WO2023218023A1 - Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives - Google Patents

Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives Download PDF

Info

Publication number
WO2023218023A1
WO2023218023A1 PCT/EP2023/062741 EP2023062741W WO2023218023A1 WO 2023218023 A1 WO2023218023 A1 WO 2023218023A1 EP 2023062741 W EP2023062741 W EP 2023062741W WO 2023218023 A1 WO2023218023 A1 WO 2023218023A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
thiazol
methanone
pyrazolidin
triazol
Prior art date
Application number
PCT/EP2023/062741
Other languages
French (fr)
Inventor
Melanie KESSLER
Azely MIRRE
Jens-Uwe Peters
Christoph SAGER
Jean-Philippe Surivet
Jodi T. Williams
Original Assignee
Idorsia Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Idorsia Pharmaceuticals Ltd filed Critical Idorsia Pharmaceuticals Ltd
Publication of WO2023218023A1 publication Critical patent/WO2023218023A1/en

Links

Classifications

    • 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
    • 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
    • A61P25/28—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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel cyclic hydrazine-N-carboxamide 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.
  • 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 (OXi and OX2 receptors).
  • the orexin-1 receptor (OX1) is selective for OX-A
  • the orexin-2 receptor (OX2) 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 system regulates homeostatic functions such as sleep-wake cycle, energy balance, emotions and reward. 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], Thus, there is a strong rationale that disturbances in the orexin system may contribute to the symptoms of mood disorders.
  • 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, 11(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.
  • orexins may play a role into several other important functions relating to arousal, especially when an organism must respond to unexpected stressors and challenges in the environment [Tsujino N and Sakurai T. Pharmacol Rev. 2009, 61 :162-176; Carter ME, Borg JS and deLecea L, Curr Op Pharmacol. 2009, 9: 39-45; C Boss, C Brisbare-Roch, F Jenck, Journal of Medicinal Chemistry 2009, 52: 891-903], 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 has been shown to decrease alertness, characterized by decreases in both active wake and locomotion; and to dose-dependently increase the time spent in both REM and NREM sleep [Brisbare-Roch et al., Nature Medicine 2007, 13, 150-155],
  • 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 (W02009/047723) which relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs).
  • the so-called and generally known "amyloid cascade hypothesis” links Ap 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], Another dual orexin receptor antagonist, N-biphenyl-2-yl-1- ⁇ [(1- methyl-1 H-benzi midazol-2-yl)sulfany l]acetyl ⁇ -
  • Orexin receptor antagonists comprising a 2-substituted saturated cyclic amide derivatives (such as 2-substituted pyrrolidine-1 -carboxamides) are known for example from W02008/020405, W02008/038251 , W02008/081399,
  • W02003/002559 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 W02003/002559 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.
  • W02003/002561 discloses certain N-aroyl cyclic amine derivatives, encompassing a benzimidazol-2-yl-methyl substituted morpholine derivative, as orexin receptor antagonists.
  • a common structural feature i.e. they contain central core ring such as a pyrrolidine, piperidine, or morpholine derivative, containing a chiral carbon center in position 2 that is substituted with an aromatic group, generally via a linker group.
  • WO2013/182972 discloses pyrrolidine derivatives that have a benzimidazole ring directly attached to a pyrrolidine amide in position 2.
  • the present pyrazolidinyl derivatives carrying particular substituents in position 1 and 2 may be potent dual orexin receptor antagonists.
  • the present invention provides novel substituted thiazoloaryl-methyl substituted cyclic hydrazine-W- carboxamide derivatives, which are dual non-peptide antagonists of the human orexin-1 and orexin-2 receptors.
  • These compounds are in particular of potential use in the treatment of disorders relating to orexinergic dysfunctions, comprising especially sleep disorders including insomnias, as well as anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders or neuropsychiatric symptoms in dementia.
  • sleep disorders including insomnias, as well as anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders or neuropsychiatric symptoms in dementia.
  • These compounds may have particular advantages such as bioavailability, capacity to cross the blood-brain barrier; and/or may have a particular metabolic and pharmacokinetic profile that may be of advantage for certain medical uses where controled periods of exposure to the active ingredient are required.
  • a first aspect of the invention relates to compounds of the Formula (I)
  • R 1 represents (Ci-3)alkyl (especially methyl), halogen (especially chloro or bromo), cyclopropyl, or trifluoromethyl; [especially R 1 represents methyl];
  • X 1 represents S or 0; [especially X 1 represents S];
  • X 2 represents CH or N; [especially X 2 represents CH];
  • Z represents -CH2-, -CHfCHs)-, or -CH2-CH2-; [especially Z represents -CH2- or -CHfCHs)-]; and in the fragment
  • R 2 independently represents hydrogen, (Ci-3)alkyl (especially methyl), halogen (especially chloro), or (Ci-3)alkoxy (especially methoxy);
  • R 2 represents methyl or chloro, especially chloro
  • R 3 independently represents hydrogen, or (Ci-3)alkyl (especially methyl) [especially R 3 represents hydrogen];
  • Y independently represents CH or N
  • the compounds of Formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- or (S)-configuration.
  • the compounds of Formula (I) 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.
  • a particular compound (or generic structure) contains one (or, likewise, more) stereogenic or asymmetric center(s), such as one (or more) asymmetric carbon atom(s), which may be present in (R)- or (S)-configuration, but where said stereogenic or asymmetric center(s) is/are not explicitly designated as (R)- or (S)-, it is understood that said stereogenic or asymmetric center may be in (R)- or (S)- configuration.
  • Such compound name or generic structure is understood to encompass the compound / generic structure where such center is in (R)- or (S)- configuration, or any mixture of epimers with regard to such center including the racemate.
  • stereogenic or asymmetric center in (RS)- configuration
  • this means that such stereogenic or asymmetric center in such compound may be present in (R)- configuration, in (S)-configuration, or in any mixture of epimers with regard to such center including the racemate.
  • two or more such stereogenic or asymmetric centers in undesignated or designated (RS)-configuration) are present in one molecule, it is understood that the order of absolute configuration does not indicate any defined relative configuration with regard to the two or more centers.
  • enriched when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
  • essentially pure when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
  • the present invention also includes isotopical ly labelled, especially 2 H (hydrogen-2, deuterium) labelled compounds of Formula (I) according to embodiments 1) to 18), which compounds are identical to the compounds of Formula (I) 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 labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g.
  • Typical positions generally considered suitable for introducing 2 H atoms, for example to modify metabolic stability, are for example hydrogen atoms attached to a non-aromatic carbon atom that is directly bound to a heteroatom such as oxygen or nitrogen (e.g. a methoxy-da group replacing the methoxy in a methoxyphenyl group).
  • the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more 2 H atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • a bond drawn as a dotted line shows the point of attachment of the radical drawn.
  • the radical drawn below is a 3-methyl-phenyl group.
  • salts refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound.
  • Definitions provided herein are intended to apply uniformly to the compounds of Formula (I), as defined in any one of embodiments 1) to 18), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.
  • substituent Whenever a substituent is denoted as optional, it is understood that such substituent may be absent, in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and / or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate.
  • halogen means fluoro/fluorine, chloro/chlorine, bromo/bromine, or iodo/iodine; especially fluoro, chloro, or bromo.
  • substituent R 1 the term especially represents chloro or bromo.
  • substituent R 2 the term especially represents chloro.
  • alkyl used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated straight or branched chain hydrocarbon group containing one to four carbon atoms.
  • (Cx-y)alkyl (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms.
  • a (Cujalkyl group contains from one to four carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -butyl.
  • a group is referred to as e.g.
  • alkoxy used alone or in combination and if not explicitly defined in a broader or more narrow way, 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 (Cujalkoxy group means a group of the formula (Ci-4)alkyl-O- 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 methoxy.
  • fluoroalkyl used alone or in combination and if not explicitly defined in a broader or more narrow way, 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; especially trifluoromethyl.
  • cyano refers to a group -CN.
  • cycloalkyl used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon ring containing three to eight carbon atoms.
  • (C x.y )cycloalkyl (x and y each being an integer), refers to a cycloalkyl containing x to y carbon atoms.
  • a (Cs-ejcycloalkyl group contains from three to six carbon atoms.
  • a preferred example is cyclopropyl.
  • aryl used alone or in combination, means phenyl or naphthyl, especially phenyl.
  • aryl groups are unsubstituted or substituted as explicitly defined.
  • heteroaryl used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms (especially one to a maximum three), each independently selected from N, 0, and S.
  • heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, furopyridinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazo
  • the term “about” placed before a numerical range “X to Y” refers in the current application to an interval extending from X minus (10% of X) to Y plus (10% of Y), and preferably to an interval extending from X minus (5% of X) to Y plus (5% of Y).
  • the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C.
  • room temperature refers to a temperature of about 25°C.
  • R 1 represents methyl, chloro, bromo, cyclopropyl, or trifluoromethyl; [especially R 1 represents methyl],
  • Another embodiment relates to compounds according to embodiment 1), wherein R 1 represents methyl.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein
  • X 1 represents S.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein
  • X 2 represents CH.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein Z represents -CH 2 - or -CH(CH 3 )-.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein, in case Z represents -CHJCHs)-, such compound of Formula (I) has the absolute configuration depicted in Formula (IA) below:
  • Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein Z represents -CH2-.
  • Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein in the fragment
  • R 2 independently represents hydrogen, methyl, chloro, or methoxy
  • R 2 independently represents methyl or chloro, especially chloro
  • R 3 independently represents hydrogen or methyl
  • Y independently represents CH or N
  • Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment wherein each Ar 1 independently is as defined in embodiment 1).
  • Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar 1 independently represents a group selected from the groups A) to D):
  • Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar 1 independently represents a group selected from the groups A) or B):
  • Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar 1 independently represents:
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 8), wherein the fragment represents a group selected from the groups A) to F): 15) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment represents a group selected from the groups A) to D):
  • Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment represents:
  • Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment
  • Another embodiment relates to compounds according to embodiment 1) selected from:
  • the compounds of Formula (I) according to any one of embodiments 1) to 18) 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, 21st 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) according to any one of embodiments 1) to 18).
  • subject refers to mammals, especially humans.
  • subject refers to the term “patient”.
  • prevention as used in the present disclosure may be understood to mean and is therefore interchangeable with the term “prophylaxis”.
  • compounds are described as useful for the prevention / prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases.
  • such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.
  • the compounds according to Formula (I) according to any one of embodiments 1) to 18) 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 disorders relating to orexinergic dysfunctions.
  • the above mentioned disorders may in particular be defined as comprising sleep disorders especially including insomnias, as well as anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders and neuropsychiatric symptoms in dementia.
  • the above mentioned disorders comprise especially anxiety disorders, addiction disorders, mood disorders and neuropsychiatric symptoms in dementia, notably anxiety disorders and addiction disorders.
  • the above mentioned disorders comprise especially sleep disorders, in particular insomnias.
  • 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 post- traumatic stress disorders.
  • Anxiety disorders especially include 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.
  • Neuropsychiatric symptoms (NPS) in dementia e.g. Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorder; especially a dementia of Alzheimer's type, in particular AD
  • a dementia of Alzheimer's type in particular AD
  • circadian syndromes of increased confusion and restlessness in a patient, wherein said patient has some form of dementia (especially a dementia of Alzheimer's type, in particular AD).
  • Such circadian syndromes especially occur late-day, i.e. in the afternoon and / or evening hours.
  • Cardinal clinical signs include increased agitation, general confusion and mood swings; such signs developing typically as natural light begins to fade.
  • Neuropsychiatric symptoms in dementia especially in a dementia of Alzheimer's type, in particular in AD especially refers to agitation and/or aggression associated with such dementia (sometimes equivalently named sundown syndrome).
  • agitation is used to describe a wide range of behaviors that include verbal outbursts, physical aggression, intense anxiety and crying, and persistent perambulation and wandering (Kales et al., J Am Geriatr Soc. 2014;62(4):762-9; Phan et al., Drugs in R&D (2019) 19:93-115).
  • the International Psychogeriatric Association (IPA) compiled a syndromic definition of agitation (see for example N. Stocking: excerpted article as reprint from IPA’s newsletter, the IPA Bulletin, Vol 31(4): https://www.ipa-online.org/news-and-issues/defining- agitation):
  • the patient meets criteria for a cognitive impairment or dementia syndrome (e.g. Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorder).
  • a cognitive impairment or dementia syndrome e.g. Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorder.
  • the patient exhibits at least one of the following behaviors that are associated with observed or inferred evidence of emotional distress (e.g. rapid changes in mood, irritability, outbursts).
  • the behavior has been persistent or frequently recurrent for a minimum of two weeks and represents a change from the patient’s usual behavior.
  • the agitation is not attributable solely to another psychiatric disorder, suboptimal care conditions, medical condition, or the physiological effects of a substance.
  • the term "late day” referred to herein relates to the afternoon and evening, notably the time about sunset and later (but not including the night / the sleep time); for example, the time from about 4 pm to about 10 pm, especially from about 4 pm to about 9 pm.
  • the term relates to the afternoon, especially from about 4 pm to about 7 pm; in another sub-embodiment the term relates to the evening, especially from about 7 pm to about 10 pm, especially from about 7 pm to about 9 pm.
  • Dementias include notably dementias of Alzheimer's type including: Alzheimer dementia (presenile dementia or senile dementia), subcortical dementia, (diffuse) Lewy body dementia, and frontotemporal dementia. Dementias further include dementias of vascular type such as: vascular dementia, multi-infarct dementia, Binswanger's dementia, boxer's dementia, arteriosclerotic dementia. Remaining types of dementia (9%) are of other etiologies such as paralytic dementia, substance-induced persisting dementia, dialysis dementia, hydrocephalic dementia, and dementias due to tumors, subdural hematoma, normal pressure hydrocephalus, vasculitis, Vitamin deficiency, or endocrine or metabolic disease. In the context of the present invention, the term preferably refers to dementias of Alzheimer's type, especially to Alzheimer dementia. It is understood that the term dementia also includes any combination of the above listed types of dementias.
  • Appetite disorders comprise eating disorders and drinking disorders.
  • 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 payability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
  • 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 nervosa (bulimia) or anorexia nervosa.
  • the term "eating disorder” in particular refers to Binge-Eating Disorder (BED); Bulimia Nervosa (BN); Anorexia Nervosa (AN) (notably binge-eating/purging type Anorexia Nervosa; especially binge-eating type Anorexia Nervosa); Pica; Other Specified Feeding and Eating Disorders (OSFED) [notably atypical Bulimia Nervosa, Binge-Eating Disorder of low frequency and/or limited duration, Bulimia Nervosa of low frequency and/or limited duration, or Night Eating Syndrome (NES)]; Unspecified Feeding or Eating Disorder (UFED); Eating Disorder Not Otherwise Specified (EDNOS); and Compulsive Overeating (CO); Loss of Control (LOG) Eating; and hyperphagia and/or binge-eating associated with Prader-Willi Syndrome (PWS).
  • BED Binge-Eating Disorder
  • BN Bulimia Nervosa
  • Eating disorders refer especially to such eating disorders comprising a compulsive, binge eating behavior. It is understood that the term “eating disorder comprising a compulsive, binge eating behavior” refers to a disorder comprising recurring episodes of binge eating, i.e. recurring episodes when a subject is eating significantly more food in a short period of time than most people would eat under similar circumstances, with episodes marked by feelings of lack of control. Eating disorder comprising a compulsive, binge eating behavior is characterized by eating large amounts of food, by eating quickly (often to the point of discomfort), and by eating even when no longer hungry.
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders
  • BED Binge-Eating Disorder
  • BED is associated with marked distress and significant physical, emotional, and social health risks such as obesity and extreme weight gain and a wide range of associated diseases such as sleep apnea, cancer, heart disease, high blood pressure, type 2 diabetes, arthritis, etc., being among the most common ones.
  • 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 especially dyssomnias and sleep disorders associated with a general medical condition, as well as parasomnias, and substance-induced sleep disorders.
  • Dyssomnias in particular include intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb movement disorder, and restless leg syndrome), extrinsic sleep disorders, and circadian-rhythm sleep disorders. Sleep disorders notably refer to insomnias including primary insomnia and idiopathic insomnia; intermittent treatment of chronic insomnia; situational transient insomnia (e.g.
  • insomnia associated to a new environment or noise sleep disorders
  • sleep disorders notably refer to dyssomnias such as breathing-related sleep disorders including (obstructive or central) sleep apnea syndrome; periodic limb movement disorder (nocturnal myoclonus); restless leg syndrome; circadian rhythm sleep disorders including shift work sleep disorder; and time-zone-change (jet-lag) syndrome.
  • sleep disorders further refer to REM sleep interruptions.
  • 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 as defined before, as well as sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder and delayed or advanced sleep phase syndrome.
  • sleep disorders further include sleep disorders associated with aging.
  • Sleep disorders associated with a general medical condition include sleep disorders (especially insomnias) related to mental or neurologic disorders; notably sleep disorders (especially insomnias) associated with mood disorders (such as depressive disorders), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and cerebral (neuro-)degenerative disorders including Alzheimer's disease and other neurodegenerative and/or cognitive impairment diseases or disorders; as well as sleep disorders (especially insomnias) associated with anxiety disorders, addiction disorders, or appetite disorders.
  • sleep disorders especially insomnias
  • mood disorders such as depressive disorders
  • epilepsy autism spectrum disorders
  • ADHD attention deficit hyperactivity disorder
  • cerebral (neuro-)degenerative disorders including Alzheimer's disease and other neurodegenerative and/or cognitive impairment diseases or disorders
  • sleep disorders especially insomnias associated with anxiety disorders, addiction disorders, or appetite disorders.
  • a particular aspect of the invention relates to a compound of Formula (I) according to any one of embodiments 1) to 18) for use in the treatment of disorders relating to orexinergic dysfunctions, especially of sleep disorders as defined herein above (in particular any type of insomnia as defined herein above, breathing-related sleep disorders including sleep apnea syndrome; periodic limb movement disorder; restless leg syndrome; circadian rhythm sleep disorders including shift work sleep disorder; and time-zone-change syndrome); wherein said treatment comprises the administration of a compound of Formula (I) according to any one of embodiments 1) to 18), wherein said compound is (to be) administered during the night, notably less than 7 hours prior to the morning / wake time; especially between about 7 hours to 2 hours prior to the morning / wake time; in particular about 4 hours to 2 hours prior to the morning / wake time.
  • sleep disorders as defined herein above (in particular any type of insomnia as defined herein above, breathing-related sleep disorders including sleep apnea syndrome; periodic limb movement disorder; restless leg syndrome; circadian rhythm sleep
  • the present compounds may be particularly useful for the treatment of such environmentally conditioned disorder or disease.
  • 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.
  • the generic groups Ar 1 , R 1 , R 2 , R 3 , X 1 , X 2 , Y, and Z are as defined for the compounds of formula (I).
  • the generic groups Ar 1 , R 1 , R 2 , R 3 , X 1 , X 2 , Y, and Z may be incompatible with the assembly illustrated in the schemes, or will require the use of protecting groups (PG).
  • protecting groups are well known in the art (see for example “Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place.
  • 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.
  • the compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts in a manner known per se.
  • the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between 20° and 60°C. Further activating agents can be found in R. C. Larock, Comprehensive Organic Transformations. A guide to Functional Group Preparations, 2nd Edition (1999), section nitriles, carboxylic acids and derivatives, p. 1941-1949 (Wiley VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto).
  • the reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, MgSO4 or Na2SO4).
  • solvent is typically toluene, Hex, THF, DCM or DCE or a mixture of solvents such as DCE/MeOH.
  • the reaction can be catalyzed by traces of acid (usually AcOH).
  • the intermediate imine is reduced with a suitable reducing agent (e.g. NaBH4, NaBHsCN, or NaBH(OAc)3 or through hydrogenation over a noble metal catalyst such as Pd/C.
  • a suitable reducing agent e.g. NaBH4, NaBHsCN, or NaBH(OAc)3 or through hydrogenation over a noble metal catalyst such as Pd/C.
  • the reaction is carried out between -10°C and 110°C, preferably between 0°C and 60°C.
  • the reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in presence of a picoline-borane complex (Tetrahedron (2004), 60, 7899- 7906).
  • the NH-containing derivative is reacted with an alkylating agent compound of formula G-CH2-LG, wherein G has the same meaning as in Formula (I) and LG represents OMs, OTf, OTs, Cl, Br or I, in presence of an inorganic base such as K2CO3 or an org. base such as TEA in a solvent such as THF, MeCN or DMF between 0°C and +80°C.
  • Iodide salts such as sodium iodide or tetrabutyl ammonium iodide can be added to promote the nucleophilic substitution reaction. Further details can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, (1999). Section Amines p.779.
  • the aromatic halide (typically a bromide) is reacted with the required boronic acid derivative or its boronate ester equivalent (e.g. pinacol ester) in the presence of a palladium catalyst and a base such as K2CO3, CS2CO3, K3PO4, tBuONa or tBuOK between 20 and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF, usually in the presence of water (20 to 50%).
  • a palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh3)4.
  • These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCys or P(tBu)3), dialkylphosphinobiphenyls (e.g. S- Phos) or ferrocenylphosphines (e.g. Q-phos).
  • a commercially available precatalyst based on palladacycle e.g. SK-CC01-A
  • N heterocyclic carbene complexes e.g. PEPPSITM-IPr
  • the reaction can also be performed by using the corresponding aromatic tritiate.
  • compounds of general Formula I can be prepared via a carbon-nitrogen bond formation reaction involving the NH-containing compounds of structure 11-1 and either an aldehyde intermediate of structure 11-2 using general reaction technique 2 or an alkylating agent of structure 11-3 using general reaction technique 3 (Scheme 2).
  • Scheme 2
  • Compounds of general Formula I can also be prepared via a cross-coupling reaction involving compounds of structure 111-1 with a boron derivative of structure-l 11-2 using general reaction technique 3 (Scheme 3).
  • LG 1 represents a leaving group selected from -OTf, -I, -Br or -Cl.
  • D 1 and D 2 represent H, methyl or ethyl or D 1 and D 2 together represent CH2C(Me)2CH2 or C(Me)2C(Me)2 Compounds of general Formula I can also be prepared via a cross-coupling reaction involving compounds of structure IV-1 with a boron derivative of structure-IV-2 using general reaction technique 4 (Scheme 4).
  • D 1 and D 2 represent H, methyl or ethyl or D 1 and D 2 together represent CH2C(Me)2CH2 or C(Me) 2 C(Me) 2
  • Compounds of general Formula I can also be prepared reacting compounds of structure V-1 with a di-bromide of structure V-2 in presence of a base such as K3PO4 in acetonitrile at a temperature ranging between 60°C and 90°C. (Scheme 5).
  • Compounds of structure I-2 can be prepared via a carbon-nitrogen bond formation reaction involving the NH- containing compounds of structure VI-1 and either an aldehyde intermediate of structure 11-2 using general reaction technique 2 or an alkylating agent of structure 11-3 using general reaction technique 3.
  • the resulting intermediates of structure VI-2 can be subsequently transformed to compounds of structure I-2 by cleavage of PGi.
  • PGi any suitable methods reported in Protecting Groups, Kocienski, P.J. Georg Thieme Verlag Stuttgart-New-York (1994) can be used.
  • PGi Boc
  • treatment with HCI in dioxane, or alternatively TFA in DCM can be used (Scheme 6).
  • Compounds of structure 11-1 can be prepared reacting the carboxylic acid of structure 1-1 with the NH-containing intermediate of structure VI-1 using one of the carbon- nitrogen bond formation methods reported in general reaction technique 1 .
  • the resulting intermediates of structure VI 1-1 can be subsequently transformed to compounds of structure 11-1 by cleavage of PGi.
  • any suitable methods reported in Protecting Groups, Kocienski, P.J. Georg Thieme Verlag Stuttgart-New-York (1994) can be used.
  • PGi is a protecting group such as Boc.
  • compounds of structure 11-1 can be prepared by reacting compounds of structure VI 11-1 with carboxylic acids of structure 1-1 using one of the carbon- nitrogen bond formation methods reported in general reaction technique 1.
  • the resulting intermediates of structure VIII-2 can be subsequently transformed to compounds of structure VII-1 by reaction with the di-bromide of structure V-2 in presence of a base such as K3PO4 in acetonitrile at a temperature ranging between 60°C and 90°C.
  • a base such as K3PO4 in acetonitrile at a temperature ranging between 60°C and 90°C.
  • the compounds of structure VII-1 can be transformed to compounds of structure 11-1 using the abovementioned methods. (Scheme 8) Scheme 8
  • PGi is a protecting group such as Boc.
  • PGi is a protecting group such as Boc
  • HBSS Hank balanced salt solution HBTU A/,A/,A/',A/'-Tetramethyl-O-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate
  • Apparatus Agilent 1100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Zorbax RRHD SB-Aq (1 .8 pm, 2.6 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.
  • Apparatus Waters Acquity UPLC with mass spectroscopy detection (MS : Waters SQ Detector or Xevo TQD).
  • MS Waters SQ Detector or Xevo TQD.
  • Detection UV (214nm) + MS.
  • Reaction mixture can generally be separated by preparative HPLC. A person skilled in the art will find suitable conditions for each separation. Product containing fractions are collected and lyophilized or freeze dried under vacuum.
  • the compound is prepared as reported in W02019043407.
  • the compound is prepared as reported in W02019043407.
  • the compound is prepared as reported in W02019043407.
  • the first-eluting isomer is 5-methyl-2-(5-methyl-1 H-pyrazol-1 -yl)benzoic acid.
  • the compound is prepared as reported in WO2008/65626.
  • the compound is prepared as reported in WO2018/202689.
  • the compound is prepared as reported in WO2019/43407.
  • the compound is commercially available and is prepared as described in WO 2014/057435
  • Oxalyl chloride (0.1 mL, 1.16 mmol) is added dropwise at r.t. to a suspension of 5-chloro-2-(2/-/-1,2,3-triazol-2- yl)benzoic acid (0.245 g, 1.1 mmol) in DCM (5mL).
  • DMF (0.02 mL) is then added dropwise. The reaction proceeded solution is stirred for 1 h30. The volatiles are removed under reduced pressure and co-evaporated twice with dry DCM (4mL).
  • the crude residue is taken up in DCM (6.5 mL) and added dropwise to an ice-chilled solution of tertbutyl pyrazolidine-1 -carboxylate (0.171 g, 0.99 mmol) and NEts (0.415 mL, 2.98 mmol) in DCM (3.2mL) is added.
  • the reaction proceeded at r.t. for 2h 15. Sat. aq. NaHCOa (10 mL) and DCM (10 mL) are added. The two layers are separated. The aqueous layer is extracted with DCM (2 x 10 mL).
  • the compound is prepared as described in US5472964.
  • Example 1 (5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin- 1-yl)methanone
  • Example 4.1 [(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazin- 1(2H)-yl)methanone
  • Example 8 (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
  • Example 7.1 To a mixture of Example 7.1 (0.014 g, 0.031 mmol), CS2CO3 (0.027 g, 0.084 mmol), Pd(dppf)Cl2 (0.003 g, 0.004 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (0.0058 mL, 0.031 mmol) in dioxane (0.2mL) is added water (0.002mL). The reaction proceeded at 100°C for 8 h. The reaction mixture is purified by prep. HPLC to afford the title compound (0.002g) as a beige solid.
  • Example 10.8 (first eluting enantiomer of Example 10.3) (0.07 g, 0.13 mmol) in MeOH (2.4 mL) and EtsN (0.06 mL, 0.4 mmol) is added under nitrogen atmosphere Pd(OH)2, 20 wt. % (0.02g). The reaction proceeded 2h under hydrogen atmosphere. The catalyst is removed by filtration and the evaporation residue is purified by prep-HPLC to yield Example 10.5 (0.04 g, 75% yield) as a white freeze dried solid.
  • Example 12.4 (5-chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl)(2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
  • Example 3.14 0.053 g, 0.10 mmol
  • MeOH-c 2.4mL
  • Pd(OH)2/C 20wt%, 0.012 g
  • the reaction proceeded under D2 atmosphere for 1 hi 5.
  • the catalyst is removed by filtration and the evaporation residue is purified by prep-HPLC to yield the title compound (0.039g, 87% yield)as a white solid.
  • Example 10.9 (0.03 g, 0.056 mmol) and proceeded as described in Example 12.4, the title compound (0.021 g) is obtained as a white solid after purification by prep-HPLC.
  • Solubility is determined by the miniaturized saturation shake flask method (screening mode).
  • the compound form is an amorphous film, from DMSO evaporation of a 10 mM stock solution, on which FaSSIF (Fasted State Simulated Intestinal Fluid) medium is added. After 24h of equilibration at 25°C, phases are separated by filtration and aqueous phase compound concentration in aqueous phase is determined by UV-HPLC.
  • Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure:
  • Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 pg/ml G418, 100 U/ml penicillin, 100 pg/ml streptomycin and 10 % heat inactivated fetal bovine serum (FBS).
  • the cells are seeded at 20’000 cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO2.
  • Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH: water (1 :1 ), diluted in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCOa 0.375g/l and 20 mM HEPES for use in the assay at a final concentration of 2 nM.
  • BSA bovine serum albumin
  • NaHCOa 0.375g/l
  • 20 mM HEPES for use in the assay at a final concentration of 2 nM.
  • Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCOa: 0.375g/l and 20 mM HEPES.
  • BSA bovine serum albumin
  • NaHCOa 0.375g/l
  • 20 mM HEPES 20 mM HEPES
  • 25 pL dye solution (HBSS containing 2 % FBS, 20 mM HEPES, NaHCCh: 0.375g/l, 5 mM probenecid (Sigma) and 4 pM of the fluorescent calcium indicator Fluo-8 AM (2 mM stock solution in DMSO)) is added to each well.
  • the 384-wel I cell-plates are incubated for 60min at 37° C in 5% CO2 followed by equilibration at RT for 15min before measurement.
  • antagonists are added to the plate in a volume of 10 pl/well, incubated for 120 min and finally 10 pl/well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by an approximate ECso (for example 2 nM) of orexin-A with vehicle in place of antagonist.
  • the IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined . Reference compounds are added on each plate. Optimized conditions are achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values may fluctuate depending on the daily cellular assay performance.
  • IC50 values from several measurements are given as geometric mean values.
  • Antagonistic activities of example compounds with respect to the 0x1 and 0x2 receptor are displayed in Table 1.
  • Compounds of the present invention may be further characterized with regard to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art; for example relating to their bioavailablility in different species (such as rat or dog); or relating to their ability to cross the blood-brain barrier, using for example a human P-glycoprotein 1 (MDR 1) substrate assay, or an in vivo assay to determine drug concentrations in the brain, e.g.
  • MDR 1 human P-glycoprotein 1
  • PBPK-PD Pharmacokinetic - Pharmacodynamic
  • Liver microsomes are subcellular fractions, which can be used to measure the intrinsic clearance of a compound and are useful in vitro models of e.g., the hepatic clearance as they contain many of the drug metabolizing enzymes found in the liver.
  • the microsomes are incubated with the test compound at 37°C in the presence of NADPH (co-factor which initiates the reaction). The disappearance of the compound is monitored over a specific time period (e.g. 45 minutes).
  • MDCK-MDR1 cells are Madin Darby canine kidney (MDCK) cells transfected with the MDR1 gene (ABCB1), the gene encoding for the efflux protein, P-glycoprotein (P-gp).
  • ABSB1 the MDR1 gene
  • P-gp P-glycoprotein
  • an efflux ratio can be determined, which can indicate whether a compound is actively being transported by P-gp, i.e., if a compound is a substrate of P-gp transporter, P-gp will efflux the drug from the inside to the cell to the apical side, preventing its permeation.
  • MDCK-MDR1 helps to gain an understanding of the mechanism of drug efflux, and highlights early potential issues with drug permeability.ln addition to intestinal permeability, MDCK-MDR1 permeability has also been found to be a useful predictor of blood brain barrier permeability.
  • MDR1-MDCK cell monolayers are grown to confluence on collagen-coated, microporous membranes in 12-well assay plates.
  • the permeability assay buffer is Hanks’ balanced salt solution containing 10 mM HEPES and 15 mM glucose at a pH of 7.4.
  • the buffer in the receiver chamber also contains 1% bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • the dosing solution concentration is 1 pM of test article in the assay buffer.
  • Cell monolayers are dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37°C with 5% CO2 in a humidified incubator. Samples are taken from the donor and receiver chambers at 120 minutes. Each determination is performed in duplicate.
  • the flux of lucifer yellow is also measured post-experimentally for each monolayer to ensure no damage is inflicted to the cell monolayers during the flux period. All samples are assayed by LC-MS/MS using electrospray ionization.
  • Electroencephalography EEG
  • EMG Electromyography
  • ECG Electrocardiographic
  • Surgical implantation is performed under general anesthesia with isoflurane and tracheal intubation, for cranial placement of one pair of EEG electrodes and a reference electrode, placement of one pair of ECG electrodes in the cardiac region, and insertion of one EMG lead in either side of the muscles of the neck.
  • dogs recover in a recovery room under obseravation and receive analgesic treatment with parecoxib for 5 d and cerfradine for 7d. All dogs are allowed 4 weeks of recovery before start of the experiment.
  • the dogs are kept in an observastion station, on a 12-h light / 12-h dark cycle, with no recording leads restricting their movements.
  • Variables analyzed include four different stages of vigilance and sleep and spontaneous activity. Sleep and wake stages are evaluated using a scoring software (Neuroscore; Data Science Int) directly processing electrical biosignals on 10 s contiguous epochs. The scoring is based on frequency estimation for EEG and amplitude discrimination for EMG and locomotor activity. Using these measurements, the software determines the probability that all components within each epoch best represent active waking (AW), quiet waking (QW), non-REM-sleep (NREM) or REM-sleep (REM). The time spent in AW, QW, NREM- and REM-sleep, total sleep and toal wake time is calculated per 12 h light or dark period and shorter time intervals.
  • Neuroscore Data Science Int
  • Test compound or vehicle is given orally in gelatine capsules.
  • Food is provided for 30 min 3 h posttreatment (1 :00 pm), and a toy is provided in the animal cages/observation station 6-h post-treatment (4:00 pm), to elicit gently stimulating anticipation in the dogs in the post-prandial phase.
  • Lights are turned off at 7:30 pm and turned on again at 7:00 am. Night-time and daytime recordings are performed under constant infrared illumination and automatic filtering by the cameras.
  • Total sleep time over 3h was 80 ⁇ 14 min and 92 ⁇ 12 min after 30 mg and 90 mg of the compound of example 3.3 as compared to placebo (46 ⁇ 13 min) with 78 ⁇ 14 min, 90 ⁇ 11 min, and 46 ⁇ 13 min (30 mg, 90 mg, placebo) spent in non-REM sleep.
  • Total wake time was 99 ⁇ 14 min, 87 ⁇ 12 min and 133 ⁇ 14 min over 3h after 30 mg and 90 mg of the compound of example 3.3 and placebo.
  • Total sleep time over 3h was 64 ⁇ 9 min and 64 ⁇ 9 min after 30 mg and 90 mg of the compound of example 10.4 as compared to placebo (36 ⁇ 9 min) with 60 ⁇ 8 min, 60 ⁇ 9 min, and 35 ⁇ 9 min (30 mg, 90 mg, placebo) spent in non-REM sleep.
  • Total wake time was 125 ⁇ 11 min, 115 ⁇ 9 min and 132 ⁇ 11 min over 3h after 30 mg and 90 mg of the compound of example 10.4 and placebo.

