WO2024088922A1 - Composés hétérocycliques en tant qu'inhibiteurs de monoacylglycérol lipase (magl) - Google Patents

Composés hétérocycliques en tant qu'inhibiteurs de monoacylglycérol lipase (magl) Download PDF

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WO2024088922A1
WO2024088922A1 PCT/EP2023/079392 EP2023079392W WO2024088922A1 WO 2024088922 A1 WO2024088922 A1 WO 2024088922A1 EP 2023079392 W EP2023079392 W EP 2023079392W WO 2024088922 A1 WO2024088922 A1 WO 2024088922A1
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heptan
azaspiro
methyl
triazol
methanone
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PCT/EP2023/079392
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Joerg Benz
Maude GIROUD
Uwe Grether
Bernd Kuhn
Fionn Susannah O'HARA
Martin Ritter
Didier Rombach
Philipp Claudio SCHMID
Matthias Beat WITTWER
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F. Hoffmann-La Roche Ag
Hoffmann-La Roche Inc.
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Publication of WO2024088922A1 publication Critical patent/WO2024088922A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to monoacylglycerol lipase (MAGL) inhibitors for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer, mental 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 associated with irritable bowel syndrome and/or visceral pain in a mammal.
  • MLM monoacylglycerol lipase
  • Endocannabinoids are signaling lipids that exert their biological actions by interacting with cannabinoid receptors (CBRs), CB1 and CB2. They modulate multiple physiological processes including neuroinflammation, neurodegeneration and tissue regeneration (Iannotti, F.A., et al., Progress in lipid research 2016, 62, 107-28.).
  • CBRs cannabinoid receptors
  • CB1 and CB2 cannabinoid receptors
  • DAGL diacyglycerol lipases
  • MAGL monoacylglycerol lipase
  • MAGL is expressed throughout the brain and in most brain cell types, including neurons, astrocytes, oligodendrocytes and microglia cells (Chanda, P.K., et al., Molecular pharmacology 2010, 78, 996; Viader, A., et al., Cell reports 2015, 12, 798.).
  • 2-AG hydrolysis results in the formation of arachidonic acid (AA), the precursor of prostaglandins (PGs) and leukotrienes (LTs).
  • Oxidative metabolism of AA is increased in inflamed tissues.
  • the cyclo- oxygenase which produces PGs
  • the 5-lipoxygenase which produces LTs.
  • PGE2 is one of the most important. These products have been detected at sites of inflammation, e.g. in the CNE/13.10.2023 cerebrospinal fluid of patients suffering from neurodegenerative disorders and are believed to contribute to inflammatory response and disease progression.
  • mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and elevated 2-AG levels in the nervous system while other arachidonoyl-containing phospho- and neutral lipid species including anandamide (AEA), as well as other free fatty acids, are unaltered.
  • levels of AA and AA-derived prostaglandins and other eicosanoids including prostaglandin E2 (PGE2), D2 (PGD2), F2 (PGF2), and thromboxane B2 (TXB2), are strongly decreased.
  • Phospholipase A2 (PLA2) enzymes have been viewed as the principal source of AA, but cPLA 2 -deficient mice have unaltered AA levels in their brain, reinforcing the key role of MAGL in the brain for AA production and regulation of the brain inflammatory process.
  • Neuroinflammation is a common pathological change characteristic of diseases of the brain including, but not restricted to, neurodegenerative diseases (e.g. multiple sclerosis, Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy and mental disorders such as anxiety and migraine).
  • neurodegenerative diseases e.g. multiple sclerosis, Alzheimer’s disease, Parkinson disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy and mental disorders such as anxiety and migraine.
  • production of eicosanoids and prostaglandins controls the neuroinflammation process.
  • the pro-inflammatory agent lipopolysaccharide produces a robust, time- dependent increase in brain eicosanoids that is markedly blunted in Mgll–/– mice.
  • LPS treatment also induces a widespread elevation in pro-inflammatory cytokines including interleukin-1-a (IL-1-a), IL-1b, IL-6, and tumor necrosis factor-a (TNF-a) that is prevented in Mgll–/– mice.
  • IL-1-a interleukin-1-a
  • IL-6 interleukin-1-a
  • TNF-a tumor necrosis factor-a
  • Neuroinflammation is characterized by the activation of the innate immune cells of the central nervous system, the microglia and the astrocytes.
  • anti- inflammatory drugs can suppress in preclinical models the activation of glia cells and the progression of disease including Alzheimer’s disease and mutiple sclerosis (Lleo A., Cell Mol Life Sci.2007, 64, 1403.).
  • genetic and/or pharmacological disruption of MAGL activity also blocks LPS-induced activation of microglial cells in the brain (Nomura, D.K., et al., Science 2011, 334, 809.).
  • genetic and/or pharmacological disruption of MAGL activity was shown to be protective in several animal models of neurodegeneration including, but not restricted to, Alzheimer’s disease, Parkinson’s disease and multiple sclerosis.
  • an irreversible MAGL inhibitor has been widely used in preclinical models of neuroinflammation and neurodegeneration (Long, J.Z., et al., Nature chemical biology 2009, 5, 37.).
  • Systemic injection of such inhibitor recapitulates the Mgll-/- mice phenotype in the brain, including an increase in 2-AG levels, a reduction in AA levels and related eicosanoids production, as well as the prevention of cytokines production and microglia activation following LPS-induced neuroinflammation (Nomura, D.K., et al., Science 2011, 334, 809.), altogether confirming that MAGL is a druggable target.
  • oligodendrocytes (OLs), the myelinating cells of the central nervous system, and their precursors (OPCs) express the cannabinoid receptor 2 (CB2) on their membrane.
  • CB2 cannabinoid receptor 2
  • 2-AG is the endogenous ligand of CB1 and CB2 receptors. It has been reported that both cannabinoids and pharmacological inhibition of MAGL attenuate OLs’s and OPCs’s vulnerability to excitotoxic insults and therefore may be neuroprotective (Bernal-Chico, A., et al., Glia 2015, 63, 163.).
