Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
• • 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
  • A61P25/06—Antimigraine agents
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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 to 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 and/or depression 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 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.
• AEA arachidonoyl-containing phospho- and neutral lipid species including anandamide
• 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 A 2 (PLA 2 ) 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.
• LPS lipopolysaccharide
• 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 MgII ⁇ / ⁇ mice.
• IL-1-a interleukin-1-a
• IL-6 IL-6
• 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. It has been reported that anti-inflammatory drugs can suppress in preclinical models the activation of glia cells and the progression of disease including Alzheimer's disease and multiple sclerosis (Lleo A., Cell Mol Life Sci. 2007, 64, 1403). Importantly, 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).
• 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 MgII ⁇ / ⁇ 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.
• 2-AG has been reported to show beneficial effects on pain with, for example, anti-nociceptive effects in mice (Ignatowska-Jankowska B. et al., J. Pharmacol. Exp. Ther. 2015, 353, 424.) and on mental disorders, such as depression in chronic stress models (Zhong P. et al., Neuropsychopharmacology 2014, 39, 1763.).
• 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.).
• 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 (Qin, H., et al., Cell Biochem. Biophys. 2014, 70, 33: Nomura D K et al., Cell 2009, 140(1), 49-61; Nomura D K et al., Chem. Biol. 2011, 18(7), 846-856).
• suppressing the action and/or the activation of MAGL is a promising new therapeutic strategy for the treatment or prevention of neuroinflammation, neurodegenerative diseases, pain, cancer and mental disorders. Furthermore, suppressing the action and/or the activation of MAGL is a promising new therapeutic strategy for providing neuroprotection and myelin regeneration. Accordingly, there is a high unmet medical need for new MAGL inhibitors.
• the present invention provides a compound of formula (I)
• the present invention provides a process of manufacturing the urea compounds of formula (I) described herein, comprising:
• the present invention provides a compound of formula (I) as described herein, when manufactured according to the processes described herein.
• the present invention provides a compound of formula (I) as described herein, for use as therapeutically active substance.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.
• the present invention provides the use of a compound of formula (I) as described herein or of a pharmaceutical composition described herein for inhibiting monoacylglycerol lipase (MAGL) in a mammal.
• a compound of formula (I) as described herein or of a pharmaceutical composition described herein for inhibiting monoacylglycerol lipase (MAGL) in a mammal.
• the present invention provides the use of a compound of formula (I) as described herein or of a pharmaceutical composition described herein for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.
• the present invention provides the use of a compound of formula (I) as described herein or of a pharmaceutical composition described herein for the treatment or to prophylaxis of multiple sclerosis.
• the present invention provides a compound of formula (I) as described herein or a pharmaceutical composition described herein 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 pharmaceutical composition described herein for use in the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.
• the present invention provides a compound of formula (I) as described herein or a pharmaceutical composition described herein, for use in the treatment or prophylaxis 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.
• 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.
• the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for inhibiting monoacylglycerol lipase in a mammal.
• the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.
• the present invention provides the use of a compound of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis 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.
• 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.
• the present invention provides a method for inhibiting monoacylglycerol lipase in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein or of a pharmaceutical composition described herein to the mammal.
• the present invention provides a method for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein or of a pharmaceutical composition described herein to the mammal.
• the present invention provides a method for the treatment or prophylaxis 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, which method comprises administering an effective amount of a compound of formula (I) as described herein or of a pharmaceutical composition described herein to the mammal.
• alkyl refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 12 carbon atoms.
• the alkyl group contains 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 3 carbon atoms, e.g., 1, 2 or 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 and tert-butyl.
• 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 12 carbon atoms. In some preferred embodiments, the alkoxy group contains 1 to 6 carbon atoms (“C 1-6 -alkoxy”). In other embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still 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.
• 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 refers to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms. 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 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 saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms.
• cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• heterocyclyl and “heterocycloalkyl” are used herein interchangeably and refer to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
• 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
• 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon.
• Bicyclic heterocyclyl refers to heterocyclic moieties consisting of two cycles having two ring 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.
• monocyclic heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, l-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 and morpholin-3-yl.
• aryl refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members, 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.
• aryl include phenyl and 9H-fluorenyl (e.g, 9H-fluoren-9-yl).
• a particularly preferred, yet non-limiting example of aryl is phenyl.
• heteroaryl refers to a mono- or multivalent, 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 in the system is aromatic, and at least one ring in the system contains one or more heteroatoms.
• heteroaryl refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
• heteroaryl refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O, S and N.
• heteroaryl examples 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. imidazole-1-yl); benzoxazolyl (e.g. benzoxazol-2-yl) and oxazolo[5,4-c]pyridin-2-yl.
• thiazolyl e.g. thiazol-2-yl
• oxazolyl e.g. oxazol-2-yl
• 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl 1,2,4-o
• hydroxy refers to an —OH group.
• cyano refers to a —CN (nitrile) group.
• haloalkyl refers to an alkyl group, 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.
• Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl (CF 3 ) and trifluoroethyl (e.g, 2,2,2-trifluoroethyl).
• haloalkoxy refers to an alkoxy group, 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.
• a particularly preferred, yet non-limiting example of haloalkoxy is trifluoromethoxy (—OCF 3 ).
• hydroxyalkyl refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group.
• hydroxyalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group have been replaced by a hydroxy group.
• Preferred, yet non-limiting examples of hydroxyalkyl are hydroxymethyl and hydroxyethyl (e.g, 2-hydroxyethyl).
• a particularly preferred, yet non-limiting example of hydroxyalkyl is hydroxymethyl.