Abstract

The present invention relates to compounds of the formula (I) Formula (I) wherein Ar1, R1, R2, R3, X1, X2, Y, and Z are as described in the description, to their preparation, to pharmaceutically 5 acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as orexin receptor antagonists.

Description

Thiazoloaryl-methyl substituted cyclic hydrazine-N-carboxamide derivatives
The present invention relates to novel cyclic hydrazine-N-carboxamide 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.
Orexins (orexin A or OX-A and orexin B or OX-B) 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 (OXi and OX2 receptors). The orexin-1 receptor (OX1) is selective for OX-A, and the orexin-2 receptor (OX2) 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).
On the other hand, orexin neuropeptides and orexin receptors play an essential and central role in regulating circadian vigilance states. In the brain, 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. This role opens large therapeutic opportunities for medically addressing numerous mental health disorders possibly relating to orexinergic dysfunctions [see for example: Tsujino N and Sakurai T, "Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward systems.", Pharmacol Rev. 2009, 61 :162-176; and Carter ME et al., "The brain hypocretins and their receptors: mediators of allostatic arousal.", Curr Op Pharmacol. 2009, 9: 39-45] that are described in the following sections. It was also observed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches to insomnia and other sleep disorders (Chemelli R.M. et a/., Cell, 1999, 98, 437-451).
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.
In addition, both anatomical and functional evidence from in vitro and in vivo studies suggest an important positive interaction of the endogenous orexin system with reward pathways of the brain [Aston-Jones G et al., Brain Res 2010, 1314, 74-90; Sharf R et al., Brain Res 2010, 1314, 130-138], Selective pharmacological OXR-1 blockade reduced cue- and stress-induced reinstatement of cocaine seeking [Boutrel B, et al., "Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior." Proc Natl Acad Sci 2005, 102(52), 19168- 19173; Smith RJ et al., "Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking." Eur J Neurosci 2009, 30(3), 493-503; Smith RJ et al., "Orexin/hypocretin is necessary for context-driven cocaine- seeking." Neuropharmacology 2010, 58(1), 179-184], cue-induced reinstatement of alcohol seeking [Lawrence AJ et al., Br J Pharmacol 2006, 148(6), 752-759] and nicotine self-administration [Hollander JA et al., Proc Natl Acad Sci 2008, 105(49), 19480-19485; LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212], Orexin-1 receptor antagonism also attenuated the expression of amphetamine- and cocaine-induced OPP [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., Neuron 2006, 49(4), 589-601 ; Quarta D et al., "The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization." Neurochem Int 2010, 56(1), 11-15],
The effect of a drug to diminish addictions may be modelled in normal or particularly sensitive mammals used as animal models [see for example Spealman et al, Pharmacol. Biochem. Behav. 1999, 64, 327-336; or T.S. Shippenberg, G.F. Koob, "Recent advances in animal models of drug addiction" in Neuropsychopharmacology: The fifth generation of progress; K.L.Davis, D. Charney, J.T.Doyle, C. Nemeroff (eds.) 2002; chapter 97, pages 1381-1397],
Several converging lines of evidence furthermore demonstrate a direct role of the orexin system as modulator of the acute stress response. For instance, stress (i.e. psychological stress or physical stress) is associated with increased arousal and vigilance which in turn is controlled by orexins [Sutcliffe, JG et al., Nat Rev Neurosci 2002, 3(5), 339-349], Orexin neurons are likely to be involved in the coordinated regulation of behavioral and physiological responses in stressful environments [Y. Kayaba et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 285: R581-593], 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 timelimited 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 (suppl_1) S71-S76],
As outlined above the orexin system regulates homeostatic functions such as sleep-wake cycle, energy balance, emotions and reward. 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], Thus, there is a strong rationale that disturbances in the orexin system may contribute to the symptoms of mood disorders. Evidence in humans, for instance, exists that depressed patients show blunted diurnal variation in CSF orexin levels [Salomon RM et al., Biol Psychiatry 2003, 54(2), 96-104], In 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 2008, 22(7): 784-791], 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). In certain instances, a modulatory effect on stress may be complementary to an effect on appetitive/reward seeking behaviour as such. For instance, 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], In addition, 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, 11(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.
A number of recent studies report that orexins may play a role into several other important functions relating to arousal, especially when an organism must respond to unexpected stressors and challenges in the environment [Tsujino N and Sakurai T. Pharmacol Rev. 2009, 61 :162-176; Carter ME, Borg JS and deLecea L, Curr Op Pharmacol. 2009, 9: 39-45; C Boss, C Brisbare-Roch, F Jenck, Journal of Medicinal Chemistry 2009, 52: 891-903], 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 (2R)-2-{(1 S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}- W-methyl-2-phenyl-acetamide (W02005/118548), a dual orexin receptor antagonist, showed clinical efficacy in humans when tested for the indication primary insomnia. In the rat, the compound has been shown to decrease alertness, characterized by decreases in both active wake and locomotion; and to dose-dependently increase the time spent in both REM and NREM sleep [Brisbare-Roch et al., Nature Medicine 2007, 13, 150-155], 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 (W02009/047723) which relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs). In addition, intact declarative and nondeclarative learning and memory has been demonstrated in rats treated with this compound [W02007/105177, H Dietrich, F Jenck, Psychopharmacology 2010, 212, 145-154], Said compound furthermore decreased brain levels of amyloid-beta (Ap) as well as Ap 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], The accumulation of the Ap 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 Ap 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’homme 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], Another dual orexin receptor antagonist, N-biphenyl-2-yl-1-{[(1- methyl-1 H-benzi midazol-2-yl)sulfany l]acetyl}-L-prol i n amide 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],
Orexin receptor antagonists comprising a 2-substituted saturated cyclic amide derivatives (such as 2-substituted pyrrolidine-1 -carboxamides) are known for example from W02008/020405, W02008/038251 , W02008/081399,
W02008/087611, W02008/117241, W02008/139416, W02009/004584, W02009/016560, W02009/016564, W02009/040730, W02009/104155, WO2010/004507, WO2010/038200, W02001/096302, W02002/044172, W02002/089800, W02002/090355, W02003/002559, W02003/032991, W02003/041711 , W02003/051368, W02003/051873, W02004/026866, W02004/041791 , W02004/041807, W02004/041816, W02009/003993, W02009/003997, W02009/124956, WO2010/060470, WO2010/060471, WO2010/060472, WO2010/063662, WO2010/063663, WO2010/072722, W02010/122151, and W02008/150364 and WO2013/182972.
W02003/002559 and 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 W02003/002559 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. W02003/002561 discloses certain N-aroyl cyclic amine derivatives, encompassing a benzimidazol-2-yl-methyl substituted morpholine derivative, as orexin receptor antagonists. Despite the great number of prior art compounds and their high structural variability, such compounds generally share a common structural feature, i.e. they contain central core ring such as a pyrrolidine, piperidine, or morpholine derivative, containing a chiral carbon center in position 2 that is substituted with an aromatic group, generally via a linker group. WO2013/182972 discloses pyrrolidine derivatives that have a benzimidazole ring directly attached to a pyrrolidine amide in position 2. It has now surprisingly been found that, despite the conformational changes that may be expected from the removal of a chiral center in the core ring structure of the compounds known in the art, the present pyrazolidinyl derivatives carrying particular substituents in position 1 and 2, may be potent dual orexin receptor antagonists.
The present invention, thus, provides novel substituted thiazoloaryl-methyl substituted cyclic hydrazine-W- carboxamide derivatives, which are dual non-peptide antagonists of the human orexin-1 and orexin-2 receptors. These compounds are in particular of potential use in the treatment of disorders relating to orexinergic dysfunctions, comprising especially sleep disorders including insomnias, as well as anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders or neuropsychiatric symptoms in dementia. These compounds may have particular advantages such as bioavailability, capacity to cross the blood-brain barrier; and/or may have a particular metabolic and pharmacokinetic profile that may be of advantage for certain medical uses where controled periods of exposure to the active ingredient are required. 1) A first aspect of the invention relates to compounds of the Formula (I)
Figure imgf000007_0001
Formula (I) wherein
R1 represents (Ci-3)alkyl (especially methyl), halogen (especially chloro or bromo), cyclopropyl, or trifluoromethyl; [especially R1 represents methyl];
X1 represents S or 0; [especially X1 represents S];
X2 represents CH or N; [especially X2 represents CH];
Z represents -CH2-, -CHfCHs)-, or -CH2-CH2-; [especially Z represents -CH2- or -CHfCHs)-]; and in the fragment
Figure imgf000007_0002
• R2 independently represents hydrogen, (Ci-3)alkyl (especially methyl), halogen (especially chloro), or (Ci-3)alkoxy (especially methoxy);
[notably R2 represents methyl or chloro, especially chloro];
• R3 independently represents hydrogen, or (Ci-3)alkyl (especially methyl) [especially R3 represents hydrogen]; and
• Y independently represents CH or N;
[especially Y represents CH];
[wherein, in a sub-embodiment of this embodiment 1), said fragment
Figure imgf000007_0003
Figure imgf000008_0001
• Ar1 independently represents:
Figure imgf000008_0002
[especially Ar1 independently represents:
Figure imgf000008_0003
The compounds of Formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- or (S)-configuration. The compounds of Formula (I) 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.
In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In case a particular compound (or generic structure) contains one (or, likewise, more) stereogenic or asymmetric center(s), such as one (or more) asymmetric carbon atom(s), which may be present in (R)- or (S)-configuration, but where said stereogenic or asymmetric center(s) is/are not explicitly designated as (R)- or (S)-, it is understood that said stereogenic or asymmetric center may be in (R)- or (S)- configuration. Such compound name or generic structure is understood to encompass the compound / generic structure where such center is in (R)- or (S)- configuration, or any mixture of epimers with regard to such center including the racemate. Likewise, in case such stereogenic or asymmetric center is designated as being in (RS)- configuration, this means that such stereogenic or asymmetric center in such compound may be present in (R)- configuration, in (S)-configuration, or in any mixture of epimers with regard to such center including the racemate. In case two or more such stereogenic or asymmetric centers (in undesignated or designated (RS)-configuration) are present in one molecule, it is understood that the order of absolute configuration does not indicate any defined relative configuration with regard to the two or more centers.
The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
The term “essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.
The present invention also includes isotopical ly labelled, especially 2H (hydrogen-2, deuterium) labelled compounds of Formula (I) according to embodiments 1) to 18), which compounds are identical to the compounds of Formula (I) 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 2H labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. Typical positions generally considered suitable for introducing 2H atoms, for example to modify metabolic stability, are for example hydrogen atoms attached to a non-aromatic carbon atom that is directly bound to a heteroatom such as oxygen or nitrogen (e.g. a methoxy-da group replacing the methoxy in a methoxyphenyl group). In one embodiment of the invention, the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more 2H atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn below
Figure imgf000010_0001
is a 3-methyl-phenyl group.
Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.
Any reference to compounds of Formula (I) according to embodiments 1) to 18) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example “Handbook of Pharmaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and “Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.
Definitions provided herein are intended to apply uniformly to the compounds of Formula (I), as defined in any one of embodiments 1) to 18), and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.
Whenever a substituent is denoted as optional, it is understood that such substituent may be absent, in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and / or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate.
The term “halogen” means fluoro/fluorine, chloro/chlorine, bromo/bromine, or iodo/iodine; especially fluoro, chloro, or bromo. For the substituent R1 the term especially represents chloro or bromo. For the substituent R2 the term especially represents chloro.
The term “alkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated straight or branched chain hydrocarbon group containing one to four carbon atoms. The term “(Cx-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (Cujalkyl group contains from one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -butyl. For avoidance of any doubt, in case a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl. Preferred are methyl and ethyl. Most preferred is methyl. The term “alkoxy”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term “(Cx-y) alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (Cujalkoxy group means a group of the formula (Ci-4)alkyl-O- in which the term “(Ci-4)alkyl” has the previously given significance. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.- butoxy, and tert.-butoxy. Preferred are methoxy.
The term "fluoroalkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, 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. The term “(Cx-y)fluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (Ci-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, and 2,2,2- trifluoroethyl; especially trifluoromethyl. Preferred are (C-i)fluoroalkyl groups such as trifluoromethyl.
The term "cyano" refers to a group -CN.
The term “cycloalkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon ring containing three to eight carbon atoms. The term "(Cx.y)cycloalkyl " (x and y each being an integer), refers to a cycloalkyl containing x to y carbon atoms. For example, a (Cs-ejcycloalkyl group contains from three to six carbon atoms. A preferred example is cyclopropyl.
The term "aryl", used alone or in combination, means phenyl or naphthyl, especially phenyl. The above-mentioned aryl groups are unsubstituted or substituted as explicitly defined.
The term "heteroaryl", used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms (especially one to a maximum three), each independently selected from N, 0, and S. Examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, furopyridinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above- mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.
Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4. Unless used regarding temperatures, the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus (10% of X) to X plus (10% of X), and preferably to an interval extending from X minus (5% of X) to X plus (5% of X). Likewise, the term “about” placed before a numerical range “X to Y” refers in the current application to an interval extending from X minus (10% of X) to Y plus (10% of Y), and preferably to an interval extending from X minus (5% of X) to Y plus (5% of Y). In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C. The term “room temperature” as used herein refers to a temperature of about 25°C.
Further embodiments of the invention are presented hereinafter:
2) Another embodiment relates to compounds according to embodiment 1), wherein R1 represents methyl, chloro, bromo, cyclopropyl, or trifluoromethyl; [especially R1 represents methyl],
3) Another embodiment relates to compounds according to embodiment 1), wherein R1 represents methyl.
4) Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein
X1 represents S.
5) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein
X2 represents CH.
6) Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein Z represents -CH2- or -CH(CH3)-.
7) Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein, in case Z represents -CHJCHs)-, such compound of Formula (I) has the absolute configuration depicted in Formula (IA) below:
Figure imgf000012_0001
Formula (IA);
(i.e. the chiral carbon atom of the pyrazolidinyl ring is in absolute (R)-configuration).
8) Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein Z represents -CH2-.
9) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein in the fragment
Figure imgf000013_0001
• R2 independently represents hydrogen, methyl, chloro, or methoxy;
[notably R2 independently represents methyl or chloro, especially chloro];
• R3 independently represents hydrogen or methyl
[especially R3 independently represents hydrogen]; and
• Y independently represents CH or N;
[especially Y represents CH]; wherein each Ar1 independently is as defined in embodiment 1).
10) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment
Figure imgf000013_0002
wherein each Ar1 independently is as defined in embodiment 1).
11) Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar1 independently represents a group selected from the groups A) to D):
A)
Figure imgf000013_0003
Figure imgf000014_0001
12) Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar1 independently represents a group selected from the groups A) or B):
A)
Figure imgf000014_0002
13) Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar1 independently represents:
Figure imgf000014_0003
14) Another embodiment relates to compounds according to any one of embodiments 1 ) to 8), wherein the fragment
Figure imgf000014_0004
represents a group selected from the groups A) to F):
Figure imgf000015_0001
15) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment
Figure imgf000016_0001
represents a group selected from the groups A) to D):
Figure imgf000016_0002
16) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment
Figure imgf000016_0003
represents:
Figure imgf000017_0001
17) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment
Figure imgf000017_0002
18) Another embodiment relates to compounds according to embodiment 1) selected from:
(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(4,5-dimethyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(3'-methyl-[1 , 1 '-bi pheny l]-2-y I) (2-((2-methy I benzo[d]th i azol-6-yl) methy l)py razol id in- 1 -yl)methanone;
(5-methyl-2-(4-methyl-1 /-/-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(5-methyl-2-(3-methyl-1 /-/-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
[1,1 '-biphenyl]-2-yl(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-methyl-2-(2-methylthiazol-4-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone; (5-methyl-2-(4-methyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(5-methyl-2-(thiazol-2-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 -yl)methanone;