  • MAGL inhibition increases the number of myelinating OLs in the brain of mice, suggesting that MAGL inhibition may promote differentiation of OPCs in myelinating OLs in vivo (Alpar, A., et al., Nature communications 2014, 5, 4421.). Inhibition of MAGL was also shown to promote remyelination and functional recovery in a mouse model of progressive multiple sclerosis (Feliu A. et al., Journal of Neuroscience 2017, 37 (35), 8385.). In recent years, metabolism is talked highly important in cancer research, especially the lipid metabolism. researchers believe that the de novo fatty acid synthesis plays an important role in tumor development.
  • MAGL as an important decomposing enzyme for both lipid metabolism and the endocannabinoids system, additionally as a part of a gene expression signature, contributes to different aspects of tumourigenesis, including in glioblastoma (Qin, H., et al., Cell Biochem. Biophys.2014, 70, 33; Nomura DK et al., Cell 2009, 140(1), 49-61; Nomura DK et al., Chem. Biol.2011, 18(7), 846-856, Jinlong Yin et al, Nature Communications 2020, 11, 2978).
  • CBRs cannabinoid receptors
  • CB1 receptors are present throughout the GI tract of animals and healthy humans, especially in the enteric nervous system (ENS) and the epithelial lining, as well as smooth muscle cells of blood vessels in the colonic wall (Wright, Rooney et al.2005), (Duncan, Davison et al.2005).
  • CB1 Activation of CB1 produces anti-emetic, anti-motility, and anti-inflammatory effect, and help to modulate pain (Perisetti, Rimu et al.2020).
  • CB2 receptors are expressed in immune cells such as plasma cells and macrophages, in the lamina intestinal of the GI tract (Wright, Rooney et al.2005), and primarily on the epithelium of human colonic tissue associated with inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • MAGL inhibition prevents TNBS-induced mouse colitis and decreases local and circulating inflammatory markers via a CB1/CB2 MoA (Marquez, Suarez et al.2009). Furthermore, MAGL inhibition improves gut wall integrity and intestinal permeability via a CB1 driven MoA (Wang, Zhang et al.2020).
  • the present invention provides compounds of formula (I) B A (I) wherein A, B, L, W, Y, Z, and R 1 to R 3 are as defined herein.
  • the invention provides compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I).
  • compositions including the compounds of formula (I), processes of manufacturing the compounds of formula (I) and methods of using the compounds of formula (I).
  • Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments.
  • alkyl refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C 1-6 -alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms.
  • the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms.
  • the alkoxy group contains 1 to 3 carbon atoms.
  • alkyl examples include methyl, ethyl, propyl, 2- propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples of alkyl are methyl, tert-butyl, and 2,2- dimethylpropyl.
  • alkoxy refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“C 1-6 -alkoxy”).
  • the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 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, yet non-limiting example of alkoxy is methoxy.
  • cycloalkylalkyl refers to a cycloalkyl group, as previously defined, attached to the parent molecular moiety via an alkyl group.
  • cycloalkylalkyl is cyclopropylmethyl.
  • halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • halogen refers to fluoro (F), chloro (Cl) or bromo (Br).
  • Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl).
  • cycloalkyl as used herein refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C 3-10 -cycloalkyl”).
  • the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
  • “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
  • the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl.
  • a particularly preferred, yet non-limiting example of cycloalkyl is cyclopropyl.
  • aryl refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members (“C6-C14-aryl”), preferably 6 to 12 ring members, and more preferably 6 to 10 ring members, and wherein at least one ring in the system is aromatic.
  • Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g.9H- fluoren-9-yl).
  • a particularly preferred, yet non-limiting example of aryl is phenyl.
  • hydroxy refers to an –OH group.
  • cyano refers to a —CN (nitrile) group.
  • sulfamoyl refers to a group H 2 N-SO 2 –.
  • haloalkyl refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro.
  • haloalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro.
  • haloalkyl are trifluoromethyl, difluoromethyl, 1,1- difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.
  • halocycloalkyl refers to a cycloalkyl group as defined herein, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a halogen atom, preferably fluoro.
  • halocycloalkyl refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by a halogen atom, most preferably fluoro.
  • Particularly preferred, yet non-limiting examples of halocycloalkyl are 1-fluorocyclopropyl and 2,2-difluorocyclopropyl.
  • hydroxycycloalkyl refers to a cycloalkyl group as defined herein, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a hydroxy group.
  • hydroxycycloalkyl refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by a hydroxy group.
  • a particularly preferred, yet non-limiting example of hydroxycycloalkyl is 1- hydroxycyclopropyl.
  • haloalkylcycloalkyl refers to a cycloalkyl group as defined herein, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by a haloalkyl group.
  • haloalkylcycloalkyl refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by a haloalkyl group.
  • haloalkylcycloalkyl refers to a cycloalkyl group wherein 1 to 2 hydrogen atoms of the cycloalkyl group have been replaced by a haloalkyl group.
  • Particularly preferred, yet non-limiting examples of haloalkylcycloalkyl are 1- (trifluoromethyl)cyclopropyl and 2-(trifluoromethyl)cyclopropyl.
  • haloalkoxy refers to an alkoxy group as defined herein, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro.
  • haloalkoxy refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro.
  • Particularly preferred, yet non-limiting examples of haloalkoxy are trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoro-1,1-dimethyl-ethoxy, (1,1,1-trifluoropropan-2-yl)oxy, and 2,2,2-trifluoroethoxy.
  • salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
  • the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular 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-acetylcystein and the like.
  • salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
  • 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 and the like.
  • the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the asymmetric carbon atom can be of the "R” or "S” configuration.
  • the abbreviation “MAGL” refers to the enzyme monoacylglycerol lipase.
  • the terms “MAGL” and “monoacylglycerol lipase” are used herein interchangeably.
  • treatment includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (2) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms).
  • the benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment.
  • neuroinflammation as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
  • neuroinflammation as used herein relates to acute and chronic inflammation of the nervous tissue, which is the main tissue component of the 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 follows injury to the central nervous system immediately, e.g., as a result of traumatic brain injury (TBI).
