Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• the present invention relates to novel 2-(1 ,2,3-triazol-2-yl)benzamide and 3-(1 ,2,3-triazol-2- yl)picolinamide derivatives of formula (I) and their use as pharmaceuticals.
• the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and their use as orexin receptor antagonists, especially as orexin-1 receptor antagonists.
• Orexins are neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OX and OX 2 receptors).
• the orexin-1 receptor (OXi) is selective for OX-A
• the orexin-2 receptor (OX 2 ) is capable to bind OX-A as well as OX-B.
• Orexin receptor antagonists are a novel type of nervous system or psychotropic drugs. Their mode of action in animals and humans involves either blockade of both orexin-1 and orexin-2 receptor (dual antagonists), or individual and selective blockade of either the orexin-1 or the orexin-2 receptor (selective antagonists) in the brain. Orexins were initially found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585).
• orexin neuropeptides and orexin receptors play an essential and central role in regulating circadian vigilance states.
• orexin neurons collect sensory input about internal and external states and send short intrahypothalamic axonal projections as well as long projections to many other brain regions.
• the particular distribution of orexin fibers and receptors in basal forebrain, limbic structures and brainstem regions - areas related to the regulation of waking, sleep and emotional reactivity- suggests that orexins exert essential functions as regulators of behavioral arousal; by activating wake-promoting cell firing, orexins contribute to orchestrate all brain arousal systems that regulate circadian activity, energy balance and emotional reactivity.
• Human memory is comprised of multiple systems that have different operating principles and different underlying neuronal substrates. The major distinction is between the capacity for conscious, declarative memory and a set of unconscious, non-declarative memory abilities. Declarative memory is further subdivided into semantic and episodic memory. Non- declariative memory is further subdivided into priming and perceptual learning, procedural memory for skills and habits, associative and non-associative learning, and some others. While semantic memory refers to the general knowledge about the world, episodic memory is autobiographical memory of events. Procedural memories refer to the ability to perform skill- based operations, as e.g. motor skills.
• Long-term memory is established during a multiple stage process through gradual changes involving diverse brain structures, beginning with learning, or memory acquisition, or formation. Subsequently, consolidation of what has been learned may stabilize memories. When long-term memories are retrieved, they may return to a labile state in which original content may be updated, modulated or disrupted. Subsequently, reconsolidation may again stabilize memories. At a late stage, long-term memory may be resistant to disruption. Long-term memory is conceptually and anatomically different from working memory, the latter of which is the capacity to maintain temporarily a limited amount of information in mind. Behavioural research has suggested that the human brain consolidates long-term memory at certain key time intervals.
• the initial phase of memory consolidation may occur in the first few minutes after we are exposed to a new idea or learning experience.
• the next, and possibly most important phase may occur over a longer period of time, such as during sleep; in fact, certain consolidation processes have been suggested to be sleep-dependent [R. Stickgold et al., Sleep-dependent memory consolidation; Nature 2005, 437, 1272-1278].
• Learning and memory processes are believed to be fundamentally affected in a variety of neurological and mental disorders, such as e.g. mental retardation, Alzheimer's disease or depression. Indeed, memory loss or impairment of memory acquisition is a significant feature of such diseases, and no effective therapy to prevent this detrimental process has emerged yet.
• Orexin-1 receptor antagonism also attenuated the expression of amphetamine- and cocaine-induced CPP [Gozzi A et al., PLoS One 2011 , 6(1 ), e16406; Hutcheson DM et al., Behav Pharmacol 2011 , 22(2), 173-181], and reduced the expression or development of locomotor sensitization to amphetamine and cocaine [Borgland SL et al.
• hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603- 1614]. Stress response may lead to dramatic, usually time-limited physiological, psychological and behavioural changes that may affect appetite, metabolism and feeding behavior [Chrousos, GP et al., JAMA 1992, 267(9), 1244-1252].
• the acute stress response may include behavioural, autonomic and endocrinological changes, such as promoting heightened vigilance, decreased libido, increased heart rate and blood pressure, or a redirection of blood flow to fuel the muscles, heart and the brain [Majzoub, JA et al., European Journal of Endocrinology 2006, 155 (suppM ) S71 -S76].
• Orexins are also involved in mediating the acute behavioral and autonomous nervous system response to stress [Zhang Wet al., "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice.” Auton Neurosci 2006, 126-127, 139-145].
• Mood disorders including all types of depression and bipolar disorder are characterized by disturbed "mood” and feelings, as well as by sleeping problems (insomnia as well as hypersomnia), changes in appetite or weight and reduced pleasure and loss of interest in daily or once enjoyed activities [Liu X et al., Sleep 2007, 30(1 ): 83-90].
• disturbances in the orexin system may contribute to the symptoms of mood disorders.
• rodent models of depression orexins were also shown to be involved. Pharmacological induction of a depressive behavioral state in rats, for instance, revealed an association with increased hypothalamic orexin levels [Feng P et al., J Psychopharmacol
• mice A chronic stress model of depression in mice also demonstrated an association of molecular orexin system disturbances with depressed behavioral states and a reversal of these molecular changes by antidepressant treatment [Nollet et al., NeuroPharm 2011 , 61 (1 -2):336-46].
• the orexin system is also involved in stress-related appetitive/reward seeking behaviour (Berridge CW et al., Brain Res 2009, 1314, 91 -102).
• a modulatory effect on stress may be complementary to an effect on appetitive/reward seeking behaviour as such.
• an OXi selective orexin receptor antagonist was able to prevent footshock stress induced reinstatement of cocaine seeking behaviour [Boutrel, B et al., Proc Natl Acad Sci 2005, 102(52), 19168-19173].
• stress is also known to play an integral part in withdrawal which occurs during cessation of drug taking (Koob, GF et al., Curr Opin Investig Drugs 2010, 1 1 (1 ), 63-71 ).