• haloaryl refers to an aryl group, wherein at least one of the hydrogen atoms of the aryl group has been replaced by a halogen atom.
• haloaryl refers to an aryl group wherein 1, 2 or 3 hydrogen atoms, more preferably 1 or 2 hydrogen atoms, most preferably 1 hydrogen atom of the aryl group have been replaced by a halogen atom.
• a particularly preferred, yet non-limiting example of haloaryl is chlorophenyl, in particular 4-chlorophenyl.
• aryloxy refers to an aryl group, as previously defined, attached to the parent molecular moiety via an oxygen atom.
• a preferred, yet non-limiting example of aryloxy is phenoxy.
• haloaryloxy refers to a haloaryl group, as previously defined, attached to the parent molecular moiety via an oxygen atom.
• a preferred, yet non-limiting example of haloaryloxy is 4-fluorophenoxy.
• 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.
• Particular pharmaceutically acceptable salts of compounds of formula (I) are hydrochloride salts.
• ester refers to esters that hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
• Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
• Representative examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates and ethylsuccinates. Examples of pharmaceutically acceptable prodrug types are described in Higuchi and Stella. Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987.
• protective group denotes the group which selectively blocks a reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
• Protective groups can be removed at the appropriate point.
• Exemplary protective groups are amino-protective groups, carboxy-protective groups or hydroxy-protective groups.
• Particular protective groups are the tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn).
• protective groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc). More particular protective group is the tert-butoxycarbonyl (Boc).
• Exemplary protective groups and their application in organic synthesis are described, for example, in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.
• urea forming reagent refers to a chemical compound that is able to render a first amine to a species that will react with a second amine, thereby forming an 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 G. Sartori et al., Green Chemistry 2000, 2, 140 are incorporated herein by reference.
• 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 diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
• the compound of formula (I) according to the invention is a cis-enantiomer of formula (Ia) or (Ib), respectively, as described herein.
• the asymmetric carbon atom can be of the “R” or “S” configuration.
• 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.
• prophylaxis 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
• TBI traumatic brain injury
• 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.
• 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
• psychiatric 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. Examples of 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.
• 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.
• a particular example of pain is neuropathic pain, which 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 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)
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ia):
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ib):
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Ic):
• said compound of formula (Ic) has an enantiomeric excess (ee) of >80%, more preferably >90%, in particular >99%.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (Id):
• said compound of formula (Id) has an enantiomeric excess (ee) of >80%, more preferably >90%, in particular >99%.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is aryl substituted with R 4 , R 5 and R 6 .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is phenyl substituted with R 4 , R 5 and R 6 .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein: A is selected from:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from phenyl, 4-tert-butylthiazol-2-yl, 4-tert-butyloxazol-2-yl, 2-chloro-4-fluoro-phenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, 4-chlorophenyl, 5,6-dihydro-4H-cyclopenta[d]thiazol-2-yl, 3-phenyl-1,2,4-oxadiazol-5-yl, 5-(trifluoromethyl)-2-pyridyl, 4-(trifluoromethyl)pyrazol-1-yl, 2-fluoro-4-(trifluoromethyl)phenyl, 2,4-difluorophenyl, 4-chloro-3-fluoro-phenyl, 4-cyanophenyl, 4,4-difluoro-1
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or methyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
• the present invention provides a compound of formula (I) as described to herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen or methyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, halogen, C 1-6 -alkyl and halo-C 1-6 -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 hydrogen, halogen and C 1-6 -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 hydrogen, fluoro and methyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from hydrogen, methyl, fluoro and trifluoromethyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halogen, halo-C 1-6 -alkoxy and halo-C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen, halo-C 1-6 -alkoxy and halo-C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from chloro, OCF 3 and CF 3 .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, chloro, fluoro, OCF 3 and CF 3 .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, C 1-6 -alkoxy, heterocycloalkyl, C 3-10 -cycloalkyl, heteroaryl and haloaryl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, cyano, halogen, heterocycloalkyl, C 3-10 -cycloalkyl and haloaryl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, cyano, fluoro, chloro, pyrrolidinyl, cyclopentyl, cyclopropyl and chlorophenyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, methyl, methoxy, cyano, fluoro, chloro, pyrolidinyl, morpholinyl, pyrazolyl, cyclopentyl, cyclopropyl and 4-chlorophenyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen or halogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen or fluoro.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydrogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, C 1-6 -alkyl, aryl and halo-C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is tert-butyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, tert-butyl, phenyl and CF 3 .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or methyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is halogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 is fluoro.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is halogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 11 is fluoro.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 are both fluoro.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 2.
• the present invention provides a compound of formula (I) as described to herein, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein q is 0.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein A is selected from:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from hydrogen, halogen, hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkanoyl, SF 5 , C 1-6 -alkoxy, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, C 3-10 -cycloalkyl, 3- to 14-membered heterocyclyl, 3- to 14-membered heterocycloalkyl substituted with R 14 and R 15 , 5- to 14-membered heteroaryl, C 6 -C 14 -aryloxy, and halo-C 6 -C 14 -aryl.
• R 4 is selected from hydrogen, halogen, hydroxy, cyano, C 1-6 -alkyl, C 1-6 -alkanoyl, SF 5 , C 1-6 -alkoxy, halo-C 1-6 -
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen, SF 5 , C 1-6 -alkyl, C 1-6 -alkoxy, halo-C 1-6 -alkoxy, halo-C 1-6 -alkyl, C 3-10 -cycloalkyl, and 3- to 14-membered heterocycloalkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from chloro, SF 5 , methyl, methoxy, OCF 3 , CF 3 , cyclopropyl, and 2-azaspiro[3.3]heptan-2-yl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C 6 -C 14 -aryl.