(5-methyl-2-(1 /-/-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-chloro-2-(1 /-/-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(2-(4-bromo-2H-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(2-(4-chloro-1 /-/-pyrazol-1-yl)-5-methylpyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(5-chloro-2-(4-methyl-1 H-pyrazol-1 -yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(2-(2/-/-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazin-1(2H)-yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[c/]thiazol-6-yl)methyl)tetrahydropyridazin-1 (2/7)- yl)methanone;
(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazin-1(2H)- yl)methanone;
(5-chloro-2-(4-methyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(5-chloro-2-(4-ethynyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[c/]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(2-((2-bromobenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylthiazolo[5,4-b]pyridin-5-yl)methyl)pyrazolidin-1- yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-chlorobenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-cyclopropylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-ethylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(/?)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(S)-(5-chloro-2-(2/-/-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone; (S)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2/-/-1,2,3-triazol-2- yl)phenyl)methanone;
(S)-(2-(4-bromo-2/7-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone;
(R)-(2-(4-bromo-2H-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone;
(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]oxazol-6-yl)methyl)pyrazolidin-1-yl)methanone; (2-(2/-/-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl-4,4-d2)methanone;
(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl-4,4- cymethanone;
(5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 -yl-4,4- cymethanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl-d)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone; and
(R)-(5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl-d)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone.
The compounds of Formula (I) according to any one of embodiments 1) to 18) 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).
The production of the pharmaceutical 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, 21st 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) according to any one of embodiments 1) to 18).
The terms “subject”, and likewise, “patient” refers to mammals, especially humans. Preferably, the term “subject” refers to the term “patient”.
The term “prevention” as used in the present disclosure may be understood to mean and is therefore interchangeable with the term “prophylaxis”.
For avoidance of any doubt, if compounds are described as useful for the prevention / prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases. Likewise, such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.
The compounds according to Formula (I) according to any one of embodiments 1) to 18) are useful for the prevention or treatment of disorders relating to orexinergic dysfunctions.
Such disorders relating to orexinergic dysfunctions are diseases or disorders where an antagonist of a human orexin receptor is required, notably mental health disorders relating to orexinergic dysfunctions. The above mentioned disorders may in particular be defined as comprising sleep disorders especially including insomnias, as well as anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders and neuropsychiatric symptoms in dementia. In one sub-embodiment, the above mentioned disorders comprise especially anxiety disorders, addiction disorders, mood disorders and neuropsychiatric symptoms in dementia, notably anxiety disorders and addiction disorders. In another sub-embodiment, the above mentioned disorders comprise especially sleep disorders, in particular insomnias.
In addition, further 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. In a subembodiment, particular examples of circumscribed threat induced anxiety disorders are phobic anxieties or post- traumatic stress disorders. Anxiety disorders especially include 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]}. In a sub-embodiment, 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. The expression "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). Such mood disorders are especially major depressive episode, major depressive disorder, mood disorder due to a general medical condition; and substance-induced mood disorder.
Neuropsychiatric symptoms (NPS) in dementia (e.g. Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorder; especially a dementia of Alzheimer's type, in particular AD) are defined as circadian syndromes of increased confusion and restlessness in a patient, wherein said patient has some form of dementia (especially a dementia of Alzheimer's type, in particular AD). Such circadian syndromes especially occur late-day, i.e. in the afternoon and / or evening hours. Cardinal clinical signs include increased agitation, general confusion and mood swings; such signs developing typically as natural light begins to fade.
Neuropsychiatric symptoms in dementia (especially in a dementia of Alzheimer's type, in particular in AD) especially refers to agitation and/or aggression associated with such dementia (sometimes equivalently named sundown syndrome).
The term “agitation” is used to describe a wide range of behaviors that include verbal outbursts, physical aggression, intense anxiety and crying, and persistent perambulation and wandering (Kales et al., J Am Geriatr Soc. 2014;62(4):762-9; Phan et al., Drugs in R&D (2019) 19:93-115). The International Psychogeriatric Association (IPA) compiled a syndromic definition of agitation (see for example N. Stocking: excerpted article as reprint from IPA’s newsletter, the IPA Bulletin, Vol 31(4): https://www.ipa-online.org/news-and-issues/defining- agitation):
• The patient meets criteria for a cognitive impairment or dementia syndrome (e.g. Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorder).
• The patient exhibits at least one of the following behaviors that are associated with observed or inferred evidence of emotional distress (e.g. rapid changes in mood, irritability, outbursts). The behavior has been persistent or frequently recurrent for a minimum of two weeks and represents a change from the patient’s usual behavior.
(a) Excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms).
(b) Verbal aggression (e.g. yelling, speaking in an excessively loud voice, using profanity, screaming, shouting).
(c) Physical aggression (e.g. grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property).
• Behaviors are severe enough to produce excess disability, which in the clinician’s opinion is beyond that due to the cognitive impairment and including at least one of the following:
(a) Significant impairment in interpersonal relationships.
(b) Significant impairment in other aspects of social functioning.
(c) Significant impairment in ability to perform or participate in daily living activities.
• While co-morbid conditions may be present, the agitation is not attributable solely to another psychiatric disorder, suboptimal care conditions, medical condition, or the physiological effects of a substance.
The term "late day" referred to herein relates to the afternoon and evening, notably the time about sunset and later (but not including the night / the sleep time); for example, the time from about 4 pm to about 10 pm, especially from about 4 pm to about 9 pm. In one sub-embodiment, the term relates to the afternoon, especially from about 4 pm to about 7 pm; in another sub-embodiment the term relates to the evening, especially from about 7 pm to about 10 pm, especially from about 7 pm to about 9 pm.
Dementias include notably dementias of Alzheimer's type including: Alzheimer dementia (presenile dementia or senile dementia), subcortical dementia, (diffuse) Lewy body dementia, and frontotemporal dementia. Dementias further include dementias of vascular type such as: vascular dementia, multi-infarct dementia, Binswanger's dementia, boxer's dementia, arteriosclerotic dementia. Remaining types of dementia (9%) are of other etiologies such as paralytic dementia, substance-induced persisting dementia, dialysis dementia, hydrocephalic dementia, and dementias due to tumors, subdural hematoma, normal pressure hydrocephalus, vasculitis, Vitamin deficiency, or endocrine or metabolic disease. In the context of the present invention, the term preferably refers to dementias of Alzheimer's type, especially to Alzheimer dementia. It is understood that the term dementia also includes any combination of the above listed types of dementias.
Appetite disorders comprise eating disorders and drinking disorders. 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 payability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance. Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake. 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 nervosa (bulimia) or anorexia nervosa. The term "eating disorder" in particular refers to Binge-Eating Disorder (BED); Bulimia Nervosa (BN); Anorexia Nervosa (AN) (notably binge-eating/purging type Anorexia Nervosa; especially binge-eating type Anorexia Nervosa); Pica; Other Specified Feeding and Eating Disorders (OSFED) [notably atypical Bulimia Nervosa, Binge-Eating Disorder of low frequency and/or limited duration, Bulimia Nervosa of low frequency and/or limited duration, or Night Eating Syndrome (NES)]; Unspecified Feeding or Eating Disorder (UFED); Eating Disorder Not Otherwise Specified (EDNOS); and Compulsive Overeating (CO); Loss of Control (LOG) Eating; and hyperphagia and/or binge-eating associated with Prader-Willi Syndrome (PWS). Eating disorders refer especially to such eating disorders comprising a compulsive, binge eating behavior. It is understood that the term “eating disorder comprising a compulsive, binge eating behavior” refers to a disorder comprising recurring episodes of binge eating, i.e. recurring episodes when a subject is eating significantly more food in a short period of time than most people would eat under similar circumstances, with episodes marked by feelings of lack of control. Eating disorder comprising a compulsive, binge eating behavior is characterized by eating large amounts of food, by eating quickly (often to the point of discomfort), and by eating even when no longer hungry. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5® or herein also referred to as DSM-5) provides diagnostic criteria for certain feeding and eating disorders. Binge-Eating Disorder (BED) is defined as recurring episodes of eating significantly more food in a short period of time than most people would eat under similar circumstances, with episodes marked by feelings of lack of control. Someone with binge eating disorder may eat too quickly, even when they are not hungry. The person may have feelings of guilt, embarrassment, or disgust and may binge eat alone to hide the behaviour. BED is associated with marked distress and significant physical, emotional, and social health risks such as obesity and extreme weight gain and a wide range of associated diseases such as sleep apnea, cancer, heart disease, high blood pressure, type 2 diabetes, arthritis, etc., being among the most common ones.
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]. Especially, the term "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 especially dyssomnias and sleep disorders associated with a general medical condition, as well as parasomnias, and substance-induced sleep disorders. Dyssomnias in particular include intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb movement disorder, and restless leg syndrome), extrinsic sleep disorders, and circadian-rhythm sleep disorders. Sleep disorders notably refer to insomnias including primary insomnia and idiopathic insomnia; intermittent treatment of chronic insomnia; situational transient insomnia (e.g. insomnia associated to a new environment or noise); (short-term) insomnia due to stress, grief, pain or illness; and insomnias related to mental or neurologic disorders including insomnias associated with mood disorders (such as depressive disorders), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and cerebral degenerative disorders including Alzheimer's disease and other neurodegenerative and/or cognitive impairment diseases or disorders. In addition, sleep disorders notably refer to dyssomnias such as breathing-related sleep disorders including (obstructive or central) sleep apnea syndrome; periodic limb movement disorder (nocturnal myoclonus); restless leg syndrome; circadian rhythm sleep disorders including shift work sleep disorder; and time-zone-change (jet-lag) syndrome. Sleep disorders further refer to REM sleep interruptions. 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 as defined before, as well as sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder and delayed or advanced sleep phase syndrome. In addition, sleep disorders further include sleep disorders associated with aging.
Sleep disorders associated with a general medical condition include sleep disorders (especially insomnias) related to mental or neurologic disorders; notably sleep disorders (especially insomnias) associated with mood disorders (such as depressive disorders), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and cerebral (neuro-)degenerative disorders including Alzheimer's disease and other neurodegenerative and/or cognitive impairment diseases or disorders; as well as sleep disorders (especially insomnias) associated with anxiety disorders, addiction disorders, or appetite disorders.
A particular aspect of the invention relates to a compound of Formula (I) according to any one of embodiments 1) to 18) for use in the treatment of disorders relating to orexinergic dysfunctions, especially of sleep disorders as defined herein above (in particular any type of insomnia as defined herein above, breathing-related sleep disorders including sleep apnea syndrome; periodic limb movement disorder; restless leg syndrome; circadian rhythm sleep disorders including shift work sleep disorder; and time-zone-change syndrome); wherein said treatment comprises the administration of a compound of Formula (I) according to any one of embodiments 1) to 18), wherein said compound is (to be) administered during the night, notably less than 7 hours prior to the morning / wake time; especially between about 7 hours to 2 hours prior to the morning / wake time; in particular about 4 hours to 2 hours prior to the morning / wake time.
In the context of the present invention, it is to be understood that, in case certain environmental conditions such as stress or fear (wherein stress may be of social origin (e.g. social stress) or of physical origin (e.g. physical stress), including stress caused by fear) facilitate or precipitate any of the disorders or diseases as defined before, the present compounds may be particularly useful for the treatment of such environmentally conditioned disorder or disease.
Preparation of compounds of Formula (I):
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 the schemes below, the generic groups Ar1, R1, R2, R3, X1, X2, Y, and Z are as defined for the compounds of formula (I). In some instances the generic groups Ar1, R1, R2, R3, X1, X2, Y, and Z may be incompatible with the assembly illustrated in the schemes, or will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. 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. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts in a manner known per se.
Compounds of formula (I) of the present invention can be prepared according to the general sequence of reactions outlined below.
General reaction techniques:
General reaction technique 1 (amide bond formation): The carboxylic acid is reacted with the hydroxylamine or amine derivative in the presence of an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or DSC, in a dry aprotic solvent such as DCM, MeCN or DMF between 20°C and 60°C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 6, p. 381). Alternatively, the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between 20° and 60°C. Further activating agents can be found in R. C. Larock, Comprehensive Organic Transformations. A guide to Functional Group Preparations, 2nd Edition (1999), section nitriles, carboxylic acids and derivatives, p. 1941-1949 (Wiley VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto).
General reaction technique 2 (reductive amination):
The reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, MgSO4 or Na2SO4). Such solvent is typically toluene, Hex, THF, DCM or DCE or a mixture of solvents such as DCE/MeOH. The reaction can be catalyzed by traces of acid (usually AcOH). The intermediate imine is reduced with a suitable reducing agent (e.g. NaBH4, NaBHsCN, or NaBH(OAc)3 or through hydrogenation over a noble metal catalyst such as Pd/C. The reaction is carried out between -10°C and 110°C, preferably between 0°C and 60°C. The reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in presence of a picoline-borane complex (Tetrahedron (2004), 60, 7899- 7906).
General reaction technique 3: alkylation:
The NH-containing derivative is reacted with an alkylating agent compound of formula G-CH2-LG, wherein G has the same meaning as in Formula (I) and LG represents OMs, OTf, OTs, Cl, Br or I, in presence of an inorganic base such as K2CO3 or an org. base such as TEA in a solvent such as THF, MeCN or DMF between 0°C and +80°C. Iodide salts such as sodium iodide or tetrabutyl ammonium iodide can be added to promote the nucleophilic substitution reaction. Further details can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, (1999). Section Amines p.779.
General reaction technique 4 (Suzuki cross-coupling reaction):
The aromatic halide (typically a bromide) is reacted with the required boronic acid derivative or its boronate ester equivalent (e.g. pinacol ester) in the presence of a palladium catalyst and a base such as K2CO3, CS2CO3, K3PO4, tBuONa or tBuOK between 20 and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF, usually in the presence of water (20 to 50%). Examples of typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh3)4. These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCys or P(tBu)3), dialkylphosphinobiphenyls (e.g. S- Phos) or ferrocenylphosphines (e.g. Q-phos). Alternatively, one can use a commercially available precatalyst based on palladacycle (e.g. SK-CC01-A) or N heterocyclic carbene complexes (e.g. PEPPSITM-IPr). The reaction can also be performed by using the corresponding aromatic tritiate. Further variations of the reaction are described in Miyaura and Suzuki, Chem. Rev. (1995), 95, 2457-2483, Beilina et al., Synthesis (2004), 2419-2440, Mauger and Mignani, Aldrichimica Acta (2006), 39, 17-24, Kantchev et al., Aldrichimica Acta (2006), 39, 97 111, Fu, Acc. Chem. Res. (2008), 41, 1555-1564, and references cited therein.
Preparation of compounds of Formula (I):
Compounds of general Formula (I) can be prepared reacting carboxylic acids of structure 1-1 with NH-containing intermediates of structure I-2 using one of the carbon- nitrogen bond formation methods reported in general reaction technique 1 (Scheme 1). Scheme 1
Figure imgf000027_0001
Alternatively, compounds of general Formula I can be prepared via a carbon-nitrogen bond formation reaction involving the NH-containing compounds of structure 11-1 and either an aldehyde intermediate of structure 11-2 using general reaction technique 2 or an alkylating agent of structure 11-3 using general reaction technique 3 (Scheme 2). Scheme 2
Figure imgf000027_0002
Compounds of general Formula I can also be prepared via a cross-coupling reaction involving compounds of structure 111-1 with a boron derivative of structure-l 11-2 using general reaction technique 3 (Scheme 3).
Figure imgf000028_0001
111-1
I
In Scheme 3, LG1 represents a leaving group selected from -OTf, -I, -Br or -Cl. D1 and D2 represent H, methyl or ethyl or D1 and D2 together represent CH2C(Me)2CH2 or C(Me)2C(Me)2 Compounds of general Formula I can also be prepared via a cross-coupling reaction involving compounds of structure IV-1 with a boron derivative of structure-IV-2 using general reaction technique 4 (Scheme 4).
Scheme 4
Figure imgf000028_0002
In Scheme 4, D1 and D2 represent H, methyl or ethyl or D1 and D2 together represent CH2C(Me)2CH2 or C(Me)2C(Me)2
Compounds of general Formula I can also be prepared reacting compounds of structure V-1 with a di-bromide of structure V-2 in presence of a base such as K3PO4 in acetonitrile at a temperature ranging between 60°C and 90°C. (Scheme 5).
Figure imgf000029_0002
Preparation of compounds of structure 1-2, 11-1, 111-1, IV-1 and V-1 :