• Orexins have been found to increase food intake and appetite [Tsujino, N, Sakurai, T, Pharmacol Rev 2009, 61 (2) 162-176]. As an additional environmental factor, stress can contribute to binge eating behaviour, and lead to obesity [Adam, TC et al. Physiol Behav 2007, 91 (4) 449-458]. Animal models that are clinically relevant models of binge eating in humans are described for example in W. Foulds Mathes et al.; Appetite 2009, 52, 545-553.
• the orexin system interacts with neural networks that regulate emotion, reward and energy homeostasis to maintain proper vigilance states. Dysfunctions in its function may thus relate to many mental health disorders in which vigilance, arousal, wakefulness or attention is disturbed.
• the compound further attenuated cardiovascular responses to conditioned fear and novelty exposure in rats [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603-1614]. It is also active in an animal model of conditioned fear: the rat fear-potentiated startle paradigm (WO2009/047723) which relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs).
• WO2009/047723 relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs).
• PTSDs post traumatic stress disorders
• intact declarative and non-declarative learning and memory has been demonstrated in rats treated with this compound [WO2007/105177, H Dietrich, F Jenck, Psychopharmacology 2010, 212, 145-154].
• Said compound furthermore decreased brain levels of amyloid-beta ( ⁇ ) as well as ⁇ plaque deposition after acute sleep restriction in amyloid precursor protein transgenic mice [JE Kang et al., "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.”, Science 2009, 326(5955): 1005-1007].
• ⁇ amyloid-beta
• the accumulation of the ⁇ in the brain extracellular space is hypothesized to be a critical event in the pathogenesis of Alzheimer's disease.
• the so-called and generally known "amyloid cascade hypothesis” links ⁇ to Alzheimer's disease and, thus, to the cognitive dysfunction, expressed as impairment of learning and memory.
• the compound has also been shown to induce antidepressant-like activity in a mouse model of depression, when administered chronically [Nollet et al., NeuroPharm 2011 , 61 (1 -2):336-46]. Moreover, the compound has been shown to attenuate the natural activation induced by orexin A in fasted hungry rats exposed to food odors [MJ Prud'Neill et al., Neuroscience 2009, 162(4), 1287-1298]. The compound also displayed pharmacological activity in a rat model of nicotine self-administration [LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212].
• N- biphenyl-2-yl-1 - ⁇ [(1 -methyl-1 H-benzimidazol-2-yl)sulfanyl]acetyl ⁇ -L-prolinamide inhibited nicotine-reinstatement for a conditioned reinforcer and reduced behavioral (locomotor sensitization) and molecular (transcriptional responses) changes induced by repeated amphetamine administration in rodents [Winrow et al., Neuropharmacology 2009, 58(1 ), 185- 94].
• WO2003/002559 discloses N-aroyl cyclic amine derivatives encompassing morpholine derivatives as orexin receptor antagonists.
• a particular pyrrolidine derived orexin-1 selective compound within the scope of WO2003/002559 is disclosed in Langmead et. al, Brit. J. Pharmacol. 2004, 141 , 340-346: 1 -(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1 -[(S)-2-(5- phenyl-[1 ,3,4]oxadiazol-2-ylmethyl)-pyrrolidin-1 -yl)-methanone.
• the present compounds are different from the compounds disclosed in WO2003/002559 in view of the particular 2-(1 ,2,3- triazol-2-yl)benzamide and 3-(1 ,2,3-triazol-2-yl)picolinamide moiety and notably in view of the present particular benzyl substituent in position 3 of the morpholine moiety.
• the present invention provides novel 2-(1 ,2,3-triazol-2-yl)benzamide and 3-(1 ,2,3-triazol-2- yl)picolinamide derivatives, which are non-peptide antagonists of human orexin receptors, especially the orexin-1 receptor.
• These compounds are in particular of potential use in the treatment of disorders relating to orexinergic dysfunctions, comprising especially anxiety disorders, addiction disorders, mood disorders, or appetite disorders, as well as cognitive dysfunctions or sleep disorders.
• the compounds of the present invention may notably be useful to treat mental health diseases or disorders relating to dysfunctions of the orexin 1 receptor.
• a first aspect of the invention relates to com ounds of the formula (I)
• Ar represents a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;
• R represents one optional substituent selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, hydroxy, and halogen;
• R 2 represents hydrogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, or cyano
• R 3 represents hydrogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 1-3 )fluoroalkyl, or halogen
• R 4 represents hydrogen, (Ci -4 )alkyl, (Ci -3 )fluoroalkyl, or halogen
• R 5 represents one optional substituent on any ring carbon atom of the morpholine ring, wherein said substituent independently is methyl or ethyl;
• Q represents CR 6 ; or, in case R 2 is (Ci -4 )alkyl or (Ci -4 )alkoxy, Q represents CR 6 or N; wherein R 6 represents hydrogen, fluoro or methyl.
• a second embodiment relates to compounds according to embodiment 1 ), wherein the morpholine ring of the compounds of formula (I):
• Ar 1 represents a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted or mono-substituted with (Ci -4 )alkyl (especially unsubstituted, or in case said heteroaryl is pyrimidinyl, optionally mono- substituted with methyl);
• R represents one optional substituent selected from methyl, methoxy, hydroxy, and halogen
• R 2 represents hydrogen, methyl, methoxy, halogen, or cyano
• R 3 represents hydrogen, methyl, methoxy, trifluoroalkyl, or halogen
• R 4 represents hydrogen, methyl, trifluoroalkyl, or halogen
• Q represents CR 6 ; or, in case R 2 is methyl, Q represents CR 6 or N;
• R 6 represents hydrogen, fluoro or methyl.
• a further embodiment relates to compounds according to embodiments 1 ) or 2), wherein the morpholine ring of the compounds of formula (I): r° is a ring selected from the group consisting of: c rt
• Another embodiment relates to compounds according to embodiments 1 ) or 2), wherein the morpholine ring of the compounds of formula (I):
• a further embodiment relates to compounds according to embodiments 1 ) or 2), wherein the morpholine ring of the compounds of formula (I):
• a second aspect of the invention relates to compounds of formula (I) according to embodiment 1 ) which are also compounds of the formula (II)
• Ar represents a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;
• R represents one optional substituent selected from (Ci -4 )alkyl, (Ci -4 )alkoxy, and halogen;
• R 2 represents hydrogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, or cyano;
• R 3 represents hydrogen, (Ci -4 )alkyl, (Ci -4 )alkoxy, or halogen;
• R 4 represents hydrogen, or halogen
• Q represents CH; or, in case R 2 is (C 1-4 )alkyl or (C 1-4 )alkoxy, Q represents CH, CF or N.