• R 5 is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, C 1-6 -alkoxy, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl, 5- to 14-membered heteroaryl, and halo-C 6 -C 14 -aryl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, cyano, halogen, C 1-6 -alkyl, halo-C 1-6 -alkyl, 3- to 14-membered heterocycloalkyl, C 3-10 -cycloalkyl and halo-C 6 -C 14 -aryl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from hydrogen, cyano, fluoro, chloro, methyl, CF 3 , pyrrolidinyl, cyclopentyl, cyclopropyl and chlorophenyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from hydrogen, C 1-6 -alkyl, C 6 -C 14 -aryl, halo-C 6 -C 14 -aryl, halo-C 6 -C 14 -aryloxy, and halo-C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1-6 -alkyl or halo-C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 7 is tert-butyl or CF 3 .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from hydrogen, halogen, C 1-6 -alkyl, and halo-C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or halo-C 1-6 -alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen or CF 3 .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from C 1-6 -alkyl, C 1-6 -alkoxy, and halogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 15 is hydrogen or halogen.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein:
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from the compounds disclosed in Table 1.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, selected from:
• the present invention provides pharmaceutically acceptable salts or esters of the compounds of formula (I) as described herein.
• the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein, especially hydrochloride salts.
• the present invention provides pharmaceutically acceptable esters of the compounds according to formula (I) as described herein.
• the present invention provides compounds according to formula (I) as described herein.
• 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.
• 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.
• 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 compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods.
• Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art.
• reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2 nd Edition , Richard C. Larock, John Wiley & Sons, New York, N.Y. 1999). It was found convenient to carry out the reactions in the presence or absence of a 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.
• the 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.
• urea forming reagent such as bis(trichloromethyl) carbonate using a suitable base and solvent such as, e.g. sodium bicarbonate in DCM, to give compounds of formula I (step a).
• a urea forming reagent such as bis(trichloromethyl) carbonate using a suitable base and solvent such as, e.g. sodium bicarbonate in DCM
• urea forming reagents include but are not limited to phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate or 1,1′-carbonyldiimidazole.
• 3-aminopiperidin-4-ol derivatives 3 in which “PG” signifies a suitable protective group such as a Cbz or Boc protective group can be acylated for example with acyl chlorides 4 in which R 1 is as defined herein and “LG” signifies a suitable leaving group (e.g., Cl or Br), using a suitable base such as sodium or potassium carbonate, sodium hydroxide or sodium acetate in an appropriate solvent such as THF, water, acetone or mixtures thereof, to provide intermediates 5 (step a).
• Intermediates 5 can be cyclized to intermediates 6 using methods well known in the art, for example by treatment of 5 with sodium hydride in THF or potassium tert-butoxide in IPA and water (step b). Reactions of that type are described in literature (e.g. Z. Rafinski et al., J. Org. Chem. 2015, 80, 7468; S. Dugar et al., Synthesis 2015, 47(5), 712; WO2005/066187).
• Intermediates 1 can be obtained as mixtures of diastereomers and enantiomers, respectively, or as single stereoisomers depending on whether racemic mixtures or enantiomerically pure forms of cis- or trans-3-aminopiperidin-4-ol derivatives 3 or intermediates 4 are employed in their syntheses.
• Intermediates 3 are commercially available and their synthesis has also been described in literature (e.g. WO2005/066187; WO2011/0059118; WO2016/185279).
• Optically pure cis-configured intermediates 1B and 1C can be obtained for example according to Scheme 3 by chiral separation of commercially available rac-(4aR,8aS)-4a,5,6,7,8,8a-hexahydro-4H-pyrido[4,3-b][1,4]oxazin-3-one (1A) (optionally in form of a salt such as, e.g. a hydrochloride salt) using methods known in the art, e.g. by diastereomeric salt crystallization or by chiral chromatography (step a).
• a salt such as, e.g. a hydrochloride salt
• intermediates 2 are intermediates of type B.
• Intermediates of type B in which A, m, n and R 2 are as described herein can be prepared by methods well known by a person skilled in the art and as exemplified by the general synthetic procedures outlined in Scheme 4.
• Ketones 7, either commercially available or prepared by methods known in the art, can be subjected for example to a Wittig reaction with alkylidene triphenylphosphoranes of type 8a in a suitable solvent such as, e.g. THF. Methyl-THF or DMSO to give intermediates 9 (step a).
• Phosphoranes 8a can be formed by treating the corresponding phosphonium salts with a suitable base such as BuLi. NaH, or KOtBu in a suitable solvent such as THF, dioxane or Methyl-THF and may be isolated or used in situ.
• Phosphonium salts in turn are readily available from an aryl/heteroaryl/heterocyclic-substituted alkylhalide (with halide being Cl, Br and iodo) and triphenylphosphine in a suitable solvent such as toluene. Heating may be applied to accelerate the reaction or drive the reaction to completion (e.g. H. J. Cristau, F. Plisset in PATAI'S Chemistry of Functional Groups, Editor(s): Frank R. Hartley, 07th August 2006, Series Editor(s): Prof Saul Patai).
• intermediates 9 can be obtained using a Homer-Wadsworth-Emmons (HWE) reaction using ketones 7 and phosphonates 8b, wherein R a is alkyl, for example methyl or ethyl.
• Phosphonates 8b are in situ ⁇ -metalated using a suitable base and solvent such as NaH, nBuLi or KOtBu in THF (step a).
• Phosphonates 8b are readily prepared using for example the Arbuzov reaction by alkylation of an aryl/heteroaryl/heterocyclic halide (with halide being Cl, Br and iodo) with commercially available trialkyl phosphite (e.g. Chem. Rev. 1984, 84, 577).