  • TBI traumatic brain injury
  • the term “traumatic brain injury” (“TBI”, also known as “intracranial injury”) relates to damage to the brain resulting from external mechanical force, such as rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile.
  • the term “neurodegenerative diseases” relates to diseases that are related to the progressive loss of structure or function of neurons, including death of neurons. Examples of neurodegenerative diseases include, but are not limited to, multiple sclerosis, Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis.
  • mental disorders also called mental illnesses or psychiatric disorders
  • mental disorders relates to behavioral or mental patterns that may cause suffering or a poor ability to function in life. Such features may be persistent, relapsing and remitting, or occur as a single episode.
  • mental disorders include, but are not limited to, anxiety and depression.
  • pain relates 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 pain and phsychogenic pain.
  • neuropathic pain is caused by damage or disease affecting any part of the nervous system involved in bodily feelings (i.e., the somatosensory system).
  • pain is neuropathic pain resulting from amputation or thoracotomy.
  • pain is chemotherapy induced neuropathy.
  • neurotoxicity relates to toxicity in the nervous system. It occurs when exposure to natural or artificial toxic substances (neurotoxins) alter the normal activity of the nervous system in such a way as to cause damage to nervous tissue.
  • neurotoxicity examples include, but are not limited to, neurotoxicity resulting from exposure to substances used in chemotherapy, radiation treatment, drug therapies, drug abuse, and organ transplants, as well as exposure to heavy metals, certain foods and food additives, pesticides, industrial and/or cleaning solvents, cosmetics, and some naturally occurring substances.
  • cancer refers to a disease characterized by the presence of a neoplasm or tumor resulting from abnormal uncontrolled growth of cells (such cells being "cancer cells").
  • cancer explicitly includes, but is not limited to, hepatocellular carcinoma, colon carcinogenesis and ovarian cancer.
  • mammal as used herein includes both humans and non-humans and includes but is not limited to humans, non-human primates, canines, felines, murines, bovines, equines, and porcines. In a particularly preferred embodiment, the term “mammal” refers to humans.
  • the present invention provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: W and Z are each independently selected from CH 2 and CH 2 CH 2 ; Y is selected from CH and N; U is selected from CH and N; V is selected from NH, O, and S; X is selected from NH and O; L is selected from CH2 and O; A is selected from: B is selected from: and a 9-membered fused bicyclic heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, the remaining ring atoms being carbon; R 1 is selected from hydrogen, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo- C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: W and Z are each independently selected from CH2 and CH2CH2; Y is selected from CH and N; U is selected from CH and N; V is selected from NH, O, and S; L is selected from CH2 and O; A is selected from: B is selected from: R 1 is selected from hydrogen, halogen, cyano, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo- C1-C6-alkyl, halo-C1-C6-alkoxy, C3-C10-cycloalkyl, halo-C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, halo-C1-C6-alkyl-C3-C10-cycloalkyl, C6-C14- aryl, sulfam
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein W and Z are both CH2. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein W and Z are both CH 2 CH 2 . In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein Y is CH. In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein Y is N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein W and Z are both CH 2 ; or W and Z are both CH 2 CH 2 ; and Y is selected from CH and N.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein W and Z are both CH2; and Y is CH.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from: , , , the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from: , , , , , , , , , , and . In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from: .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from: .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from:
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from:
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is CH2.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is . In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from hydrogen, cyano, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 3 -C 10 - cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, halo-C1-C6-alkyl-C3-C10- cycloalkyl, C - 6 C14-aryl, sulfamoyl, a group , and (C1-C6- alkyl) 2 PO-; R 1a is selected from C 1 -C 6 -alkyl and halo-C 1 -C 6 -alkyl; and X is selected from NH and O.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from hydrogen, methyl, ethyl, tert-butyl, cyano, CHF2, CF3, 1,1- difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, sulfamoyl, dimethylphosphoryl, phenyl, and (CF3)cyclopropyl; R 1a is selected from methyl and CF3; and X is selected from NH and O.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from halo-C1-C6-alkyl, C3-C10-cycloalkyl, halo-C1-C6-alkyl-C3-C10- cycloalkyl, and a group R 1a is halo-C 1 -C 6 -alkyl; and X is selected from NH and O.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from CHF2, CF3, 2,2,2-trifluoroethyl, cyclopropyl, (CF3)cyclopropyl, and a group R 1a is CF 3 ; and X is selected from NH and O.
  • R 1 is selected from CHF2, CF3, 2,2,2-trifluoroethyl, cyclopropyl, (CF3)cyclopropyl, and a group
  • R 1a is CF 3
  • X is selected from NH and O.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1- C 6 -alkyl, halo-C 1 -C 6 -alkyl-C 3 -C 10 -cycloalkyl, C 6 -C 14 -aryl, sulfamoyl, and (C 1 -C 6 - alkyl) 2 PO-.
  • R 1 is selected from hydrogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1- C 6 -alkyl, halo-C 1 -C 6 -alkyl-
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, methyl, ethyl, tert-butyl, cyano, CHF 2 , CF 3 , 1,1-difluoroethyl, 2,2,2- trifluoroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, sulfamoyl, dimethylphosphoryl, phenyl, and (CF3)cyclopropyl.
  • R 1 is selected from hydrogen, methyl, ethyl, tert-butyl, cyano, CHF 2 , CF 3 , 1,1-difluoroethyl, 2,2,2- trifluoroethyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, sulfamoyl, dimethylphosphoryl, phenyl, and (CF3)cyclo
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from halo-C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, and halo-C 1 -C 6 -alkyl-C 3 -C 10 -cycloalkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CHF 2 , CF 3 , 2,2,2-trifluoroethyl, cyclopropyl, and (CF 3 )cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CF 3 , cyclopropyl, and 1-(trifluoromethyl)cyclopropyl.