• Ar 1 represents pyrrol-1 -yl, pyrazol-1 -yl, [1 ,2,3]triazol-1 -yl, [1 ,2,3]triazol-2-yl, [1 ,2,4]triazol-1 -yl, oxazol-2-yl, thiazol-2-yl, [1 ,2,4]oxadiazol-3-yl, thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, and pyridazin-3-yl, which groups are unsubstituted or mono-substituted with (Ci -4 )alkyl (especially methyl)).
• Ar 1 represents pyrrol-1 -yl, pyrazol-1 -yl, [1 ,2,3]triazol-2-yl, oxazol-2-yl, thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrazin-2-yl, and pyridazin-3-yl, which groups are unsubstituted or mono-substituted, wherein the substituents are independently selected from (Ci -4 )alkyl.
• Ar 1 represents a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxadiazolyl, thiophenyl, 2-pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted, or in case said heteroaryl is pyrimidinyl, optionally mono-substituted with methyl.
• Ar 1 represents a 5- or 6-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, oxadiazolyl, and pyrimidinyl; wherein said heteroaryl is unsubstituted, or in case said heteroaryl is pyrimidinyl, optionally mono-substituted with methyl.
• Ar 1 represents pyrrol-1 -yl, pyrazol-1 -yl, [1 ,2,3]triazol-2-yl, [1 ,2,4]oxadiazol-3-yl, thiophen-2-yl, pyridin-2-yl, pyrimidin-2-yl, pyrazin-2-yl, and pyridazin-3-yl, which groups are unsubstituted, or in case of pyrimidin-2-yl, optionally mono-substituted with methyl.
• a preferred embodiment relates to compounds according to any one of embodiments 1 ) to 6), wherein Ar 1 represents pyrazol-1 -yl, [1 ,2,3]triazol-2-yl, [1 ,2,4]oxadiazol-3-yl, and pyrimidin-2-yl, which groups are unsubstituted, or in case of pyrimidin-2-yl, optionally mono- substituted with methyl.
• Another preferred embodiment relates to compounds according to any one of embodiments 1 ) to 6), wherein Ar represents unsubstituted [1 ,2,4]oxadiazol-3-yl, or unsubstituted [1 ,2,3]triazol-2-yl.
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 6), wherein Ar 1 represents unsubstituted pyrazol-1 -yl, or unsubstituted [1 ,2,3]triazol-2-yl.
• Another preferred embodiment relates to compounds according to any one of embodiments 1 ) to 6), wherein Ar 1 represents unsubstituted [1 ,2,3]triazol-2-yl.
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 15), wherein R is absent, or R represents (Ci -4 )alkoxy (especially methoxy).
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 15), wherein R is absent, or R represents methoxy in position 4 of the phenyl ring (i.e. in para position to the point of attachment of the -CH 2 - group which links the phenyl ring to the rest of the molecule and ortho to the point of attachment of Ar 1 ).
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 15), wherein R is absent; or R represents halogen (especially fluoro or chloro) in position 2 or 3 of the phenyl ring; or R represents methyl in position 2, 3, or 4 of the phenyl ring; or R represents methoxy in position 4 of the phenyl ring [it being understood that the point of attachment of the -CH 2 - group which links the phenyl ring to the rest of the molecule is position 1 , and the point of attachment of Ar 1 is in position 5 of the phenyl ring].
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 15), wherein R is absent, or R represents halogen (especially fluoro or chloro) in position 2 of the phenyl ring (i.e. in para position to the point of attachment of Ar 1 ).
• R 2 represents hydrogen, methyl, methoxy, cyano, fluoro, or chloro
• R 3 represents hydrogen, methyl, methoxy, or fluoro
• R 4 represent hydrogen, or fluoro
• Q represents CR 6 ; or, in case R 2 is methyl, Q represents CH; or, in case R 2 is (C 1 -4 )alkyl or (Ci -4 )alkoxy, Q represents CH, or N.
• a preferred embodiment relates to compounds according to any one of embodiments 1 ) to 5), or 7) to 19); wherein R 2 represents hydrogen, methyl, methoxy, cyano, fluoro, or chloro; R 3 represents hydrogen, methyl, trifluoromethyl, fluoro, or chloro; R 4 represent hydrogen, methyl, trifluoromethyl, or fluoro; and Q represents CR 6 ; or, in case R 2 is methyl, Q represents CR 6 or N; wherein R 6 represents hydrogen, fluoro or methyl. 22) Another embodiment relates to compounds according to any one of embodiments 1) to 19), wherein R 2 represents hydrogen, methyl, methoxy, cyano, fluoro, or chloro.
• Another embodiment relates to compounds according to any one of embodiments 1) to 19) or 21 ), wherein R 2 represents hydrogen, fluoro, or chloro.
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 5), 7) to 19), 21 ) or 23), wherein R 3 represents hydrogen, methyl, trifluoromethyl, or chloro.
• Another embodiment relates to compounds according to any one of embodiments 1) to 19), or 22), wherein R 3 represents hydrogen, methyl, methoxy, or fluoro.
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 5), 7) to 19), 21 ), 23), or 24), wherein R 4 represents hydrogen or methyl.
• FIG. 27 Another embodiment relates to compounds according to any one of embodiments 1 ) to 19), 22) or 25), wherein R 4 represents hydrogen, or fluoro.