• intermediates 2 are intermediates of type C.
• compounds 11a,b can be subjected to a reductive amination reaction with aldehydes of type 13 using a suitable reducing agent and solvent such as NaBH 3 CN in MeOH, AcOH or mixtures thereof to give intermediates 14a,b (step a).
• a suitable reducing agent and solvent such as NaBH 3 CN in MeOH, AcOH or mixtures thereof
• compounds of formula I are compounds of type Ie.
• compounds 1 can be coupled with mono-protected piperazine or 1,4-diazepane derivatives lib in which PG signifies a suitable protective group such as a Cbz or Boc protective group applying for example the conditions outlined under Scheme 1, step a, to give intermediates 16 (step c).
• PG signifies a suitable protective group such as a Cbz or Boc protective group applying for example the conditions outlined under Scheme 1, step a, to give intermediates 16 (step c).
• step d Removal of the protective group by published methods or as described under Scheme 5, step c, furnishes intermediates 15 (step d).
• intermediates 2 are intermediates of type D.
• Intermediates of type D in which A, m, n and R 2 are as described herein and R 3 is selected from hydrogen, halogen, C 1-6 -alkoxy, C 1-6 -alkyl and halo-C 1-6 -alkyl, can be prepared by methods well known in the art and as exemplified by the general synthetic procedures outlined in Scheme 7.
• Alcohols of type 17 can be subjected to a Mitsunobu reaction with intermediates 18 in which PG is a suitable protective group such as a Cbz, Boc or Bn, using an appropriate phosphine such as triphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIAD in a suitable solvent such as THF to give intermediates 19 (step a).
• Mitsunobu reactions of that type are broadly described in literature (e.g. Org. Chem. Front. 2015, 2, 739 ; Chem. Rev. 2009, 109 (6), 2551).
• step c furnishes intermediates D (step b).
• intermediates 19 may be prepared from alcohols 17 that can be alkylated with compounds 20 in which LG is a suitable leaving group such as chlorine, bromine, iodine.
• LG is a suitable leaving group such as chlorine, bromine, iodine.
• OSO 2 alkyl e.g. methanesulfonate
• OSO 2 fluoroalkyl e.g. trifluoromethanesulfonate
• OSO 2 aryl e.g. p-toluenesulfonate using a suitable base in an appropriate solvent (e.g. sodium hydride in DMF) at temperatures between 0° C. and the boiling temperature of the solvent (step c).
• intermediates 19 may be synthesized via alkylation of alcohols of type 18 with compounds 21 under the conditions described under step c (step d).
• intermediates 2 are intermediates of type E.
• Intermediates of type E in which A, m, n, R 2 and R 3 are as described herein, can be prepared by methods well known in the art and as exemplified by the general synthetic procedures outlined in Scheme 8.
• R 3 is a hydroxy group a suitable protective group strategy known to those skilled in the art may be applied.
• Intermediates 23 can be reacted with compounds of type 24, either commercially available or synthesized by methods known in the art and as described below to yield intermediates 25 (step b).
• Compounds 25 can be further converted into compounds 26 by a deoxyfluorination reaction using a suitable fluorinating agent such as DAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or aminodifluorosulfinium tetrafluoroborates (XtalFluor-E®, XtalFluor-M® in the presence of, e.g. triethylamine trihydrofluoride and TEA or DBU) in a suitable solvent such as DCM or ACN (step d).
• a suitable fluorinating agent such as DAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or aminodifluorosulfinium tetrafluoroborates (XtalFluor-E®, XtalFluor-M® in the presence of, e.g. triethylamine tri
• step c furnishes intermediates E (step e).
• intermediates 2 are intermediates of type F.
• Intermediates F in which A, m, n, R 2 and R 3 are as described herein, can be prepared by methods well known in the art and as exemplified by the general synthetic procedures outlined in Scheme 9.
• R 3 is a hydroxy group a suitable protective group strategy known to those skilled in the art may be applied.
• Intermediates 30 can be reacted with compounds of type 31, either commercially available or synthesized by methods known in the art and as described below to yield intermediates 32 (step b).
• magnesium e.g. magnesium turnings optionally in the presence of catalytic amounts of iodine, powder in the presence of LiCl or Rieke magnesium, organic halides
• halogen-magnesium exchange by treating 34 in which Hal
• Compounds 32 can be further converted into compounds 35 by a deoxyfluorination reaction using a suitable fluorinating agent such as DAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or aminodifluorosulfinium tetrafluoroborates (XtalFluor-E®, XtalFluor-M® in the presence of, e.g. triethylamine trihydrofluoride and TEA or DBU) in a suitable solvent such as DCM or ACN (step e).
• a suitable fluorinating agent such as DAST, Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) or aminodifluorosulfinium tetrafluoroborates (XtalFluor-E®, XtalFluor-M® in the presence of, e.g. triethylamine tri
• step c Removal of the protective group from intermediates 35 applying literature methods and as described for example under Scheme 3, step c, furnishes intermediates F (step f).
• intermediates 2 are intermediates of type G.
• Intermediates of type G in which A, m, n, R 2 are as described herein and R 3 is hydrogen, C 1-6 -alkoxy, C 1-6 -alkyl and halo-C 1-6 -alkyl, can be prepared by methods well known in the art and as exemplified by the general synthetic procedures outlined in Scheme 10.
• Intermediates 38 may be prepared from alcohols 36 in which PG is a suitable protective group such as a Cbz, Boc or Bn, that can be alkylated with compounds 37 in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO 2 alkyl (e.g. methanesulfonate), OSO 2 fluoroalkyl (e.g. trifluoromethanesulfonate) or OSO 2 aryl (e.g. p-toluenesulfonate) using a suitable base, such as sodium hydride, potassium tert-butoxide, in an appropriate solvent (e.g. in DMF or THF) at temperatures between 0° C. and the boiling temperature of the solvent (step a).