  • R 1 is selected from CF 3 , cyclopropyl, and 1-(trifluoromethyl)cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is halo-C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is CF 3 .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, C1-C6-alkyl, and halo-C1-C6-alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, methyl, ethyl, and CF3.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, methyl, and CF3.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 3 -C 10 - cycloalkyl, hydroxy-C 3 -C 10 -cycloalkyl, amino-C 3 -C 10 -cycloalkyl, and halo-C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from cyclopropyl, 1-hydroxycyclopropyl, 1-aminocyclopropyl, and CF 3 .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C3-C10- cycloalkyl, hydroxy-C 3 -C 10 -cycloalkyl, halo-C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 3 -C 10 -cycloalkyl and halo-C 1 -C 6 -alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from cyclopropyl, hydroxycyclopropyl, and CF 3 .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from cyclopropyl and CF3.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is C3-C10- cycloalkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is cyclopropyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected CF3.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: W and Z are each independently selected from CH 2 and CH 2 CH 2 ; Y is selected from CH and N; U is selected from CH and N; V is selected from NH, O, and S; X is selected from NH and O; L is selected from CH2 and O; A is selected from B is selected from: R 1 is selected from hydrogen, cyano, C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl, C 3 -C 10 - cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkyl-C 3 -C 10 - cycloalkyl, C -C -ar 6 14 yl, sulfamoyl, a group , and (C1-C6- alkyl,
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: W and Z are both CH2; or W and Z are both CH 2 CH 2 ; Y is selected from CH and N; X is selected from NH and O; L is CH 2 ; A is selected from and ; B is selected from: ; R 1 is selected from halo-C1-C6-alkyl, C3-C10-cycloalkyl, halo-C1-C6-alkyl-C3-C10- cycloalkyl, and a group R 1a is halo-C 1 -C 6 -alkyl; R 2 is selected from hydrogen, C1-C6-alkyl, and halo-C1-C6-alkyl; and R 3 is selected from C 3 -C 10 -cycloalkyl, hydroxy-C 3 -C 10 -cycloalkyl, halo-C 1 -C 6
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: W and Z are both CH 2 ; or W and Z are both CH 2 CH 2 ; Y is selected from CH and N; X is selected from NH and O; L is CH 2 ; A is selected from B is selected from: , , , , , , and ; R 1 is selected from CHF 2 , CF 3 , 2,2,2-trifluoroethyl, cyclopropyl, (CF 3 )cyclopropyl, and a group R 1a is CF3; R 2 is selected from hydrogen, methyl, and CF 3 ; and R 3 is selected from cyclopropyl, hydroxycyclopropyl, and CF3.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: W and Z are each independently selected from CH 2 and CH 2 CH 2 ; Y is selected from CH and N; U is selected from CH and N; V is selected from NH, O, and S; L is selected from CH2 and O; A is selected from B is selected from: R 1 is selected from hydrogen, cyano, C1-C6-alkyl, halo-C1-C6-alkyl, C3-C10- cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, halo-C1-C6-alkyl-C3-C10- cycloalkyl, C 6 -C 14 -aryl, sulfamoyl, and (C 1 -C 6 -alkyl) 2 PO-; R 2 is selected from hydrogen, C1-C6-alkyl, and halo-C
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: W and Z are both CH 2 ; or W and Z are both CH2CH2; Y is selected from CH and N; L is CH 2 ; A is selected from B is selected from: ; R 1 is selected from halo-C1-C6-alkyl, C3-C10-cycloalkyl, and halo-C1-C6-alkyl-C3- C10-cycloalkyl; R 2 is selected from hydrogen, C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkyl; and R 3 is selected from C3-C10-cycloalkyl, hydroxy-C3-C10-cycloalkyl, halo-C1-C6- alkyl.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: W and Z are both CH2; or W and Z are both CH 2 CH 2 ; Y is selected from CH and N; L is CH2; A is selected from B is selected from: , , , , , , and ; R 1 is selected from CHF 2 , CF 3 , 2,2,2-trifluoroethyl, cyclopropyl, and (CF3)cyclopropyl; R 2 is selected from hydrogen, methyl, and CF3; and R 3 is selected from cyclopropyl, hydroxycyclopropyl, and CF 3 .
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from [6-[3-(1-hydroxycyclopropyl)-1,2,4-triazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]-[6-[[1- methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone; [6-[3-(1-hydroxycyclopropyl)-1,2,4-triazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]-[6-[[1- methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone; [6-[3-(1-hydroxycyclopropyl)-1,2,4-triazol
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from [6-[3-(1-hydroxycyclopropyl)-1,2,4-triazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]-[6-[[1- methyl-5-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone; [6-[3-(1-hydroxycyclopropyl)-1,2,4-triazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]-[6-[[1- methyl-5-(trifluoromethyl)pyrazol-3-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone; [6-[3-(1-hydroxycyclopropyl)-1,2,4-triazol
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is [6-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]-[6-[[5- (trifluoromethyl)-1H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is [6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]-[6-[[5- (trifluoromethyl)-1H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is [6-[[5-[1-(trifluoromethyl)cyclopropyl]-1H-1,2,4-triazol-3-yl]methyl]-2- azaspiro[3.3]heptan-2-yl]-[6-[3-(trifluoromethyl)-1,2,4-triazol-1-yl]-2- azaspiro[3.3]heptan-2-yl]methanone.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is [6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]-[6-[[5-[1- (trifluoromethyl)cyclopropyl]-1H-1,2,4-triazol-3-yl]methyl]-2-azaspiro[3.3]heptan-2- yl]methanone.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is [6-[[5-(trifluoromethyl)-1H-pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]-[6-[3- (trifluoromethyl)-1,2,4-triazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]methanone.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is [6-[(3-cyclopropyl-1H-pyrazol-5-yl)methyl]-2-azaspiro[3.3]heptan-2-yl]-[6-[3- (trifluoromethyl)-1,2,4-triazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]methanone.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is [6-(3-cyclopropyl-1,2,4-triazol-1-yl)-2-azaspiro[3.3]heptan-2-yl]-[6-[[3- (trifluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptan-2-yl]methanone.
  • the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein.
  • the present invention provides compounds according to formula (I) as described herein as free bases.
  • the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number.
  • isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure.
  • isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 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 I, respectively.
  • 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 isotopes tritium, i.e.
  • a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
  • Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • 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 as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Processes of Manufacturing The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.
  • one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps
  • appropriate protective groups as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.
  • Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.
  • compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically/enantiomerically enriched starting materials and intermediates.
  • the solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent.
  • the described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux.
  • the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds.
  • reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section.
  • the present compounds of formula I can be prepared by reacting an activated intermediate of formula 2 with the nucleophilic amine 1 by heating in a solvent such as DMF or CH3CN in the presence of a base such as DIPEA.
  • the activated intermediate can be formed on the other coupling partner (1) that will make the urea of formula I.
  • Scheme 1 The activated intermediate 2 can be generated transiently in the reaction mixture, or by reacting an amine 3 with a coupling agent such as di(1H-1,2,4-triazol-1-yl)methanone in a solvent such as CH 2 Cl 2 in the presence of a base such as DIPEA (Scheme 2).
  • a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride
  • Scheme 5 1. alkylation 2. deprotection 1 1 10 Scheme 5
  • building blocks of formula 12 can be prepared by a Mitsunobu type reaction of heterocycle B (13) with a hydroxyl building block 14 (e.g.
  • building blocks of formula 12 can be prepared by conversion of hydroxyl building block 14 to a mesylate (e.g. using MsCl, Et3N) followed by an SN2 reaction with the heterocycle B (13) in the presence of a base such as NaH. 1.
  • the nitrile derivatives can be generated from the hydroxyl derivatives (19) via conversion to a mesylate (e.g. using MsCl, Et 3 N) followed by S N 2 displacement of the mesylate group with cyanide (e.g. using KCN).
  • the diketone derivatives can be generated from the commercial ester derivatives (20) (Scheme 7).
  • a base e.g. NaH, LDA
  • Building blocks 1 can also be subjected to further functionalization reactions (e.g. formation of an amide under standard conditions, alkylation of an alcohol (e.g. using NaH and an alkylating agent in DMF), conversion of boron-containing groups to hydroxyl using alkaline peroxide conditions, oxidation of thioethers to sulfones, or installation of small alkyl groups in place of Br or I groups using metal catalyzed cross-coupling conditions such as Buchwald or Suzuki reactions) before or after deprotection of the nucleophilic amine, to yield other building blocks of formula 1.
  • building blocks could be generated from commercially available fragments using standard functional group interconversion techniques (e.g. installation of a halide (e.g.
  • NIS or NBS NIS or NBS
  • removal of a halide e.g. under hydrogenation conditions
  • conversion of halides to other groups e.g. small amine, small alkyl using metal catalyzed cross-coupling conditions such as Buchwald or Suzuki reactions
  • conversion of iodide to a trifluoromethyl group using a trifluoromethylating reagent e.g.
  • the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein the process is as described in any one of schemes 1 to 12.
  • the present invention provides a process for manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula 2; wherein A and R 3 are as defined herein, with a compound of formula 1; wherein R 1 , R 2 , B, L, W, Y, and Z are as defined herein; by heating in a solvent, such as DMF or CH3CN, in the presence of a base, such as DIPEA, to form said compound of formula (I).
  • a solvent such as DMF or CH3CN
  • a base such as DIPEA
  • the present invention provides the use of compounds of formula (I) as described herein for inhibiting MAGL in a mammal.
  • the present invention provides compounds of formula (I) as described herein for use in a method of inhibiting MAGL in a mammal.
  • the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for inhibiting MAGL in a mammal.
  • the present invention provides a method for inhibiting MAGL in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.
  • the amount of arachidonic acid formed was traced by an online SPE system (Agilent Rapidfire) coupled to a triple quadrupole mass spectrometer.
  • a C18 SPE cartridge (Agilent G9205A) was used in an acetonitrile/water liquid setup.
  • the mass spectrometer was operated in negative electrospray mode following the mass transitions 303.1 259.1 for arachidonic acid and 311.1 267.0 for d8-arachidonic acid.
  • the activity of the compounds was calculated based on the ratio of intensities [arachidonic acid / d8-arachidonic acid].
  • the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein for use as a therapeutically active substance.
  • the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting monoacylglycerol lipase in a mammal.
  • 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 diseases or disorders that are associated with monoacylglycerol lipase in a mammal.
  • the present invention provides a method for the treatment or prophylaxis of diseases or disorders that are associated with monoacylglycerol lipase in a mammal, which method comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein to the mammal.
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein in the preparation of a medicament for the treatment or prophylaxis of diseases or disorders that are associated with monoacylglycerol lipase in a mammal.
  • the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as described herein for the treatment or prophylaxis of diseases or disorders that are associated with monoacylglycerol lipase in a mammal.
  • said diseases or disorders that are associated with monoacylglycerol lipase are selected from neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders and/or inflammatory bowel disease.
  • said diseases or disorders that are associated with monoacylglycerol lipase are selected from 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, visceral pain, and inflammatory bowel disease.
  • said diseases or disorders that are associated with monoacylglycerol lipase are selected from neuroinflammation, neurodegenerative diseases, pain, cancer, mental disorders, and inflammatory bowel disease in a mammal. In one embodiment, said diseases or disorders that are associated with monoacylglycerol lipase are selected from multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease in a mammal. In one embodiment, said diseases or disorders that are associated with monoacylglycerol lipase are multiple sclerosis. In one embodiment, said diseases or disorders that are associated with monoacylglycerol lipase are selected from neuroinflammation and neurodegenerative diseases.
  • said diseases or disorders that are associated with monoacylglycerol lipase are neurodegenerative diseases. In one embodiment, said diseases or disorders that are associated with monoacylglycerol lipase are cancer. In one embodiment, said diseases or disorders that are associated with monoacylglycerol lipase are inflammatory bowel disease. In one embodiment, said diseases or disorders that are associated with monoacylglycerol lipase are pain.
  • Pharmaceutical Compositions and Administration provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier. In one embodiment, there is provided a pharmaceutical composition according to Example 310 or 311.