• R 2 , R 3 and R 4 represent hydrogen; or R 2 represents methyl, and R 3 and R 4 represent hydrogen; or R 2 represents methoxy, and R 3 and R 4 represent hydrogen; or R 2 represents chloro, and R 3 and R 4 represent hydrogen; or R 3 represents methyl, and R 2 and R 4 represent hydrogen; or R 2 and R 3 represent methyl, and R 4 represents hydrogen; or R 2 represents methoxy, R 3 represents methyl or methoxy, and R 4 represents hydrogen.
• Another embodiment relates to compounds according to any one of embodiments 1) to 28), wherein Q represents CH; or, in case R 2 is (C 1-4 )alkyl or (C 1-4 )alkoxy, Q represents CH, or N.
• Another embodiment relates to compounds according to any one of embodiments 1) to 28), wherein R 2 is methyl and Q represents N.
• Another embodiment relates to compounds according to any one of embodiments 1 ) to 5), 7) to 19), 21 ), 23), 24), or 26), wherein Q represents CR 6 ; wherein R 6 represents hydrogen, fluoro or methyl.
• a preferred embodiment relates to compounds according to any one of embodiments 1 ) to 28), wherein Q represents CH.
• Another preferred embodiment relates to compounds according to any one of embodiments 1 ) to 5), or 7) to 19), wherein R 2 represents hydrogen or chloro; R 3 represents hydrogen, chloro, methyl or trifluoromethyl, R 4 represent hydrogen or methyl; and Q represents CH. 34) Another preferred embodiment relates to compounds according to any one of mbodiments 1) to 5), or 7) to 19), wherein the group
• each of the above groups A) to F) form a particular sub-embodiment.
• Another preferred embodiment relates to compounds according to any one of the mbodiments 1 ) to 5), or 7) to 19), wherein the group
• Another embodiment relates to compounds according to any one of the embodiments 1 ) to 19 wherein the group
• Another embodiment relates to compounds according to any one of the embodiments 1 ) to 36), wherein the group
• Another embodiment relates to compounds according to any one of the embodiments 1 ) to 36), wherein the group
• a preferred embodiment relates to compounds according to any one of the embodiments 1 ) to 6), or 20) to 36), wherein the group
• Another preferred embodiment relates to compounds according to any one of the embodiments 1 ) to 6), or 20) to 36), wherein the group
• the invention thus, relates to compounds of the formula (I) as defined in embodiment 1), compounds of the formula (II) as defined in embodiment 6); or to such compounds further limited by the characteristics of any one of embodiments 2) to 40), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of mental health disorders relating to orexinergic dysfunctions, which disorders are as defined below and which are especially selected from anxiety disorders, addiction disorders, mood disorders, and appetite disorders.
• the following embodiments relating to the compounds of formula (I) and (II) are thus possible and intended and herewith specifically disclosed in individualized form:
• the compounds of formula (I) and (II) contain at least one stereogenic center which is situated in position 3 of the morpholine moiety. It is understood that the absolute configuration of said chiral center is as depicted in formula (I) and (II), i.e. it is in absolute (R) configuration.
• the compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
• the compounds of formula (I) and (II) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
• the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and (II), which compounds are identical to the compounds of formula (I) and (II) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
• Isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and (I I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g.
• the compounds of formula (I) and (I I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) and (I I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) and (I I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
• a dotted line shows the point of attachment of the radical drawn.
• salts refers to non-toxic, inorg. or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201 -217.
• halogen means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
• alkyl refers to a saturated straight or branched chain alkyl group containing one to six carbon atoms.
• (C x-y )alkyl refers to an alkyl group as defined before, containing x to y carbon atoms.
• a (Ci -4 )alkyl group contains from one to four carbon atoms.
• alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert.-butyl. Preferred are methyl and ethyl. Most preferred is methyl.
• alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
• (C x-y )alkoxy (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms.
• a (Ci -4 )alkoxy group means a group of the formula (Ci -4 )alkyl-0- in which the term "(Ci -4 )alkyl” has the previously given significance.
• alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy and especially methoxy.
• fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
• (C x - y )fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
• a (Ci -3 )fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
• fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (Ci)fluoroalkyl groups such as trifluoromethyl.
• fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
• (C x-y )fluoroalkoxy (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
• a (Ci-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
• fluoroalkoxy groups include trifluoromethoxy, difluorom ethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy.
• Preferred are (Ci)fluoroalkoxy groups such as trifluoromethoxy and difluorom ethoxy.
• heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy" are notably pyrrolyl (in particular pyrrol-1 -yl), pyrazolyl (in particular pyrazol-1 -yl), triazolyl (in particular [1 ,2,3]triazol-1 -yl,
• particular examples are pyrrol- 1 -yl, pyrazol-1 -yl, [1 ,2,3]triazol-2-yl, oxazol-2-yl, thiophen-2-yl, pyridin-2-yl, pyridin-3-yl, pyrimidin-2-yl, pyrazin-2-yl, and pyridazin-3-yl.
• particular examples are pyrazol-1 -yl, and especially [1 ,2,3]triazol-2-yl.
• the above mentioned groups may be unsubstituted or substituted as explicitly defined.
• a further embodiment relates to particular compounds of formula (I) according to embodiment 1 ) which are selected from the following compounds:
• a further embodiment relates to particular compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
• the compounds of formula (I) and (II) according to any one of embodiments 1 ) to 44) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
• compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21 st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
• the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) and (II) according to any one of embodiments 1 ) to 44).
• the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
• the compounds of formula (I) and (II) according to any one of embodiments 1 ) to 44) are useful for the prevention or treatment of disorders relating to orexinergic dysfunctions.
• disorders relating to orexinergic dysfunctions are diseases or disorders where an antagonist of a human orexin receptor is required, notably mental health diseases or disorders relating to orexinergic dysfunctions, notably of the orexin 1 receptor.
• the above mentioned disorders may in particular be defined as comprising anxiety disorders, addiction disorders, mood disorders, or appetite disorders, as well as cognitive dysfunctions or sleep disorders.
• the above mentioned disorders comprise anxiety disorders, addiction disorders and mood disorders, notably anxiety disorders and addiction disorders.
