where PG means a suitable protecting group such as, for example, a Boc, Cbz, or Bn protecting group, is either commercially available or can be prepared by methods known in the art and can be converted into the acid chloride (LG=Cl) or Weinreb amide (LG=NMeOMe) by applying methods widely described in the literature to give intermediates 51 (step a).

[0161] Intermediate 51 is either commercially available or can be synthesized by methods known in the art and can be reacted with compounds of type 52 as described below to produce intermediate 53 (step b).

[0162] Compound 53 can be further converted to compound 54 by a deoxyfluorination reaction using a suitable fluorinating agent such as DAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or aminodifluorosulfinium tetrafluoroborate (e.g., XtalFluor-E®, XtalFluor-M® in the presence of triethylamine trihydrofluoride and TEA or DBU) in a suitable solvent such as DCM or ACN (step c).

[0163] Removal of the protecting groups from intermediate 54 by applying literature methods and methods described, for example, in Scheme 8, step c below, gives intermediate 1g (step d).

[0164] If compounds 52 are not commercially available, they can be prepared analogously to literature methods. For example, deprotonation of the reactive methyl group in optionally substituted heterocycle 55 with a suitable base such as nBuLi or LiHMDS in a suitable solvent, e.g., THF, hexane, or a mixture thereof, at temperatures ranging from −78° C. to room temperature, gives intermediate 52, where MX=Li (Step e).

[0165] Compound 52 (Grignard reagent) where MX = MgHal, where Hal is Cl, Br, or I, can be prepared by reaction of the corresponding substituted benzyl halide 56 with magnesium in a suitable solvent such as THF, optionally in the presence of a catalytic amount of iodine, at a temperature ranging between 0°C and the boiling point of the solvent (step f).

[0166] In another embodiment, intermediate 1 is an intermediate of type 1h. 1 , R 2 , R 3 Intermediates of type 1h, where A and B are as described herein, can be prepared by methods well known in the art, as exemplified by the general synthetic procedure outlined in Scheme 16. [ka]

[0167] The carboxylic acid functionality in intermediate 57, where PG means a suitable protecting group such as, for example, a Boc, Cbz, or Bn protecting group, is either commercially available or can be prepared by methods known in the art, e.g., by conversion into the acid chloride (LG=Cl) or Weinreb amide (LG=NMeOMe) applying methods widely described in the literature, to give intermediate 58 (step a).

[0168] Intermediate 58 is either commercially available or can be synthesized by methods known in the art and can be reacted with compounds of type 59 as described below to produce intermediate 60 (step b).

[0169] Compound 60 can be further converted to compound 61 by a deoxyfluorination reaction using a suitable fluorinating agent such as DAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or aminodifluorosulfinium tetrafluoroborate (e.g., XtalFluor-E®, XtalFluor-M® in the presence of triethylamine trihydrofluoride and TEA or DBU) in a suitable solvent such as DCM or ACN (step c).

[0170] Removal of the protecting groups from intermediate 61 by applying literature methods and methods described, for example, in Scheme 8, step c below, gives intermediate 1h (step d).

[0171] If compounds 59 are not commercially available, they can be prepared analogously to literature methods. For example, deprotonation of optionally substituted aryl or heteroaryl ring 62 with a suitable base such as nBuLi, secBuLi, tertBuLi, LiHMDS, NaH, or KH in a suitable solvent such as THF, n-hexane, or a mixture thereof at temperatures ranging from −78° C. to room temperature provides intermediate 59, where MX=Li, Na, or K, depending on the base used (Step e).

[0172] Compounds 59 (Grignard reagents) in which MX = MgHal and Hal is Cl, Br, or I can be prepared by reaction of the corresponding optionally substituted aryl or heteroaryl halides 63 by direct magnesium insertion (e.g., powder in the presence of catalytic amounts of iodine, LiCl, or Rieke magnesium, magnesium turnings, optionally in the presence of an organic halide) or by halogen-magnesium exchange by treating 63, in which Hal is preferably bromine or iodine, with an alkylmagnesium halide such as iPrMgCl (optionally in the presence of LiCl) in a suitable solvent such as diethyl ether or THF at a temperature ranging between 0°C and the boiling point of the solvent (step f).

[0173] In one aspect, the present invention provides a process for making a compound of formula (IA) or (IB) described herein, comprising: (d) an amine of formula 2: [ka] wherein X, Y, and Z are as described herein. to the carboxylic acid 3a: [ka] (Wherein L, A, B, and R 1 ~R 3 are as described herein) in the presence of a coupling reagent such as CDI, DCC, HATU, HBTU, HOBT, TBTU, T3P or Mukaiyama reagent, and optionally in the presence of a base such as TEA, DIPEA (Huenig base) or DMAP, to give a compound of formula (IB): [ka] (Wherein X, Y, Z, L, A, B and R 1 ~R 3 is as defined herein) or forming a compound of (e) an amine of formula 2: [ka] wherein X, Y, and Z are as described herein. to the carboxylic acid chloride 3b: [ka] (Wherein L, A, B, and R 1 ~R 3 are as described herein) in the presence of a base such as TEA, Huenig's base, pyridine, DMAP, or lithium bis(trimethylsilyl)amide to form a compound of formula (IB), 1 ~R 3 is as defined herein; or (f) a first amine of Formula 1: [ka] (Wherein A, B, L, and R 1 and R 3 are as described herein) to the second amine 2: [ka] wherein X, Y, and Z are as described herein. in the presence of a base such as sodium bicarbonate and a urea-forming reagent such as bis(trichloromethyl)carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate, or 1,1′-carbonyldiimidazole to produce a compound of formula (IA): [ka] (Wherein X, Y, Z, L, A, B and R 1 ~R 3 is as defined herein) To form a compound of The present invention provides a process including:

[0174] In one aspect, the present invention provides a compound of formula (I) as described herein when prepared according to any one of the processes described herein.

[0175] MAGL inhibitory activity The compounds of the present invention are MAGL inhibitors. Thus, in one aspect, the present invention provides the use of a compound of formula (I) described herein for inhibiting MAGL in a mammal.

[0176] In a further aspect, the present invention provides a compound of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.

[0177] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal.

[0178] In a further aspect, the present invention provides a method for inhibiting MAGL in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein.

[0179] Compounds were profiled for MAGL inhibitory activity by determining the enzyme activity following the hydrolysis of the natural substrate, 2-arachidonoylglycerol, to generate arachidonic acid. Mass spectrometry may then be performed. This assay is hereinafter abbreviated as "2-AG assay."

[0180] The 2-AG assay was performed in a 384-well assay plate (PP, Greiner, catalog no. 784201) in a total volume of 20 μL. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in 3-fold dilution steps in the polypropylene plate to give a final concentration range in the assay of 12.5 μM to 0.8 pM. 0.25 μL of compound dilution (100% DMSO) was added to 9 μL of MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 mL), 0.01% (v / v) Tween). After shaking, the plate was incubated at room temperature for 15 minutes. 10 μL of 2-arachidonoylglycerol in assay buffer was added to initiate the reaction. The final concentrations in the assay were 50 pM MAGL and 8 μM 2-arachidonoylglycerol. After shaking and incubation at room temperature for 30 min, the reaction was quenched by adding 40 μL of acetonitrile containing 4 μM d8-arachidonic acid. The amount of arachidonic acid was monitored using an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer (Agilent 6460). A C18 SPE cartridge (G9205A) was used with an acetonitrile / water liquid setup. The mass spectrometer was operated in negative electrospray mode, following the mass transitions of 303.1 → 259.1 for arachidonic acid and 311.1 → 267.0 for d8-arachidonic acid. Compound activity was calculated based on the intensity ratio (arachidonic acid / d8-arachidonic acid). [Table 1]

[0181] In one aspect, the present invention provides compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein, wherein the compounds of formula (I) and their pharmaceutically acceptable salts or esters have an IC50 or IC60 for MAGL inhibition as measured in the MAGL assay as described herein. 50is less than 25 μM, preferably less than 10 μM, more preferably less than 5 μM.

[0182] In one embodiment, the compounds of formula (I) described herein, and their pharmaceutically acceptable salts or esters, have an IC 50 (MAGL inhibition) values ​​range from 0.000001 μM to 25 μM, and certain compounds have IC 50 The IC values ​​are between 0.000005 μM and 10 μM, and certain compounds have IC 50 The value is between 0.00005 μM and 5 μM.

[0183] Uses of the Compounds of the Invention In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0184] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a mammal.

[0185] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0186] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a neurodegenerative disease in a mammal.

[0187] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of cancer in a mammal.

[0188] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of inflammatory bowel disease in a mammal.

[0189] In one embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of pain in a mammal.

[0190] In one aspect, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and / or spasticity associated with pain in a mammal.

[0191] In a preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in a mammal.

[0192] In a particularly preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of multiple sclerosis in a mammal.

[0193] In one aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a mammal.

[0194] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0195] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer in a mammal.

[0196] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a neurodegenerative disease in a mammal.

[0197] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of inflammatory bowel disease in a mammal.

[0198] In one embodiment, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of pain in a mammal.

[0199] In one aspect, the present invention provides a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and / or spasticity associated with pain in a mammal.

[0200] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in a mammal.

[0201] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of multiple sclerosis in a mammal.

[0202] In one aspect, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a mammal.

[0203] In one embodiment, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a neuroinflammatory and / or neurodegenerative disease in a mammal.

[0204] In one embodiment, the invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of a neurodegenerative disease in a mammal.

[0205] In one embodiment, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of cancer in a mammal.

[0206] In one embodiment, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of inflammatory bowel disease in a mammal.

[0207] In one embodiment, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of pain in a mammal.

[0208] In a further aspect, the present invention provides the use of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain and / or spasticity associated with pain in a mammal.

[0209] In a preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in a mammal.

[0210] In a particularly preferred embodiment, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of multiple sclerosis in a mammal.