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations).
  • the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories).
  • the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules.
  • Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules.
  • Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi- solid substances and liquid polyols, etc.
  • Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
  • Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
  • Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi- solid or liquid polyols, etc.
  • the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
  • a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper limit given herein can be exceeded when this is shown to be indicated. Examples The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.
  • the pure enantiomers can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography (e.g., chiral SFC) or crystallization. All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise.
  • Step c) N-[1-[1-(2-azaspiro[3.3]heptan-6-yl)-1,2,4-triazol-3-yl]cyclopropyl]carbamic acid tert- butyl ester; acetic acid (A.7)
  • a solution of 6-[3-[1-(tert-butoxycarbonylamino)cyclopropyl]-1,2,4-triazol-1-yl]-2- azaspiro[3.3]heptane-2-carboxylic acid benzyl ester (4160 mg, 9.17 mmol) in methanol (30 mL) and AcOH (1.57 mL) in a pressure vessel was placed under argon.
  • the catalyst 20% Pd(OH)2/C (wet) was added (416 mg), the vessel was exacuated and filled with hydrogen. The reaction was stirred under H 2 (3 bar) at 40 °C for 18 h, cooled and filtered. The vessel and filter cake were rinsed with methanol. The filtrate was evaporated down to dryness to give 4.3 gg of the crude title compound which was used without further purification (purity approx.80%).
  • tert-butyl 6- methylsulfonyloxy-2-azaspiro[3.3]heptane-2-carboxylate 250.0 g, 858.05 mmol
  • cesium carbonate 559.14 g, 1716.09 mmol
  • NMP NMP
  • tert-butyl 6-(3-cyclopropyl-3-oxo-propanoyl)-2-azaspiro[3.3]heptane-2-carboxylate 1.0 g, 3.25 mmol
  • hydrazine hydrate 325.72 mg, 6.51 mmol
  • 1,4-dioxane (20 mL) was stirred at 90 °C for 12 h .
  • the reaction was diluted with 50 mL water, and extracted with EtOAc.
  • N-methoxymethanamine hydrochloride (927.78 mg, 9.52 mmol) was added at 20°C and the resulting mixture was stirred at 20°C for 12 h.
  • the reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered and evaporated. Purification by FC (SiO2; PE/EtOAc) gave the desired compound (2.8 g, 92.06% yield) as a yellow oil.
  • methylmagnesium bromide (0.6605 mL, 3M in diethyl ether)
  • reaction mixture was quenched by addition of saturated aqueous NH4Cl (50 mL) at 25 °C, and then diluted with H 2 O (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , filtered and evaporated to give the desired compound (2.0 g, 80.93% yield) as a yellow oil.
  • 2-tert-butoxycarbonyl-2-azaspiro[3.3]heptane-6-carboxylic acid 3000.0 mg, 12.43 mmol
  • TEA 1.89 mL, 13.68 mmol
  • 2-methylpropyl carbonochloridate 1.87 g, 13.68 mmol
  • LDA 5.91 mL, 11.82 mmol
  • Example B.34 5-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1,2,4-thiadiazole; 4- methylbenzenesulfonic acid
  • n-BuLi (227 mL, 568 mmol) was added dropwise, and the reaction mixture was stirred at the same temperature for 30 min. Next, the reaction was cooled to –60 °C, and a solution of 4,4,5,5-tetramethyl-2-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)methyl]-1,3,2-dioxaborolane (136 g, 506 mmol) in THF (750 mL) was added dropwise.
  • Step b) tert-butyl 6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate 5-bromo-3-(trifluoromethyl)-1,2,4-thiadiazole (CAS: 1781783-65-0) (7.0 g, 30.0 mmol), tert- butyl 6-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]-2-azaspiro[3.3]heptane-2- carboxylate (8.5 g, 25.4 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (4.14 g, 5.07 mmol) and potassium carbonate (7.01 g, 50.7 mmol) were dissolved in 1,4-dioxane (71 mL) and water
  • the reaction mixture was heated to 90 °C under argon for 18 h.
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was partitioned between ethyl acetate and water.
  • the organic layer was washed with brine.
  • the extract was dried over sodium sulfate, filtered through a thin layer of silica gel and evaporated.
  • the crude product was purified by flash chromatography (hexane/ethyl acetate 0- 35%) to afford tert-butyl 6-[[3-(trifluoromethyl)-1,2,4-thiadiazol-5-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate (6.5 g, 18.0 mmol, 70.9% yield) as grey solid.
  • Example B.353 used tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (CAS: 1363381-22- 9) in place of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate in Step a).
  • the synthesis was planned to include removal of an additional Br group in the hydrogenation step.
  • Example B.32 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4- methylbenzenesulfonic acid
  • a solution of tert-butyl 6-[[4-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2- carboxylate (675 mg, 1.95 mmol) and p-toluenesulfonic acid (404 mg, 2.35 mmol) in EtOAc (6 mL) was stirred at 80 °C for 12 h. The mixture was concentrated under vacuum to give a residue.
  • the aqueous phase was extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine (200 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (eluent of 0 to 30% ethyl acetate/petroleum ether) to give a crude product which was purified by reversed-phase HPLC (0.1% FA condition) to give the title compound (640 mg, 31% yield) as a brown solid.
  • Example B.347 5-(2,6-diazaspiro[3.3]heptan-2-ylmethyl)-2-(trifluoromethyl)thiazole; 4- methylbenzenesulfonic acid
  • tert-butyl 6-[[2-(trifluoromethyl)thiazol-5-yl]methyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate 2000 mg, 5.5 mmol
  • EtOAc (20 mL)
  • p- toluenesulfonic acid monohydrate 3141 mg, 16.5 mmol, 3.0 eq
  • Example B.360 3-cyclopropyl-5-(2,6-diazaspiro[3.3]heptan-2-ylmethyl)-1,2,4-thiadiazole; 4- methylbenzenesulfonic acid
  • tert-butyl 6-[(3-cyclopropyl-1,2,4-thiadiazol-5-yl)methyl]-2,6- diazaspiro[3.3]heptane-2-carboxylate 558 mg, 1.66 mmol
  • ACN 5 mL
  • p-toluenesulfonic acid monohydrate 789 mg, 4.15 mmol
  • 2,7- diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester and tert-butyl 2,6-diazaspiro[3.4]octane- 2-carboxylate respectively can be used in place of 2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester.