• disorders relating to orexinergic dysfunctions are selected from treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis including acute mania and bipolar disorder; treating or controlling stroke, particularly ischemic or haemorrhagic stroke; blocking an emetic response i.e. nausea and vomiting; and treating or controlling agitation, in isolation or co-morbid with another medical condition.
• Anxiety disorders can be distinguished by the primary object or specificity of threat, ranging from rather diffuse as in generalized anxiety disorder, to circumscribed as encountered in phobic anxieties (PHOBs) or post-traumatic stress disorders (PTSDs).
• Anxiety disorders may, thus, be defined as comprising generalized anxiety disorders (GAD), obsessive compulsive disorders (OCDs), acute stress disorders, posttraumatic stress disorders (PTSDs), panic anxiety disorders (PADs) including panic attacks, phobic anxieties (PHOBs), specific phobia, social phobia (social anxiety disorder), avoidance, somatoform disorders including hypochondriasis, separation anxiety disorder, anxiety disorders due to a general medical condition, and substance induced anxiety disorders.
• circumscribed threat induced anxiety disorders are phobic anxieties or posttraumatic stress disorders.
• Anxiety disorders especially include generalized anxiety disorders, post-traumatic stress disorders, obsessive compulsive disorders, panic attacks, phobic anxieties, and avoidance.
• Addiction disorders may be defined as addictions to one or more rewarding stimuli, notably to one rewarding stimulus.
• Such rewarding stimuli may be of either natural or synthetic origin.
• Examples of such rewarding stimuli are substances / drugs ⁇ of either natural or synthetic origin; such as cocaine, amphetamines, opiates [of natural or (semi-)synthetic origin such as morphine or heroin], cannabis, ethanol, mescaline, nicotine, and the like ⁇ , which substances / drugs may be consumed alone or in combination; or other rewarding stimuli ⁇ of either natural origin (such as food, sweet, fat, or sex, and the like), or synthetic origin [such as gambling, or internet/IT (such as immoderate gaming, or inappropriate involvement in online social networking sites or blogging), and the like] ⁇ .
• natural origin such as food, sweet, fat, or sex, and the like
• synthetic origin such as gambling, or internet/IT (such as immoderate gaming, or inappropriate involvement in online social networking sites or blogging), and the like
• addiction disorders relating to psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components.
• Substance-related addiction disorders especially include substance use disorders such as substance dependence, substance craving and substance abuse; substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced delirium.
• substance use disorders such as substance dependence, substance craving and substance abuse
• substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced delirium.
• prevention or treatment of addictions i.e.
• preventive or curative treatment of patients who have been diagnosed as having an addiction, or as being at risk of developing addictions refers to diminishing addictions, notably diminishing the onset of addictions, to weakening their maintenance, to facilitating withdrawal, to facilitating abstinence, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction (especially to diminishing the onset of addictions, to facilitating withdrawal, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction).
• Mood disorders include major depressive episode, manic episode, mixed episode and hypomanic episode; depressive disorders including major depressive disorder, dysthymic disorders; bipolar disorders including bipolar I disorder, bipolar II disorder (recurrent major depressive episodes with hypomanic episodes), cyclothymic disorder; mood disorders including mood disorder due to a general medical condition (including the subtypes with depressive features, with major depressive-like episode, with manic features, and with mixed features), substance-induced mood disorder (including the subtypes with depressive features, with manic features, and with mixed features).
• mood disorders are especially major depressive episode, major depressive disorder, mood disorder due to a general medical condition; and substance-induced mood disorder.
• Appetite disorders comprise eating disorders and drinking disorders.
• Eating disorders may be defined as comprising eating disorders associated with excessive food intake and complications associated therewith; anorexias; compulsive eating disorders; obesity (due to any cause, whether genetic or environmental); obesity-related disorders including overeating and obesity observed in Type 2 (non-insulin-dependent) diabetes patients; bulimias including bulimia nervosa; cachexia; and binge eating disorder.
• Particular eating disorders comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; bulimia or anorexia nervosa.
• eating disorders may be defined as especially comprising anorexia nervosa, bulimia, cachexia, binge eating disorder, or compulsive obesities.
• Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
• Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
• Cognitive dysfunctions include deficits in attention, learning and especially memory functions occurring transiently or chronically in psychiatric, neurologic, neurodegenerative, cardiovascular and immune disorders, and also occurring transiently or chronically in the normal, healthy, young, adult, or especially aging population. Cognitive dysfunctions especially relate to the enhancement or maintenance of memory in patients who have been diagnosed as having, or being at risk of developing, diseases or disorders in which diminished memory (notably declarative or procedural) is a symptom [in particular dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease].
• prevention or treatment of cognitive dysfunctions relates to the enhancement or maintenance of memory in patients who have a clinical manifestation of a cognitive dysfunction, especially expressed as a deficit of declarative memory, linked to dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease. Furthermore, the term “prevention or treatment of cognitive dysfunctions” also relates to improving memory consolidation in any of the above mentioned patient populations.
• Sleep disorders comprise dyssomnias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders.
• dyssomnias include intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb movement disorder, and restless leg syndrome), extrinsic sleep disorders, and circadian-rythm sleep disorders.
• Dyssomnias notably include insomnia, primary insomnia, idiopathic insomnia, insomnias associated with depression, emotional/mood disorders, aging, Alzheimer's disease or cognitive impairment; REM sleep interruptions; breathing-related sleep disorders; sleep apnea; periodic limb movement disorder (nocturnal myoclonus), restless leg syndrome, circadian rhythm sleep disorder; shift work sleep disorder; and jet-lag syndrome.
• Parasomnias include arousal disorders and sleep-wake transition disorders; notably parasomnias include nightmare disorder, sleep terror disorder, and sleepwalking disorder.
• Sleep disorders associated with a general medical condition are in particular sleep disorders associated with diseases such as mental disorders, neurological disorders, neuropathic pain, and heart and lung diseases.