Compounds of structure I-2 can be prepared via a carbon-nitrogen bond formation reaction involving the NH- containing compounds of structure VI-1 and either an aldehyde intermediate of structure 11-2 using general reaction technique 2 or an alkylating agent of structure 11-3 using general reaction technique 3. The resulting intermediates of structure VI-2 can be subsequently transformed to compounds of structure I-2 by cleavage of PGi. Depending on the nature of PGi, any suitable methods reported in Protecting Groups, Kocienski, P.J. Georg Thieme Verlag Stuttgart-New-York (1994) can be used. For instance, when PGi = Boc, treatment with HCI in dioxane, or alternatively TFA in DCM can be used (Scheme 6).
Scheme 6
Figure imgf000029_0001
In Scheme 6, Ar1, PGi is a protecting group such as Boc.
Compounds of structure 11-1 can be prepared reacting the carboxylic acid of structure 1-1 with the NH-containing intermediate of structure VI-1 using one of the carbon- nitrogen bond formation methods reported in general reaction technique 1 . The resulting intermediates of structure VI 1-1 can be subsequently transformed to compounds of structure 11-1 by cleavage of PGi. Depending on the nature of PGi, any suitable methods reported in Protecting Groups, Kocienski, P.J. Georg Thieme Verlag Stuttgart-New-York (1994) can be used. For instance, when PGi = Boc, a treatment with HCI in dioxane, or alternatively TFA in DCM can be used (Scheme 7).
Figure imgf000030_0003
In Scheme 7, PGi is a protecting group such as Boc.
Alternatively, compounds of structure 11-1 can be prepared by reacting compounds of structure VI 11-1 with carboxylic acids of structure 1-1 using one of the carbon- nitrogen bond formation methods reported in general reaction technique 1. The resulting intermediates of structure VIII-2 can be subsequently transformed to compounds of structure VII-1 by reaction with the di-bromide of structure V-2 in presence of a base such as K3PO4 in acetonitrile at a temperature ranging between 60°C and 90°C. Finally, the compounds of structure VII-1 can be transformed to compounds of structure 11-1 using the abovementioned methods. (Scheme 8) Scheme 8
Figure imgf000030_0001
In Scheme 8, PGi is a protecting group such as Boc.
Compounds of structure 111-1 can be prepared as described in Scheme I for the preparation of compounds of general
Formula I, replacing the carboxylic acids of structure 1-1 by carboxylic acids of structure IX- 1 wherein LGi is a leaving group such as OTf, -I, -Br or -Cl. R2, R3 and Y have the same meaning as in formula I
Figure imgf000030_0002
Compounds of structure IV- 1 can be prepared as described in Scheme 2 for the preparation of compounds of general Formula I, replacing aldehydes of structure II-2 or alkylating agents of structure II-3 by aldehydes of structure X-1 or alkylating agents of structure X-2 respectively, -Br or -Cl. X1 and X2 have the same meaning as in formula I
Figure imgf000031_0001
Compounds of structure V-1 can be obtained from compounds of structure VIII-2, first cleaving PGi. Depending on the nature of PGi, any suitable methods reported in Protecting Groups, Kocienski, P.J. Georg Thieme Verlag Stuttgart-New-York (1994) can be used. For instance, when PGi = Boc, a treatment with HCI in dioxane, or alternatively TFA in DCM can be used. The resulting compounds of XI-1 can eventually be transformed to compounds of structure V-1 by reacting it with aldehydes of structure II-2 using general reaction technique 2 (Scheme 9).
Scheme 9
Figure imgf000031_0002
In Scheme 9, PGi is a protecting group such as Boc
Compounds of structures 1-1, II-2, II-3, III-2, IV-2, V-2, VI-1, VI 11-1 , IX-1 , X-1 and X-2 are either commercially available or prepared in analogy to procedures well known in the art or procedures disclosed in the experimental part.
Part
I. Chemistry
All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise specified, all reactions were carried out in oven-dried glassware under an atmosphere of nitrogen. Unless otherwise stated, reaction mixtures are quenched with an appropriate aqueous medium and extracted with an appropriate organic solvents. The organic extracts are combined, washed with a minimal volume of brine, dried over sodium sulfate, filtered and concentrated to dryness to afford a so-called evaporation residue Compounds were obtained after purification of the evaporation residue using either flash column chromatography on silica gel or a preparative HPLC method. Compounds described in the invention are characterised by LC-MS data (retention time IR is given in min; molecular weight obtained from the mass spectrum is given in g/mol) using the conditions listed below. In cases where compounds of the present invention appear as a mixture of conformational isomers, particularly visible in their LC-MS spectra, the retention time of the most abundant conformer is given. Racemates can be separated into their enantiomers by preparative HPLC (column: ChiralPaK IC 250x4.6 mm, 5 pm, 45% ethanol in heptane).
Abbrevations (as used herein and in the description above):
Ac Acetyl (such as in OAc = acetate, AcOH = acetic acid)
Acac acetyl acetonate aq. aqueous
Boc tert-Butoxycarbonyl
BOC2O di-fert-Butyl dicarbonate
Bu Butyl such as in tBu = tert-butyl = tertiary butyl
Carb, acid carboxylic acid comm. commercial
DCM Dichloromethane
DI PEA Diisopropylethylamine
DMA W,W-Dimethylacetamide
DMF W,W-Dimethylformamide
DMSO Dimethyl sulfoxide dppf bis(diphenylphosphino)ferrocene
ELSD Evaporative Light-Scattering Detection eq Equivalent(s)
ES Electron spray
Et Ethyl
Et20 Diethyl ether
EtOAc Ethyl acetate
EtOH Ethanol
Ex. Example / compound of Example
FC Flash Chromatography on silica gel
FCS Foatal calf serum h Hour(s)
HATU 1-[Bis(dimethylamino)methylene]-1/7-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
HBSS Hank’s balanced salt solution HBTU A/,A/,A/',A/'-Tetramethyl-O-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate
HEPES 4-(2-Hydroxyethyl)-piperazine-1 -ethanesulfonic acid
1H-NMR Nuclear magnetic resonance of the proton
HPLC High performance liquid chromatography
LC-MS Liquid chromatography - Mass Spectroscopy
Lit. Literature
M Exact mass (as used for LC-MS)
Me Methyl
MeCN Acetonitrile
MeOH Methanol pil microliter min Minute(s)
MS Mass spectroscopy
N Normality
Pd(OAc)2 Palladium diacetate
Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)
Ph Phenyl prep. preparative r.t. Room temperature sat. Saturated
TBTU O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate
TEA Triethylamine
TFA trifluoroacetic acid
THF Tetrahydrofuran tR Retention time
UV Ultra violet
Analytical conditions for LC-MS
Unless notified otherwise, the following conditions were used for analytical LC-MS data:
(A)
Apparatus: Agilent 1100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Zorbax RRHD SB-Aq (1 .8 pm, 2.6 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.
(B)
Apparatus: Agilent 1100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Waters XBridge C18 (5 pm, 4.6 x 50 mm). Conditions: MeCN [eluent A]; 13 mmol/l NH3 in water [eluent B], Gradient: 95% B — > 5% B over 1 .5 min. (flow: 4.5 ml/min.). Detection: UVA/is + MS. (C)
Apparatus: Waters Acquity UPLC with mass spectroscopy detection (MS : Waters SQ Detector or Xevo TQD). Column: Acquity UPLC CSH C18 (1.7 m, 2.1 x 50 mm). Conditions: MeCN+0.045% formic acid [eluent A]; water + 0.05% formic acid [eluent B], Gradient: 98% B — > 2% B over 2 min. (flow: 1 ml/min.). Detection: UV (214nm) + MS.
Preparative HPLC
Reaction mixture can generally be separated by preparative HPLC. A person skilled in the art will find suitable conditions for each separation. Product containing fractions are collected and lyophilized or freeze dried under vacuum.
Automated FC
Classical flash chromatography is often replaced by automated systems. This does not change the separation process perse. A person skilled in the art will be able to replace a classical FC process by an automated one, and wee versa. Typical automated systems can be used, as they are provided by Buchi, Isco (Combiflash), or Biotage for instance.
The following examples illustrate the preparation of compounds of the invention but do not at all limit the scope thereof.
Preparation of precursors and intermediates:
Preparation A: 2-methyl-6-(pyrazolidin-1-ylmethyl)benzo[d]thiazole dihydrochloride
A.i. tert-Butyl 2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1-carboxylate'.
To a solution of tert-butyl 1-pyrazolidinecarboxylate (4.63 g, 26.9 mmol) in DCM (190 mL) are added successively at r.t. 2-methyl-1 ,3-benzothiazole-6-carbaldehyde (5.02 g, 26.9 mmol) and NaBH(OAc)3 (14.78 g, 67.6 mmol). The resulting mixture is stirred for 23h. Sat. aq. NaHCOa (100 mL) and water (100 mL) are added. The two layers are separated and the aq. layer is extracted with DCM (2 x 75 mL). The evaporation residue is purified by FC (heptane- EtOAc with gradient) to afford the title product (7.18 g) as a colourless oil of 86% purity. LC-MS (A): IR = 0.83 min; [M+H]+ = 334.15. 1H NMR (DMSO-d6) 5 7.99 (d, J = 1.2 Hz, 1 H), 7.85 (d, J = 8.3 Hz, 1 H), 7.49 (dd, J = 1.6, 8.3 Hz, 1 H), 3.80 (s, 2H), 3.43 (t, J = 6.8 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2 H), 2.79 (s, 3 H), 2.07 (m, 2H), 1 .29 (s, 9H).
A.ii. 2-Methyl-6-(pyrazolidin-1-ylmethyl)benzo[d]thiazole dihydrochloride:
Intermediate A.i (7.19 g, 21.6 mmol) is dissolved in 4N HCI in dioxane (100 mL, 416 mmol) at r.t. The reaction mixture is stirred for 16 h. The reaction mixture is concentrated to dryness and the resulting solid is dried under vacuum to a constant weight to afford the title compound (6.6 g) as a yellowish solid. LC-MS (A): IR = 0.53 min; [M+H]+ = 234.20.
Preparation B: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(pyrazolidin-1-yl)methanone hydrochloride
B.i. tert-Butyl 2-(5-methyl-2-(2H-1 , 2, 3-triazol-2-yl)'benzoyl)pyrazolidine-1-carboxylate:
To a solution of tert-butyl 1-pyrazolidinecarboxylate (1.0 g, 5.8 mmol) and 5-methyl-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid (1.18 g, 5.84 mmol) in DMF (20 mL) are added successively DIPEA (2.03 mL, 11.6 mmol) and HATU (2.38 g, 6.13 mmol). The reaction proceeded at r.t. for 16 h. Sat. NaHCOa (60 mL) and DCM (60 mL) are added. The two layers are separated and the aqueous layer is extracted with DCM (2 x 40 mL). The evaporation residue is purifid by FC (heptane/TBME/MeOH with gradient) to afford the title compound (2.2 g) as an off-white solid. LC-MS (A): tR = 0.90 min; [M+H]+ = 358.41 . 1H NMR (DMSO-d6) 5 8.09 (s, 2 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.41 (dd, J = 1.3, 8.3 Hz, 1 H), 7.34 (d, J = 1.3 Hz, 1 H), 4.04-3.96 (m, 2H), 3.59-3.52 (m, 2H), 3.18-3.12 (m, 2H), 3.08 (s, 3H), 1.11 (s, 9H)
B. ii . (5-Methyl-2-(2H-1,2, 3-triazol-2-yl)phenyl) (pyrazolidin-l-yl)methanone hydrochloride:
Starting from intermediate B.i. (2.24 g, 5.33 mmol) and proceeding according to the procedure described in Preparation A, step A.ii, the title compound (1 .75 g) is prepared as an off-white solid of 90% purity. LC-MS (A): tR = 0.58 min; [M+H]+ = 257.97.
Preparation C: 5-methyl-2-(thiazol-2-yl)nicotinic acid, lithium salt
C.i. Methyl 5-methyl-2-(thiazol-2-yl)nicotinate'.
To a solution of methyl 2-bromo-5-methylnicotinate (0.350 g, 1.48 mmol) in dioxane (2 mL) are added Cui (0.05g, 0.24mmol), Pd(PPh3)4 (0.03g, 0.03mmol) and 2-(tributylstannyl)-1 ,3-thiazole (0.697 g, 1.77 mmol). The reaction proceeded at 100°C for 16h. After cooling to r.t., the reaction mixture is directly purified by FC (heptane-EtOAc with gradient) to afford the title compound (0.310 g) as a yellowish solid. LC-MS (A): tR = 0.81 min; [M+H]+ = 234.9. 1H NMR (DMSO-d6) 5: 8.60 (d, J = 0.8 Hz, 1 H), 7.96 (d, J = 3.1 Hz, 1 H), 7.88 (d, J = 3.1 Hz, 1 H), 7.86 (s, 1 H), 3.81 (s, 3H), 2.39 (s, 3H).
C.ii. 5-Methyl-2-(thiazol-2-yl)nicotinic acid, lithium salt.
Starting for the intermediate C.i (0.310 g, 1.32 mmmol) and proceeding as described in Preparation H, step H.ii, the crude title salt (0.310g) is obtained as a greyish solid. LC-MS (A): tR = 0.69 min; [M+H]+ = 221.19.
Preparation D: (2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl methanesulfonate in mixture with 6- (chloromethyl)-2-(trifluoromethyl)benzo[d]thiazole
D.i. (2-(Trifluoromethyl)benzo[d]thiazol-6-yl)methanol:
To a solution of 2-(trifluoromethyl)benzo[d]thiazole-6-carboxylic acid (0.105 g, 0.404 mmol) in THF (2.5 mL), cooled to - 10°C, is slowly added a solution of borane.tetrahydrofuran complex (1.0 M in THF; 0.8 mL, 0.8 mmol). The reaction mixture is warmed to r.t. and stirred for 2 h. MeOH (1.5 mL) is slowly added. After 15 min stirring, the volatiles are removed in vacuo and the residue is co-evaporated twice with MeOH (2 x 5 mL). The evaporation residue is purified by prep. HPLC to afford the title compound (0.013 g) as a yellowish oil. 1H NMR (DMSO-d6) S'. 8.29 (d, J = 0.9Hz, 1 H), 8.21 (d, J = 8.5 Hz, 1 H), 7.65 (dd, J = 0.9, 8.5Hz, 1 H), 5.51 (t, J = 5.5Hz, 1 H), 4.71 (d, J = 5.5Hz, 2H).
D.ii. (2-(Trifluoromethyl)benzo[d]thiazol-6-yl)methyl methanesulfonate in mixture with 6-(chloromethyl)-2- (trifluoromethyl)benzo[d]thiazole: To an ice-chilled suspension of intermediate P.1 .i (0.012 g, 0.0515 mmol) and TEA (0.0143 mL, 0.103 mmol) in DCM (0.5 mL) is added methanesulfonyl chloride (0.006 mL, 0.077 mmol). The reaction proceeded at 0°C for 40 min. The reaction mixture is partitioned between DCM (5 mL) and water (5 mL). The aq. layer is extracted once with DCM (5 mLJ.The evaporation residue afforded the crude title compound in a 1-1 mixture with 6-(chloromethyl)- 2-(trifluoromethyl)benzo[d]thiazole (0.016 g, yellowish oil). The mixture is used without further purification. 1H NMR (DMSO-c/6) (1-1 mixture)^: 8.46 (m, 0.5H), 8.45 (m, 0.5H), 8.31 (d, J = 8.5Hz, 0.5H), 8.27 (d, J = 8.5Hz, 0.5H), 7.79 (m, 0.5H), 7.77 (m, 0.5H), 5.48 (s, 2 x 0.5H), 4.98 (s, 2 x 0.5H), 3.29 (s, 3 x 0.5H).
Preparation E: 5-methyl-2-(4-methyl-1H-pyrazol-1-yl)benzoic acid
To a solution of 2-iodo-5-methylbenzoic acid (0.798 g, 2.95 mmol), cesium carbonate (1.06 g, 3.25 mmol) and copper iodide (0.112 g, 0.591 mmol) in DMF (18.3 mL) are added trans-N, W'-dimethylcyclohexane-1,2-diamine (0.086 g, 0.591 mmol) and 4-methyl-1 H-pyrazole (0.247 mL, 2.95 mmol). The resulting mixture is heated to 120°C for 15 h. After cooling to r.t., water (20 mL) is added. The two layers are separated and the aq. layer is washed with DCM. The resulting organic layer is discarded. The aqueous layer is acidified to pH 1 using 1 M HCI. The resulting solution is extracted with DCM (2 x 20 mLJ.The evaporation residue is purified by prep. HPLC to afford the title compound (0.255 g) as a white solid. LC-MS (A): tR = 0.72 min; [M+H]+ = 217.18. 1H NMR (DMSO-d6) 5: 12.80 (s, 1 H), 7.83 (m, 1 H), 7.50 (m, 1 H), 7.46 (s, 1 H), 7.41-7.38 (m, 2 H), 2.38 (s, 3H), 2.09 (s, 3H).
Preparation F: 6-methyl-3-(2-methylthiazol-4-yl)picolinic acid
F.i. Methyl 3-(1-ethoxyvinyl)-6-methylpicolinate'.
To a solution of methyl 3-bromo-6-methylpicolinate (0.475 g, 1.96 mmol) and tributyl(1-ethoxyvinyl)tin (0.767 g, 2.06 mmol) in dioxane (8.64 mL) is added bis(triphenylphosphine)palladium(l I) dichloride (0.055 g, 0.0785 mmol). The reaction proceeded at 80°C for 17 hours. The reaction mixture is diluted with EtOAc (20 mL) is washed with water (10 mL) and brine (10 mL). The residue is purified by prep. HPLC to afford the title compound (0.373 g) as a yellow oil. LC-MS (B): tR = 0.81 min; [M+H]+ = 222.14.
F.ii. Methyl 3-(2-bromoacetyl)-6-methylpicolinate'.
To a solution of the intermediate F.i (0.37 g, 1.67 mmol) in dioxane (4.5 mL) is added dropwise a solution of bromine (0.0865 mL, 1 .67 mmol) in dioxane (4.5 mL) at 0 °C. The reaction mixture is stirred at r.t. for 1 h. Water (10 mL) is added The solvents are evaporated under reduced pressure. The resulting residue is purified by prep. HPLC to afford the title product (0.052 g) as a white solid. LC-MS (A): tR = 0.70 min; [M+H]+ = 272.07 / 273.80.
F.iii. Methyl 6-methyl-3-(2-methylthiazol-4-yl)picolinate'.
A solution of thioacetamide (0.014 g, 0.184 mmol) in MeCN (0.13 mL) is added dropwise to a mixture of the intermediate F.ii (0.050 g, 0.184 mmol) and 4A molecular sieves (0.017 g) in MeCN (0.3 mL). The reaction mixture is stirred at r.t. for 2 h. The reaction mixture is cooled to 0°C. The solids are removed by filtration and the filter cake is rinsed with MeOH. The latter solid is suspended in MeOH (0.5 mL) and heatedat 50°C for 1 h. The solution is concentrated in vacuo to afford the title compound (0.046 g) as a yellow solid. LC-MS (A): tR = 0.71 min; [M+H]+ = 249.14. F.iv. 6-Methyl-3-(2-methylthiazol-4-yl)picolinic acid'.
To a solution of the intermediate F.iii. (0.045 g, 0.181 mmol) in EtOH (0.86 mL) is added , 2 N NaOH aq. (0.91 mL). The reaction proceeded at r.t. for 2 h. 2N HCI is added to reach acidic pH <2. The solution is concentrated under reduced pressure to afford the title acid (0.043 g)as a slightly yellow solid. LC-MS (A): IR = 0.40 min; [M+H]+ = 235.01.
Preparation G: 6-methyl-3-(4-methyl-2H-1,2,3-triazol-2-yl)picolinic acid
Starting from 4-methyl-1 H-1 ,2,3-triazole (0.258 g, 2.95 mmol) and-3-bromo-6-methyl-pyridine-2-carboxylic acid (0.658 g, 2.95 mmol) and proceeding as described in Preparation E, the title product (0.27 g) is obtained as a white solid after purification by prep. HPLC. LC-MS (A): tR = 0.48 min; [M+H]+ = 219.16.
Preparation H: 2-(1-methyl-1H-pyrazol-3-yl)benzoic acid, lithium salt
H.i. Ethyl 2-(1-methyl-1H-pyrazol-3-yl)benzoate'.
To a solution of 2-ethoxycarbonylphenylboronic acid (0.231 g, 1.17 mmol) in dioxane (4.7 mL) and EtOH (2.3 mL) are added 3-iodo-1 -methyl-1 H-pyrazole (0.250 g, 1.17 mmol), 2 M aq. Na2CO3 (1.75 mL, 3.5 mmol) and [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium.DCM (0.057 g, 0.07 mmol), The reaction mixture is partitioned between water (15 mL) and EtOAc (15 mL). The two layers are separated and the aqueous layer is extracted with EtOAc (2 x 15 mL). The evaporation residue is purified by prep. HPLC to afford the title product (0.144 g) as a green oil. LC-MS (A): tR = 0.48 min; [M+H]+ = 219.16.
H.ii. 2-(1-Methyl-1H-pyrazol-3-yl)benzoic acid, lithium salt.
To a solution of intermediate H.i (0.14 g, 0.608 mmol) in a THF-water mixture (10: 1, 5.5 mL) is added UOH.H2O (0.028 g, 0.669 mmol). The reaction proceeded at r.t. for 25 h. The reaction mixture is concentrated to dryness, and the residue is triturated in MeCN. The solid is recovered by filtration and dried to a constant weight to afford the title product (0.058 g) as a beige solid. LC-MS (A): tR = 0.80 min; [M+H]+ = 231.17.
Preparation I: ethyl 2-(4-methylpyrimidin-2-yl)benzoate
Starting from 2-chloro-4-methylpyrimidine (0.153 g, 1.17 mmol) and 2-ethoxycarbonylphenylboronic acid (0.231 g,
I .17 mmol) and proceeding as described in Preparation H. step H.i, the title ester (0.126 g) is obtained as a brownish oil after purification by prep. HPLC. LC-MS (A): tR = 0.76 min; [M+H]+ = 243.11.
Preparation J: 6-methyl-3-(2H-1,2,3-triazol-2-yl)pyrazine-2-carboxylic acid
The compound is prepared as reported in W02019043407.
Preparation K: 6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid
The compound is prepared as reported in W02019043407.
Preparation L: 6-methyl-3-pyrazol-1-ylpyridine-2-carboxylic acid
The compound is prepared as reported in W02019043407.
Preparation M: 6-methyl-3-(1,3-thiazol-2-yl)pyridine-2-carboxylic acid
The compound is prepared as reported in W02019043407. Preparation N: 5-methyl-2-(1H-pyrazol-1-yl)nicotinic acid
Starting from methyl 2-bromo-5-methylnicotinate (0.180 g, 0.759 mmol) and pyrazole (0.105 g, 1.52 mmol) and proceeding as described in Preparation E, the title acid (0.101 g) is obtained as a yellowish solid after purification by prep. HPLC. LC-MS (A): tR = 0.58 min; [M+H]+ = 204.29.
Preparation O: 5-methyl-2-(3-methyl-1H-pyrazol-1-yl)benzoic acid and 5-methyl-2-(5-methyl-1H-pyrazol-1- yl)benzoic acid
Starting from methyl 2-iodo-5-methylbenzoic acid (0.800 g, 2.95 mmol) and 3-methylpyrazole (0.250 g, 2.95 mmol) and proceeding as described in Preparation E, the title acids (0.233 g) are obtained as a mixture (yellowish solid) after purification by prep. HPLC. LC-MS (A): tR = 0.67 and 0.69 min; [M+H]+ = 217.18.
The first-eluting isomer is 5-methyl-2-(5-methyl-1 H-pyrazol-1 -yl)benzoic acid.
Preparation P: 5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid
P. i . 2-(4-Bromo-5-methyl-2H-1 ,2, 3-triazol-2-yl)-5-methylbenzoic acid:
Starting from 5-bromo-4-methyl-1 H-1 , 2, 3-tri azole (0.1 g, 0.599 mmol, 1 eq)and 2-iodo-5-methylbenzoic acid methyl ester (0.104 mL, 0.599 mmol) and proceeding as described in Preparation E, the title acid (0.053 g) is obtained as an off-white solid after purification by prep. HPLC. LC-MS (A): tR = 0.84 min; [M+H]+ = 298.12 / 296.08.
P. ii . 5-Methyl-2-(4-methyl-2H-1 ,2, 3-triazol-2-yl)benzoic acid:
To a mixture of intermediate P.i (0.040 g, 0.135 mmol) and sodium acetate (0.033 g, 0.405 mmol) in EtOAc (1.8 mL) and EtOH (0.6 mL) is added palladium hydroxide on carbon (20%; 0.014 g). The reaction proceeded under normal hydrogen atmosphere for 72h. The catalyst is removed by filtration and the filtrate is concentrated to dryness to afford the crude title acid as a white solid. LC-MS (A): tR = 0.69 min; [M+H]+ = 218.06.
Preparation Q: 5-methyl-2-(2-methylthiazol-4-yl)benzoic acid, lithium salt
Starting from 4-bromo-2-methyl-1 ,3-thiazole (0.081 g, 0.456 mmol) and 2-methoxycarbonyl-4-methylphenylboronic acid (0.093 g, 0.456 mmol) and proceeding successively as described in Preparation H, steps H.i and H.ii, the title salt (0.048 g) is obtained as an off-white solid. LC-MS (A): tR = 0.68 min; [M+H]+ = 234.13.
Preparation R: 2-methyl-5-(m-tolyl)thiazole-4-carboxylic acid
The compound is prepared as reported in WO2008/65626.
Preparation S: 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid
The compound is prepared as reported in WO2018/202689.
Preparation T: 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid
The compound is prepared as reported in WO2019/43407.
Preparation U: 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid
The compound is prepared as reported in WO2019/43407
Preparation V: 4,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid Starting from 2-iodo-4,5-dimethylbenzoic acid (0.5 g, 1.81 mmol) and 1 H-1 ,2,3-triazole (0.25 g, 3.62 mmol) and proceeding as described in Preparation E, the title compound (0.1 g) is obtained as a white solid after purification by prep. HPLC. LC-MS (A): tR = 0.68 min; [M+H]+ = 218.10.
Preparation W: 5-methoxy-2-(1H-pyrazol-1-yl)benzoic acid
The compound is commercially available and is prepared as described in WO 2014/057435
Preparation X: 5-chloro-2-(1H-pyrazol-1-yl)nicotinic acid
Starting from 2-bromo-5-chloronicotinic acid (0.500 g, 2.07 mmol) and pyrazole (0.173 g, 2.49 mmol) and proceeding as described in Preparation E, the title acid (0.121 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): tR = 0.63 min; [M+H]+ = 224.14.
Preparation Y: 2-methyl-6-((tetrahydropyridazin-1(2H)-yl)methyl)benzo[d]thiazole hydrochloride
Starting from tert-butyl tetrahydro-1 (2H)-pyrid azine carboxylate (0.2 g, 1 .02 mmol) and 2-methyl-1 ,3-benzothiazole- 6-carbaldehyde (0.191 g, 1.02 mmol) and proceeding successively as described in Preparation A, steps A.i and A.ii, the title compound (0.252 g) is obtained as a yellowish solid. LC-MS (A): tR = 0.54 min; [M+H]+ = 248.2.14.
Preparation Z: 2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorobenzoic acid
2-Bromo-5-chlorobenzoic acid (0.1 g, 0.416 mmol), Cui (0.004 g, 0.0208 mmol) and K2CO3 (0.129 g, 0.936 mmol) are suspended in dioxane (2.5 mL). 4-Bromo-1 /7-1,2,3-triazole (0.13 g, 0.832 mmol) ) is added and the reaction mixture is heated at reflux for 1 h. Water (0.06 mL) is added and heating is pursued for 1 h. After collong, the volatiles are removed in vacuo and the residue is diluted with water (2 mL) and acidified to pH 2 with aq 20% H2SO4. The resulting mixture is purified by prep HPLC to afford the title compound (0.12 g) as an oil which cristallized on standing. 1H NMR (DMSO-cfe) 5: 13.50 (br s, 1 H), 8.33 (s, 1 H), 7.85 (m, 1 H), 7.81 (m, 2H).
Preparation AA: 2-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid
Starting from 4-chloro-1 H-pyrazole (0.155 g, 1.47 mmol) and methyl 2-bromo-5-methylnicotinate (0..2 g, 0.843 mmol) and proceeding as described in Preparation E, the title acid (0.138 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): tR = 0.70 min; [M+H]+ = 238.12.
Preparation AB: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(pyrazolidin-1-yl)methanone dihydrochloride
AB.i. tert-Butyl 2-(5-chloro-2-(2H-1 , 2, 3-triazol-2-yl)benzoyl)pyrazolidine-1 -carboxylate:
Oxalyl chloride (0.1 mL, 1.16 mmol) is added dropwise at r.t. to a suspension of 5-chloro-2-(2/-/-1,2,3-triazol-2- yl)benzoic acid (0.245 g, 1.1 mmol) in DCM (5mL). DMF (0.02 mL) is then added dropwise. The reaction proceeded solution is stirred for 1 h30. The volatiles are removed under reduced pressure and co-evaporated twice with dry DCM (4mL). The crude residue is taken up in DCM (6.5 mL) and added dropwise to an ice-chilled solution of tertbutyl pyrazolidine-1 -carboxylate (0.171 g, 0.99 mmol) and NEts (0.415 mL, 2.98 mmol) in DCM (3.2mL) is added. The reaction proceeded at r.t. for 2h 15. Sat. aq. NaHCOa (10 mL) and DCM (10 mL) are added. The two layers are separated. The aqueous layer is extracted with DCM (2 x 10 mL). The evaporation residue is purified by FC (heptane-EtOAc) to afford the title compound (0.311 g) as a yellowish oil. LC-MS (A): tR = 0.95 min; [M+H]+ = 378.15. AB.ii. (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(pyrazolidin-1-yl)methanone dihydrochloride'.
Starting from the intermediate AB. i (0.299 g, 0.791 mmol) and proceeding as described in Preparation A, step A.ii, the title compound (0.285 g) is obtained as a yellowish solid. LC-MS (A): tR = 0.64 min; [M+H]+ = 278.18.
Preparation AC: 5-chloro-2-(4-methyl-1H-pyrazol-1-yl)nicotinic acid
Starting from 4-methyl-1 H-pyrazole (0.15 g, 1.79 mmol) and 2-bromo-5-chloronicotinic acid (0.36 g, 1.49 mmol) and proceeding as described in Preparation E, the title acid (0.18 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): tR = 0.73 min; [M+H]+ = 238.18.
Preparation AD: 5-methyl-2-(4-methyl-1H-pyrazol-1-yl)nicotinic acid
Starting from 4-methyl-1 H-pyrazole (0.15 g, 1.79 mmol) and methyl 2-bromo-5-methylnicotinate (0.36 g, 1.52 mmol) and proceeding as described in Preparation E, the title acid (0.14 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): tR = 0.67 min; [M+H]+ = 218.27.
Preparation AE: 5-chloro-2-(4-methyl-1H-pyrazol-1-yl)benzoic acid
Starting from 4-methyl-1 H-pyrazole (0.2 g, 2.0 mmol) and methyl 2-bromo-5-chlorobenzoate (0.5 g, 2.0 mmol) and proceeding as described in Preparation E, the title acid (0.344 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): tR = 0.74 min; [M+H]+ = 237.16.
Preparation AF: 5-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinic acid
Starting from 3-methyl-1 H-pyrazole (0.353 g, 4.22 mmol) and methyl 2-bromo-5-methylnicotinate (0.5 g, 2.11 mmol) and proceeding as described in Preparation E, the title acid (0.18 g) is obtained as a greenish solid after purification by prep. HPLC. LC-MS (A): tR = 0.64 min; [M+H]+ = 218.26.
Preparation AG: 2-bromobenzo[d]thiazole-6-carbaldehyde
AG . i . ( 2-bromobenzo[d]thiazol-6-yl)methanol'.
To a suspension of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (0.3 g, 1.07 mmol) in DCM (5 mL) at -78°C, DIBAL-H in toluene (2.67mL, 2.67mmol) is added dropwise keeping the temperature below -72°C. The reaction proceeded at the same temperature for 2h then is allowed to reach r.t. during 45 min. Water (0.11 mL), 1 M. NaOH (0.11 mL), water (0.26mL) are added. DCM (5mL) is added and filtered. The evaporation residue is purified by FC (heptane-EtOAc) to afford the title compound (0.189 g) as an off-white solid. LC-MS (A): tR = 0.70 min; [M+H]+ = 244.05-246.03.
AG . ii 2-bromobenzo[d]thiazole-6-carbaldehyde'.
To a solution of the intermediate AG.i (0.189 g, 0.76 mmol) in a mixture of DCM (4 mL) and THF (2 mL) is added MnO2 (0.46 g, 5.3 mmol). The reaction mixture is stirred overnight at r.t. The reaction mixture is filtered over celite and washed with DCM (2 x 10 mL). The filtrate is concentrated to dryness to afford the title compound (0.182g) as a white solid. 1H NMR (DMSO-cfe) 5: 10.12 (s, 1 H), 8.74 (dd, J= 1.6 Hz, 1 H), 8.18 (d, J = 8.4 Hz, 1 H), 8.05 (dd, J= 1.6, 8.4 Hz, 1 H).
Preparation AH: (RS)-2-methyl-6-((4-methylpyrazolidin-1-yl)methyl)benzo[d]thiazole hydrochloride AH.i. 1-benzyl 2-(tert-butyl) (RS)-4-methylpyrazolidine-1,2-dicarboxylate'.
To a suspension of 1-benzyl 2-(fert-butyl) 1 ,2-hydrazine dicarboxylate (0.4 g, 1.5 mmol), K3PO4 (0.7 g, 3.3 mmol) in MeCN (4 mL) is added 1,3-dibromo-2-methylpropane (0.376 g, 1.65 mmol). The reaction proceeded at 55°C for 20 h.More K3PO4 (0.16g, 0.75mmol) is added and the reaction proceeded at 60°C for 48h. After cooling water (5 mL) and TBME (5 mL) are added. The two layers are separated and the aq. layer is extracted with TBME (5 mL). The evaporation residue is purified by FC (heptane-EtOAc gradient) to afford the title compound (0.22 g) as a colorless oil which cristallised on standing. LC-MS (A): tR = 0.99 min; [M+H]+ = 321.16.
AH.ii. tert-butyl (RS)-4-methylpyrazolidine-1-carboxylate'.
To a solution of intermediate AH.i (0.215 g, 0.671 mmol) in MeOH (2mL) is added Pearlman's catalyst (0.011 g, 0.0201 mmol. The reaction proceeded at r.t. for 1 h under normal hydrogen atmosphere. The catalyst is removed by filtration and the filtrate is concentrated to dryness to afford the title compound (0.123g) as a colorless oil. LC- MS (A): tR = 0.48 min; [M+H]+ = 187.39.
AH.iii. (RS)-2-methyl-6-((4-methylpyrazolidin-1-yl)methyl)benzo[d]thiazole hydrochloride'.
Starting from intermediate AH.ii. (0.12 g, 0.644 mmol) and 2-methyl-1 ,3-benzothiazole-6-carbaldehyde (0.132 g, 0.709 mmol) and proceeding successively as described in Preparation A, steps A.i and A.ii. the title compound (0.12 g) is prepared as a yellowish solid. LC-MS (A): tR = 0.56 min; [M+H]+ = 248.23.
Preparation Al: 2-methyl-[1,3]thiazolo[5,4-b]pyridine-5-carbaldehyde
The compound is prepared as described in US5472964.
Preparation AJ: 2-chlorobenzo[d]thiazole-6-carbaldehyde:
Starting from methyl 2-chloro-1,3-benzothiazole-6-carboxylate (0.305 g, 1.27 mmol) and proceeding successively as reported in Preparation AG, steps AG.i and AG.ii, the title aldehyde (0.15 g) is obtained as a white solid after purification by FC (heptane-EtOAc). 1H NMR (DMSO-cfe) 5: 10.12 (s, 1 H), 8.74 (dd, J= 1.6 Hz, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 8.08 (dd, J= 1.6, 8.4 Hz, 1 H).
Preparation AK: (S)-2-methyl-6-((4-methylpyrazolidin-1-yl)methyl)benzo[d]thiazole hydrochloride
AK.i. tert-butyl (R)-2-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)hydrazine-1-carboxylate:
To a solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl 4-methylbenzenesulfonate (prepared as described in J.Org.Chem. 2003, 68, 5568; 1.5 g, 4.18 mmol) in DMF (10 mL) is added tert-butyl carbazate (2.2 g, 16.7 mmol). The reaction proceeded at 80°C for 24h. After cooling, the solvent is removed in vacuo and the residue is purified by FC (heptane-EtOAc) to afford the title compound (0.675 g; 51 % yield) as a colorless oil. 1H NMR (CDCI3) 6: 6.10 (br s, 1 H); 3.58-3.51 (m, 2H), 2.89 (dd, J= 6.8, 11.5 Hz, 1 H), 2.73 (dd, J= 6.3, 11.5 Hz, 1 H), 1.84 (m, 1 H), 1 .48 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.06 (s, 6H). LC-MS (A): tR = 0.96 min; [M+H]+ = 319.28.
AK.ii. tert-butyl (R)-2-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-2-((2-methylbenzo[d]thiazol-6- yl)methyl)hydrazine-1-carboxylate'.
Starting from intermediate AK.i. (0.65 g, 2.04 mmol) and 2-methyl-1,3-benzothiazole-6-carbaldehyde (0.362 g, 2.04 mmol) and proceeding successively as described in Preparation A, step A.i, the title compound (0.42 g, 43% yield) is prepared as a colorless oil. 1H NMR (CDCh) 5: 7.89 (d, J = 8.3 Hz, 1 H), 7.86 (s, 1 H), 7.45 (dd, J= 1.6, 8.3 Hz, 1 H), 5.63 (br s, 1 H), 4.10 (br s, 2H), 3.51-3.63 (m, 2H), 2.86 (overlapped m, 1 H), 2.84 (s, 3H), 2.63 (br s, 1 H), 1.88 (m, 1 H), 1.39 (s, 9H), 0.97 (d, J= 6.7Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H). LC-MS (A): tR = 1.28 min; [M+H]+ = 480.27.
AK. Hi. tert-butyl (R)-2-( 3-hydroxy-2-methylpropyl) -2-( ( 2-methylbenzo[d]thiazol-6-yl)methyl)hydrazine-1- carboxylate:
To a solution of intermediate AK.ii (0.42 g, 0.875 mmol) in THF (5 mL) is added TBAF (1 M in THF; 1.5 mL, 1.5mmol). The reaction proceeded at room temperature for 2h. The solvent is removed in vacuo and the residue is purified by FC (heptane-EtOAc) to afford the title compound (0.32 g, 100% yield) as a colorless oil. 1H NMR (CDCh) 5: 7.92 (d, J = 8.3 Hz, 1 H), 7.85 (s, 1 H), 7.43 (dd, J= 1.6, 8.3 Hz, 1 H), 5.51 (br s, 1 H), 4.15 (br s, 1 H), 3.94 (m, 1 H), 3.72 (m, 1 H), 3.53 (m, 1 H), 3.51-3.63 (m, 2H), 2.88 (overlapped m, 1 H), 2.85 (s, 3H), 2.74 (m, 1 H), 2.08 (m, 1 H), 1.35 (s, 9H), 0.84 (d, J= 6.9Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H).
AK. iv. tert-butyl ( R) -2-( 2-methyl-3-(tosyloxy) propyl) -2-( ( 2-methylbenzo[d]thiazol-6-yl)methyl)hydrazine-1- carboxylate:
To a solution of intermediate AK.iii (0.32 g, 0.875 mmol) in DCM (8 mL) are added at room temperature 4-DMAP (0.177 g; 1.45 mmol)), TEA (0.3 mL, 2.16mmol) and pTsCI (0.33 g, 1.75 mmol). The reaction proceeded at room temperature for 2h. The reaction mixture is directly purified by FC (heptane-EtOAc) to afford the title compound (0.39 g, 86% yield) as a colorless oil. LC-MS (A): tR = 1.11 min; [M+H]+ = 520.18.
AK.v. tert-butyl (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1-carboxylate:
To a solution of intermediate AK.iv (0.39 g, 0.75 mmol) in acetonitrile (5mL) is added potassium phosphate tribasic (0.319g). The reacction proceeded for 16h at 80°C. After cooling, the solids are filtered off, washed with acetonitrile and the filtrate is concentrated to dryness. The residue is chromatographed (heptane-EtOAc) to afford the title compound (0.25 g, 96% yield) as a colorless oil. 1H NMR (CDC ) 6: 7.82-7.95 (m, 2 H), 7.45 (d, J = 8.3 Hz, 1 H), 4.06 (m, 1 H), 3.94 (m, 1 H), 3.78 (m, 1 H), 3.03-3.16 (m, 2 H), 2.85 (s, 3 H), 2.52-2.66 (m, 2 H), 1.48 (s, 9 H), 1.08 (d, J = 5.9 Hz, 3 H); LC-MS (A): tR = 0.89 min; [M+H]+ = 348.18.
AK.vi. (S)-2-methyl-6-((4-methylpyrazolidin-1-yl)methyl)benzo[d]thiazole hydrochloride'.
Starting from intermediate AK.v. (0.25 g, 0.644 mmol) and proceeding as described in Preparation A, step A.ii. the title compound (0.2 g, 99% yield) is prepared as a yellowish solid. LC-MS (A): tR = 0.56 min; [M+H]+ = 248.23.
Preparation AL: 2-methyl-6-((pyrazolidin-1-yl-4,4-d2)methyl)benzo[d]thiazole dihydrochloride
ALL propane-1, 3-diyl-2,2-d2 bis(4-methylbenzenesulfonate):
To an ice-chilled solution of 1 ,3-propane-2,2-d2-diol (0.5 g, 6.4 mmol) in DCM (20 mL) are added EtsN (2.68 mL, 19.2 mmol), DMAP (0.08 g, 0.63 mmol) and pTsCI (2.71 g, 14.1 mmol). The resulting solution is stirred for 3 h at rt rt during the course of the reaction. Sat. aq. NaHCOa (5 mL) is added and the two layers are separated. The aq. layer is extracted with DCM (5 mL). The combined org. layers are washed with sat. aq. CU2SO (5mL) and brine (5mL).The evaporation residue is purified by FC (Heptane-EtOAc) to afford the title compound (0.72 g, 29% yield) as a white solid. LC-MS (A): tR = 1.02 min; [M+H]+ = 387.2. 1H NMR (500 MHz, DMSO) 5: 7.74 (d, J = 8.3 Hz, 4 H), 7.48 (d, J = 7.9 Hz, 4 H), 4.00 (s, 4 H), 2.43 (s, 6 H).
AL.ii. 2-methyl-6-((pyrazolidin-1-yl-4,4-d2)methyl)benzo[d]thiazole dihydrochloride'.
Starting from the intermediate AL.i. (0.718 g, 1.86 mmol) and 1-benzyl 2-(tert-butyl) 1 ,2-hydrazine dicarboxylate (0.45 g, 1.69 mmol) and proceeding as described in Preparation AH, steps AH. i and AH.ii (except MeOH-d4 and D2 gas are employed) and Preparation A, steps A.i and A.ii, the title compound (0.099g) is obtained as a yellowish solid. LC-MS (A): tR = 0.51 min; [M+H]+ = 236.1 1H NMR (500 MHz, DMSO) 5: 8.09 (s, 1 H), 7.93 (d, J = 8.3 Hz, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 4.32 (s, 2 H), 3.28 (br. s, 2 H), 3.03-3.12 (m, 2 H), 2.81 (s, 3 H)
Preparation of Examples
Example 1 : (5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin- 1-yl)methanone
To a solution of the compound of Preparation B (0.018 g, 0.061 mmol) and 2-methylbenzo[d]thiazole-6- carbaldehyde (0.010 g, 0.061 mmol) in DMF (0.5 mL) is added sodium triacetoxyborohydride (0.034 g, 0.153 mmol). The reaction proceeded at r.t. for 16h. The reaction mixture is dissolved in DMF (1 mL) and 0.5% aq. NH4OH. The resulting solution is purified by prep. HPLC to afford the title compound (0.012 g) as a white solid.
Figure imgf000043_0001
Example 2: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
To a solution of the compound of Preparation D (0.016 g, 0.051 mmol) in MeCN (0.25 mL) are successively added Nal (0.0015 g, 0.01 mmol), K2CO3 (0.014 g, 0.1 mmol) and the compound of Preparation B (0.015 g, 0.05 mmol). The reaction mixture is refluxed for 2 h. After cooling to r.t., the volatiles are removed in vacuo and the residue is purified by prep. HPLC to afford the title compound (0.001 g) as a white solid. LC-MS (C): tR = 1.239 min; [M+H]+ = 473.3.
Example 3.1: (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone
To a solution of the compound of Preparation A (0.020 g, 0.065 mmol) in DMF (0.5 mL) are added 2-(2H-1,2,3- triazol-2-yl)benzoic acid (0.012 g, 0.043 mmol), DIPEA (0.072 mL, 0.41 mmol) and HATU (0.034 g, 0.09 mmol). The reaction proceeds at r.t. for 2h. The reaction mixture is dissolved in DMF (1 mL) and 0.5% aq. NH4OH. The resulting solution is purified by prep. HPLC to afford the title compound (0.0035 g) as a white solid. In analogy to the procedure described herein before, the following examples 3.1 to 3.16 are prepared using the corresponding carboxylic acid:
Figure imgf000044_0001
Figure imgf000045_0001
Example 4.1: [(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazin- 1(2H)-yl)methanone
To a solution of the compound of Preparation Y (0.020 g, 0.07 mmol) in DMF (0.5 mL) are added 2-(2H-1,2,3- triazol-2-yl)benzoic acid (0.013 g, 0.07 mmol), DIPEA (0.072 mL, 0.41 mmol) and HATU (0.034 g, 0.09 mmol). The reaction proceeded at r.t. for 2h. The reaction mixture is dissolved in DMF (1 mL) and 0.5% aq. NH4OH. The resulting solution is purified by prep. HPLC to afford the title compound (0.0048 g) as a white solid.
In analogy to the procedure described herein before, the following examples 4.1 to 4.3 are prepared using the corresponding carboxylic acid:
Figure imgf000045_0002
Example 5: (5-chloro-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
To a mixture of example 3.14 (0.03 g, 0.06 mmol), K2CO3 (0.02 g, 0.17 mmol), Pd(PPh3)4 (0.01 g, 0.012 mmol), in dioxane (1 mL) is added trimethylboroxine (0.01 mL, 0.08 mmol). The reaction proceeded at 100°C for 2 h. After cooling, the evaporation residue is purified by prep. HPLC to afford the title compound (0.02 g) as a white solid. LC-MS (C): tR = 1.075 min; [M+H]+ = 453.1.
Example 6: (5-chloro-2-(4-ethynyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
6.i. (5-chloro-2-(4-((trimethylsilyl)ethynyl)-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone'.
To a mixture of Cui (0.002 g, 0.01 mmol) and PdCl2(PPhs)2 (0.004 g, 0.01 mmol) are added a solution of example 3.14 (0.030 g, 0.0579 mmol) in THF (0.45mL) and then trimethylsilylacetylene (0.01 mL, 0.07 mmol) and triethylamine (0.02 mL, 0.15 mmol). The reaction proceeded at 50°C for 2h. After cooling the crude mixture is purified by prep HPLC to afford the title compound (0.022 g, 73% yield) as an off-white solid. LC-MS (C): tR = 1.17 min; [M+H]+ = 535.3.
6.ii. (5-chloro-2-(4-ethynyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone'.
To a solution of intermediate 6.i (0.02 g, 0.04 mmol) in MeOH (0.15 mL) is added K2CO3 (0.01 g, 0.07 mmol). The reaction proceeded at r.t. for 2h. The reaction mixture is purified by prep. HPLC to afford the title compound (0.016 g) as a white solid. LC-MS (C): tR = 1.113 min; [M+H]+ = 463.2.
Example 7.1 : (2-((2-bromobenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-chloro-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone
To a solution of the compound of Preparation AB (0.215 g, 0.684 mmol) and the compound of Preparation AG (0.182 g, 0.753 mmol) in DCM (7 mL) is added sodium triacetoxyborohydride (0.23 g, 1.03 mmol). The reaction proceeded at r.t. for 16h. The reaction mixture is partitioned between DCM (15 mL) and sat. NaHCOs (15 mL). The two layers are separated and the evaporation residue is purified by FC (heptane-EtOAc) to afford the title compound (0.275 g) as a white foam. LC-MS (C): tR = 1.176 min; [M+H]+ = 505.1.
In analogy to the procedure described herein before, the following reference examples 7.1 to 7. are prepared using the indicated intermediates:
Figure imgf000046_0001
Figure imgf000047_0001
Example 8: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
To a solution of Example 7.1 (0.02 g, 0.0496 mmol) in DMF (0.15 mL) are added Cui (0.011 g, 0.0595 mmol), 2,6- lutidine (0.00701 mL, 0.0595 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.03 g, 0.149 mmol). The reaction proceeded at 80°C for 18 h. After cooling, the reaction mixture is directly is purified by prep. HPLC to afford the title product (0.011 g) as an off-white solid. LC-MS (C): IR = 1 .236 min; [M+H]+= 493.2.
Example 9.1: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-cyclopropylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