  • Cs 2 CO 3 was used in place of K 2 CO 3 .
  • alternative salts of the commercial spirocyclic amine building block was used (e.g. hydrochloride).
  • Example B.311 6-[[5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4- methylbenzenesulfonic acid
  • tert-butyl 6-[[5-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane-2- carboxylate 200 mg, 0.58 mmol
  • EtOAc 2 mL
  • p-toluenesulfonic acid 110 mg, 0.64 mmol
  • Example B.317 2-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazole; 4-methylbenzenesulfonic acid
  • 6-[[5-[1-(trifluoromethyl)cyclopropyl]-1,3,4-oxadiazol-2-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (3.22 g, 8.31 mmol ) in isopropyl acetate (163 mL) was added p-toluenesulfonic acid monohydrate (1.9 g, 9.97 mmol).
  • the RM was cooled to 0 °C, hydrazine monohydrate (1.47 g, 1.42 mL, 29.4 mmol) was added, and the mixture was stirred at RT for 30 min.
  • the reaction mixture was poured into EtOAc/THF 2:1, washed with water and brine, dried over Na 2 SO 4 and concentrated in vacuo to afford the title compound (3.85 g, 99%) as a white solid.
  • Step a) tert-butyl 6-(methylsulfonyloxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate
  • a stirred solution of tert-butyl 6-(hydroxymethyl)-2-azaspiro[3.3]heptane-2-carboxylate (CAS: 1363381-93-4) (14.9 g, 65.7 mmol) in DCM (299 mL) was added triethylamine (13.7 mL, 98.6 mmol), cooled the reaction mixture to 0 °C followed by dropwise addition of methanesulfonyl chloride (6.1 mL, 78.9 mmol) then reaction mixture was stirred at room temperature for 4 h.
  • Step b) tert-butyl 6-[[4-(trifluoromethyl)triazol-2-yl]methyl]-2-azaspiro[3.3]heptane-2- carboxylate
  • 4-(trifluoromethyl)-1H-triazole 2.69 g, 19.7 mmol
  • lithium bromide 3.41 g, 39.3 mmol
  • acetonitrile 300 mL
  • tert-butyl 6-(methylsulfonyloxymethyl)-2- azaspiro[3.3]heptane-2-carboxylate 6.0 g, 19.65 mmol, 1 eq, CAS 2740574-92-7.
  • Example P.62 6-[[3-(Difluoromethyl)-1H-pyrazol-5-yl]methyl]-2-azaspiro[3.3]heptane; 2,2,2- trifluoroacetic acid
  • tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3- yl]methyl]-2-azaspiro[3.3]heptane-2-carboxylate (6 g, 13.1 mmol) in dichloromethane (40 mL) was added 2,2,2-trifluoroacetic acid (20 mL) at 0 °C. The mixture was stirred at 20 °C for 16 h.
  • Step b) tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate
  • tert-butyl 6-[[5-(difluoromethyl)-2-(2-trimethylsilylethoxymethyl)pyrazol-3- yl]methylene]-2-azaspiro[3.3]heptane-2-carboxylate 7 g, 15.4 mmol) in EtOAc (100 mL) was added Pd/C 10% (2 g, 4.61 mmol, 0.3 eq) under N 2 atmosphere.
  • Example B.376 6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]oxy-2-azaspiro[3.3]heptane; 2,2,2- trifluoroacetic acid
  • tert-butyl 6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]oxy-2- azaspiro[3.3]heptane-2-carboxylate 315 mg, 0.87 mmol
  • DCM (10 mL) trifluoroacetic acid 0.4 mL, 5.23 mmol
  • Example B.349 3-(2-azaspiro[3.3]heptan-6-ylmethyl)-5-(trifluoromethyl)-1,2,4-thiadiazole;4- methylbenzenesulfonic acid
  • Step b) tert-butyl 6-[2-(hydroxyamino)-2-imino-ethyl]-2-azaspiro[3.3]heptane-2-carboxylate
  • TEA 3426 mg, 33.9 mmol
  • tert-butyl 6-(cyanomethyl)-2- azaspiro[3.3]heptane-2-carboxylate 4000 mg, 16.9 mmol
  • the mixture was stirred at 70 °C for 12 h under O2.
  • the reaction mixture was purified by prep-HPLC and lyophilized. The residue was triturated in petroleum ether (10 mL) and stirred for 10 min. The solid was collected by filtration to give the title compound (2867 mg, 8.09 mmol, 59% yield) as an off-white solid.
  • Example B.379 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2-azaspiro[3.3]heptane; 4- methylbenzenesulfonic acid
  • tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate 790 mg, 2.05 mmol
  • EtOAc 8 mL
  • p- toluenesulfonic acid (388 mg, 2.25 mmol) at 25 °C, then the reaction mixture was stirred at 80 °C for 12 h.
  • reaction mixture was concentrated under reduced pressure to give a residue.20 mL deionized water and 2 mL ACN was added to the residue, which was then lyophilized to give the title compound (811 mg, 1.77 mmol, 85% yield) as a yellow oil.
  • Step b) tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate
  • cyclopropylboronic acid 600 mg, 6.99 mmol
  • DCE 6 mL
  • boric acid 108 mg, 1.75 mmol
  • copper diacetate 698 mg, 3.5 mmol
  • Step c) tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate
  • tert-butyl 6-[[1-cyclopropyl-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate (720 mg, 1.88 mmol) in EtOAc (15 mL) was added Pd/C (wet, 216 mg, 10 %) at 25 °C, then the reaction mixture was stirred at 25 °C for 0.5 h under H 2 (15 Psi).