• Substance-induced sleep disorders include especially the subtypes insomnia type, parasomnia type and mixed type, and notably include conditions due to drugs which cause reductions in REM sleep as a side effect. Sleep disorders especially include all types of insomnias, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder, delayed or advanced sleep phase syndrome, or insomnias related to psychiatric disorders.
• sleep disorders further include sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
• the present compounds may be particularly useful for the treatment of such environmentally conditioned disorder or disease.
• the present invention also relates to the compounds of formula (I) and (I I), and/or to pharmaceutical compositions comprising, as active principle, one or more compounds of formula (I) and / or (II) for use in the treatment of the above-mentioned disorders relating to orexinergic dysfunctions, in combination with one or more further pharmaceutically active ingredients.
• pharmaceutical compositions comprising, as active principle, one or more compounds of formula (I) and / or (II) for use in the treatment of the above-mentioned disorders relating to orexinergic dysfunctions, in combination with one or more further pharmaceutically active ingredients.
• the compounds of formula (I) can be prepared by the methods given below, by the methods given in the experimental part below or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimisation procedures. In some cases the final product may be further modified, for example, by manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the following reaction schemes, and/or reaction steps, may be varied to facilitate the reaction or to avoid unwanted reaction products.
• Compounds of formula (I) are prepared by reaction of an amine of Structure 1 , or a salt such as a hydrochloride salt thereof, with an acid of Structure 2 in the presence of an amide- coupling reagent such as TBTU, HATU, EDC, DCC or PyBOP and a base like DIPEA or TEA in a solvent such as MeCN or DMF.
• an amide- coupling reagent such as TBTU, HATU, EDC, DCC or PyBOP and a base like DIPEA or TEA in a solvent such as MeCN or DMF.
• coupling can be achieved via the corresponding acid chloride of Structure 2, prepared conventionally using a chlorinating reagent like oxalyl chloride or thionyl chloride.
• Compounds of Structure 1 may be prepared by one of the synthetic pathways described below.
• Compounds of Structure 1 may be prepared in analogy to the procedure described in WO2008047109 and as illustrated in Reaction Scheme A.
• a Boc-protected iodophenyl alanine derivative A-1 racemic or enantiomerically enriched, either commercially available or prepared following the procedure described by Greenspan et at. in J. Med. Chem. 2001 , 44, 4524-4534, can be Boc-deprotected by treatment with 4M HCI in dioxane or with TFA to give the corresponding iodophenyl alanine as its HCI or TFA salt A-2.
• Iodophenyl alanine A-2 racemic or enantiomerically enriched, either commercially available or prepared as described above can be reduced with borane in a solvent like THF to furnish the corresponding amino alcohol A-3.
• Acylation of A-3 with chloroacetyl chloride furnishes amide A-4 which upon treatment with a base like sodium hydride or potassium ieributoxide in a solvent like THF affords morpholinone A-5.
• Arylation of A-5 can be accomplished under metal catalysed conditions employing for example copper, palladium or zinc catalysts to give intermediates of type A-6.
• conversion of A-5 into it's corresponding boronic acid or ester followed by a Suzuki reaction gives intermediates of type A-6.
• Reduction of A-6 with borane in lvent like THF furnishes compounds of Structure 1.
• Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme B.
• Reduction of morpholinone B-1 with borane in a solvent like THF gives the corresponding morpholine B-2 which can be boc-protected under standard conditions to furnish intermediates of type B-3.
• Arylation of B-3 can be achieved by following one of several methods. For example, under metal catalysed conditions as described above, or alternatively, conversion of B-3 into it's corresponding boronic pinacol ester by treatment with bis(pinacolato) diboron in a solvent like DMSO followed by a Suzuki reaction.
• Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme C.
• Intermediate C-1 can be prepared from p-methoxyphenyl alanine in analogy to the sequence of reactions described in Reaction Scheme A.
• lodination of morpholinone C-1 with NIS in the presence of an acid like triflic acid in a solvent like DCM or MeCN gives the corresponding morpholinone C-2.
• Arylation of C-2 can be accomplished under metal catalysed conditions employing for example copper or palladium catalysts to give intermediates of type C-3.
• intermediate D-1 can be prepared from p-methoxyphenyl alanine in analogy to the sequence of reactions described in Reaction Scheme A.
• Reduction of morpholinone D-1 with borane in a solvent like THF gives the corresponding morpholine D-2.
• Reaction of D-2 with an acid of Structure 2 in the presence of an amide-coupling reagent such as TBTU, HATU or EDC, and a base like DIPEA or TEA in a solvent such as MeCN or DMF furnishes intermediates of type D-3.
• lodination of D-3 in the presence of an acid like triflic acid in a solvent like DCM or MeCN gives intermediates of type D-4.
• Arylation of D-4 can be accomplished under metal catalysed conditions employing for example copper or palladium catalysts to give final compounds.
• metal catalysed conditions employing for example copper or palladium catalysts to give final compounds.
• conversion of D-4 into it's corresponding boronic pinacol ester by treatment with bis(pinacolato) diboron in a solvent like DMSO followed by a Suzuki reaction with the appropriate aryl halide furnishes final compounds.
• Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme G.
• Conversion of G-5 into compounds of Structure 1 can be accomplished by following the sequence of transformations as described in Reaction Scheme A.
• Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme H.
• Reaction of commercially available a-aminoester H-1 with trimethylacetaldehyde in a solvent like DCM in the presence of a dehydrating agent like MgS0 4 gives the corresponding imine H-2.
• Alkylation of H-2 with benzyl bromides H-3, prepared as described in Reaction Scheme G, in a solvent like toluene gives after imine hydrolysis intermediates of type H-4.
• Conversion of H-4 into compounds of Structure 1 can be accomplished by following the sequence of transformations as described in Reaction Scheme A.
• Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme I.
• Intermediate 1-1 prepared according to Reaction Schemes A, C or G can be Boc-protected following the procedure described by Terashima et al. in Tetrahedron, 1994, 50, 6221 -6238 to give Boc-morpholinone I-2.