To a mixture of Example 7.1 (0.014 g, 0.031 mmol), CS2CO3 (0.027 g, 0.084 mmol), Pd(dppf)Cl2 (0.003 g, 0.004 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (0.0058 mL, 0.031 mmol) in dioxane (0.2mL) is added water (0.002mL). The reaction proceeded at 100°C for 8 h. The reaction mixture is purified by prep. HPLC to afford the title compound (0.002g) as a beige solid. LC-MS (C): IR = 1.130 min; [M+H]+= 465.2.
Example 9.2: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-ethylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone
Starting from Example 7.1 (0.025 g, 0.049 mmol) and triethyl-1 ,3,5,2,4,6-trioxatriborinane (0.026 g, 0.149 mmol) and proceeding as described in Example 9.1, the title compound (0.011 g) is prepared as a white solid after purification by prep. HPLC. LC-MS (C): IR = 1.103 min; [M+H]+= 453.2.
Example 10.1 : (RS)-(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2H- 1,2,3-triazol-2-yl)phenyl)methanone
Starting from the compound of Preparation AH (0.040 g, 0141 mmol) and 5-methyl-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid (0.031 g, 0.155 mmol) and proceeding according to the procedure of Example 3.1 , the title compound (0.022 g) is prepared as a white solid, after purification by prep. HPLC.
In analogy to the procedure described herein before, the following examples 10.1 to 10.3 are prepared using the corresponding carboxylic acid:
Figure imgf000048_0001
Example 10.4: (R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone and
Example 10.5: (S)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
Two enantiomers of (RS)-(5-chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-[4-methyl-2-(2-methyl-benzothiazol-6-ylmethyl)- pyrazolidin-1 -yl]-methanone are separated using chiral HPLC to get first (R)-(5-chloro-2-(2H-1 ,2,3-triazol-2- yl) phenyl) (4-methy l-2-((2-methyl benzo[d]th iazol-6-y I) methyl) pyrazolid i n- 1 -yl)methanone and then (S)-(5-chloro-2- (2H-1 ,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone.
Preparative chiral HPLC conditions: ChiralPak IH column 30x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/2-propanol 1 :1; 10Obar; flow: 160 mL/min; tR (S-configurated enantiomer, Example 10.5) = 2.9 min, tR (R-configurated enantiomer, Example 10.4) = 3.5 min. Analytical chiral HPLC conditions: ChiralPak IH column 4.6x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/2-propanol 1 :1 (isocratic, 35%B); 150bar; flow: 4 mL/min; t (S-configurated enantiomer, Example 10.5) = 2.5 min, t (R-configurated enantiomer, Example 10.4) = 2.9 min
The absolute configuration and retention time of (R)-(5-chloro-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2- methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 -yl)methanone is determined by synthesizing an authentic sample as follows:
Starting from the compound of Preparation AK (0.2 g, 0.719 mmol) and 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.169 g, 0.755 mmol) and proceeding according to the procedure of Example 3.1 , Example 10.4 (0.26 g, 80% yield) is prepared as a white solid, after purification by FC (Heptane-EtOAc). LC-MS (C): tR = 1.103 min; [M+H]+= 453.2. Analytical chiral HPLC conditions: ChiralPak IH column 4.6x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/2-propanol 1 :1 (isocratic, 35%B); 150bar; flow: 4 mL/min tR (R-configured enantiomer, Example 10.4) = 2.9 min Example 10.6: (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2H-1,2,3- triazol-2-yl)phenyl)methanone and
Example 10.7: (S)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2H-1,2,3- triazol-2-yl)phenyl)methanone
Two enantiomers of (RS)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2/-/-1,2,3- triazol-2-yl)phenyl)methanone are separated using chiral HPLC to get (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6- yl) methyl) pyrazol idi n- 1 -yl)(5-methy l-2-(2/7- 1 ,2,3-triazol-2-yl)phenyl)methanone and (S)-4-methyl-2-((2- methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)methanone. Chiral HPLC conditions: ChiralPak OZ-H column 30x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/EtOH1 :1 ; 10Obar; flow: 160 mL/min; tR = 2.3 and 3.3 min.
The absolution configuration of each enantiomer is not assigned.
Example 10.8: (S)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol- 6-yl)methyl)pyrazolidin-1-yl)methanone and
Example 10.9: (R)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol- 6-yl)methyl)pyrazolidin-1-yl)methanone
Two enantiomers of (RS)-(2-(4-bromo-2H-1, 2, 3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol- 6-yl)methyl)pyrazolidin-1-yl)methanone are separated using chiral HPLC to get first (S)-(2-(4-bromo-2H-1,2,3- triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone and (/?)- (2-(4-bromo-2H-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone. Chiral HPLC conditions: ChiralCel OJ-H column 30x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/EtOH1 :1 (15%); 100bar; flow: 160 mL/min; tR = 3.2 and 3.99 min.
The absolute configuration and retention time of (S)-(2-(4-bromo-2/7-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2- ((2-methylbenzo[e/]thiazol-6-yl)methyl)pyrazolidin-1 -yl)methanone is assigned as follows:
To a solution Example 10.8 (first eluting enantiomer of Example 10.3) (0.07 g, 0.13 mmol) in MeOH (2.4 mL) and EtsN (0.06 mL, 0.4 mmol) is added under nitrogen atmosphere Pd(OH)2, 20 wt. % (0.02g). The reaction proceeded 2h under hydrogen atmosphere. The catalyst is removed by filtration and the evaporation residue is purified by prep-HPLC to yield Example 10.5 (0.04 g, 75% yield) as a white freeze dried solid. LC-MS (A): tR = 0.98 min; [M+H]+= 453.2. Analytical chiral HPLC conditions: ChiralPak IH column 4.6x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/2-propanol 1 :1 (isocratic, 35%B); 150bar; flow: 4 mL/min tR (S-configured enantiomer, Example 10.5) = 2.5 min. Example 11 : (5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]oxazol-6-yl)methyl)pyrazolidin- 1-yl)methanone
Starting from the compound of Preparation B (0.018 g, 0.061 mmol) and 2-methyl-benzo[d]oxazole-6-carbaldehyde (0.006g, 0.061 mmol) and proceeding as described in Example 1.1 , the title compound (0.010 g) is prepared as a white solid after purification by prep. HPLC. LC-MS (C): IR = 0.930 min; [M+H]+ = 403.3.
Example 12.1: (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl-4,4- d2)methanone
To a solution of the compound of Preparation AL (0.025 g, 0.092 mmol) in DMF (0.5 mL) are added 2-(2H-1,2,3- triazol-2-yl)benzoic acid (0.017 g, 0.092 mmol), DIPEA (0.047 mL, 0.27 mmol) and HATU (0.042 g, 0.11 mmol). The reaction proceeded at r.t. for 16h. The reaction mixture is dissolved in DMF (1 mL) and 0.5% aq. NH4OH. The resulting solution is purified by prep. HPLC to afford the title compound (0.0027 g) as a white solid.
In analogy to the procedure described herein before, the following examples 12.1 to 12.3 are prepared using the corresponding carboxylic acid:
Figure imgf000050_0001
Example 12.4: (5-chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl)(2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
To a solution of Example 3.14 (0.053 g, 0.10 mmol) in MeOH-c (2.4mL) under N2 is added Pd(OH)2/C (20wt%, 0.012 g). The reaction proceeded under D2 atmosphere for 1 hi 5. The catalyst is removed by filtration and the evaporation residue is purified by prep-HPLC to yield the title compound (0.039g, 87% yield)as a white solid. LC- MS (C): tR = 1.015 min; [M+H]+ = 440.3. 1H NMR (500 MHz, DMSO-cfe) 5: 8.07 (s, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 7.58 (dd, J = 2.4, 8.7 Hz, 1 H), 7.43 (d, J = 1.3 Hz, 1 H), 7.00 (s, 1 H), 6.87 (dd, J = 1.6, 8.3 Hz, 1 H), 3.64 (s, 2 H), 3.77-3.50 (overlapped m, 2 H), 2.77 (s, 3 H), 2.64-2.49 (overlapped m, 1 H), 2.26-1.79 (m, 3 H). Example 12.5: (R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone
Starting from Example 10.9 (0.03 g, 0.056 mmol) and proceeded as described in Example 12.4, the title compound (0.021 g) is obtained as a white solid after purification by prep-HPLC. LC-MS (C): IR = 1.091 min; [M+H]+ = 454.3.
Reference Examples
Reference Example RE1.1: (2-(benzo[d]thiazol-6-ylmethyl)pyrazolidin-1-yl)(5-chloro-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone
To a solution of the compound of Preparation AB (0.02 g, 0.057 mmol) and 6-benzo[d]thiazolecarbaldehyde (0.010 g, 0.061 mmol) in DCM (0.5 mL) is added sodium triacetoxyborohydride (0.019 g, 0.089 mmol). The reaction proceeded at r.t. for 16h. The reaction mixture is partitioned between (DCM (5 mL) and sat. NaHCOa (5 mL). The two layers are separated and the evaporation residue is purified by prep. HPLC to afford the title compound (0.013 g) as a white solid.
In analogy to the procedure described herein before, the following reference examples RE1.1 and RE1.2 are prepared using commercially available aldehydes and the indicated intermediates:
Figure imgf000051_0001
Reference Example RE1.3: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-5- yl)methyl)pyrazolidin-1-yl)methanone
RE 1.3. i . 2-methyl-5-(pyrazolidin-1-ylmethyl)benzo[d]thiazole hydrochloride'.
Starting from tert-butyl 1-pyrazolidinecarboxylate (0.250 g, 1.45 mmol) and 2-methyl-benzothiazole-5- carbaldehyde (0.271 g, 1 .47 mmol) and proceeding successively as described in Preparation A, steps A.i and A.ii, the title compound (0.103 g) is obtained as an orange solid. LC-MS (A): IR = 0.50 min; [M+H]+ = 234.17.
RE1.3.ii. (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-5-yl)methyl)pyrazolidin-1- yl)methanone'.
Starting form the intermediate RE.1.3J (0.020 g, 0.0741 mmol) and 5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid (0.0188 g, 0.0815 mmol) and proceeding as described in Example 3.1, the title compound (0.016 g) is obtained as a white solid after purification by prep. HPLC. LC-MS (C): IR = 1 .041 min; [M+H]+ = 439.2. Reference Example RE1.4: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methyl-1H-benzo[d]imidazol-6- yl)methyl)pyrazolidin-1-yl)methanone
Starting from the compound of Preparation AB (0.03 g, 0.0955 mmol) and 2-methyl-1 H-1 ,3-benzodiazole-5- carbaldehyde (0.02g, O.H mmol) and proceeding as described in Example 7.1, the title compound (0.015 g) is prepared as a white solid after purification by prep. HPLC. LC-MS (C): IR = 0.476 min; [M+H]+ = 422.3.
Reference Example RE1.5: (2-((2-methyl-1H-benzo[d]imidazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2H- 1,2,3-triazol-2-yl)phenyl)methanone
Starting from the compound of Preparation B (0.025 g, 0.0955 mmol) and 2-methyl-1 H-1 ,3-benzodiazole-5- carbaldehyde (0.016g, 0.093mmol) and proceeding as described in Example 7.1 , the title compound (0.016 g) is prepared as a white solid after purification by prep. HPLC. LC-MS (C): IR = 0.476 min; [M+H]+ = 402.3.
Physical characterization
Solubility is determined by the miniaturized saturation shake flask method (screening mode). The compound form is an amorphous film, from DMSO evaporation of a 10 mM stock solution, on which FaSSIF (Fasted State Simulated Intestinal Fluid) medium is added. After 24h of equilibration at 25°C, phases are separated by filtration and aqueous phase compound concentration in aqueous phase is determined by UV-HPLC.
Results: Solubility of the compound of example 3.3: 497 pg/mL; compound of example 10.4: > 770 pg/mL.
Biological assays
Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure:
In vitro assay: Intracellular calcium measurements:
Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 pg/ml G418, 100 U/ml penicillin, 100 pg/ml streptomycin and 10 % heat inactivated fetal bovine serum (FBS). The cells are seeded at 20’000 cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO2.
Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH: water (1 :1 ), diluted in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCOa 0.375g/l and 20 mM HEPES for use in the assay at a final concentration of 2 nM.
Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCOa: 0.375g/l and 20 mM HEPES. On the day of the assay, cells are washed twice with 100 l assay buffer (HBSS containing NaHCCh: 0.375g/l, 20 mM HEPES and 5 mM Probenecid) using a BioTek EL406 cell washer, 25 pl assay buffer is left on the cells after the washes. 25 pL dye solution (HBSS containing 2 % FBS, 20 mM HEPES, NaHCCh: 0.375g/l, 5 mM probenecid (Sigma) and 4 pM of the fluorescent calcium indicator Fluo-8 AM (2 mM stock solution in DMSO)) is added to each well. The 384-wel I cell-plates are incubated for 60min at 37° C in 5% CO2 followed by equilibration at RT for 15min before measurement.
Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), antagonists are added to the plate in a volume of 10 pl/well, incubated for 120 min and finally 10 pl/well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by an approximate ECso (for example 2 nM) of orexin-A with vehicle in place of antagonist. The IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined . Reference compounds are added on each plate. Optimized conditions are achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Average IC50 values from several measurements are given as geometric mean values. Antagonistic activities of example compounds with respect to the 0x1 and 0x2 receptor are displayed in Table 1.
Figure imgf000053_0001
Compounds of the present invention may be further characterized with regard to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art; for example relating to their bioavailablility in different species (such as rat or dog); or relating to their ability to cross the blood-brain barrier, using for example a human P-glycoprotein 1 (MDR 1) substrate assay, or an in vivo assay to determine drug concentrations in the brain, e.g. in rats after oral dosing; or relating to their functional behavior in different disease related animal models {for example: the sedative effect of the compound using Electroencephalography (EEG) and Electromyography (EMG) signal measurments [F. Jenck et al., Nature Medicine 2007, 13, 150-155]; the effect of the compound in the fear-potentiated startle paradigm [Fendt M et al., Neuroscience Biobehav Rev. 1999, 23, 743- 760; W02009/0047723]; the effect of the compound on stress-induced hyperthermia [Vinkers CH et al., European J Pharmacol. 2008, 585, 407-425]; the effect of the compound on morphine-induced locomotor sensitization [Vanderschuren LJMJ et al., in Self DW, Staley JK (eds.) "Behavioral Neuroscience of Drug Addiction", Current Topics in Behavioral Neurosciences 3 (2009), 179-195] }; or for their properties with regard to drug safety and/or toxicological properties using conventional assays well known in the art, for example relating to cytochrome P450 enzyme inhibition and time dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.
Figure imgf000054_0001
Physiologically Based Pharmacokinetic - Pharmacodynamic (PBPK-PD) models are employed to support preclinical development by prioritizing candidate compounds with desirable pharmacokinetic and pharmacodynamic properties/profiles. The models are developed by combining in vitro measured parameters and in silico predicted values, while taking into account the physiology of the respective species.
Measurements of metabolic stability in human liver microsomes and permeability in MDCK-MDR1 cells Microsomal stability assay
Liver microsomes are subcellular fractions, which can be used to measure the intrinsic clearance of a compound and are useful in vitro models of e.g., the hepatic clearance as they contain many of the drug metabolizing enzymes found in the liver. Usually, the microsomes are incubated with the test compound at 37°C in the presence of NADPH (co-factor which initiates the reaction). The disappearance of the compound is monitored over a specific time period (e.g. 45 minutes).
MDCK-MDR1
MDCK-MDR1 cells are Madin Darby canine kidney (MDCK) cells transfected with the MDR1 gene (ABCB1), the gene encoding for the efflux protein, P-glycoprotein (P-gp).When measuring drug transport in both directions (apical to basolateral (A-B) and basolateral to apical (B-A)) across the cell monolayer, an efflux ratio can be determined, which can indicate whether a compound is actively being transported by P-gp, i.e., if a compound is a substrate of P-gp transporter, P-gp will efflux the drug from the inside to the cell to the apical side, preventing its permeation. MDCK-MDR1 helps to gain an understanding of the mechanism of drug efflux, and highlights early potential issues with drug permeability.ln addition to intestinal permeability, MDCK-MDR1 permeability has also been found to be a useful predictor of blood brain barrier permeability.
In this particular assay, MDR1-MDCK cell monolayers are grown to confluence on collagen-coated, microporous membranes in 12-well assay plates. The permeability assay buffer is Hanks’ balanced salt solution containing 10 mM HEPES and 15 mM glucose at a pH of 7.4. The buffer in the receiver chamber also contains 1% bovine serum albumin (BSA). The dosing solution concentration is 1 pM of test article in the assay buffer. Cell monolayers are dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37°C with 5% CO2 in a humidified incubator. Samples are taken from the donor and receiver chambers at 120 minutes. Each determination is performed in duplicate. The flux of lucifer yellow is also measured post-experimentally for each monolayer to ensure no damage is inflicted to the cell monolayers during the flux period. All samples are assayed by LC-MS/MS using electrospray ionization.
For example, compounds show the following permeability coefficients:
Figure imgf000055_0001
Sedative effects: EEG, EMG and behavioural indices of alertness recorded by radiotelemetry in vivo in beagle dogs. Electroencephalography (EEG), Electromyography (EMG), and Electrocardiographic (ECG) signals are measured by telemetry using D70-EEE radiotelemetric implants (Data Science Int.) with three pairs of differential leads.
Surgical implantation is performed under general anesthesia with isoflurane and tracheal intubation, for cranial placement of one pair of EEG electrodes and a reference electrode, placement of one pair of ECG electrodes in the cardiac region, and insertion of one EMG lead in either side of the muscles of the neck. After surgery, dogs recover in a recovery room under obseravation and receive analgesic treatment with parecoxib for 5 d and cerfradine for 7d. All dogs are allowed 4 weeks of recovery before start of the experiment. For accurate and stress- free acquisition of biosignals during a experiment using the telemetric technology, the dogs are kept in an observastion station, on a 12-h light / 12-h dark cycle, with no recording leads restricting their movements. Variables analyzed include four different stages of vigilance and sleep and spontaneous activity. Sleep and wake stages are evaluated using a scoring software (Neuroscore; Data Science Int) directly processing electrical biosignals on 10 s contiguous epochs. The scoring is based on frequency estimation for EEG and amplitude discrimination for EMG and locomotor activity. Using these measurements, the software determines the probability that all components within each epoch best represent active waking (AW), quiet waking (QW), non-REM-sleep (NREM) or REM-sleep (REM). The time spent in AW, QW, NREM- and REM-sleep, total sleep and toal wake time is calculated per 12 h light or dark period and shorter time intervals. Recording is started immediately before test compound or vehicle is given at 10 am. Test compound or vehicle is given orally in gelatine capsules. Food is provided for 30 min 3 h posttreatment (1 :00 pm), and a toy is provided in the animal cages/observation station 6-h post-treatment (4:00 pm), to elicit gently stimulating anticipation in the dogs in the post-prandial phase. Lights are turned off at 7:30 pm and turned on again at 7:00 am. Night-time and daytime recordings are performed under constant infrared illumination and automatic filtering by the cameras.
Total sleep time over 3h was 80 ± 14 min and 92 ± 12 min after 30 mg and 90 mg of the compound of example 3.3 as compared to placebo (46 ± 13 min) with 78 ± 14 min, 90 ± 11 min, and 46 ± 13 min (30 mg, 90 mg, placebo) spent in non-REM sleep. Total wake time was 99 ± 14 min, 87 ± 12 min and 133 ± 14 min over 3h after 30 mg and 90 mg of the compound of example 3.3 and placebo.
Total sleep time over 3h was 64 ± 9 min and 64 ± 9 min after 30 mg and 90 mg of the compound of example 10.4 as compared to placebo (36 ± 9 min) with 60 ± 8 min, 60 ± 9 min, and 35 ± 9 min (30 mg, 90 mg, placebo) spent in non-REM sleep. Total wake time was 125 ± 11 min, 115 ± 9 min and 132 ± 11 min over 3h after 30 mg and 90 mg of the compound of example 10.4 and placebo.