  • Example B.381 6-[[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]methyl]-2-azaspiro[3.3]heptane; 4- methylbenzenesulfonic acid
  • Example B.390 6-(1-methylpyrazol-4-yl)oxy-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid
  • tert-butyl 6-(1-methylpyrazol-4-yl)oxy-2-azaspiro[3.3]heptane-2-carboxylate 970 mg, 3.31 mmol
  • EtOAc 20 mL
  • TsOH 968 mg, 5.62 mmol
  • Step a) tert-butyl 6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methylene]-2- azaspiro[3.3]heptane-2-carboxylate
  • cesium carbonate 5694 mg, 17.5 mmol
  • DMF 20 mL
  • 2,2,2-trifluoroethyl trifluoromethanesulfonate 2704 mg, 11.7 mmol
  • Step b) tert-butyl 6-[[1-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-4-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate
  • EtOAc 10 mL
  • Pd/C 300 mg, 10 %, wet.
  • Example B.409 6-[(3-cyclopropyl-1H-pyrazol-5-yl)methyl]-2-azaspiro[3.3]heptane; 2,2,2-trifluoroacetic acid
  • TFA 647 mg, 437 ⁇ L, 5.67 mmol
  • Step b) tert-butyl 6-[(5-cyclopropyl-1H-pyrazol-3-yl)methyl]-2-azaspiro[3.3]heptane-2- carboxylate
  • tert-butyl 6-(4-cyclopropyl-2,4-dioxo-butyl)-2-azaspiro[3.3]heptane-2- carboxylate 540 mg, 1.68 mmol
  • Ethanol 5 mL
  • hydrazine 108 mg, 3.36 mmol
  • Example B.414 5-(2-azaspiro[3.3]heptan-6-ylmethyl)-3-(trifluoromethyl)-1,2,4-oxadiazole; 4- methylbenzenesulfonic acid
  • tert-butyl 6-[[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]methyl]-2- azaspiro[3.3]heptane-2-carboxylate 118.0 mg, 0.34 mmol
  • EtOAc 2 mL
  • p- toluenesulfonic acid 70.2 mg, 0.41 mmol
  • 2,2,2- trifluoroethyl trifluoromethanesulfonate (2016 mg, 8.69 mmol) was added at 20 °C, and the reaction stirred for 12 h. The reaction was quenched by ice slowly and then extracted with EtOAc (20 mL ⁇ 3). The combined organic phase was washed with brine (20mL ⁇ 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo.
  • N'-hydroxy-1-(trifluoromethyl)cyclopropanecarboxamidine (CAS: 2172624-76-7) (951 mg, 5.66 mmol) was added to the solution and stirred at 30 °C for 12 h.
  • the reaction was purified by prep-HPLC (water (NH4HCO3)-ACN 27%-57) to afford the title compound (670 mg, 1.65 mmol, 29 % yield) as a white solid.
  • Example B.528 6-[(4-methylsulfonylpyrazol-1-yl)methyl]-2-azaspiro[3.3]heptane; 4-methylbenzenesulfonic acid
  • Example C.17 3-bromo-5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazole
  • ACN a solution of 5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrazol-3-amine (2.3 g, 12.0 mmol) in ACN (40 mL) was added a solution of isopentyl nitrite (1.55 g, 13.2 mmol) in ACN (5 mL) dropwise at 0 °C.
  • the reaction was stirred at 0 °C for 1 h.
  • CuBr 2 (1.61 g, 7.22 mmol) was added into the mixture at 0 °C and the resulting mixture was stirred at 20 °C for 12 h.
  • Example C.22 1-(3,3,3-trifluoropropyl)pyrazole-3-carbaldehyde
  • 1H-pyrazole-3-carbaldehyde 5.0 g, 52.0 mmol
  • N,N-dimethylformamide 100 mL
  • 1,1,1-trifluoro-3-iodopropane 17.5 g, 78.1 mmol
  • Cs2CO3 33.9 g, 104 mmol, 2.0 eq
  • 18-crown-6 (6.88 g, 26.02 mmol, 0.5 eq).
  • the reaction mixture was stirred at 90 °C for 3 h.
  • 1,1,1-trifluoro-3-iodopropane (17.5 g, 78.1 mmol) and 18-crown-6 (6.88 g, 26.0 mmol) was added into the mixture and the resulting mixture was stirred at 90 °C for another 60 h.
  • the reaction mixture was poured into water (200 mL) and then extracted with ethyl acetate (100 mLx 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Example C.23 2-[[2-bromo-4-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane A mixture of trimethyl-[2-[[4-(trifluoromethyl)imidazol-1-yl]methoxy]ethyl]silane (30.0 g, 113 mmol), N-bromosuccinimide (26.1 g, 146 mmol) and AIBN (3.7 g, 22.5 mmol) in Carbon tetrachloride (300 mL) was stirred at 60 °C for 12 h. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give a residue.
  • a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg
  • Example 362 A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn

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Abstract

L'invention concerne de nouveaux composés hétérocycliques de formule générale (I) AB (I) dans laquelle A, B, L, W, Y, Z, et R1 à R3 sont tels que décrits dans la description, des compositions comprenant les composés, des procédés de fabrication des composés et des procédés d'utilisation de ces composés.
PCT/EP2023/079392 2022-10-24 2023-10-23 Composés hétérocycliques en tant qu'inhibiteurs de monoacylglycérol lipase (magl) WO2024088922A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2020104494A1 (fr) * 2018-11-22 2020-05-28 F. Hoffmann-La Roche Ag Nouveaux composés hétérocycliques
WO2021058445A1 (fr) * 2019-09-24 2021-04-01 F. Hoffmann-La Roche Ag Nouveaux inhibiteurs hétérocycliques de la monoacylglycérol lipase (magl)

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Publication number Priority date Publication date Assignee Title
WO2020104494A1 (fr) * 2018-11-22 2020-05-28 F. Hoffmann-La Roche Ag Nouveaux composés hétérocycliques
WO2021058445A1 (fr) * 2019-09-24 2021-04-01 F. Hoffmann-La Roche Ag Nouveaux inhibiteurs hétérocycliques de la monoacylglycérol lipase (magl)

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