[0211] In one aspect, the present invention provides a method for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders and / or inflammatory bowel disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0212] In one embodiment, the present invention provides a method for the treatment or prevention of a neuroinflammatory and / or neurodegenerative disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein.

[0213] In one embodiment, the present invention provides a method for the treatment or prevention of a neurodegenerative disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein.

[0214] In one embodiment, the present invention provides a method for the treatment or prevention of cancer in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein.

[0215] In one embodiment, the present invention provides a method for the treatment or prevention of inflammatory bowel disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein.

[0216] In one embodiment, the present invention provides a method for the treatment or prevention of pain in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described herein.

[0217] In a further aspect, the present invention provides a method for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, pain-associated spasticity, abdominal pain, abdominal pain associated with irritable bowel syndrome and / or visceral pain in a mammal, which method comprises administering to the mammal an effective amount of a compound of formula (I), as described herein, or a pharmaceutically acceptable salt thereof.

[0218] In a preferred embodiment, the present invention provides a method for the treatment or prevention of multiple sclerosis, Alzheimer's disease and / or Parkinson's disease in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0219] In a particularly preferred embodiment, the present invention provides a method for the treatment or prevention of multiple sclerosis in a mammal, comprising administering to the mammal an effective amount of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0220] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) described herein and a therapeutically inert carrier.

[0221] In one embodiment, the present invention provides pharmaceutical compositions as disclosed in Examples 11 and 12.

[0222] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicines (e.g., in the form of pharmaceutical preparations). Pharmaceutical preparations can be administered to the body orally (e.g., in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions, or suspensions), nasally (e.g., in the form of nasal drops), or rectally (e.g., in the form of suppositories). However, administration can also be carried out parenterally, such as intramuscularly or intravenously (e.g., in the form of injections).

[0223] The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert inorganic or organic adjuvants for the preparation of tablets, coated tablets, sugar-coated tablets, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid, or its salts, etc., can be used as adjuvants for tablets, sugar-coated tablets, and hard gelatin capsules, for example.

[0224] Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid substances, and liquid polyols.

[0225] Suitable adjuvants for the production of solutions and syrups are, by way of example, water, polyols, saccharose, invert sugar, glucose etc.

[0226] Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

[0227] Suitable adjuvants for suppositories are, by way of example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols etc.

[0228] Furthermore, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for varying osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparations of the present invention may further contain other therapeutically valuable substances.

[0229] Dosage can vary widely and will of course be adapted to the individual requirements of each particular case.Generally, for oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (for example, about 300 mg / person) will be appropriate, preferably divided into 1 to 3 individual doses, for example, of the same amount.However, it is clear that the upper limit given herein can be exceeded if indicated. [Example]

[0230] The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the claims to the examples.

[0231] Where preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0232] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0233] The present invention will be more fully understood by reference to the following examples, which, however, should not be construed as limiting the scope of the claims to the examples.

[0234] Where preparations are obtained as mixtures of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0235] Unless otherwise stated, all reactions and intermediates were prepared under an argon atmosphere.

[0236] Example 1 [3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[rac-(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-g]indazol-7-yl]methanone [ka]

[0237] To a suspension of 3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidine-4-methylbenzenesulfonic acid (120 mg, 285 μmol, 1.0 equiv; CAS RN 2135785-94-1) in ACN (1 mL) was added TEA (202 mg, 279 μL, 2 mmol, 7.0 equiv), followed by the addition of di(1H-1,2,4-triazol-1-yl)methanone (46.9 mg, 285 μmol, 1.0 equiv; CAS RN 41864-22-6) in one portion. The mixture was stirred at room temperature for 60 min. After adding a solution of rac-(5aR,8aS)-1,4,5,5a,6,7,8,8a-octahydropyrrolo[3,4-g]indazole hydrochloride (114 mg, 285 μmol, 1.0 equiv; BB 1) in ACN (0.5 mL), the mixture was stirred at 70 °C for 20 h. The reaction mixture was completely evaporated, and the product was purified by preparative HPLC (Gemini NX column) using a gradient of ACN:water (containing 0.1% TEA) (20:80 to 98:2) to give the title compound as a colorless foam (12 mg, 10%). MS (ESI): m / z = 439.3 [M+H] + .

[0238] Example 2 [3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-dien-11-yl]methanone [ka]

[0239] rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 To a cloudy solution of ]dodeca-2(6),4-diene (44 mg, 266 μmol, 1.0 equiv; BB 2) in ACN (1 mL) was added TEA (260 μL, 1.86 mmol, 7.0 equiv), followed by the addition of di(1H-1,2,4-triazol-1-yl)methanone (43.7 mg, 266 μmol, 1.0 equiv) in one portion. The suspension was stirred at room temperature for 1.25 h. After the addition of 3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidine 4-methylbenzenesulfonic acid (112 mg, 266 μmol, 1.0 equiv; CAS RN 2135785-94-1), stirring was continued overnight at 50 °C. The reaction mixture was evaporated, the residue was dissolved in water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed once with water, dried over MgSO4, filtered, treated with silica gel, and evaporated. The compound was purified by silica gel chromatography on a 4 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc / EtOH 3 / 1 (100:0 to 0:100). Further purification by silica gel chromatography on a 4 g column using an MPLC (ISCO) system eluting with a gradient of DCM: MeOH (100:0 to 90:10) afforded the title compound as a colorless solid (24 mg, 21%). MS (ESI): m / z = 441.3 [M+H] + .