Claims

Claims
1. A compound of Formula
Figure imgf000057_0001
Formula (I) wherein
R1 represents (Ci-3)alkyl, halogen, cyclopropyl, or trifluoromethyl;
X1 represents S or 0;
X2 represents CH or N;
Z represents -CH2-, -CHfCHs)-, or -CH2-CH2-; and in the fragment
Figure imgf000057_0002
• R2 independently represents hydrogen, (Ci-3)alkyl, halogen, or (Ci-3)alkoxy;
• R3 independently represents hydrogen, or (Ci-3)alkyl; and
• Y independently represents CH or N; and
• Ar1 independently represents:
Figure imgf000057_0003
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 ; wherein R1 represents methyl, chloro, bromo, cyclopropyl, or trifluoromethyl; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1; wherein R1 represents methyl; or a pharmaceutically acceptable salt thereof.
4. A compound according to any one of claims 1 to 3; wherein X1 represents S; or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 4; wherein X2 represents CH; or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 5; wherein Z represents -CH2- or -CH(CH3)-; or a pharmaceutically acceptable salt thereof.
7. A compound according to any one of claims 1 to 6; wherein the fragment
Figure imgf000058_0001
or a pharmaceutically acceptable salt thereof.
8. A compound according to any one of claims 1 to 7; wherein Ar1 independently represents a group selected from the groups A) to D):
A)
Figure imgf000058_0002
Figure imgf000059_0001
or a pharmaceutically acceptable salt thereof.
9. A compound according to any one of claims 1 to 6; wherein the fragment
Figure imgf000059_0002
Figure imgf000060_0001
or a pharmaceutically acceptable salt thereof.
10. A compound according to any one of claims 1 to 6; wherein the fragment
Figure imgf000060_0002
or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 1; wherein said compound is (5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone; (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[c/]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(4,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(3'-methyl-[1 , 1 '-bi pheny l]-2-y I) (2-((2-methy I benzo[d]th i azol-6-yl) methy l)py razol id in- 1 -yl)methanone;
(5-methyl-2-(4-methyl-1 /-/-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(5-methyl-2-(3-methyl-1 /-/-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
[1,1 '-biphenyl]-2-yl(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-methyl-2-(2-methylthiazol-4-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 -yl)methanone;
(5-methyl-2-(4-methyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(5-methyl-2-(thiazol-2-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 -yl)methanone;
(5-methyl-2-(1 /-/-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-chloro-2-(1 /-/-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(2-(4-bromo-2/-/-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(2-(4-chloro-1 H-pyrazol-1 -yl)-5-methylpyridin-3-yl)(2-((2-methylbenzo[c/]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(5-chloro-2-(4-methyl-1 H-pyrazol-1 -yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(2-(2/-/-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazin-1(2H)-yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[c/]thiazol-6-yl)methyl)tetrahydropyridazin-1 (2/7)- yl)methanone;
(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazin-1 (2/7)- yl)methanone;
(5-chloro-2-(4-methyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(5-chloro-2-(4-ethynyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[c/]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(2-((2-bromobenzo[<7]thiazol-6-yl)methyl)pyrazolidin-1 -yl)(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylthiazolo[5,4-b]pyridin-5-yl)methyl)pyrazolidin-1- yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-chlorobenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone; (5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)(2-((2-cyclopropylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 - yl)methanone;
(5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)(2-((2-ethylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;
(R)-(5-chloro-2-(2/-/-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(S)-(5-chloro-2-(2/-/-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;
(R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2/-/-1,2,3-triazol-2- yl)phenyl)methanone;
(S)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone;
(S)-(2-(4-bromo-2/7-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone;
(R)-(2-(4-bromo-2H-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone;
(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]oxazol-6-yl)methyl)pyrazolidin-1-yl)methanone; (2-(2/-/-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl-4,4-d2)methanone;
(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl-4,4- cymethanone;
(5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 -yl-4,4- cymethanone;
(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl-d)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone; or
(R)-(5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl-d)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone; or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising, as active principle, one or more compounds according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
13. A compound according to any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, for use as a medicament.
14 A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders, or neuropsychiatric symptoms in dementia.
15. Use of a compound according to any one of claims 1 to 11, or of a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the prevention or treatment of sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders, or neuropsychiatric symptoms in dementia.
16. A method for the prophylaxis or treatment of sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders, or neuropsychiatric symptoms in dementia comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) according to any one of claims 1 to 11, or of a pharmaceutically acceptable salt thereof.
PCT/EP2023/062741 2022-05-13 2023-05-12 Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives WO2023218023A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP2022063015 2022-05-13
EPPCT/EP2022/063015 2022-05-13

Publications (1)

Publication Number Publication Date
WO2023218023A1 true WO2023218023A1 (en) 2023-11-16

Family

ID=86604875

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2023/062741 WO2023218023A1 (en) 2022-05-13 2023-05-12 Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives

Country Status (2)

Country Link
TW (1) TW202400149A (en)
WO (1) WO2023218023A1 (en)

Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5472964A (en) 1992-12-22 1995-12-05 Merck Frosst Canada, Inc. Diaryl 5,6-fused heterocyclic acids as leukotriene antagonists
WO2001096302A1 (en) 2000-06-16 2001-12-20 Smithkline Beecham P.L.C. Piperidines for use as orexin receptor antagonists
WO2002044172A1 (en) 2000-11-28 2002-06-06 Smithkline Beecham P.L.C. Morpholine derivatives as antagonists of orexin receptors
WO2002089800A2 (en) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. N-aroyl cyclic amine derivatives as orexin receptor antagonists
WO2002090355A1 (en) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. N-aroyl cyclic amines
WO2003002559A2 (en) 2001-06-28 2003-01-09 Smithkline Beecham P.L.C. Piperidine compounds for use as orexin receptor antagonist
WO2003002561A1 (en) 2001-06-28 2003-01-09 Smithkline Beecham P.L.C. N-aroyl cyclic amine derivatives as orexin receptor antagonists
WO2003032991A1 (en) 2001-10-11 2003-04-24 Smithkline Beecham Plc N-aroyl piperazine derivatives as orexin receptor antagonists
WO2003041711A1 (en) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Piperazine bis-amide derivatives and their use as antagonists of the orexin receptor
WO2003051368A1 (en) 2001-12-19 2003-06-26 Smithkline Beecham Plc N-aroyl cyclic amine derivatives as orexin receptor antagonists
WO2003051873A1 (en) 2001-12-19 2003-06-26 Smithkline Beecham Plc Piperazine compounds and their phamaceutical use
WO2004026866A1 (en) 2002-09-18 2004-04-01 Glaxo Group Limited N-aroyl cyclic amines as orexin receptor antagonists
WO2004041816A1 (en) 2002-11-06 2004-05-21 Glaxo Group Limited Azacyclic compounds as orexin receptor antagonist
WO2004041791A1 (en) 2002-11-06 2004-05-21 Glaxo Group Limited N-aryl acetyl cyclic amine derivatives as orexin antagonists
WO2004041807A1 (en) 2002-11-06 2004-05-21 Glaxo Group Limited Novel compounds
WO2005118548A1 (en) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2007105177A1 (en) 2006-03-15 2007-09-20 Actelion Pharmaceuticals Ltd Tetrahydroisoquinoline derivatives to enhance memory function
WO2008020405A2 (en) 2006-08-15 2008-02-21 Actelion Pharmaceuticals Ltd Azetidine compounds as orexin receptor antagonists
WO2008038251A2 (en) 2006-09-29 2008-04-03 Actelion Pharmaceuticals Ltd 3-aza-bicyclo[3.1.0]hexane derivatives
WO2008065626A2 (en) 2006-12-01 2008-06-05 Actelion Pharmaceuticals Ltd 3-heteroaryl (amino or amido)-1- (biphenyl or phenylthiazolyl) carbonylpiperidine derivativesas orexin receptor inhibitors
WO2008081399A2 (en) 2006-12-28 2008-07-10 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[3.1.0]hexane derivatives as orexin receptor antagonists
WO2008087611A2 (en) 2007-01-19 2008-07-24 Actelion Pharmaceuticals Ltd Pyrrolidine- and piperidine- bis-amide derivatives
WO2008117241A2 (en) 2007-03-26 2008-10-02 Actelion Pharmaceuticals Ltd Thiazolidine derivatives as orexin receptor antagonists
WO2008139416A1 (en) 2007-05-14 2008-11-20 Actelion Pharmaceuticals Ltd 2-cyclopropyl-thiazole derivatives
WO2008150364A1 (en) 2007-05-23 2008-12-11 Merck & Co., Inc. Cyclopropyl pyrrolidine orexin receptor antagonists
WO2009003997A1 (en) 2007-07-03 2009-01-08 Glaxo Group Limited Imidazo [1, 2-c] pyrimidin-2-ylmethylpiperidines as orexin receptor antagonists
WO2009003993A1 (en) 2007-07-03 2009-01-08 Glaxo Group Limited Piperidine derivatives useful as orexin receptor antagonists
WO2009004584A1 (en) 2007-07-03 2009-01-08 Actelion Pharmaceuticals Ltd 3-aza-bicyclo[3.3.0]octane compounds
WO2009016564A2 (en) 2007-07-27 2009-02-05 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[3.3.0]octane derivatives
WO2009016560A2 (en) 2007-07-27 2009-02-05 Actelion Pharmaceuticals Ltd Trans-3-aza-bicyclo[3.1.0]hexane derivatives
WO2009040730A2 (en) 2007-09-24 2009-04-02 Actelion Pharmaceuticals Ltd Pyrrolidines and piperidines as orexin receptor antagonists
WO2009047723A2 (en) 2007-10-10 2009-04-16 Actelion Pharmaceuticals Ltd Tetrahydroquinoline derivatives for treating post-traumatic stress disorders
WO2009104155A1 (en) 2008-02-21 2009-08-27 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[2.2.1]heptane derivatives
WO2009124956A1 (en) 2008-04-10 2009-10-15 Glaxo Group Limited Pyridine derivatives used to treat orexin related disorders
WO2010004507A1 (en) 2008-07-07 2010-01-14 Actelion Pharmaceuticals Ltd Thiazolidine compounds as orexin receptor antagonists
WO2010038200A1 (en) 2008-10-01 2010-04-08 Actelion Pharmaceuticals Ltd Oxazolidine compounds as orexin receptor antagonists
WO2010060472A1 (en) 2008-11-26 2010-06-03 Glaxo Group Limited Imidazopyridazine derivatives acting as orexin antagonists
WO2010060471A1 (en) 2008-11-26 2010-06-03 Glaxo Group Limited Piperidine derivatives useful as orexin receptor antagonists
WO2010060470A1 (en) 2008-11-26 2010-06-03 Glaxo Group Limited Piperidine derivatives useful as orexin receptor antagonists
WO2010063663A1 (en) 2008-12-02 2010-06-10 Glaxo Group Limited N-{[(ir,4s,6r-3-(2-pyridinylcarbonyl)-3-azabicyclo [4.1.0]hept-4-yl] methyl}-2-heteroarylamine derivatives and uses thereof
WO2010063662A1 (en) 2008-12-02 2010-06-10 Glaxo Group Limited N-{[(ir,4s,6r-3-(2-pyridinylcarbonyl)-3-azabicyclo [4.1.0] hept-4-yl] methyl}-2-heteroarylamine derivatives and uses thereof
WO2010072722A1 (en) 2008-12-23 2010-07-01 Glaxo Group Limited Piperidine derivatives useful as orexin antagonists
WO2010122151A1 (en) 2009-04-24 2010-10-28 Glaxo Group Limited 3 -azabicyclo [4.1.0] heptanes used as orexin antagonists
WO2013068935A1 (en) * 2011-11-08 2013-05-16 Actelion Pharmaceuticals Ltd 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide derivatives as orexin receptor antagonists
WO2013182972A1 (en) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Benzimidazole-proline derivatives
WO2014057435A1 (en) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Orexin receptor antagonists which are [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone derivatives
WO2015123355A1 (en) * 2014-02-12 2015-08-20 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
WO2016086357A1 (en) * 2014-12-02 2016-06-09 Merck Sharp & Dohme Corp. Methyl oxazole orexin receptor antagonists
WO2018202689A1 (en) 2017-05-03 2018-11-08 Idorsia Pharmaceuticals Ltd Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives
WO2019043407A1 (en) 2017-09-01 2019-03-07 Chronos Therapeutics Limited Substituted 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane derivatives as orexin receptor antagonists

Patent Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5472964A (en) 1992-12-22 1995-12-05 Merck Frosst Canada, Inc. Diaryl 5,6-fused heterocyclic acids as leukotriene antagonists
WO2001096302A1 (en) 2000-06-16 2001-12-20 Smithkline Beecham P.L.C. Piperidines for use as orexin receptor antagonists
WO2002044172A1 (en) 2000-11-28 2002-06-06 Smithkline Beecham P.L.C. Morpholine derivatives as antagonists of orexin receptors
WO2002089800A2 (en) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. N-aroyl cyclic amine derivatives as orexin receptor antagonists
WO2002090355A1 (en) 2001-05-05 2002-11-14 Smithkline Beecham P.L.C. N-aroyl cyclic amines
WO2003002559A2 (en) 2001-06-28 2003-01-09 Smithkline Beecham P.L.C. Piperidine compounds for use as orexin receptor antagonist
WO2003002561A1 (en) 2001-06-28 2003-01-09 Smithkline Beecham P.L.C. N-aroyl cyclic amine derivatives as orexin receptor antagonists
WO2003032991A1 (en) 2001-10-11 2003-04-24 Smithkline Beecham Plc N-aroyl piperazine derivatives as orexin receptor antagonists
WO2003041711A1 (en) 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Piperazine bis-amide derivatives and their use as antagonists of the orexin receptor
WO2003051368A1 (en) 2001-12-19 2003-06-26 Smithkline Beecham Plc N-aroyl cyclic amine derivatives as orexin receptor antagonists
WO2003051873A1 (en) 2001-12-19 2003-06-26 Smithkline Beecham Plc Piperazine compounds and their phamaceutical use
WO2004026866A1 (en) 2002-09-18 2004-04-01 Glaxo Group Limited N-aroyl cyclic amines as orexin receptor antagonists
WO2004041816A1 (en) 2002-11-06 2004-05-21 Glaxo Group Limited Azacyclic compounds as orexin receptor antagonist
WO2004041791A1 (en) 2002-11-06 2004-05-21 Glaxo Group Limited N-aryl acetyl cyclic amine derivatives as orexin antagonists
WO2004041807A1 (en) 2002-11-06 2004-05-21 Glaxo Group Limited Novel compounds
WO2005118548A1 (en) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2007105177A1 (en) 2006-03-15 2007-09-20 Actelion Pharmaceuticals Ltd Tetrahydroisoquinoline derivatives to enhance memory function
WO2008020405A2 (en) 2006-08-15 2008-02-21 Actelion Pharmaceuticals Ltd Azetidine compounds as orexin receptor antagonists
WO2008038251A2 (en) 2006-09-29 2008-04-03 Actelion Pharmaceuticals Ltd 3-aza-bicyclo[3.1.0]hexane derivatives
WO2008065626A2 (en) 2006-12-01 2008-06-05 Actelion Pharmaceuticals Ltd 3-heteroaryl (amino or amido)-1- (biphenyl or phenylthiazolyl) carbonylpiperidine derivativesas orexin receptor inhibitors
WO2008081399A2 (en) 2006-12-28 2008-07-10 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[3.1.0]hexane derivatives as orexin receptor antagonists
WO2008087611A2 (en) 2007-01-19 2008-07-24 Actelion Pharmaceuticals Ltd Pyrrolidine- and piperidine- bis-amide derivatives
WO2008117241A2 (en) 2007-03-26 2008-10-02 Actelion Pharmaceuticals Ltd Thiazolidine derivatives as orexin receptor antagonists
WO2008139416A1 (en) 2007-05-14 2008-11-20 Actelion Pharmaceuticals Ltd 2-cyclopropyl-thiazole derivatives
WO2008150364A1 (en) 2007-05-23 2008-12-11 Merck & Co., Inc. Cyclopropyl pyrrolidine orexin receptor antagonists
WO2009003997A1 (en) 2007-07-03 2009-01-08 Glaxo Group Limited Imidazo [1, 2-c] pyrimidin-2-ylmethylpiperidines as orexin receptor antagonists
WO2009003993A1 (en) 2007-07-03 2009-01-08 Glaxo Group Limited Piperidine derivatives useful as orexin receptor antagonists
WO2009004584A1 (en) 2007-07-03 2009-01-08 Actelion Pharmaceuticals Ltd 3-aza-bicyclo[3.3.0]octane compounds
WO2009016564A2 (en) 2007-07-27 2009-02-05 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[3.3.0]octane derivatives
WO2009016560A2 (en) 2007-07-27 2009-02-05 Actelion Pharmaceuticals Ltd Trans-3-aza-bicyclo[3.1.0]hexane derivatives
WO2009040730A2 (en) 2007-09-24 2009-04-02 Actelion Pharmaceuticals Ltd Pyrrolidines and piperidines as orexin receptor antagonists
WO2009047723A2 (en) 2007-10-10 2009-04-16 Actelion Pharmaceuticals Ltd Tetrahydroquinoline derivatives for treating post-traumatic stress disorders
WO2009104155A1 (en) 2008-02-21 2009-08-27 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[2.2.1]heptane derivatives
WO2009124956A1 (en) 2008-04-10 2009-10-15 Glaxo Group Limited Pyridine derivatives used to treat orexin related disorders
WO2010004507A1 (en) 2008-07-07 2010-01-14 Actelion Pharmaceuticals Ltd Thiazolidine compounds as orexin receptor antagonists
WO2010038200A1 (en) 2008-10-01 2010-04-08 Actelion Pharmaceuticals Ltd Oxazolidine compounds as orexin receptor antagonists
WO2010060472A1 (en) 2008-11-26 2010-06-03 Glaxo Group Limited Imidazopyridazine derivatives acting as orexin antagonists
WO2010060471A1 (en) 2008-11-26 2010-06-03 Glaxo Group Limited Piperidine derivatives useful as orexin receptor antagonists
WO2010060470A1 (en) 2008-11-26 2010-06-03 Glaxo Group Limited Piperidine derivatives useful as orexin receptor antagonists
WO2010063663A1 (en) 2008-12-02 2010-06-10 Glaxo Group Limited N-{[(ir,4s,6r-3-(2-pyridinylcarbonyl)-3-azabicyclo [4.1.0]hept-4-yl] methyl}-2-heteroarylamine derivatives and uses thereof
WO2010063662A1 (en) 2008-12-02 2010-06-10 Glaxo Group Limited N-{[(ir,4s,6r-3-(2-pyridinylcarbonyl)-3-azabicyclo [4.1.0] hept-4-yl] methyl}-2-heteroarylamine derivatives and uses thereof
WO2010072722A1 (en) 2008-12-23 2010-07-01 Glaxo Group Limited Piperidine derivatives useful as orexin antagonists
WO2010122151A1 (en) 2009-04-24 2010-10-28 Glaxo Group Limited 3 -azabicyclo [4.1.0] heptanes used as orexin antagonists
WO2013068935A1 (en) * 2011-11-08 2013-05-16 Actelion Pharmaceuticals Ltd 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide derivatives as orexin receptor antagonists
WO2013182972A1 (en) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Benzimidazole-proline derivatives
WO2014057435A1 (en) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Orexin receptor antagonists which are [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone derivatives
WO2015123355A1 (en) * 2014-02-12 2015-08-20 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
WO2016086357A1 (en) * 2014-12-02 2016-06-09 Merck Sharp & Dohme Corp. Methyl oxazole orexin receptor antagonists
WO2018202689A1 (en) 2017-05-03 2018-11-08 Idorsia Pharmaceuticals Ltd Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives
WO2019043407A1 (en) 2017-09-01 2019-03-07 Chronos Therapeutics Limited Substituted 2-azabicyclo[3.1.1]heptane and 2-azabicyclo[3.2.1]octane derivatives as orexin receptor antagonists

Non-Patent Citations (58)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical Salts and Co-crystals", 2012, RSC PUBLISHING
ADAM, TC ET AL., PHYSIOL BEHAV, vol. 91, no. 4, 2007, pages 449 - 458
ASTON-JONES G ET AL., BRAIN RES, vol. 1314, 2010, pages 130 - 138
BELLINA ET AL., SYNTHESIS, 2004, pages 2419 - 2440
BERRIDGE CW ET AL., BRAIN RES, vol. 1314, 2009, pages 91 - 102
BORGLAND SL ET AL., NEURON, vol. 49, no. 4, 2006, pages 589 - 601
BOUTREL B ET AL.: "Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior", PROC NATL ACAD SCI, vol. 102, no. 52, 2005, pages 19168 - 19173
BOUTREL, B ET AL., PROC NATL ACAD SCI, vol. 102, no. 52, 2005, pages 19168 - 19173
BRISBARE-ROCH ET AL., NATURE MEDICINE, vol. 13, 2007, pages 150 - 155
C BOSSC BRISBARE-ROCHF JENCK, JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, 2009, pages 891 - 903
CARTER ME ET AL.: "The brain hypocretins and their receptors: mediators of allostatic arousal.", CURR OP PHARMACOL., vol. 9, 2009, pages 39 - 45, XP025916388, DOI: 10.1016/j.coph.2008.12.018
CARTER MEBORG JSDELECEA L., CURR OP PHARMACOL., vol. 9, 2009, pages 39 - 45
CHEMELLI R.M. ET AL., CELL, vol. 98, 1999, pages 437 - 451
CHROUSOS, GP ET AL., JAMA, vol. 267, no. 9, 1992, pages 1244 - 1252
FENDT M ET AL., NEUROSCIENCE BIOBEHAV REV., vol. 23, 1999, pages 1941 - 1949
FENG P ET AL., J PSYCHOPHARMACOL, vol. 22, no. 7, 2008, pages 784 - 791
FU, ACC. CHEM., vol. 41, 2008, pages 1555 - 1564
FURLONG T M ET AL., EUR J NEUROSCI, vol. 30, no. 8, 2009, pages 1603 - 1614
G. BENZ: "Comprehensive Organic Synthesis", vol. 6, 1991, PERGAMON PRESS, pages: 381
GOZZI A ET AL., PLOS ONE, vol. 6, no. 1, 2011, pages e16406
H DIETRICHF JENCK, PSYCHOPHARMACOLOGY, vol. 212, no. 2, 2010, pages 145 - 154
HOLLANDER ET AL., PROC NATL ACAD, vol. 105, no. 49, 2008, pages 19480 - 19485
HUTCHESON DM ET AL., BEHAV PHARMACOL, vol. 22, no. 2, 2011, pages 173 - 181
J.ORG.CHEM., vol. 68, 2003, pages 5568
JE KANG ET AL.: "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.", SCIENCE, vol. 326, no. 5955, 2009, pages 1005 - 1007
KALES ET AL., J AM GERIATR SOC., vol. 62, no. 4, 2014, pages 762 - 9
KANTCHEV ET AL., ALDRICHIMICA ACTA, vol. 39, 2006, pages 97 111 - 24
KOCIENSKI, P.J.: "Protecting Groups", 1994, GEORG THIEME VERLAG
KOOB, GF ET AL., CURR OPIN INVESTIG DRUGS, vol. 11, no. 1, 2010, pages 63 - 71
LANGMEAD, BRIT. J. PHARMACOL., vol. 141, 2004, pages 340 - 346
LAWRENCE AJ ET AL., BR J PHARMACOL, vol. 148, no. 6, 2006, pages 752 - 759
LIU X ET AL., SLEEP, vol. 30, no. 1, 2007, pages 83 - 90
MAJZOUB, JA ET AL., EUROPEAN JOURNAL OF ENDOCRINOLOGY, vol. 155, no. 1, 2006, pages S71 - S76
MIYAURASUZUKI, CHEM. REV., vol. 95, 1995, pages 2457 - 2483
MJ PRUD'HOMME ET AL., NEUROSCIENCE, vol. 162, no. 4, 2009, pages 1287 - 1298
N. STOCKING, IPA'S NEWSLETTER, THE IPA BULLETIN, vol. 31, no. 4
NOLLET ET AL., NEUROPHARM, vol. 61, no. 1-2, 2011, pages 336 - 46
PHAN ET AL., DRUGS IN R&D, vol. 19, 2019, pages 93 - 115
QUARTA D ET AL.: "The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization.", NEUROCHEM INT, vol. 56, no. 1, 2010, pages 11 - 15, XP026906710, DOI: 10.1016/j.neuint.2009.08.012
R. STICKGOLD ET AL.: "Sleep-dependent memory consolidation", NATURE, vol. 437, 2005, pages 1272 - 1278
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS, article "Pharmaceutical Manufacturing"
SAKURAI T. ET AL., CELL, vol. 92, 1998, pages 573 - 585
SALOMON RM ET AL., BIOL PSYCHIATRY, vol. 54, no. 2, 2003, pages 96 - 104
SMITH RJ ET AL.: "Orexin/hypocretin is necessary for context-driven cocaine-seeking", NEUROPHARMACOLOGY, vol. 58, no. 1, 2010, pages 179 - 184, XP026736770, DOI: 10.1016/j.neuropharm.2009.06.042
SMITH RJ ET AL.: "Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking.", EUR J NEUROSCI, vol. 30, no. 3, 2009, pages 493 - 503
SPEALMAN ET AL., PHARMACOL. BIOCHEM. BEHAV., vol. 64, 1999, pages 327 - 336
SUTCLIFFE, JG ET AL., NAT REV NEUROSCI, vol. 3, no. 5, 2002, pages 339 - 349
T.S. SHIPPENBERGG.F. KOOB: "Recent advances in animal models of drug addiction", NEUROPSYCHOPHARMACOLOGY: THE FIFTH GENERATION OF PROGRESS
TETRAHEDRON, vol. 60, 2004, pages 7899 - 7906
TSUJINO NSAKURAI T, PHARMACOL REV., vol. 61, 2009, pages 162 - 176
TSUJINO NSAKURAI T: "Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward systems.", PHARMACOL REV., vol. 61, 2009, pages 162 - 176, XP055180000, DOI: 10.1124/pr.109.001321
TSUJINO, NSAKURAI, T, PHARMACOL REV, vol. 61, no. 2, 2009, pages 162 - 176
VANDERSCHUREN LJMJ ET AL.: "Behavioral Neuroscience of Drug Addiction", CURRENT TOPICS IN BEHAVIORAL NEUROSCIENCES, vol. 3, 2009, pages 179 - 195
VINKERS CH ET AL., EUROPEAN J PHARMACOL., vol. 585, 2008, pages 407 - 425
W. FOULDS MATHES ET AL., APPETITE, vol. 52, 2009, pages 545 - 553
WINROW ET AL., NEUROPHARMACOLOGY, vol. 58, no. 1, 2009, pages 185 - 94
Y. KAYABA ET AL., AM. J. PHYSIOL. REGUL. INTEGR. COMP. PHYSIOL, vol. 285, 2003, pages R581 - 593
ZHANG WET: "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice.", AUTON NEUROSCI, 2006, pages 126 - 127,139-145

Also Published As

Publication number Publication date
TW202400149A (en) 2024-01-01

Similar Documents

Publication Publication Date Title
US11040966B2 (en) Benzimidazole-proline derivatives
US9458157B2 (en) Pyrazole derivative
AU2012335194B2 (en) 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide derivatives as orexin receptor antagonists
EP2516437A1 (en) Disubstituted heteroaryl-fused pyridines
WO2013050938A1 (en) 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7-diazabicyclo[3.3.1]nonane derivatives
AU2014358742B2 (en) Crystalline form of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists
EP3077390B1 (en) Crystalline salt form of (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
JP6786566B2 (en) Heteroaryl compounds and how to use them
WO2012085852A1 (en) 3,8-diaza-bicyclo[4.2.0]oct-8-yl amides
WO2020007977A1 (en) 7-trifluoromethyl-[1,4]diazepan derivatives
WO2020007964A1 (en) 2-(2-azabicyclo[3.1.0]hexan-1-yl)-1h-benzimidazole derivatives
WO2023218023A1 (en) Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives
WO2020099511A1 (en) Benzimidazole-2-methyl-morpholine derivatives

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23726942

Country of ref document: EP

Kind code of ref document: A1