• Reaction of I-2 with an appropriate alkyl-metal reagent like alkyl lithium reagents in a solvent like THF at a temperature of -78°C gives the ring-opened ketone I-3.
• Boc-deprotection of I-3 by treatment with 4M HCI in dioxane or with TFA leads to cyclic imines of type I-4 that can be subsequently reduced with NaBH 4 in a solvent like MeOH to furnish compounds of Structure 1.
• Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme K.
• Dess-Martin oxidation of K-2 gives the corresponding aldehyde K-3 which can be alkylated with an alkyl zinc or magnesium reagent to give the 2° alcohol K-4.
• Boc-deprotection of K-4 by treatment with 4M HCI in dioxane or with TFA leads to the amino alcohol K-5 which can be converted into compounds of Structure 1 by following the sequence of transformations described above in Reaction Scheme A.
• Final compounds of the present invention may also be prepared as illustrated in Reaction Scheme L.
• Arylation of L-2 can be accomplished under metal catalysed conditions employing for example copper or palladium catalysts to give final compounds.
• conversion of L-2 into it's corresponding boronic pinacol ester by treatment with bis(pinacolato) diboron in a solvent like DMSO followed by a Suzuki reaction with the appropriate aryl halide furnishes final compounds.
• Carboxylic acid derivatives of Structure 2 are well known in the art and can be especially prepared following the procedures reported in WO2008069997, WO2008008517, WO2010048012, WO2010063662, WO2010063663, WO201 1050198, WO201 1050200 and WO201 1050202. In addition, they may be prepared in analogy to the methods given in the experimental part.
• the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 ⁇ ) column, a Daicel ChiralCel OD-H (5-10 ⁇ ) column, or a Daicel ChiralPak IA (10 ⁇ ), IC (5 ⁇ ) or AD-H (5 ⁇ ) column.
• a chiral stationary phase such as a Regis Whelk-01 (R,R) (10 ⁇ ) column, a Daicel ChiralCel OD-H (5-10 ⁇ ) column, or a Daicel ChiralPak IA (10 ⁇ ), IC (5 ⁇ ) or AD-H (5 ⁇ ) column.
• Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine or diethylamine) and eluent B (heptane), at a flow rate of
• Method A Agilent 1 100 series with mass spectrometry detection (MS: Finnigan single quadrupole). Column: Zorbax SB-aq (3.5 ⁇ , 4.6 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B ⁇ 5% B over 1.5 min (flow: 4.5 mL/min). Detection: UVA/is + MS.
• Method B Agilent 1 100 series with mass spectrometry detection (MS: Finnigan single quadrupole). Column: Waters XBridge C18 (2.5 ⁇ , 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B ⁇ 5% B over 1.5 min (flow: 4.5 mL/min). Detection: UVA/is + MS.
• Method C Agilent 1 100 series with mass spectrometry detection (MS: Finnigan single quadrupole). Column: Zorbax Extend C18 (5 ⁇ , 4.6 x 50 mm). Conditions: MeCN [eluent A]; 13 mmol/L NH 3 in water [eluent B]. Gradient: 95% B ⁇ 5% B over 1 .5 min (flow: 4.5 mL/min). Detection: UVA/is + MS.
• Method D Agilent 1 100 series with mass spectrometry detection (MS: Finnigan single quadrupole).
• MS Finnigan single quadrupole
• Column Waters XBridge C18 (5 ⁇ , 4.6 x 50 mm).
• Conditions MeCN [eluent A]; 13 mmol/L NH 3 in water [eluent B].
• Gradient 95% B ⁇ 5% B over 1 .5 min (flow: 4.5 mL/min).
• Detection UVA/is + MS.
• Method E Column: Waters XBridge (10 ⁇ , 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCOOH [eluent B]; Gradient: 90% B ⁇ 5% B over 6.4 min (flow: 75 mL/min). Detection: UV/Vis + MS.
• Method F Column: Waters XBridge (10 ⁇ , 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH 4 OH (25% aq.) [eluent B]; Gradient: 90% B ⁇ 5% B over 6.5 min (flow: 75 mL/min). Detection: UV/Vis + MS.
• Table 1 Described in Table 1 below are morpholinones of type A-6 prepared from the corresponding Boc- protected halophenyl alanine derivative G-5, in analogy to the sequence of reactions described for A-13. In most cases the isolated racemic morpholinone was subsequently separated into its R- and S-enantiomers by prep, chiral HPLC. Table 1
• Table 2 Listed in Table 2 below are compounds of Structure 1 prepared from the corresponding intermediates of type A-6, in analogy to the procedure described for A-12.
• Example 1 [( ?)-3-(3-[1 ,2,4]Oxadiazol-3-yl-benzyl)-morpholin-4-yl]-(2-[1 ,2,3]triazol-2-yl- phenyl)-methanone
• Step 1 Hydroxylamine -50% in H 2 0 (72 ⁇ , 1 .17 mmol) was added to a RT suspension of 3-[(R)-4-(2-[1 ,2,3]triazol-2-yl-benzoyl)-morpholin-3-ylmethyl]-benzonitrile B-29 (30 mg, 0.08 mmol) in EtOH (1 mL) and the resulting suspension was heated to 70°C for 45 min. The volatiles were removed in vacuo and the crude hydroxyamidine intermediate was used directly in step 2.
• Step 2 p-Toluenesulfonic acid monohydrate (1 mg, 5 mol%) was added to a solution of crude hydroxyamidine from step 1 in trimethyl orthoformate (1 mL) and the resulting mixture was heated to 100°C for 15 min. The reaction mixture was cooled to RT and filtered through a silica plug (eluting with EtOAc) to give the crude product that was subsequently purified by prep. HPLC (method F) to give the title compound as a white solid.
• Table 5 Listed in Table 5 below are example compounds, prepared from D-8 according to the above Suzuki procedure. Table 5
• Step 1 K 2 C0 3 (8.18 g, 59.2 mmol) was added to a RT solution of 2-fluoro-3- methylbenzonitrile (4.0 g, 29.6 mmol) and 1 H-1 ,2,3-triazole (1 .72 mL, 29.6 mmol) in DMF (80 mL) and the resulting suspension was heated to 120°C for 4h. The reaction mixture was cooled to RT and quenched with water before being extracted with EtOAc (3x).