[0240] Examples 3 and 4 (-) or (+)-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone [ka] and (+) or (-)-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone [ka]

[0241] rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6To a cloudy solution of ]dodeca-2(6),4-diene (100 mg, 605 μmol, 1.0 equiv; BB 2) in ACN (2.5 mL) was added TEA (591 μL, 4.24 mmol, 7.0 equiv), followed by di(1H-1,2,4-triazol-1-yl)methanone (99.4 mg, 605 μmol, 1.0 equiv) in one portion. The suspension was stirred at room temperature for 1.25 h to give a clear solution. After the addition of 3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)azetidine 4-methylbenzenesulfonate (250 mg, 605 μmol, 1.0 equiv; BB 3), stirring was continued overnight at 50 °C. The reaction mixture was evaporated. The residue was dissolved in water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed once with water, dried over MgSO, filtered, and evaporated. The racemic products were separated by preparative SFC (OJ-H column) using an isocratic mixture of MeOH:carbon dioxide (15:85) to give (-) or (+)-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone (57 mg, 22%; first eluting compound) as a colorless solid (MS(ESI): m / z = 433.3 [M+H]). + ), and (+) or (-)-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone (59 mg, 23%; second eluting compound) as a colorless solid (MS(ESI): m / z = 433.3 [M+H] + ) was obtained.

[0242] Examples 5 and 6 (-) or (+)-[6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-dien-11-yl]methanone [ka] and (+) or (-)-[6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-dien-11-yl]methanone [ka]

[0243] rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6To a cloudy solution of ]dodeca-2(6),4-diene (64 mg, 387 μmol, 1.0 equiv; BB 2) in ACN (1.5 mL) was added TEA (392 mg, 540 μL, 3.87 mmol, 10.0 equiv), followed by di(1H-1,2,4-triazol-1-yl)methanone (63.6 mg, 387 μmol, 1.0 equiv) in one portion. The suspension was stirred at room temperature for 1.25 h to give a clear solution. After adding a solution of 6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetic acid (131 mg, 387 μmol, 1.0 equiv; BB 4) in DCM (1.5 mL), stirring was continued at 50 °C overnight. The reaction mixture was evaporated. The residue was dissolved in water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed once with water, dried over MgSO4, filtered, and evaporated. The product was purified by preparative HPLC (Gemini NX column) using a gradient of ACN:water (containing 0.1% TEA) (20:80 to 98:2). The racemic product (colorless oil, 40 mg) was separated by preparative chiral HPLC (Chiralpak-NR column) using an isocratic mixture of EtOH (0.8% NHOAc):n-heptane (60:40) to give (-) or (+)-[6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone (13 mg, 8%; first eluting compound) as a colorless solid (MS(ESI): m / z = 415.3 [M+H]). + ), and (+) or (-)-[6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; (13 mg, 8%; second eluting compound) as a colorless solid (MS(ESI): m / z = 415.3 [M+H] + ) was obtained.

[0244] Examples 7 and 8 (-) or (+)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone [ka] and (+) or (-)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aS,8aR)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]-methanone [ka]

[0245] To a cloudy solution of rac-(5aR,8aS)-1,4,5,5a,6,7,8,8a-octahydropyrrolo[3,4-e]benzotriazole (90 mg, 548 μmol, 1.0 equiv; BB 5) in MeCN (2 mL) was added TEA (535 μL, 3.84 mmol, 7.0 equiv), followed by di(1H-1,2,4-triazol-1-yl)methanone (90 mg, 548 μmol, 1.0 equiv) in one portion. The suspension was stirred at room temperature for 1.25 h to obtain a clear solution. After the addition of 3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidine 4-methylbenzenesulfonate (231 mg, 548 μmol, 1.0 equiv; CAS RN 2135785-94-1), stirring was continued overnight at 50 °C. The reaction mixture was evaporated. The residue was dissolved in water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed once with water, dried over MgSO4, filtered, and evaporated. The racemic product was separated by preparative SFC (AD-H column) using an isocratic mixture of MeOH:carbon dioxide (30:70) to give (-) or (+)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone (66 mg, 27%; first eluting compound) as a light brown solid (MS(ESI): m / z = 440.4 [M+H] + ), and (+) or (-)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aS,8aR)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]-methanone (55 mg, 22%; second eluting compound) as a light brown solid (MS(ESI): m / z = 440.4 [M+H] + Obtained.