• PG is a suitable protective group such as a Cbz, Boc or Bn
• LG is a suitable leaving group such as chlorine, bromine, iodine
• OSO 2 alkyl e.g. methane
• step c furnishes intermediates G (step b).
• intermediates 2 are intermediates of type H.
• Intermediates of type H in which A, m, n, R 2 and R 3 are as described herein, can be prepared by methods well known in the art and as exemplified by the general synthetic procedures outlined in Scheme 11.
• Alcohols of type 17 can be subjected to a Mitsunobu reaction with intermediates 39 in which PG is a suitable protective group such as a Cbz, Boc or Bn, using an appropriate phosphine such as triphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIAD in a suitable solvent such as THF to give intermediates 41 (step a).
• Mitsunobu reactions of that type are broadly described in literature (e.g. Org. Chem. Front. 2015, 2, 739 ; Chem. Rev. 2009, 109 (6), 2551).
• step c furnishes intermediates H (step b).
• intermediates 41 may be prepared from alcohols 17 that can be alkylated with compounds 40 in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO 2 alkyl (e.g. methanesulfonate), OSO 2 fluoroalkyl (e.g. trifluoromethanesulfonate) or OSO 2 aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs 2 CO 3 , NaH, in an appropriate solvent, such as DMF at temperatures between 0° C. and the boiling temperature of the solvent (step c).
• LG is a suitable leaving group such as chlorine, bromine, iodine
• OSO 2 alkyl e.g. methanesulfonate
• OSO 2 fluoroalkyl e.g. trifluoromethanesulfonate
• OSO 2 aryl e.g. p-toluenesulfon
• step a Reacting intermediates H with intermediates 1, for example using the conditions described under scheme 1, step a, affords compounds of type If, wherein A, R 1 , R 2 , R 3 , m and n are as defined herein.
• Alcohols of type 17 can be subjected to a Mitsunobu reaction with intermediates 42, using 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 that type are broadly described in literature (e.g. Org. Chem. Front. 2015, 2, 739 ; Chem. Rev. 2009, 109 (6), 2551).
• compounds ID may be directly prepared from alcohols 17 that can be alkylated with compounds 43 in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO 2 alkyl (e.g. methanesulfonate), OSO 2 fluoroalkyl (e.g. trifluoromethanesulfonate) or OSO 2 aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs 2 CO 3 , NaH, in an appropriate solvent, such as DMF at temperatures between 0° C. and the boiling temperature of the solvent (step b).
• LG is a suitable leaving group such as chlorine, bromine, iodine
• OSO 2 alkyl e.g. methanesulfonate
• OSO 2 fluoroalkyl e.g. trifluoromethanesulfonate
• OSO 2 aryl e.g. p-toluenesulfon
• intermediates 2 are intermediates of type J.
• Intermediates of type J in which A, m, n, R 2 and R 3 are as described herein, can be prepared by methods well known in the art and as exemplified by the general synthetic procedures outlined in Scheme 13.
• Intermediates 46 may be prepared from heterocycloalkyls or heteroaryls 45 that can be alkylated with compounds 44 in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO 2 alkyl (e.g. methanesulfonate), OSO 2 fluoroalkyl (e.g. trifluoromethanesulfonate) or OSO 2 aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs 2 CO 3 , K 2 CO 3 , NaH, in an appropriate solvent, such as DMF at temperatures between 0° C. and the boiling temperature of the solvent (step a).
• LG is a suitable leaving group such as chlorine, bromine, iodine
• OSO 2 alkyl e.g. methanesulfonate
• OSO 2 fluoroalkyl e.g. trifluoromethanesulfonate
• OSO 2 aryl
• step c furnishes intermediates J (step b).
• compounds of type Ig may be directly prepared from heterocycloalkyls or heteroaryls 45 that can be alkylated with compounds 47 in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO 2 alkyl (e.g. methanesulfonate), OSO 2 fluoroalkyl (e.g. trifluoromethanesulfonate) or OSO 2 aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs 2 CO 3 , K 2 CO 3 , NaH, in an appropriate solvent, such as DMF at temperatures between 0° C. and the boiling temperature of the solvent (Scheme 14).
• LG is a suitable leaving group such as chlorine, bromine, iodine
• OSO 2 alkyl e.g. methanesulfonate
• OSO 2 fluoroalkyl e.g. trifluoromethanesulfonate
• intermediates 2 are intermediates of type K.
• Intermediates of type K in which A, m, n, R 2 and R 3 are as described herein, can be prepared by methods well known in the art and as exemplified by the general synthetic procedures outlined in Scheme 15.
• Alcohols of type 48 can be subjected to a Mitsunobu reaction with intermediates 39 in which PG is a suitable protective group such as a Cbz, Boc or Bn, using an appropriate phosphine such as triphenylphosphine and a dialkyl azodicarboxylate such as DEAD or DIAD in a suitable solvent such as THF to give intermediates 49 (step a).
• Mitsunobu reactions of that type are broadly described in literature (e.g. Org. Chem. Front. 2015, 2, 739 ; Chem. Rev. 2009, 109 (6), 2551).
• step c furnishes intermediates K (step b).
• intermediates 49 may be prepared from alcohols 48 that can be alkylated with compounds 40 in which LG is a suitable leaving group such as chlorine, bromine, iodine, OSO 2 alkyl (e.g. methanesulfonate), OSO 2 fluoroalkyl (e.g. trifluoromethanesulfonate) or OSO 2 aryl (e.g. p-toluenesulfonate) using a suitable base such as Cs 2 CO 3 , NaH, in an appropriate solvent, such as DMF at temperatures between 0° C. and the boiling temperature of the solvent (step c).