• Step 2 4M aq. NaOH (10 mL, 40.2 mmol) was added to a RT solution of 3-methyl-2-(2H- 1 ,2,3-triazol-2-yl)benzonitrile (1 .48 g, 8.04 mmol) in MeOH (15 mL) and the resulting mixture was heated to 90°C for 50h. The reaction mixture was cooled to RT and diluted with water before the organic solvent was removed in vacuo. The remaining aqueous phase was acidified with 1 M aq. HCI and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over Na 2 S0 4 , filtered and evaporated in vacuo to give the title compound that was used further without purification.
• CS2CO3 (742 mg, 2.28 mmol) was added portionwise to a RT solution of 2-bromo-5-chloro-4- methyl-benzoic acid methyl ester (300 mg, 1.14 mmol) in DMF (3 mL) followed by 1 H-1 ,2,3- triazole (0.1 mL, 1.71 mmol), Cu(l)l (13 mg, 0.068 mmol) and DMCDA (40 ⁇ , 0.23 mmol). The resulting suspension was heated to 120°C for 4h. The reaction mixture was cooled to RT, quenched with 2M aq. HCI and extracted with EtOAc (3x).
• Table 7 Listed in Table 7 below are intermediates of type G-2, prepared from the corresponding commercially available carboxylic acid according to the above procedure. Table 7
• Table 8 Listed in Table 8 below are intermediates of type G-3, prepared from the corresponding benzyl alcohol G-2, according to the above procedure. Table 8
• Table 9 Listed in Table 9 below are intermediates of type G-4, prepared from the corresponding benzyl bromide G-3, according to the above procedure. Table 9
• Step 1 A suspension of DL-alanine ethyl ester hydrochloride (10 g, 65.1 mmol) in DCM (150 ml_) was washed with 2M aq. NaOH and the layers were separated. The organic phase was dried over Na 2 S0 4 , filtered and the filtrate was cooled to 0°C before MgS0 4 hydrate (1 1 .3 g) followed by pivalaldeyde (7.72 g, 89.6 mmol) were added and the resulting mixture was warmed to RT and stirred for 16h. The reaction mixture was filtered and evaporated in vacuo to give rac-ethyl 2-((2,2-dimethylpropylidene)amino)propanoate that was used further without purification.
• Step 2 3-lodobenzyl bromide (14.4 g, 48.6 mmol) was added to a RT solution of rac-ethyl 2- ((2,2-dimethylpropylidene)amino)propanoate (10 g, 48.6 mmol) from above in toluene (100 ml_) under argon and the resulting mixture was cooled to -10°C before KO'Bu (10.9 g, 97.2 mmol) was added portionwise. The reaction mixture was stirred at 0°C for 4h before being quenched with water. The toluene was evaporated in vacuo and the remaining aqueous phase was extracted with EtOAC (3x).
• Boc 2 0 (1.79 g, 8.19 mmol) was added in one portion to a RT solution of (R)-5-(3- [1 ,2,3]triazol-2-yl-benzyl)-morpholin-3-one A-13 (1.06 g, 4.09 mmol) and DMAP (51 mg, 0.41 mmol) in Et 3 N:MeCN 3:1 (16 mL) under Argon and the resulting mixture was stirred for 1.5h. The reaction mixture was diluted with EtOAc, transferred to a separating funnel and washed successively with 3% aq. HCI, sat. aq. NaHC0 3 and brine.
• Step 1 [(R)-2-(2-Oxo-propoxy)-1 -(3-[1 ,2,3]triazol-2-yl-benzyl)-ethyl]-carbamic acid tert-butyl ester (I-6) (500 mg, 1.34 mmol) was dissolved in TFA (5 mL) at 0°C and stirred for 1 h. The reaction mixture was evaporated in vacuo and used directly in Step 2.
• Step 2 The Boc-cleaved intermediate from above was dissolved in MeOH (10 mL) and cooled to 0°C. Sodium borohydride (52 mg, 1.37 mmol) was then added and the resulting mixture was stirred for 1 h. The reaction mixture was quenched with water and the solvent was evaporated in vacuo. The remaining aqueous phase was extracted once with DCM and this extract was discarded. The aqueous layer was basified with 5M aq. NaOH and re- extracted with DCM (3x).
• Example compounds prepared according to General Method F-2 include Examples 68 to 74.
• Tables 1 1 and 12 Listed in Tables 1 1 and 12 below are example compounds, prepared according to the above- mentioned methods F-1 and F-2, from the corresponding amine 1 , prepared as described above and the corresponding carboxylic acid 2, prepared as described above.
• A-12 E-3 (5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-pyrazol-1-yl- benzyl)-morpholin-4-yl]-methanone;
• A-12 E-7 (5-Fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-pyrazol-1-yl- benzyl)-morpholin-4-yl]-methanone;
• A-18 E-3 (5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1 ,2,4]triazol-1 - yl-benzyl)-morpholin-4-yl]-methanone;
• A-15 E-7 (5-Fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1 ,2,3]triazol-2- yl-benzyl)-morpholin-4-yl]-methanone;
• A-15 E-5 (5-Chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1 ,2,3]triazol-2- yl-benzyl)-morpholin-4-yl]-methanone;
• A-15 E-12 (4,5-Dimethoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3- [1 ,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone;
• A-15 E-6 (4,5-Dimethyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3- [1 ,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone;
• A-15 E-8 (4-Fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-[1 ,2,3]triazol-2- yl-benzyl)-morpholin-4-yl]-methanone;
• A-20 E-3 (5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3-pyrrol-1-yl- benzyl)-morpholin-4-yl]-methanone;
• A-34 E-4 [(R)-3-(2-Fluoro-5-[1 ,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]- (4-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
• A-15 E-16 (3,5-Dimethyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[(R)-3-(3- [1 ,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-methanone;

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