[0246] Examples 9 and 10 (-) or (+)-[3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1S,9R)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone [ka] and (+) or (-)-[3-[[2-Fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1R,9S)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone [ka]

[0247] rac-(1S,9R)-8-oxa-3,4,5,11-tetraazatricyclo[7.3.0.0 2,6To a cloudy solution of ]dodeca-2(6),4-diene (73 mg, 439 μmol, 1.0 equiv; BB 6) in MeCN (1.5 mL) was added TEA (429 μL, 3.08 mmol, 7.0 equiv), followed by the addition of di(1H-1,2,4-triazol-1-yl)methanone (72.1 mg, 439 μmol, 1.0 equiv) in one portion. The suspension was stirred at room temperature for 2 h. After the addition of 3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidine 4-methylbenzenesulfonic acid (185 mg, 439 μmol, 1.0 equiv; CAS RN 2135785-94-1), stirring was continued at 50 °C for 1.5 h. A suspension was formed, which was cooled to room temperature and filtered. The product was purified by preparative HPLC (Gemini NX column) using a gradient of ACN:water (containing 0.1% TEA) (20:80 to 98:2). Separation of the racemic product by preparative SFC (AD-H column) using an isocratic mixture of MeOH:carbon dioxide (30:70) gave (-) or (+)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1S,9R)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone (53 mg, 27%; first eluting compound) as a light brown solid (MS(ESI): m / z = 442.3 [M+H]). + ), and (+) or (-)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1R,9S)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone (29 mg, 15%; second eluting compound) as a light brown solid (MS(ESI): m / z = 442.3 [M+H] + ) was obtained.

[0248] Composition of Components BB 1 rac-(5aR,8aS)-1,4,5,5a,6,7,8,8a-Octahydropyrrolo[3,4-g]indazole hydrochloride

[0249] Step 1: rac-(3aS,5Z,7aR)-2-benzyl-5-(dimethylaminomethylene)-1,3,3a,6,7,7a-hexahydroisoindol-4-one

[0250] To a solution of rac-(3aR,7aS)-2-benzyloctahydro-4H-isoindol-4-one (200 mg, 872 μmol, 1.0 equiv; CAS RN 163484-15-9) in anhydrous toluene (1.5 mL) under Ar, 1,1-dimethoxy-N,N-dimethylmethanamine (232 μL, 1.74 mmol, 2.0 equiv; CAS RN 4637-24-5) was added, and the mixture was stirred in a sealed tube at 111° C. for 3 h and 130° C. for 19 h. After cooling to room temperature, the solution was evaporated, and the light brown oil was used in the next step without further purification.

[0251] Step 2: rac-(5aR,8aS)-7-benzyl-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-g]indazole

[0252] To a solution of rac-(3aS,5Z,7aR)-2-benzyl-5-(dimethylaminomethylene)-1,3,3a,6,7,7a-hexahydroisoindol-4-one (248 mg, 872 μmol, 1.0 equiv.) and hydrazine dihydrochloride (91.5 mg, 872 μmol, 1.0 equiv.) in MeOH was added dropwise NaOH (1.74 mL, 3.49 mmol, 4.0 equiv.; 2 M in water) at 0°C, and the mixture was stirred at 77°C in a sealed tube. The reaction mixture was poured into half-saturated aqueous NH4Cl and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layer was washed once with brine, dried over MgSO4, filtered, and evaporated to give the desired compound as a yellow foam (147 mg, 57%). MS (ESI): m / z = 254.2 [M+H] + .

[0253] BB 2 rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-diene

[0254] Step 1: rac-(3aR,7aS)-2-benzyl-3,3a,4,7a-tetrahydro-1H-pyrano[3,4-c]pyrrol-7-one

[0255] To a solution of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (2 mL, 7.82 mmol, 1.05 equiv; CAS RN 93102-05-7) and 2H-pyran-3(6H)-one (729 mg, 7.43 mmol, 1.0 equiv; CAS RN 98166-23-5) in anhydrous toluene (20 mL) was added TFA (57.2 μL, 743 μmol, 1.0 equiv), and the mixture was stirred at room temperature for 18 h. To the clear, pale yellow solution was added TEA (104 μL, 743 μmol, 0.1 equiv), and the mixture was treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 40 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc / EtOH 3 / 1 (100:0 to 0:100) to give the desired compound as a yellow oil (1.15 g, 61%). MS (ESI): m / z = 232.2 [M+H] + .

[0256] Step 2: rac-(3aR,6E,7aS)-2-benzyl-6-(dimethylaminomethylene)-3,3a,4,7a-tetrahydro-1H-pyrano[3,4-c]pyrrol-7-one

[0257] To a solution of rac-(3aR,7aS)-2-benzyl-3,3a,4,7a-tetrahydro-1H-pyrano[3,4-c]pyrrol-7-one (395 mg, 1.71 mmol, 1.0 equiv.) in anhydrous toluene (3 mL) under argon, 1,1-dimethoxy-N,N-dimethylmethanamine (454 μL, 3.42 mmol, 2.0 equiv.; CAS RN 4637-24-5) was added, and the mixture was stirred at 130 °C overnight. Evaporation of the solution afforded the desired compound as a brown oil (515 mg), which was used in the next step without further purification. MS (ESI): m / z = 287.3 [M+H] + .