• LG is a suitable leaving group such as chlorine, bromine, iodine
• OSO 2 alkyl e.g. methanesulfonate
• OSO 2 fluoroalkyl e.g. trifluoromethanesulfonate
• OSO 2 aryl e.g. p-toluenesulfon
• intermediates 2 are intermediates of type L.
• Intermediates of type L in which A, m, n, R 2 and R 3 are as described herein can be prepared by methods well known by a person skilled in the art and as exemplified by the general synthetic procedures outlined in Scheme 16.
• Intermediates 51 can be prepared for example from aldehydes 50, either commercially available or prepared by methods known in the art, using a Wittig reaction or Homer-Wadsworth-Emmons (HWE) reaction using alkylidene triphenylphosphoranes of type 8a and phosphonates 8b, respectively, as described under step a in Scheme 4 (step a).
• HWE Homer-Wadsworth-Emmons
• the present invention provides a process of manufacturing the urea compounds of formula (I) described herein, comprising:
• urea forming reagent is selected from bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate and 1,1′-carbonyldiimidazole, preferably wherein said urea forming reagent is bis(trichloromethyl) carbonate.
• the present invention provides a compound of formula (I) as described herein, when manufactured according to any one of the processes described herein.
• compositions of the present invention are MAGL inhibitors.
• 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 4-NPA assay was carried out in 384 well assay plates (black with clear bottom, non-binding surface treated, Coming Ref 3655) in a total volume of 40 ⁇ L.
• Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in a polypropylene plate in 3-fold dilution steps to give a final concentration range in the assay from 25 ⁇ M to 1.7 nM.
• 1 ⁇ L compound dilutions (100% DMSO) were added to 19 ⁇ L MAGL (recombinant wild-type) in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 ml)).
• the plate was shaked for 1 min at 2000 rpm (Variomag Teleshake) and then incubated for 15 min at RT.
• 20 ⁇ L 4-Nitrophenlyacetate (Sigma N-8130) in assay buffer with 6% EtOH was added.
• the final concentrations in the assay were 1 nM MAGL and 300 ⁇ M 4-Nitrophenylacetate.
• the absorbance at 405 nm was measured for a fist time (Molecular Devices, SpectraMax Paradigm).
• a second measurement was then done after incubation for 80 min at RT. From the two measurements, the slope was calculated by subtracting the first from the second measurement.
• the 2-AG assay was carried out in 384 well assay plates (PP. Greiner Cat #784201) in a total volume of 20 ⁇ L. Compound dilutions were made in 100% DMSO (VWR Chemicals 23500.297) in a polypropylene plate in 3-fold dilution steps to give a final concentration range in the assay from 12.5 ⁇ M to 0.8 ⁇ M. 0.25 ⁇ L compound dilutions (100% DMSO) were added to 9 ⁇ L MAGL in assay buffer (50 mM TRIS (GIBCO, 15567-027), 1 mM EDTA (Fluka, 03690-100 ml), 0.01% (v/v) Tween.
• a C18 SPE cartridge (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 compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein, wherein said compounds of formula (I) and their pharmaceutically acceptable salts or esters have IC 50 's for MAGL inhibition below 25 ⁇ M, preferably below 10 ⁇ M, more preferably below 5 ⁇ M as measured in the MAGL assay described herein.
• compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein have IC 50 (MAGL inhibition) values between 0.0000001 ⁇ M and 25 ⁇ M, particular compounds have IC 50 values between 0.000005 ⁇ M and 10 ⁇ M, further particular compounds have IC 50 values between 0.00005 ⁇ M and 5 ⁇ M, as measured in the MAGL assay described herein.
• IC 50 MAGL inhibition
• the present invention provides compounds of formula (I) and their pharmaceutically acceptable salts or esters as described herein, wherein said compounds of formula (I) and their pharmaceutically acceptable salts or esters have an IC 50 for MAGL below 25 ⁇ M, preferably below 10 ⁇ M, more preferably below 5 ⁇ M as measured in an assay comprising the steps of:
• the present invention provides compounds of formula (I) as described herein for use as therapeutically active substance.
• the present invention provides the use of compounds of formula (I) as described herein for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the treatment or prophylaxis of neuroinflammation and/or neurodegenerative diseases in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the treatment or prophylaxis of neurodegenerative diseases in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the treatment or prophylaxis of cancer in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the treatment or prophylaxis of multiple sclerosis.
• the present invention provides the use of compounds of formula (I) as described herein for the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the treatment or prophylaxis of multiple sclerosis in a mammal.
• the present invention provides compounds of formula (I) as described herein for use in the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.
• the present invention provides compounds of formula (I) as described herein for use in the treatment or prophylaxis of neuroinflammation and/or neurodegenerative diseases in a mammal.
• the present invention provides compounds of formula (I) as described herein for use in the treatment or prophylaxis of cancer in a mammal.
• the present invention provides compounds of formula (I) as described herein for use in the treatment or prophylaxis of neurodegenerative diseases in a mammal.
• the present invention provides compounds of formula (I) as described herein for use in the treatment or prophylaxis 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.
• the present invention provides compounds of formula (I) as described herein for use in the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal.
• the present invention provides compounds of formula (I) as described herein for use in the treatment or prophylaxis of multiple sclerosis in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of neuroinflammation and/or neurodegenerative diseases in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of neurodegenerative diseases in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of cancer in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis 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.
• the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal.