[0258] Step 3: rac-(1S,9R)-11-benzyl-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-diene

[0259] A mixture of rac-(3aR,6E,7aS)-2-benzyl-6-(dimethylaminomethylene)-3,3a,4,7a-tetrahydro-1H-pyrano[3,4-c]pyrrol-7-one (480 mg, 1.68 mmol, 1.0 equiv.) and hydrazine monohydrate (122 μL, 2.51 mmol, 1.5 equiv.) in EtOH (1 mL) was heated in a sealed tube at 85 °C for 2 h. Silica gel was added and the suspension was evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane: EtOAc / EtOH 3 / 1 (80:20 to 0:100) to give the desired compound as a pale yellow gum (89 mg, 21%). MS (ESI): m / z = 256.3 [M+H] + .

[0260] Step 4: rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-diene

[0261] rac-(1S,9R)-11-benzyl-7-oxa-3,4,11-triazatricyclo[7.3.0.0 2,6 To a solution of ]dodeca-2(6),4-diene (85 mg, 333 μmol, 1.0 equiv.) in MeOH (2 mL) and EtOAc (1 mL) was added Pd / C (20 mg, 18.8 μmol, 0.06 equiv.; 10% by weight), and the mixture was stirred under a hydrogen atmosphere at 50° C. and 20 bar for 19 h. The suspension was cooled to room temperature and filtered. The filtrate was completely evaporated to give a colorless oil (55 mg, 100%), which was used in the next step without further purification. MS (ESI): m / z=166.1 [M+H] + .

[0262] BB 3 3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)azetidine 4-methylbenzenesulfonate

[0263] A mixture of tert-butyl 3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)azetidine-1-carboxylate (12.23 g, 35.8 mmol, 1.0 equiv; CAS RN 2377009-83-9) and p-toluenesulfonic acid monohydrate (7.16 g, 37.6 mmol, 1.05 equiv) in EtOAc (122 mL) was heated to reflux for 1 h. The suspension was cooled in an ice bath for 2 h and then filtered. The filter cake was washed with a small amount of cold EtOAc (20 mL) to give the desired compound as a colorless solid (13.4 g, 90%). MS (ESI): m / z = 242.2 [M+H] + .

[0264] BB 4 6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetic acid

[0265] Step 1: (2,4-difluorophenyl)methyl-triphenylphosphonium bromide

[0266] A mixture of triphenylphosphine (1.27 g, 4.83 mmol, 1.0 equiv.) and 1-(bromomethyl)-2,4-difluorobenzene (1.0 g, 620 μl, 4.83 mmol, 1.0 equiv.) in MeCN (10 mL) was stirred at 80° C. for 3 h. The mixture was cooled to room temperature, and TBME (100 mL) was added. The solid was filtered off and washed with some TBME to give the desired compound as a colorless solid (2.18 g, 96%). MS (ESI): m / z = 389.2 [M-Br] + .

[0267] Step 2: tert-butyl 6-[(4,6-difluorocyclohexa-2,4-dien-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate

[0268] To a solution of (2,4-difluorophenyl)methyl-triphenylphosphonium bromide (1.7 g, 3.62 mmol, 1.0 equiv.) in dry THF (10 mL) was added LHMDS (7.24 mL, 7.24 mmol, 2.0 equiv.; 1 M in THF) at -78 °C. The reaction mixture was stirred at -78 °C for 2 h. The mixture was warmed to ice bath temperature. At 2-5 °C, tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1.53 g, 7.24 mmol, 2.0 equiv.; CAS RN 1181816-12-5) was added, and the mixture was stirred at 85 °C overnight. After cooling to room temperature, TBME was added, and the resulting suspension was filtered. The filtrate was evaporated and the residue was purified by silica gel chromatography on a 50 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc (100:0 to 30:70) to give the desired compound as a colorless solid (352 mg, 30%). MS (ESI): m / z = 266.2 [M + 2H-tBu] + .

[0269] Step 3: tert-butyl 6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[0270] To a solution of tert-butyl 6-[(4,6-difluorocyclohexa-2,4-dien-1-yl)methylene]-2-azaspiro[3.3]heptane-2-carboxylate (350 mg, 1.09 mmol, 1.0 equiv.) in 10 mL of EtOAc, Pd / C (116 mg, 109 μmol, 0.1 equiv.; 10% by weight) was added, and the mixture was stirred under a hydrogen atmosphere (1 bar) at room temperature for 2 h. The suspension was filtered, and the filtrate was evaporated to give the desired compound as a colorless solid (345 mg, 98%). MS (ESI): m / z = 268.2 [M + 2H-tBu] + .

[0271] Step 4: 6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptane 2,2,2-trifluoroacetic acid

[0272] To a solution of tert-butyl 6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (55 mg, 170 μmol, 1.0 equiv.) in DCM (1 mL) was added TFA (52.4 μL, 680 μmol, 4.0 equiv.), and the solution was stirred at room temperature for 20 h. The mixture was evaporated to dryness. The residue was mixed with anhydrous toluene and evaporated to give the desired product, which was used in the next step without further purification. MS (ESI): m / z = 224.2 [M+H] + .