• the present invention provides the use of compounds of formula (I) as described herein for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis in a mammal.
• the present invention provides a method for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.
• the present invention provides a method for the treatment or prophylaxis of neuroinflammation and/or neurodegenerative diseases in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.
• the present invention provides a method for the treatment or prophylaxis of neurodegenerative diseases in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.
• the present invention provides a method for the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression and/or pain in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.
• the present invention provides a method for the treatment or prophylaxis of multiple sclerosis, Alzheimer's disease and/or Parkinson's disease in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.
• the present invention provides a method for the treatment or prophylaxis of multiple sclerosis in a mammal, which method comprises administering an effective amount of a compound of formula (I) as described herein to the mammal.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.
• the compounds of formula (I) and their pharmaceutically acceptable salts and esters 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 and esters 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.
• the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prophylaxis of type 2 diabetes related microvascular complications (such as, but not limited to diabetic retinopathy, diabetic neuropathy and diabetic nephropathy), coronary artery disease, obesity and underlying inflammatory diseases, chronic inflammatory and autoimmune/inflammatory diseases.
• type 2 diabetes related microvascular complications such as, but not limited to diabetic retinopathy, diabetic neuropathy and diabetic nephropathy
• coronary artery disease such as, but not limited to diabetic retinopathy, diabetic neuropathy and diabetic nephropathy
• obesity underlying inflammatory diseases
• chronic inflammatory and autoimmune/inflammatory diseases such as, chronic inflammatory and autoimmune/inflammatory diseases.
• 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.
• a microwave vial was heat gun-dried and charged with bis(trichloromethyl) carbonate (26.6 mg, 89.6 ⁇ mol) and sodium bicarbonate (32.3 mg, 384 mol).
• the flask was placed under argon and DCM (1 mL) was added to give a suspension.
• the suspension was cooled by an ice-bath and 4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine; hydrochloride salt (36.1 mg, 121 mol, BB15) was added. The mixture was stirred at 0° C. for 15 min and at RT overnight.
• reaction mixture was cooled down in an-ice bath and DCM (500 ⁇ L) and DIPEA (49.7 mg, 67.1 ⁇ L, 384 ⁇ mol) followed by (4aR,8aS)-6-(4-((2-chloro-4-fluorophenoxy)methyl)-4-fluoropiperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (21.1 mg, 47.5 ⁇ mol, BB1a) were added. The resulting off-white suspension was stirred at room temperature for 7 h. The reaction mixture was poured on water, DCM was added and the layers were separated. The aqueous layer was extracted twice with DCM.
• Step b) (4aS,8aR)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 42) and (4aR 8aS)-6-(4-(((6-(trifluoromethyl)pyridin-3-yl)oxy)methyl)piperidine-1-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one (Example 43)
• example 117 The stereoisomers of example 117 were separated by preparative chiral HPLC (Reprosil Chiral NR column) using an isocratic mixture of EtOH (containing 0.05% of NH 4 OAc): n-heptane (40:60) to provide examples 103 and 104 as single isomers and example 105 as mixture of two stereoisomers. The fractions were evaporated to provide the desired compounds as colorless solids.
• BB7 a crude racemic product
• the crude material was directly submitted for a chiral SFC separation to yield enantiomer BB7b (2.72 g, second eluting to enantiomer) as a yellow solid and enantiomer BB7a (3.25 g, first eluting enantiomer) as a light beige solid but contaminated with BB7b.
• a further SFC chiral separation was carried out to yield 2.71 g of BB7a.
• MS (ESI): m/z 322.2 [M+H] + for both enantiomers.
• Trifluoroacetic acid (2 g, 1.35 mL, 17.5 mmol) was added to a solution of tert-butyl 3-((2-chloro-4-(trifluoromethyl)phenoxy)methyl)azetidine-1-carboxylate (320 mg, 875 ⁇ mol) in DCM (4.37 mL) and the solution was stirred at RT for 2 h. The solvent was removed under reduced pressure and the resulting pale oil (470 mg) was diluted with EtOAc and washed with aq. Na 2 CO 3 solution.
• the organic layers were washed twice with H 2 O, dried over MgSO 4 , filtered, treated with silica gel and evaporated.
• the compound was purified by silica gel chromatography on a 120 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (50 to 100 in 30 min.) to provide the compound as a light yellow solid (2.48 g) which could be used in the following step without further purification.
• Step a) Benzyl 3-(((2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethyl)amino)methyl)azetidine-1-carboxylate
• benzyl 3-(aminomethyl)azetidine-1-carboxylate 0.5 g, 2.27 mmol
• NEt 3 689 mg, 949 ⁇ L, 6.81 mmol
• 2,2,2-trifluoro-1-(3-(trifluoromethyl)phenyl)ethan-1-one 554 mg, 391 ⁇ L, 2.27 mmol
• dry DCM 15 mL
• Titanium tetrachloride 1M in DCM (1.13 mL, 1.13 mmol) was added via a syringe and the flask was cooled in an ice bath (exothermic).
• the reaction was basified with sat. NaHCO 3 .
• the obtained insoluble material was filtered over celite and the filtrate was extracted with DCM.
• the organic layers were combined, washed with brine, dried over Na 2 SO 4 and concentrated.
• the crude material was purified by flash chromatography (silica gel, 50 g, 0% to 50% EtOAc in n-heptane) to give the desired compound as a colorless oil (1 g).