[0273] BB 5 rac-(5aR,8aS)-1,4,5,5a,6,7,8,8a-Octahydropyrrolo[3,4-e]benzotriazole

[0274] Step 1: rac-(5aR,8aS)-7-(cyclohexa-2,4-dien-1-ylmethyl)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazole

[0275] To a mixture of rac-(3aR,7aS)-2-benzyloctahydro-4H-isoindol-4-one (215 mg, 938 μmol, 1.0 equiv; CAS RN 163484-15-9) and 1-azido-4-nitrobenzene (200 mg, 1.22 mmol, 1.3 equiv; CAS RN 1516-60-5) in DMF (2 mL) was added ammonium acetate (361 mg, 4.69 mmol, 5.0 equiv) under Ar, and the dark solution was stirred at 80 °C for 4 h. The reaction mixture was poured onto water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc. There was no clear distribution of the desired product in the organic phase. Therefore, all layers were evaporated and combined. The product was purified by preparative HPLC (Gemini NX column) using a gradient of ACN:water (containing 0.1% TEA) (20:80 to 98:2) to give the desired compound as a light brown gum (39 mg; 16%). MS (ESI): m / z = 255.3 [M+H] + .

[0276] Step 2: rac-(5aR,8aS)-1,4,5,5a,6,7,8,8a-octahydropyrrolo[3,4-e]benzotriazole

[0277] To a solution of rac-(5aR,8aS)-7-(cyclohexa-2,4-dien-1-ylmethyl)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazole (153 mg, 602 μmol, 1.0 equiv.) in MeOH (3 mL), Pd / C (18 mg, 16.9 μmol, 0.03 equiv.; 10% by weight) was added, and the mixture was stirred under a hydrogen atmosphere (20 bar) at 60° C. for 18 h. The suspension was cooled to room temperature and filtered. The filtrate was completely evaporated to give a colorless oil (93 mg, 94%), which was used in the next step without further purification. MS (ESI): m / z = 165.1 [M+H] + .

[0278] BB 6 rac-(1S,9R)-8-oxa-3,4,5,11-tetraazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-diene

[0279] Step 1: rac-(4aR,7aR)-6-benzyl-4a,5,7,7a-tetrahydropyrano[2,3-c]pyrrol-4-one

[0280] A solution of 4H-pyran-4-one (2.75 g, 28.6 mmol, 1.0 equiv; CAS RN 108-97-4) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (7.32 mL, 28.6 mmol, 1.0 equiv) in MeCN (12 mL) under Ar was stirred at 44 °C for 40 h. Then, another batch of N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (3.66 mL, 14.3 mmol, 0.5 equiv) was added, and stirring was continued at 44 °C over the weekend. After 88 h, silica gel was added, and the mixture was evaporated. The compound was purified by silica gel chromatography on a 40 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane: EtOAc (100:0 to 0:100). A second purification step using silica gel chromatography on a 40 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane: EtOAc (100:0 to 20:80) afforded the desired compound as a light brown oil (0.92 g, 13%). MS (ESI): m / z = 230.2 [M+H] + .

[0281] Step 2: rac-(4aR,7aR)-6-benzyl-2,3,4a,5,7,7a-hexahydropyrano[2,3-c]pyrrol-4-one

[0282] To a solution of rac-(4aR,7aR)-6-benzyl-4a,5,7,7a-tetrahydropyrano[2,3-c]pyrrol-4-one (1.2 g, 5.23 mmol, 1.0 equiv.) in EtOAc (5 mL) and MeOH (5 mL) was added Pd / C (111 mg, 105 μmol, 0.02 equiv.; 10% by weight). The suspension was stirred overnight at room temperature under a hydrogen atmosphere (1 bar) and then filtered. The filtrate was treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 12 g column using an MPLC system eluting with a gradient of n-heptane: EtOAc (100:0 to 0:100) to give the desired compound as a light brown oil (0.41 g, 30%). MS (ESI): m / z = 232.2 [M+H] + .

[0283] Step 3: rac-(1S,9R)-11-benzyl-8-oxa-3,4,5,11-tetraazatricyclo[7.3.0.0 2,6 ]dodeca-2(6),4-diene

[0284] To a mixture of rac-(4aR,7aR)-6-benzyl-2,3,4a,5,7,7a-hexahydropyrano[2,3-c]pyrrol-4-one (190 mg, 821 μmol, 1.0 equiv.) and 1-azido-4-nitrobenzene (175 mg, 1.07 mmol, 1.3 equiv.; CAS RN 1516-60-5) in DMF (1.5 mL) was added ammonium acetate (317 mg, 4.11 mmol, 5.0 equiv.) under Ar, and the solution was stirred at 80 °C in a sealed tube for 15 h. The reaction mixture was purified by preparative HPLC (Gemini NX column) using a gradient of ACN:water (containing 0.1% TEA) (20:80 to 98:2) to give the desired compound as a light brown foam (55 mg; 26%). MS (ESI): m / z = 257.2 [M+H] + .

[0285] Step 4: rac-(1S,9R)-8-oxa-3,4,5,11-tetraazatricyclo[7.3.0.02,6]dodeca-2(6),4-diene

[0286] rac-(1S,9R)-11-benzyl-8-oxa-3,4,5,11-tetraazatricyclo[7.3.0.0 2,6 To a solution of ]dodeca-2(6),4-diene (113 mg, 441 μmol, 1.0 equiv.) in MeOH (4 mL) was added Pd / C (27 mg, 25.4 μmol, 0.06 equiv.; 10% by weight), and the mixture was stirred under a hydrogen atmosphere (20 bar) at 60° C. for 36 h. The suspension was cooled to room temperature and filtered. The filtrate was completely evaporated to give a colorless oil (73 mg, 100%), which was used in the next step without further purification. MS (ESI): m / z=167.1 [M+H] + .

[0287] Example 11 The compounds of formula (I) can be used in a manner known per se as active ingredient to prepare tablets of the following composition:

[0288] Per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Cornstarch 25mg Talc 25mg Hydroxypropyl methylcellulose 20mg 425mg

[0289] Example 12 The compounds of formula (I) can be used in a manner known per se as active ingredients to prepare capsules of the following composition:

[0290] Per capsule Active ingredient 100.0mg Cornstarch 20.0mg Lactose 95.0mg Talc 4.5mg Magnesium stearate 0.5mg 220.0mg

Claims

1. Formula (IA): 【Chemistry 1】 (In the formula, X is CH or N; Y and Z are CH ２ or O, and at most one of Y and Z is O; L is a covalent bond, -CHR ４ - and -CH ２ O-; A is C ６ -C １４ -aryl; B is a 4- to 7-membered heterocycle containing one nitrogen atom; R1 is halogen, halo-C １－６ -alkyl, and halo-C 1-6 -alkyl substituted C ３ -C １０ -cycloalkyl; R 2 is selected from hydrogen and halogen; R ３ and R ４ are both hydrogen) or a pharmaceutically acceptable salt thereof.

2. Y is CH ２ or O; Z is CH ２ 2. The compound of claim 1, wherein:

3. L represents a covalent bond and -CH ２ O-; R １ But, Halo-C １－６ -alkyl and halo-C １－６ -C substituted with alkyl ３ -C １０ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: -cycloalkyl.

4. L is a covalent bond and -CH ２ O-; A is phenyl; R １ But CF ３ and (trifluoromethyl)cyclopropyl; R ２ 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and fluoro.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein B is azetidinyl.

6. Y is CH ２ or O; Z is CH ２ and L is a covalent bond and -CH ２ O-; R １ But, Halo-C １－６ -alkyl and halo-C １－６ -C substituted with alkyl ３ -C １０ -cycloalkyl, or a pharmaceutically acceptable salt thereof.

7. Y is CH ２ or O; Z is CH ２ and L is a covalent bond and -CH ２ O-; A is phenyl; B is azetidinyl; R １ But CF ３ and (trifluoromethyl)cyclopropyl; R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from hydrogen and fluoro.

8. [3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[rac-(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-g]indazol-7-yl]methanone; [3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[rac-(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; (-) or (+)-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone; (+) or (-)-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]-[3-[4-[1-(trifluoromethyl)cyclopropyl]phenyl]azetidin-1-yl]methanone; (-) or (+)-[6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1S,9R)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; (+) or (-)-[6-[(2,4-difluorophenyl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[(1R,9S)-7-oxa-3,4,11-triazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; (-) or (+)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aR,8aS)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone; (+) or (-)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(5aS,8aR)-4,5,5a,6,8,8a-hexahydro-1H-pyrrolo[3,4-e]benzotriazol-7-yl]methanone; (-) or (+)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1S,9R)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone; and (+) or (-)-[3-[[2-fluoro-4-(trifluoromethyl)phenyl]methoxy]azetidin-1-yl]-[(1R,9S)-8-oxa-3,4,5,11-tetrazatricyclo[7.3.0.02,6]dodeca-2(6),4-dien-11-yl]methanone 2. The compound of claim 1 selected from:

9. A method for producing a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, comprising: A first amine of Formula 1: 【Chemistry 2】 (Wherein A, B, L, and R １ ~R ３ is as defined in any one of claims 1 to 8) to the second amine 2: 【Transformation 3】 wherein X, Y, and Z are as defined in any one of claims 1 to 8. in the presence of a base and a urea-forming reagent to produce a compound of formula (IA): 【Chemistry 4】 (Wherein X, Y, Z, L, A, B, and R １ ~R ３ is as defined in any one of claims 1 to 8) To form a compound of A method comprising:

10. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

12. A compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for use in the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, and / or inflammatory bowel disease in a mammal.

13. 12. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, for use in the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, pain-associated spasticity, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain in a mammal.

14. 10. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer, psychiatric disorders, and / or inflammatory bowel disease in a mammal.

15. 10. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy-induced neuropathy, acute pain, chronic pain, spasticity associated with pain, abdominal pain, abdominal pain associated with irritable bowel syndrome, and / or visceral pain in a mammal.

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