• Step b) Benzyl 3-(((1-(2,4-dichlorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate
• tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate 80.7 mg, 375 ⁇ mol was dissolved in DMF (1.5 mL), then NaH in Oil 60% (18 mg, 450 ⁇ mol) was added at room temperature, the mixture was stirred for 20 min, then 5-bromo-3-methyl-2-(trifluoromethyl)pyridine (90 mg, 60 ⁇ L, 375 ⁇ mol) was added, and it was stirred for 2 hr at RT, yielding a brown solution. 10 mL sat. NH 4 C were added, it was extracted with water/ethyl acetate, dried over MgSO 4 , the solvent was removed at 40° C./150 mbar.
• Step a Benzyl 3-(((1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carboxylate
• benzyl 3-(aminomethyl)azetidine-1-carboxylate 0.5 g, 2.27 mmol
• triethylamine 689 mg, 949 ⁇ L, 6.81 mmol
• 1-(2-chloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone 519 mg, 2.27 mmol
• dry DCM 15 mL
• Titanium tetrachloride 1M in DCM (1.13 mL, 1.13 mmol) was added via a syringe to the ice-cooled flask (exothermic).
• the reaction was stirred overnight at RT, carefully quenched with a methanolic solution of sodium cyanoborohydride (428 mg, 6.81 mmol) in methanol (4.36 g, 5.51 mL, 136 mmol)+Acetic Acid (0.1 mL) and stirred overnight at RT.
• the reaction was basified with sat. NaHCO 3 .
• the insoluble material obtained was filtered away over celite, the filtrate was extracted with DCM, the organic layers were combined, washed with brine, dried over Na 2 SO 4 and concentrated.
• tert-butyl-3-hydroxy-2-methylazetidine-1-carboxylate (215 mg, 1.15 mmol) was dissolved in DMF (5 mL) to give a colorless solution.
• sodium hydride (60% dispersion in mineral oil) (41.8 mg, 1.05 mmol) was added.
• the reaction mixture was stirred at 0° C. for 15 min.
• 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.250 g, 1.05 mmol) was added at 0° C.
• the reaction mixture was stirred at RT overnight.
• the reaction mixture was poured onto 20 mL sat.
• intermediates BB20, BB25 and BB61 of the following table were prepared from the commercially available phen9ols. Where trifluoroacetate salts are indicated, the crude product resulting from concentration of the reaction mixture was used directly without further neutralization or purification.
• step a the following building blocks were prepared from the respective starting materials.
• tert-butyl 3-(3-bromo-4-chlorophenoxy)azetidine-1-carboxylate (0.075 g, 0.165 mmol), cyclopropylboronic acid (0.021 g, 0.248 mmol) and K 2 CO 3 (0.046 g, 0.331 mmol) were mixed in dioxane (1.6 mL). Then, water (0.4 mL) was added followed by bis(triphenylphosphine)palladium (II) chloride (0.012 g, 0.016 mmol) and the reaction mixture heated at 130° C. under microwave irradiation for 1 hour.
• (+)-(4aR,8aS)-6-[3-[3-bromo-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB 205, 0.2 g, 0.420 mmol), Zn(CN) 2 (0.098 g, 0.840 mmol), Zn (0.027 g, 0.420 mmol), dppf (0.232 g, 0.420 mmol).
• Hünig's base (0.108 g, 0.840 mmol) were mixed in DMA (10 mL) and the mixture was degassed.
• (+)-(4aR,8aS)-6-[3-[3-bromo-4-(trifluoromethyl)phenoxy]azetidine-1-carbonyl]-4,4a,5,7,8,8a-hexahydropyrido[4,3-b][1,4]oxazin-3-one (BB203, 0.2 g, 0.420 mmol), 2-azaspiro[3.3]heptane (CAS RN 665-04-03, 0.117 g, 0.630 mmol), BINAP (0.052 g, 0.080 mmol) and K 2 CO 3 (0.173 g, 1.25 mmol) were mixed in DMF (10 mL) and the mixture was degassed.
• Example 265 The following examples listed in the table below were prepared in analogy to the procedure described for the preparation of Example 265 by using the indicated intermediates and/or commercially available compounds and using the mentioned purification method such as reversed-phase HPLC or silica gel flash chromatography.
• tert-butyl 4-(hydroxymethyl)azepane-1-carboxylate (480 mg, 2.09 mmol) was dissolved in THF (10 ml). Subsequently, 2-chloro-4-fluorophenol (337 mg, 251 ⁇ l, 2.3 mmol) and triphenylphosphine (604 mg, 2.3 mmol) were added and the clear solution was stirred for 5 min at rt. The mixture was cooled to 0° C. and DEAD (401 mg, 365 ⁇ l, 2.3 mmol) was added in portions over 10 min.
• Triphenylphosphine (1.84 g, 7 mmol) and 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.61 g, 6.74 mmol) were dissolved in xylene (35 ml).
• the reaction mixture was heated to reflux at 155° C. for 3.5 h and then cooled to room temperature.
• the precipitated white crystalline solid was collected by filtration, washed with diethyl ether and dried in vacuo.
• the final compound (3.30 g, 6.58 mmol, 97.7% yield) was obtained as a white powder and directly used on the next step.
• Step b tert-butyl (E)-4-(4-(trifluoromethyl)benzylidene)azepane-1-carboxylate
• Step c tert-butyl 4-(4-(trifluoromethyl)benzyl)azepane-1-carboxylate
• the compound was prepared in analogy to BB99, step a, and used in the next step without further purification.
• the sulfoxide intermediate was isolated from the synthesis of the according sulfone building block BB99, step b.
• the product was obtained as a white lyophilized powder (50 mg, 13.9%)
• MS (ESI): m/z 328.1 [M ⁇ 56+H] + .
• step a) tert-Butyl 3-((2-fluoro-6-(trifluoromethyl)benzyl)thio)azetidine-1-carboxylate
• Step a tert-Butyl 4-[3-bromo-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate

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